Sexually Transmitted Infections Treatment Guidelines, 2021

Morbidity and Mortality Weekly Report

Recommendations and Reports / Vol. 70 / No. 4 July 23, 2021

Sexually Transmitted Infections Treatment

Guidelines, 2021

U.S. Department of Health and Human Services

Centers for Disease Control and Prevention

The MMWR series of publications is published by the Center for Surveillance, Epidemiology, and Laboratory Services, Centers for Disease Control and Prevention (CDC),

U.S. Department of Health and Human Services, Atlanta, GA 30329-4027.

Suggested citation: [Author names; first three, then et al., if more than six.] [Title]. MMWR Recomm Rep 2021;70(No. RR-#):[inclusive page numbers].

Centers for Disease Control and Prevention

Rochelle P. Walensky, MD, MPH, Director

Debra Houry, MD, MPH, Acting Principal Deputy Director

Daniel B. Jernigan, MD, MPH, Acting Deputy Director for Public Health Science and Surveillance

Rebecca Bunnell, PhD, MEd, Director, Office of Science

Jennifer Layden, MD, PhD, Deputy Director, Office of Science

Michael F. Iademarco, MD, MPH, Director, Center for Surveillance, Epidemiology, and Laboratory Services

MMWR Editorial and Production Staff (Serials)

Charlotte K. Kent, PhD, MPH, Editor in Chief

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Visual Information Specialists

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David W. Fleming, MD

William E. Halperin, MD, DrPH, MPH

Jewel Mullen, MD, MPH, MPA

Jeff Niederdeppe, PhD

Celeste Philip, MD, MPH

Patricia Quinlisk, MD, MPH

Patrick L. Remington, MD, MPH

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Visual Information Specialist

Recommendations and Reports

CONTENTS

Introduction ............................................................................................................1

Methods ....................................................................................................................1

Clinical Prevention Guidance ............................................................................ 2

STI Detection Among Special Populations ............................................... 11

HIV Infection ......................................................................................................... 24

Diseases Characterized by Genital, Anal, or Perianal Ulcers ............... 27

Syphilis ................................................................................................................... 39

Management of Persons Who Have a History of Penicillin Allergy .. 56

Diseases Characterized by Urethritis and Cervicitis ............................... 60

Chlamydial Infections ....................................................................................... 65

Gonococcal Infections ...................................................................................... 71

Mycoplasma genitalium .................................................................................... 80

Diseases Characterized by Vulvovaginal Itching, Burning, Irritation,

Odor, or Discharge ........................................................................................... 82

Pelvic Inflammatory Disease .......................................................................... 94

Epididymitis .......................................................................................................... 98

Human Papillomavirus Infections ..............................................................100

Viral Hepatitis ..................................................................................................... 113

Proctitis, Proctocolitis, and Enteritis ..........................................................124

Ectoparasitic Infections .................................................................................. 126

Sexual Assault and Abuse and STIs ............................................................128

References ...........................................................................................................135

Recommendations and Reports

MMWR / July 23, 2021 / Vol. 70 / No. 4 1

US Department of Health and Human Services/Centers for Disease Control and Prevention

Sexually Transmitted Infections Treatment Guidelines, 2021

Kimberly A. Workowski, MD

1,2

; Laura H. Bachmann, MD

; Philip A. Chan, MD

1,3

; Christine M. Johnston, MD

1,4

; Christina A. Muzny, MD

1,5

;

Ina Park, MD

1,6

; Hilary Reno, MD

1,7

; Jonathan M. Zenilman, MD

1,8

; Gail A. Bolan, MD

Division of STD Prevention, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC, Atlanta, Georgia;

Emory University, Atlanta, Georgia;

Brown University, Providence, Rhode Island;

University of Washington, Seattle, Washington;

University of Alabama at Birmingham, Birmingham, Alabama;

University of California San Francisco, San Francisco, California;

Washington University, St. Louis, Missouri;

Johns Hopkins University, Baltimore, Maryland

Summary

These guidelines for the treatment of persons who have or are at risk for sexually transmitted infections (STIs) were updated by

CDC after consultation with professionals knowledgeable in the field of STIs who met in Atlanta, Georgia, June 11–14, 2019.

The information in this report updates the 2015 guidelines. These guidelines discuss 1) updated recommendations for treatment of

Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis; 2) addition of metronidazole to the recommended

treatment regimen for pelvic inflammatory disease; 3) alternative treatment options for bacterial vaginosis; 4) management of

Mycoplasma genitalium; 5) human papillomavirus vaccine recommendations and counseling messages; 6) expanded risk factors

for syphilis testing among pregnant women; 7) one-time testing for hepatitis C infection; 8) evaluation of men who have sex with

men after sexual assault; and 9) two-step testing for serologic diagnosis of genital herpes simplex virus. Physicians and other health

care providers can use these guidelines to assist in prevention and treatment of STIs.

Corresponding preparer: Kimberly A. Workowski, MD, Division of

STD Prevention, National Center for HIV/AIDS, Viral Hepatitis,

STD, and TB Prevention, CDC. Telephone: 404-639-1898; Email:

[email protected].

Introduction

The term “sexually transmitted infection” (STI) refers to

a pathogen that causes infection through sexual contact,

whereas the term “sexually transmitted disease” (STD) refers

to a recognizable disease state that has developed from an

infection. Physicians and other health care providers have a

crucial role in preventing and treating STIs. These guidelines

are intended to assist with that effort. Although the guidelines

emphasize treatment, prevention strategies and diagnostic

recommendations also are discussed.

This report updates Sexually Transmitted Diseases Treatment

Guidelines, 2015 (1) and should be regarded as a source of

clinical guidance rather than prescriptive standards. Health care

providers should always consider the clinical circumstances of

each person in the context of local disease prevalence. These

guidelines are applicable to any patient care setting that serves

persons at risk for STIs, including family planning clinics,

HIV care clinics, correctional health care settings, private

physicians’ offices, Federally Qualified Health Centers, clinics

for adolescent care, and other primary care facilities. These

guidelines are focused on treatment and counseling and do

not address other community services and interventions that

are essential to STI and HIV prevention efforts.

These STI treatment guidelines complement Recommendations

for Providing Quality Sexually Transmitted Diseases Clinical

Services, 2020 (2) regarding quality clinical services for STIs

in primary care and STD specialty care settings. This guidance

specifies operational determinants of quality services in various

clinical settings, describes on-site treatment and partner

services, and indicates when STI-related conditions should be

managed through consultation with or referral to a specialist.

Methods

These guidelines were developed by CDC staff who worked

with subject matter experts with expertise in STI clinical

management from other federal agencies, nongovernmental

academic and research institutions, and professional medical

organizations. CDC staff identified governmental and

nongovernmental subject matter experts on the basis of their

expertise and assisted them in developing questions to guide

individual literature reviews. CDC staff informed the subject

matter experts that they were being consulted to exchange

information and observations and to obtain their individual

input. All subject matter experts disclosed potential conflicts

of interest. STI Treatment Guidelines, 2021, Work Group

members are listed at the end of this report.

In 2018, CDC staff identified key questions about treatment

and clinical management to guide an update of the 2015

STD treatment guidelines (1). To answer these questions

and synthesize new information available since publication

of the 2015 guidelines, subject matter experts and CDC staff

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US Department of Health and Human Services/Centers for Disease Control and Prevention

collaborated to conduct systematic literature reviews by using

an extensive MEDLINE database evidence-based approach for

each section of the 2015 guidelines (e.g., using English-language

published abstracts and peer reviewed journal articles). These

systematic reviews were focused on four principal outcomes

of STI therapy for each disease or infection: 1) treatment

of infection on the basis of microbiologic eradication;

2) alleviation of signs and symptoms; 3) prevention of sequelae;

and 4) prevention of transmission, including advantages (e.g.,

cost-effectiveness, single-dose formulations, and directly

observed therapy) and disadvantages (e.g., adverse effects)

of specific regimens. The outcome of the literature reviews

guided development of background materials, including tables

of evidence from peer-reviewed publications summarizing

the type of study (e.g., randomized controlled trial or case

series), study population and setting, treatments or other

interventions, outcome measures assessed, reported findings,

and weaknesses and biases in study design and analysis.

In June 2019, the subject matter experts presented their

assessments of the literature reviews at an in-person meeting

of governmental and nongovernmental participants. Each

key question was discussed and pertinent publications were

reviewed in terms of strengths, weaknesses, and relevance.

Participants evaluated the quality of evidence, provided their

input, and discussed findings in the context of the modified

rating system used by the U.S. Preventive Services Task Force

(USPSTF). The discussions were informal and not structured

to reach consensus. CDC staff also reviewed the publications

from other professional organizations, including the American

College of Obstetricians and Gynecologists (ACOG), USPSTF,

the American Cancer Society (ACS), the American Society

for Colposcopy and Cervical Pathology (ASCCP), and the

Advisory Committee on Immunization Practices (ACIP).

The discussion culminated in a list of participants’ opinions

on all the key STI topic areas for consideration by CDC.

(More detailed descriptions of the key questions, search terms,

systematic search, evidence tables, and review process are

available at https://www.cdc.gov/std/treatment-guidelines/

default.htm).

CDC staff then independently reviewed the tables of evidence

prepared by the subject matter experts, individual comments

from the participants and professional organizations, and existing

guidelines from other organizations to determine whether

revisions to the 2015 STD treatment guidelines were warranted.

CDC staff ranked evidence as high, medium, and low on the

basis of each study’s strengths and weaknesses according to the

USPSTF ratings (https://www.uspreventiveservicestaskforce.

org/uspstf/us-preventive-services-task-force-ratings). CDC staff

then developed draft recommendations that were peer reviewed

by public health and clinical experts as defined by the Office of

Management and Budget for influential scientific information.

A public webinar was held to provide an overview of the draft

recommendations and invite questions and comments on the

draft recommendations. The peer review comments, webinar,

questions, and responses were considered by CDC staff in

developing the final recommendations for the updated STI

treatment guidelines. Recommendations for HIV, hepatitis C,

cervical cancer screening, STI screening in pregnancy, human

papillomavirus (HPV) testing, and hepatitis A virus (HAV) and

hepatitis B virus (HBV) vaccination were developed after CDC

staff reviewed existing published recommendations. The English-

language literature was searched periodically by CDC staff to

identify subsequently published articles warranting consideration.

Throughout this report, the evidence used as the basis for

specific recommendations is discussed briefly. Publication

of comprehensive, annotated discussions of such evidence

is planned in a supplemental issue of the journal Clinical

Infectious Diseases after publication of the treatment guidelines.

When more than one therapeutic regimen is recommended

and the listed regimens have similar efficacy and similar

rates of intolerance or toxicity, the recommendations are

listed alphabetically. If differences are specified, regimens are

prioritized on the basis of these differences. Recommended

regimens should be used primarily; alternative regimens can be

considered in instances of notable drug allergy or other medical

contraindications to the recommended regimens. Alternative

regimens are considered inferior to recommended regimens on

the basis of available evidence regarding the principal outcomes

and disadvantages of the regimens.

Clinical Prevention Guidance

Prevention and control of STIs are based on the following

five major strategies (3):

1. Accurate risk assessment and education and counseling

of persons at risk regarding ways to avoid STIs through

changes in sexual behaviors and use of recommended

prevention services

2. Pre-exposure vaccination for vaccine-preventable STIs

3. Identification of persons with an asymptomatic

infection and persons with symptoms associated with

an STI

4. Effective diagnosis, treatment, counseling, and follow-

up of persons who are infected with an STI

5. Evaluation, treatment, and counseling of sex partners

of persons who are infected with an STI

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US Department of Health and Human Services/Centers for Disease Control and Prevention

STI and HIV Infection Risk Assessment

Primary prevention of STIs includes assessment of behavioral

risk (i.e., assessing the sexual behaviors that can place persons

at risk for infection) and biologic risk (i.e., testing for risk

markers for STI and HIV acquisition or transmission). As part

of the clinical encounter, health care providers should routinely

obtain sexual histories from their patients and address risk

reduction as indicated in this report. Guidance for obtaining

a sexual history is available at the Division of STD Prevention

resource page (https://www.cdc.gov/std/treatment/resources.

htm) and in the curriculum provided by the National Network

of STD Clinical Prevention Training Centers (https://www.

nnptc.org). Effective interviewing and counseling skills,

characterized by respect, compassion, and a nonjudgmental

attitude toward all patients, are essential to obtaining a

thorough sexual history and delivering effective prevention

messages. Effective techniques for facilitating rapport with

patients include using open-ended questions (e.g., “Tell me

about any new sex partners you’ve had since your last visit” and

“What has your experience with using condoms been like?”);

understandable, nonjudgmental language (e.g., “What gender

are your sex partners?”and “Have you ever had a sore or scab

on your penis?”); and normalizing language (e.g., “Some of my

patients have difficulty using a condom with every sex act. How

is it for you?”). The “Five P’s” approach to obtaining a sexual

history is one strategy for eliciting information about the key

areas of interest (Box 1). In addition, health care professionals

can consider assessing sexual history by asking patients such

questions as, “Do you have any questions or concerns about

your sexual health?” Additional information about gaining

cultural competency when working with certain populations

(e.g., gay, bisexual, or other men who have sex with men

[MSM]; women who have sex with women [WSW] or with

women and men [WSWM]; or transgender men and women

or adolescents) is available in sections of these guidelines related

to these populations.

In addition to obtaining a behavioral risk assessment, a

comprehensive STI and HIV risk assessment should include

STI screening as recommended in these guidelines because

STIs are biologic markers of risk, particularly for HIV

acquisition and transmission among certain MSM. In most

clinical settings, STI screening is an essential and underused

component of an STI and HIV risk assessment. Persons

seeking treatment or evaluation for a particular STI should be

screened for HIV and other STIs as indicated by community

prevalence and individual risk factors (see Chlamydial

Infections; Gonococcal Infections; Syphilis). Persons should

be informed about all the tests for STIs they are receiving and

notified about tests for common STIs (e.g., genital herpes,

BOX 1. The Five P’s approach for health care providers obtaining sexual histories: partners, practices, protection from sexually

transmitted infections, past history of sexually transmitted infections, and pregnancy intention

1. Partners

• “Are you currently having sex of any kind?”

• “What is the gender(s) of your partner(s)?”

2. Practices

• “To understand any risks for sexually transmitted

infections (STIs), I need to ask more specific questions

about the kind of sex you have had recently.”

• “What kind of sexual contact do you have or have you had?”

“Do you have vaginal sex, meaning ‘penis in vagina’ sex?”

“Do you have anal sex, meaning ‘penis in rectum/anus’

sex?”

“Do you have oral sex, meaning ‘mouth on penis/vagina’?”

3. Protection from STIs

• “Do you and your partner(s) discuss prevention of STIs

and human immunodeficiency virus (HIV)?”

• “Do you and your partner(s) discuss getting tested?”

• For condoms:

“What protection methods do you use? In what

situations do you use condoms?”

4. Past history of STIs

• “Have you ever been tested for STIs and HIV?”

• “Have you ever been diagnosed with an STI in the past?”

• “Have any of your partners had an STI?”

Additional questions for identifying HIV and viral

hepatitis risk:

• “Have you or any of your partner(s) ever injected drugs?”

• “Is there anything about your sexual health that you

have questions about?”

5. Pregnancy intention

• “Do you think you would like to have (more) children

in the future?”

• “How important is it to you to prevent pregnancy

(until then)?”

• “Are you or your partner using contraception or

practicing any form of birth control?”

• “Would you like to talk about ways to prevent

pregnancy?”

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US Department of Health and Human Services/Centers for Disease Control and Prevention

trichomoniasis, Mycoplasma genitalium, and HPV) that are

available but not being performed and reasons why they are

not always indicated. Persons should be informed of their test

results and recommendations for future testing. Efforts should

be made to ensure that all persons receive STI care regardless

of personal circumstances (e.g., ability to pay, citizenship

or immigration status, gender identity, language spoken, or

specific sex practices).

STI and HIV Infection

Prevention Counseling

After obtaining a sexual history from their patients, all

providers should encourage risk reduction by offering

prevention counseling. Prevention counseling is most effective

if provided in a nonjudgmental and empathetic manner

appropriate to the patient’s culture, language, sex and gender

identity, sexual orientation, age, and developmental level.

Prevention counseling for STIs and HIV should be offered

to all sexually active adolescents and to all adults who have

received an STI diagnosis, have had an STI during the

previous year, or have had multiple sex partners. USPSTF

recommends intensive behavioral counseling for all sexually

active adolescents and for adults at increased risk for STIs and

HIV (4). Such interactive counseling, which can be resource

intensive, is directed at a person’s risk, the situations in which

risk occurs, and the use of personalized goal-setting strategies.

One such approach, known as client-centered STI and HIV

prevention counseling, involves tailoring a discussion of risk

reduction to the person’s situation. Although one large study in

STI clinics (Project RESPECT) demonstrated that this approach

was associated with lower acquisition of curable STIs (e.g.,

trichomoniasis, chlamydia, gonorrhea, and syphilis) (5), another

study conducted 10 years later in the same settings but different

contexts (Project AWARE) did not replicate this result (6).

With the challenges that intensive behavioral counseling poses,

health care professionals might find brief prevention messages

and those delivered through video or in a group session to be

more accessible for the client. A review of 11 studies evaluated

brief prevention messages delivered by providers and health

counselors and reported them to be feasible and to decrease

subsequent STIs in STD clinic settings (7) and HIV care

settings (8). Other approaches use motivational interviewing

to move clients toward achievable risk-reduction goals. Client-

centered counseling and motivational interviewing can be used

effectively by clinicians and staff trained in these approaches.

CDC provides additional information on these and other

effective behavioral interventions at https://www.cdc.gov/

std/program/interventions.htm. Training in client-centered

counseling and motivational interviewing is available through

the STD National Network of Prevention Training Centers

(https://www.nnptc.org).

In addition to one-on-one STI and HIV prevention

counseling, videos and large group presentations can provide

explicit information concerning STIs and reducing disease

transmission (e.g., how to use condoms consistently and

correctly and the importance of routine screening). Group-

based strategies have been effective in reducing the occurrence

of STIs among persons at risk, including those attending

STD clinics (9). Brief, online, electronic-learning modules for

young MSM have been reported to be effective in reducing

incident STIs and offer a convenient client platform for

effective interventions (10). Because the incidence of certain

STIs, most notably syphilis, is higher among persons with

HIV infection, use of client-centered STI counseling for

persons with HIV continues to be encouraged by public health

agencies and other health organizations (https://www.cdc.gov/

std/statistics/2019/default.htm). A 2014 guideline from CDC,

the Health Resources and Services Administration, and the

National Institutes of Health recommends that clinical and

nonclinical providers assess a person’s behavioral and biologic

risks for acquiring or transmitting STIs and HIV, including

having sex without condoms, having recent STIs, and having

partners recently treated for STIs (https://stacks.cdc.gov/

view/cdc/44064). That federal guideline is for clinical and

nonclinical providers to offer or make referral for regular

screening for multiple STIs, on-site STI treatment when

indicated, and risk-reduction interventions tailored to the

person’s risks. Brief risk-reduction counseling delivered by

medical providers during HIV primary care visits, coupled

with routine STI screening, has been reported to reduce STI

incidence among persons with HIV infection (8). Other

specific methods have been designed for the HIV care setting

(https://www.cdc.gov/hiv/effective-interventions/index.html).

Primary Prevention Methods

Pre-Exposure Vaccination

Pre-exposure vaccination is one of the most effective methods

for preventing transmission of HPV, HAV, and HBV, all

of which can be sexually transmitted. HPV vaccination is

recommended routinely for males and females aged 11 or

12 years and can be administered beginning at age 9 years.

HPV vaccination is recommended through age 26 years for

those not previously vaccinated (11). Sharing clinical decision-

making about HPV vaccination is recommended for certain

adults aged 27–45 years who are not adequately vaccinated

in accordance with existing guidance (https://www.cdc.gov/

vaccines/hcp/acip-recs/vacc-specific/hpv.html).

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US Department of Health and Human Services/Centers for Disease Control and Prevention

Hepatitis B vaccination is recommended for all unvaccinated,

uninfected persons who are sexually active with more than

one partner or are being evaluated or treated for an STI (12).

In addition, hepatitis A and B vaccines are recommended for

MSM, persons who inject drugs, persons with chronic liver

disease, and persons with HIV or hepatitis C infections who

have not had hepatitis A or hepatitis B (12). HAV vaccine is

also recommended for persons who are homeless (13). Details

regarding HAV and HBV vaccination, including routine

childhood vaccination, are available at https://www.cdc.gov/

hepatitis and at the ACIP website (https://www.cdc.gov/

vaccines/hcp/acip-recs/vacc-specific/index.html).

Condoms

External Condoms

When used consistently and correctly, external latex

condoms, also known as male condoms, are effective in

preventing the sexual transmission of HIV infection (http://

www.ashasexualhealth.org/pdfs/Male_and_Female_Condoms.

pdf). In heterosexual HIV mixed-status relationships (i.e., those

involving one infected and one uninfected partner) in which

condoms were used consistently, HIV-negative partners were

71%–80% less likely to become infected with HIV, compared

with persons in similar relationships in which condoms were

not used (14,15). Two analyses of MSM mixed-status couple

studies estimated the protective effect of condom use to be 70%

and 91%, respectively (16,17). Moreover, studies demonstrate

that consistent condom use reduces the risk for other STIs,

including chlamydia, gonorrhea, hepatitis B, and trichomoniasis

(18–21). By limiting lower genital tract infections, condoms

also might reduce the risk for pelvic inflammatory disease

(PID) among women (22). In addition, consistent and correct

use of latex condoms reduces the risk for HPV infection

and HPV-associated diseases, genital herpes, syphilis, and

chancroid when the infected area or site of potential exposure

is covered (23–27). Additional information is available at

https://www.cdc.gov/condomeffectiveness/index.html and

www.factsaboutcondoms.com/professional.php. Condoms

are regulated as medical devices and are subject to random

sampling and testing by the Food and Drug Administration

(FDA). Each latex condom manufactured in the United States

is tested electronically for holes before packaging. The rate of

condom breakage during sexual intercourse and withdrawal in

the United States is approximately two broken condoms per

100 condoms. Rates of breakage and slippage might be slightly

higher during anal intercourse (28,29). The failure of condoms

to protect against STIs or unintended pregnancy usually results

from inconsistent or incorrect use rather than condom breakage

(30). Users should check the expiration or manufacture date

on the box or individual package. Latex condoms should not

be used beyond their expiration date or >5 years after the

manufacturing date. Condoms made of materials other than

latex are available in the United States and can be classified

into two general categories: 1) polyurethane, polyisoprene, or

other synthetic condoms and 2) natural membrane condoms.

Polyurethane external condoms provide protection against

STIs and HIV and pregnancy comparable to that of latex

condoms (20,31). These can be substituted for latex condoms

by persons with latex sensitivity, are typically more resistant to

deterioration, and are compatible with use of both oil-based

and water-based lubricants. The effectiveness of other synthetic

external condoms to prevent STIs has not been extensively

studied, and FDA labeling restricts their recommended use

to persons who are sensitive to or allergic to latex. Natural

membrane condoms (frequently called natural skin condoms

or [incorrectly] lambskin condoms) are made from lamb cecum

and can have pores up to 1,500 nm in diameter. Although

these pores do not allow the passage of sperm, they are more

than 10 times the diameter of HIV and more than 25 times

that of HBV. Moreover, laboratory studies demonstrate that

sexual transmission of viruses, including HBV, herpes simplex

virus (HSV), and HIV, can occur with natural membrane

condoms (31). Therefore, natural membrane condoms are not

recommended for prevention of STIs and HIV.

Providers should advise that condoms must be used

consistently and correctly to be effective in preventing STIs and

HIV while noting that any condom use is better than no condom

use. Providing instructions about the correct use of condoms

can be useful. Communicating the following recommendations

can help ensure that patients use external condoms correctly:

• Use a new condom with each sex act (i.e., oral, vaginal,

and anal).

• Carefully handle the condom to avoid damaging it with

fingernails, teeth, or other sharp objects.

• Put the condom on after the penis is erect and before any

genital, oral, or anal contact with the partner.

• Use only water-based or silicone-based lubricants (e.g.,

K-Y Jelly, Astroglide, AquaLube, or glycerin) with latex

condoms. Oil-based lubricants (e.g., petroleum jelly,

shortening, mineral oil, massage oils, body lotions, or

cooking oil) can weaken latex and should not be used;

however, oil-based lubricants typically can be used with

polyurethane or other synthetic condoms.

• Ensure adequate lubrication during vaginal and anal sex,

which might require using exogenous water-based

lubricants.

• Hold the condom firmly against the base of the penis

during withdrawal, and withdraw while the penis is still

erect to prevent the condom from slipping off.

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US Department of Health and Human Services/Centers for Disease Control and Prevention

Additional information about external condoms is available

at https://www.cdc.gov/condomeffectiveness.

Internal Condoms

Condoms for internal vaginal use, also known as female

condoms, are available worldwide (e.g., the FC2 Female

Condom, Reddy condom, Cupid female condom, and Woman’s

condom) (31,32). Use of internal condoms can provide

protection from acquisition and transmission of STIs, although

data are limited. Internal condoms are more costly compared

with external condoms; however, they offer the advantage of

being controlled by the receptive partner as an STI and HIV

prevention method, and the newer versions might be acceptable

to all persons. Although the internal condom also has been used

during receptive anal intercourse, efficacy associated with this

practice remains unknown (33). Additional information about

the internal condom is available at http://www.ashasexualhealth.

org/pdfs/Male_and_Female_Condoms.pdf.

Cervical Diaphragms

In observational studies, diaphragm use has been

demonstrated to protect against cervical gonorrhea, chlamydia,

and trichomoniasis (34). However, a trial examining the effect

of a diaphragm plus lubricant on HIV acquisition among

women in Africa reported no additional protective effect when

compared with the use of male condoms alone. Likewise, no

difference by study arm in the rate of acquisition of chlamydia,

gonorrhea, or herpes occurred (35,36). Diaphragms should

not be relied on as the sole source of protection against HIV

and other STIs.

Multipurpose Prevention Technologies

Methods that combine STI and HIV prevention

with pregnancy prevention are known as multipurpose

prevention technologies (MPTs) (37) (https://www.who.int/

reproductivehealth/topics/linkages/mpts/en). Internal and

external condoms are both examples of MPTs because they are

effective prevention measures when used correctly for STI and

HIV transmission or pregnancy prevention. The multicenter

Evidence for Contraception Options and HIV Outcomes

(ECHO) trial observed no statistically significant differences in

HIV incidence rates among women randomly assigned to one

of three contraceptive methods (depot medroxyprogesterone

acetate [DMPA], levonorgestrel implant, and copper-

containing intrauterine device [IUD]); however, rates of HIV

infection were high in all groups, indicating a need for MPTs

(38). Development of MPTs is complex and ongoing; products

under study include microbicides with contraceptive devices

(e.g., tenofovir with a vaginal ring contraceptive delivery

package) and other innovative methods (39).

Topical Microbicides and Spermicides

Nonspecific topical microbicides are ineffective for

preventing HIV infection (40–45). Tenofovir gel has been

studied for prevention of herpes simplex virus 2 (HSV-2)

and HIV infections (46,47). Adherence can be low (48), and

prevention of HIV infection, especially among women, has not

been demonstrated (47,49).Vaginal rings containing dapivirine

have provided some reduction in HIV infection (50,51). For

men and transgender women who have anal intercourse,

tenofovir gel appears safe when applied before and after anal

sex (52). Spermicides containing nonoxynol-9 (N-9) might

disrupt genital or rectal epithelium and have been associated

with an increased risk for HIV infection. Condoms with N-9

are no more effective than condoms without N-9; therefore,

N-9 alone or in a condom is not recommended for STI and

HIV prevention (40). N-9 use also has been associated with

an increased risk for bacterial urinary tract infections among

women (53,54).

Nonbarrier Contraception, Female Surgical

Sterilization, and Hysterectomy

Contraceptive methods that are not mechanical barriers

offer no protection against HIV or other STIs. The ECHO

study observed no differences in HIV incidence rates among

women randomly assigned to DMPA, levonorgestrel implant,

or copper-containing IUD contraceptive methods (38). A

systematic review of epidemiologic evidence reported that the

majority of studies demonstrated no association between use

of oral contraceptives and HIV acquisition among women

(55). Whether hormonal contraception alters a woman’s risk

for other STIs is uncertain (56,57).

Sexually active women who use contraceptive methods

other than condoms should be counseled about STI and HIV

infection prevention measures. These include pre-exposure

prophylaxis (PrEP) and postexposure prophylaxis (PEP),

limiting the number of sex partners, and correct and consistent

use of condoms.

Emergency Contraception

Unprotected intercourse exposes women to risks for STIs

and unplanned pregnancy. Providers should offer counseling

about the option of emergency contraception if pregnancy

is not desired. Options for emergency contraception in the

United States include copper-containing IUDs and emergency

contraceptive pills (ECPs) (58,59). More information is available

at https://www.acog.org/clinical/clinical-guidance/practice-

bulletin/articles/2015/09/emergency-contraception?utm_

source=redirect&utm_medium=web&utm_campaign=otn.

ECPs are available in the following formulations: ulipristal

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acetate in a single dose (30 mg) available by prescription,

levonorgestrel in a single dose (1.5 mg) available over the

counter or by prescription, or a combined estrogen and

progestin pill regimen. Insertion of a copper-containing

IUD ≤5 days after unprotected sex can reduce pregnancy risk

from a sex act by approximately 99% (60). ECPs are most

efficacious when initiated as soon as possible after unprotected

sex. Ulipristal acetate is effective ≤5 days after unprotected sex,

and levonorgestrel is most effective ≤3 days after unprotected

sex but has some efficacy at ≤5 days. ECPs are ineffective

(but not harmful) if the woman is already pregnant (61). A

2019 Cochrane review summarized the efficacy, safety, and

convenience of different emergency contraception methods (61).

More information about emergency contraception is

available in Contraceptive Technology, 21st Edition (31), in the

2016 U.S. Selected Practice Recommendations (U.S. SPR)

for Contraceptive Use (emergency contraception) available

at https://www.cdc.gov/reproductivehealth/contraception/

mmwr/spr/emergency.html, and in the 2016 U.S. Medical

Eligibility Criteria (U.S. MEC) for Contraceptive Use (copper

IUDs for emergency contraception) available at https://

www.cdc.gov/reproductivehealth/contraception/mmwr/mec/

appendixj.html.

Providers should educate males and females about emergency

contraception, especially if other methods of contraception

were used incorrectly or not at all and pregnancy is not desired

(62). An advance supply of ECPs can be provided or prescribed

so that ECPs will be available when needed (59).

Male Circumcision

Male circumcision reduces the risk for HIV infection and

certain STIs among heterosexual men. Three randomized,

controlled trials performed in regions of sub-Saharan Africa,

where generalized HIV epidemics involving predominantly

heterosexual transmission were occurring, demonstrated that

male circumcision reduces the risk for HIV acquisition among

men by 50%–60% (63–65). In those trials, circumcision

also was protective against other STIs, including high-risk

genital HPV infection and genital herpes (66–68). Follow-up

studies have demonstrated sustained benefit of circumcision

for HIV prevention (69) and that the effect is not mediated

solely through a reduction in HSV-2 infection or genital ulcer

disease (GUD) (70).

The World Health Organization (WHO) and the Joint

United Nations Programme on HIV/AIDS (UNAIDS)

recommend that male circumcision efforts be scaled up as an

effective intervention for preventing heterosexually acquired HIV

infection (71) in countries with hyperendemic and generalized

HIV epidemics within the context of ensuring universal access

to comprehensive HIV prevention, treatment, care, and support

(https://www.afro.who.int/publications/voluntary-medical-male-

circumcision-hiv-prevention). In the United States, the American

Academy of Pediatrics (AAP) recommends that newborn male

circumcision be available to families that desire it because the

benefits of the procedure, including prevention of penile cancers,

urinary tract infections, GUD, and HIV infection, outweigh the

risks. ACOG has also endorsed AAP’s policy statement. In light

of these benefits, the American Urological Association states

that male circumcision should be considered an option for risk

reduction, among other strategies (72). Additional information

for providers counseling male patients and parents regarding

male circumcision for preventing HIV, STIs, and other adverse

health outcomes is available at https://www.cdc.gov/hiv/risk/

male-circumcision.html.

No definitive data exist to determine whether male

circumcision reduces HIV acquisition among MSM, although

one meta-analysis of 62 observational studies reported that

circumcision was protective against HIV acquisition in low- to

middle-income countries but not in high-income countries

(73). Further studies are needed to confirm any potential

benefit of male circumcision for this population.

Pre-Exposure Prophylaxis for HIV

Daily oral antiretroviral PrEP with a fixed-dose combination

of emtricitabine (FTC) and either tenofovir disoproxil fumarate

(TDF) or tenofovir alafenamide (TAF) have demonstrated

safety (74) and a substantial reduction in the rate of HIV

acquisition for MSM (75). TDF/FTC has demonstrated

safety and efficacy for mixed-status heterosexual couples (76)

and heterosexual men and women recruited individually

(77); however, no evidence is yet available regarding TAF/

FTC among heterosexually active women. In addition, one

clinical trial involving persons who inject drugs (78) and one

involving heterosexual mixed-status couples (76) demonstrated

substantial efficacy and safety of daily oral PrEP with TDF

alone. High adherence to oral PrEP was strongly associated

with protection from HIV infection. Studies conducted with

MSM have demonstrated that taking PrEP at specific times

before and after sexual intercourse was effective in preventing

HIV; however, less experience exits with this regimen, it is

not FDA cleared, and it has not been studied among other

populations (79).

Comprehensive clinical practice guidelines are available

for providers in prescribing PrEP to reduce the risk for HIV

infection (80). Among HIV-negative sexually active men

and women, bacterial STIs are key indicators of risk for

HIV acquisition. Studies have documented the risk for HIV

acquisition among MSM within 1 year after infection with

rectal gonorrhea or chlamydia (one in 15 men), primary

or secondary syphilis (one in 18), and among men with no

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rectal STI or syphilis infection (one in 53) (81–83). Sexually

active adults and adolescents should be screened for STIs

(e.g., chlamydia, gonorrhea, and syphilis) in accordance with

recommendations, and persons with infection should be

offered PrEP. The USPSTF recommends that persons at risk

for HIV acquisition be offered PrEP (84). Persons at risk for

HIV acquisition include HIV-negative persons whose sexual

partner or partners have HIV infection (especially if viral load

is detectable or unknown), persons who have had gonorrhea

or syphilis during the previous 6 months, and injecting drug

users who share injection equipment (84). Clinical practice

guidelines recommend STI screening for persons taking PrEP

(80) because increased rates of STI acquisition have been

described (85–87).

Pre-Exposure Prophylaxis for STIs

Providing HSV treatment to persons with HIV and HSV

infection has not demonstrated benefit in reducing HIV

acquisition among uninfected partners. A large randomized

controlled trial evaluated mixed-status heterosexual couples

among the partners with HIV infection who also were

seropositive for HSV-2 (88). Use of acyclovir had no effect

on HIV transmission. These findings are consistent with a

previous trial that reported no benefit of acyclovir in preventing

HIV acquisition among persons seropositive for HSV-2 (89).

Doxycycline prophylaxis has been examined for preventing

bacterial STIs. In a pilot study, 30 MSM living with HIV with

previous syphilis (two or more episodes since HIV diagnosis)

were randomly assigned to doxycycline 100 mg for 48 weeks

versus a financial incentive–based behavioral intervention (90).

That study demonstrated a 73% reduction in any bacterial STI

at any site, without substantial differences in sexual behavior.

Additional studies examining doxycycline prophylaxis are

under way or in development (91).

Postexposure Prophylaxis for HIV and STIs

Guidelines for using PEP aimed at preventing HIV and other

STIs as a result of sexual exposure are available at https://www.

cdc.gov/hiv/pdf/programresources/cdc-hiv-npep-guidelines.

pdf. Sexually active persons seeking HIV PEP should be

evaluated for PrEP after completing their PEP course and

testing negative for HIV. HIV PEP is also discussed elsewhere

in this report (see Sexual Assault and Abuse and STIs). Genital

hygiene methods (e.g., vaginal washing and douching) after

sexual exposure are ineffective in protecting against HIV and

STIs and might increase the risk for bacterial vaginosis (BV),

certain STIs, and HIV infection (92).

STI PEP in the form of doxycycline 200 mg taken after

unprotected anal sex has been studied among MSM and

transgender women; results demonstrated reduction in incident

chlamydia and syphilis by 70% and 73%, respectively, but no

effect on gonorrhea (93). Other studies are under way or in

development regarding doxycycline prophylaxis for bacterial

STIs (91). No long-term data are available regarding the impact

of STI PEP on antimicrobial resistance and the microbiome.

Further studies are needed to determine whether STI PEP is

an effective and beneficial strategy for STI prevention.

HIV Treatment as Prevention: Antiretroviral

Treatment of Persons with HIV to Prevent HIV

Among Partners

In 2011, the randomized controlled trial HPTN 052

demonstrated that, among HIV mixed-status heterosexual

couples, HIV antiretroviral therapy (ART) for the infected

partner decreased the risk for transmission to the uninfected

partner by 96% (94). Therefore, ART not only is beneficial to

the health of persons with HIV infection, it also reduces the

risk for transmission. Additional studies of HIV mixed-status

couples, heterosexual and MSM couples (PARTNER study),

and MSM couples (Opposites Attract and PARTNERS2

studies) reported that patients with HIV taking ART who

maintain an undetectable viral load demonstrate no risk for

transmitting HIV to their HIV-negative sex partners (95–97).

For those reasons, ART should be offered to all persons with

HIV infection to obtain viral suppression. Detailed guidance

regarding ART regimens is available in the U.S. Department of

Health and Human Services’ HIV treatment guidelines (98).

HIV Seroadaptive Strategies

Seroadaptive strategies for HIV prevention have largely

originated within communities of MSM. They are predicated

on knowledge of self and partner HIV status. One specific

seroadaptive practice is serosorting, which includes limiting

anal sex without a condom to partners with the same HIV

status as their own or choosing to selectively use condoms

with HIV mixed-status partners. Another practice among

mixed-status couples is seropositioning, in which the

person with HIV infection is the receptive partner for anal

intercourse. Observational studies have consistently reported

that serosorting confers greater risk for HIV infection than

consistent condom use but has lower risk compared with anal

intercourse without a condom and without serosorting (99–

101). Serosorting practices have been associated with increased

risk for STIs, including chlamydia and gonorrhea (102,103).

Serosorting is not recommended for the following reasons:

many MSM who have HIV infection do not know they

have HIV because they have not been tested recently, men’s

assumptions about the HIV status of their partners might be

wrong, and some men with HIV infection might not disclose or

might misrepresent their HIV status. All of these factors increase

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the risk that serosorting can lead to HIV infection. Serosorting

has not been studied among heterosexually active persons.

Abstinence and Reduction of Number of

Sex Partners

Abstinence from oral, vaginal, and anal sex and participating

in a long-term, mutually monogamous relationship with a

partner known to be uninfected are prevention approaches to

avoid transmission of STIs. For persons who are being treated

for an STI (or whose partners are undergoing treatment),

counseling that encourages abstinence from sexual intercourse

until completion of the entire course of medication is vital

for preventing reinfection. A trial conducted among women

regarding the effectiveness of counseling messages when

patients have cervicitis or vaginal discharge demonstrated

that women whose sex partners have used condoms might

benefit from a hierarchical message that includes condoms

but women without such experience might benefit more from

an abstinence-only message (104). A more comprehensive

discussion of abstinence and other sexual practices that can help

persons reduce their risk for STIs is available in Contraceptive

Technology, 21st Edition (31).

Partner Services

The term “partner services” refers to a continuum of clinical

evaluation, counseling, diagnostic testing, and treatment

designed to increase the number of infected persons brought to

treatment and to reduce transmission among sexual networks.

This continuum includes efforts of health departments,

medical providers, and patients themselves. The term “public

health partner services” refers to efforts by public health

departments to identify the sex and needle-sharing partners

of infected persons to ensure their medical evaluation and

treatment. Health departments are increasingly incorporating

referral to additional services, as indicated, into the partner services

continuum. Aside from the general benefit to patients and partners,

service referrals and linkage can mitigate the circumstances that

increase risk for future STI and HIV acquisition.

The types and comprehensiveness of public health partner

services and the specific STIs for which they are offered vary

by public health agency, their resources, and the geographic

prevalence of STIs. In most areas of the United States, health

departments routinely attempt to provide partner services to

all persons with infectious syphilis (primary or secondary)

and persons with a new diagnosis of HIV infection. Health

departments should provide partner services for persons who

might have cephalosporin-resistant gonorrhea. In contrast,

relatively few U.S. health departments routinely provide

STI partner services to persons with gonorrhea, chlamydia,

trichomoniasis, or other STIs (105). Because STI diagnoses

often can serve as risk markers for HIV acquisition (83), public

health services might include follow-up of MSM with an STI

to offer HIV PrEP. Public health services can also include HIV

and STI prevention interventions including HIV and STI

testing, linkage and relinkage of persons with HIV infection

to HIV care clinics, and referral of partners of persons with

STIs or HIV infection to HIV PrEP, as indicated (106–109).

Clinicians should familiarize themselves with public health

practices in their area; however, in most instances, providers

should understand that responsibility for discussing the

treatment of partners of persons with STIs rests with the

diagnosing provider and the patient. State laws require a good

faith effort by the provider to inform partners, and providers

should familiarize themselves with public health laws.

Clinicians who do not notify partners of patients directly

can still provide partner services by counseling infected persons

and providing them with written information and medication

to give to their partners (if recommended and allowable by

state law), directly evaluating and treating sex partners, and

cooperating with state and local health departments. Clinicians’

efforts to ensure treatment of patients’ sex partners can reduce

the risk for reinfection and potentially diminish transmission

of STIs (110). Therefore, clinicians should encourage all

persons with STIs to notify their sex partners and urge them

to seek medical evaluation and treatment. Exceptions to this

practice include circumstances posing a risk for intimate

partner violence (111). Available data are limited regarding

the rate of intimate partner violence directly attributable

to partner notification (112,113); however, because of the

reported prevalence of intimate partner violence in the general

population (114), providers should consider the potential

risk before notifying partners of persons or encouraging

partner notification. Time spent counseling patients about the

importance of notifying partners is associated with improved

notification outcomes (115). When possible, clinicians should

advise persons to bring their primary sex partner with them

when returning for treatment and should concurrently treat

both persons. Although this approach can be effective for a

main partner (116,117), it might not be a feasible approach

for additional sex partners. Evidence indicates that providing

patients with written information to share with sex partners

can increase rates of partner treatment (110).

Certain health departments now use technology (e.g.,

email, texting, mobile applications, and social media outlets)

to facilitate partner services for locating and notifying the

sex partners of persons with STIs, including HIV (118,119).

Patients now have the option to use Internet sites to send

anonymous email or text messages advising partners of their

exposure to an STI (120); anonymous notification via the

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Internet is considered better than no notification at all.

However, because the extent to which these sites affect partner

notification and treatment is uncertain, patients should be

encouraged to notify their partners in person or by telephone,

email, or text message; alternatively, patients can authorize a

medical provider or public health professional to notify their

sex partners.

Expedited Partner Therapy

Expedited partner therapy (EPT) is a harm-reduction

strategy and the clinical practice of treating the sex partners

of persons with diagnosed chlamydia or gonorrhea, who are

unable or unlikely to seek timely treatment, by providing

medications or prescriptions to the patient as allowable by law.

Patients then provide partners with these therapies without

the health care provider having examined the partner (https://

www.cdc.gov/std/ept). Unless prohibited by law or other

regulations, medical providers should routinely offer EPT

to patients with chlamydia when the provider cannot ensure

that all of a patient’s sex partners from the previous 60 days

will seek timely treatment. If the patient has not had sex

during the 60 days before diagnosis, providers should offer

EPT for the patient’s most recent sex partner. Because EPT

must be an oral regimen and current gonorrhea treatment

involves an injection, EPT for gonorrhea should be offered

to partners unlikely to access timely evaluation after linkage

is explored. EPT is legal in the majority of states but varies

by chlamydial or gonococcal infection. Providers should visit

https://www.cdc.gov/std/ept to obtain updated information for

their state. Providing patients with packaged oral medication

is the preferred approach because the efficacy of EPT using

prescriptions has not been evaluated, obstacles to EPT can exist

at the pharmacy level (121,122), and many persons (especially

adolescents) do not fill the prescriptions provided to them by

a sex partner (123,124). Medication or prescriptions provided

for EPT should be accompanied by educational materials for

the partner, including treatment instructions, warnings about

taking medications (e.g., if the partner is pregnant or has an

allergy to the medication), general health counseling, and a

statement advising that partners seek medical evaluation as

soon as possible for HIV infection and any symptoms of STIs,

particularly PID.

Evidence supporting EPT is based on three U.S. clinical

trials involving heterosexual men and women with chlamydia

or gonorrhea (125–127). All three trials reported that more

partners were treated when patients were offered EPT. Two

reported statistically significant decreases in the rate of

reinfection, and one observed a lower risk for persistent or

recurrent infection that was statistically nonsignificant. A

fourth trial in the United Kingdom did not demonstrate a

difference in the risk for reinfection or in the numbers of

partners treated between persons offered EPT and those

advised to notify their sex partners (128). U.S. trials and a

meta-analysis of EPT revealed that the magnitude of reduction

in reinfection of index patients, compared with patient referral,

differed according to the STI and the sex of the index patient

(110,125–127). However, across trials, reductions in chlamydia

prevalence at follow-up were approximately 20%, and

reductions in gonorrhea were approximately 50% at follow-up.

Existing data indicate that EPT also might have a role in

partner management for trichomoniasis; however, no partner

management intervention has been reported to be more

effective than any other in reducing trichomoniasis reinfection

rates (129,130). No data support use of EPT in the routine

management of patients with syphilis.

Data are limited regarding use of EPT for gonococcal

or chlamydial infections among MSM, compared with

heterosexuals (131,132). Published studies, including recent

data regarding extragenital testing, indicated that male partners

of MSM with diagnosed gonorrhea or chlamydia might have

other bacterial STIs (gonorrhea or syphilis) or HIV (133–135).

Studies have reported that 5% of MSM have a new diagnosis

of HIV when evaluated as partners of men with gonococcal

or chlamydial infections (133,134); however, more recent data

indicate that, in certain settings, the frequency of HIV infection

is much lower (135). Considering limited data and potential

for other bacterial STIs among MSM partners, shared clinical

decision-making regarding EPT is recommended. All persons

who receive bacterial STI diagnoses and their sex partners,

particularly MSM, should be tested for HIV, and those at risk

for HIV infection should be offered HIV PrEP (https://www.

cdc.gov/hiv/pdf/risk/prep/cdc-hiv-prep-guidelines-2017.pdf).

Reporting and Confidentiality

Accurate and timely reporting of STIs is integral to public

health efforts in assessing morbidity trends, allocating limited

resources, and assisting local health authorities with partner

notification and treatment. STI and HIV/AIDS cases should

be reported in accordance with state and local statutory

requirements. Syphilis (including congenital syphilis),

gonorrhea, chlamydia, chancroid, and HIV are reportable

diseases in every state. Because the requirements for reporting

other STIs differ by state, clinicians should be familiar with the

reporting requirements applicable within their jurisdictions.

Reporting can be provider based, laboratory based, or

both. Clinicians who are unsure of state and local reporting

requirements should seek advice from state or local health

department STI programs. STI and HIV reports are kept

confidential. In most jurisdictions, such reports are protected

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by statute or regulation. Before conducting a follow-up

of a person with a positive STI test result, public health

professionals should consult the patient’s health care provider,

if possible, to inform them of the purpose of the public health

visit, verify the diagnosis, determine the treatments received,

and ascertain the best approaches to patient follow-up.

Retesting After Treatment to Detect

Repeat Infections

Retesting 3 months after diagnosis of chlamydia, gonorrhea,

or trichomoniasis can detect repeat infection and potentially

can be used to enhance population-based prevention (136,137).

Any person who has a positive test for chlamydia or gonorrhea,

along with women who have a positive test for trichomonas,

should be rescreened 3 months after treatment. Any person

who receives a syphilis diagnosis should undergo follow-up

serologic syphilis testing per current recommendations

and follow-up testing for HIV (see Syphilis). Additional

information regarding retesting is available elsewhere in this

report (see Chlamydial Infections; Gonococcal Infections;

Syphilis; Trichomoniasis).

STI Detection Among Special

Populations

Pregnant Women

Intrauterine or perinatally transmitted STIs can have

debilitating effects on pregnant women, their fetuses, and their

partners. All pregnant women and their sex partners should be

asked about STIs, counseled about the possibility of perinatal

infections, and provided access to recommended screening and

treatment, if needed.

Recommendations for screening pregnant women for

STIs to detect asymptomatic infections are based on disease

severity and sequelae, prevalence among the population, costs,

medicolegal considerations (e.g., state laws), and other factors.

The following screening recommendations for pregnant

women summarize clinical guidelines from federal agencies

and medical professional organizations.

Screening Recommendations

HIV Infection

All pregnant women in the United States should be tested

for HIV at the first prenatal visit, even if they have been

previously tested (138). Testing pregnant women for HIV

and prompt linkage to care of women with HIV infection are

vital for women’s health and reducing perinatal transmission of

HIV through ART and obstetrical interventions. HIV testing

should be offered as part of the routine panel of prenatal tests

(i.e., opt-out testing). For women who decline HIV testing,

providers should address their concerns and, when appropriate,

continue to encourage testing. Partners of pregnant patients

should be offered HIV testing if their status is unknown (139).

Retesting in the third trimester (preferably before 36 weeks’

gestation) is recommended for women at high risk for

acquiring HIV infection. Examples of women at high risk

include those who inject drugs, have STIs during pregnancy,

have multiple sex partners during pregnancy, have a new

sex partner during pregnancy, or have partners with HIV

infection; those who are receiving care in health care facilities

in settings with HIV incidence ≥1 per 1,000 women per year;

those who are incarcerated; those who live in areas with high

rates of HIV infection; or those who have signs or symptoms

of acute HIV infection (e.g., fever, lymphadenopathy, skin

rash, myalgia, arthralgia, headache, oral ulcers, leukopenia,

thrombocytopenia, or transaminase elevation) (140).

Rapid HIV testing should be performed for any woman in labor

who has not been tested for HIV during pregnancy or whose HIV

status is unknown, unless she declines. If a rapid HIV test result

is positive, ART should be administered without waiting for the

results of confirmatory testing (https://clinicalinfo.hiv.gov/sites/

default/files/inline-files/PerinatalGL.pdf).

Syphilis

During 2012–2019, congenital syphilis rates in the United

States increased from 8.4 to 48.5 cases per 100,000 births,

a 477.4% increase (141). At least 45 states have a prenatal

syphilis testing requirement, with high variability among those

requirements (142). In the United States, all pregnant women

should be screened for syphilis at the first prenatal visit, even

if they have been tested previously (143). Prenatal screening

for syphilis has been reported to be suboptimal in the United

States (144,145). Testing in the third trimester and at delivery

can prevent congenital syphilis cases (146,147). Partners of

pregnant women with syphilis should be evaluated, tested,

and treated.

When access to prenatal care is not optimal, a stat rapid

plasma reagin (RPR) card test and treatment, if that test is

reactive, should be administered at the time that a pregnancy

is confirmed or when the pregnancy test is performed, if

follow-up is uncertain. Pregnant women should be retested

for syphilis at 28 weeks’ gestation and at delivery if the mother

lives in a community with high syphilis rates or is at risk for

syphilis acquisition during pregnancy (e.g., misuses drugs or

has an STI during pregnancy, having multiple sex partners,

having a new sex partner, or having a sex partner with an STI).

Neonates should not be discharged from the hospital unless

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the syphilis serologic status of the mother has been determined

at least once during pregnancy. Any woman who delivers a

stillborn infant should be tested for syphilis.

Hepatitis B

All pregnant women should be routinely tested for hepatitis

B surface antigen (HBsAg) at the first prenatal visit even if they

have been previously vaccinated or tested (148). Women who

are HBsAg positive should be provided with, or referred for,

counseling and medical management. Women who are HBsAg

negative but at risk for HBV infection should be vaccinated.

Women who were not screened prenatally, those who engage

in behaviors that put them at high risk for infection (e.g.,

having had more than one sex partner during the previous

6 months, having been evaluated or treated for an STI,

having had recent or current injection drug use, or having an

HBsAg-positive sex partner), and those with clinical hepatitis

should be tested at the time of admission to the hospital

for delivery. To avoid misinterpreting a transient positive

HBsAg result during the 21 days after vaccination, HBsAg

testing should be performed before vaccine administration.

All laboratories that conduct HBsAg tests should test initially

reactive specimens with a licensed neutralizing confirmatory

test. When pregnant women are tested for HBsAg at the time

of admission for delivery, shortened testing protocols can be

used, and initially reactive results should prompt expedited

administration of immunoprophylaxis to neonates (148).

Pregnant women who are HBsAg positive should be reported

to the local or state health department to ensure that they

are entered into a case-management system and that timely

and age-appropriate prophylaxis is provided to their infants.

Information concerning the pregnant woman’s HBsAg status

should be provided to the hospital where delivery is planned

and to the health care provider who will care for the newborn.

In addition, household and sexual contacts of women who are

HBsAg positive should be vaccinated.

Chlamydia

All pregnant women aged <25 years as well as older women

at increased risk for chlamydia (e.g., those aged ≥25 years who

have a new sex partner, more than one sex partner, a sex partner

with concurrent partners, or a sex partner who has an STI)

should be routinely screened for Chlamydia trachomatis at the first

prenatal visit (149). Pregnant women who remain at increased

risk for chlamydial infection also should be retested during the

third trimester to prevent maternal postnatal complications and

chlamydial infection in the neonate. Pregnant women identified

as having chlamydia should be treated immediately and have a

test of cure to document chlamydial eradication by a nucleic acid

amplification test (NAAT) 4 weeks after treatment. All persons

diagnosed with a chlamydial infection should be rescreened

3 months after treatment.

Gonorrhea

All pregnant women aged <25 years as well as women aged

≥25 years at increased risk for gonorrhea (e.g., those with other

STIs during pregnancy or those with a new sex partner, more

than one sex partner, a sex partner with concurrent partners,

or a sex partner who has an STI or is exchanging sex for money

or drugs) should be screened for Neisseria gonorrhoeae at the

first prenatal visit (149). Pregnant women who remain at high

risk for gonococcal infection also should be retested during the

third trimester to prevent maternal postnatal complications and

gonococcal infection in the neonate. Clinicians should consider

the communities they serve and might choose to consult local

public health authorities for guidance on identifying groups

that are more vulnerable to gonorrhea acquisition on the basis

of local disease prevalence. Gonococcal infection, in particular,

is concentrated among specific geographic locations and

communities (https://www.cdc.gov/std/statistics/2019/default.

htm). Pregnant women identified as having gonorrhea should

be treated immediately. All persons diagnosed with gonorrhea

should be rescreened 3 months after treatment.

Hepatitis C Virus

The rate of hepatitis C virus (HCV) infection has increased

among pregnant women in recent years (150–153). HCV

screening should be performed for all pregnant women

during each pregnancy, except in settings where the HCV

infection (HCV positivity) rate is <0.1% (154–156). The most

important risk factor for HCV infection is past or current

injecting drug use (157). Additional risk factors include having

had a blood transfusion or organ transplantation before July

1992, having received clotting factor concentrates produced

before 1987, having received an unregulated tattoo, having

been on long-term hemodialysis, having other percutaneous

exposures, or having HIV infection. All women with HCV

infection should receive counseling, supportive care, and

linkage to care (https://www.hcvguidelines.org). No vaccine

is available for preventing HCV transmission.

Cervical Cancer

Pregnant women should undergo cervical cancer screening

and at the same frequency as nonpregnant women; however,

management differs slightly during pregnancy (158).

Colposcopy is recommended for the same indications during

pregnancy as for nonpregnant women. However, biopsies

may be deferred, and endocervical sampling should not

be performed. Treatment should not be performed during

pregnancy unless cancer is detected.

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Bacterial Vaginosis, Trichomoniasis, and

Genital Herpes

Evidence does not support routine screening for BV among

asymptomatic pregnant women at high risk for preterm

delivery (159). Symptomatic women should be evaluated

and treated (see Bacterial Vaginosis). Evidence does not

support routine screening for Trichomonas vaginalis among

asymptomatic pregnant women. Women who report symptoms

should be evaluated and treated (see Trichomoniasis). In

addition, evidence does not support routine HSV-2 serologic

screening among asymptomatic pregnant women. However,

type-specific serologic tests might be useful for identifying

pregnant women at risk for HSV-2 infection and for guiding

counseling regarding the risk for acquiring genital herpes

during pregnancy. Routine serial cultures for HSV are not

indicated for women in the third trimester who have a history

of recurrent genital herpes.

For more detailed discussions of STI screening and treatment

among pregnant women, refer to the following references:

Screening for HIV Infection: U.S. Preventive Services Task Force

Recommendation Statement (138); Recommendations for the Use

of Antiretroviral Drugs in Pregnant Women with HIV Infection

and Interventions to Reduce Perinatal HIV Transmission in

the United States (https://clinicalinfo.hiv.gov/sites/default/

files/inline-files/PerinatalGL.pdf); Guidelines for Perinatal

Care (160); Prevention of Hepatitis B Virus Infection in the

United States: Recommendations of the Advisory Committee

on Immunization Practices (12); Screening for Chlamydia and

Gonorrhea: U.S. Preventive Services Task Force Recommendation

Statement (149); Screening for Bacterial Vaginosis in Pregnant

Persons to Prevent Preterm Delivery: U.S. Preventive Services

Task Force Recommendation Statement (159); Screening for

Syphilis Infection in Pregnant Women: U.S. Preventive Services

Task Force Recommendation Statement (161); Serologic Screening

for Genital Herpes Infection: U.S. Preventive Services Task Force

Recommendation Statement (162); Screening for HIV Infection

in Pregnant Women: A Systematic Review for the U.S. Preventive

Services Task Force (163); Screening for Hepatitis B in Pregnant

Women: Updated Evidence Report and Systematic Review

for the U.S. Preventive Services Task Force (164); and CDC

Recommendations for Hepatitis C Screening Among Adults —

United States, 2020 (156).

Adolescents

In the United States, prevalence rates of certain STIs are

highest among adolescents and young adults (141). For

example, reported rates of chlamydia and gonorrhea are highest

among females during their adolescent and young adult years,

and many persons acquire HPV infection during that time.

Persons who initiate sex early in adolescence are at higher risk

for STIs, as are adolescents living in detention facilities; those

receiving services at STD clinics; those who are involved in

commercial sex exploitation or survival sex and are exchanging

sex for drugs, money, food, or housing; young males who

have sex with males (YMSM); transgender youths; and youths

with disabilities, substance misuse, or mental health disorders.

Factors contributing to increased vulnerability to STIs during

adolescence include having multiple sex partners, having

sequential sex partnerships of limited duration or concurrent

partnerships, failing to use barrier protection consistently

and correctly, having lower socioeconomic status, and facing

multiple obstacles to accessing health care (141,165).

All 50 states and the District of Columbia explicitly allow

minors to consent for their own STI services. No state requires

parental consent for STI care, although the age at which a

minor can provide consent for specified health care services

(i.e., HPV vaccination and HIV testing and treatment) varies

among states. In 2019, a total of 18 states allowed but did not

require physicians to notify parents of a minor’s receipt of STI

services, including states where minors can legally provide their

own consent to the service (https://www.cdc.gov/hiv/policies/

law/states/minors.html).

Protecting confidentiality for STI care, particularly for

adolescents enrolled in private health insurance plans, presents

multiple problems. After a claim has been submitted, many

states mandate that health plans provide a written statement

to the beneficiary indicating the service performed, the charges

covered, what the insurer allows, and the amount for which the

patient is responsible (i.e., explanation of benefits [EOB]) (166–

169). In addition, federal laws obligate notices to beneficiaries

when claims are denied, including alerting beneficiaries who

need to pay for care until the allowable deductible is reached.

For STI testing and treatment-related care, an EOB or

medical bill that is received by a parent might disclose services

provided and list STI laboratory tests performed or treatment

administered. Some states have instituted mechanisms for

protecting adolescents’ confidentiality and limiting EOBs.

Additional risks to confidentiality breaches can inadvertently

occur through electronic health records, although technology

continues to evolve to assist with ensuring confidential care.

AAP and the Society for Adolescent Health and Medicine

(SAHM) have published guidance on strategies to address

emerging risks for confidentiality breaches associated with

health information technology (169).

AAP and the SAHM recommend that providers have

time alone with their adolescent patients that includes

assessment for sexual behavior. The AAP recommendations

are available at https://services.aap.org/en/news-room/

campaigns-and-toolkits/adolescent-health-care and the SAHM

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recommendations are available at https://www.adolescenthealth.

org/My-SAHM/Login-or-Create-an-Account.aspx?returnurl=

%2fResources%2fClinical-Care-Resources%2fConfidentiality.

aspx. Discussions concerning sexual behavior should be tailored

for the patient’s developmental level and be aimed at identifying

risk behaviors (e.g., multiple partners; oral, anal, or vaginal

sex; or drug misuse behaviors). Careful, nonjudgmental, and

thorough counseling is particularly vital for adolescents who

might not feel comfortable acknowledging their engagement in

behaviors that make them more vulnerable to acquiring STIs.

Screening Recommendations

Recommendations for screening adolescents for STIs to

detect asymptomatic infections are based on disease severity

and sequelae, prevalence among the population, costs,

medicolegal considerations (e.g., state laws), and other factors.

Routine laboratory screening for common STIs is indicated

for all sexually active adolescents. The following screening

recommendations summarize published clinical prevention

guidelines for sexually active adolescents from federal agencies

and medical professional organizations.

Chlamydia

Routine screening for C. trachomatis infection on an annual

basis is recommended for all sexually active females aged

<25 years (149). Rectal chlamydial testing can be considered

for females on the basis of reported sexual behaviors and

exposure, through shared clinical decision-making between the

patient and the provider (170,171). Evidence is insufficient

to recommend routine screening for C. trachomatis among

sexually active young males, on the basis of efficacy and cost-

effectiveness. However, screening of sexually active young males

should be considered in clinical settings serving populations

of young men with a high prevalence of chlamydial infections

(e.g., adolescent service clinics, correctional facilities, and STD

clinics). Chlamydia screening, including pharyngeal or rectal

testing, should be offered to all YMSM at least annually on

the basis of sexual behavior and anatomic site of exposure (see

Men Who Have Sex with Men).

Gonorrhea

Routine screening for N. gonorrhoeae on an annual basis is

recommended for all sexually active females aged <25 years

(149). Extragenital gonorrhea screening (pharyngeal or rectal)

can be considered for females on the basis of reported sexual

behaviors and exposure, through shared clinical-decision

between the patient and the provider (170,171). Gonococcal

infection is more prevalent among certain geographic

locations and communities (141). Clinicians should consider

the communities they serve and consult local public health

authorities for guidance regarding identifying groups that are

more vulnerable to gonorrhea acquisition on the basis of local

disease prevalence. Evidence is insufficient to recommend

routine screening, on the basis of efficacy and cost-effectiveness,

for N. gonorrhoeae among asymptomatic sexually active young

males who have sex with females only. Screening for gonorrhea,

including pharyngeal or rectal testing, should be offered to

YMSM at least annually (see Men Who Have Sex with Men).

Providers might consider opt-out chlamydia and gonorrhea

screening (i.e., the patient is notified that testing will be

performed unless the patient declines, regardless of reported

sexual activity) for adolescent and young adult females during

clinical encounters. Cost-effectiveness analyses indicate that

opt-out chlamydia screening among adolescent and young

adult females might substantially increase screening, be cost-

saving (172), and identify infections among patients who do

not disclose sexual behavior (173).

HIV Infection

HIV screening should be discussed and offered to all

adolescents. Frequency of repeat screenings should be based on

the patient’s sexual behaviors and the local disease prevelance

(138). Persons with HIV infection should receive prevention

counseling and linkage to care before leaving the testing site.

Cervical Cancer

Guidelines from USPSTF and ACOG recommend that

cervical cancer screening begin at age 21 years (174,175). This

recommendation is based on the low incidence of cervical

cancer and limited usefulness of screening for cervical cancer

among adolescents (176). In contrast, the 2020 ACS guidelines

recommend that cervical cancer screening begin at age 25 years

with HPV testing. This change is recommended because the

incidence of invasive cervical cancer in women aged <25 years

is decreasing because of vaccination (177). Adolescents

with HIV infection who have initiated sexual intercourse

should have cervical screening cytology in accordance with

HIV/AIDS guidelines (https://clinicalinfo.hiv.gov/en/

guidelines/adult-and-adolescent-opportunistic-infection/

human-papillomavirus-disease?view=full).

Other Sexually Transmitted Infections

YMSM and pregnant females should be routinely screened

for syphilis (see Pregnant Women; Men Who Have Sex with

Men). Local disease prevalence can help guide decision-

making regarding screening for T. vaginalis, especially among

adolescent females in certain areas. Routine screening of

adolescents and young adults who are asymptomatic for certain

STIs (e.g., syphilis, trichomoniasis, BV, HSV, HAV, and HBV)

is not typically recommended.

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Primary Prevention Recommendations

Primary prevention and anticipatory guidance for recognizing

symptoms and behaviors associated with STIs are strategies that

should be incorporated into all types of health care visits for

adolescents and young adults. The following recommendations

for primary prevention of STIs (i.e., vaccination and

counseling) are based on published clinical guidelines for

sexually active adolescents and young adults from federal

agencies and medical professional organizations.

• HPV vaccination is recommended through age 26 years

for those not vaccinated previously at the routine age of

11 or 12 years (https://www.cdc.gov/vaccines/hcp/acip-

recs/vacc-specific/hpv.html).

• The HBV vaccination series is recommended for all adolescents

and young adults who have not previously received the universal

HBV vaccine series during childhood (12).

• The HAV vaccination series should be offered to

adolescents and young adults as well as those who have

not previously received the universal HAV vaccine series

during childhood (https://www.cdc.gov/vaccines/

schedules/hcp/imz/child-indications.html#note-hepa).

• Information regarding HIV transmission, prevention, testing,

and implications of infection should be regarded as an essential

component of the anticipatory guidance provided to all

adolescents and young adults as part of routine health care.

• CDC and USPSTF recommend offering HIV PrEP to

adolescents weighing ≥35 kg and adults who are HIV

negative and at substantial risk for HIV infection (80,178).

YMSM should be offered PrEP in youth-friendly settings

with tailored adherence support (e.g., text messaging and

visits per existing guidelines). Indications for PrEP, initial

and follow-up prescribing guidance, and laboratory testing

recommendations are the same for adolescents and adults

(https://www.cdc.gov/hiv/risk/prep).

• Medical providers who care for adolescents and young

adults should integrate sexuality education into clinical

practice. Health care providers should counsel adolescents

about the sexual behaviors that are associated with risk for

acquiring STIs and should educate patients regarding

evidence-based prevention strategies, which includes a

discussion about abstinence and other risk-reduction

behaviors (e.g., consistent and correct condom use and

reduction in the number of sex partners including

concurrent partners). Interactive counseling approaches

(e.g., patient-centered counseling and motivational

interviewing) are effective STI and HIV prevention

strategies and are recommended by USPSTF. Educational

materials (e.g., handouts, pamphlets, and videos) can

reinforce office-based educational efforts.

Children

Management of children who have STIs requires close

cooperation among clinicians, laboratorians, and child-

protection authorities. Official investigations, when indicated,

should be initiated promptly. Certain diseases (e.g., gonorrhea,

syphilis, HIV, chlamydia, and trichomoniasis), if acquired after

the neonatal period, strongly indicate sexual contact. For other

diseases (e.g., HSV, HPV and anogenital warts, and vaginitis),

the association with sexual contact is not as clear (see Sexual

Assault and Abuse and STIs).

Men Who Have Sex with Men

MSM comprise a diverse group in terms of behaviors,

identities, and health care needs (179). The term “MSM” often

is used clinically to refer to sexual behavior alone, regardless of

sexual orientation (e.g., a person might identify as heterosexual

but still be classified as MSM). Sexual orientation is

independent of gender identity. Classification of MSM can vary

in the inclusion of transgender men and women on the basis

of whether men are defined by sex at birth (i.e., transgender

women included) or current gender identity (i.e., transgender

men included). Therefore, sexual orientation as well as gender

identity of individual persons and their sex partners should be

obtained during health care visits. MSM might be at increased

risk for HIV and other STIs because of their sexual network or

behavioral or biologic factors, including number of concurrent

partners, condomless sex, anal sex, or substance use (180–182).

These factors, along with sexual network or higher community

disease prevalence, can increase the risk for STIs among MSM

compared with other groups (183,184).

Performing a detailed and comprehensive sexual history is

the first step in identifying vulnerability and providing tailored

counseling and care (3). Factors associated with increased

vulnerability to STI acquisition among MSM include having

multiple partners, anonymous partners, and concurrent

partners (185,186). Repeat syphilis infections are common and

might be associated with HIV infection, substance use (e.g.,

methamphetamines), Black race, and multiple sex partners

(187). Similarly, gonorrhea incidence has increased among MSM

and might be more likely to display antimicrobial resistance

compared with other groups (188,189). Gonococcal infection

among MSM has been associated with similar risk factors to

syphilis, including having multiple anonymous partners and

substance use, especially methamphetamines (190). Disparities

in gonococcal infection are also more pronounced among certain

racial and ethnic groups of MSM (141).

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HIV Risk Among Men Who Have Sex with Men

MSM are disproportionately at risk for HIV infection. In

the United States, the estimated lifetime risk for HIV infection

among MSM is one in six, compared with heterosexual men at

one in 524 and heterosexual women at one in 253 (191). These

disparities are further exacerbated by race and ethnicity, with

African American/Black and Hispanic/Latino MSM having a

one in two and a one in four lifetime risk for HIV infection,

respectively. For HIV, transmission occurs much more readily

through receptive anal sex, compared with penile-vaginal sex

(192). Similar to other STIs, multiple partners, anonymous

partners, condomless sex, and substance use are all associated

with HIV infection (193–196). Importantly, other STIs

also might significantly increase the risk for HIV infection

(197–199). An estimated 10% of new HIV infections were

attributable to chlamydial or gonococcal infection (81). A

substantial number of MSM remain unaware of their HIV

diagnosis (200). Clinical care involving MSM, including

those who have HIV infection, should involve asking about

STI-related risk factors and routine STI testing. Clinicians

should routinely ask MSM about their sexual behaviors and

symptoms consistent with common STIs, including urethral

discharge, dysuria, ulcers, rash, lymphadenopathy, and

anorectal symptoms that might be consistent with proctitis

(e.g., discharge, rectal bleeding, pain on defecation, or pain

during anal sex). However, certain STIs are asymptomatic,

especially at rectal and pharyngeal sites, and routine testing

is recommended. In addition, clinicians should provide

education and counseling regarding evidence-based safer-sex

approaches that have demonstrated effectiveness in reducing

STI incidence (see HIV Infection, Detection, Counseling,

and Referral).

Pre-Exposure Prophylaxis for HIV Prevention

PrEP is the use of medications for preventing an infection

before exposure. Studies have demonstrated that a daily oral

medication TDF/FTC is effective in preventing HIV acquisition,

and specifically among MSM (74,75,201). PrEP guidelines

provide information regarding sexually active persons who are at

substantial risk for acquiring HIV infection (having had anal or

vaginal sex during the previous 6 months with either a partner

with HIV infection, a bacterial STI in the past 6 months, or

inconsistent or no condom use with a sex partner) or persons

who inject drugs (injecting partner with HIV infection or sharing

injection equipment) (80). Those guidelines provide information

regarding daily PrEP use for either TDF/FTC (men or women)

or tenofovir alafenamide and emtricitabine for MSM. Screening

for bacterial STIs should occur at least every 6 months for all

sexually active patients and every 3 months among MSM or

among patients with ongoing risk behaviors. MSM taking PrEP

might compensate for decreased HIV acquisition risk by using

condoms less frequently or modifying their behavior in other ways

(202,203), although data regarding this behavior are inconsistent.

Studies have reported that MSM taking PrEP have high rates of

STIs, and frequent screening is warranted (204–206).

Importance of Rectal and Pharyngeal Testing

Rectal and pharyngeal testing by NAAT for gonorrhea

and chlamydia is recognized as an important sexual health

consideration for MSM. Rectal gonorrhea and chlamydia are

associated with HIV infection (82,207), and men with repeat

rectal infections can be at substantially higher risk for HIV

acquisition (208). Pharyngeal infections with gonorrhea or

chlamydia might be a principal source of urethral infections

(209–211). Studies have demonstrated that among MSM,

prevalence of rectal gonorrhea and chlamydia ranges from

0.2% to 24% and 2.1% to 23%, respectively, and prevalence

of pharyngeal gonorrhea and chlamydia ranges from 0.5% to

16.5% and 0% to 3.6%, respectively (171). Approximately

70% of gonococcal and chlamydial infections might be

missed if urogenital-only testing is performed among MSM

(212–216) because most pharyngeal and rectal infections are

asymptomatic. Self-collected swabs have been reported to be

an acceptable means of collection for pharyngeal and rectal

specimens (217–219), which can enhance patient comfort

and reduce clinical workloads.

A detailed sexual history should be taken for all MSM to

identify anatomic locations exposed to infection for screening.

Clinics that provide services for MSM at high risk should

consider implementing routine extragenital screening for

N. gonorrhoeae and C. trachomatis infections, and screening is

likely to be cost-effective (220).

Screening Recommendations

STI screening among MSM has been reported to be

suboptimal. In a cross-sectional sample of MSM in the United

States, approximately one third reported not having had an

STI test during the previous 3 years, and MSM with multiple

sex partners reported less frequent screening (221). MSM

living with HIV infection and engaged in care also experience

suboptimal rates of STI testing (222,223). Limited data exist

regarding the optimal frequency of screening for gonorrhea,

chlamydia, and syphilis among MSM, with the majority of

evidence derived from mathematical modeling. Models from

Australia have demonstrated that increasing syphilis screening

frequency from two times a year to four times a year resulted

in a relative decrease of 84% from peak prevalence (224). In

a compartmental model applied to different populations in

Canada, quarterly syphilis screening averted more than twice

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the number of syphilis cases, compared with semiannual

screening (225). Furthermore, MSM screening coverage

needed for eliminating syphilis among a population is

substantially reduced from 62% with annual screening to 23%

with quarterly screening (226,227). In an MSM transmission

model that explored the impact of HIV PrEP use on STI

prevalence, quarterly chlamydia and gonorrhea screening was

associated with an 83% reduction in incidence (205). The only

empiric data available that examined the impact of screening

frequency come from an observational cohort of MSM using

HIV PrEP in which quarterly screening identified more

bacterial STIs, and semiannual screening would have resulted

in delayed treatment of 35% of total identified STI infections

(206). In addition, quarterly screening was reported to have

prevented STI exposure in a median of three sex partners

per STI infection (206). On the basis of available evidence,

quarterly screening for gonorrhea, chlamydia, and syphilis for

certain sexually active MSM can improve case finding, which

can reduce the duration of infection at the population level,

reduce ongoing transmission and, ultimately, prevalence among

this population (228).

Preventive screening for common STIs is indicated for all

MSM. The following screening recommendations summarize

published federal agency and USPSTF clinical prevention

guidelines for MSM and should be performed at least annually.

HIV Infection

HIV serologic testing is indicated if HIV status is unknown

or if HIV negative and the patient or their sex partner has had

more than one sex partner since the most recent HIV test.

Syphilis

Syphilis serologic testing is indicated to establish whether

persons with reactive tests have untreated syphilis, have partially

treated syphilis, or are manifesting a slow or inadequate

serologic response to recommended previous therapy.

Gonorrhea and Chlamydia

The following testing is recommended for MSM:

• A test for urethral infection* with N. gonorrhoeae and

C. trachomatis among men who have had insertive

intercourse during the preceding year (urine NAAT

is preferred).

• A test for rectal infection* with N. gonorrhoeae and

C. trachomatis among men who have had receptive anal

intercourse during the preceding year (rectal NAAT

is preferred).

* Regardless of condom use during exposure.

• A test for pharyngeal infection* with N. gonorrhoeae among

men who have had receptive oral intercourse during the

preceding year (pharyngeal NAAT is preferred).

• Testing for C. trachomatis pharyngeal infection is not

recommended.

Basing screening practices solely on history might be

suboptimal because providers might feel uncomfortable

taking a detailed sexual history (229), men might also feel

uncomfortable sharing personal sexual information with

their provider, and rectal and pharyngeal infections can be

identified even in the absence of reported risk behaviors (171).

Furthermore, the role of saliva, kissing, and rimming (i.e.,

oral-rectal contact) in the transmission of N. gonorrhoeae and

C. trachomatis has not been well studied (230–232).

Rectal and pharyngeal testing (provider-collected or self-

collected specimens) should be performed for all MSM who

report exposure at these sites. Testing can be offered to MSM

who do not report exposure at these sites after a detailed

explanation, due to known underreporting of risk behaviors.

All MSM with HIV infection entering care should be screened

for gonorrhea and chlamydia at appropriate anatomic sites of

exposure as well as for syphilis.

More frequent STI screening (i.e., for syphilis, gonorrhea,

and chlamydia) at 3- to 6-month intervals is indicated for

MSM, including those taking PrEP and those with HIV

infection, if risk behaviors persist or if they or their sex partners

have multiple partners. In addition, providers can consider

the benefits of offering more frequent HIV screening (e.g.,

every 3–6 months) to MSM at increased risk for acquiring

HIV infection.

Hepatitis B Virus

All MSM should be screened with HBsAg, HBV core

antibody, and HBV surface antibody testing to detect HBV

infection (233). Vaccination against both HAV and HBV

is recommended for all MSM for whom previous infection

or vaccination cannot be documented. Serologic testing can

be considered before vaccinating if the patient’s vaccination

history is unknown; however, vaccination should not be

delayed. Vaccinating persons who have had previous infection

or vaccination does not increase the risk for vaccine-related

adverse events (see Hepatitis A Virus; Hepatitis B Virus).

Hepatitis C Virus

CDC recommends HCV screening at least once for all

adults aged ≥18 years, except in settings where the prevalence

of HCV infection (HCV RNA positivity) is <0.1% (156).

The American Association for the Study of Liver Diseases/

Infectious Diseases Society of America guidelines recommend

all MSM with HIV infection be screened for HCV during the

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initial HIV evaluation and at least annually thereafter (https://

www.hcvguidelines.org). More frequent screening depends

on ongoing risk behaviors, high-risk sexual behavior, and

concomitant ulcerative STIs or STI-related proctitis. Sexual

transmission of HCV can occur and is most common among

MSM with HIV infection (234–237). Screening for HCV in

this setting is cost-effective (238,239). Screening should be

performed by using HCV antibody assays followed by HCV

RNA testing for those with a positive antibody test. Suspicion

for acute HCV infection (e.g., clinical evidence of hepatitis and

risk behaviors) should prompt consideration for HCV RNA

testing, despite a negative antibody test.

Human Papillomavirus

HPV infection and associated conditions (e.g., anogenital

warts and anal squamous intraepithelial lesions) are highly

prevalent among MSM. The HPV vaccination is recommended

for all men, including MSM and transgender persons or

immunocompromised males, including those with HIV

infection, through age 26 years (11). More information is

available at https://www.cdc.gov/hpv/downloads/9vhpv-

guidance.pdf.

A digital anorectal examination (DARE) should be

performed to detect early anal cancer among persons with HIV

and MSM without HIV but who have a history of receptive

anal intercourse. Data are insufficient to recommend routine

anal cancer screening with anal cytology in populations at risk

for anal cancer (see Anal Cancer). Health centers that initiate a

cytology-based screening program should only do so if referrals

to high-resolution anoscopy (HRA) and biopsy are available.

Herpes Simplex Virus-2

Evaluation for HSV-2 infection with type-specific serologic

tests also can be considered if infection status is unknown

among persons with previously undiagnosed genital tract

infection (see Genital Herpes).

Postexposure Prophylaxis and Pre-Exposure

Prophylaxis for STI Prevention

Studies have reported that a benefit might be derived

from STI PEP and PrEP for STI prevention. One study

demonstrated that monthly oral administration of a 1-g dose

of azithromycin reduced infection with N. gonorrhoeae and

C. trachomatis but did not decrease the incidence of HIV

transmission (240). Among MSM, doxycycline taken as PEP in

a single oral dose ≤24 hours after sex decreased infection with

Treponema pallidum and C. trachomatis; however, no substantial

effect was observed for infection with N. gonorrhoeae (93).

Doxycycline taken as STI PrEP as 100 mg orally once daily

also demonstrated a substantial reduction in gonorrhea,

chlamydia, and syphilis among MSM (90). However, these

studies had limitations because of small sample size, short

duration of therapy, and concerns about antibiotic resistance,

specifically regarding N. gonorrhoeae (241). Further study is

needed to determine the effectiveness of using antimicrobials

for STI PrEP or PEP.

Counseling and Education Approaches

Different counseling and STI prevention strategies are

needed to effectively engage different groups of MSM.

Outreach efforts should be guided by local surveillance efforts

and community input. Engaging MSM at risk through social

media, specifically online hookup sites, is an important

outreach effort to consider. Hookup sites are Internet sites

and mobile telephone applications that men might use for

meeting other men for sex. Internet use might facilitate sexual

encounters and STI transmission among MSM, and many

men report using hookup sites to meet partners (242–245).

The ease and accessibility of meeting partners online might

reduce stigma and barriers of meeting partners through

other settings. Moreover, these sites offer an opportunity for

effective STI prevention messaging (246), although the cost

might be limiting (247). Different groups of MSM might use

different hookup sites, and efforts should be guided by local

community input. Studies have demonstrated the acceptability

and feasibility of reaching MSM through these hookup sites

to promote STI prevention efforts (248,249).

Enteric Infections Among Men Who Have Sex

with Men

The importance of sexual transmission of enteric pathogens

among MSM has been recognized since the 1970s, after the

first report of MSM-associated shigellosis was reported in

San Francisco (250,251). Global increases in the incidence

of shigellosis among adult MSM have been more recently

observed (252–256). Sporadic outbreaks of Shigella sonnei

and Shigella flexneri have been reported among MSM

(257–262). Transmission occurs through oral-anal contact

or sexual contact, and transmission efficiency is enhanced by

both biologic or host and behavioral factors. HIV without

viral suppression can be an independent risk factor that

can contribute to transmission by increasing shedding of

the enteric pathogen, increasing susceptibility of the host,

or both (255,263). Surveillance data in England during

2004–2015 demonstrated that 21% of nontravel-associated

Shigella diagnoses among MSM were among persons with

HIV infection (255).

Other enteric organisms might also cause disease among

MSM through sexual activities leading to oral-anal contact,

including bacteria such as Escherichia coli (264) and

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Campylobacter jejuni or Campylobacter coli (265,266); viruses

such as HAV (267); and parasites such as Giardia lamblia or

Entamoeba histolytica (268,269). Behavioral characteristics

associated with the sexual transmission of enteric infections

are broadly similar to those associated with other STIs (e.g.,

gonorrhea, syphilis, and lymphogranuloma venereum [LGV]).

This includes multiple sex partners and online hookup sites

that increase opportunities for sexual mixing, which might

create dense sexual networks that facilitate STI transmission

among MSM (270). Specific behaviors associated with sexually

transmitted enteric infections among MSM involve attendance

at sex parties and recreational drug use including chem sex

(i.e., using crystal methamphetamine, gamma-butyrolactone,

or mephedrone before or during sex), which might facilitate

condomless sex, group sex, fisting, use of sex toys, and scat play

(253,271). The growing number of sexually transmitted enteric

infections might be attributable in part to the emergence of

antimicrobial resistance. This is well reported regarding Shigella

species, for which rapid intercontinental dissemination of a

S. flexneri 3a lineage with high-level resistance to azithromycin

through sexual transmission among MSM (272) and clusters

of multidrug resistant shigella cases among MSM have recently

been reported (273). Multidrug-resistant Campylobacter species

have also been documented (266,274). For MSM patients with

diarrhea, clinicians should request laboratory examinations,

including stool culture; provide counseling about the risk for

infection with enteric pathogens during sexual activity (oral-

anal, oral-genital, anal-genital, and digital-anal contact) that

could expose them to enteric pathogens; and choose treatment,

when needed, according to antimicrobial drug susceptibility.

Women Who Have Sex with Women and

Women Who Have Sex with

Women and Men

WSW and WSWM comprise diverse groups with variations

in sexual identity, practices, and risk behaviors. Studies

indicate that certain WSW, particularly adolescents, young

women, and WSWM, might be at increased risk for STIs

and HIV on the basis of reported risk behaviors (275–280).

Studies have highlighted the diversity of sexual practices and

examined use of protective or risk-reduction strategies among

WSW populations (281–283). Use of barrier protection with

female partners (e.g., gloves during digital-genital sex, external

condoms with sex toys, and latex or plastic barriers [also known

as dental dams for oral-genital sex]) was infrequent in all

studies. Although health organizations have online materials

directed to patients, few comprehensive and reliable resources

of sexual health information for WSW are available (284).

Recent studies regarding STI rates among WSW and

WSWM indicate that WSWM experience higher rates of STIs

than WSW, with rates comparable with women who have sex

with men (WSM) in all studies reviewed (279,285,286). These

studies indicate that WSW might experience STIs at lower

rates than WSWM and WSM, although still at significant

rates (287). One study reported higher sexual-risk behaviors

among adolescent WSWM and WSW than among adolescent

WSM (280). WSW report reduced knowledge of STI risks

(288), and both WSW and WSWM experience barriers to care,

especially Black WSW and WSWM (289,290). In addition, a

continuum of sexual behaviors reported by WSW and WSWM

indicates the need for providers to not assume lower risk for

WSW, highlighting the importance of an open discussion

about sexual health.

Few data are available regarding the risk for STIs conferred

by sex between women; however, transmission risk probably

varies by the specific STI and sexual practice (e.g., oral-genital

sex; vaginal or anal sex using hands, fingers, or penetrative

sex items; and oral-anal sex) (291,292). Practices involving

digital-vaginal or digital-anal contact, particularly with shared

penetrative sex items, present a possible means for transmission

of infected cervicovaginal or anal secretions. This possibility

is most directly supported by reports of shared trichomonas

infections (293,294) and by concordant drug-resistance

genotype testing and phylogenetic linkage analysis identifying

HIV transmitted sexually between women (295,296). The

majority of WSW (53%–97%) have had sex with men in the

past and continue to do so, with 5%–28% of WSW reporting

male partners during the previous year (292,297–300).

HPV can be transmitted through skin-to-skin contact,

and sexual transmission of HPV likely occurs between WSW

(301–303). HPV DNA has been detected through polymerase

chain reaction (PCR)–based methods from the cervix, vagina,

and vulva among 13%–30% of WSW (301,302) and can

persist on fomites, including sex toys (304). Among WSW

who report no lifetime history of sex with men, 26% had

antibodies to HPV-16, and 42% had antibodies to HPV-6

(301). High-grade squamous intraepithelial lesions (HSIL) and

low-grade squamous intraepithelial lesions (LSIL) have been

detected on Papanicolaou smears (Pap tests) among WSW

who reported no previous sex with men (301,302). WSWM

are at risk for acquiring HPV from both their female partners

and male partners and thus are at risk for cervical cancer.

Therefore, routine cervical cancer screening should be offered

to all women, regardless of sexual orientation or practices,

and young adult WSW and WSWM should be offered HPV

vaccination in accordance with recommendations (11) (https://

www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/hpv.html).

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Genital transmission of HSV-2 between female sex partners

is inefficient but can occur. A U.S. population-based survey

among women aged 18–59 years demonstrated an HSV-2

seroprevalence of 30% among women reporting same-sex

partners during the previous year, 36% among women

reporting same-sex partners in their lifetime, and 24% among

women reporting no lifetime same-sex behavior (299). HSV-2

seroprevalence among women self-identifying as homosexual

or lesbian was 8%, similar to a previous clinic-based study of

WSW (299,305) but was 26% among Black WSW in one

study (287). The relatively frequent practice of orogenital sex

among WSW and WSWM might place them at higher risk

for genital infection with HSV-1, a hypothesis supported by

the recognized association between HSV-1 seropositivity and

previous number of female partners. Thus, sexual transmission

of HSV-1 and HSV-2 can occur between female sex partners.

This information should be communicated to women as part

of sexual health counseling.

Trichomonas is a relatively common infection among WSW

and WSWM, with prevalence rates higher than for chlamydia

or gonorrhea (306,307), and direct transmission of trichomonas

between female partners has been demonstrated (293,294).

Limited information is available regarding transmission

of bacterial STIs between female partners. Transmission of

syphilis between female sex partners, probably through oral

sex, has been reported. Although the rate of transmission of

C. trachomatis or N. gonorrhoeae between women is unknown,

infection also might be acquired from past or current male

partners. Data indicate that C. trachomatis infection among

WSW can occur (275,286,308,309). Data are limited

regarding gonorrhea rates among WSW and WSWM (170).

Reports of same-sex behavior among women should not deter

providers from offering and providing screening for STIs,

including chlamydia, according to guidelines.

BV is common among women, and even more so among

women with female partners (310–312). Epidemiologic data

strongly demonstrate that BV is sexually transmitted among

women with female partners. Evidence continues to support

the association of such sexual behaviors as having a new partner,

having a partner with BV, having receptive oral sex, and having

digital-vaginal and digital-anal sex with incident BV (313,314).

A study including monogamous couples demonstrated

that female sex partners frequently share identical genital

Lactobacillus strains (315). Within a community-based

cohort of WSW, extravaginal (i.e., oral and rectal) reservoirs

of BV-associated bacteria were a risk factor for incident BV

(316). Studies have examined the impact of specific sexual

practices on the vaginal microflora (306,317–319) and on

recurrent (320) or incident (321,322) BV among WSW. A

BV pathogenesis study in WSW reported that Prevotella bivia,

Gardnerella vaginalis, and Atopobium vaginae might have

substantial roles in development of incident BV (323). These

studies have continued to support, although have not proven,

the hypothesis that sexual behaviors, specific BV-associated

bacteria, and possibly exchange of vaginal or extravaginal

microbiota (e.g., oral bacterial communities) between partners

might be involved in the pathogenesis of BV among WSW.

Although BV is common among WSW, routine screening

for asymptomatic BV is not recommended. Results of one

randomized trial used a behavioral intervention to reduce

persistent BV among WSW through reduced sharing of vaginal

fluid on hands or sex toys. Women randomly assigned to the

intervention were 50% less likely to report receptive digital-

vaginal contact without gloves than control subjects, and they

reported sharing sex toys infrequently. However, these women

had no reduction in persistent BV at 1 month posttreatment

and no reduction in incident episodes of recurrent BV (324).

Trials have not been reported examining the benefits of treating

female partners of women with BV. Recurrent BV among

WSW is associated with having a same-sex partner and a lack of

condom use (325). Increasing awareness of signs and symptoms

of BV among women and encouraging healthy sexual practices

(e.g., avoiding shared sex toys, cleaning shared sex toys, and

using barriers) might benefit women and their partners.

Sexually active women are at risk for acquiring bacterial,

viral, and protozoal STIs from current and previous partners,

both male and female. WSW should not be presumed to be at

low or no risk for STIs on the basis of their sexual orientation.

Report of same-sex behavior among women should not deter

providers from considering and performing screening for STIs

and cervical cancer according to guidelines. Effective screening

requires that care providers and their female patients engage in

a comprehensive and open discussion of sexual and behavioral

risks that extends beyond sexual identity.

Transgender and Gender Diverse Persons

Transgender persons often experience high rates of stigma and

socioeconomic and structural barriers to care that negatively

affect health care usage and increase susceptibility to HIV and

STIs (326–332). Persons who are transgender have a gender

identity that differs from the sex that they were assigned at birth

(333,334). Transgender women (also known as trans women,

transfeminine persons, or women of transgender experience)

are women who were assigned male sex at birth (born with

male anatomy). Transgender men (also known as trans men,

transmasculine persons, or men of transgender experience)

are men who were assigned female sex at birth (i.e., born with

female anatomy). In addition, certain persons might identify

outside the gender binary of male or female or move back and

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forth between different gender identities and use such terms

as “gender nonbinary,” “genderqueer,” or “gender fluid” to

describe themselves. Persons who use terms such as “agender”

or “null gender” do not identify with having any gender. The

term “cisgender” is used to describe persons who identify with

their assigned sex at birth. Prevalence studies of transgender

persons among the overall population have been limited and

often are based on small convenience samples.

Gender identity is independent of sexual orientation. Sexual

orientation identities among transgender persons are diverse.

Persons who are transgender or gender diverse might have sex

with cisgender men, cisgender women, or other transgender

or gender nonbinary persons.

Clinical Environment Assessment

Providers should create welcoming environments that

facilitate disclosure of gender identity and sexual orientation.

Clinics should document gender identity and sex assigned

at birth for all patients to improve sexual health care for

transgender and gender nonbinary persons. Assessment of

gender identity and sex assigned at birth has been validated

among diverse populations, has been reported to be acceptable

(335,336), and might result in increased patients identifying

as transgender (337).

Lack of medical provider knowledge and other barriers to care

(e.g., discrimination in health care settings or denial of services)

often result in transgender and gender nonbinary persons

avoiding or delaying preventive care services (338–340) and

incurring missed opportunities for HIV and STI prevention

services. Gender-inclusive and trauma-guided health care

might increase the number of transgender patients who seek

sexual health services, including STI testing (341), because

transgender persons are at high risk for sexual violence (342).

Primary care providers should take a comprehensive sexual

history, including a discussion of STI screening, HIV PrEP

and PEP, behavioral health, and social determinants of sexual

health. Clinicians can improve the experience of sexual health

screening and counseling for transgender persons by asking for

their choice of terminology or modifying language (e.g., asking

patients their gender pronouns) to be used during clinic visits

and history taking and examination (343). Options for fertility

preservation, pregnancy potential, and contraception options

should also be discussed, if indicated. For transgender persons

who retain a uterus and ovaries, ovulation might continue in

the presence of testosterone therapy, and pregnancy potential

exists (https://transcare.ucsf.edu).

Transgender Women

A systematic review and meta-analysis of HIV infection

among transgender women estimated that HIV prevalence in

the United States is 14% among transgender women, with the

highest prevalence among Black (44%) and Hispanic (26%)

transgender women (344). Data also demonstrate high rates of

HIV infection among transgender women worldwide (345).

Bacterial STI prevalence varies among transgender women and

is based largely on convenience samples. Despite limited data,

international and U.S. studies have indicated elevated incidence

and prevalence of gonorrhea and chlamydia among transgender

women similar to rates among cisgender MSM (346–348). A

recent study using data from the STD Surveillance Network

revealed that the proportions of transgender women with

extragenital chlamydial or gonococcal infections were similar

to those of cisgender MSM (349).

Providers caring for transgender women should have

knowledge of their patients’ current anatomy and patterns

of sexual behavior before counseling them about STI and

HIV prevention. The majority of transgender women have

not undergone genital-affirmation surgery and therefore

might retain a functional penis; in these instances, they

might engage in insertive oral, vaginal, or anal sex as well as

receptive oral or anal sex. In the U.S. Transgender Survey, 12%

of transgender women had undergone vaginoplasty surgery,

and approximately 50% more were considering surgical

intervention (350). Providers should have knowledge about

the type of tissue used to construct the neovagina, which

can affect future STI and HIV preventive care and screening

recommendations. The majority of vaginoplasty surgeries

conducted in the United States use penile and scrotal tissue

to create the neovagina (351). Other surgical techniques

use intestinal tissue (e.g., sigmoid colon graft) or split-skin

grafts (352). Although these surgeries involve penectomy and

orchiectomy, the prostate remains intact. Transgender women

who have had a vaginoplasty might engage in receptive vaginal,

oral, or anal sex.

Neovaginal STIs have infrequently been reported in

the literature and include HSV and HPV/genital warts in

penile-inversion vaginoplasty, C. trachomatis in procedures

that involved penile skin and grafts with urethra mucosa or

abdominal peritoneal lining (353), and N. gonorrhoeae in

both penile-inversion and colovaginoplasty (354–359). If

the vaginoplasty used an intestinal graft, a risk also exists for

bowel-related disease (e.g., adenocarcinoma, inflammatory

bowel disease, diversion colitis, and polyps) (360–362).

Transgender Men

The few studies of HIV prevalence among transgender men

indicated that they have a lower prevalence of HIV infection

than transgender women. A recent estimate of HIV prevalence

among transgender men was 2% (344). However, transgender

men who have sex with cisgender men might be at elevated

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risk for HIV infection (332,363,364). Data are limited

regarding STI prevalence among transgender men, and the

majority of studies have used clinic-based data or convenience

sampling. Recent data from the STD Surveillance Network

demonstrated higher prevalence of gonorrhea and chlamydia

among transgender men, similar to rates reported among

cisgender MSM (365).

The U.S. Transgender Survey indicated that the proportion

of transgender men and gender diverse persons assigned

female sex at birth who have undergone gender-affirmation

genital surgery is low. Providers should consider the anatomic

diversity among transgender men because a person can undergo

a metoidioplasty (a procedure to increase the length of the

clitoris), with or without urethral lengthening, and might not

have a hysterectomy and oophorectomy and therefore be at risk

for bacterial STIs, HPV, HSV, HIV, and cervical cancer (366).

For transgender men using gender-affirming hormone therapy,

the decrease in estradiol levels caused by exogenous testosterone

can lead to vaginal atrophy (367,368) and is associated with a

high prevalence of unsatisfactory sample acquisition (369). The

impact of these hormonal changes on mucosal susceptibility

to HIV and STIs is unknown.

Transgender men who have not chosen to undergo

hysterectomy with removal of the cervix remain at risk for

cervical cancer. These persons often avoid cervical cancer

screening because of multiple factors, including discomfort

with medical examinations and fear of discrimination

(338,370). Providers should be aware that conducting a

speculum examination can be technically difficult after

metoidioplasty surgery because of narrowing of the introitus.

In these situations, high-risk HPV testing using a swab can

be considered; self-collected swabs for high-risk HPV testing

has been reported to be an acceptable option for transgender

men (371).

Screening Recommendations

The following are screening recommendations for

transgender and gender diverse persons:

• Because of the diversity of transgender persons regarding

surgical gender-affirming procedures, hormone use, and

their patterns of sexual behavior, providers should remain

aware of symptoms consistent with common STIs and

screen for asymptomatic infections on the basis of the

patient’s sexual practices and anatomy.

• Gender-based screening recommendations should be

adapted on the basis of anatomy (e.g., routine screening

for C. trachomatis and N. gonorrhoeae) as recommended

for all sexually active females aged <25 years on an annual

basis and should be extended to transgender men and

nonbinary persons with a cervix among this age group.

• HIV screening should be discussed and offered to all

transgender persons. Frequency of repeat screenings should

be based on level of risk.

• For transgender persons with HIV infection who have sex

with cisgender men and transgender women, STI

screening should be conducted at least annually, including

syphilis serology, HCV testing, and urogenital and

extragenital NAAT for gonorrhea and chlamydia.

• Transgender women who have had vaginoplasty surgery

should undergo routine STI screening for all exposed sites

(e.g., oral, anal, or vaginal). No data are available regarding

the optimal screening method (urine or vaginal swab) for

bacterial STIs of the neovagina. The usual techniques for

creating a neovagina do not result in a cervix; therefore,

no rationale exists for cervical cancer screening (368).

• If transgender men have undergone metoidioplasty surgery

with urethral lengthening and have not had a vaginectomy,

assessment of genital bacterial STIs should include a

cervical swab because a urine specimen will be inadequate

for detecting cervical infections.

• Cervical cancer screening for transgender men and

nonbinary persons with a cervix should follow current

screening guidelines (see Human Papillomavirus Infections).

Persons in Correctional Facilities

Multiple studies have demonstrated that persons entering

correctional facilities have a high prevalence of STIs, HIV, and

viral hepatitis, especially those aged ≤35 years (141,372,373).

Risk behaviors for acquiring STIs (e.g., having condomless

sex, having multiple sex partners, substance misuse, and

engaging in commercial, survival, or coerced sex) are common

among incarcerated populations. Before their incarceration,

many persons have had limited access to medical care. Other

social determinants of health (e.g., insufficient social and

economic support or living in communities with high local

STI prevalence) are common. Addressing STIs in correctional

settings is vital for addressing the overall STI impact among

affected populations.

Growing evidence demonstrates the usefulness of expanded

STI screening and treatment services in correctional settings,

including short-term facilities (jails), long-term institutions

(prisons), and juvenile detention centers. For example, in

jurisdictions with comprehensive, targeted jail screening, more

chlamydial infections among females (and males if screened)

are detected and subsequently treated in the correctional setting

than in any other single reporting source (141,374) and might

represent the majority of reported cases in certain jurisdictions

(375). Screening in the jail setting has the potential to reach

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substantially more persons at risk than screening among the

prison population alone.

Both males and females aged ≤35 years in juvenile and adult

detention facilities have been reported to have higher rates of

chlamydia and gonorrhea than nonincarcerated persons in

the community (141,374,376). Syphilis seroprevalence rates,

which can indicate previously treated or current infection, are

considerably higher among incarcerated adult men and women

than among adolescents, which is consistent with the overall

national syphilis trends (141,374). Detection and treatment

of early syphilis in correctional facilities might affect rates

of transmission among adults and prevention of congenital

syphilis (377).

In jails, approximately half of entrants are released back

into the community within 48 hours. As a result, treatment

completion rates for those screened for STIs and who receive

STI diagnoses in short-term facilities might not be optimal.

However, because of the mobility of incarcerated populations

in and out of the community, the impact of screening in

correctional facilities on the prevalence of infections among

detainees and subsequent transmission in the community

after release might be considerable (378). Moreover, treatment

completion rates of ≥95% in short-term facilities can be

achieved by offering screening at or shortly after intake,

thus facilitating earlier receipt of test results and, if needed,

follow-up of untreated persons can be conducted through

public health outreach.

Universal, opt-out screening for chlamydia and gonorrhea

among females aged ≤35 years entering juvenile and adult

correctional facilities is recommended (379). Males aged

<30 years entering juvenile and adult correctional facilities

should also be screened for chlamydia and gonorrhea (380).

Opt-out screening has the potential to substantially increase

the number tested and the number of chlamydia and gonorrhea

infections detected (381–385). Point-of-care (POC) NAAT

might also be considered if the tests have demonstrated

sufficient sensitivity and specificity. Studies have demonstrated

high prevalence of trichomoniasis among incarcerated

females (386–392).

Screening Recommendations

Chlamydia and Gonorrhea

Females aged ≤35 years and males aged <30 years housed

in correctional facilities should be screened for chlamydia and

gonorrhea. This screening should be conducted at intake and

offered as opt-out screening.

Trichomonas

Females aged ≤35 years housed in correctional facilities

should be screened for trichomonas. This screening should be

conducted at intake and offered as opt-out screening.

Syphilis

Opt-out screening for incarcerated persons should be

conducted on the basis of the local area and institutional

prevalence of early (primary, secondary, or early latent)

infectious syphilis. Correctional facilities should stay apprised

of local syphilis prevalence. In short-term facilities, screening

at entry might be indicated.

Viral Hepatitis

All persons housed in juvenile and adult correctional facilities

should be screened at entry for viral hepatitis, including HAV,

HBV, and HCV, depending on local prevalence and the

person’s vaccination status. Vaccination for HAV and HBV

should be offered if the person is susceptible.

Cervical Cancer

Women and transgender men who are housed in correctional

facilities should be screened for cervical cancer as for women

who are not incarcerated (393,394) (see Cervical Cancer).

HIV Infection

All persons being housed in juvenile and adult correctional

facilities should be screened at entry for HIV infection;

screening should be offered as opt-out screening. For those

identified as being at risk for HIV infection (e.g., with

diagnosed gonorrhea or syphilis or persons who inject drugs)

and being released into the community, starting HIV PrEP

(or providing linkage to a community clinic for HIV PrEP)

for HIV prevention should be considered (395,396). Persons

are likely to engage in high-risk activities immediately after

release from incarceration (397). For those identified with

HIV infection, treatment should be initiated. Those persons

receiving PrEP or HIV treatment should have linkage to

care established before release. Correctional settings should

consider implementing other STI prevention approaches,

both during incarceration and upon release, which might

include educational and behavioral counseling interventions

(398–401), vaccination (e.g., for HPV) (402,403), condom

distribution (404,405), EPT (125), and PrEP to prevent HIV

infection (see Primary Prevention Methods).

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HIV Infection

Detection, Counseling, and Referral

Infection with HIV causes an acute but brief and nonspecific

influenza-like retroviral syndrome that can include fever,

malaise, lymphadenopathy, pharyngitis, arthritis, or skin

rash. Most persons experience at least one symptom; however,

some might be asymptomatic or have no recognition of illness

(406–409). Acute infection transitions to a multiyear, chronic

illness that progressively depletes CD4

T lymphocytes crucial

for maintenance of effective immune function. Ultimately,

persons with untreated HIV infection experience symptomatic,

life-threatening immunodeficiency (i.e., AIDS).

Effective ART that suppresses HIV replication to undetectable

levels reduces morbidity, provides a near-normal lifespan, and

prevents sexual transmission of HIV to others (95–97,410–

412). Early diagnosis of HIV and rapid linkage to care are

essential for achieving these goals. Guidelines from both the

U.S. Department of Health and Human Services and the

International AIDS Society–USA Panel recommend that all

persons with HIV infection be offered effective ART as soon

as possible, both to reduce morbidity and mortality and to

prevent HIV transmission (413).

STD specialty or sexual health clinics are a vital partner in

reducing HIV infections in the United States. These clinics

provide safety net services to vulnerable populations in need

of HIV prevention services who are not served by the health

care system and HIV partner service organizations. Diagnosis

of an STI is a biomarker for HIV acquisition, especially among

persons with primary or secondary syphilis or, among MSM,

rectal gonorrhea or chlamydia (197). STD clinics perform only

approximately 20% of all federally funded HIV tests nationally

but identify approximately 30% of all new infections (414).

Among testing venues, STD clinics are high performing in

terms of linkage to HIV care within 90 days of diagnosis;

during 2013–2017, the percentage of persons with a new

diagnosis in an STD clinic and linked to care within 90 days

increased from 55% to >90% (415,415).

Screening Recommendations

The following recommendations apply to testing for HIV:

• HIV testing is recommended for all persons seeking STI

evaluation who are not already known to have HIV infection.

Testing should be routine at the time of the STI evaluation,

regardless of whether the patient reports any specific behavioral

risks for HIV. Testing for HIV should be performed at the time

of STI diagnosis and treatment if not performed at the initial

STI evaluation and screening (82,195,416).

• CDC and USPSTF recommend HIV screening at least

once for all persons aged 15–65 years (417).

• Persons at higher risk for HIV acquisition, including

sexually active gay, bisexual, and other MSM, should be

screened for HIV at least annually. Providers can consider

the benefits of offering more frequent screening (e.g., every

3–6 months) among MSM at increased risk for acquiring

HIV (418,419).

• All pregnant women should be tested for HIV during the

first prenatal visit. A second test during the third trimester,

preferably at <36 weeks’ gestation, should be considered

and is recommended for women who are at high risk for

acquiring HIV infection, women who receive health care

in jurisdictions with high rates of HIV, and women

examined in clinical settings in which HIV incidence is

≥1 per 1,000 women screened per year (138,140).

• HIV screening should be voluntary and free from coercion.

Patients should not be tested without their knowledge.

• Opt-out HIV screening (notifying the patient that an HIV

test will be performed, unless the patient declines) is

recommended in all health care settings. CDC also

recommends that consent for HIV screening be

incorporated into the general informed consent for

medical care in the same manner as other screening or

diagnostic tests.

• Requirement of specific signed consent for HIV testing is

not recommended. General informed consent for medical

care is considered sufficient to encompass informed

consent for HIV testing.

• Providers should use a laboratory-based antigen/antibody

(Ag/Ab) combination assay as the first test for HIV, unless

persons are unlikely to follow up with a provider to receive

their HIV test results; in those cases screening with a rapid

POC test can be useful.

• Preliminary positive screening tests for HIV should be

followed by supplemental testing to establish the diagnosis.

• Providing prevention counseling as part of HIV screening

programs or in conjunction with HIV diagnostic testing is

not required (6). However, persons might be more likely to

think about HIV and consider their risk-related behavior

when undergoing an HIV test. HIV testing gives providers

an opportunity to conduct STI and HIV prevention

counseling and communicate risk-reduction messages.

• Acute HIV infection can occur among persons who report

recent sexual or needle-sharing behavior or who have had

an STI diagnosis.

• Providers should test for HIV RNA if initial testing according

to the HIV testing algorithm recommended by CDC is

negative or indeterminate when concerned about acute HIV

infection (https://stacks.cdc.gov/view/cdc/50872).

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• Providers should not assume that a laboratory report of a

negative HIV Ag/Ab or antibody test indicates that the requisite

HIV RNA testing for acute HIV infection has been conducted.

They should consider explicitly requesting HIV RNA testing

when concerned about early acute HIV infection.

• Providers should assess eligibility of all persons seeking

STI services for HIV PrEP and PEP. For persons with

substantial risk whose results are HIV negative, providers

should offer or provide referral for PrEP services, unless

the last potential HIV exposure occurred <72 hours, in

which case PEP might be indicated.

Diagnostic Considerations

HIV infection can be diagnosed by HIV 1/2 Ag/Ab

combination immunoassays. All FDA-cleared HIV tests are

highly sensitive and specific. Available serologic tests can

detect all known subtypes of HIV-1. The majority also detect

HIV-2 and uncommon variants of HIV-1 (e.g., group O and

group N).

According to an algorithm for HIV diagnosis, CDC

recommends that HIV testing begin with a laboratory-

based HIV-1/HIV-2 Ag/Ab combination assay, which, if

repeatedly reactive, is followed by a laboratory-based assay

with a supplemental HIV-1/HIV-2 antibody differentiation

assay (https://stacks.cdc.gov/view/cdc/50872). This algorithm

confers an additional advantage because it can detect HIV-2

antibodies after the initial immunoassay. Although HIV-2 is

uncommon in the United States, accurate identification is

vital because monitoring and therapy for HIV-2 differs from

that for HIV-1 (420). RNA testing should be performed

on all specimens with reactive immunoassay but negative

supplemental antibody test results to determine whether the

discordance represents acute HIV infection.

Rapid POC HIV tests can enable clinicians to make a

preliminary diagnosis of HIV infection in <20 minutes. The

majority of rapid antibody assays become reactive later in the

course of HIV infection than conventional laboratory-based

assays and thus can produce negative results among persons

recently infected (e.g., acutely infected persons). Furthermore,

HIV home-test kits only detect HIV antibodies and therefore

will not detect acute HIV infection. If early or acute infection

is suspected and a rapid HIV antibody assay is negative,

confirmatory testing with combined laboratory-based assays or

RNA testing should be performed. CDC recommends that all

persons with reactive rapid tests be assessed with a laboratory-

based Ag/Ab assay. Additional details about interpretation of

results by using the HIV testing algorithm recommended by

CDC are available at https://stacks.cdc.gov/view/cdc/48472.

Acute HIV Infection

Providers serving persons at risk for STIs are in a position

to diagnose HIV infection during its acute phase. Diagnosing

HIV infection during the acute phase is particularly important

because persons with acute HIV have highly infectious

disease due to the concentration of virus in plasma and

genital secretions, which is extremely elevated during that

stage of infection (421,422) (https://clinicalinfo.hiv.gov/en/

guidelines/adult-and-adolescent-arv/acute-and-recent-early-

hiv-infection?view=full). ART during acute HIV infection

is recommended because it substantially reduces infection

transmission to others, improves laboratory markers of

disease, might decrease severity of acute disease, lowers viral

setpoint, reduces the size of the viral reservoir, decreases

the rate of viral mutation by suppressing replication, and

preserves immune function (https://clinicalinfo.hiv.gov/en/

guidelines/adult-and-adolescent-arv/acute-and-recent-early-

hiv-infection?view=full). Persons who receive an acute HIV

diagnosis should be referred immediately to an HIV clinical

care provider, provided prevention counseling (e.g., advised to

reduce the number of partners and to use condoms correctly

and consistently), and screened for STIs. Information should be

provided regarding availability of PEP for sexual and injecting

drug use partners not known to have HIV infection if the

most recent contact was <72 hours preceding HIV diagnosis.

When providers test by using the CDC algorithm, specimens

collected during acute infection might give indeterminate or

negative results because insufficient anti-HIV antibodies and

potentially insufficient antigen are present to be reactive on

Ag/Ab combination assays and supplemental HIV-1/HIV-2

antibody differentiation assays. Whenever acute HIV infection

is suspected (e.g., initial testing according to the CDC algorithm

is negative or indeterminate after a possible sexual exposure to

HIV within the previous few days to weeks, especially if the

person has symptoms or has primary or secondary syphilis,

gonorrhea, or chlamydia), additional testing for HIV RNA

is recommended. If this additional testing for HIV RNA is

also negative, repeat testing in a few weeks is recommended

to rule out very early acute infection when HIV RNA might

not be detectable. A more detailed discussion of testing in

the context of acute HIV infection is available at https://

clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/

initiation-antiretroviral-therapy?view=full.

Treatment

ART should be initiated as soon as possible for all persons with

HIV infection regardless of CD4

T-cell count, both for individual

health and to prevent HIV transmission (https://clinicalinfo.hiv.

gov/sites/default/files/inline-files/AdultandAdolescentGL.pdf).

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Persons with HIV infection who achieve and maintain a viral load

suppressed to <200 copies/mL with ART have effectively no risk

for sexually transmitting HIV (95–97,421). Early HIV diagnosis

and treatment is thus not only vital for individual health but also as

a public health intervention to prevent new infections. Knowledge

of the prevention benefit of treatment can help reduce stigma and

increase the person’s commitment to start and remain adherent

to ART (423). The importance of adherence should be stressed

as well as the fact that ART does not protect against other STIs

that can be prevented by using condoms. Interventions to assist

persons to remain adherent to their prescribed HIV treatment, to

otherwise reduce the possibility of transmission to others, and to

protect themselves against STIs, have been developed for diverse

populations at risk (424) (https://clinicalinfo.hiv.gov/sites/default/

files/inline-files/AdultandAdolescentGL.pdf).

Comprehensive HIV treatment and care services might not

be available in facilities focused primarily on STI treatment.

Providers in such settings should be knowledgeable about HIV

treatment and care options available in their communities

and promptly link persons who have newly diagnosed HIV

infection and any persons with HIV infection who are not

engaged in ongoing effective care to a health care provider

or facility experienced in caring for persons living with HIV

(https://clinicalinfo.hiv.gov/sites/default/files/inline-files/

AdultandAdolescentGL.pdf).

Other HIV Management Considerations

Behavioral and psychosocial services are integral to caring for

persons with HIV infection. Providers should expect persons

to be distressed when first informed that they have HIV. They

face multiple adaptive challenges, including coping with the

reactions of others to a stigmatizing illness, developing and

adopting strategies to maintain physical and emotional health,

initiating changes in behavior to prevent HIV transmission to

others, and reducing the risk for acquiring additional STIs.

Many persons will require assistance gaining access to health

care and other support services and coping with changes in

personal relationships.

Persons with HIV infection might have additional needs

(e.g., referral for substance use or mental health disorders).

Others require assistance to secure and maintain employment

and housing. Persons capable of reproduction might require

family planning counseling, information about reproductive

health choices, and referral for reproductive health care.

The following recommendations apply to managing persons

with diagnosed HIV infection:

• Link persons with HIV infection to care and start them

on ART as soon as possible.

• Report cases (in accordance with local requirements) to

public health and initiate partner services.

• Provide prevention counseling to persons with diagnosed

HIV infection.

• Ensure all persons with HIV infection are informed that

if they achieve and maintain a suppressed viral load, they

have effectively no risk for transmitting HIV. Stress that

a suppressed viral load is not a substitute for condoms and

behavioral modifications because ART does not protect

persons with HIV against other STIs.

• Provide additional counseling, either on-site or through

referral, about the psychosocial and medical implications

of having HIV infection.

• Assess the need for immediate medical care and

psychosocial support.

• Link persons with diagnosed HIV infection to services

provided by health care personnel experienced in managing

HIV infection. Additional services that might be needed

include substance misuse counseling and treatment,

treatment for mental health disorders or emotional distress,

reproductive counseling, risk-reduction counseling, and

case management. Providers should follow up to ensure

that patients have received services for any identified needs.

• Persons with HIV infection should be educated about the

importance of ongoing medical care and what to expect

from these services.

STI Screening of Persons with HIV Infection in HIV

Care Settings

At the initial HIV care visit, providers should screen all

sexually active persons for syphilis, gonorrhea, and chlamydia,

and perform screening for these infections at least annually

during the course of HIV care (425). Specific testing

includes syphilis serology and NAAT for N. gonorrhoeae and

C. trachomatis at the anatomic site of exposure. Women should

also be screened for trichomoniasis at the initial visit and

annually thereafter. Women should be screened for cervical

cancer precursor lesions per existing guidelines (98).

More frequent screening for syphilis, gonorrhea, and

chlamydia (e.g., every 3 or 6 months) should be tailored

to individual risk and the local prevalence of specific STIs.

Certain STIs can be asymptomatic; their diagnosis might

prompt referral for partner services, might identify sexual and

needle-sharing partners who can benefit from early diagnosis

and treatment of HIV, and might prompt reengagement in

care or HIV prevention services (e.g., PEP or PrEP) (8). More

detailed information on screening, testing, and treatment is

provided in pathogen-specific sections of this report.

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Partner Services and Reporting

Partner notification is a key component in the evaluation

of persons with HIV infection. Early diagnosis and treatment

of HIV among all potentially exposed sexual and injecting

drug sharing partners can improve their health and reduce

new infections. For those partners without HIV infection,

partner services also provide an opportunity for offering HIV

prevention services, including PrEP or PEP (if exposure was

<72 hours previous) and STI testing and treatment.

Health care providers should inform persons with diagnosed

HIV infection about any legal obligations of providers to report

cases of HIV to public health; the local confidential processes

for managing partner services, including that a public health

department still might be in contact to follow up in their care

and partner services; and the benefits and risks of partner

notification and services. Health care providers should also

encourage persons with a new HIV diagnosis to notify their

partners and provide them with referral information for their

partners about HIV testing. Partner notification for exposure

to HIV should be confidential. Health care providers can assist

in the partner notification process, either directly or by referral

to health department partner notification programs. Health

department staff are trained to use public health investigation

strategies for confidentially locating persons who can benefit

from HIV treatment, care, or prevention services. Guidance

regarding spousal notification varies by jurisdiction. Detailed

recommendations for notification, evaluation, and treatment of

exposed partners are available in Recommendations for Partner

Services Programs for HIV Infection, Syphilis, Gonorrhea, and

Chlamydial Infections (111).

Special Considerations

Pregnancy

All pregnant women should be tested for HIV during the

first prenatal visit. A second test during the third trimester,

preferably at <36 weeks’ gestation, should be considered and

is recommended for women who are at high risk for acquiring

HIV, women who receive health care in jurisdictions with high

rates of HIV infection, and women served in clinical settings

in which prenatal screening identifies ≥1 pregnant woman

with HIV per 1,000 women screened (138). Diagnostic

algorithms for HIV for pregnant women do not differ from

those for nonpregnant women (see STI Detection Among

Special Populations). Pregnant women should be informed

that HIV testing will be performed as part of the routine panel

of prenatal tests (138); for women who decline HIV testing,

providers should address concerns that pose obstacles, discuss

the benefits of testing (e.g., early HIV detection, treatment, and

care for improving health of the mother and reducing perinatal

transmission of HIV), and encourage testing at subsequent

prenatal visits. Women who decline testing because they have

had a previous negative HIV test result should be informed

about the importance of retesting during each pregnancy.

Women with no prenatal care should be tested for HIV at the

time of delivery.

Testing pregnant women is crucial because knowledge of

infection status can help maintain the woman’s health, and

it enables receipt of interventions (i.e., ART or specialized

obstetrical care) that can substantially reduce the risk for

perinatal transmission of HIV. Pregnant women with

diagnosed HIV infection should be educated about the benefits

of ART for their own health and for reducing the risk for HIV

transmission to their infant. In the absence of ART, a mother’s

risk for transmitting HIV to her neonate is approximately

30%; however, risk can be reduced to <2% through ART,

obstetrical interventions (i.e., elective cesarean delivery at

38 weeks’ pregnancy), and breastfeeding avoidance (https://

clinicalinfo.hiv.gov/sites/default/files/inline-files/PerinatalGL.

pdf). Pregnant women with HIV infection should be linked

to an HIV care provider experienced in managing HIV in

pregnancy and provided antenatal and postpartum treatment

and advice. Detailed and regularly updated recommendations

for managing pregnant patients with HIV infection are

available at https://clinicalinfo.hiv.gov/sites/default/files/inline-

files/PerinatalGL.pdf.

HIV Infection Among Neonates, Infants, and Children

Diagnosis of HIV infection in a pregnant woman indicates

the need for evaluating and managing the HIV-exposed

neonate and considering whether the woman’s other children,

if any, might be infected. Detailed recommendations regarding

diagnosis and management of HIV infection among neonates

and children of mothers with HIV are beyond the scope of

these guidelines but are available at https://clinicalinfo.hiv.

gov/en/guidelines. Exposed neonates and children with HIV

infection should be referred to physicians with expertise in

neonatal and pediatric HIV management.

Diseases Characterized by Genital,

Anal, or Perianal Ulcers

In the United States, the majority of young, sexually active

patients who have genital, anal, or perianal ulcers have either

genital herpes or syphilis. The frequency of each condition

differs by geographic area and population; however, genital

herpes is the most prevalent of these diseases. More than one

etiologic agent (e.g., herpes and syphilis) can be present in

any genital, anal, or perianal ulcer. Less common infectious

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causes of genital, anal, or perianal ulcers include chancroid,

LGV, and granuloma inguinale (donovanosis). GUDs (e.g.,

syphilis, herpes, and LGV) might also present as oral ulcers.

Genital herpes, syphilis, chlamydia, gonorrhea, and chancroid

have been associated with an increased risk for HIV acquisition

and transmission. Genital, anal, or perianal lesions can also be

associated with infectious and noninfectious conditions that

are not sexually transmitted (e.g., yeast, trauma, carcinoma,

aphthae or Behcet’s disease, fixed drug eruption, or psoriasis).

A diagnosis based only on medical history and physical

examination frequently can be inaccurate. Therefore, all

persons who have genital, anal, or perianal ulcers should be

evaluated. Specific evaluation of genital, anal, or perianal ulcers

includes syphilis serology tests and darkfield examination

from lesion exudate or tissue, or NAAT if available; NAAT

or culture for genital herpes type 1 or 2; and serologic testing

for type-specific HSV antibody. In settings where chancroid is

prevalent, a NAAT or culture for Haemophilus ducreyi should

be performed.

No FDA-cleared NAAT for diagnosing syphilis is available

in the United States; however, multiple FDA-cleared NAATs

are available for diagnosing HSV-1 and HSV-2 in genital

specimens. Certain clinical laboratories have developed their

own syphilis and HSV NAATs and have conducted Clinical

Laboratory Improvement Amendment (CLIA) verification

studies with genital specimens. Type-specific serology for

HSV-2 might aid in identifying persons with genital herpes

(see Genital Herpes). In addition, biopsy of ulcers with

immunohistochemistry can help identify the cause of ulcers

that are unusual or that do not respond to initial therapy. HIV

testing should be performed on all persons not known to have

HIV infection who present with genital, anal, or perianal ulcers

(see Diagnostic Considerations in disease-specific sections).

NAAT testing at extragenital sites should be considered for

cases in which GUDs are suspected (e.g., oral manifestations

of syphilis, herpes, or LGV). Commercially available NAATs

have not been cleared by FDA for these indications; however,

they can be used by laboratories that have met regulatory

requirements for an off-label procedure.

Because early syphilis treatment decreases transmission

possibility, public health standards require health care

providers to presumptively treat any patient with a suspected

case of infectious syphilis at the initial visit, even before test

results are available. Presumptive treatment of a patient with a

suspected first episode of genital herpes also is recommended

because HSV treatment benefits depend on prompt therapy

initiation. The clinician should choose the presumptive

treatment on the basis of the clinical presentation (i.e., HSV

lesions begin as vesicles and primary syphilis as a papule) and

epidemiologic circumstances (e.g., high incidence of disease

among populations and communities and travel history). For

example, syphilis is so common among MSM that any male

who has sex with men presenting with a genital ulcer should be

presumptively treated for syphilis at the initial visit after syphilis

and HSV tests are performed. After a complete diagnostic

evaluation, >25% of patients who have genital ulcers might

not have a laboratory-confirmed diagnosis (426).

Chancroid

Chancroid prevalence has declined in the United States

(141). When infection does occur, it is usually associated

with sporadic outbreaks. Worldwide, chancroid appears to

have decreased as well, although infection might still occur in

certain Africa regions and the Caribbean. Chancroid is a risk

factor in HIV transmission and acquisition (197).

Diagnostic Considerations

A definitive diagnosis of chancroid requires identifying

H. ducreyi on special culture media that is not widely

available from commercial sources; even when these media

are used, sensitivity is <80% (427). No FDA-cleared NAAT

for H. ducreyi is available in the United States; however,

such testing can be performed by clinical laboratories that

have developed their own NAAT and have conducted CLIA

verification studies on genital specimens.

The combination of one or more deep and painful

genital ulcers and tender suppurative inguinal adenopathy

indicates the chancroid diagnosis; inguinal lymphadenitis

typically occurs in <50% of cases (428). For both clinical and

surveillance purposes, a probable diagnosis of chancroid can

be made if all of the following four criteria are met: 1) the

patient has one or more painful genital ulcers; 2) the clinical

presentation, appearance of genital ulcers and, if present,

regional lymphadenopathy are typical for chancroid; 3) the

patient has no evidence of T. pallidum infection by darkfield

examination or NAAT (i.e., ulcer exudate or serous fluid) or

by serologic tests for syphilis performed at least 7–14 days

after onset of ulcers; and 4) HSV-1 or HSV-2 NAAT or HSV

culture performed on the ulcer exudate or fluid are negative.

Treatment

Successful antimicrobial treatment for chancroid cures

the infection, resolves the clinical symptoms, and prevents

transmission to others. In advanced cases, genital scarring and

rectal or urogenital fistulas from suppurative buboes can result

despite successful therapy.

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Recommended Regimens for Chancroid

Azithromycin 1 g orally in a single dose

Ceftriaxone 250 mg IM in a single dose

Ciprofloxacin 500 mg orally 2 times/day for 3 days

Erythromycin base 500 mg orally 3 times/day for 7 days

Azithromycin and ceftriaxone offer the advantage of

single-dose therapy (429). Worldwide, several isolates with

intermediate resistance to either ciprofloxacin or erythromycin

have been reported. However, because cultures are not routinely

performed, and chancroid is uncommon, data are limited

regarding prevalence of H. ducreyi antimicrobial resistance.

Other Management Considerations

Men who are uncircumcised and persons with HIV infection

do not respond as well to treatment as persons who are

circumcised or are HIV negative (430). Patients should be

tested for HIV at the time chancroid is diagnosed. If the initial

HIV test results were negative, the provider can consider the

benefits of offering more frequent testing and HIV PrEP to

persons at increased risk for HIV infection.

Follow-Up

Patients should be reexamined 3–7 days after therapy

initiation. If treatment is successful, ulcers usually improve

symptomatically within 3 days and objectively within 7 days

after therapy. If no clinical improvement is evident, the clinician

should consider whether the diagnosis is correct, another STI

is present, the patient has HIV infection, the treatment was

not used as instructed, or the H. ducreyi strain causing the

infection is resistant to the prescribed antimicrobial. The time

required for complete healing depends on the size of the ulcer;

large ulcers might require >2 weeks. In addition, healing can

be slower for uncircumcised men who have ulcers under the

foreskin. Clinical resolution of fluctuant lymphadenopathy is

slower than that of ulcers and might require needle aspiration

or incision and drainage, despite otherwise successful therapy.

Although needle aspiration of buboes is a simpler procedure,

incision and drainage might be preferred because of reduced

need for subsequent drainage procedures.

Management of Sex Partners

Regardless of whether disease symptoms are present, sex

partners of patients with chancroid should be examined and

treated if they had sexual contact with the patient during the

10 days preceding the patient’s symptom onset.

Special Considerations

Pregnancy

Data indicate ciprofloxacin presents a low risk to the

fetus during pregnancy but has potential for toxicity during

breastfeeding (431). Alternative drugs should be used if the

patient is pregnant or lactating. No adverse effects of chancroid

on pregnancy outcome have been reported.

HIV Infection

Persons with HIV infection who have chancroid infection

should be monitored closely because they are more likely to

experience chancroid treatment failure and to have ulcers

that heal slowly (430,432). Persons with HIV might require

repeated or longer courses of therapy, and treatment failures

can occur with any regimen. Data are limited concerning

the therapeutic efficacy of the recommended single-dose

azithromycin and ceftriaxone regimens among persons with

HIV infection.

Children

Because sexual contact is the major primary transmission route

among U.S. patients, diagnosis of chancroid ulcers among infants

and children, especially in the genital or perineal region, is highly

suspicious of sexual abuse. However, H. ducreyi is recognized as a

major cause of nonsexually transmitted cutaneous ulcers among

children in tropical regions and, specifically, countries where

yaws is endemic (433–435). Acquisition of a lower-extremity

ulcer attributable to H. ducreyi in a child without genital ulcers

and reported travel to a region where yaws is endemic should

not be considered evidence of sexual abuse.

Genital Herpes

Genital herpes is a chronic, lifelong viral infection. Two types

of HSV can cause genital herpes: HSV-1 and HSV-2. Most

cases of recurrent genital herpes are caused by HSV-2, and

11.9% of persons aged 14–49 years are estimated to be infected

in the United States (436). However, an increasing proportion

of anogenital herpetic infections have been attributed to

HSV-1, which is especially prominent among young women

and MSM (186,437,438).

The majority of persons infected with HSV-2 have not

had the condition diagnosed, many of whom have mild or

unrecognized infections but shed virus intermittently in the

anogenital area. Consequently, most genital herpes infections

are transmitted by persons unaware that they have the

infection or who are asymptomatic when transmission occurs.

Management of genital HSV should address the chronic nature

of the infection rather than focusing solely on treating acute

episodes of genital lesions.

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Diagnostic Considerations

Clinical diagnosis of genital herpes can be difficult because the

self-limited, recurrent, painful, and vesicular or ulcerative lesions

classically associated with HSV are absent in many infected persons

at the time of clinical evaluation. If genital lesions are present,

clinical diagnosis of genital herpes should be confirmed by type-

specific virologic testing from the lesion by NAAT or culture (186).

Recurrences and subclinical shedding are much more frequent for

HSV-2 genital herpes infection than for HSV-1 genital herpes

(439,440). Therefore, prognosis and counseling depend on which

HSV type is present. Type-specific serologic tests can be used to

aid in the diagnosis of HSV infection in the absence of genital

lesions. Both type-specific virologic and type-specific serologic tests

for HSV should be available in clinical settings that provide care

to persons with or at risk for STIs. HSV-2 genital herpes infection

increases the risk for acquiring HIV twofold to threefold; therefore,

all persons with genital herpes should be tested for HIV (441).

Virologic Tests

HSV NAAT assays are the most sensitive tests because

they detect HSV from genital ulcers or other mucocutaneous

lesions; these tests are increasingly available (442–444).

Although multiple FDA-cleared assays exist for HSV detection,

these tests vary in sensitivity from 90.9% to 100%; however,

they are considered highly specific (445–447). PCR is also

the test of choice for diagnosing HSV infections affecting the

central nervous system (CNS) and systemic infections (e.g.,

meningitis, encephalitis, and neonatal herpes). HSV PCR

of the blood should not be performed to diagnose genital

herpes infection, except in cases in which concern exists for

disseminated infection (e.g., hepatitis). In certain settings, viral

culture is the only available virologic test. The sensitivity of viral

culture is low, especially for recurrent lesions, and decreases

rapidly as lesions begin to heal (443,448). Viral culture

isolates and PCR amplicons should be typed to determine

whether HSV-1 or HSV-2 is causing the infection. Failure to

detect HSV by NAAT or culture, especially in the presence

of older lesions or the absence of active lesions, does not

indicate an absence of HSV infection because viral shedding

is intermittent. Similarly, random or blind genital swabs in

the absence of lesions should not be used to diagnose genital

HSV infection because sensitivity is low, and a negative result

does not exclude the presence of HSV infection.

Cytologic detection of cellular changes associated with HSV

infection is an insensitive and nonspecific method of diagnosing

genital lesions (i.e., Tzanck preparation) and therefore should

not be relied on. Although a direct immunofluorescence

assay using fluorescein-labeled monoclonal antibodies is also

available for detecting HSV antigen from genital specimens,

this assay lacks sensitivity and is not recommended (449).

Type-Specific Serologic Tests

Both type-specific and type-common antibodies to HSV

develop during the first weeks after infection and persist

indefinitely. The majority of available, accurate type-

specific HSV serologic assays are based on the HSV-specific

glycoprotein G2 (gG2) (HSV-2) and glycoprotein G1 (gG1)

(HSV-1). Type-common antibody tests do not distinguish

between HSV-1 and HSV-2 infection; therefore, type-specific

serologic assays should be requested (450–452).

Both laboratory-based assays and POC tests that provide

results for HSV-2 antibodies from capillary blood or serum

during a clinic visit are available. The sensitivity of glycoprotein

G type-specific tests for detecting HSV-2 antibody varies from

80% to 98%; false-negative results might be more frequent

at early stages of infection (451,453,454). Therefore, in

cases of recent suspected HSV-2 acquisition, repeat type-

specific antibody testing 12 weeks after the presumed time

of acquisition is indicated. The most commonly used test,

HerpeSelect HSV-2 enzyme immunoassay (EIA), often is

falsely positive at low index values (1.1–3.0) (457–457). One

study reported an overall specificity of 57.4%, with a specificity

of 39.8% for index values of 1.1–2.9 (458). Because of the

poor specificity of commercially available type-specific EIAs,

particularly with low index values (<3.0), a confirmatory test

(Biokit or Western blot) with a second method should be

performed before test interpretation. Use of confirmatory

testing with the Biokit or the Western blot assays have been

reported to improve accuracy of HSV-2 serologic testing (459).

The HerpeSelect HSV-2 immunoblot should not be used for

confirmation because it uses the same antigen as the HSV-2

EIA. If confirmatory tests are unavailable, patients should be

counseled about the limitations of available testing before

obtaining serologic tests, and health care providers should

be aware that false-positive results occur. Immunoglobulin

M (IgM) testing for HSV-1 or HSV-2 is not useful because

IgM tests are not type specific and might be positive during

recurrent genital or oral episodes of herpes (460). Therefore,

HSV IgM testing is not recommended.

Because approximately all HSV-2 infections are sexually

acquired, presence of type-specific HSV-2 antibody implies

anogenital infection. In this instance, education and counseling

for persons with genital HSV infections should be provided.

The presence of HSV-1 antibody alone is more difficult

to interpret. HSV-1 serologic testing does not distinguish

between oral and genital infection and typically should not

be performed for diagnosing genital HSV-1 infection. Persons

with HSV-1 antibodies often have oral HSV infection acquired

during childhood, which might be asymptomatic. Lack of

symptoms in a person who is HSV-1 seropositive does not

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distinguish anogenital from orolabial or cutaneous infection,

and, regardless of site of infection, these persons remain at risk

for acquiring HSV-2. In addition, HSV-1 serologic testing

has low sensitivity for detection of HSV-1 antibody (458).

However, acquisition of HSV-1 genital herpes is increasing,

and HSV-1 genital herpes also can be asymptomatic (437–

439,461,462). Diagnosis of HSV-1 infection is confirmed by

virologic tests from genital lesions.

Type-specific HSV-2 serologic assays for diagnosing

HSV-2 are useful in the following scenarios: recurrent or

atypical genital symptoms or lesions with a negative HSV

PCR or culture result, clinical diagnosis of genital herpes

without laboratory confirmation, and a patient’s partner has

genital herpes. HSV-2 serologic screening among the general

population is not recommended. Patients who are at higher

risk for infection (e.g., those presenting for an STI evaluation,

especially for persons with ≥10 lifetime sex partners, and

persons with HIV infection) might need to be assessed for a

history of genital herpes symptoms, followed by type-specific

HSV serologic assays to diagnose genital herpes for those with

genital symptoms.

Genital Herpes Management

Antiviral medication offers clinical benefits to symptomatic

patients and is the mainstay of management. The goals for

use of antiviral medications to treat genital herpes infection

are to treat or prevent symptomatic genital herpes recurrences

and improve quality of life and suppress the virus to prevent

transmission to sexual partners. Counseling regarding the

natural history of genital herpes, risks for sexual and perinatal

transmission, and methods for reducing transmission is also

integral to clinical management.

Systemic antiviral drugs can partially control the signs and

symptoms of genital herpes when used to treat first clinical and

recurrent episodes or when used as daily suppressive therapy.

However, these drugs neither eradicate latent virus nor affect

the risk, frequency, or severity of recurrences after the drug

is discontinued. Randomized trials have indicated that three

FDA-approved antiviral medications provide clinical benefit

for genital herpes: acyclovir, valacyclovir, and famciclovir

(463–471). Valacyclovir is the valine ester of acyclovir and has

enhanced absorption after oral administration, allowing for

less frequent dosing than acyclovir. Famciclovir also has high

oral bioavailability. Topical therapy with antiviral drugs offers

minimal clinical benefit and is discouraged.

First Clinical Episode of Genital Herpes

Newly acquired genital herpes can cause a prolonged

clinical illness with severe genital ulcerations and neurologic

involvement. Even persons with first-episode herpes who have

mild clinical manifestations initially can experience severe or

prolonged symptoms during recurrent infection. Therefore,

all patients with first episodes of genital herpes should receive

antiviral therapy.

Recommended Regimens for First Clinical Episode of Genital

Herpes*

Acyclovir

†

400 mg orally 3 times/day for 7–10 days

Famciclovir 250 mg orally 3 times/day for 7–10 days

Valacyclovir 1 g orally 2 times/day for 7–10 days

* Treatment can be extended if healing is incomplete after 10 days of therapy.

†

Acyclovir 200 mg orally 5 times/day is also effective but is not

recommended because of the frequency of dosing.

Recurrent HSV-2 Genital Herpes

Almost all persons with symptomatic first-episode HSV-2

genital herpes subsequently experience recurrent episodes of

genital lesions. Intermittent asymptomatic shedding occurs

among persons with HSV-2 genital herpes infection, even

those with longstanding clinically silent infection. Antiviral

therapy for recurrent genital herpes can be administered either

as suppressive therapy to reduce the frequency of recurrences

or episodically to ameliorate or shorten the duration of lesions.

Certain persons, including those with mild or infrequent

recurrent outbreaks, benefit from antiviral therapy; therefore,

options for treatment should be discussed. Many persons prefer

suppressive therapy, which has the additional advantage of

decreasing the risk for transmitting HSV-2 genital herpes to

susceptible partners (472,473).

Suppressive Therapy for Recurrent HSV-2

Genital Herpes

Suppressive therapy reduces frequency of genital herpes

recurrences by 70%–80% among patients who have frequent

recurrences (469–472). Persons receiving such therapy

often report having experienced no symptomatic outbreaks.

Suppressive therapy also is effective for patients with less

frequent recurrences. Long-term safety and efficacy have

been documented among patients receiving daily acyclovir,

valacyclovir, and famciclovir (474). Quality of life is improved

for many patients with frequent recurrences who receive

suppressive therapy rather than episodic treatment (475).

Providers should discuss with patients on an annual basis

whether they want to continue suppressive therapy because

frequency of genital HSV-2 recurrence diminishes over time

for many persons. However, neither treatment discontinuation

nor laboratory monitoring is necessary because adverse events

and development of HSV antiviral resistance related to long-

term antiviral use are uncommon.

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Treatment with valacyclovir 500 mg daily decreases the rate

of HSV-2 transmission for discordant heterosexual couples

in which a partner has a history of genital HSV-2 infection

(473). Such couples should be encouraged to consider

suppressive antiviral therapy as part of a strategy for preventing

transmission, in addition to consistent condom use and

avoidance of sexual activity during recurrences. Suppressive

antiviral therapy for persons with a history of symptomatic

genital herpes also is likely to reduce transmission when used

by those who have multiple partners. HSV-2 seropositive

persons without a history of symptomatic genital herpes

have a 50% decreased risk for genital shedding, compared

with those with symptomatic genital herpes (476). No data

are available regarding efficacy of suppressive therapy for

preventing HSV-2 transmission among discordant couples in

which a partner has a history of asymptomatic HSV-2 infection

identified by a positive HSV-2 serologic test. Among HSV-2

seropositive persons without HIV infection, oral TDF/FTC

and intravaginal tenofovir are ineffective at reducing the risk

for HSV-2 shedding or recurrences (477).

Recommended Regimens for Suppression of Recurrent HSV-2

Genital Herpes

Acyclovir 400 mg orally 2 times/day

Valacyclovir 500 mg orally once a day*

Valacyclovir 1 g orally once a day

Famciclovir 250 mg orally 2 times/day

* Valacyclovir 500 mg once a day might be less effective than other

valacyclovir or acyclovir dosing regimens for persons who have frequent

recurrences (i.e., ≥10 episodes/year).

Famciclovir appears somewhat less effective for suppression of

viral shedding (478). Ease of administration and cost also are

key considerations for prolonged treatment.

Recurrent HSV-1 Genital Herpes

Recurrences are less frequent after the first episode of HSV-1

genital herpes, compared with genital HSV-2 genital herpes,

and genital shedding rapidly decreases during the first year of

infection (479). No data are available regarding the efficacy

of suppressive therapy for preventing transmission among

persons with HSV-1 genital herpes infection. Because of

the decreased risk for recurrences and shedding, suppressive

therapy for HSV-1 genital herpes should be reserved for those

with frequent recurrences through shared clinical decision-

making between the patient and the provider.

Episodic Therapy for Recurrent HSV-2 Genital Herpes

Episodic treatment of recurrent herpes is most effective if

therapy is initiated within 1 day of lesion onset or during the

prodrome that precedes some outbreaks. The patient should

be provided with a supply of drug or a prescription for the

medication with instructions to initiate treatment immediately

when symptoms begin. Acyclovir, famciclovir, and valacyclovir

appear equally effective for episodic treatment of genital herpes

(466–470).

Recommended Regimens for Episodic Therapy for Recurrent

HSV-2 Genital Herpes*

Acyclovir 800 mg orally 2 times/day for 5 days

Acyclovir 800 mg orally 3 times/day for 2 days

Famciclovir 1 g orally 2 times/day for 1 day

Famciclovir 500 mg orally once, followed by 250 mg 2 times/day for

2 days

Famciclovir 125 mg orally 2 times/day for 5 days

Valacyclovir 500 mg orally 2 times/day for 3 days

Valacyclovir 1 g orally once daily for 5 days

* Acyclovir 400 mg orally 3 times/day for 5 days is also effective but is not

recommended because of frequency of dosing.

Severe Disease

Intravenous (IV) acyclovir therapy (5–10 mg/kg body weight

IV every 8 hours) should be provided for patients who have severe

HSV disease or complications that necessitate hospitalization

(e.g., disseminated infection, pneumonitis, or hepatitis) or

CNS complications (e.g., meningitis or encephalitis). HSV-2

meningitis is a rare complication of HSV-2 genital herpes

infection that affects women more than men (480). IV therapy

should be considered until clinical improvement followed by

oral antiviral therapy to complete >10 days of total therapy.

Longer duration is recommended for CNS complications.

HSV-2 meningitis is characterized clinically by signs of

headache, photophobia, fever, meningismus, and cerebrospinal

fluid (CSF) lymphocytic pleocytosis, accompanied by mildly

elevated protein and normal glucose (481). Optimal therapies

for HSV-2 meningitis have not been well studied (482);

however, acyclovir 5–10 mg/kg body weight IV every 8 hours

until clinical improvement is observed, followed by high-dose

oral antiviral therapy (valacyclovir 1 g 3 times/day) to complete

a 10- to 14-day course of total therapy, is recommended.

For patients with previous episodes of documented HSV-2

meningitis, oral valacyclovir may be used for the entire

course during episodes of recurrent HSV-2 meningitis. A

randomized clinical trial indicated that suppressive therapy

(valacyclovir 500 mg 2 times/day) did not prevent recurrent

HSV-2 meningitis episodes; however, the dose might not

have been sufficient for CNS penetration (483). Valacyclovir

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500 mg 2 times/day is not recommended for suppression of

HSV-2 meningitis; higher doses have not been studied in

clinical trials. HSV meningitis should be distinguished from

encephalitis, which requires a longer course (14–21 days) of

IV therapy. Impaired renal function warrants an adjustment

in acyclovir dosage.

Hepatitis

Hepatitis is a rare manifestation of disseminated HSV

infection, often reported among pregnant women who

acquire HSV during pregnancy (484). Pregnant women in

any trimester can present with fever and hepatitis (markedly

elevated transaminases) but might not have any genital or skin

lesions. HSV hepatitis is associated with fulminant liver failure

and high mortality (25%). Therefore, a high index of suspicion

for HSV is necessary, with a confirmatory diagnosis by HSV

PCR from blood (485). Among pregnant women with fever

and unexplained severe hepatitis, disseminated HSV infection

should be considered, and empiric IV acyclovir should be

initiated pending confirmation (484).

Prevention

Consistent and correct condom use has been reported

in multiple studies to decrease, but not eliminate, the risk

for HSV-2 transmission from men to women (486–488).

Condoms are less effective for preventing transmission from

women to men (489). Two randomized clinical trials of

medical male circumcision (MMC) demonstrated a decreased

risk for HSV-2 acquisition among men in Uganda and

South Africa (66,68). Results from a third trial conducted

in Kenya did not demonstrate a substantial difference in

HSV-2 acquisition among men who received MMC (490).

A systematic review indicated high consistency for decreased

risk for HSV-2 acquisition among women with a male partner

who underwent MMC (491). These data indicate that MMC

can be associated with decreased risk for HSV-2 acquisition

among adult heterosexual men and with decreased risk for

HSV-2 transmission from male to female partners.

Randomized clinical trials have demonstrated that PrEP with

daily oral TDF/FTC decreases the risk for HSV-2 acquisition

by 30% in heterosexual partnerships (492). Pericoital

intravaginal tenofovir 1% gel also decreases the risk for HSV-2

acquisition among heterosexual women (493). Among MSM

and transgender women, daily oral TDF/FTC decreases the

risk for severe ulcers with symptomatic genital HSV-2 infection

but not for HSV-2 acquisition (494). Insufficient evidence

exists that TDF/FTC use among those who are not at risk for

HIV acquisition will prevent HSV-2 infection, and it should

not be used for that sole purpose. Oral TDF does not prevent

HSV-2 acquisition among persons with HIV infection who

are taking TDF as part of their ART regimen (495). No data

indicate that antivirals (acyclovir, valacyclovir, or famciclovir)

can be taken as PrEP by persons without HSV-2 to prevent

its acquisition.

Counseling

Counseling of persons with genital herpes and their sex

partners is crucial for management. The goals of counseling

include helping patients cope with the infection and preventing

sexual and perinatal transmission. Although initial counseling

can be provided at the first visit, patients often benefit from

learning about the chronic aspects of the disease after the acute

illness subsides. Multiple resources, including Internet sites and

printed materials, are available to assist patients, their partners,

and clinicians who provide counseling (496,497) (https://www.

ashasexualhealth.org and https://www.cdc.gov/std/herpes).

Although the psychological effect of a serologic diagnosis of

HSV-2 infection in a person with asymptomatic or unrecognized

genital herpes appears minimal and transient (498,499), certain

persons with HSV infection might express anxiety concerning

genital herpes that does not reflect the actual clinical severity

of their disease; the psychological effect of HSV infection can

be substantial. Common concerns about genital herpes include

the severity of initial clinical manifestations, recurrent episodes,

sexual relationships and transmission to sex partners, and ability

to bear healthy children.

Symptomatic HSV-2 Genital Herpes

When counseling persons with symptomatic HSV-2 genital

herpes infection, the provider should discuss the following:

• The natural history of the disease, with emphasis on the

potential for recurrent episodes, asymptomatic viral

shedding, and the attendant risks for sexual transmission

of HSV to occur during asymptomatic periods

(asymptomatic viral shedding is most frequent during the

first 12 months after acquiring HSV-2).

• The effectiveness of daily suppressive antiviral therapy for

preventing symptomatic recurrent episodes of genital

herpes for persons experiencing a first episode or recurrent

genital herpes.

• The effectiveness of daily use of valacyclovir in reducing

risk for transmission of HSV-2 among persons without

HIV (473) and use of episodic therapy to shorten the

duration of recurrent episodes.

• The importance of informing current sex partners about

genital herpes and informing future partners before

initiating a sexual relationship.

• The importance of abstaining from sexual activity with

uninfected partners when lesions or prodromal symptoms

are present.

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• The effectiveness of male latex condoms, which when used

consistently and correctly can reduce, but not eliminate,

the risk for genital herpes transmission (486–488).

• The type-specific serologic testing of partners of persons

with symptomatic HSV-2 genital herpes to determine

whether such partners are already HSV seropositive or

whether risk for acquiring HSV exists.

• The low risk for neonatal HSV except when genital herpes

is acquired late in pregnancy or if prodrome or lesions are

present at delivery.

• The increased risk for HIV acquisition among HSV-2

seropositive persons who are exposed to HIV (76,471).

• The lack of effectiveness of episodic or suppressive therapy

among persons with HIV infection to reduce risk for

transmission to partners who might be at risk for

HSV-2 acquisition.

Asymptomatic HSV-2 Genital Herpes

When counseling persons with asymptomatic HSV-2 genital

herpes infection, the provider should consider the following:

• Asymptomatic persons who receive a diagnosis of HSV-2

by type-specific serologic testing (with confirmatory testing,

if needed) should receive education about the symptoms of

genital herpes infection (see Diagnostic Considerations).

• Episodic and suppressive antiviral therapies are used

predominantly to treat recurrences, prevent recurrences,

and prevent transmission to sex partners of persons with

symptomatic HSV-2 infection.

• For patients with serological evidence of HSV-2 (with

combination testing if needed) without symptomatic

recurrences, neither episodic nor suppressive therapy is

indicated for prevention of recurrences (see Diagnostic

Considerations).

• Among persons with asymptomatic infection, the efficacy

of suppressive therapy to prevent HSV-2 transmission to

sex partners has not been studied.

• Because of the decreased risk for shedding among those

with asymptomatic HSV-2 genital herpes, the benefit of

suppressive therapy for preventing transmission is

unknown among this population.

HSV-1 Genital Herpes

When counseling persons with HSV-1 genital herpes

infection, the provider should consider the following:

• Persons with virologic laboratory-documented

symptomatic HSV-1 genital herpes infection should be

educated that the risk for recurrent genital herpes and

genital shedding is lower with HSV-1 infection, compared

with HSV-2 infection.

• Because of the decreased risk for recurrences and shedding,

suppressive therapy for HSV-1 genital herpes should be

reserved for those with frequent recurrences.

• For patients with frequently recurring HSV-1 genital

herpes, suppressive therapy might be considered.

Suppressive therapy to prevent HSV-1 transmission to sex

partners has not been studied.

For persons with symptomatic HSV-1 genital herpes or

asymptomatic HSV-2 genital herpes, suppressive therapy can

be considered for those who have substantial psychosocial

distress caused by the diagnosis of genital herpes. For women

who have genital herpes, the providers who care for them

during pregnancy and those who will care for their newborn

infant should be informed of their infection (see Genital

Herpes During Pregnancy).

Management of Sex Partners

The sex partners of persons who have symptomatic

genital herpes can benefit from evaluation and counseling.

Symptomatic sex partners should be evaluated and treated in

the same manner as patients who have symptomatic genital

herpes. Asymptomatic sex partners of patients who have

symptomatic genital herpes should be asked about a history

of genital symptoms and offered type-specific serologic testing

for HSV-2. For partners without genital herpes, no data are

available on which to base a recommendation for PEP or

PrEP with antiviral medications or that they would prevent

acquisition, and this should not be offered to patients as a

prevention strategy.

Special Considerations

Drug Allergy, Intolerance, or Adverse Reactions

Allergic and other adverse reactions to oral acyclovir,

valacyclovir, and famciclovir are rare. Desensitization to

acyclovir has been described (500).

HIV Infection

Immunocompromised patients can have prolonged or severe

episodes of genital, perianal, or oral herpes. Lesions caused by

HSV are common among persons with HIV infection and

might be severe, painful, and atypical (501). HSV shedding is

increased among persons with HIV infection (502). Whereas

ART reduces the severity and frequency of symptomatic genital

herpes, frequent subclinical shedding still occurs (503,504).

Clinical manifestations of genital herpes might worsen during

immune reconstitution early after initiation of ART. HSV-2

type-specific serologic testing can be considered for persons

with HIV infection during their initial evaluation, particularly

among those with a history of genital symptoms indicative of

HSV infection.

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Recommended therapy for first-episode genital herpes is

the same as for persons without HIV infection, although

treatment courses might need to be extended for lesion

resolution. Suppressive or episodic therapy with oral antiviral

agents is effective in decreasing the clinical manifestations of

HSV infection among persons with HIV (503,504). The risk

for GUD increases during the first 6 months after starting

ART, especially among persons who have a CD4

T-cell count

<200 cell/mm

. Suppressive antiviral therapy reduces the risk

for GUD among this population and can be continued for

6 months after ART initiation (504) when the risk for GUD

returns to baseline levels. Suppressive antiviral therapy among

persons with HIV and HSV infection does not reduce the

risk for either HIV transmission or HSV-2 transmission to

susceptible sex partners (88,505). Suppressive antiviral therapy

does not delay HIV disease progression and is not associated

with decreased risk for HIV-related inflammation among

persons taking ART (506). For severe HSV disease, initiating

therapy with acyclovir 5–10 mg/kg IV every 8 hours might

be necessary.

Recommended Regimens for Daily Suppression of Genital

Herpes Among Persons with HIV Infection

Acyclovir 400–800 mg orally 2–3 times/day

Famciclovir 500 mg orally 2 times/day

Valacyclovir 500 mg orally 2 times/day

Recommended Regimens for Episodic Genital Herpes Infection

Among Persons with HIV Infection

Acyclovir 400 mg orally 3 times/day for 5–10 days

Famciclovir 500 mg orally 2 times/day for 5–10 days

Valacyclovir 1 g orally 2 times/day for 5–10 days

Antiviral-Resistant HSV Infection

If lesions persist or recur in a patient receiving antiviral

treatment, acyclovir resistance should be suspected and a viral

culture obtained for phenotypic sensitivity testing (507).

Molecular testing for acyclovir resistance is not available.

Such persons should be managed in consultation with an

infectious disease specialist, and alternative therapy should be

administered. All acyclovir-resistant strains are also resistant

to valacyclovir, and the majority are resistant to famciclovir.

Foscarnet (40–80 mg/kg body weight IV every 8 hours until

clinical resolution is attained) is the treatment of choice for

acyclovir-resistant genital herpes (508,509). Intravenous

cidofovir 5 mg/kg body weight once weekly might also be

effective. Foscarnet and cidofovir are nephrotoxic medications

that require intensive laboratory monitoring and infectious

disease specialist consultation. Imiquimod 5% applied to the lesion

for 8 hours 3 times/week until clinical resolution is an alternative

that has been reported to be effective (510,511). Topical cidofovir

gel 1% can be applied to lesions 2–4 times daily; however, cidofovir

must be compounded at a pharmacy (512).

Prevention of antiviral resistance remains challenging among

persons with HIV infection. Experience with another group

of immunocompromised persons (e.g., hematopoietic stem-

cell recipients) demonstrated that persons receiving daily

suppressive antiviral therapy were less likely to experience

acyclovir-resistant HSV infection compared with those who

received episodic therapy for outbreaks (513).

Genital Herpes During Pregnancy

Prevention of neonatal herpes depends both on preventing

acquisition of genital herpes during late pregnancy and

avoiding exposure of the neonate to herpetic lesions and viral

shedding during delivery. Mothers of newborns who acquire

neonatal herpes often lack histories of clinically evident genital

herpes (514,515). The risk for transmission to the neonate from

an infected mother is high (30%–50%) among women who

acquire genital herpes near the time of delivery and low (<1%)

among women with prenatal histories of recurrent herpes or

who acquire genital herpes during the first half of pregnancy

(516,517). Women who acquire HSV in the second half of

pregnancy should be managed in consultation with maternal-

fetal medicine and infectious disease specialists.

All pregnant women should be asked whether they have

a history of genital herpes or genital symptoms concerning

for HSV infection. At the onset of labor, all women should

be questioned thoroughly about symptoms of genital herpes,

including prodromal symptoms (e.g., pain or burning at site

before appearance of lesion), and all women should be examined

thoroughly for herpetic lesions. Women without symptoms or

signs of genital herpes or its prodrome can deliver vaginally.

Although cesarean delivery does not eliminate the risk for HSV

transmission to the neonate (517), women with recurrent genital

herpetic lesions at the onset of labor should have a cesarean

delivery to reduce the risk for neonatal HSV infection.

Routine HSV-2 serologic screening of pregnant women is not

recommended. Women without known genital herpes should

be counseled to abstain from vaginal intercourse during the

third trimester with partners known to have or suspected of

having genital herpes. In addition, to prevent HSV-1 genital

herpes, pregnant women without known orolabial herpes

should be advised to abstain from receptive oral sex during the

third trimester with partners known to have or suspected to

have orolabial herpes. Type-specific serologic tests can be useful

for identifying pregnant women at risk for HSV infection and

for guiding counseling regarding the risk for acquiring genital

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herpes during pregnancy. For example, such testing might be

offered to a woman with no history of genital herpes whose

sex partner has HSV infection. Many fetuses are exposed to

acyclovir each year, and the medication is believed to be safe

for use during all trimesters of pregnancy. A case-control study

reported an increased risk for the rare neonatal outcome of

gastroschisis among women who used antiviral medications

between the month before conception and the third month of

pregnancy (518). Acyclovir is also believed to be safe during

breastfeeding (431,519). Although data regarding prenatal

exposure to valacyclovir and famciclovir are limited, data from

animal trials indicate that these drugs also pose a low risk

among pregnant women (520). Acyclovir can be administered

orally to pregnant women with first-episode genital herpes or

recurrent herpes and should be administered IV to pregnant

women with severe HSV (see Genital Herpes, Hepatitis).

Suppressive acyclovir treatment starting at 36 weeks’ gestation

reduces the frequency of cesarean delivery among women who

have recurrent genital herpes by diminishing the frequency of

recurrences at term (521–523). However, such treatment might

not protect against transmission to neonates in all cases (524).

No data support use of antiviral therapy among asymptomatic

HSV-seropositive women without a history of genital herpes.

In addition, the effectiveness of antiviral therapy among sex

partners with a history of genital herpes to decrease the risk

for HSV transmission to a pregnant woman has not been

studied. Additional information on the clinical management

of genital herpes in pregnancy is available through existing

guidelines (525).

Recommended Regimen for Suppression of Recurrent Genital

Herpes Among Pregnant Women*

Acyclovir 400 mg orally 3 times/day

Valacyclovir 500 mg orally 2 times/day

* Treatment recommended starting at 36 weeks’ gestation.

Neonatal Herpes

Newborn infants exposed to HSV during birth, as

documented by virologic testing of maternal lesions at delivery

or presumed by observation of maternal lesions, should be

followed clinically in consultation with a pediatric infectious

disease specialist. Detailed guidance is available regarding

management of neonates who are delivered vaginally in the

presence of maternal genital herpes lesions and is beyond the

scope of these guidelines; more information is available from

the AAP (https://redbook.solutions.aap.org). Surveillance

cultures or PCR of mucosal surfaces of the neonate to detect

HSV infection might be considered before the development of

clinical signs of neonatal herpes to guide treatment initiation.

In addition, administration of acyclovir might be considered

for neonates born to women who acquired HSV near term

because the risk for neonatal herpes is high for these newborn

infants. All newborn infants who have neonatal herpes should

be promptly evaluated and treated with systemic acyclovir.

The recommended regimen for infants treated for known or

suspected neonatal herpes is acyclovir 20 mg/kg body weight

IV every 8 hours for 14 days if disease is limited to the skin and

mucous membranes, or for 21 days for disseminated disease

and disease involving the CNS.

Granuloma Inguinale (Donovanosis)

Granuloma inguinale (donovanosis) is a genital ulcerative

disease caused by the intracellular gram-negative bacterium

Klebsiella granulomatis (formerly known as Calymmatobacterium

granulomatis). The disease occurs rarely in the United States;

however, sporadic cases have been described in India, South

Africa, and South America (526–535). Although granuloma

inguinale was previously endemic in Australia, it is now

extremely rare (536,537). Clinically, the disease is characterized

as painless, slowly progressive ulcerative lesions on the genitals

or perineum without regional lymphadenopathy; subcutaneous

granulomas (pseudobuboes) also might occur. The lesions

are highly vascular (i.e., beefy red appearance) and can bleed.

Extragenital infection can occur with infection extension to

the pelvis, or it can disseminate to intra-abdominal organs,

bones, or the mouth. The lesions also can develop secondary

bacterial infection and can coexist with other sexually

transmitted pathogens.

Diagnostic Considerations

The causative organism of granuloma inguinale is difficult

to culture, and diagnosis requires visualization of dark-staining

Donovan bodies on tissue crush preparation or biopsy.

Although no FDA-cleared molecular tests for the detection of

K. granulomatis DNA exist, molecular assays might be useful

for identifying the causative agent.

Treatment

Multiple antimicrobial regimens have been effective;

however, only a limited number of controlled trials have

been published (538). Treatment has been reported to halt

progression of lesions, and healing typically proceeds inward

from the ulcer margins. Prolonged therapy is usually required to

permit granulation and reepithelialization of the ulcers. Relapse

can occur 6–18 months after apparently effective therapy.

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Recommended Regimen for Granuloma Inguinale (Donovanosis)

Azithromycin 1 g orally once/week or 500 mg daily for >3 weeks and

until all lesions have completely healed

Alternative Regimens

Doxycycline 100 mg orally 2 times/day for at least 3 weeks and until all

lesions have completely healed

Erythromycin base 500 mg orally 4 times/day for >3 weeks and until all

lesions have completely healed

Trimethoprim-sulfamethoxazole one double-strength (160 mg/800

mg) tablet orally 2 time/day for >3 weeks and until all lesions have

completely healed

The addition of another antibiotic to these regimens can be

considered if improvement is not evident within the first few

days of therapy.

Other Management Considerations

Patients should be followed clinically until signs and

symptoms have resolved. All persons who receive a diagnosis

of granuloma inguinale should be tested for HIV.

Follow-Up

Patients should be followed clinically until signs and

symptoms resolve.

Management of Sex Partners

Persons who have had sexual contact with a patient who has

granuloma inguinale within the 60 days before onset of the

patient’s symptoms should be examined and offered therapy.

However, the value of empiric therapy in the absence of clinical

signs and symptoms has not been established.

Special Considerations

Pregnancy

Use of doxycycline in pregnancy might be associated

with discoloration of teeth; however, the risk is not well

defined. Doxycycline is compatible with breastfeeding (431).

Sulfonamides can be associated with neonatal kernicterus

among those with glucose-6-phospate dehydrogenase

deficiency and should be avoided during the third trimester

and while breastfeeding (431). For these reasons, pregnant and

lactating women with granuloma inguinale should be treated

with a macrolide regimen (erythromycin or azithromycin).

HIV Infection

Persons with granuloma inguinale and HIV infection should

receive the same regimens as those who do not have HIV.

Lymphogranuloma Venereum

LGV is caused by C. trachomatis serovars L1, L2, or L3

(539,540). LGV can cause severe inflammation and invasive

infection, in contrast with C. trachomatis serovars A–K that

cause mild or asymptomatic infection. Clinical manifestations

of LGV can include GUD, lymphadenopathy, or proctocolitis.

Rectal exposure among MSM or women can result in

proctocolitis, which is the most common presentation of

LGV infection (541), and can mimic inflammatory bowel

disease with clinical findings of mucoid or hemorrhagic

rectal discharge, anal pain, constipation, fever, or tenesmus

(542,543). Outbreaks of LGV proctocolitis have been

reported among MSM with high rates of HIV infection

(544–547). LGV proctocolitis can be an invasive, systemic

infection and, if it is not treated early, can lead to chronic

colorectal fistulas and strictures; reactive arthropathy has also

been reported. However, reports indicate that rectal LGV can

also be asymptomatic (548). A common clinical manifestation

of LGV among heterosexuals is tender inguinal or femoral

lymphadenopathy that is typically unilateral. A self-limited

genital ulcer or papule sometimes occurs at the site of inoculation.

However, by the time persons seek care, the lesions have often

disappeared. LGV-associated lymphadenopathy can be severe,

with bubo formation from fluctuant or suppurative inguinal or

femoral lymphadenopathy. Oral ulceration can occur and might

be associated with cervical adenopathy (549–551). Persons with

genital or colorectal LGV lesions can also experience secondary

bacterial infection or can be infected with other sexually and

nonsexually transmitted pathogens.

Diagnostic Considerations

A definitive LGV diagnosis can be made only with LGV-

specific molecular testing (e.g., PCR-based genotyping). These

tests can differentiate LGV from non–LGV C. trachomatis in

rectal specimens. However, these tests are not widely available,

and results are not typically available in a time frame that

would influence clinical management. Therefore, diagnosis is

based on clinical suspicion, epidemiologic information, and a

C. trachomatis NAAT at the symptomatic anatomic site, along

with exclusion of other etiologies for proctocolitis, inguinal

lymphadenopathy, or genital, oral, or rectal ulcers (551,552).

Genital or oral lesions, rectal specimens, and lymph node

specimens (i.e., lesion swab or bubo aspirate) can be tested

for C. trachomatis by NAAT or culture. NAAT is the preferred

approach for testing because it can detect both LGV strains and

non–LGV C. trachomatis strains (553). Therefore, all persons

presenting with proctocolitis should be tested for chlamydia

with a NAAT performed on rectal specimens. Severe symptoms

of proctocolitis (e.g., bloody discharge, tenesmus, and rectal

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ulcers) indicate LGV. A rectal Gram stain with >10 white

blood cells (WBCs) has also been associated with rectal LGV

(545,554,555).

Chlamydia serology (complement fixation or

microimmunofluorescence) should not be used routinely as a

diagnostic tool for LGV because the utility of these serologic

methods has not been established, interpretation has not been

standardized, and validation for clinical proctitis presentation

has not been done. It might support an LGV diagnosis in

cases of isolated inguinal or femoral lymphadenopathy for

which diagnostic material for C. trachomatis NAAT cannot

be obtained.

Treatment

At the time of the initial visit (before diagnostic NAATs

for chlamydia are available), persons with a clinical syndrome

consistent with LGV should be presumptively treated.

Presumptive treatment for LGV is indicated among patients

with symptoms or signs of proctocolitis (e.g., bloody

discharge, tenesmus, or ulceration); in cases of severe inguinal

lymphadenopathy with bubo formation, particularly if the

patient has a recent history of a genital ulcer; or in the presence

of a genital ulcer if other etiologies have been ruled out. The

goal of treatment is to cure infection and prevent ongoing tissue

damage, although tissue reaction to the infection can result in

scarring. Buboes might require aspiration through intact skin

or incision and drainage to prevent formation of inguinal or

femoral ulcerations.

Recommended Regimen for Lymphogranuloma Venereum

Doxycycline 100 mg orally 2 times/day for 21 days

Alternative Regimens

Azithromycin 1 g orally once weekly for 3 weeks*

Erythromycin base 500 mg orally 4 times/day for 21 days

* Because this regimen has not been validated, a test of cure with C. trachomatis

NAAT 4 weeks after completion of treatment can be considered.

The optimal treatment duration for symptomatic LGV has

not been studied in clinical trials. The recommended 21-day

course of doxycycline is based on long-standing clinical practice

and is highly effective, with an estimated cure rate of >98.5%

(555,556). Shorter courses of doxycycline might be effective

on the basis of a small retrospective study of MSM with rectal

LGV, 50% of whom were symptomatic, who received a 7- to

14-day course of doxycycline and had a 97% cure rate (558).

Randomized prospective studies of shorter-course doxycycline

for treating LGV are needed. Longer courses of therapy might

be required in the setting of fistulas, buboes, and other forms

of severe disease (559).

A small nonrandomized study from Spain involving patients

with rectal LGV demonstrated cure rates of 97% with a

regimen of azithromycin 1 g once weekly for 3 weeks (560).

Pharmacokinetic data support this dosing strategy (561);

however, this regimen has not been validated. Fluoroquinolone-

based treatments also might be effective; however, the optimal

duration of treatment has not been evaluated. The clinical

significance of asymptomatic LGV is unknown, and it is

effectively treated with a 7-day course of doxycycline (562).

Other Management Considerations

Patients should be followed clinically until signs and

symptoms have resolved. Persons who receive an LGV diagnosis

should be tested for other STIs, especially HIV, gonorrhea, and

syphilis. Those whose HIV test results are negative should be

offered HIV PrEP.

Follow-Up

All persons who have been treated for LGV should be retested

for chlamydia approximately 3 months after treatment. If

retesting at 3 months is not possible, providers should retest

at the patient’s next visit for medical care within the 12-month

period after initial treatment.

Management of Sex Partners

Persons who have had sexual contact with a patient who

has LGV within the 60 days before onset of the patient’s

symptoms should be evaluated, examined, and tested for

chlamydial infection, depending on anatomic site of exposure.

Asymptomatic partners should be presumptively treated with

a chlamydia regimen (doxycycline 100 mg orally 2 times/day

for 7 days).

Special Considerations

Pregnancy

Use of doxycycline in pregnancy might be associated with

discoloration of teeth; however, the risk is not well defined

(563). Doxycycline is compatible with breastfeeding (431).

Azithromycin might prove useful for LGV treatment during

pregnancy, at a presumptive dose of 1 g weekly for 3 weeks;

no published data are available regarding an effective dose and

duration of treatment. Pregnant and lactating women with

LGV can be treated with erythromycin, although this regimen

is associated with frequent gastrointestinal side effects. Pregnant

women treated for LGV should have a test of cure performed

4 weeks after the initial C. trachomatis NAAT-positive test.

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HIV Infection

Persons with LGV and HIV infection should receive the

same regimens as those who do not have HIV. Prolonged

therapy might be required because a delay in resolution of

symptoms might occur.

Syphilis

Syphilis is a systemic disease caused by T. pallidum. The

disease has been divided into stages on the basis of clinical

findings, which guide treatment and follow-up. Persons who

have syphilis might seek treatment for signs or symptoms.

Primary syphilis classically presents as a single painless ulcer

or chancre at the site of infection but can also present with

multiple, atypical, or painful lesions (564). Secondary syphilis

manifestations can include skin rash, mucocutaneous lesions,

and lymphadenopathy. Tertiary syphilis can present with

cardiac involvement, gummatous lesions, tabes dorsalis, and

general paresis.

Latent infections (i.e., those lacking clinical manifestations)

are detected by serologic testing. Latent syphilis acquired

within the preceding year is referred to as early latent syphilis;

all other cases of latent syphilis are classified as late latent

syphilis or latent syphilis of unknown duration.

T. pallidum can infect the CNS, which can occur at any stage

of syphilis and result in neurosyphilis. Early neurologic clinical

manifestations or syphilitic meningitis (e.g., cranial nerve

dysfunction, meningitis, meningovascular syphilis, stroke,

and acute altered mental status) are usually present within

the first few months or years of infection. Late neurologic

manifestations (e.g., tabes dorsalis and general paresis) occur

10 to >30 years after infection.

Infection of the visual system (ocular syphilis) or auditory

system (otosyphilis) can occur at any stage of syphilis but is

commonly identified during the early stages and can present

with or without additional CNS involvement. Ocular syphilis

often presents as panuveitis but can involve structures in

both the anterior and posterior segment of the eye, including

conjunctivitis, anterior uveitis, posterior interstitial keratitis,

optic neuropathy, and retinal vasculitis. Ocular syphilis can

result in permanent vision loss. Otosyphilis typically presents

with cochleo-vestibular symptoms, including tinnitus, vertigo,

and sensorineural hearing loss. Hearing loss can be unilateral or

bilateral, have a sudden onset, and progress rapidly. Otosyphilis

can result in permanent hearing loss.

Diagnostic Considerations

Darkfield examinations and molecular tests for detecting

T. pallidum directly from lesion exudate or tissue are

the definitive methods for diagnosing early syphilis and

congenital syphilis (565). Although no T. pallidum direct-

detection molecular NAATs are commercially available,

certain laboratories provide locally developed and validated

PCR tests for detecting T. pallidum DNA. A presumptive

diagnosis of syphilis requires use of two laboratory serologic

tests: a nontreponemal test (i.e., Venereal Disease Research

Laboratory [VDRL] or rapid plasma reagin [RPR] test)

and a treponemal test (i.e., the T. pallidum passive particle

agglutination [TP-PA] assay, various EIAs, chemiluminescence

immunoassays [CIAs] and immunoblots, or rapid treponemal

assays) (566–568). At least 18 treponemal-specific tests are

cleared for use in the United States. Use of only one type of

serologic test (nontreponemal or treponemal) is insufficient

for diagnosis and can result in false-negative results among

persons tested during primary syphilis and false-positive results

among persons without syphilis or previously treated syphilis.

Nontreponemal Tests and Traditional Algorithm

False-positive nontreponemal test results can be associated

with multiple medical conditions and factors unrelated to

syphilis, including other infections (e.g., HIV), autoimmune

conditions, vaccinations, injecting drug use, pregnancy,

and older age (566,569). Therefore, persons with a reactive

nontreponemal test should always receive a treponemal test

to confirm the syphilis diagnosis (i.e., traditional algorithm).

Nontreponemal test antibody titers might correlate with disease

activity and are used for monitoring treatment response. Serum

should be diluted to identify the highest titer, and results should

be reported quantitatively. A fourfold change in titer, equivalent

to a change of two dilutions (e.g., from 1:16 to 1:4 or from 1:8

to 1:32), is considered necessary for demonstrating a clinically

significant difference between two nontreponemal test results

obtained by using the same serologic test, preferably from the

same manufacturer to avoid variation in results. Sequential

serologic tests for a patient should be performed using the

same testing method (VDRL or RPR), preferably by the same

laboratory. VDRL and RPR are equally valid assays; however,

quantitative results from the two tests cannot be compared

directly with each other because the methods are different,

and RPR titers frequently are slightly higher than VDRL titers.

Nontreponemal test titers usually decrease after treatment

and might become nonreactive with time. However, for certain

persons, nontreponemal antibodies might decrease less than

fourfold after treatment (i.e., inadequate serologic response)

or might decline appropriately but fail to serorevert and

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persist for a long period. Atypical nontreponemal serologic

test results (e.g., unusually high, unusually low, or fluctuating

titers) might occur regardless of HIV status. When serologic

tests do not correspond with clinical findings indicative of

primary, secondary, or latent syphilis, presumptive treatment is

recommended for persons with risk factors for syphilis, and use

of other tests (e.g., biopsy for histology and immunostaining

and PCR of lesion) should be considered. For the majority

of persons with HIV infection, serologic tests are accurate

and reliable for diagnosing syphilis and evaluating response

to treatment.

Treponemal Tests and Reverse

Sequence Algorithm

The majority of patients who have reactive treponemal tests

will have reactive tests for the remainder of their lives, regardless

of adequate treatment or disease activity. However, 15%–25%

of patients treated during the primary stage revert to being

serologically nonreactive after 2–3 years (570). Treponemal

antibody titers do not predict treatment response and therefore

should not be used for this purpose.

Clinical laboratories sometimes screen syphilis serologic

samples by using automated treponemal immunoassays,

typically by EIA or CIA (571–573). This reverse sequence

algorithm for syphilis testing can identify persons previously

treated for syphilis, those with untreated or incompletely

treated syphilis, and those with false-positive results that can

occur with a low likelihood of infection (574). Persons with

a positive treponemal screening test should have a standard

quantitative nontreponemal test with titer performed

reflexively by the laboratory to guide patient management

decisions. If the nontreponemal test is negative, the laboratory

should perform a treponemal test different from the one used

for initial testing, preferably TP-PA or treponemal assay based

on different antigens than the original test, to adjudicate the

results of the initial test.

If a second treponemal test is positive (e.g., EIA reactive,

RPR nonreactive, or TP-PA reactive), persons with a history

of previous treatment will require no further management

unless sexual history indicates a reexposure. In this instance, a

repeat nontreponemal test 2–4 weeks after a confirmed medical

history and physical examination is recommended to evaluate

for early infection. Those without a history of treatment for

syphilis should be offered treatment. Unless a medical history

or results of a physical examination indicate a recent infection,

previously untreated persons should be treated for syphilis of

unknown duration or late latent syphilis.

If the second treponemal test is negative (e.g., EIA reactive,

RPR nonreactive, TP-PA nonreactive) and the epidemiologic

risk and clinical probability for syphilis are low, further

evaluation or treatment is not indicated.

Multiple studies demonstrate that high quantitative index

values or high signal-to-cutoff ratio from treponemal EIA

or CIA tests correlate with TP-PA positivity, which might

eliminate the need for additional confirmatory testing;

however, the range of index values varies among different

treponemal immunoassays, and the values that correspond to

high levels of reactivity with confirmatory testing might differ

by immunoassay (567,575–582).

Cerebrospinal Fluid Evaluation

Further testing with CSF evaluation is warranted for

persons with clinical signs of neurosyphilis (e.g., cranial nerve

dysfunction, meningitis, stroke, acute or chronic altered mental

status, or loss of vibration sense). All patients with ocular

symptoms and reactive syphilis serology need a full ocular

examination, including cranial nerve evaluation. If cranial nerve

dysfunction is present, a CSF evaluation is needed. Among

persons with isolated ocular symptoms (i.e., no cranial nerve

dysfunction or other neurologic abnormalities), confirmed

ocular abnormalities on examination, and reactive syphilis

serology, a CSF examination is unnecessary before treatment.

CSF analysis can be helpful in evaluating persons with ocular

symptoms and reactive syphilis serology who do not have ocular

findings or cranial nerve dysfunction on examination. Among

patients with isolated auditory abnormalities and reactive

syphilis serology, CSF evaluation is likely to be normal and is

unnecessary before treatment (583,584).

Laboratory testing is helpful in supporting the diagnosis of

neurosyphilis; however, no single test can be used to diagnose

neurosyphilis in all instances. Diagnosis of neurosyphilis

depends on a combination of CSF tests (e.g., CSF cell count,

protein, or reactive CSF-VDRL) in the presence of reactive

serologic test (nontreponemal and treponemal) results and

neurologic signs and symptoms. CSF laboratory abnormalities

are common for persons with early syphilis and are of

unknown medical significance in the absence of neurologic

signs or symptoms (585). CSF-VDRL is highly specific but

insensitive. For a person with neurologic signs or symptoms, a

reactive CSF-VDRL (in the absence of blood contamination)

is considered diagnostic of neurosyphilis.

When CSF-VDRL is negative despite clinical signs of

neurosyphilis, reactive serologic tests results, lymphocytic

pleocytosis, or protein, neurosyphilis should be considered.

In that instance, additional evaluation by using fluorescent

treponemal-antibody absorption (FTA-ABS) or TP-PA testing

on CSF might be warranted. The CSF FTA-ABS test is less

specific for neurosyphilis than the CSF-VDRL but is highly

sensitive. Fewer data are available regarding CSF TP-PA;

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however, the sensitivity and specificity appear similar to the

CSF FTA-ABS (586). Neurosyphilis is highly unlikely with

a negative CSF FTA-ABS or TP-PA test, especially among

persons with nonspecific neurologic signs and symptoms (587).

Among persons with HIV infection, CSF leukocyte count

can be elevated (>5 WBCs/mm

); the association with CSF

leukocyte count and plasma HIV viral suppression has not been

well characterized. Using a higher cutoff (>20 WBCs/mm

)

might improve the specificity of neurosyphilis diagnosis among

this population (588).

Treatment

Penicillin G, administered parenterally, is the preferred drug

for treating patients in all stages of syphilis. The preparation

used (i.e., benzathine, aqueous procaine, or aqueous

crystalline), dosage, and length of treatment depend on the

stage and clinical manifestations of the disease. Treatment for

late latent syphilis (>1 years’ duration) and tertiary syphilis

requires a longer duration of therapy because organisms

theoretically might be dividing more slowly (the validity of this

rationale has not been assessed). Longer treatment duration is

required for persons with latent syphilis of unknown duration

to ensure that those who did not acquire syphilis within the

preceding year are adequately treated.

Selection of the appropriate penicillin preparation is

important because T. pallidum can reside in sequestered sites

(e.g., the CNS and aqueous humor) that are poorly accessed

by certain forms of penicillin. Combinations of benzathine

penicillin, procaine penicillin, and oral penicillin preparations

are not considered appropriate for syphilis treatment. Reports

have indicated that practitioners have inadvertently prescribed

combination long- and short-acting benzathine-procaine

penicillin (Bicillin C-R) instead of the standard benzathine

penicillin product (Bicillin L-A) recommended in the United

States for treating primary, secondary, and latent syphilis.

Practitioners, pharmacists, and purchasing agents should be

aware of the similar names of these two products to avoid

using the incorrect combination therapy agent for treating

syphilis (589).

Penicillin’s effectiveness for treating syphilis was well

established through clinical experience even before the value of

randomized controlled clinical trials was recognized. Therefore,

approximately all recommendations for treating syphilis are

based not only on clinical trials and observational studies, but

on many decades of clinical experience.

Special Considerations

Pregnancy

Parenteral penicillin G is the only therapy with documented

efficacy for syphilis during pregnancy. Pregnant women with

syphilis at any stage who report penicillin allergy should be

desensitized and treated with penicillin (see Management of

Persons Who Have a History of Penicillin Allergy).

Jarisch-Herxheimer Reaction

The Jarisch-Herxheimer reaction is an acute febrile reaction

frequently accompanied by headache, myalgia, and fever that

can occur within the first 24 hours after the initiation of any

syphilis therapy; it is a reaction to treatment and not an allergic

reaction to penicillin. Patients should be informed about this

possible adverse reaction and how to manage it if it occurs. The

Jarisch-Herxheimer reaction occurs most frequently among

persons who have early syphilis, presumably because bacterial

loads are higher during these stages. Antipyretics can be used

to manage symptoms; however, they have not been proven to

prevent this reaction. The Jarisch-Herxheimer reaction might

induce early labor or cause fetal distress in pregnant women;

however, this should not prevent or delay therapy (590) (see

Syphilis During Pregnancy).

Management of Sex Partners

Sexual transmission of T. pallidum is thought to occur only

when mucocutaneous syphilitic lesions are present. Such

manifestations are uncommon after the first year of infection.

Persons exposed through sexual contact with a person who

has primary, secondary, or early latent syphilis should be

evaluated clinically and serologically and treated according to

the following recommendations:

• Persons who have had sexual contact with a person who

receives a diagnosis of primary, secondary, or early latent

syphilis <90 days before the diagnosis should be treated

presumptively for early syphilis, even if serologic test results

are negative.

• Persons who have had sexual contact with a person who

receives a diagnosis of primary, secondary, or early latent

syphilis >90 days before the diagnosis should be treated

presumptively for early syphilis if serologic test results are

not immediately available and the opportunity for

follow-up is uncertain. If serologic tests are negative, no

treatment is needed. If serologic tests are positive,

treatment should be based on clinical and serologic

evaluation and syphilis stage.

• In certain areas or among populations with high syphilis

infection rates, health departments recommend notification

and presumptive treatment of sex partners of persons with

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syphilis of unknown duration who have high nontreponemal

serologic test titers (i.e., >1:32) because high titers might

be indicative of early syphilis. These partners should be

managed as if the index patient had early syphilis.

• Long-term sex partners of persons who have late latent

syphilis should be evaluated clinically and serologically for

syphilis and treated on the basis of the evaluation’s findings.

• The following sex partners of persons with syphilis are

considered at risk for infection and should be confidentially

notified of the exposure and need for evaluation: partners

who have had sexual contact within 3 months plus the

duration of symptoms for persons who receive a diagnosis

of primary syphilis, within 6 months plus duration of

symptoms for those with secondary syphilis, and within

1 year for persons with early latent syphilis.

Primary and Secondary Syphilis

Treatment

Parenteral penicillin G has been used effectively for achieving

clinical resolution (i.e., the healing of lesions and prevention of

sexual transmission) and for preventing late sequelae. However,

no comparative trials have been conducted to guide selection

of an optimal penicillin regimen. Substantially fewer data are

available for nonpenicillin regimens.

Recommended Regimen for Primary and Secondary Syphilis*

Among Adults

Benzathine penicillin G 2.4 million units IM in a single dose

* Recommendations for treating syphilis among persons with HIV infection

and pregnant women are discussed elsewhere in this report (see Syphilis

Among Persons with HIV Infection; Syphilis During Pregnancy).

Available data demonstrate that use of additional doses of

benzathine penicillin G, amoxicillin, or other antibiotics do

not enhance efficacy of this recommended regimen when used

to treat primary and secondary syphilis, regardless of HIV

status (591–593).

Recommended Regimen for Syphilis Among Infants and

Children

Benzathine penicillin G 50,000 units/kg body weight IM, up to the adult

dose of 2.4 million units in a single dose

Infants and children aged ≥1 month who receive a syphilis

diagnosis should have birth and maternal medical records

reviewed to assess whether they have congenital or acquired

syphilis (see Congenital Syphilis). Infants and children aged

≥1 month with primary and secondary syphilis should be

managed by a pediatric infectious disease specialist and

evaluated for sexual abuse (e.g., through consultation with child

protective services) (see Sexual Assault or Abuse of Children).

Other Management Considerations

All persons who have primary and secondary syphilis should

be tested for HIV at the time of diagnosis and treatment. Those

persons whose HIV test results are negative should be offered

HIV PrEP. In geographic areas in which HIV prevalence is

high, persons who have primary or secondary syphilis should

be offered PrEP and retested for HIV in 3 months if the initial

HIV test result was negative.

Persons who have syphilis and symptoms or signs indicating

neurologic disease (e.g., cranial nerve dysfunction, meningitis,

stroke, or altered mental state) should have an evaluation

that includes CSF analysis. Persons with syphilis who have

symptoms or signs of ocular syphilis (e.g., uveitis, iritis,

neuroretinitis, or optic neuritis) should have a thorough cranial

nerve examination and ocular slit-lamp and ophthalmologic

examinations. CSF evaluation is not always needed for persons

with ocular syphilis if no evidence of cranial nerves 2, 3, 4,

5, and 6 dysfunction or other evidence of neurologic disease

exists. If symptoms and signs of otic syphilis are present then

an otologic examination is needed; CSF evaluation in persons

with otic syphilis does not aid in the clinical management

and therefore is not recommended (see Cerebrospinal Fluid

Evaluation). Treatment should be guided by the results of these

evaluations. Invasion of CSF by T. pallidum accompanied

by CSF laboratory abnormalities is common among adults

who have primary or secondary syphilis but has unknown

medical significance (585). In the absence of clinical

neurologic findings, no evidence supports variation from the

recommended treatment regimen for primary or secondary

syphilis. Symptomatic neurosyphilis after treatment with the

penicillin regimens recommended for primary and secondary

syphilis is rare. Therefore, unless clinical signs or symptoms of

neurologic or ophthalmic involvement are present, routine CSF

analysis is not recommended for persons who have primary or

secondary syphilis.

Follow-Up

Clinical and serologic evaluation should be performed at

6 and 12 months after treatment; more frequent evaluation

might be prudent if opportunity for follow-up is uncertain

or if repeat infection is a clinical concern. Serologic response

(i.e., titer) should be compared with the titer at the time of

treatment. However, assessing serologic response to treatment

can be difficult, and definitive criteria for cure or failure by

serologic criteria have not been well established. In addition,

nontreponemal test titers might decrease more slowly for

persons previously treated for syphilis (594,595).

Persons who have signs or symptoms that persist or recur

and those with at least a fourfold increase in nontreponemal

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test titer persisting for >2 weeks likely were reinfected or

experienced treatment failure. Among persons who have

neurologic findings or persons with no neurologic findings

without any reported sexual exposure during the previous

3–6 months indicating that treatment failure might be possible,

a CSF examination is recommended with treatment guided

by CSF findings. These persons should also be reevaluated for

HIV infection.

Among persons with no neurologic findings after a thorough

neurologic examination and who are sexually active, reinfection

is likely and repeat treatment for early syphilis is recommended.

These persons should also be reevaluated for HIV infection.

Failure of nontreponemal test titers to decrease fourfold

within 12 months after therapy for primary or secondary

syphilis (inadequate serologic response) might be indicative

of treatment failure. However, clinical trial data have

demonstrated that 10%–20% of persons with primary and

secondary syphilis treated with the recommended therapy

will not achieve the fourfold decrease in nontreponemal titer

within 12 months after treatment (591,596,597). Serologic

response to treatment appears to be associated with multiple

factors, including the person’s syphilis stage (earlier stages are

more likely to decrease fourfold and become nonreactive),

initial nontreponemal antibody titers (titers <1:8 are less likely

to decline fourfold than higher titers), and age (titers among

older patients might be less likely to decrease fourfold than

those of younger patients) (596–598). Optimal management

of persons who have an inadequate serologic response after

syphilis treatment is unclear. At a minimum, these persons

should receive additional neurologic examinations, clinical

and serologic follow-up annually, and reevaluation for HIV

infection. If neurologic symptoms or signs are identified,

a CSF evaluation is recommended, with findings guiding

management. If additional follow-up cannot be ensured,

retreatment is recommended. Because treatment failure might

be the result of unrecognized CNS infection, CSF examination

can be considered in situations in which follow-up is uncertain.

For retreatment, weekly injections of benzathine penicillin

G 2.4 million units intramuscularly (IM) for 3 weeks is

recommended, unless CSF examination indicates that

neurosyphilis is present (see Neurosyphilis, Ocular Syphilis,

and Otosyphilis). Serologic titers might not decrease, despite

a negative CSF examination and a repeated 3-week therapy

course (599). In these circumstances, the benefit of additional

therapy or repeated CSF examinations is unclear, and it is not

typically recommended. Serologic and clinical monitoring at

least annually should continue to monitor for any sustained

increases in nontreponemal titer.

Management of Sex Partners

See Syphilis, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Data to support use of alternatives to penicillin in treating

primary and secondary syphilis are limited. However, multiple

therapies might be effective for nonpregnant persons with

penicillin allergy who have primary or secondary syphilis.

Doxycycline (100 mg orally 2 times/day for 14 days) (600,601)

and tetracycline (500 mg orally 4 times/day for 14 days) have

been used for years and can be effective. Compliance is likely to

be better with doxycycline than tetracycline because tetracycline

can cause more gastrointestinal side effects and requires more

frequent dosing. Limited clinical studies, along with biologic

and pharmacologic evidence, indicate that ceftriaxone (1 g daily

either IM or IV for 10 days) is effective for treating primary

and secondary syphilis; however, the optimal dose and duration

of ceftriaxone therapy have not been defined (602,603).

Azithromycin as a single 2-g oral dose has been effective

for treating primary and secondary syphilis among certain

populations (602,604,605). However, because of T. pallidum

chromosomal mutations associated with azithromycin and

other macrolide resistance and documented treatment failures

in multiple U.S. geographic areas, azithromycin should not be

used as treatment for syphilis (606–608). Thorough clinical

and serologic follow-up of persons receiving any alternative

therapy is essential.

Persons with a penicillin allergy whose compliance with

therapy or follow-up cannot be ensured should be desensitized

and treated with benzathine penicillin G. Skin testing for

penicillin allergy might be useful in circumstances in which

the reagents and expertise are available for performing the test

adequately (see Management of Persons Who Have a History

of Penicillin Allergy).

Pregnancy

Pregnant women with primary or secondary syphilis who

are allergic to penicillin should be desensitized and treated

with penicillin G. Skin testing or oral graded penicillin dose

challenge might be helpful in identifying women at risk for

acute allergic reactions (see Management of Persons Who Have

a History of Penicillin Allergy; Syphilis During Pregnancy).

HIV Infection

Persons with HIV infection who have primary or secondary

syphilis should be treated similarly to those without HIV (see

Syphilis Among Persons with HIV Infection).

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Latent Syphilis

Latent syphilis is defined as syphilis characterized by

seroreactivity without other evidence of primary, secondary,

or tertiary disease. Persons who have latent syphilis and who

acquired syphilis during the preceding year are classified as

having early latent syphilis (early nonprimary, nonsecondary).

Persons can receive a diagnosis of early latent syphilis if, during

the year preceding the diagnosis, they had a documented

seroconversion or a sustained (>2 weeks) fourfold or greater

increase in nontreponemal test titers in a previously treated

person; unequivocal symptoms of primary or secondary

syphilis; or a sex partner documented to have primary,

secondary, or early latent syphilis. In addition, for persons

with reactive nontreponemal and treponemal tests whose only

possible exposure occurred during the previous 12 months,

early latent syphilis can be assumed.

In the absence of these conditions associated with latent

syphilis, an asymptomatic person should be considered to

have latent syphilis of unknown duration or late latent syphilis

(>1 year’s duration). Nontreponemal serologic titers usually are

higher early in the course of syphilis infection. However, early

latent syphilis cannot be reliably diagnosed solely on the basis

of nontreponemal titers. All persons with latent syphilis should

have careful examination of all accessible mucosal surfaces to

evaluate for mucosal lesions (primary or secondary syphilis)

before making a latent syphilis diagnosis. Physical examination

should include the oral cavity, perianal area, perineum, rectum,

and genitals (vagina and cervix for women; scrotum, penis, and

underneath the foreskin for uncircumcised men).

Treatment

Because latent syphilis is not transmitted sexually, the

objective of treating persons in this disease stage is to prevent

medical complications of syphilis. Latent syphilis can also be

vertically transmitted to a fetus; therefore, the goal of treating

a pregnant woman is to prevent congenital syphilis. Although

clinical experience supports the effectiveness of penicillin in

achieving this goal, limited evidence is available for guiding

choice of specific regimens or duration. Available data

demonstrate that additional doses of benzathine penicillin G,

amoxicillin, or other antibiotics in early latent syphilis do not

enhance efficacy, regardless of HIV status (592,593,609).

Recommended Regimens for Latent Syphilis* Among Adults

Early latent syphilis: Benzathine penicillin G 2.4 million units IM in a

single dose

Late latent syphilis: Benzathine penicillin G 7.2 million units total,

administered as 3 doses of 2.4 million units IM each at 1-week intervals

* Recommendations for treating syphilis in persons with HIV and pregnant

women are discussed elsewhere in this report (see Syphilis Among

Persons with HIV Infection; Syphilis During Pregnancy).

Infants and children aged ≥1 month with diagnosed latent

syphilis should be managed by a pediatric infectious disease

specialist and receive a CSF examination. In addition, birth

and maternal medical records should be reviewed to assess

whether these infants and children have congenital or acquired

syphilis. For those with congenital syphilis, treatment should

be undertaken as described (see Congenital Syphilis). Those

with acquired syphilis should be evaluated for sexual abuse

(e.g., through consultation with child protection services) (see

Sexual Assault or Abuse of Children). These regimens are for

children who are not allergic to penicillin who have acquired

syphilis and who have normal CSF examinations.

Other Management Considerations

All persons who have latent syphilis should be tested for HIV

at the time of diagnosis or treatment. Those persons whose

HIV test results are negative should be offered HIV PrEP. In

geographic areas in which the prevalence of HIV infection is

high or among populations vulnerable to HIV acquisition,

persons who have early latent or late latent syphilis should be

offered PrEP and retested for HIV in 3 months if the first HIV

test result was negative.

Persons who receive a diagnosis of latent syphilis and have

neurologic or ocular signs and symptoms (e.g., cognitive

dysfunction, motor or sensory deficits, ophthalmic or auditory

symptoms, cranial nerve palsies, or symptoms or signs of

meningitis or stroke) should be evaluated for neurosyphilis, ocular

syphilis, or otosyphilis according to their clinical presentation

(see Neurosyphilis, Ocular Syphilis, and Otosyphilis).

If a person receives a delayed dose of penicillin in a course of

weekly therapy for late latent syphilis or syphilis of unknown

duration, the course of action that should be recommended

is unclear. Clinical experience indicates that an interval of

10–14 days between doses of benzathine penicillin for latent

syphilis might be acceptable before restarting the sequence of

injections (i.e., if dose 1 is administered on day 0, dose 2 is

administered on days 10–14). Pharmacologic considerations

indicate that an interval of 7–9 days between doses, if feasible,

might be preferred (610–612). Delayed doses are not optimal

for pregnant women receiving therapy for latent syphilis (613).

Pregnant women who have delays in any therapy dose >9 days

between doses should repeat the full course of therapy.

Follow-Up

Quantitative nontreponemal serologic tests should be

repeated at 6, 12, and 24 months. These serologic titers should

be compared with the titer at the time of treatment. Persons

with at least a fourfold sustained increase in nontreponemal

test titer persisting for >2 weeks or who experienced signs

or symptoms attributable to primary or secondary syphilis

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were likely reinfected or experienced treatment failure. These

persons should be retreated and reevaluated for HIV infection.

Among persons who have neurologic findings after a thorough

neurologic examination or among persons with no neurologic

findings and no sexual exposure during the previous year, a CSF

examination is recommended. Treatment should be guided by

CSF findings. Among persons with no neurologic findings after

neurologic examination and who are sexually active, treatment

with weekly injections of benzathine penicillin G 2.4 million

units IM for 3 weeks is recommended.

Optimal management of persons who have less than a

fourfold decrease in titers 24 months after treatment (i.e., an

inadequate serologic response) is unclear, especially if the initial

titer was <1:8. At a minimum, these persons should receive

additional clinical and serologic follow-up and be evaluated for

HIV infection. If neurologic symptoms or signs are identified,

a CSF evaluation is recommended, with the findings guiding

management. If additional follow-up cannot be ensured or if

an initially high titer (>1:32) does not decrease at least fourfold

24 months after treatment, retreatment with weekly injections

of benzathine penicillin G 2.4 million units IM for 3 weeks is

recommended. Because treatment failure might be the result

of unrecognized CNS infection, CSF examination can be

considered in such situations where follow-up is uncertain or

initial high titers do not decrease after 24 months.

If the CSF examination is negative, repeat treatment for

latent syphilis is recommended. Serologic titers might not

decrease despite a negative CSF examination and a repeated

course of therapy, especially if the initial nontreponemal titer

is low (<1:8); in these circumstances, the need for additional

therapy or repeated CSF examinations is unclear but is usually

not recommended. Serologic and clinical monitoring at

least annually should continue to monitor for any sustained

increases in nontreponemal titer.

Management of Sex Partners

See Syphilis, Management of Sex Partners.

Special Considerations

Penicillin Allergy

The effectiveness of alternatives to penicillin in treating

latent syphilis has not been well documented. Nonpregnant

patients allergic to penicillin who have clearly defined early

latent syphilis should respond to antibiotics recommended as

alternatives to penicillin for treating primary and secondary

syphilis (see Primary and Secondary Syphilis). The only

acceptable alternatives for treating late latent syphilis or

syphilis of unknown duration are doxycycline (100 mg orally

2 times/day) or tetracycline (500 mg orally 4 times/day),

each for 28 days. The efficacy of these alternative regimens

among persons with HIV infection has not been well studied.

These therapies should be used only in conjunction with close

serologic and clinical follow-up, especially among persons

with HIV infection. On the basis of biologic plausibility and

pharmacologic properties, ceftriaxone might be effective for

treating latent syphilis. However, the optimal dose and duration

of ceftriaxone therapy have not been defined; treatment

decisions should be discussed in consultation with a specialist.

Persons with a penicillin allergy whose compliance with

therapy or follow-up cannot be ensured should be desensitized

and treated with benzathine penicillin G. Skin testing for

penicillin allergy might be useful in circumstances in which

the reagents and expertise are available for performing the test

adequately (see Management of Persons Who Have a History

of Penicillin Allergy).

Pregnancy

Pregnant women who are allergic to penicillin should be

desensitized and treated with penicillin G. Skin testing for

penicillin allergy might be useful in circumstances in which

the reagents and expertise are available for performing the test

adequately (see Management of Persons Who Have a History

of Penicillin Allergy; Syphilis During Pregnancy).

HIV Infection

Persons with HIV infection who have latent syphilis should

be treated similarly to persons who do not have HIV (see

Syphilis Among Persons with HIV Infection).

Tertiary Syphilis

Tertiary syphilis refers to gummas, cardiovascular syphilis,

psychiatric manifestations (e.g., memory loss or personality

changes), or late neurosyphilis. Guidelines for all forms of

neurosyphilis (e.g., early or late neurosyphilis) are discussed

elsewhere in these recommendations (see Neurosyphilis,

Ocular Syphilis, and Otosyphilis). Persons with gummas

and cardiovascular syphilis who are not allergic to penicillin

and have no evidence of neurosyphilis by clinical and CSF

examination should be treated with the following regimen.

Recommended Regimen for Tertiary Syphilis Among Adults

Tertiary syphilis with normal CSF examination: Benzathine penicillin

G 7.2 million units total, administered as 3 doses of 2.4 million units IM

each at 1-week intervals

Other Management Considerations

All persons who have tertiary syphilis should receive a CSF

examination before therapy is initiated and have an HIV test.

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Those persons whose HIV test results are negative should be

offered HIV PrEP. Persons with CSF abnormalities should be

treated with a neurosyphilis regimen. Certain providers treat all

persons who have cardiovascular syphilis with a neurosyphilis

regimen. These persons should be managed in consultation

with an infectious disease specialist. Limited information is

available concerning clinical response and follow-up of persons

who have tertiary syphilis.

Management of Sex Partners

See Syphilis, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Any person allergic to penicillin should be treated in

consultation with an infectious disease specialist.

Pregnancy

Pregnant women who are allergic to penicillin should be

desensitized and treated with penicillin G. Skin testing or oral

graded penicillin dose challenge might be helpful in identifying

women at risk for acute allergic reactions (see Management

of Persons Who Have a History of Penicillin Allergy; Syphilis

During Pregnancy).

HIV Infection

Persons with HIV infection who have tertiary syphilis should

be treated as described for persons without HIV (see Syphilis

Among Persons with HIV Infection).

Neurosyphilis, Ocular Syphilis, and

Otosyphilis

Treatment

CNS involvement can occur during any stage of syphilis,

and CSF laboratory abnormalities are common among

persons with early syphilis, even in the absence of clinical

neurologic findings. No evidence exists to support variation

from recommended diagnosis and treatment for syphilis at

any stage for persons without clinical neurologic findings,

except tertiary syphilis. If clinical evidence of neurologic

involvement is observed (e.g., cognitive dysfunction, motor or

sensory deficits, cranial nerve palsies, or symptoms or signs of

meningitis or stroke), a CSF examination should be performed

before treatment.

Syphilitic uveitis or other ocular syphilis manifestations

(e.g., neuroretinitis and optic neuritis) can occur at any stage

of syphilis and can be isolated abnormalities or associated with

neurosyphilis. All persons with ocular symptoms and reactive

syphilis serology need a full ocular examination, including

cranial nerve evaluation. If cranial nerve dysfunction is present,

a CSF evaluation is needed. Among persons with isolated ocular

symptoms (no cranial nerve dysfunction or other neurologic

abnormalities), reactive syphilis serology, and confirmed ocular

abnormalities on examination, CSF examination is unnecessary

before treatment. CSF analysis might be helpful in evaluating

persons with ocular symptoms and reactive syphilis serology

who do not have ocular findings on examination. If ocular

syphilis is suspected, immediate referral to and management

in collaboration with an ophthalmologist is crucial. Ocular

syphilis should be treated similarly to neurosyphilis, even if a

CSF examination is normal.

Hearing loss and other otologic symptoms can occur at any

stage of syphilis and can be isolated abnormalities or associated

with neurosyphilis, especially of cranial nerve 8. However,

among persons with isolated auditory symptoms, normal

neurologic examination, and reactive syphilis serology, CSF

examination is likely to be normal and is not recommended

before treatment. Otosyphilis should be managed in

collaboration with an otolaryngologist and treated by using

the same regimen as for neurosyphilis.

Recommended Regimen for Neurosyphilis, Ocular Syphilis, or

Otosyphilis Among Adults

Aqueous crystalline penicillin G 18–24 million units per day,

administered as 3–4 million units IV every 4 hours or continuous

infusion for 10–14 days

If compliance with therapy can be ensured, the following

alternative regimen might be considered.

Alternative Regimen

Procaine penicillin G 2.4 million units IM once daily

plus

Probenecid 500 mg orally 4 times/day, both for 10–14 days

The durations of the recommended and alternative regimens

for neurosyphilis are shorter than the duration of the regimen

used for latent syphilis. Therefore, benzathine penicillin,

2.4 million units IM once per week for 1–3 weeks, can be

considered after completion of these neurosyphilis treatment

regimens to provide a comparable total duration of therapy.

Other Management Considerations

The following are other considerations in the management

of persons who have neurosyphilis:

• All persons who have neurosyphilis, ocular syphilis, or

otosyphilis should be tested for HIV at the time of

diagnosis. Those whose HIV test results are negative

should be offered HIV PrEP.

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• Although systemic steroids are used frequently as

adjunctive therapy for otosyphilis and for ocular syphilis,

such drugs have not been proven to be beneficial.

Follow-Up

Data from two studies indicate that, among immunocompetent

persons and persons with HIV infection who are on effective

ART, normalization of the serum RPR titer predicts

normalization of abnormal CSF parameters after neurosyphilis

treatment (614,615). Therefore, repeated CSF examinations

are unnecessary for persons without HIV infection or persons

with HIV infection who are on ART and who exhibit serologic

and clinical responses after treatment.

Management of Sex Partners

See Syphilis, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Limited data indicate that ceftriaxone 1–2 g daily either IM

or IV for 10–14 days can be used as an alternative treatment

for persons with neurosyphilis (603,616,617). Cross-sensitivity

between ceftriaxone and penicillin can occur; however, the

risk for penicillin cross-reactivity between third-generation

cephalosporins is negligible (618–621) (see Management of

Persons Who Have a History of Penicillin Allergy). If concern

exists regarding ceftriaxone safety for a patient with neurosyphilis,

skin testing should be performed to confirm penicillin allergy

and, if necessary, penicillin desensitization in consultation with

a specialist is recommended. Other regimens have not been

adequately evaluated for treatment of neurosyphilis.

Pregnancy

Pregnant women who are allergic to penicillin should be

desensitized and treated with penicillin G. Skin testing or oral

graded penicillin dose challenge might be helpful in identifying

women at risk for acute allergic reactions (see Management of

Persons Who Have a History of Penicillin Allergy).

HIV Infection

Persons with HIV infection who have neurosyphilis should

be treated as described for persons without HIV (see Syphilis

Among Persons with HIV Infection).

Syphilis Among Persons with HIV Infection

Diagnostic Considerations

Interpretation of treponemal and nontreponemal serologic

tests for persons with HIV infection is the same as for persons

without HIV. Although rare, unusual serologic responses have

been observed among persons with HIV infection who have

syphilis. The majority of reports have involved posttreatment

serologic titers that were higher than expected (i.e., high serofast)

or fluctuated, and false-negative serologic test results and delayed

appearance of seroreactivity have also been reported (622).

When clinical findings are indicative of syphilis, but serologic

tests are nonreactive or their interpretation is unclear, alternative

tests (e.g., biopsy of a lesion, darkfield examination, or PCR of

lesion material) might be useful for diagnosis. Neurosyphilis,

ocular syphilis, and otosyphilis should be considered in the

differential diagnosis of neurologic, ocular, and other signs

and symptoms among persons with HIV infection.

Treatment

Persons with HIV infection who have early syphilis might

be at increased risk for neurologic complications (623) and

might have higher rates of inadequate serologic response

with recommended regimens. The magnitude of these risks is

not defined precisely but is likely small. Although long-term

(>1 year) comparative data are lacking, no treatment regimens

for syphilis have been demonstrated to be more effective in

preventing neurosyphilis among persons with HIV infection

than the syphilis regimens recommended for persons without

HIV (609). Careful follow-up after therapy is essential. Using

ART per current HIV guidelines might improve clinical

outcomes among persons coinfected with HIV and syphilis;

concerns regarding adequate treatment of syphilis among

persons with HIV infection might not apply to those with

HIV virologic suppression (624,625).

Primary and Secondary Syphilis Among Persons

with HIV Infection

Recommended Regimen for Primary and Secondary Syphilis

Among Persons with HIV Infection

Benzathine penicillin G 2.4 million units IM in a single dose

Available data demonstrate that additional doses of

benzathine penicillin G, amoxicillin, or other antibiotics in

primary and secondary syphilis among persons with HIV

infection do not result in enhanced efficacy (592,593,609).

Other Management Considerations

The majority of persons with HIV infection respond

appropriately to the recommended benzathine penicillin G

treatment regimen for primary and secondary syphilis (626).

CSF abnormalities (e.g., mononuclear pleocytosis and elevated

protein levels) can be common among persons with HIV, even

those without syphilis. The clinical and prognostic significance

of such CSF laboratory abnormalities among persons with

primary and secondary syphilis who lack neurologic symptoms

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is unknown. Certain studies have demonstrated that among

persons with HIV infection and syphilis, CSF abnormalities

are associated with a CD4

T-cell count of ≤350 cells/mL or

an RPR titer of ≥1:32 (614,627). However, CSF examination

followed by treatment for neurosyphilis on the basis of

laboratory abnormalities has not been associated with improved

clinical outcomes in the absence of neurologic signs and

symptoms. All persons with HIV infection and primary and

secondary syphilis should have a thorough neurologic, ocular,

and otic examination (614,622,625). CSF examination should

be reserved for those with an abnormal neurologic examination.

Follow-Up

Persons with HIV infection and primary or secondary

syphilis should be evaluated clinically and serologically for

possible treatment failure at 3, 6, 9, 12, and 24 months after

therapy; those who meet the criteria for treatment failure

(i.e., signs or symptoms that persist or recur or a sustained

[>2 weeks] fourfold or greater increase in titer) should be

managed in the same manner as persons without HIV infection

(i.e., depending on history of sexual activity and on findings of

neurologic examination, either repeat treatment with weekly

injections of benzathine penicillin G 2.4 million units IM for

3 weeks or CSF examination and repeat treatment guided by

CSF findings) (see Primary and Secondary Syphilis).

In addition, CSF examination and retreatment can be

considered for persons whose nontreponemal test titers do

not decrease fourfold within 24 months of therapy. If CSF

examination is normal, treatment with benzathine penicillin

G administered as 2.4 million units IM at weekly intervals for

3 weeks is recommended. Serologic titers might not decrease

despite a negative CSF examination and a repeated 3-week

course of therapy (599). Especially if the initial nontreponemal

titer is low (<1:8) in these circumstances, the benefit of

additional therapy or repeated CSF examinations is unclear but

is not usually recommended. Serologic and clinical monitoring

at least annually should continue to monitor for any sustained

increases in nontreponemal titer.

Management of Sex Partners

See Syphilis, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Persons with HIV infection who are allergic to penicillin

and have primary or secondary syphilis should be managed

according to the recommendations for persons without HIV

who are allergic to penicillin (see Primary and Secondary

Syphilis). Persons with penicillin allergy whose compliance

with alternative therapy or follow-up cannot be ensured should

be desensitized and treated with penicillin G (see Management

of Persons Who Have a History of Penicillin Allergy). Using

penicillin alternatives has not been well studied among persons

with HIV infection; azithromycin is not recommended for

persons with HIV and primary or secondary syphilis infection.

Alternative therapies should be used only in conjunction with

close serologic and clinical follow-up. Persons with HIV and

latent syphilis should be treated similarly to persons who do

not have HIV (see Latent Syphilis).

Latent Syphilis Among Persons with HIV Infection

Recommended Regimen for Early Latent Syphilis Among

Persons with HIV Infection

Benzathine penicillin G 2.4 million units IM in a single dose

Recommended Regimen for Late Latent Syphilis or Latent

Syphilis of Unknown Duration Among Persons with HIV

Infection

Benzathine penicillin G 7.2 million units total, administered as 3 doses

of 2.4 million units IM at 1-week intervals

Other Management Considerations

All persons with HIV and latent syphilis infection should

undergo a thorough neurologic, ocular, and otic examination;

those with neurologic symptoms or signs should undergo

immediate CSF examination. In the absence of neurologic

symptoms or signs, CSF examination has not been associated

with improved clinical outcomes and therefore is not

recommended. Those with ocular or otic symptoms or

signs should be evaluated for ocular syphilis and otosyphilis

according to those clinical presentations (see Neurosyphilis,

Ocular Syphilis, and Otosyphilis).

Follow-Up

Patients with HIV and latent syphilis infection should

be evaluated clinically and serologically at 6, 12, 18, and

24 months after therapy. Those persons who meet the criteria

for treatment failure (i.e., signs or symptoms that persist or

recur or a sustained [>2 weeks] fourfold or greater increase

in titer) should be managed in the same manner as persons

without HIV (i.e., depending on history of sexual activity and

on findings of neurologic examination, either repeat treatment

with weekly injections of benzathine penicillin G 2.4 million

units IM for 3 weeks or CSF examination and repeat treatment

guided by CSF findings) (see Latent Syphilis).

In addition, CSF examination and retreatment can be

considered for persons whose nontreponemal test titers do

not decrease fourfold within 24 months of therapy. If CSF

examination is normal, treatment with benzathine penicillin

G administered as 2.4 million units IM at weekly intervals for

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3 weeks is recommended. Serologic titers might not decrease

despite a negative CSF examination and a repeated 3-week

course of therapy (599). Especially if the initial nontreponemal

titer is low (<1:8) in these circumstances, the benefit of

additional therapy or repeated CSF examinations is unclear but

is not usually recommended. Serologic and clinical monitoring

at least annually should continue to ensure nontreponemal

titers remain stable without any sustained titer increases.

Management of Sex Partners

See Syphilis, Management of Sex Partners.

Special Considerations

Penicillin Allergy

The efficacy of alternative nonpenicillin regimens for latent

syphilis for persons living with HIV infection has not been well

studied, and these therapies should be used only in conjunction

with close serologic and clinical follow-up. Patients with

penicillin allergy whose compliance with alternative therapy

or follow-up cannot be ensured should be desensitized and

treated with penicillin G (see Management of Persons Who

Have a History of Penicillin Allergy).

Neurosyphilis, Ocular Syphilis, and Otic Syphilis

Among Persons with HIV Infection

All persons with HIV and syphilis infection should receive a

careful neurologic ocular and otic examination. Persons with

HIV infection and neurosyphilis should be treated according

to the recommendations for persons with neurosyphilis and

without HIV infection (see Neurosyphilis, Ocular Syphilis,

and Otosyphilis).

Follow-Up

Persons with HIV and neurosyphilis infection should be

managed according to the recommendations for persons without

HIV infection. Serum RPR can be followed for necessary

treatment success rather than following CSF parameters (see

Neurosyphilis, Ocular Syphilis, and Otosyphilis). Limited data

indicate that changes in CSF parameters might occur more

slowly among persons with HIV infection, especially those

with more advanced immunosuppression (588,624).

Management of Sex Partners

See Syphilis, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Persons with HIV who are allergic to penicillin and have

neurosyphilis infection should be managed according to the

recommendations for persons without HIV infection with

neurosyphilis who are allergic to penicillin (see Neurosyphilis,

Ocular Syphilis, and Otosyphilis). Small observational studies

conducted among persons with HIV and neurosyphilis report

that ceftriaxone 1–2 g IV daily for 10–14 days might be

effective as an alternative agent (628–630). The possibility

of cross-sensitivity between ceftriaxone and penicillin exists;

however, the risk for penicillin cross-reactivity between

third-generation cephalosporins is negligible (619–621,631)

(see Management of Persons Who Have a History of Penicillin

Allergy). If concern exists regarding the safety of ceftriaxone

for a person with HIV and neurosyphilis, skin testing should

be performed to confirm penicillin allergy and, if necessary,

penicillin desensitization in consultation with a specialist is

recommended. Other regimens have not been adequately

evaluated for treatment of neurosyphilis.

Syphilis During Pregnancy

All women should be screened serologically for syphilis

at the first prenatal care visit (174), which is mandated by

the majority of states (142). Among populations for whom

receipt of prenatal care is not optimal, serologic screening and

treatment (if serologic test is reactive) should be performed at

the time of pregnancy testing (632). Antepartum screening can

be performed by manual nontreponemal antibody testing (e.g.,

RPR) by using the traditional syphilis screening algorithm or

by treponemal antibody testing (e.g., immunoassays) using the

reverse sequence algorithm.

Pregnant women with positive treponemal screening tests

(e.g., EIA, CIA, or immunoblot) should have additional

quantitative nontreponemal testing because titers are essential

for monitoring treatment response. Serologic testing should

also be performed twice during the third trimester: at 28 weeks’

gestation and at delivery for pregnant women who live in

communities with high rates of syphilis and for women who

have been at risk for syphilis acquisition during pregnancy.

Maternal risk factors for syphilis during pregnancy include

sex with multiple partners, sex in conjunction with drug

use or transactional sex, late entry to prenatal care (i.e., first

visit during the second trimester or later) or no prenatal

care, methamphetamine or heroine use, incarceration of the

woman or her partner, and unstable housing or homelessness

(174,633–636). Moreover, as part of the management of

pregnant women who have syphilis, providers should obtain

information concerning ongoing risk behaviors and treatment

of sex partners to assess the risk for reinfection.

Any woman who has a fetal death after 20 weeks’ gestation

should be tested for syphilis. No mother or neonate should

leave the hospital without maternal serologic status having been

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documented at least once during pregnancy. Any woman who at

the time of delivery has no prenatal care history or has been at

risk for syphilis acquisition during pregnancy (e.g., misuses drugs;

has had another STI during pregnancy; or has had multiple sex

partners, a new partner, or a partner with an STI) should have the

results of a syphilis serologic test documented before discharge.

Diagnostic Considerations

Pregnant women seropositive for syphilis should be

considered infected unless an adequate treatment history is

clearly documented in the medical records and sequential

serologic antibody titers have decreased as recommended for

the syphilis stage. The risk for antepartum fetal infection or

congenital syphilis at delivery is related to the syphilis stage

during pregnancy, with the highest risk occurring during

the primary and secondary stages. Quantitative maternal

nontreponemal titer, especially if >1:8, might be a marker of

early infection and bacteremia. However, risk for fetal infection

is still substantial among pregnant women with late latent

syphilis and low titers. Pregnant women with stable, serofast

low nontreponemal titers who have previously been treated

for syphilis might not require additional treatment; however,

increasing or high antibody titers in a pregnant woman

previously treated might indicate reinfection or treatment

failure, and treatment should be offered.

If an automated treponemal test (e.g., EIA or CIA) is used for

antepartum syphilis screening, all positive tests should be reflexed

to a quantitative nontreponemal test (e.g., RPR or VDRL). If

the nontreponemal test is negative, the results are considered

discrepant and a second treponemal test (TP-PA is preferred)

should be performed, preferably on the same specimen.

If the second treponemal test is positive (e.g., EIA positive,

RPR negative, or TP-PA positive), current or previous syphilis

infection can be confirmed. For women with a history of

adequately treated syphilis who do not have ongoing risk, no

further treatment is necessary. Women without a history of

treatment should have the syphilis stage determined and should

be treated accordingly with a recommended penicillin regimen.

If the second treponemal test is negative (e.g., EIA positive,

RPR negative, or TP-PA negative), the positive EIA or CIA is

more likely to represent a false-positive test result for women

who are living in communities with low rates of syphilis, have

a partner who is uninfected, and have no history of treated

syphilis (637,638). If the woman is at low risk for syphilis,

lacks signs or symptoms of primary syphilis, has a partner

with no clinical or serologic evidence of syphilis, and is likely

to follow up with clinical care, repeat serologic testing within 4

weeks can be considered to determine whether the EIA or CIA

remains positive or if the RPR, VDRL, or TP-PA result becomes

positive. If both the RPR and TP-PA remain negative, no further

treatment is necessary. If follow-up is not likely, women with an

isolated reactive treponemal test and without a history of treated

syphilis should be treated according to the syphilis stage.

Treatment

Penicillin G is the only known effective antimicrobial for

treating fetal infection and preventing congenital syphilis

(639). Evidence is insufficient to determine the optimal

penicillin regimen during pregnancy (640).

Recommended Regimen for Syphilis During Pregnancy

Pregnant women should be treated with the recommended penicillin

regimen for their stage of infection

Other Management Considerations

The following recommendations should be considered for

pregnant women with syphilis infection:

• Certain evidence indicates that additional therapy is

beneficial for pregnant women to prevent congenital

syphilis. For women who have primary, secondary, or early

latent syphilis, a second dose of benzathine penicillin G

2.4 million units IM can be administered 1 week after the

initial dose (641–643).

• When syphilis is diagnosed during the second half of

pregnancy, management should include a sonographic fetal

evaluation for congenital syphilis. However, this evaluation

should not delay therapy. Sonographic signs of fetal or

placental syphilis (e.g., hepatomegaly, ascites, hydrops, fetal

anemia, or a thickened placenta) indicate a greater risk for

fetal treatment failure (644); cases accompanied by these

signs should be managed in consultation with obstetric

specialists. A second dose of benzathine penicillin G

2.4 million units IM after the initial dose might be beneficial

for fetal treatment in these situations.

• Women treated for syphilis during the second half of

pregnancy are at risk for premature labor or fetal distress

if the treatment precipitates the Jarisch-Herxheimer

reaction (590). These women should be advised to seek

obstetric attention after treatment if they notice any fever,

contractions, or decrease in fetal movements. Stillbirth is

a rare complication of treatment; however, concern for

this complication should not delay necessary treatment.

No data are available to support that corticosteroid

treatment alters the risk for treatment-related complications

during pregnancy.

• Missed doses >9 days between doses are not acceptable for

pregnant women receiving therapy for late latent syphilis

(613). An optimal interval between doses is 7 days for

pregnant women. If a pregnant woman does not return

for the next dose on day 7, every effort should be made

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to contact her and link her to immediate treatment within

2 days to avoid retreatment. Pregnant women who miss a

dose of therapy should repeat the full course of therapy.

• All women who have syphilis should be offered testing for

HIV at the time of diagnosis.

Follow-Up

Coordinated prenatal care and treatment are vital because

providers should document that women are adequately

treated for the syphilis stage and ensure that the clinical and

antibody responses are appropriate for the patient’s disease

stage. If syphilis is diagnosed and treated at or before 24 weeks’

gestation, serologic titers should not be repeated before 8 weeks

after treatment (e.g., at 32 weeks’ gestation) but should be

repeated again at delivery. Titers should be repeated sooner

if reinfection or treatment failure is suspected. For syphilis

diagnosed and treated after 24 weeks’ gestation, serologic titers

should be repeated at delivery.

A majority of women will not achieve a fourfold decrease

in titers before delivery, although this does not indicate

treatment failure (645). However, a fourfold increase in titer

after treatment (e.g., from 1:8 to 1:32) that is sustained for

>2 weeks is concerning for reinfection or treatment failure.

Nontreponemal titers can increase immediately after treatment,

presumably related to the treatment response. Therefore, unless

symptoms and signs exist of primary or secondary syphilis,

follow-up titer should not be repeated until approximately

8 weeks after treatment. Inadequate maternal treatment is

likely if delivery occurs within 30 days of therapy, clinical signs

of infection are present at delivery, or the maternal antibody

titer at delivery is fourfold higher than the pretreatment titer.

Management of Sex Partners

See Syphilis, Management of Sex Partners.

Special Considerations

Penicillin Allergy

No proven alternatives to penicillin are available for

treatment of syphilis during pregnancy. Pregnant women who

have a history of penicillin allergy should be desensitized and

treated with penicillin G. Skin testing or oral graded penicillin

dose challenge might be helpful in identifying women at risk

for acute allergic reactions (see Management of Persons Who

Have a History of Penicillin Allergy).

Tetracycline and doxycycline are to be avoided in the second

and third trimesters of pregnancy (431). Erythromycin and

azithromycin should not be used because neither reliably cures

maternal infection nor treats an infected fetus (640). Data are

insufficient to recommend ceftriaxone or other cephalosporins

for treatment of maternal infection and prevention of

congenital syphilis (646,647).

HIV Infection

Placental inflammation from congenital syphilis infection

might increase the risk for perinatal transmission of HIV. All

women with HIV infection should be evaluated for syphilis and

receive a penicillin regimen appropriate for the syphilis stage.

Data are insufficient to recommend any alternative regimens

for pregnant women with syphilis and HIV infection (see

Syphilis Among Persons with HIV).

Congenital Syphilis

The rate of reported congenital syphilis in the United States

has increased dramatically since 2012. During 2019, a total of

1,870 cases of congenital syphilis were reported, including 94

stillbirths and 34 infant deaths (141). The 2019 national rate

of 48.5 cases per 100,000 live births represents a 41% increase

relative to 2018 (34.3 cases per 100,000 live births) and a 477%

increase relative to 2012 (8.4 cases per 100,000 live births).

During 2015–2019, the rate of congenital syphilis increased

291.1% (12.4 to 48.5 per 100,000 live births), which mirrors

increases in the rate of primary and secondary syphilis among

females aged 15–44 years (a 171.9% increase, from 3.2 to 8.7

per 100,000 females).

Effective prevention and detection of congenital syphilis

depend on identifying syphilis among pregnant women and,

therefore, on the routine serologic screening of pregnant

women during the first prenatal visit and at 28 weeks’ gestation

and at delivery for women who live in communities with high

rates of syphilis, women with HIV infection, or those who

are at increased risk for syphilis acquisition. Certain states

have recommended screening three times during pregnancy

for all women; clinicians should screen according to their

state’s guidelines.

Maternal risk factors for syphilis during pregnancy include

sex with multiple partners, sex in conjunction with drug

use or transactional sex, late entry to prenatal care (i.e., first

visit during the second trimester or later) or no prenatal

care, methamphetamine or heroine use, incarceration of the

woman or her partner, and unstable housing or homelessness

(174,633–636). Moreover, as part of the management of

pregnant women who have syphilis, providers should obtain

information concerning ongoing risk behaviors and treatment

of sex partners to assess the risk for reinfection.

Routine screening of neonatal sera or umbilical cord blood

is not recommended because diagnosis at that time does not

prevent congenital syphilis in certain newborns. No mother

or newborn infant should leave the hospital without maternal

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serologic status having been documented at least once during

pregnancy. Any woman who had no prenatal care before

delivery or is considered at increased risk for syphilis acquisition

during pregnancy should have the results of a syphilis serologic

test documented before she or her neonate is discharged. A

quantitative RPR is needed at the time of delivery to compare

with the neonate’s nontreponemal test result. If a stat RPR

is unavailable and a rapid treponemal test is performed at

delivery, the results should be confirmed by using standard

syphilis serologic laboratory tests (e.g., RPR and treponemal

test) and algorithms.

Evaluation and Treatment of Neonates

Diagnosis of congenital syphilis can be difficult because

maternal nontreponemal and treponemal immunoglobulin G

(IgG) antibodies can be transferred through the placenta to the

fetus, complicating the interpretation of reactive serologic tests

for syphilis among neonates (infants aged <30 days). Therefore,

treatment decisions frequently must be made on the basis of

identification of syphilis in the mother; adequacy of maternal

treatment; presence of clinical, laboratory, or radiographic

evidence of syphilis in the neonate; and comparison of maternal

(at delivery) and neonatal nontreponemal serologic titers (e.g.,

RPR or VDRL) by using the same test, preferably conducted

by the same laboratory. Any neonate at risk for congenital

syphilis should receive a full evaluation and testing for HIV.

All neonates born to mothers who have reactive nontreponemal

and treponemal test results should be evaluated with a

quantitative nontreponemal serologic test (RPR or VDRL)

performed on the neonate’s serum because umbilical cord blood

can become contaminated with maternal blood and yield a

false-positive result, and Wharton’s jelly within the umbilical

cord can yield a false-negative result. The nontreponemal

test performed on the neonate should be the same type of

nontreponemal test performed on the mother.

Conducting a treponemal test (e.g., TP-PA, immunoassay-

EIA, CIA, or microbead immunoassay) on neonatal serum is

not recommended because it is difficult to interpret, as passively

transferred maternal antibodies can persist for >15 months.

Commercially available IgM tests are not recommended.

All neonates born to women who have reactive nontreponemal

serologic tests for syphilis at delivery should be examined

thoroughly for evidence of congenital syphilis (e.g., nonimmune

hydrops, conjugated or direct hyperbilirubinemia

†

cholestatic jaundice or cholestasis, hepatosplenomegaly,

rhinitis, skin rash, or pseudoparalysis of an extremity).

Pathologic examination of the placenta or umbilical cord using

specific staining (e.g., silver) or a T. pallidum PCR test using

†

Direct hyperbilirubinemia is direct bilirubin level >2 mg/dL (34 umol/L) or

20% of the total bilirubin level.

a CLIA-validated test should be considered; direct fluorescence

antibody (DFA-TP) reagents are unavailable (565). Darkfield

microscopic examination or PCR testing of suspicious lesions

or body fluids (e.g., bullous rash or nasal discharge) also should

be performed. In addition to these tests, for stillborn infants,

skeletal survey demonstrating typical osseous lesions might aid

in the diagnosis of congenital syphilis because these

abnormalities are not detected on fetal ultrasound.

The following scenarios describe the recommended

congenital syphilis evaluation and treatment of neonates born

to women who had reactive nontreponemal and treponemal

serologic tests for syphilis during pregnancy (e.g., RPR reactive,

TP-PA reactive or EIA reactive, RPR reactive) and have a

reactive nontreponemal test at delivery (e.g., RPR reactive).

Maternal history of infection with T. pallidum and treatment

for syphilis should be considered when evaluating and treating

the neonate for congenital syphilis in most scenarios, except

when congenital syphilis is proven or highly probable.

Scenario 1: Confirmed Proven or Highly Probable

Congenital Syphilis

Any neonate with

• an abnormal physical examination that is consistent with

congenital syphilis;

• a serum quantitative nontreponemal serologic titer that is

fourfold

(or greater) higher than the mother’s titer at

delivery (e.g., maternal titer = 1:2, neonatal titer ≥1:8 or

maternal titer=1:8, neonatal titer ≥1:32)

; or

• a positive darkfield test or PCR of placenta, cord, lesions, or

body fluids or a positive silver stain of the placenta or cord.

Recommended Evaluation

• CSF analysis for VDRL, cell count, and protein**

One dilution is within the test performance of nontreponemal tests and is not

a significant change.

The absence of a fourfold or greater titer for a neonate does not exclude

congenital syphilis.

** Interpretation of CSF test results requires a nontraumatic lumbar puncture

(i.e., a CSF sample that is not contaminated with blood). CSF test results

obtained during the neonatal period can be difficult to interpret; normal values

differ by gestational age and are higher among preterm infants. Studies indicate

that 95% of healthy neonates have values of ≤16–19 WBCs/mm

or protein

levels of ≤115–118 mg/dL on CSF examination. During the second month

of life, 95% of healthy infants have ≤9–11 WBCs/mm

or protein levels of

≤89–91 mg/dL. Lower values (i.e., 5 WBCs/mm

and protein level of 40 mg/

dL) might be considered the upper limits of normal for older infants. Other

causes of elevated values should be considered when an infant is being evaluated

for congenital syphilis (Sources: Kestenbaum LA, Ebberson J, Zorc JJ,

Hodinka RL, Shah SS. Defining cerebrospinal fluid white blood cell count

reference values in neonates and young infants. Pediatrics 2010;125:257–64;

Shah SS, Ebberson J, Kestenbaum LA, Hodinka RL, Zorc JJ. Age-specific

reference values for cerebrospinal fluid protein concentration in neonates and

young infants. J Hosp Med 2011;6:22–7; Thomson J, Sucharew H, Cruz AT,

et al.; Pediatric Emergency Medicine Collaborative Research Committee [PEM

CRC] HSV Study Group. Cerebrospinal fluid reference values for young

infants undergoing lumbar puncture. Pediatrics 2018;141:e20173405.)

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• Complete blood count (CBC) and differential and

platelet count

• Long-bone radiographs

• Other tests as clinically indicated (e.g., chest radiograph,

liver function tests, neuroimaging, ophthalmologic

examination, and auditory brain stem response)

Recommended Regimens, Confirmed or Highly Probable

Congenital Syphilis

Aqueous crystalline penicillin G 100,000–150,000 units/kg/body

weight/day, administered as 50,000 units/kg body weight/dose IV every

12 hours during the first 7 days of life and every 8 hours thereafter for a

total of 10 days

Procaine penicillin G 50,000 units/kg body weight/dose IM in a single

daily dose for 10 days

If >1 day of therapy is missed, the entire course should

be restarted. Data are insufficient regarding use of other

antimicrobial agents (e.g., ampicillin). When possible, a full

10-day course of penicillin is preferred, even if ampicillin was

initially provided for possible sepsis (648–650). Using agents

other than penicillin requires close serologic follow-up for

assessing therapy adequacy.

Scenario 2: Possible Congenital Syphilis

Any neonate who has a normal physical examination and a

serum quantitative nontreponemal serologic titer equal to or

less than fourfold of the maternal titer at delivery (e.g., maternal

titer=1:8, neonatal titer ≤1:16) and one of the following:

• The mother was not treated, was inadequately treated, or

has no documentation of having received treatment.

• The mother was treated with erythromycin or a regimen

other than those recommended in these guidelines (i.e., a

nonpenicillin G regimen).

††

• The mother received the recommended regimen but

treatment was initiated <30 days before delivery.

Recommended Evaluation

• CSF analysis for VDRL, cell count, and protein**

• CBC, differential, and platelet count

• Long-bone radiographs

This evaluation is not necessary if a 10-day course of

parenteral therapy is administered, although such evaluations

might be useful. For instance, a lumbar puncture might

document CSF abnormalities that would prompt close

follow-up. Other tests (e.g., CBC, platelet count, and long-

bone radiographs) can be performed to further support a

diagnosis of congenital syphilis.

††

A women treated with a regimen other than recommended in these guidelines

should be considered untreated.

Recommended Regimens, Possible Congenital Syphilis

Aqueous crystalline penicillin G 100,000–150,000 units/kg body

weight/day, administered as 50,000 units/kg body weight/dose IV every

12 hours during the first 7 days of life and every 8 hours thereafter for a

total of 10 days

Procaine penicillin G 50,000 units/kg body weight/dose IM in a single

daily dose for 10 days

Benzathine penicillin G 50,000 units/kg body weight/dose IM in a

single dose

Before using the single-dose benzathine penicillin G regimen,

the recommended evaluation (i.e., CSF examination, long-

bone radiographs, and CBC with platelets) should be normal,

and follow-up should be certain. If any part of the neonate’s

evaluation is abnormal or not performed, if the CSF analysis

is uninterpretable because of contamination with blood, or

if follow-up is uncertain, a 10-day course of penicillin G

is required.

If the neonate’s nontreponemal test is nonreactive and

the provider determines that the mother’s risk for untreated

syphilis is low, treatment of the neonate with a single IM

dose of benzathine penicillin G 50,000 units/kg body weight

for possible incubating syphilis can be considered without

an evaluation. Neonates born to mothers with untreated

early syphilis at the time of delivery are at increased risk for

congenital syphilis, and the 10-day course of penicillin G

should be considered even if the neonate’s nontreponemal

test is nonreactive, the complete evaluation is normal, and

follow-up is certain.

Scenario 3: Congenital Syphilis Less Likely

Any neonate who has a normal physical examination and a

serum quantitative nontreponemal serologic titer equal or less

than fourfold of the maternal titer at delivery (e.g., maternal

titer=1:8, neonatal titer ≤1:16) and both of the following

are true:

• The mother was treated during pregnancy, treatment was

appropriate for the infection stage, and the treatment

regimen was initiated ≥30 days before delivery.

• The mother has no evidence of reinfection or relapse.

Recommended Evaluation

No evaluation is recommended.

Recommended Regimen, Congenital Syphilis Less Likely

Benzathine penicillin G 50,000 units/kg body weight/dose IM in a

single dose*

* Another approach involves not treating the newborn if follow-up is

certain but providing close serologic follow-up every 2–3 months for 6

months for infants whose mothers’ nontreponemal titers decreased at

least fourfold after therapy for early syphilis or remained stable for low-

titer, latent syphilis (e.g., VDRL <1:2 or RPR <1:4).

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Scenario 4: Congenital Syphilis Unlikely

Any neonate who has a normal physical examination and a

serum quantitative nontreponemal serologic titer equal to or

less than fourfold of the maternal titer at delivery

and both

of the following are true:

• The mother’s treatment was adequate before pregnancy.

• The mother’s nontreponemal serologic titer remained low

and stable (i.e., serofast) before and during pregnancy and

at delivery (e.g., VDRL ≤1:2 or RPR ≤1:4).

Recommended Evaluation

No evaluation is recommended.

Recommended Regimen, Congenital Syphilis Unlikely

No treatment is required. However, any neonate with reactive

nontreponemal tests should be followed serologically to ensure the

nontreponemal test returns to negative (see Follow-Up). Benzathine

penicillin G 50,000 units/kg body weight as a single IM injection might

be considered, particularly if follow-up is uncertain and the neonate has

a reactive nontreponemal test.

The following situations describe management of neonates

born to women screened during pregnancy by using the reverse

sequence algorithm with reactive treponemal serologic tests

and a nonreactive nontreponemal serologic test.

Reactive maternal treponemal serologies with a

nonreactive nontreponemal serology (e.g., EIA reactive,

RPR nonreactive, or TP-PA reactive) during pregnancy.

Syphilis is highly unlikely for neonates born to mothers with

a nonreactive nontreponemal test after adequate treatment

for syphilis during pregnancy or documentation of adequate

treatment before pregnancy (with no evidence of reinfection

of relapse). If testing is performed again at delivery and 1) the

maternal nontreponemal test remains nonreactive and 2) the

neonate has a normal physical examination and nonreactive

nontreponemal test (e.g., RPR nonreactive), the provider

should consider managing similarly to Scenario 4 without

a laboratory evaluation and with no treatment required.

Benzathine penicillin G 50,000 units/kg body weight as a

single IM injection might be considered if syphilis exposure

is possible within 1 month of delivery and follow-up of the

mother and infant is uncertain.

Isolated reactive maternal treponemal serology (e.g.,

EIA reactive, RPR nonreactive, or TP-PA nonreactive)

during pregnancy. Syphilis is unlikely for neonates born to

mothers screened with the reverse sequence algorithm with

isolated reactive maternal treponemal serology. Among low-

prevalence populations, these are likely false-positive results and

might become nonreactive with repeat testing (638). If these

neonates have a normal physical examination and the risk for

syphilis is low in the mother, no evaluation and treatment are

recommended for the neonate. If syphilis exposure is possible

or unknown in the mother or the mother desires further

evaluation to definitively rule out syphilis, repeat serology

within 4 weeks is recommended to evaluate for early infection

(see Syphilis During Pregnancy).

Isolated reactive maternal treponemal serology (e.g., rapid

treponemal test) at delivery. For mothers with late or no

prenatal care with a reactive rapid treponemal test at delivery,

confirmatory laboratory-based testing should be performed;

however, results should not delay evaluation and treatment of

the neonate. These neonates should be evaluated and treated

with a 10-day course of penicillin as recommended in Scenario

1, and consultation with a specialist is recommended.

Follow-Up

All neonates with reactive nontreponemal tests should receive

thorough follow-up examinations and serologic testing (i.e., RPR

or VDRL) every 2–3 months until the test becomes nonreactive.

For a neonate who was not treated because congenital syphilis

was considered less likely or unlikely, nontreponemal antibody

titers should decrease by age 3 months and be nonreactive

by age 6 months, indicating that the reactive test result was

caused by passive transfer of maternal IgG antibody. At age

6 months, if the nontreponemal test is nonreactive, no further

evaluation or treatment is needed; if the nontreponemal test is

still reactive, the infant is likely infected and should be treated.

Treated neonates who exhibit persistent nontreponemal test

titers by age 6–12 months should be reevaluated through CSF

examination and managed in consultation with an expert.

Retreatment with a 10-day course of a penicillin G regimen

might be indicated.

Neonates with a negative nontreponemal test at birth and

whose mothers were seroreactive at delivery should be retested

at age 3 months to rule out serologically negative incubating

congenital syphilis at the time of birth. Treponemal tests should

not be used to evaluate treatment response because the results

are qualitative, and passive transfer of maternal IgG treponemal

antibody might persist for >15 months.

Neonates whose initial CSF evaluations are abnormal do

not need repeat lumbar puncture unless they exhibit persistent

nontreponemal serologic test titers at age 6–12 months.

Persistent nontreponemal titers and CSF abnormalities should

be managed in consultation with an expert.

Special Considerations

Penicillin Allergy

Neonates who require treatment for congenital syphilis

but who have a history of penicillin allergy or develop an

allergic reaction presumed secondary to penicillin should

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be desensitized and then treated with penicillin G (see

Management of Persons Who Have a History of Penicillin

Allergy). Skin testing remains unavailable for neonates because

the procedure has not been standardized for this age group.

Data are insufficient regarding use of other antimicrobial agents

(e.g., ceftriaxone) for congenital syphilis among neonates. If

a nonpenicillin G agent is used, close clinical and serologic

follow-up is required in consultation with an expert. Repeat

CSF examination should be performed if the initial CSF

examination was abnormal.

Penicillin Shortage

During periods when the availability of aqueous crystalline

penicillin G is compromised, the following is recommended

(https://www.cdc.gov/std/treatment/drug-notices.htm):

• For neonates with clinical evidence of congenital syphilis

(see Scenario 1), check local sources for aqueous crystalline

penicillin G (potassium or sodium) and notify CDC and

FDA of limited supply. If IV penicillin G is limited,

substitute some or all daily doses with procaine penicillin G

(50,000 units/kg body weight/dose IM/day in a single

daily dose for 10 days).

• If aqueous or procaine penicillin G is unavailable,

ceftriaxone (50–75 mg/kg body weight/day IV every

24 hours) can be considered with thorough clinical and

serologic follow-up and in consultation with an expert

because evidence is insufficient to support using ceftriaxone

for treating congenital syphilis. Ceftriaxone should be used

with caution in neonates with jaundice.

• For neonates without any clinical evidence of congenital

syphilis (see Scenario 2 and Scenario 3), use

procaine penicillin G 50,000 units/kg body weight/

dose/day IM in a single dose for 10 days, or

benzathine penicillin G 50,000 units/kg body weight

IM as a single dose.

• If any part of the evaluation for congenital syphilis is

abnormal or was not performed, CSF examination is not

interpretable, or follow-up is uncertain, procaine penicillin

G is recommended. A single dose of ceftriaxone is

inadequate therapy.

• For premature neonates who have no clinical evidence of

congenital syphilis (see Scenario 2 and Scenario 3) and

might not tolerate IM injections because of decreased

muscle mass, IV ceftriaxone can be considered with

thorough clinical and serologic follow-up and in

consultation with an expert. Ceftriaxone dosing should

be adjusted according to birthweight.

HIV Infection

Evidence is insufficient to determine whether neonates who

have congenital syphilis and HIV infection or whose mothers

have HIV require different therapy or clinical management

than is recommended for all neonates. All neonates with

congenital syphilis should be managed similarly, regardless of

HIV status.

Evaluation and Treatment of Infants and Children

with Congenital Syphilis

Infants and children aged ≥1 month who are identified as

having reactive serologic tests for syphilis (e.g., RPR reactive,

TP-PA reactive or EIA reactive, RPR reactive) should be

examined thoroughly and have maternal serology and records

reviewed to assess whether they have congenital or acquired

syphilis (see Primary and Secondary Syphilis; Latent Syphilis;

Sexual Assault or Abuse of Children). In the case of extremely

early or incubating syphilis at the time of delivery, all maternal

serologic tests might have been negative; thus, infection might

be undetected until a diagnosis is made later in the infant or

child. Any infant or child at risk for congenital syphilis should

receive a full evaluation and testing for HIV infection.

International adoptee, immigrant, or refugee children from

countries where treponemal infections (e.g., yaws or pinta) are

endemic might have reactive nontreponemal and treponemal

serologic tests, which cannot distinguish between syphilis and

other subspecies of T. pallidum (651). These children might

also have syphilis (T. pallidum subspecies pallidum) and should

be evaluated for congenital syphilis.

Recommended Evaluation

The following evaluations should be performed:

• CSF analysis for VDRL, cell count, and protein

• CBC, differential, and platelet count

• Other tests as clinically indicated (e.g., long-bone

radiographs, chest radiograph, liver function tests,

abdominal ultrasound, ophthalmologic examination,

neuroimaging, and auditory brain-stem response)

Recommended Regimen for Congenital Syphilis Among Infants

and Children

Aqueous crystalline penicillin G 200,000–300,000 units/kg body

weight/day IV, administered as 50,000 units/kg body weight every 4–6

hours for 10 days

If the infant or child has no clinical manifestations of

congenital syphilis and the evaluation (including the CSF

examination) is normal, treatment with <3 weekly doses of

benzathine penicillin G 50,000 units/kg body weight IM

can be considered. A single dose of benzathine penicillin

G 50,000 units/kg body weight IM up to the adult dose of

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2.4 million units in a single dose can be considered after the

10-day course of IV aqueous penicillin G to provide more

comparable duration for treatment in those who have no

clinical manifestations and normal CSF. All of these treatment

regimens should also be adequate for children who might have

other treponemal infections.

Follow-Up

Thorough follow-up examinations and serologic testing (i.e.,

RPR or VDRL) of infants and children treated for congenital

syphilis after the neonatal period (aged >30 days) should be

performed every 3 months until the test becomes nonreactive

or the titer has decreased fourfold. The serologic response

after therapy might be slower for infants and children than

neonates. If these titers increase at any point >2 weeks or do

not decrease fourfold after 12–18 months, the infant or child

should be evaluated (e.g., CSF examination), treated with

a 10-day course of parenteral penicillin G, and managed in

consultation with an expert. Treponemal tests (e.g., EIA, CIA,

or TP-PA) should not be used to evaluate treatment response

because the results are qualitative and persist after treatment,

and passive transfer of maternal IgG treponemal antibody

might persist for >15 months after delivery. Infants or children

whose initial CSF evaluations are abnormal do not need repeat

lumbar puncture unless their serologic titers do not decrease

fourfold after 12–18 months. After 18 months of follow-up,

abnormal CSF indices that persist and cannot be attributed to

other ongoing illness indicate that retreatment is needed for

possible neurosyphilis and should be managed in consultation

with an expert.

Special Considerations

Penicillin Allergy

Infants and children who require treatment for congenital

syphilis but who have a history of penicillin allergy or develop

an allergic reaction presumed secondary to penicillin should be

desensitized and treated with penicillin G (see Management

of Persons Who Have a History of Penicillin Allergy). Skin

testing remains unavailable for infants and children because the

procedure has not been standardized for this age group. Data

are insufficient regarding use of other antimicrobial agents (e.g.,

ceftriaxone) for congenital syphilis among infants and children.

If a nonpenicillin G agent is used, close clinical, serologic, and

CSF follow-up is required in consultation with an expert.

Penicillin Shortage

During periods when availability of penicillin G is

compromised, management options are similar to options

for the neonate (see Evaluation and Treatment of Neonates).

• For infants and children with clinical evidence of

congenital syphilis, if IV penicillin is limited after checking

local sources and notifying CDC and FDA about limited

supplies, procaine penicillin G (50,000 units/kg body

weight/dose IM up to the adult dose of 2.4 million units

a day in a single daily dose for 10 days) is recommended.

• If procaine penicillin G is not available, ceftriaxone (in doses

for age and weight) can be considered with thorough clinical

and serologic follow-up. Infants and children receiving

ceftriaxone should be managed in consultation with an expert

because evidence is insufficient to support use of ceftriaxone

for treatment of congenital syphilis among infants or children.

For infants aged ≥30 days, use ceftriaxone 75 mg/kg body

weight/day IV or IM in a single daily dose for 10–14 days

(dose adjustment might be necessary on the basis of current

weight). For children, ceftriaxone 100 mg/kg body weight/

day in a single daily dose is recommended.

• For infants and children without any clinical evidence of

infection (see Scenario 2 and Scenario 3), use

procaine penicillin G 50,000 units/kg body weight/dose

IM up to the adult dose of 2.4 million units a day in a

single dose for 10 days, or

benzathine penicillin G 50,000 units/kg body weight

IM up to the adult dose of 2.4 million units as a

single dose.

• If any part of the evaluation for congenital syphilis is

abnormal or not performed, CSF examination is not

interpretable, or follow-up is uncertain, procaine penicillin

G is recommended. In these scenarios, a single dose of

ceftriaxone is inadequate therapy.

HIV Infection

Evidence is insufficient to determine whether infants and

children who have congenital syphilis and HIV infection or

whose mothers have HIV require different therapy or clinical

management than what is recommended for all infants and

children. All infants and children with congenital syphilis

should be managed similarly, regardless of HIV status.

Management of Persons Who Have a

History of Penicillin Allergy

Penicillin and other ß-lactam antibiotics have a crucial

role in treating STIs. Penicillin is recommended for all

clinical stages of syphilis, and no proven alternatives exist for

treating neurosyphilis, congenital syphilis, or syphilis during

pregnancy. Ceftriaxone, a third-generation cephalosporin, is

recommended for gonorrhea treatment. For extragenital site

infections, especially pharyngeal, failure rates of nonceftriaxone

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regimens can be substantial. In most clinical settings, patients

who report a penicillin allergy are not treated with ß-lactam

antimicrobials. For patients with a diagnosis of gonorrhea and

a concomitant reported allergy to penicillin, ceftriaxone is often

avoided, even though the cross-reactivity between penicillin

allergy and third-generation cephalosporins is low (652–654).

Prevalence of reported allergy to penicillin is approximately

10% among the U.S. population and higher among hospital

inpatients and residents in health care–related facilities (655–

658). One large study in an STI clinic revealed that 8.3% of

patients reported penicillin or another ß-lactam antibiotic

allergy (659). Penicillin allergy is often overreported, with the

majority of patients who report penicillin allergy able to tolerate

the medication (660). The prevalence of reported penicillin

allergy in low-income countries is unknown; however, limited

data indicate that penicillin is one of the most frequently

reported antibiotic allergies (661).

Patients often are incorrectly labeled as allergic to penicillin

and are therefore denied the benefit of a ß-lactam therapy.

The presence of a penicillin allergy label considerably reduces

prescribing options for affected patients. Moreover, penicillin

allergy labels lead to the use of more expensive and less effective

drugs and can result in adverse consequences, including longer

length of hospital stay and increased risk for infection. Multiple

studies have described that persons with reported penicillin or

another ß-lactam antibiotic allergy have higher rates of surgical-

site infections, methicillin-resistant Staphylococcus aureus

infections, and higher medical care usage (653,662–664).

The overreported prevalence of penicillin allergy is

secondary to imprecise use of the term “allergy” by families

and clinicians and lack of clarity to differentiate between

immunoglobulin E (IgE)-mediated hypersensitivity reactions,

drug intolerances, and other idiosyncratic reactions that can

occur days after exposure. Approximately 80% of patients

with a true IgE-mediated allergic reaction to penicillin have

lost the sensitivity after 10 years (658). Thus, patients with

recent reactions are more likely to be allergic than patients

with remote reactions, and patients who had allergic reactions

in the distant past might no longer be reactive.

In a Baltimore, Maryland, STI clinic study, only 7.1% of

the patients who reported allergy to penicillin or to another

ß-lactam antibiotic had an objective positive test for penicillin

allergy (659). Moreover, in studies that have incorporated

penicillin skin testing and graded oral challenge among persons

with reported penicillin allergy, the true rates of allergy are low,

ranging from 1.5% to 6.1% (665–667). Studies in preoperative

surgical patients with reported penicillin allergy, evaluated

for cardiovascular surgery (668) or orthopedics (669), have

rates of skin test positivity <8.5%. However, when patients

with high-risk penicillin allergy histories are excluded, 99%

of patients could receive ß-lactams. In hospitalized patients

and other populations with comorbidities, the typical rates of

validated penicillin allergy among patients who report a history

of penicillin allergy are 2.5%–9.0% (670–673).

Cross-Reactivity with Cephalosporins

Penicillin and cephalosporins both contain a ß-lactam ring.

This structural similarity has led to considerable confusion

regarding cross-reactivity of these drugs and the risks for

allergic reactions from cephalosporins among penicillin-

allergic patients. In most clinical settings, patients with

reported penicillin allergy are precluded from treatment

with such cephalosporin antibiotics as ceftriaxone. Third-

generation cephalosporins (e.g., ceftriaxone and cefixime) have

lower cross-reactivity with IgE-mediated penicillin-allergic

patients (<1%) compared with first- and second-generation

cephalosporins (range: 1%–8%). Moreover, anaphylaxis

secondary to cephalosporins is extremely rare among persons

who report a penicillin allergy and is estimated to occur at a rate

of one per 52,000 persons (652). Data from the Kaiser health

care system reported that among 3,313 patients with self-

reported cephalosporin allergy who received a cephalosporin

(mostly first generation), no cases of anaphylaxis were reported

(652). Use of third- and fourth-generation cephalosporins

and carbapenems is safe for patients without a history of any

IgE-mediated symptoms (e.g., anaphylaxis or urticaria) from

penicillin during the preceding 10 years.

Validating Penicillin or Another ß-Lactam

Antibiotic Allergy

Evaluating a patient who reports a penicillin or another

ß-lactam antibiotic allergy involves three steps: 1) obtaining

a thorough medical history, including previous exposures to

penicillin or other ß-lactam antibiotics (658); 2) performing

a skin test evaluation by using the penicillin major and minor

determinants; and 3) among those who have a negative

penicillin skin test, performing an observed oral challenge with

250 mg amoxicillin before proceeding directly to treatment

with the indicated ß-lactam therapy (667,675).

For persons who have a positive skin test reactive to penicillin

(either to the major or minor determinants), treatment with a

ß-lactam antibiotic is not usually advised, and other effective

antimicrobials should be used (656,658). For persons among

whom the only therapy option is a penicillin antibiotic (e.g., a

patient with neurosyphilis or a pregnant woman with syphilis)

and among whom a penicillin skin test is positive, induction

of penicillin tolerance (also referred to as desensitization) is

required (675). Desensitization protocols to penicillin should

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be performed by allergists, and they require a monitored

inpatient environment.

Penicillin Skin Testing

Penicillin skin testing with a major determinant

analog (penicilloyl-polylysine) and minor determinants

(benzylpenicilloate, benzylpenilloate, or benzylpenicillin

isomers of penicillin) are used for skin test evaluation for

IgE-dependent penicillin allergy and can reliably identify

persons at high risk for IgE-mediated reactions to penicillin

(658,660,676). Until recently, penicillin skin testing in the

United States only included the major determinant benzyl

penicillin poly-L-lysine (Pre-Pen) in addition to penicillin

G. This test identifies approximately 90%–99% of the IgE-

mediated penicillin-allergic patients. Because the remaining

1%–10% of penicillin-allergic patients who are not captured

by this penicillin skin test are due to minor determinants IgE

antibodies, the standard practice is to follow skin testing with

an observed oral challenge of amoxicillin 250 mg with 1 hour

of observation. If the skin test and oral challenge are both

negative, the risk for IgE-mediated anaphylaxis approaches zero

and is equivalent to that of a person who has never reported

an allergy to penicillin.

A revised version of the penicillin skin test kit, which includes

the major determinant reagent Pre-Pen, minor determinants,

and amoxicillin, is being evaluated by FDA. This penicillin

skin test kit has been evaluated among 455 patients (677)

with previous allergy history and has a negative predictive

value of 98%. If approved, this kit might eliminate the need

for oral challenge.

Penicillin skin testing has become a clinically significant

element in antibiotic stewardship programs, and the

procedure has been increasingly used by hospital-based

pharmacists, hospitalists, and infectious disease physicians

(670,672,673,678,679) as part of overall antibiotic stewardship

interventions. When integrated into stewardship, the rates of

ß-lactam antibiotic use increased substantially (670).

Recommendations

Persons with a history of severe adverse cutaneous

reaction (e.g., Stevens-Johnson syndrome or toxic epidermal

necrolysis) and other severe non–IgE-mediated reactions (e.g.,

interstitial nephritis or hemolytic anemia) are not candidates

for penicillin skin testing or challenge. Penicillin and any

other ß-lactam antibiotics should be avoided indefinitely

among these patients, who should be referred to an allergy

center for further evaluation. Similarly, patients who deny

penicillin allergy, but who report previous IgE-type reactions

to cephalosporins, should be referred to an allergist for specific

cephalosporin testing.

In a time of increasing antimicrobial resistance, following

recommended use of antibiotic treatments is crucial. STI

programs and clinicians should promote increased access to

penicillin allergy testing. Allergy testing is being provided by

clinicians in primary care and hospital settings. If appropriate,

STI programs and ambulatory settings should consider

developing expanded access to penicillin or ß-lactam allergy

assessment.

Persons with high-risk symptom histories (e.g., anaphylaxis

within the previous 10 years) should not be administered

penicillin or a ß-lactam antibiotic in an ambulatory setting.

Furthermore, these persons with high-risk symptoms should

not receive penicillin skin testing or amoxicillin oral challenge

in an ambulatory STI setting and should be referred to an

allergist for further evaluation.

High-risk symptom histories include development of

the following after penicillin or ß-lactam administration:

anaphylaxis within 6 hours or severe adverse cutaneous reaction

(e.g., eosinophilia and systemic symptoms, Stevens-Johnson

syndrome, toxic epidermal necrolysis, or acute generalized

exanthematous pustulosis) and other severe non–IgE-mediated

reactions (e.g., kidney or hepatic injury, hemolytic anemia, or

thrombocytopenia).

Direct Treatment Approach for Ceftriaxone

Among persons with confirmed IgE-mediated penicillin

allergy, the level of cross-reactivity with third-generation

cephalosporins is low (652,680,681). If a patient has a low-

risk history for an IgE-mediated penicillin allergy, ambulatory

settings often treat with third-generation cephalosporins

without further testing. Low-risk history includes one

nonspecific symptom (e.g., gastrointestinal intolerance,

headache, fatigue, or nonurticarial rash) (Box 2). In addition,

a family history of penicillin or ß-lactam allergy alone is not a

contraindication for treatment with ß-lactam antibiotics. This

practice is increasingly being used in ambulatory settings and

for preoperative prophylaxis (658,663,680,682–684).

BOX 2. Low-risk history in patients who report penicillin allergy

Gastrointestinal symptoms

Headache

Pruritis without rash

Localized rash

Delayed onset rash (>24 hours)

Symptoms unknown

Family history of penicillin or another drug allergy

Patient denies allergy but it is on the medical record

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Patients at Low Risk for Oral Challenge

If the patient gives only a low-risk history of IgE-mediated

penicillin allergy that includes symptoms such gastrointestinal

intolerance, headache, fatigue, or nonspecific pruritus, or gives

a family history only, an oral challenge can be administered

to document the absence of allergy (Box 2). If the reaction

occurred in the distant past (>10 years), the likelihood is

reduced even further (653,658,663,682,683,685,686). The

risk for severe amoxicillin-mediated anaphylaxis has decreased

over time and is rare. In the United Kingdom during 1972–

2007, one fatal case of amoxicillin-medicated anaphylaxis was

reported (684).

Skin Testing for Penicillin Allergy

Skin testing for penicillin allergy should be performed if

any indication exists that the symptoms were secondary to an

IgE-mediated hypersensitivity. Testing is also indicated as a

potential diagnostic procedure to definitively rule out penicillin

allergy and document a negative allergy status in the medical

record (i.e., delabeling). Because penicillin allergy testing

does not test for multiple minor determinants, a person with

a negative skin test should follow up with an oral challenge to

confirm the negative status.

Persons with negative results of a penicillin skin test, followed by

an amoxicillin oral challenge, can receive conventional penicillin

therapy safely if needed. Persons with positive skin test results and

for whom no other clinical options exist (e.g., neurosyphilis and

syphilis in a pregnant woman) should be referred to an allergist

and desensitized before initiating treatment.

Testing Procedures

Penicillin skin testing includes use of skin test reagents for

identifying persons at risk for adverse reactions (Box 3), followed

by initial pinprick screening with penicillin major determinants

(Pre-Pen) and penicillin G, followed by intradermal testing if

pinprick results are negative. Penicillin testing procedures are

performed in accordance with the Pre-Pen test kit instructions

(https://penallergytest.com/wp-content/uploads/PRE-PEN-

Package-Insert.pdf). Saline negative controls and histamine

positive controls are an integral part of the procedure. Penicillin

skin testing should not be performed for patients who have

taken antihistamines within the past 7 days.

Skin testing can be safely performed by trained

nonallergists and has been implemented as an antimicrobial

stewardship intervention by internal medicine physicians,

pharmacists, hospitalists, and infectious disease physicians

(670,673,678,679). Patients tested should also receive

documentation of status, and the results should be entered in

the medical record.

Penicillin skin testing during pregnancy is considered safe.

For pregnant persons who report a penicillin or ß-lactam

allergy, penicillin allergy is an important consideration in

treating syphilis during pregnancy and the potential for group

B streptococcal infection and preoperative prophylaxis if a

cesarean delivery is required. However, oral challenges should

not be performed unless in a setting where additional support

services are available.

Managing Persons Being Tested

Patients who have a positive skin test should not receive

ß-lactam drugs in the ambulatory setting and should be

referred to an allergist or penicillin allergy expert for further

evaluation. The allergy testing results should be documented

in the medical record. Patients who test negative should be

informed that their risk for anaphylaxis is extremely low and is

equivalent to a person who does not report an allergy history. If

treatment with penicillin or ceftriaxone is indicated, it can be

administered safely. Documentation of testing results should

be provided to the patient.

Desensitization

Desensitization is required for persons who have a

documented penicillin allergy and for whom no therapeutic

alternatives exist (e.g., syphilis during pregnancy and persons

with neurosyphilis). Modified protocols might be considered

BOX 3. Skin test reagents for identifying persons at risk for

adverse reactions to penicillin

Major determinant

• Benzylpenicilloyl polylysine injection (Pre-Pen)

(AllerQuest) (6 × 10

-5

Minor determinant precursors

• Benzylpenicillin G (10

-2

M, 3.3 mg/mL, 10,000 units/mL)

• Benzylpenicilloate (10

-2

M, 3.3 mg/mL)

• Benzylpenicilloate (or penicilloyl propylamine)

(10

-2

M, 3.3 mg/mL)

Aged penicillin is not an adequate source of minor

determinants. Penicillin G should either be freshly

prepared or come from a fresh-frozen source.

Positive control

• Commercial histamine for scratch testing (1.0 mg/mL)

Negative control

• Diluent (usually saline) or allergen diluent

Source: Adapted from Saxon A, Beall GN, Rohr AS, Adelman DC. Immediate

hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med

1987;107:204−15.

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on the basis of the clinical syndrome, drug of choice, and route

of administration (687–690). Patients might require referral

to a specialty center where desensitization can be performed.

Allergy Referral Resources

With increased access to skin testing kits and the need to

better target therapy for gonorrhea and syphilis, programs

should identify local allergy consultant resources.

Diseases Characterized by Urethritis

and Cervicitis

Urethritis

Urethritis, as characterized by urethral inflammation, can

result from either infectious or noninfectious conditions.

Symptoms, if present, include dysuria, urethral pruritis,

and mucoid, mucopurulent, or purulent discharge. Signs of

urethral discharge on examination can also be present among

persons without symptoms. Although N. gonorrhoeae and C.

trachomatis are well established as clinically important infectious

causes of urethritis, M. genitalium has been strongly associated

with urethritis and, less commonly, prostatitis (691–697). If

POC diagnostic tools (e.g., Gram, methylene blue [MB], or

gentian violet [GV] stain microscopy) are unavailable, drug

regimens effective against both gonorrhea and chlamydia

should be administered. Further testing to determine the

specific etiology is recommended for preventing complications,

reinfection, and transmission because a specific diagnosis might

improve treatment compliance, delivery of risk-reduction

interventions, and partner services. Both chlamydia and

gonorrhea are reportable to health departments. NAATs are

preferred for detecting C. trachomatis and N. gonorrhoeae, and

urine is the preferred specimen for males (553). NAAT-based

tests for diagnosing T. vaginalis among men with urethritis

have not been cleared by FDA; however, laboratories have

performed the CLIA-compliant validation studies (698)

needed to provide such testing.

Etiology

Multiple organisms can cause infectious urethritis. The

presence of gram-negative intracellular diplococci (GNID)

or purple intracellular diplococci (MB or GV) on urethral

smear is indicative of presumed gonococcal infection,

which is frequently accompanied by chlamydial infection.

Nongonococcal urethritis (NGU), which is diagnosed when

microscopy of urethral secretions indicate inflammation

without GNID or MB or GV purple intracellular diplococci,

is caused by C. trachomatis in 15%–40% of cases; however,

prevalence varies by age group, with a lower proportion of

disease occurring among older men (699). Documentation

of chlamydial infection as NGU etiology is essential because

of the need for partner referral for evaluation and treatment

to prevent complications of chlamydia, especially for female

partners. Complications of C. trachomatis–associated NGU

among males include epididymitis, prostatitis, and reactive

arthritis.

M. genitalium is associated with symptoms of urethritis and

urethral inflammation and accounts for 15%–25% of NGU

cases in the United States (691–693,696,697,700). Among

men with symptoms of urethritis, M. genitalium was detected

in 11% of those with urethritis in Australia (701), 12%–15%

in the United Kingdom (702–704), 15% in South Africa (696),

19% in China (705), 21% in Korea, 22% in Japan (706), and

28.7% in the United States (range: 20.4%–38.8%) (697). Data

are inconsistent regarding other Mycoplasma and Ureaplasma

species as etiologic agents of urethritis (707). The majority

of men with Ureaplasma infections do not have overt disease

unless a high organism load is present.

T. vaginalis can cause urethritis among heterosexual

men; however, the prevalence varies substantially by U.S.

geographic region, age, and sexual behavior and within specific

populations. Studies among men with and without overt

urethritis in developed countries document relatively low

rates of T. vaginalis in the Netherlands (0.5%) (708), Japan

(1.3%) (706,709), the United States (2.4%) (710), and the

United Kingdom (3.6%) (703). Studies in other countries have

documented higher rates, such as in Croatia (8.2%) (711) and

Zimbabwe (8.4%) (712), particularly among symptomatic

patients.

Neisseria meningitidis can colonize mucosal surfaces and

cause urethritis (713). Urogenital N. meningitidis rates

and duration of carriage, prevalence of asymptomatic and

symptomatic infection, and modes of transmission have

not been systematically described; however, studies indicate

that N. meningitidis can be transmitted through oral-

penile contact (i.e., fellatio) (714–716). N. meningitidis

has similar colony morphology appearance on culture and

cannot be distinguished from N. gonorrhoeae on Gram stain.

Identification of N. meningitidis as the etiologic agent with

presumed gonococcal urethritis on the basis of Gram stain

but negative NAAT for gonorrhea requires a confirmation

by culture. Meningococcal urethritis is treated with the same

antimicrobial regimens as gonococcal urethritis. Although

evidence is limited regarding the risk for sexual transmission or

recurrent infections with meningococcal urethritis, treatment

of sex partners of patients with meningococcal urethritis with

the same antimicrobial regimens as for exposure to gonococcal

infection can be considered. No indication exists for treating

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persons with N. meningitidis identified in their oropharynx

when not also associated with symptomatic urethritis.

In other instances, NGU can be caused by HSV, Epstein-

Barr virus, and adenovirus (699) acquired by fellatio (i.e., oral-

penile contact). In a retrospective review of 80 cases of HSV

urethritis in Australia (717), the majority of infections were

associated with HSV-1 with clinical findings of meatitis (62%),

genital ulceration (37%), and dysuria (20%). Adenovirus can

present with dysuria, meatal inflammation, and conjunctivitis

(718). Enteric bacteria have been identified as an uncommon

cause of NGU and might be associated with insertive anal

intercourse (699).

Other bacterial pathogens have been implicated as potential

causes of clinical urethritis, either in clustered case series or as

sporadic cases such as Haemophilus influenzae and Haemophilus

parainfluenzae (719–723). Haemophilus was identified in 12.6%

of cases among 413 men (mostly MSM reporting insertive oral

sex) (724), and high rates of azithromycin resistance (39.5%)

were identified among Haemophilus urethritis patients (725).

Individual case reports have linked NGU to multiple bacterial

species, including Corynebacterium propinquum (726), Kurthia

gibsonii (727), Corynebacterium glucuronolyticum (728,729),

Corynebacterium striatrium (730), Aerococcus urinae (731),

and Neisseria elongata (732). Diagnostic testing and treatment

for less-common organisms are reserved for situations in

which these infections are suspected (e.g., sexual partner with

trichomoniasis, urethral lesions, or severe dysuria and meatitis)

or when NGU is not responsive to recommended therapy.

Even in settings that provide comprehensive diagnostic

testing, etiology can remain obscure in half of cases. Idiopathic

NGU was reported in 772 (59%) of 1,295 first presentations

of NGU among men seeking sexual health services in Australia

(701). In a case-control study of 211 men with NGU

symptoms in Denmark, no identifiable pathogen was identified

in 24% of acute cases and 33% of chronic cases (733). NGU’s

importance if not caused by a defined pathogen is uncertain;

neither complications (e.g., urethral stricture or epididymitis)

nor adverse outcomes among sex partners have been identified

in these cases.

Associations between NGU and insertive anal and oral

exposure have been reported (734), as have higher rates

of BV-associated Leptotrichia or Sneathia species among

heterosexual men with urethritis (735). These studies increase

concern for possible undetected infectious rectal or vaginal

pathogens, or alternatively, a transient reactive dysbiosis after

exposure to a new microbiome or even a noninfectious reactive

etiology (736).

Diagnostic Considerations

Clinicians should attempt to obtain objective evidence of

urethral inflammation. If POC diagnostic tests (e.g., Gram

stain or MB or GV microscopy) are unavailable, urethritis

can be documented on the basis of any of the following signs

or laboratory tests:

• Mucoid, mucopurulent, or purulent discharge on examination.

• Gram stain is a POC diagnostic test for evaluating

urethritis that is highly sensitive and specific for

documenting both urethritis and the presence or absence

of gonococcal infection; MB or GV stain of urethral

secretions is an alternative POC diagnostic test with

performance characteristics similar to Gram stain; thus,

the cutoff number for WBCs per oil immersion field

should be the same (737).

Presumed gonococcal infection is established by

documenting the presence of WBCs containing GNID

in Gram stain or intracellular purple diplococci in MB

or GV smears; men should be tested for C. trachomatis

and N. gonorrhoeae by NAATs and presumptively treated

and managed accordingly for gonococcal infection (see

Gonococcal Infections).

If no intracellular gram-negative or purple diplococci

are present, men should receive NAATs for C. trachomatis

and N. gonorrhoeae and can be managed for NGU as

recommended (see Nongonococcal Urethritis).

Gram stain of urethral secretions exist that demonstrate

≥2 WBCs per oil immersion field (738). The microscopy

diagnostic cutoff might vary, depending on background

prevalence (≥2 WBCs/high power field [HPF] in high-

prevalence settings [STI clinics] or ≥5 WBCs/HPF in

lower-prevalence settings).

§§

For urethral microscopy, the cutoff for diagnosing urethritis is ≥2 WBCs/HPF

(Sources: Rietmeijer CA, Mettenbrink CJ. Recalibrating the Gram stain

diagnosis of male urethritis in the era of nucleic acid amplification testing. Sex

Transm Dis 2012;39:18–20; Rietmeijer CA, Mettenbrink CJ. The diagnosis

of nongonococcal urethritis in men: can there be a universal standard? Sex

Transm Dis 2017;44:195–6). An additional evaluation supported this cutoff

by demonstrating NGU sensitivity of 92.6% for cutoff of ≥2 versus 55.6%

sensitivity for cutoff of ≥5 (Source: Sarier M, Sepin N, Duman I, et al.

Microscopy of Gram-stained urethral smear in the diagnosis of urethritis: which

threshold value should be selected? Andrologia 2018;50:e13143). Diagnostic

cutoffs for 369 symptomatic and asymptomatic heterosexual men seeking STI

care in Seattle revealed a maximal sensitivity and specificity achieved with a

cutoff of ≥5 WBCs/HPF. Using a lower cutoff of ≥2 WBCs/HPF would miss

13% of C. trachomatis and M. genitalium and overtreat 45% of persons who

have negative tests (Source: Leipertz G, Chambers L, Lowens S, et al. P796

Reassessing the Gram stain smear [GSS] polymorphonuclear leukocyte [PMN]

cutoff for diagnosing non-gonococcal urethritis [NGU]. Sex Transm Infect

2019;95[Suppl 1]:A339). Another study discussed that the WBC/HPF cutoff

value should discriminate on the basis of the prevalence of chlamydia,

mycoplasma, and gonorrhea among a clinic population (Source: Moi H,

Hartgill U, Skullerud KH, Reponen EJ, Syvertsen L, Moghaddam A.

Microscopy of stained urethral smear in male urethritis: which cutoff should

be used? Sex Transm Dis 2017;44:189–94).

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• Positive leukocyte esterase test on first-void urine or

microscopic examination of sediment from a spun first-

void urine demonstrating ≥10 WBCs/HPF.

Men evaluated in settings in which Gram stain or MB or

GV smear is unavailable who meet at least one criterion for

urethritis (i.e., urethral discharge, positive leukocyte esterase

test on first void urine, or microscopic examination of first-

void urine sediment with ≥10 WBCs/HPF) should be tested

for C. trachomatis and N. gonorrhoeae by NAATs and treated

with regimens effective against gonorrhea and chlamydia.

If symptoms are present but no evidence of urethral

inflammation is present, NAATs for C. trachomatis and

N. gonorrhoeae might identify infections (739). Persons

with chlamydia or gonorrhea should receive recommended

treatment, and sex partners should be referred for evaluation

and treatment. If none of these clinical criteria are present,

empiric treatment of men with symptoms of urethritis is

recommended only for those at high risk for infection who are

unlikely to return for a follow-up evaluation or test results. Such

men should be treated with drug regimens effective against

gonorrhea and chlamydia.

Nongonococcal Urethritis

NGU is a nonspecific diagnosis that can have various

infectious etiologies. C. trachomatis has been well established

as an NGU etiology; however, prevalence varies across

populations and accounts for <50% of overall cases (712,740–

742). M. genitalium is estimated to account for 10%–25% of

cases (696,697,701,703,704,706,733,743), and T. vaginalis

for 1%–8% of cases depending on population and location

(703,706,708,710,712). Other etiologies include different

bacteria, such as Haemophilus species (724,725), N. meningitidis

(713,716), HSV (706,717), and adenovirus (744). However,

even when extensive testing is performed, no pathogens are

identified in approximately half of cases (701,733).

Diagnostic Considerations

Clinical presentation can include urethral discharge,

irritation, dysuria, or meatal pruritus (697,743,745). NGU is

confirmed for symptomatic men when diagnostic evaluation of

urethral secretions indicates inflammation, without evidence

of diplococci by Gram, MB, or GV smear on microscopy

(712,746,747). Visible discharge or secretions can be collected

by a swab without inserting it into the urethra; if no visible

secretions, the swab can be inserted into the urethral meatus

and rotated, making contact with the urethral wall before

removal. If microscopy is unavailable, urine testing for

leukocyte esterase can be performed on first-void urine, and

microscopic examination of sediment from a spun first-void

urine demonstrating ≥10 WBCs/HPF has a high negative

predictive value.

All men who have suspected or confirmed NGU should

be tested for chlamydia and gonorrhea by using NAATs.

A specific diagnosis can potentially reduce complications,

reinfection, and transmission. M. genitalium testing should be

performed for men who have persistent or recurrent symptoms

after initial empiric treatment. Testing for T. vaginalis should

be considered in areas or among populations with high

prevalence, in cases where a partner is known to be infected,

or for men who have persistent or recurrent symptoms after

initial empiric treatment.

Treatment

Ideally, treatment should be pathogen based; however,

diagnostic information might not be immediately available.

Presumptive treatment should be initiated at NGU diagnosis.

Doxycycline is highly effective for chlamydial urethral

infections and is also effective for chlamydial infections of

the rectum; it also has some activity against M. genitalium.

In contrast, reports have increased of azithromycin treatment

failures for chlamydial infection (748,749), and the incidence

of macrolide resistance in M. genitalium also has been rapidly

rising (697,702,705,750,751). Pharmacokinetic data indicate

that changing azithromycin dosing from a single-dose strategy

to a multiday strategy might protect against inducing resistance

in M. genitalium infections (745,752) (see Mycoplasma

genitalium).

Recommended Regimen for Nongonococcal Urethritis

Doxycycline 100 mg orally 2 times/day for 7 days

Alternative Regimens

Azithromycin 1 g orally in a single dose

Azithromycin 500 mg orally in a single dose; then 250 mg orally daily

for 4 days

To maximize compliance with recommended therapies,

medications should be dispensed on-site at the clinic, and,

regardless of the number of doses involved in the regimen,

the first dose should be directly observed. Erythromycin is no

longer recommended for NGU because of its gastrointestinal

side effects and dosing frequency. Levofloxacin is no longer

recommended for NGU because of its inferior efficacy,

especially for M. genitalium.

Management Considerations

To minimize transmission and reinfections, men treated for

NGU should be instructed to abstain from sexual intercourse

until they and their partners have been treated (i.e., until

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completion of a 7-day regimen and symptoms have resolved or

for 7 days after single-dose therapy). Men with NGU should

be tested for HIV and syphilis.

Follow-Up

Men should be provided their testing results obtained as

part of the NGU evaluation. Those with a specific diagnosis

of chlamydia, gonorrhea, or trichomoniasis should be

offered partner services and instructed to return 3 months

after treatment for repeat testing because of high rates of

reinfection, regardless of whether their sex partners were treated

(136,137,753,754) (see Chlamydial Infections; Gonococcal

Infections; Trichomoniasis).

If symptoms persist or recur after therapy completion, men

should be instructed to return for reevaluation and should be

tested for M. genitalium and T. vaginalis. Symptoms alone,

without documentation of signs or laboratory evidence of

urethral inflammation, are insufficient basis for retreatment.

Providers should be alert to the possible diagnosis of chronic

prostatitis or chronic pelvic pain syndrome in men experiencing

persistent perineal, penile, or pelvic pain or discomfort;

voiding symptoms; pain during or after ejaculation; or new-

onset premature ejaculation lasting for >3 months. Men with

persistent pain should be referred to a urologist with expertise

in pelvic pain disorders.

Management of Sex Partners

All sex partners of men with NGU within the preceding

60 days should be referred for evaluation and testing and

presumptive treatment with a drug regimen effective against

chlamydia. All partners should be evaluated and treated

according to the management section for their respective

pathogen; EPT could be an alternate approach if a partner is

unable to access timely care. To avoid reinfection, sex partners

should abstain from sexual intercourse until they and their

partners are treated.

Persistent or Recurrent Nongonococcal Urethritis

The objective diagnosis of persistent or recurrent NGU

should be made before considering additional antimicrobial

therapy. Symptomatic recurrent or persistent urethritis might

be caused by treatment failure or reinfection after successful

treatment. Among men who have persistent symptoms after

treatment without objective signs of urethral inflammation, the

value of extending the duration of antimicrobials has not been

demonstrated. Treatment failure for chlamydial urethritis has

been estimated at 6%–12% (755). The most common cause

of persistent or recurrent NGU is M. genitalium, especially

after doxycycline therapy (756,757). Treatment failure for

M. genitalium is harder to determine because certain men

achieve clinical cure (i.e., resolution of symptoms) but can

still have detectable M. genitalium in urethral specimens (758).

The initial step in recurrent urethritis is assessing compliance

with treatment or potential reexposure to an untreated sex

partner (697,743). If the patient did not comply with the

treatment regimen or was reexposed to an untreated partner,

retreatment with the initial regimen can be considered. If

therapy was appropriately completed and no reexposure

occurred, therapy is dependent on the initial treatment

regimen. Ideally, diagnostic testing among men with recurrent

or persistent symptoms, including those with gonorrhea,

chlamydia, M. genitalium, and trichomoniasis, can be used to

guide further management decisions.

T. vaginalis is also known to cause urethritis among men who

have sex with women. In areas where T. vaginalis is prevalent,

men who have sex with women with persistent or recurrent

urethritis should be tested for T. vaginalis and presumptively

treated with metronidazole 2 g orally in a single dose or

tinidazole 2 g orally in a single dose; their partners should be

referred for evaluation and treatment, if needed.

If T. vaginalis is unlikely (MSM with NGU or negative

T. vaginalis NAAT), men with recurrent NGU should be tested

for M. genitalium by using an FDA-cleared NAAT. Treatment

for M. genitalium includes a two-stage approach, ideally using

resistance-guided therapy. If M. genitalium resistance testing is

available it should be performed, and the results should be used

to guide therapy (see Mycoplasma genitalium). If M. genitalium

resistance testing is not available, doxycycline 100 mg orally

2 times/day for 7 days followed by moxifloxacin 400 mg orally

once daily for 7 days should be used. The rationale for this

approach is that although not curative, doxycycline decreases

the M. genitalium bacterial load, thereby increasing likelihood

of moxifloxacin success (759). Higher doses of azithromycin

have not been effective for M. genitalium after azithromycin

treatment failures. Men with persistent or recurrent NGU after

treatment for M. genitalium or T. vaginalis should be referred

to an infectious disease or urology specialist.

Special Considerations

HIV Infection

NGU might facilitate HIV transmission (760). Persons with

NGU and HIV infection should receive the same treatment

regimen as those who do not have HIV.

Cervicitis

Two major diagnostic signs characterize cervicitis: 1) a

purulent or mucopurulent endocervical exudate visible in

the endocervical canal or on an endocervical swab specimen

(commonly referred to as mucopurulent cervicitis), and

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2) sustained endocervical bleeding easily induced by gentle

passage of a cotton swab through the cervical os. Either or both

signs might be present. Cervicitis frequently is asymptomatic;

however, certain women might report an abnormal vaginal

discharge and intermenstrual vaginal bleeding (e.g., especially

after sexual intercourse). The criterion of using an increased

number of WBCs on endocervical Gram stain in the diagnosis

of cervicitis has not been standardized; it is not sensitive,

has a low positive predictive value for C. trachomatis and

N. gonorrhoeae infections, and is not available in most clinical

settings (297,761). Leukorrhea, defined as >10 WBCs/HPF on

microscopic examination of vaginal fluid, might be a sensitive

indicator of cervical inflammation with a high negative

predictive value (i.e., cervicitis is unlikely in the absence of

leukorrhea) (762,763). Finally, although the presence of gram-

negative intracellular diplococci on Gram stain of endocervical

exudate might be specific for diagnosing gonococcal cervical

infection when evaluated by an experienced laboratorian, it is

not a sensitive indicator of infection (764).

Etiology

C. trachomatis or N. gonorrhoeae is the most common etiology

of cervicitis defined by diagnostic testing. Trichomoniasis,

genital herpes (especially primary HSV-2 infection), or

M. genitalium (761,765–768) also have been associated

with cervicitis. However, in many cases of cervicitis, no

organism is isolated, especially among women at relatively

low risk for recent acquisition of these STIs (e.g., women aged

>30 years) (769). Limited data indicate that BV and frequent

douching might cause cervicitis (770–772). The majority

of persistent cases of cervicitis are not caused by reinfection

with C. trachomatis or N. gonorrhoeae; other factors might

be involved (e.g., persistent abnormality of vaginal flora,

M. genitalium, douching or exposure to other types of chemical

irritants, dysplasia, or idiopathic inflammation in the zone of

ectopy). Available data do not indicate an association between

group B streptococcus colonization and cervicitis (773,774).

No specific evidence exists for a role for Ureaplasma parvum or

Ureaplasma urealyticum in cervicitis (707,761,765,775,776).

Diagnostic Considerations

Because cervicitis might be a sign of upper genital tract

infection (e.g., endometritis), women should be assessed for

signs of PID and tested for C. trachomatis and N. gonorrhoeae

with NAAT on vaginal, cervical, or urine samples (553) (see

Chlamydial Infections; Gonococcal Infections). Women

with cervicitis also should be evaluated for concomitant BV

and trichomoniasis. Because sensitivity of microscopy for

detecting T. vaginalis is relatively low (approximately 50%),

symptomatic women with cervicitis and negative wet-mount

microscopy for trichomonads should receive further testing

(i.e., NAAT, culture, or other FDA-cleared diagnostic test)

(see Trichomoniasis). Testing for M. genitalium with the FDA-

cleared NAAT can be considered. Although HSV-2 infection

has been associated with cervicitis, the utility of specific testing

(i.e., PCR or culture) for HSV-2 is unknown. Testing for

U. parvum, U. urealyticum, Mycoplasma hominis, or genital

culture for group B streptococcus is not recommended.

Treatment

Multiple factors should affect the decision to provide

presumptive therapy for cervicitis. Presumptive treatment with

antimicrobials for C. trachomatis and N. gonorrhoeae should

be provided for women at increased risk (e.g., those aged

<25 years and women with a new sex partner, a sex partner

with concurrent partners, or a sex partner who has an STI), if

follow-up cannot be ensured, or if testing with NAAT is not

possible. Trichomoniasis and BV should be treated if detected

(see Bacterial Vaginosis; Trichomoniasis). For women at lower

risk for STIs, deferring treatment until results of diagnostic

tests are available is an option. If treatment is deferred and

C. trachomatis and N. gonorrhoeae NAATs are negative, a

follow-up visit to determine whether the cervicitis has resolved

can be considered.

Recommended Regimen for Cervicitis*

Doxycycline 100 mg orally 2 times/day for 7 days

* Consider concurrent treatment for gonococcal infection if the patient is

at risk for gonorrhea or lives in a community where the prevalence of

gonorrhea is high (see Gonococcal Infections).

Alternative Regimen

Azithromycin 1 g orally in a single dose

Other Management Considerations

To minimize transmission and reinfection, women treated

for cervicitis should be instructed to abstain from sexual

intercourse until they and their partners have been treated

(i.e., until completion of a 7-day regimen or for 7 days after

single-dose therapy) and symptoms have resolved. Women

who receive a cervicitis diagnosis should be tested for syphilis

and HIV in addition to other recommended diagnostic tests.

Follow-Up

Women receiving treatment should return to their provider

for a follow-up visit to determine whether cervicitis has

resolved. For women who are untreated, a follow-up visit gives

providers an opportunity to communicate test results obtained

as part of the cervicitis evaluation. Providers should treat on

the basis of any positive test results and determine whether

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cervicitis has resolved. Women with a specific diagnosis of

chlamydia, gonorrhea, or trichomoniasis should be offered

partner services and instructed to return in 3 months after

treatment for repeat testing because of high rates of reinfection,

regardless of whether their sex partners were treated (753). If

symptoms persist or recur, women should be instructed to

return for reevaluation.

Management of Sex Partners

Management of sex partners of women treated for cervicitis

should be tailored for the specific infection identified or

suspected. All sex partners during the previous 60 days should

be referred for evaluation, testing, and presumptive treatment

if chlamydia, gonorrhea, or trichomoniasis was identified. EPT

and other effective partner referral strategies are alternative

approaches for treating male partners of women who have

chlamydial or gonococcal infection (125–127) (see Partner

Services). To avoid reinfection, sex partners should abstain

from sexual intercourse until they and their partners are treated.

Persistent or Recurrent Cervicitis

Women with persistent or recurrent cervicitis despite

antimicrobial therapy should be reevaluated for possible

reexposure or treatment failure. If relapse or reinfection with

a specific infection has been excluded, BV is not present, and

sex partners have been evaluated and treated, management

options for persistent cervicitis are undefined. In addition,

the usefulness of repeated or prolonged administration of

antimicrobial therapy for persistent symptomatic cervicitis

remains unknown. The etiology of persistent cervicitis,

including the potential role of M. genitalium (777), is unclear.

M. genitalium might be considered for cases of cervicitis that

persist after azithromycin or doxycycline therapy in which

reexposure to an infected partner or medical nonadherence is

unlikely. Among women with persistent cervicitis who were

previously treated with doxycycline or azithromycin, testing

for M. genitalium can be considered and treatment initiated on

the basis of results of diagnostic testing (318) (see Mycoplasma

genitalium). For women with persistent symptoms that are

clearly attributable to cervicitis, referral to a gynecologic

specialist can be considered for evaluation of noninfectious

causes (e.g., cervical dysplasia or polyps) (778).

Special Considerations

HIV Infection

Women with cervicitis and HIV infection should receive

the same treatment regimen as those who do not have HIV.

Cervicitis can increase cervical HIV shedding, and treatment

reduces HIV shedding from the cervix and thereby might

reduce HIV transmission to susceptible sex partners (779–783).

Pregnancy

Diagnosis and treatment of cervicitis for pregnant women

does not differ from that for women who are not pregnant (see

Diagnostic Considerations; Treatment).

Contraceptive Management

According to U.S. Medical Eligibility Criteria for Contraceptive

Use, 2016, leaving an IUD in place during treatment for

cervicitis is advisable (58). However, current recommendations

specify that an IUD should not be placed if active cervicitis

is diagnosed (59).

Chlamydial Infections

Chlamydial Infection Among

Adolescents and Adults

Chlamydial infection is the most frequently reported

bacterial infectious disease in the United States, and prevalence

is highest among persons aged ≤24 years (141,784). Multiple

sequelae can result from C. trachomatis infection among

women, the most serious of which include PID, ectopic

pregnancy, and infertility. Certain women who receive a

diagnosis of uncomplicated cervical infection already have

subclinical upper genital tract infection.

Asymptomatic infection is common among both men and

women. To detect chlamydial infection, health care providers

frequently rely on screening tests. Annual screening of all

sexually active women aged <25 years is recommended, as is

screening of older women at increased risk for infection (e.g.,

women aged ≥25 years who have a new sex partner, more

than one sex partner, a sex partner with concurrent partners,

or a sex partner who has an STI) (149). In a community-

based cohort of female college students, incident chlamydial

infection was also associated with BV and high-risk HPV

infection (785). Although chlamydia incidence might be higher

among certain women aged ≥25 years in certain communities,

overall, the largest proportion of infection is among women

aged <25 years (141).

Chlamydia screening programs have been demonstrated

to reduce PID rates among women (786,787). Although

evidence is insufficient to recommend routine screening for

C. trachomatis among sexually active young men because of

certain factors (i.e., feasibility, efficacy, and cost-effectiveness),

screening of sexually active young men should be considered

in clinical settings with a high prevalence of chlamydia (e.g.,

adolescent clinics, correctional facilities, or STD specialty

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clinics) or for populations with a high burden of infection

(e.g., MSM) (149,788). Among women, the primary focus of

chlamydia screening should be to detect and treat chlamydia,

prevent complications, and test and treat their partners,

whereas targeted chlamydia screening for men should be

considered only when resources permit, prevalence is high, and

such screening does not hinder chlamydia screening efforts for

women (789–791). More frequent screening than annual for

certain women (e.g., adolescents) or certain men (e.g., MSM)

might be indicated on the basis of risk behaviors.

Diagnostic Considerations

For women, C. trachomatis urogenital infection can be

diagnosed by vaginal or cervical swabs or first-void urine. For

men, C. trachomatis urethral infection can be diagnosed by

testing first-void urine or a urethral swab. NAATs are the most

sensitive tests for these specimens and are the recommended

test for detecting C. trachomatis infection (553). NAATs that

are FDA cleared for use with vaginal swab specimens can be

collected by a clinician or patient in a clinical setting. Patient-

collected vaginal swab specimens are equivalent in sensitivity

and specificity to those collected by a clinician using NAATs

(792,793), and this screening strategy is highly acceptable

among women (794,795). Optimal urogenital specimen

types for chlamydia screening by using NAAT include first-

catch urine (for men) and vaginal swabs (for women) (553).

Recent studies have demonstrated that among men, NAAT

performance on self-collected meatal swabs is comparable

to patient-collected urine or provider-collected urethral

swabs (796–798). Patient collection of a meatal swab for

C. trachomatis testing might be a reasonable approach for men

who are either unable to provide urine or prefer to collect their

own meatal swab over providing urine. Previous evidence

indicates that the liquid-based cytology specimens collected for

Pap smears might be acceptable specimens for NAAT, although

test sensitivity using these specimens might be lower than that

associated with use of cervical or vaginal swab specimens (799);

regardless, certain NAATs have been cleared by FDA for use

on liquid-based cytology specimens.

Rectal and oropharyngeal C. trachomatis infection among

persons engaging in receptive anal or oral intercourse can be

diagnosed by testing at the anatomic exposure site. NAATs have

been demonstrated to have improved sensitivity and specificity,

compared with culture, for detecting C. trachomatis at rectal

and oropharyngeal sites (553,800–804), and certain NAAT

platforms have been cleared by FDA for these anatomic sites

(805). Data indicate that NAAT performance on self-collected

rectal swabs is comparable to clinician-collected rectal swabs,

and this specimen collection strategy for rectal C. trachomatis

screening is highly acceptable among men (217,806).

Self-collected rectal swabs are a reasonable alternative to

clinician-collected rectal swabs for C. trachomatis screening by

NAAT, especially when clinicians are not available or when self-

collection is preferred over clinician collection. Annual screening

for rectal C. trachomatis infection should be performed among

men who report sexual activity at the rectal site. Extragenital

chlamydial testing at the rectal site can be considered for

females on the basis of reported sexual behaviors and exposure

through shared clinical decision-making bythe patient and the

provider. The majority of persons with C. trachomatis detected

at oropharyngeal sites do not have oropharyngeal symptoms.

The clinical significance of oropharyngeal C. trachomatis

infection is unclear, and prevalence is low, even among

populations at high risk. However, when gonorrhea testing

is performed at the oropharyngeal site, chlamydia test results

might be reported because certain NAATs detect both bacteria

from a single specimen.

POC tests for C. trachomatis among asymptomatic persons

can expedite treatment of infected persons and their sex

partners. Among symptomatic patients, POC tests for

C. trachomatis can optimize treatment by limiting unnecessary

presumptive treatment at the time of clinical decision-making

and improve antimicrobial stewardship. Thus, using a POC

test will likely be a cost-effective diagnostic strategy for

C. trachomatis infection (807). Newer NAAT-based POC tests

have promising performance and are becoming commercially

available (807–809).

Treatment

Treating persons with C. trachomatis prevents adverse

reproductive health complications and continued sexual

transmission. Furthermore, treating their sex partners

can prevent reinfection and infection of other partners.

Treating pregnant women usually prevents transmission of

C. trachomatis to neonates during birth. Treatment should be

provided promptly for all persons with chlamydial infection;

treatment delays have been associated with complications (e.g.,

PID) in a limited proportion of women (810).

Recommended Regimen for Chlamydial Infection Among

Adolescents and Adults

Doxycycline 100 mg orally 2 times/day for 7 days

Alternative Regimens

Azithromycin 1 g orally in a single dose

Levofloxacin 500 mg orally once daily for 7 days

A meta-analysis and a Cochrane systematic review evaluated

data from randomized clinical trials of azithromycin versus

doxycycline for treating urogenital chlamydial infection

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determined that microbiologic treatment failure among men

was higher for azithromycin than for doxycycline (748,749).

Observational studies have also demonstrated that doxycycline

is more efficacious for rectal C. trachomatis infection for men

and women than azithromycin (748,811). A randomized trial

for the treatment of rectal chlamydia infection among MSM

reported microbiologic cure was 100% with doxycycline and

74% with azithromycin (812). A published review reported

that C. trachomatis was detected at the anorectal site among

33%–83% of women who had urogenital C. trachomatis

infection, and its detection was not associated with report of

receptive anorectal sexual activity (813).

Although the clinical significance of oropharyngeal

C. trachomatis infection is unclear and routine oropharyngeal

screening is not recommended, oropharyngeal C. trachomatis

can be sexually transmitted to genital sites (211,814); therefore,

if C. trachomatis is identified from an oropharyngeal specimen

while screening for pharyngeal gonorrhea, it should be treated.

Evidence is limited regarding the efficacy of antimicrobial

regimens for oropharyngeal chlamydia; however, a recently

published observational study indicates doxycycline might

be more efficacious than azithromycin for oropharyngeal

chlamydia (815).

Available evidence supports that doxycycline is efficacious

for C. trachomatis infections of urogenital, rectal, and

oropharyngeal sites. Although azithromycin maintains high

efficacy for urogenital C. trachomatis infection among women,

concern exists regarding effectiveness of azithromycin for

concomitant rectal C. trachomatis infection, which can occur

commonly among women and cannot be predicted by reported

sexual activity. Inadequately treated rectal C. trachomatis

infection among women who have urogenital chlamydia

can increase the risk for transmission and place women at

risk for repeat urogenital C. trachomatis infection through

autoinoculation from the anorectal site (816). Doxycycline is

also available in a delayed-release 200-mg tablet formulation,

which requires once-daily dosing for 7 days and is as effective

as doxycycline 100 mg twice daily for 7 days for treating

urogenital C. trachomatis infection in men and women. It is

more costly but also has lower frequency of gastrointestinal

side effects (817). Levofloxacin is an effective treatment

alternative but is more expensive. Erythromycin is no longer

recommended because of the frequency of gastrointestinal side

effects, which can result in nonadherence. When nonadherence

to doxycycline regimen is a substantial concern, azithromycin

1 g regimen is an alternative treatment option but might

require posttreatment evaluation and testing because it has

demonstrated lower treatment efficacy among persons with

rectal infection.

Among persons receiving multidose regimens, medication

should be dispensed with all doses involved, on-site and in

the clinic, and the first dose should be directly observed. To

maximize adherence with recommended therapies, on-site,

directly observed single-dose therapy with azithromycin should

always be available for persons for whom adherence with

multiday dosing is a considerable concern.

Other Management Considerations

To minimize disease transmission to sex partners, persons

treated for chlamydia should be instructed to abstain from

sexual intercourse for 7 days after single-dose therapy or until

completion of a 7-day regimen and resolution of symptoms if

present. To minimize risk for reinfection, patients also should

be instructed to abstain from sexual intercourse until all of their

sex partners have been treated. Persons who receive a diagnosis

of chlamydia should be tested for HIV, gonorrhea, and syphilis.

MSM who are HIV negative with a rectal chlamydia diagnosis

should be offered HIV PrEP.

Follow-Up

Test of cure to detect therapeutic failure (i.e., repeat testing

4 weeks after completing therapy) is not advised for nonpregnant

persons treated with the recommended or alternative regimens,

unless therapeutic adherence is in question, symptoms persist,

or reinfection is suspected. Moreover, using chlamydial NAATs

at <4 weeks after completion of therapy is not recommended

because the continued presence of nonviable organisms

(553,818,819) can lead to false-positive results.

A high prevalence of C. trachomatis infection has been

observed among women and men who were treated

for chlamydial infection during the preceding months

(753,755,820–822). The majority of posttreatment infections

do not result from treatment failure but rather from reinfection

caused by failure of sex partners to receive treatment or

initiation of sexual activity with a new infected partner (823),

indicating a need for improved education and treatment of

sex partners. Repeat infections confer an elevated risk for PID

and other complications among women. Men and women

who have been treated for chlamydia should be retested

approximately 3 months after treatment, regardless of whether

they believe their sex partners were treated; scheduling the

follow-up visit at the time of treatment is encouraged (753).

If retesting at 3 months is not possible, clinicians should retest

whenever persons next seek medical care <12 months after

initial treatment.

Management of Sex Partners

Sex partners should be referred for evaluation, testing, and

presumptive treatment if they had sexual contact with the

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partner during the 60 days preceding the patient’s onset of

symptoms or chlamydia diagnosis. Although the exposure

intervals defining identification of sex partners at risk are

based on limited data, the most recent sex partner should be

evaluated and treated, even if the time of the last sexual contact

was >60 days before symptom onset or diagnosis.

If health department partner management strategies (e.g.,

disease intervention specialists) are impractical or unavailable

for persons with chlamydia, and if a provider is concerned

that sex partners are unable to promptly access evaluation and

treatment services, EPT should be considered as permitted by

law (see Partner Services). Compared with standard patient

referral of partners, this approach to therapy, which involves

delivering the medication itself or a prescription by the

patient or collaborating pharmacy, has been associated with

decreased rates of persistent or recurrent chlamydia among

women (125–127). Providers should provide patients with

written educational materials to give to their partners about

chlamydia, which should include notification that partners

have been exposed and information about the importance

of treatment. These materials also should inform partners

about potential therapy-related allergies and adverse effects,

along with symptoms indicative of complications (e.g.,

testicular pain among men and pelvic or abdominal pain

among women). Educational materials for female partners

should include information about the importance of seeking

medical evaluation, especially if PID symptoms are present;

undertreatment of PID among female partners and missed

opportunities for diagnosing other STIs among women

are concerning. MSM with chlamydia have a high risk for

coexisting infections, especially undiagnosed HIV, among

their partners and might have partners without HIV who

could benefit from HIV PrEP. Data are also limited regarding

effectiveness of EPT in reducing persistent or recurrent

chlamydia among MSM (123,133,134); thus, shared clinical

decision-making regarding EPT for MSM is recommended.

Having partners accompany patients when they return for

treatment is another strategy that has been used successfully

for ensuring partner treatment (see Partner Services). To avoid

reinfection, sex partners should be instructed to abstain from

condomless sexual intercourse until they and their sex partners

have been treated (i.e., after completion of a 7-day regimen)

and any symptoms have resolved.

Special Considerations

Pregnancy

Clinical experience and published studies indicate that

azithromycin is safe and effective during pregnancy (824–826).

Doxycycline is contraindicated during the second and third

trimesters of pregnancy because of risk for tooth discoloration.

Human data reveal that levofloxacin presents a low risk to the

fetus during pregnancy but has potential for toxicity during

breastfeeding; however, data from animal studies increase

concerns regarding cartilage damage to neonates (431).

Test of cure (i.e., repeat testing after completion of therapy)

to document chlamydial eradication, preferably by NAAT,

at approximately 4 weeks after therapy completion during

pregnancy is recommended because severe sequelae can occur

among mothers and neonates if the infection persists. In

addition, all pregnant women who have chlamydial infection

diagnosed should be retested 3 months after treatment.

Detection of C. trachomatis infection during the third semester

is not uncommon among adolescent and young adult women,

including those without C. trachomatis detected at the time of

initial prenatal screening (827). Women aged <25 years and

those at increased risk for chlamydia (i.e., those who have a

new sex partner, more than one sex partner, a sex partner with

concurrent partners, or a sex partner who has an STI) should

be screened at the first prenatal visit and rescreened during the

third trimester to prevent maternal postnatal complications

and chlamydial infection in the infant (149).

Recommended Regimen for Chlamydial Infection During

Pregnancy

Azithromycin 1 g orally in a single dose

Alternative Regimen

Amoxicillin 500 mg orally 3 times/day for 7 days

Because of concerns regarding chlamydia persistence

after exposure to penicillin-class antibiotics that has been

demonstrated in animal and in vitro studies, amoxicillin is

listed as an alternative therapy for C. trachomatis for pregnant

women (828,829). Erythromycin is no longer recommended

because of the frequency of gastrointestinal side effects that can

result in therapy nonadherence. In addition, systematic reviews

and meta-analyses have noted an association with macrolide

antimicrobials, especially erythromycin, during pregnancy and

adverse child outcomes, indicating cautious use in pregnancy

(830–831).

HIV Infection

Persons who have chlamydia and HIV infection should

receive the same treatment regimen as those who do not

have HIV.

Chlamydial Infection Among Neonates

Prenatal screening and treatment of pregnant women is

the best method for preventing chlamydial infection among

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neonates. C. trachomatis infection of neonates results from

perinatal exposure to the mother’s infected cervix. Initial

C. trachomatis neonatal infection involves the mucous

membranes of the eye, oropharynx, urogenital tract, and

rectum, although infection might be asymptomatic in these

locations. Instead, C. trachomatis infection among neonates

is most frequently recognized by conjunctivitis that develops

5–12 days after birth. C. trachomatis also can cause a subacute,

afebrile pneumonia with onset at ages 1–3 months. Although

C. trachomatis has been the most frequent identifiable

infectious cause of ophthalmia neonatorum, neonatal

chlamydial infections, including ophthalmia and pneumonia,

have occurred less frequently since institution of widespread

prenatal screening and treatment of pregnant women. Neonates

born to mothers at high risk for chlamydial infection, with

untreated chlamydia, or with no or unconfirmed prenatal care,

are at high risk for infection. However, presumptive treatment

of the neonate is not indicated because the efficacy of such

treatment is unknown. Infants should be monitored to ensure

prompt and age-appropriate treatment if symptoms develop.

Processes should be in place to ensure communication between

physicians and others caring for the mother and the newborn

to ensure thorough monitoring of the newborn after birth.

Ophthalmia Neonatorum Caused by

C. trachomatis

A chlamydial etiology should be considered for all infants aged

≤30 days who experience conjunctivitis, especially if the mother

has a history of chlamydial infection. These infants should receive

evaluation and age-appropriate care and treatment.

Preventing Ophthalmia Neonatorum Caused by

C. trachomatis

Neonatal ocular prophylaxis with erythromycin, the only

agent available in the United States for this purpose, is

ineffective against chlamydial ophthalmia neonatorum (or

pneumonia) (833). As an alternative, prevention efforts should

focus on prenatal screening for C. trachomatis, including

• screening pregnant women at risk for C. trachomatis

infection at the first prenatal visit (e.g., women aged

<25 years and those aged ≥25 years who have a new sex

partner, more than one sex partner, a sex partner with

concurrent partners, or a sex partner who has an STI);

• treating all pregnant women with C. trachomatis during

pregnancy and performing a test of cure 4 weeks after

treatment to verify chlamydial eradication; these women

should also be retested 3 months after treatment and again

in the third trimester or at time of delivery, and their

partners should also be tested and treated;

• retesting pregnant women during the third trimester who

initially tested negative but remained at increased risk for

acquiring infection (e.g., women aged <25 years and those

aged ≥25 years who have a new sex partner, more than one

sex partner, a sex partner with concurrent partners, or a

sex partner who has an STI); and

• screening at delivery those pregnant women who were not

screened for C. trachomatis during pregnancy if at risk or

who had no prenatal care; physicians and others caring

for the mother and the newborn should communicate to

ensure follow-up on the results of laboratory tests

performed at delivery, and if positive, prompt and age-

appropriate treatment for the newborn and the mother.

Neonates born to mothers for whom prenatal chlamydia

screening has been confirmed and the results are negative are

not at high risk for infection.

Diagnostic Considerations

Sensitive and specific methods for diagnosing chlamydial

ophthalmia in the neonate include both tissue culture and

nonculture tests (e.g., DFA tests and NAATs). DFA is the

only nonculture FDA-cleared test for detecting chlamydia

from conjunctival swabs. NAATs are not cleared by FDA for

detecting chlamydia from conjunctival swabs, and clinical

laboratories should verify the procedure according to CLIA

regulations. Specimens for culture isolation and nonculture

tests should be obtained from the everted eyelid by using a

Dacron (DuPont)-tipped swab or the swab specified by the

manufacturer’s test kit; for culture and DFA, specimens must

contain conjunctival cells, not exudate alone. Ocular specimens

from neonates being evaluated for chlamydial conjunctivitis

also should be tested for N. gonorrhoeae (see Ophthalmia

Neonatorum Caused by N. gonorrhoeae).

Treatment

Recommended Regimen for Chlamydial Infection Among

Neonates

Erythromycin base or ethyl succinate 50 mg/kg body weight/day

orally, divided into 4 doses daily for 14 days*

* An association between oral erythromycin and azithromycin and infantile

hypertrophic pyloric stenosis (IHPS) has been reported among infants

aged <6 weeks. Infants treated with either of these antimicrobials should

be followed for IHPS signs and symptoms.

Although data regarding use of azithromycin for treating

neonatal chlamydial infection are limited, available data

demonstrate that a short therapy course might be effective

(834). Topical antibiotic therapy alone is inadequate for

treating ophthalmia neonatorum caused by chlamydia and is

unnecessary when systemic treatment is administered.

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Follow-Up

Because the efficacy of erythromycin treatment for

ophthalmia neonatorum is approximately 80%, a second

course of therapy might be required (834,835). Data regarding

the efficacy of azithromycin for ophthalmia neonatorum are

limited. Therefore, follow-up of infants is recommended to

determine whether the initial treatment was effective. The

possibility of concomitant chlamydial pneumonia should be

considered (see Infant Pneumonia Caused by C. trachomatis).

Management of Mothers and Their Sex Partners

Mothers of infants who have ophthalmia caused by chlamydia

and the sex partners of these women should be evaluated and

presumptively treated for chlamydia (see Chlamydial Infection

Among Adolescents and Adults).

Infant Pneumonia Caused by C. trachomatis

Chlamydial pneumonia among infants typically occurs at age

1–3 months and is a subacute pneumonia. Characteristic signs

of chlamydial pneumonia among infants include a repetitive

staccato cough with tachypnea and hyperinflation and bilateral

diffuse infiltrates on a chest radiograph. In addition, peripheral

eosinophilia (≥400 cells/mm

) occurs frequently. Because

clinical presentations differ, all infants aged 1–3 months

suspected of having pneumonia, especially those whose

mothers have a history of, are at risk for (e.g., aged <25 years

and those aged ≥25 years who have a new sex partner, more

than one sex partner, a sex partner with concurrent partners,

or a sex partner who has an STI), or suspected of having a

chlamydial infection should be tested for C. trachomatis and

treated if infected.

Diagnostic Considerations

Specimens for chlamydial testing should be collected from

the nasopharynx. Tissue culture is the definitive standard

diagnostic test for chlamydial pneumonia. Nonculture

tests (e.g., DFA and NAAT) can be used. DFA is the only

nonculture FDA-cleared test for detecting C. trachomatis from

nasopharyngeal specimens; however, DFA of nasopharyngeal

specimens has a lower sensitivity and specificity than culture.

NAATs are not cleared by FDA for detecting chlamydia from

nasopharyngeal specimens, and clinical laboratories should

verify the procedure according to CLIA regulations (553).

Tracheal aspirates and lung biopsy specimens, if collected,

should be tested for C. trachomatis.

Treatment

Because test results for chlamydia often are unavailable at the

time initial treatment decisions are being made, treatment for

C. trachomatis pneumonia frequently is based on clinical and

radiologic findings, age of the infant (i.e., 1–3 months), and

risk for chlamydia in the mother (i.e., aged <25 years, history

of chlamydial infection, multiple sex partners, a sex partner

with a concurrent partner, or a sex partner with a history of

an STI). In the absence of laboratory results in a situation

with a high degree of suspicion of chlamydial infection and

the mother is unlikely to return with the infant for follow-up,

exposed infants can be presumptively treated with the shorter-

course regimen of azithromycin 20 mg/kg body weight/day

orally, 1 dose daily for 3 days.

Recommended Regimen for Chlamydial Pneumonia Among

Infants

Erythromycin base or ethyl succinate 50 mg/kg body weight/day orally

divided into 4 doses daily for 14 days

Alternative Regimen

Azithromycin suspension 20 mg/kg/day orally, 1 dose daily for 3 days

Follow-Up

Because erythromycin effectiveness in treating pneumonia

caused by C. trachomatis is approximately 80%, a second

course of therapy might be required (836). Data regarding

effectiveness of azithromycin in treating chlamydial pneumonia

are limited. Follow-up of infants is recommended to determine

whether the pneumonia has resolved, although certain infants

with chlamydial pneumonia continue to have abnormal

pulmonary function tests later during childhood.

Management of Mothers and Their Sex Partners

Mothers of infants who have chlamydial pneumonia and the

sex partners of these women should be evaluated, tested, and

presumptively treated for chlamydia (see Chlamydial Infection

Among Adolescents and Adults).

Chlamydial Infection Among Infants and

Children

Sexual abuse should be considered a cause of chlamydial

infection among infants and children. However, perinatally

transmitted C. trachomatis infection of the nasopharynx,

urogenital tract, and rectum can persist for 2–3 years (see

Sexual Assault or Abuse of Children).

Diagnostic Considerations

NAATs can be used to test vaginal and urine specimens

from girls and urine in boys (see Sexual Assault or Abuse

of Children). Data are lacking regarding use of NAATs for

specimens from extragenital sites (rectum and pharynx) among

boys and girls (553); other nonculture tests (e.g., DFA) are

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not recommended because of specificity concerns. Although

data regarding NAATs for specimens from extragenital sites for

children are more limited and performance is test dependent

(553), no evidence supports that NAAT performance

for detecting C. trachomatis for extragenital sites among

children would differ from that among adults. Because of

the implications of a diagnosis of C. trachomatis infection in

a child, only CLIA-validated, FDA-cleared NAAT should be

used for extragenital site specimens (837).

Recommended Regimens for Chlamydial Infection Among

Infants and Children

For infants and children weighing <45 kg: Erythromycin base or ethyl

succinate 50 mg/kg body weight/day orally divided into 4 doses daily

for 14 days

Data are limited regarding the effectiveness and optimal dose of

azithromycin for treating chlamydial infection among infants and

children weighing <45 kg.

For children weighing ≥45 kg but aged <8 years: Azithromycin 1 g

orally in a single dose

For children aged ≥8 years: Azithromycin 1 g orally in a single dose

Doxycycline 100 mg orally 2 times/day for 7 days

Other Management Considerations

See Sexual Assault or Abuse of Children.

Follow-Up

A test of cure to detect therapeutic failure ensures treatment

effectiveness and should be obtained at a follow-up visit

approximately 4 weeks after treatment is completed.

Gonococcal Infections

Gonococcal Infection Among

Adolescents and Adults

In the United States, an estimated 1,568,000 new

N. gonorrhoeae infections occur each year (141,838), and

gonorrhea is the second most commonly reported bacterial

communicable disease. Urethral infections caused by

N. gonorrhoeae can produce symptoms among men that cause

them to seek curative treatment soon enough to prevent

sequelae, but often not soon enough to prevent transmission

to others. Among women, gonococcal infections are commonly

asymptomatic or might not produce recognizable symptoms

until complications (e.g., PID) have occurred. PID can result in

tubal scarring that can lead to infertility or ectopic pregnancy.

Annual screening for N. gonorrhoeae infection is recommended

for all sexually active women aged <25 years and for older

women at increased risk for infection (e.g., those aged ≥25 years

who have a new sex partner, more than one sex partner, a sex

partner with concurrent partners, or a sex partner who has

an STI) (149). Additional risk factors for gonorrhea include

inconsistent condom use among persons who are not in

mutually monogamous relationships, previous or coexisting

STIs, and exchanging sex for money or drugs. Clinicians

should consider the communities they serve and consult local

public health authorities for guidance regarding identifying

groups at increased risk. Gonococcal infection, in particular, is

concentrated in specific geographic locations and communities.

MSM at high risk for gonococcal infection (e.g., those with

multiple anonymous partners or substance abuse) or those at

risk for HIV acquisition should be screened at all anatomic

sites of exposure every 3–6 months (see Men Who Have Sex

with Men). At least annual screening is recommended for all

MSM. Screening for gonorrhea among heterosexual men and

women aged >25 years who are at low risk for infection is

not recommended (149). A recent travel history with sexual

contacts outside the United States should be part of any

gonorrhea evaluation.

Diagnostic Considerations

Specific microbiologic diagnosis of N. gonorrhoeae infection

should be performed for all persons at risk for or suspected of

having gonorrhea; a specific diagnosis can potentially reduce

complications, reinfections, and transmission. Culture, NAAT,

and POC NAAT, such as GeneXpert (Cepheid), are available

for detecting genitourinary infection with N. gonorrhoeae

(149); culture requires endocervical (women) or urethral

(men) swab specimens. Culture is also available for detecting

rectal, oropharyngeal, and conjunctival gonococcal infection.

NAATs and POC NAATs) allow for the widest variety of

FDA-cleared specimen types, including endocervical and

vaginal swabs and urine for women, urethral swabs and urine

for men, and rectal swabs and pharyngeal swabs for men and

women (www.accessdata.fda.gov/cdrh_docs/reviews/K121710.

pdf). However, product inserts for each NAAT manufacturer

should be consulted carefully because collection methods

and specimen types vary. Certain NAATs that have been

demonstrated to detect commensal Neisseria species might

have comparable low specificity when testing oropharyngeal

specimens for N. gonorrhoeae (553). NAAT sensitivity for

detecting N. gonorrhoeae from urogenital and nongenital

anatomic sites is superior to culture but varies by NAAT type

(553,800–803). For urogenital infections, optimal specimen

types for gonorrhea screening using NAATs include first-void

urine for men and vaginal swab specimens for women (553).

Patient-collected samples can be used in place of provider-

collected samples in clinical settings when testing by NAAT

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for urine (men and women), vaginal swabs, rectal swabs, and

oropharyngeal swabs after patient instructions have been

provided (209,806,839–842). Patient-collected specimens

are reasonable alternatives to provider-collected swabs for

gonorrhea screening by NAAT.

In cases of suspected or documented treatment failure,

clinicians should perform both culture and antimicrobial

susceptibility testing because NAATs cannot provide

antimicrobial susceptibility results. Because N. gonorrhoeae

has demanding nutritional and environmental growth

requirements, optimal recovery rates are achieved when

specimens are inoculated directly and when the growth

medium is promptly incubated in an increased carbon dioxide

(CO

) environment (553). Nonnutritive swab transport

systems are available that might maintain gonococcal viability

for <48 hours in ambient temperatures (843–845).

Because of its high specificity (>99%) and sensitivity

(>95%), a Gram stain of urethral discharge or secretions that

demonstrate polymorphonuclear leukocytes with intracellular

gram-negative diplococci can be considered diagnostic for

infection with N. gonorrhoeae among symptomatic men.

However, because of lower sensitivity, a negative Gram stain

should not be considered sufficient for ruling out infection

among asymptomatic men. Infection detection by using

Gram stain of endocervical, pharyngeal, and rectal specimens

also is insensitive and is not recommended. MB or GV stain

of urethral secretions is an alternative POC diagnostic test

with performance characteristics similar to Gram stain.

Gonococcal infection is diagnosed among symptomatic men by

documenting the presence of a WBC-containing intracellular

purple diplococci in MB or GV smears.

Antimicrobial-Resistant N. gonorrhoeae

Gonorrhea treatment is complicated by the ability of

N. gonorrhoeae to develop resistance to antimicrobials

(846–848). In 1986, the Gonococcal Isolate Surveillance

Project (GISP), a national sentinel surveillance system, was

established to monitor trends in antimicrobial susceptibilities

of urethral N. gonorrhoeae strains in the United States

(849). The epidemiology of antimicrobial resistance guides

decisions about gonococcal treatment recommendations

and has evolved because of shifts in antimicrobial resistance

patterns. During 2007, emergence of fluoroquinolone-

resistant N. gonorrhoeae in the United States prompted CDC

to cease recommending fluoroquinolones for gonorrhea

treatment, leaving cephalosporins as the only remaining

class of antimicrobials available for gonorrhea treatment in

the United States (850). Reflecting concern about emerging

gonococcal resistance, CDC’s 2010 STD treatment guidelines

recommended dual therapy for gonorrhea with a cephalosporin

plus either azithromycin or doxycycline, even if NAAT for

C. trachomatis was negative at the time of treatment (851).

However, during 2006–2011, the minimum concentrations of

cefixime needed to inhibit in vitro growth of the N. gonorrhoeae

strains circulating in the United States and other countries

increased, demonstrating that cefixime effectiveness might be

waning (851). In addition, treatment failures with cefixime or

other oral cephalosporins were reported in Asia (852–855),

Europe (856–860), South Africa (861), and Canada (862,863).

During that time, case reports of ceftriaxone treatment failures

for pharyngeal infections reported in Australia (864,865),

Japan (866), and Europe were concerning (856,867).

Consequently, CDC no longer recommends cefixime as a

first-line regimen for gonorrhea treatment in the United

States (868). Since 2013, the proportion of GISP isolates

that demonstrate reduced susceptibility (minimal inhibitory

concentration [MIC] ≥2.0 µg/mL) to azithromycin has

increased almost tenfold, to 5.1% in 2019 (141). Unlike the

appearance of ciprofloxacin resistance in the early 2000s, and

cefixime reduced-susceptibility isolates during 2010–2011,

emergence of azithromycin resistance is not concentrated

among certain populations (e.g., MSM in the western United

States). Azithromycin has unique pharmacokinetic properties

that might predispose to resistance due to its prolonged half-life

(869,870). With the exception of a small cluster of gonorrhea

strains with azithromycin resistance and reduced susceptibility

to cefixime and ceftriaxone among seven patients during 2016,

all gonorrhea strains identified by GISP are susceptible to

either or both azithromycin and ceftriaxone or cefixime. In

addition, since 2013, antimicrobial stewardship has become

an urgent public health concern in the United States as

described in Antimicrobial Resistant Threats in the United States

(871). Emergence of azithromycin resistance is not isolated to

N. gonorrhoeae; it has also been demonstrated in M. genitalium

and such enteric pathogens as Shigella and Campylobacter (see

Mycoplasma genitalium; Proctitis, Proctocolitis, and Enteritis).

Finally, concern exists regarding azithromycin treatment

efficacy for chlamydia (see Chlamydial Infections).

Dual therapy for gonococcal infection with ceftriaxone

and azithromycin recommended in previous guidance

might have mitigated emergence of reduced susceptibility to

ceftriaxone in N. gonorrhoeae; however, concerns regarding

potential harm to the microbiome and the effect on other

pathogens diminishes the benefits of maintaining dual therapy.

Consequently, only ceftriaxone is recommended for treating

gonorrhea in the United States (872). Clinicians remaining

vigilant for treatment failures is paramount, and CDC plans

to continue to monitor for changing ceftriaxone MICs

until additional antimicrobials or a vaccine is available. In

cases in which chlamydial infection has not been excluded,

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patients should also receive antichlamydial therapy. CDC

and state health departments participate in CDC-supported

gonorrhea surveillance activities (https://www.cdc.gov/std/

gisp) and can provide the most current information regarding

gonococcal susceptibility.

Criteria for resistance to cefixime and ceftriaxone have not

been defined by the Clinical and Laboratory Standards Institute

(CLSI). However, isolates with cefixime or ceftriaxone MICs

≥0.5 µg/mL are considered to have decreased susceptibility

(873). In the United States, the proportion of isolates in

GISP demonstrating decreased susceptibility to ceftriaxone

or cefixime has remained low; during 2019, <0.1% of isolates

with decreased susceptibility (MIC ≥0.5 µg/mL) to ceftriaxone

or cefixime were identified (141). Because increasing MICs

might predict resistance emergence, GISP established lower

cephalosporin MIC threshold values that are lower than the

susceptibility breakpoints set by CLSI to provide greater

sensitivity in detecting decreasing gonococcal susceptibility

for surveillance purposes. The percentage of isolates with

cefixime MICs ≥0.25 µg/mL increased from 0.1% during

2006 to 1.4% during 2011 (851,874) and declined to

0.3% during 2019 (141). The percentage of isolates with

ceftriaxone MICs ≥0.125 µg/mL increased from <0.1% in

2006 to 0.4% in 2011 and decreased to 0.1% in 2019 (141).

Isolates with high-level cefixime and ceftriaxone MICs (MICs

= 1.5–8.0 µg/mL and MICs = 1.5–4.0 µg/mL, respectively)

have been identified in Japan (866), France (867,875), Spain

(876,877), the United Kingdom, and Australia (878,879).

Decreased susceptibility of N. gonorrhoeae to cephalosporins

and other antimicrobials is expected to continue; state and

local surveillance for antimicrobial resistance is crucial for

guiding local therapy recommendations (846,847). Although

approximately 3% of all U.S. men who have gonococcal

infections are sampled through GISP, surveillance by clinicians

also is crucial. Clinicians who diagnose N. gonorrhoeae infection

in a person with suspected cephalosporin treatment failure

should perform culture and AST of relevant clinical specimens,

consult an infectious disease specialist or an STD clinical

expert (https://www.stdccn.org/render/Public) for guidance

in clinical management, and report the case to CDC through

state and local public health authorities within 24 hours.

Isolates should be saved and sent to CDC through local and

state public health laboratory mechanisms. Health departments

should prioritize notification and culture evaluation for sexual

partners of persons with N. gonorrhoeae infection thought

to be associated with cephalosporin treatment failure or

persons whose isolates demonstrate decreased susceptibility

to cephalosporin. Agar dilution is the reference standard

and preferred method of antimicrobial susceptibility testing

with N. gonorrhoeae. Antibiotic gradient strips, such as Etest

(bioMérieux), can be used and are considered an acceptable

alternative for quantitative antimicrobial susceptibility testing with

N. gonorrhoeae when manufacturer instructions are followed. Disc

diffusion only provides qualitative susceptibility results.

Uncomplicated Gonococcal Infection of the

Cervix, Urethra, or Rectum

Recommended Regimen for Uncomplicated Gonococcal

Infection of the Cervix, Urethra, or Rectum Among Adults and

Adolescents

Ceftriaxone 500 mg* IM in a single dose for persons weighing <150 kg

If chlamydial infection has not been excluded, treat for chlamydia with

doxycycline 100 mg orally 2 times/day for 7 days.

* For persons weighing ≥150 kg, 1 g ceftriaxone should be administered.

Although clinical data confirm that a single injection

of ceftriaxone 250 mg is >99% (95% confidence interval

[CI]:97.6%–99.7%) effective in curing anogenital gonorrhea

of circulating isolates (MIC = 0.03 µg/mL), a higher dose is

likely necessary for isolates with elevated MICs (880,881).

Effective treatment of uncomplicated urogenital gonorrhea with

ceftriaxone requires concentrations higher than the strain MIC

for approximately 24 hours; although individual variability

exists in the pharmacokinetics of ceftriaxone, a 500-mg dose

of ceftriaxone is expected to achieve in approximately 50 hours

MIC >0.03 µg/mL (880,881). The pharmacokinetics of

ceftriaxone might be different in the pharynx with longer times

higher than the strain MIC likely needed to prevent selection

of mutant strains in the pharynx (882).

Single-dose injectable cephalosporin regimens, other than

ceftriaxone, that are safe and have been effective against

uncomplicated urogenital and anorectal gonococcal infections

in the past include ceftizoxime (500 mg IM), cefoxitin (2 g IM

with probenecid 1 g orally), and cefotaxime (500 mg IM).

None of these injectable cephalosporins offer any advantage

over ceftriaxone 250 mg for urogenital infection, and efficacy

for pharyngeal infection is less certain (883,884). Because the

ceftriaxone dose has been increased and the pharmacokinetics

of other cephalosporins have not been evaluated, these dosing

regimens might be at a disadvantage over ceftriaxone 500 mg.

Alternative Regimens if Ceftriaxone Is Not Available

Gentamicin 240 mg IM in a single dose

plus

Azithromycin 2 g orally in a single dose

Cefixime* 800 mg orally in a single dose

* If chlamydial infection has not been excluded, providers should treat for

chlamydia with doxycycline 100 mg orally 2 times/day for 7 days.

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In one clinical trial, dual treatment with single doses of

IM gentamicin 240 mg plus oral azithromycin 2 g cured

100% of cases (lower one-sided 95% CI bound:98.5%) and

can be considered an alternative to ceftriaxone for persons

with cephalosporin allergy (885). This trial was not powered

enough to provide reliable estimates of the efficacy of these

regimens for treatment of rectal or pharyngeal infection;

however, this regimen cured the few extragenital infections

among study participants. Notably, gastrointestinal adverse

events, primarily vomiting <1 hour after dosing, occurred

among 3%–4% of persons treated with gentamicin plus

azithromycin, necessitating retreatment with ceftriaxone

and azithromycin. A similar trial that studied gentamicin

240 mg plus azithromycin 1 g determined lower cure rates at

extragenital sites; 80% (95% CI:72%–88%) of pharyngeal

and 90% (95% CI:84%–95%) of rectal infections were cured

with this regimen (886). Gemifloxacin plus azithromycin has

been studied and is no longer recommended as an alternative

regimen because of limited availability, cost, and antimicrobial

stewardship concerns (885).

An 800-mg oral dose of cefixime should be considered only

as an alternative cephalosporin regimen because it does not

provide as high, nor as sustained, bactericidal blood levels as a

500-mg IM dose of ceftriaxone. Furthermore, it demonstrates

limited efficacy for treatment of pharyngeal gonorrhea (92.3%

cure; 95% CI:74.9%–99.1%); in older clinical studies,

cefixime cured 97.5% of uncomplicated urogenital and

anorectal gonococcal infections (95% CI:95.4%–99.8%)

(883,884). The increase in the prevalence of isolates obtained

through GISP with elevated cefixime MICs might indicate

early stages of development of clinically significant gonococcal

resistance to cephalosporins. Changes in cefixime MICs can

result in decreasing effectiveness of cefixime for treating

urogenital gonorrhea. Furthermore, as cefixime becomes

less effective, continued used of cefixime might hasten the

development of resistance to ceftriaxone, a safe, well-tolerated,

injectable cephalosporin and the last antimicrobial known to

be highly effective in a single dose for treatment of gonorrhea

at all anatomic infection sites. Other oral cephalosporins (e.g.,

cefpodoxime and cefuroxime) are not recommended because of

inferior efficacy and less favorable pharmacodynamics (883).

Monotherapy with azithromycin 2 g orally as a single

dose has been demonstrated to be 99.2% effective against

uncomplicated urogenital gonorrhea (95% CI:97.3%–99.9%)

(883). However, monotherapy is not recommended because

of concerns about the ease with which N. gonorrhoeae can

develop resistance to macrolides, the high proportion of isolates

with azithromycin decreased susceptibility, and documented

azithromycin treatment failures (859). Strains of N. gonorrhoeae

circulating in the United States are not adequately susceptible

to penicillin, tetracycline, and older macrolides (e.g.,

erythromycin), and thus use of these antimicrobials cannot

be recommended.

Spectinomycin is effective (98.2% in curing uncomplicated

urogenital and anorectal gonococcal infections) but has poor

efficacy for pharyngeal infections (883,887). It is unavailable

in the United States, and the gentamicin alternative regimen

has replaced the need for spectinomycin, if a cephalosporin

allergy exists, in the United States.

Uncomplicated Gonococcal Infection of

the Pharynx

The majority of gonococcal infections of the pharynx are

asymptomatic and can be relatively common among certain

populations (800,801,888–890). Although these infections

rarely cause complications, they have been reported to be a

major source of community transmission and might be a driver

of antimicrobial resistance (891,892). Gonococcal infections

of the pharynx are more difficult to eradicate than infections

at urogenital and anorectal sites (862). Few antimicrobial

regimens reliably cure >90% of gonococcal pharyngeal

infections (883,884). Providers should ask their patients with

urogenital or rectal gonorrhea about oral sexual exposure; if

reported, pharyngeal testing should be performed.

Recommended Regimen for Uncomplicated Gonococcal

Infection of the Pharynx Among Adolescents and Adults

Ceftriaxone 500 mg* IM in a single dose for persons weighing <150 kg

* For persons weighing ≥150 kg, 1 g ceftriaxone should be administered.

If chlamydial infection is identified when pharyngeal

gonorrhea testing is performed, treat for chlamydia with

doxycycline 100 mg orally 2 times/day for 7 days. No reliable

alternative treatments are available for pharyngeal gonorrhea.

For persons with an anaphylactic or other severe reaction

(e.g., Stevens Johnson syndrome) to ceftriaxone, consult

an infectious disease specialist for an alternative treatment

recommendation.

Other Management Considerations

To maximize adherence with recommended therapies

and reduce complications and transmission, medication

for gonococcal infection should be provided on-site and

directly observed. If medications are unavailable when

treatment is indicated, linkage to an STI treatment facility

should be provided for same-day treatment. To minimize

disease transmission, persons treated for gonorrhea should

be instructed to abstain from sexual activity for 7 days after

treatment and until all sex partners are treated (7 days after

receiving treatment and resolution of symptoms, if present).

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All persons who receive a diagnosis of gonorrhea should be

tested for other STIs, including chlamydia, syphilis, and HIV.

Those persons whose HIV test results are negative should be

offered HIV PrEP.

Follow-Up

A test of cure (i.e., repeat testing after completion of

therapy) is unnecessary for persons who receive a diagnosis of

uncomplicated urogenital or rectal gonorrhea who are treated

with any of the recommended or alternative regimens. Any

person with pharyngeal gonorrhea should return 7–14 days

after initial treatment for a test of cure by using either culture or

NAAT; however, testing at 7 days might result in an increased

likelihood of false-positive tests. If the NAAT is positive, effort

should be made to perform a confirmatory culture before

retreatment, especially if a culture was not already collected. All

positive cultures for test of cure should undergo antimicrobial

susceptibility testing. Symptoms that persist after treatment

should be evaluated by culture for N. gonorrhoeae (with or

without simultaneous NAAT) and antimicrobial susceptibility.

Persistent urethritis, cervicitis, or proctitis also might be caused

by other organisms (see Urethritis; Cervicitis; Proctitis).

A high prevalence of N. gonorrhoeae infection has been

observed among men and women previously treated for

gonorrhea (137,753,754,893). The majority of these infections

result from reinfection caused by failure of sex partners to

receive treatment or the initiation of sexual activity with a

new infected partner, indicating a need for improved patient

education and treatment of sex partners. Men or women who

have been treated for gonorrhea should be retested 3 months

after treatment regardless of whether they believe their sex

partners were treated; scheduling the follow-up visit at the

time of treatment is encouraged. If retesting at 3 months is not

possible, clinicians should retest whenever persons next seek

medical care <12 months after initial treatment.

Management of Sex Partners

Recent sex partners (i.e., persons having sexual contact with

the infected patient <60 days preceding onset of symptoms or

gonorrhea diagnosis) should be referred for evaluation, testing,

and presumptive treatment. If the patient’s last potential sexual

exposure was >60 days before onset of symptoms or diagnosis,

the most recent sex partner should be treated.

If health department partner-management strategies (e.g.,

disease intervention specialists) are impractical or unavailable

for persons with gonorrhea and partners’ access to prompt

clinical evaluation and treatment is limited, EPT can be

delivered to the partner by the patient or a collaborating

pharmacy as permitted by law (see Partner Services). Treatment

of the sexual partner with cefixime 800 mg as a single dose

is recommended, provided that concurrent chlamydial

infection has been excluded. If a chlamydia test result has not

been documented, the partner may be treated with a single

dose of oral cefixime 800 mg plus oral doxycycline 100 mg

2 times/day for 7 days. If adherence with multiday dosing is

a considerable concern, azithromycin 1 g can be considered

but has lower treatment efficacy among persons with rectal

chlamydia (see Chlamydial Infections). Provision of medication

by EPT should be accompanied by written materials (125,127)

for educating partners about gonorrhea, their exposure to

gonorrhea, and the importance of therapy. These materials

should also educate partners about seeking clinical evaluation

for adverse reactions or complications and general follow-up

when able. Educational materials for female partners should

include information about the importance of seeking medical

evaluation for PID, especially if symptomatic; undertreatment

of PID among female partners and missed opportunities for

diagnosing other STIs among women are of concern. MSM

with gonorrhea have a high risk for coexisting infections

(especially undiagnosed HIV) among their partners, and they

might have partners without HIV who could benefit from

PrEP. Data are also limited regarding the effectiveness of EPT

in reducing persistent or recurrent gonorrhea among MSM

(133,135); thus, shared clinical decision-making regarding

EPT for MSM is recommended (see Partner Services). To avoid

reinfection, sex partners should be instructed to abstain from

condomless sexual intercourse for 7 days after they and their

sex partners have completed treatment and after resolution of

symptoms, if present.

Suspected Cephalosporin Treatment Failure

Cephalosporin treatment failure is the persistence of

N. gonorrhoeae infection despite recommended cephalosporin

treatment; such failure is indicative of infection with

cephalosporin-resistant gonorrhea among persons whose

partners were treated and whose risk for reinfection is

low. Suspected treatment failure has been reported among

persons receiving oral and injectable cephalosporins (852–

855,857,859,861,863,864,867,875,894). Treatment failure

should be considered for persons whose symptoms do not

resolve within 3–5 days after recommended treatment and

report no sexual contact during the posttreatment follow-up

period and persons with a positive test of cure (i.e., positive

culture >72 hours or positive NAAT >7 days after receiving

recommended treatment) when no sexual contact is reported

during the posttreatment follow-up period (874). Treatment

failure should also be considered for persons who have a

positive culture on test of cure, if obtained, if evidence exists

of decreased susceptibility to cephalosporins on antimicrobial

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susceptibility testing, regardless of whether sexual contact is

reported during the posttreatment follow-up period.

The majority of suspected treatment failures in the United

States are likely to be reinfections rather than actual treatment

failures (137,753,754,894). However, in cases in which

reinfection is unlikely and treatment failure is suspected,

before retreatment, relevant clinical specimens should be

obtained for culture (preferably with simultaneous NAAT)

and antimicrobial susceptibility testing if N. gonorrhoeae is

isolated. Phenotypic antimicrobial susceptibility testing should

be performed by using Etest or agar dilution. All isolates

of suspected treatment failures should be sent to CDC for

antimicrobial susceptibility testing by agar dilution; local

laboratories should store isolates for possible further testing if

needed. Testing or storage of specimens or isolates should be

facilitated by the state or local health department according to

local public health protocol. Instructions for shipping isolates

to CDC are available at https://www.cdc.gov/std/gonorrhea/

arg/specimen_shipping_instructions1-29-08.pdf.

For persons with suspected cephalosporin treatment failure,

the treating clinician should consult an infectious disease

specialist, the National Network of STD Clinical Prevention

Training Center clinical consultation line (https://www.stdccn.

org/render/Public), the local or state health department STI

program, or CDC (telephone: 800-232-4636) for advice about

obtaining cultures, antimicrobial susceptibility testing and

treatment. Suspected treatment failure should be reported to

CDC through the local or state health department <24 hours

after diagnosis.

Patients with suspected treatment failures should first be

retreated routinely with the initial regimen used (ceftriaxone

500 mg IM), with the addition of doxycycline if chlamydia

infection exists, because reinfections are more likely than

actual treatment failures. However, in situations with a higher

likelihood of treatment failure than reinfection, relevant

clinical specimens should be obtained for culture (preferably

with simultaneous NAAT) and antimicrobial susceptibility

testing before retreatment. Dual treatment with single doses

of IM gentamicin 240 mg plus oral azithromycin 2 g can be

considered, particularly when isolates are identified as having

elevated cephalosporin MICs (885,886,895). Persons with

suspected treatment failure after treatment with the alternative

regimen (cefixime or gentamicin) should be treated with

ceftriaxone 500 mg as a single IM dose or as a single dose with

or without an antichlamydial agent on the basis of chlamydia

infection status. A test of cure at relevant clinical sites should

be obtained 7–14 days after retreatment; culture is the

recommended test, preferably with simultaneous NAAT, and

antimicrobial susceptibility testing of N. gonorrhoeae if isolated.

Clinicians should ensure that the patients’ sex partners from

the preceding 60 days are evaluated promptly with culture

and presumptively treated by using the same regimen used

for the patients.

Special Considerations

Drug Allergy, Intolerance, and Adverse Reactions

The risk for penicillin cross-reactivity is highest with

first-generation cephalosporins but is rare (<1%) with

third-generation cephalosporins (e.g., ceftriaxone and

cefixime) (631,680,896). Clinicians should first thoroughly

assess a patient’s allergy history, including type of reaction,

associated medications, and previous prescription records.

If IgE-mediated penicillin allergy is strongly suspected, dual

treatment with single doses of IM gentamicin 240 mg plus oral

azithromycin 2 g can be administered (885,886). If a patient

is asymptomatic and the treating facility is able to perform

gyrase A (gyrA) testing to identify ciprofloxacin susceptibility

(wild type), oral ciprofloxacin 500 mg in a single dose can be

administered. Providers treating persons with IgE-mediated

cephalosporin or penicillin allergy should refer to the section

of these guidelines regarding evaluation (see Management of

Persons Who Have a History of Penicillin Allergy).

Pregnancy

Pregnant women infected with N. gonorrhoeae should be

treated with ceftriaxone 500 mg in a single IM dose plus

treatment for chlamydia if infection has not been excluded.

When cephalosporin allergy or other considerations preclude

treatment with this regimen, consultation with an infectious

disease specialist or an STD clinical expert is recommended.

Gentamicin use is cautioned during pregnancy because of risk

for neonatal birth defects, nephrotoxicity, or ototoxicity (897)

(https://www.stdccn.org/render/Public).

HIV Infection

Persons who have gonorrhea and HIV infection should

receive the same treatment regimen as those who do not

have HIV.

Gonococcal Conjunctivitis

In the only published study of the treatment regarding

gonococcal conjunctivitis among adults, all 12 study

participants responded to a single 1-g IM injection of

ceftriaxone (898). Because gonococcal conjunctivitis is

uncommon and data regarding treatment of gonococcal

conjunctivitis among adults are limited, consultation with an

infectious disease specialist should be considered.

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Recommended Regimen for Gonococcal Conjunctivitis Among

Adolescents and Adults

Ceftriaxone 1 g IM in a single dose

Providers should consider one-time lavage of the infected eye with

saline solution.

Management of Sex Partners

Patients should be instructed to refer their sex partners

for evaluation and treatment (see Gonococcal Infections,

Management of Sex Partners).

Disseminated Gonococcal Infection

Infrequently, N. gonorrhoeae can cause disseminated

infection. Disseminated gonococcal infection (DGI) frequently

results in petechial or pustular acral skin lesions, asymmetric

polyarthralgia, tenosynovitis, or oligoarticular septic arthritis

(899–901). Rarely, DGI is complicated by perihepatitis

associated with gonococcal PID, endocarditis, or meningitis.

Certain strains of N. gonorrhoeae that cause DGI can cause

minimal genital inflammation, and urogenital or anorectal

infections are often asymptomatic among DGI patients.

If DGI is suspected, NAATs or culture specimens from all

exposed urogenital and extragenital sites should be collected

and processed, in addition to disseminated sites of infection

(e.g., skin, synovial fluid, blood, or CSF). All N. gonorrhoeae

isolates should be tested for antimicrobial susceptibility.

Risk factors for dissemination have included female sex,

menstruation, pregnancy, and terminal complement deficiency

(899); however, reports are increasing among men (900,901).

Persons receiving eculizumab, a monoclonal antibody that

inhibits terminal complement activation, also might be at

higher risk for DGI (902).

Hospitalization and consultation with an infectious disease

specialist are recommended for initial therapy, especially

for persons who might not comply with treatment, have an

uncertain diagnosis, or have purulent synovial effusions or

other complications. Examination for clinical evidence of

endocarditis and meningitis should be performed.

Treatment of Arthritis and Arthritis-Dermatitis

Syndrome

Recommended Regimen for Gonococcal-Related Arthritis and

Arthritis-Dermatitis Syndrome

Ceftriaxone 1 g IM or IV every 24 hours

If chlamydial infection has not been excluded, providers should treat for

chlamydia with doxycycline 100 mg orally 2 times/day for 7 days.

Alternative Regimens

Cefotaxime 1 g IV every 8 hours

Ceftizoxime 1 g every 8 hours

If chlamydial infection has not been excluded, providers should treat for

chlamydia with doxycycline 100 mg orally 2 times/day for 7 days.

When treating for the arthritis-dermatitis syndrome, the

provider can switch to an oral agent guided by antimicrobial

susceptibility testing 24–48 hours after substantial clinical

improvement, for a total treatment course of >7 days.

Treatment of Gonococcal Meningitis and Endocarditis

Recommended Regimen for Gonococcal Meningitis and

Endocarditis

Ceftriaxone 1–2 g IV every 24 hours

If chlamydial infection has not been excluded, providers should treat for

chlamydia with doxycycline 100 mg orally 2 times/day for 7 days.

No recent studies have been published regarding treatment

of DGI involving the CNS or cardiovascular system. The

duration of treatment for DGI in these situations has not been

systematically studied and should be determined in consultation

with an infectious disease specialist. Treatment for DGI should

be guided by the results of antimicrobial susceptibility testing.

Length of treatment should be determined based on clinical

presentation. Therapy for meningitis should be continued with

recommended parenteral therapy for 10–14 days. Parenteral

antimicrobial therapy for endocarditis should be administered

for >4 weeks. Treatment of gonococcal perihepatitis should be

managed in accordance with the recommendations for PID

in these guidelines.

Management of Sex Partners

Gonococcal infection frequently is asymptomatic among sex

partners of persons who have DGI. Providers should instruct

patients to refer partners with whom they have had sexual

contact during the previous 60 days for evaluation, testing,

and presumptive treatment (see Gonococcal Infections,

Management of Sex Partners).

Gonococcal Infection Among Neonates

Prenatal screening and treatment of pregnant women for

gonorrhea is the best method for preventing N. gonorrhoeae

infection among neonates. Gonococcal infection among

neonates results from perinatal exposure to the mother’s infected

cervix. It is usually an acute illness that manifests 2–5 days after

birth. Prevalence of infection among neonates depends on the

prevalence of infection among pregnant women and whether

pregnant women are screened and treated for gonorrhea during

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pregnancy. The most severe manifestations of N. gonorrhoeae

infection among neonates are ophthalmia neonatorum and

sepsis, which can include arthritis and meningitis. Less severe

manifestations include rhinitis, vaginitis, urethritis, and scalp

infection at sites of previous fetal monitoring.

Preventing Ophthalmia Neonatorum Caused by

N. gonorrhoeae

Ocular prophylaxis and preventive gonorrhea screening

and treatment of infected pregnant women are especially

important because ophthalmia neonatorum can result in

perforation of the globe of the eye and blindness (903).

Ocular prophylaxis for gonococcal ophthalmia neonatorum

has a long history of preventing sight-threatening gonococcal

ocular infections. Cases in the United States are uncommon,

which is likely attributable to gonorrhea screening programs

for women, including pregnant women, that have contributed

substantially to reduction in ophthalmia neonatorum (904).

Neonatal ocular prophylaxis with erythromycin, the only agent

available in the United States, is required by law in most states

and is recommended because of safety, low cost, and ease of

administration. It can contribute to preventing gonococcal

blindness because not all pregnant women are screened for

gonorrhea. The USPSTF recommends ocular prophylaxis

with erythromycin ointment for all newborns <24 hours

after birth (903). In addition to continuing routine ocular

prophylaxis, prevention should focus on prenatal screening

for N. gonorrhoeae, including

• screening pregnant women at risk (e.g., women aged

<25 years and those aged ≥25 years who have a new sex

partner, more than one sex partner, a sex partner with

concurrent partners, a sex partner who has an STI, or live

in a community with high rates of gonorrhea) for

N. gonorrhoeae infection at the first prenatal visit;

• treating all pregnant women with N. gonorrhoeae infection

during pregnancy and retesting in 3 months, in the third

trimester or at time of delivery (sex partners should be

tested and treated);

• retesting pregnant women in the third trimester who

initially tested negative but remained at increased risk for

acquiring infection (e.g., women aged <25 years and those

aged ≥25 years who have a new sex partner, more than one

sex partner, a sex partner with concurrent partners, a sex

partner who has an STI, or live in a community with high

rates of gonorrhea); and

• screening for gonorrhea at delivery for women not tested

during pregnancy and at risk for infection (e.g., women

aged <25 years and those aged ≥25 years who have a new

sex partner, more than one sex partner, a sex partner with

concurrent partners, a sex partner who has an STI, or live

in a community with high rates of gonorrhea) or received

no prenatal care; providers caring for the mother and the

newborn should communicate to ensure follow-up on the

results of laboratory tests performed at delivery, and if

positive, prompt appropriate treatment of the newborn

and mother.

Erythromycin is the only ophthalmic ointment recommended

for use among neonates. Silver nitrate and tetracycline

ophthalmic ointments are no longer manufactured in the

United States, bacitracin is ineffective, and povidone iodine

has not been studied adequately (905,906). Gentamicin

ophthalmic ointment has been associated with severe ocular

reactions (907,908). If erythromycin ointment is unavailable,

infants at risk for exposure to N. gonorrhoeae, especially those

born to a mother at risk for gonococcal infection or with no

prenatal care, can be administered ceftriaxone 25–50 mg/kg

body weight IV or IM, not to exceed 250 mg in a single dose.

Recommended Regimen to Prevent Ophthalmia Neonatorum

Caused by N. gonorrhoeae

Erythromycin 0.5% ophthalmic ointment in each eye in a single

application at birth

Erythromycin ophthalmic ointment should be instilled

into both eyes of neonates as soon as possible after delivery,

regardless of whether they are delivered vaginally or by

cesarean delivery. Ideally, ointment should be applied by using

single-use tubes or ampules rather than multiple-use tubes. If

prophylaxis is delayed (i.e., not administered in the delivery

room), a monitoring system should be established to ensure

that all newborns receive prophylaxis <24 hours after delivery.

Diagnostic Considerations

Newborns at increased risk for gonococcal ophthalmia

include those who did not receive ophthalmic prophylaxis

and whose mothers had no prenatal care, have a history

of STIs during pregnancy, or have a history of substance

misuse. Gonococcal ophthalmia is strongly suspected when

intracellular gram-negative diplococci are identified on Gram

stain of conjunctival exudate, justifying presumptive treatment

for gonorrhea after appropriate cultures and antimicrobial

susceptibility testing for N. gonorrhoeae are performed.

Presumptive treatment for N. gonorrhoeae might be indicated

for newborns at increased risk for gonococcal ophthalmia who

have increased WBCs (no GNID) in a Gram-stained smear

of conjunctival exudate. Nongonococcal causes of neonatal

ophthalmia include Moraxella catarrhalis and other Neisseria

species, which are organisms that are indistinguishable from

N. gonorrhoeae on Gram-stained smear but can be differentiated

in the microbiology laboratory.

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Treatment of Gonococcal Ophthalmia Neonatorum

Recommended Regimen for Gonococcal Ophthalmia

Neonatorum

Ceftriaxone 25–50 mg/kg body weight IV or IM in a single dose, not to

exceed 250 mg

One dose of ceftriaxone is adequate therapy for gonococcal

ophthalmia. Ceftriaxone should be administered cautiously

to neonates with hyperbilirubinemia, especially those born

prematurely. Cefotaxime 100 mg/kg body weight IV or IM as

a single dose can be administered for those neonates unable to

receive ceftriaxone because of simultaneous administration of

IV calcium. Topical antibiotic therapy alone is inadequate and

unnecessary if systemic treatment is administered.

Other Management Considerations

Chlamydial testing should be performed simultaneously from

the inverted eyelid specimen (see Ophthalmia Neonatorum

Caused by C. trachomatis). Newborns who have gonococcal

ophthalmia should be evaluated for signs of disseminated

infection (e.g., sepsis, arthritis, and meningitis). Newborns

who have gonococcal ophthalmia should be managed in

consultation with an infectious disease specialist.

Management of Mothers and Their Sex Partners

Mothers of newborns with ophthalmia neonatorum caused by

N. gonorrhoeae should be evaluated, tested, and presumptively

treated for gonorrhea, along with their sex partners (see

Gonococcal Infection Among Adolescents and Adults).

Disseminated Gonococcal Infection and

Gonococcal Scalp Abscesses Among Neonates

DGI might present as sepsis, arthritis, or meningitis and

is a rare complication of neonatal gonococcal infection.

Localized gonococcal infection of the scalp can result

from fetal monitoring through scalp electrodes. Detecting

gonococcal infection among neonates who have sepsis, arthritis,

meningitis, or scalp abscesses requires cultures of blood, CSF,

or joint aspirate. Specimens obtained from the conjunctiva,

vagina, oropharynx, and rectum are useful for identifying the

primary site or sites of infection. Antimicrobial susceptibility

testing of all isolates should be performed. Positive Gram-

stained smears of abscess exudate, CSF, or joint aspirate provide

a presumptive basis for initiating treatment for N. gonorrhoeae.

Treatment

Recommended Regimens for Disseminated Gonococcal

Infection Among Neonates

Ceftriaxone 25–50 mg/kg body weight/day IV or IM in a single

daily dose for 7 days, with a duration of 10–14 days if meningitis is

documented

Cefotaxime 25 mg/kg body weight/day IV or IM every 12 hours for

7 days, with a duration of 10–14 days if meningitis is documented

Ceftriaxone should be administered cautiously to neonates

with hyperbilirubinemia, especially those born prematurely.

Cefotaxime 100 mg/kg body weight IV or IM as a single

dose can be administered for those neonates unable to

receive ceftriaxone because of simultaneous administration

of IV calcium.

Other Management Considerations

Chlamydial testing should be performed simultaneously

among neonates with gonococcal infection (see Chlamydial

Infection Among Neonates). Neonates who have DGI should

be managed in consultation with an infectious disease specialist.

Management of Mothers and Their Sex Partners

Mothers of newborns who have DGI or scalp abscesses caused

by N. gonorrhoeae should be evaluated, tested, and presumptively

treated for gonorrhea, along with their sex partners (see

Gonococcal Infection Among Adolescents and Adults).

Neonates Born to Mothers Who Have Gonococcal

Infection

Neonates born to mothers who have untreated gonorrhea

are at high risk for infection. Neonates should be tested for

gonorrhea at exposed sites (e.g., conjunctiva, vagina, rectum,

and oropharynx) and treated presumptively for gonorrhea.

Treatment in the Absence of Signs of Gonococcal

Infection

Recommended Regimen for Neonates Without Signs of

Gonococcal Infection

Ceftriaxone 20–50 mg/kg body weight IV or IM in a single dose, not to

exceed 250 mg

Other Management Considerations

Ceftriaxone should be administered cautiously to neonates

with hyperbilirubinemia, especially those born prematurely.

Cefotaxime 100 mg/kg body weight IV or IM as a single

dose can be administered for those neonates unable to

receive ceftriaxone because of simultaneous administration

of IV calcium. Age-appropriate chlamydial testing should be

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performed simultaneously among neonates with gonococcal

infection (see Chlamydial Infection Among Neonates).

Follow-up examination is not required.

Management of Mothers and Their Sex Partners

Mothers who have gonorrhea and their sex partners should

be evaluated, tested, and presumptively treated for gonorrhea

(see Gonococcal Infection Among Adolescents and Adults).

Gonococcal Infection Among

Infants and Children

Sexual abuse is the most frequent cause of gonococcal

infection among infants and children (see Sexual Assault or

Abuse of Children). For preadolescent girls, vaginitis is the

most common manifestation of this infection; gonococcal-

associated PID after vaginal infection can be less common

among preadolescents than adults. Among sexually abused

children, anorectal and pharyngeal infections with N.

gonorrhoeae are frequently asymptomatic.

Diagnostic Considerations

Culture can be used to test urogenital and extragenital sites for

girls and boys. NAAT can be used to test for N. gonorrhoeae from

vaginal and urine specimens from girls and urine for boys (see

Sexual Assault or Abuse of Children). Although data regarding

NAAT from extragenital sites (rectum and pharynx) among

children are more limited, and performance is test dependent,

no evidence supports that performance of NAAT for detection

of N. gonorrhoeae among children differs from that among adults

(553). Because of the implications of a N. gonorrhoeae diagnosis

in a child, only validated FDA-cleared NAAT assays should be

used with extragenital specimens. Consultation with an expert

is necessary before using NAAT to minimize the possibility of

cross-reaction with nongonococcal Neisseria species and other

commensals (e.g., N. meningitidis, Neisseria sicca, Neisseria

lactamica, Neisseria cinerea, or M. catarrhalis) and to ensure

correct interpretation of results.

Gram stains are inadequate for evaluating prepubertal children

for gonorrhea and should not be used to diagnose or exclude

gonorrhea. If evidence of DGI exists, gonorrhea culture and

antimicrobial susceptibility testing should be obtained from

relevant clinical sites (see Disseminated Gonococcal Infection).

Recommended Regimen for Uncomplicated Gonococcal

Vulvovaginitis, Cervicitis, Urethritis, Pharyngitis, or Proctitis

Among Infants and Children Weighing ≤45 kg

Ceftriaxone 25–50 mg/kg body weight IV or IM in a single dose, not to

exceed 250 mg IM

Recommended Regimen for Uncomplicated Gonococcal

Vulvovaginitis, Cervicitis, Urethritis, Pharyngitis, or Proctitis

Among Children Weighing >45 kg

Treat with the regimen recommended for adults

(see Gonococcal Infections)

Recommended Regimen for Bacteremia or Arthritis Among

Children Weighing ≤45 kg

Ceftriaxone 50 mg/kg body weight (maximum dose: 2 g) IM or IV in a

single dose daily every 24 hours for 7 days

Recommended Regimen for Bacteremia or Arthritis Among

Children Weighing >45 kg

Ceftriaxone 1 g IM or IV in a single dose daily every 24 hours for 7 days

Other Management Considerations

Follow-up cultures are unnecessary. Only parenteral

cephalosporins (i.e., ceftriaxone) are recommended for use

among children. All children identified as having gonococcal

infections should be tested for C. trachomatis, syphilis, and

HIV (see Sexual Assault or Abuse of Children).

Mycoplasma genitalium

M. genitalium causes symptomatic and asymptomatic

urethritis among men and is the etiology of approximately

15%–20% of NGU, 20%–25% of nonchlamydial NGU,

and 40% of persistent or recurrent urethritis (697,909,910).

Infection with C. trachomatis is common in selected geographic

areas (911–913), although M. genitalium is often the sole

pathogen. Data are insufficient to implicate M. genitalium

infection with chronic complications among men (e.g.,

epididymitis, prostatitis, or infertility). The consequences

of asymptomatic infection with M. genitalium among men

are unknown.

Among women, M. genitalium has been associated with

cervicitis, PID, preterm delivery, spontaneous abortion, and

infertility, with an approximately twofold increase in the risk

for these outcomes among women infected with M. genitalium

(766). M. genitalium infections among women are also

frequently asymptomatic, and the consequences associated

with asymptomatic M. genitalium infection are unknown.

M. genitalium can be detected among 10%–30% of women

with clinical cervicitis (767,770,772,914–916). The existing

evidence between M. genitalium and cervicitis is mostly

supportive of a causal association. Elevated proinflammatory

cytokines have been demonstrated among women with

M. genitalium, with return to baseline levels after clearance of

the pathogen (917).

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M. genitalium is identified in the cervix or endometrium

of women with PID more often than in women without PID

(918–924). Prevalence of M. genitalium among women with

PID ranges from 4% to 22% (925,926) and was reported

as 60% in one study of women with postabortal PID (918).

The association with PID is supported by early studies among

nonhuman primates that determined that endosalpingitis

develops after inoculation with M. genitalium (927). Recent

studies evaluating the lower and upper genital tract using

highly sensitive M. genitalium NAAT assays or the role of

M. genitalium in histologically defined endometritis have

reported significantly elevated risk for PID (928). However,

most studies of M. genitalium and PID, even those that

controlled extensively for other infections and behavioral and

biologic risk, are cross-sectional. The few prospective studies

that have evaluated the role of M. genitalium in establishing

subsequent PID demonstrated increased PID risk; however,

these were not statistically significant associations, often

because of a lack of statistical power. No clinical trial data are

available that demonstrate that treating M. genitalium cervical

infection prevents development of PID or endometritis.

Although data regarding the benefits of testing women with

PID for M. genitalium and the importance of directing

treatment against this organism are limited, the associations of

M. genitalium with cervicitis and PID in cross-sectional studies

using NAAT testing are consistent (928).

Data from case-control serologic studies (929–931)

and a meta-analysis of clinical studies (766) indicate a

potential role in causing infertility. However, seroassays are

suboptimal and inconclusive. Similarly, evidence for a role for

M. genitalium infection during pregnancy as a cause of perinatal

complications, including preterm delivery, spontaneous

abortion, or low birthweight, are conflicting because evidence is

insufficient to attribute cause (766,932–934). Data are limited

regarding ectopic pregnancy and neonatal M. genitalium

infection (935,936).

Rectal infection with M. genitalium has been reported among

1%–26% of MSM (937–940) and among 3% of women

(941). Rectal infections often are asymptomatic, although

higher prevalence of M. genitalium has been reported among

men with rectal symptoms. Similarly, although asymptomatic

M. genitalium has been detected in the pharynx, no evidence

exists of it causing oropharyngeal symptoms or systemic disease.

Urogenital M. genitalium infection is associated with HIV

among both men and women (942–944); however, the data

are from case-control and cross-sectional studies. Risk for HIV

infection is increased among women with M. genitalium, and

evidence indicates that HIV shedding occurs more often among

persons with M. genitalium and HIV infection who are not taking

ART than among persons without M. genitalium (942,944).

Antimicrobial Resistance

Resistance to azithromycin has been rapidly increasing

and has been confirmed in multiple studies. Prevalence of

molecular markers for macrolide resistance, which highly

correlates with treatment failure, ranges from 44% to 90%

in the United States, Canada, Western Europe, and Australia

(697,702,945–953). Treatment with azithromycin alone

has been reported to select for resistance (705,954,955),

with treatment of macrolide-susceptible infections with a

1-g dose of azithromycin resulting in selection of resistant-

strain populations in 10%–12% of cases. The prevalence of

quinolone resistance markers is much lower (697,956–959).

The first clinical treatment failures after moxifloxacin were

associated specifically with the S83I mutation in the parC gene

(954,960). Prevalence of the S83I mutation in the United

States ranges from 0% to 15% (947); however, correlation

with fluoroquinolone treatment failure is less consistent than

that with mutations associated with macrolide resistance

(953,961,962). Clinically relevant quinolone resistance often

is associated with coexistent macrolide resistance (954).

Diagnostic Considerations

M. genitalium is an extremely slow-growing organism. Culture

can take up to 6 months, and technical laboratory capacity is

limited to research settings. NAAT for M. genitalium is FDA

cleared for use with urine and urethral, penile meatal, endocervical,

and vaginal swab samples (https://www.hologic.com/package-

inserts/diagnostic-products/aptima-mycoplasma-genitalium-

assay). Molecular tests for macrolide (i.e., azithromycin) or

quinolone (i.e., moxifloxacin) resistance markers are not

commercially available in the United States. However, molecular

assays that incorporate detection of mutations associated with

macrolide resistance are under evaluation.

Men with recurrent NGU should be tested for M. genitalium

using an FDA-cleared NAAT. If resistance testing is available,

it should be performed and the results used to guide therapy.

Women with recurrent cervicitis should be tested for

M. genitalium, and testing should be considered among women

with PID. Testing should be accompanied with resistance

testing, if available. Screening of asymptomatic M. genitalium

infection among women and men or extragenital testing

for M. genitalium is not recommended. In clinical practice,

if testing is unavailable, M. genitalium should be suspected

in cases of persistent or recurrent urethritis or cervicitis and

considered for PID.

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Treatment

M. genitalium lacks a cell wall, and thus antibiotics targeting

cell-wall biosynthesis (e.g., ß-lactams including penicillins and

cephalosporins) are ineffective against this organism. Because

of the high rates of macrolide resistance with treatment failures

(707) and efficient selection of additional resistance, a 1-g dose

of azithromycin should not be used.

Two-stage therapy approaches, ideally using resistance-

guided therapy, are recommended for treatment. Resistance-

guided therapy has demonstrated cure rates of >90% and

should be used whenever possible (759,963); however, it

requires access to macrolide-resistance testing. As part of this

approach, doxycycline is provided as initial empiric therapy,

which reduces the organism load and facilitates organism

clearance, followed by macrolide-sensitive M. genitalium

infections treated with high-dose azithromycin; macrolide-

resistant infections are treated with moxifloxacin (964,965).

Recommended Regimens if M. genitalium Resistance Testing Is

Available

If macrolide sensitive: Doxycycline 100 mg orally 2 times/day for

7 days, followed by azithromycin 1 g orally initial dose, followed by

500 mg orally daily for 3 additional days (2.5 g total)

If macrolide resistant: Doxycycline 100 mg orally 2 times/day for 7 days

followed by moxifloxacin 400 mg orally once daily for 7 days

Recommended Regimen if M. genitalium Resistance Testing Is

Not Available

If M. genitalium is detected by an FDA-cleared NAAT: Doxycycline

100 mg orally 2 times/day for 7 days, followed by moxifloxacin 400 mg

orally once daily for 7 days

Although the majority of M. genitalium strains are sensitive

to moxifloxacin, resistance has been reported, and adverse

side effects and cost should be considered with this regimen.

In settings without access to resistance testing and when

moxifloxacin cannot be used, an alternative regimen can be

considered, based on limited data: doxycycline 100 mg orally

2 times/day for 7 days, followed by azithromycin (1 g orally

on day 1 followed by 500 mg once daily for 3 days) and a test

of cure 21 days after completion of therapy (963). Because of

the high prevalence of macrolide resistance and high likelihood

of treatment failure, this regimen should be used only when

a test of cure is possible, and no other alternatives exist. If

symptomatic treatment failure or a positive test of cure occurs

after this regimen, expert consultation is recommended.

Data are limited regarding use of minocycline in instances of

treatment failure (966).

Recommended PID treatment regimens are not effective

against M. genitalium. Initial empiric therapy for PID, which

includes doxycycline 100 mg orally 2 times/day for 14 days,

should be provided at the time of presentation for care. If

M. genitalium is detected, a regimen of moxifloxacin 400 mg

orally once daily for 14 days has been effective in eradicating the

organism. Nevertheless, no data have been published that assess

the benefits of testing women with PID for M. genitalium, and

the importance of directing treatment against this organism

is unknown.

Follow-Up

Test of cure is not recommended for asymptomatic persons

who received treatment with a recommended regimen. In

settings in which M. genitalium testing is available, persons

with persistent urethritis, cervicitis, or PID accompanied by

detection of M. genitalium should be treated with moxifloxacin.

Management of Sex Partners

Recent studies report a high concordance of M. genitalium

among partners of males, females, and MSM; however, no

studies have determined whether reinfection is reduced with

partner treatment (940,967,968). Sex partners of patients

with symptomatic M. genitalium infection can be tested, and

those with a positive test can be treated to possibly reduce the

risk for reinfection. If testing the partner is not possible, the

antimicrobial regimen that was provided to the patient can

be provided.

Special Considerations

HIV Infection

Persons who have M. genitalium and HIV infection should

receive the same treatment regimen as those persons without HIV.

Diseases Characterized by

Vulvovaginal Itching, Burning,

Irritation, Odor, or Discharge

The majority of women will have a vaginal infection,

characterized by discharge, itching, burning, or odor, during

their lifetime. With the availability of complementary and

alternative therapies and over-the-counter medications for

candidiasis, symptomatic women often seek these products

before or in addition to an evaluation by a medical provider.

Obtaining a medical history alone has been reported to

be insufficient for accurate diagnosis of vaginitis and can

lead to inappropriate administration of medication (969).

Therefore, a careful history, examination, and laboratory

testing to determine the etiology of any vaginal symptoms

are warranted. Information regarding sexual behaviors and

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practices, sex of sex partners, menses, vaginal hygiene practices

(e.g., douching), and self-treatment with oral and intravaginal

medications or other products should be elicited. The

infections most frequently associated with vaginal symptoms

are BV (i.e., replacement of the vaginal flora by an overgrowth

of anaerobic bacteria including G. vaginalis, Prevotella bivia,

A. vaginae, Megasphaera type 1, and numerous other fastidious

or uncultivated anaerobes), trichomoniasis, and vulvovaginal

candidiasis (VVC). Cervicitis can also cause an abnormal

vaginal discharge. Although VVC is usually not sexually

transmitted, it is included in this section because it is frequently

diagnosed among women who have vaginal symptoms or are

being evaluated for an STI.

Multiple diagnostic methods are available for identifying the

etiology of vaginal symptoms. Clinical laboratory testing can

identify the vaginitis cause in the majority of women and is

discussed in detail in the sections of this report dedicated to

each condition. In the clinician’s office, the cause of vaginal

symptoms can often be determined by pH, a potassium

hydroxide (KOH) test, and microscopic examination of a wet

mount of fresh samples of vaginal discharge. The pH of the

vaginal secretions can be measured by pH paper; an elevated

pH (i.e., >4.5) is common with BV or trichomoniasis (although

trichomoniasis can also be present with a normal vaginal pH).

Because pH testing is not highly specific, vaginal discharge

should be further examined microscopically by first diluting

one sample in 1 or 2 drops of 0.9% normal saline solution on

one slide and a second sample in 10% KOH solution (samples

that emit an amine odor immediately upon application of

KOH suggest BV or trichomoniasis). Coverslips are then

placed on the slides, and they are examined under a microscope

at low and high power. The saline-solution specimen might

display motile trichomonads or clue cells (i.e., epithelial cells

with borders obscured by small anaerobic bacteria), which

are characteristic of BV. The KOH specimen typically is used

to identify hyphae or blastospores observed with candidiasis.

However, absence of trichomonads in saline or fungal elements

in KOH samples does not rule out these infections because the

sensitivity of microscopy is approximately 50% compared with

NAAT (trichomoniasis) or culture (yeast) (670). Presence of

WBCs without evidence of trichomonads or yeast might also

indicate cervicitis (see Cervicitis).

In settings where pH paper, KOH, and microscopy

are unavailable, a broad range of clinical laboratory tests,

described in the diagnosis section for each disease, can be

used. Presence of objective signs of vulvovaginal inflammation

in the absence of vaginal pathogens after laboratory testing

indicates the possibility of mechanical, chemical, allergic, or

other noninfectious causes of vulvovaginal signs or symptoms.

For women with persistent symptoms and no clear etiology,

referral to a specialist should be considered.

Bacterial Vaginosis

BV is a vaginal dysbiosis resulting from replacement of normal

hydrogen peroxide and lactic-acid–producing Lactobacillus

species in the vagina with high concentrations of anaerobic

bacteria, including G. vaginalis, Prevotella species, Mobiluncus

species, A. vaginae, and other BV-associated bacteria. A notable

feature is the appearance of a polymicrobial biofilm on vaginal

epithelial cells (970). Certain women experience transient

vaginal microbial changes, whereas others experience them for

longer intervals (971). BV is a highly prevalent condition and

the most common cause of vaginal discharge worldwide (972).

However, in a nationally representative survey, the majority of

women with BV were asymptomatic (310).

BV is associated with having multiple male sex partners,

female partners, sexual relationships with more than one person

(973), a new sex partner, lack of condom use (974), douching

(975,976), and HSV-2 seropositivity (977). Male circumcision

reduces the risk for BV among women (978). In addition, BV

prevalence increases during menses (979,980). Women who

have never been sexually active are rarely affected (981). The

cause of the microbial alteration that precipitates BV is not

fully understood, and whether BV results from acquisition

of a single sexually transmitted pathogen is unknown. BV

prevalence has been reported to increase among women with

copper-containing IUDs (972,982). Hormonal contraception

does not increase risk for BV (983) and might protect against

BV development (983,984). Vitamin D deficiency has not

been reported to be a risk factor for BV (985).

Women with BV are at increased risk for STI acquisition,

such as HIV, N. gonorrhoeae, C. trachomatis, T. vaginalis

(977), M. genitalium (986), HPV (987), and HSV-2 (988);

complications after gynecologic surgery; complications of

pregnancy; and recurrence of BV (971,989–991). BV also

increases HIV infection acquisition (992) because specific

BV-associated bacteria can increase susceptibility to HIV

(993,994) and the risk for HIV transmission to male

sex partners (187). Evaluation of short-term valacyclovir

suppression among women with HSV-2 did not decrease the

risk for BV, despite effective suppression of HSV-2 (995).

Although BV-associated bacteria can be identified on male

genitalia (996,997), treatment of male sex partners has not been

beneficial in preventing the recurrence of BV (998). Among

WSW, a high level of BV concordance occurs between sex

partners (292); however, no studies have evaluated treatment

of female sex partners of WSW to prevent BV recurrence.

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Diagnostic Considerations

BV can be diagnosed by using clinical criteria (i.e.,

Amsel’s diagnostic criteria) (999) or by determining the

Nugent score from a vaginal Gram stain (1000). Vaginal

Gram stain, considered the reference standard laboratory

method for diagnosing BV, is used to determine the relative

concentration of lactobacilli (i.e., long gram-positive rods),

small gram-negative and gram-variable rods (i.e., G. vaginalis or

Bacteroides), and curved gram-negative rods (i.e., Mobiluncus)

characteristic of BV. A Nugent score of 0–3 is consistent with

a Lactobacillus-predominant vaginal microbiota, 4–6 with

intermediate microbiota (emergence of G. vaginalis), and 7–10

with BV. Clinical diagnosis of BV by Amsel criteria requires at

least three of the following four symptoms or signs:

• Homogeneous, thin discharge (milklike consistency) that

smoothly coats the vaginal walls

• Clue cells (e.g., vaginal epithelial cells studded with

adherent bacteria) on microscopic examination

• pH of vaginal fluid >4.5

• A fishy odor of vaginal discharge before or after addition

of 10% KOH (i.e., the whiff test)

Detection of at least three Amsel criteria has been correlated

with results by Gram stain (1001). The sensitivity and

specificity of the Amsel criteria are 37%–70% and 94%–99%,

respectively, compared with the Nugent score (1002).

In addition to the Amsel criteria, multiple POC tests are

available for BV diagnosis. The Osom BV Blue test (Sekisui

Diagnostics) detects vaginal sialidase activity (1003,1004).

The Affirm VP III (Becton Dickinson) is an oligonucleotide

probe test that detects high concentrations of G. vaginalis

nucleic acids (>5 x 10

CFU of G. vaginalis/mL of vaginal

fluid) for diagnosing BV, Candida species, and T. vaginalis.

This test has been reported to be most useful for symptomatic

women in conjunction with vaginal pH measurement and

presence of amine odor (sensitivity of 97%); specificity is

81% compared with Nugent. Finally, the FemExam Test

Card (Cooper Surgical) measures vaginal pH, presence of

trimethylamine (a metabolic by-product of G. vaginalis),

and proline aminopeptidase (1005). Sensitivity is 91% and

specificity is 61%, compared with Nugent. This test has

primarily been studied in resource-poor settings (1005), and

although it has been reported to be beneficial compared with

syndromic management, it is not a preferred diagnostic method

for BV diagnosis.

Multiple BV NAATs are available for BV diagnosis among

symptomatic women (1002). These tests are based on detection

of specific bacterial nucleic acids and have high sensitivity

and specificity for BV (i.e., G. vaginalis, A. vaginae, BVAB2,

or Megasphaera type 1) (1006) and certain lactobacilli (i.e.,

Lactobacillus crispatus, Lactobacillus jensenii, and Lactobacillus

gasseri). They can be performed on either clinician- or self-

collected vaginal specimens with results available in <24 hours,

depending on the availability of the molecular diagnostic

platform (1002). Five quantitative multiplex PCR assays are

available: Max Vaginal Panel (Becton Dickinson) (1007),

Aptima BV (Hologic), NuSwab VG (LabCorp) (1008),

OneSwab BV Panel PCR with Lactobacillus Profiling by qPCR

(Medical Diagnostic Laboratories) (1009), and SureSwab BV

(Quest Diagnostics). Two of these assays are FDA cleared (BD

Max Vaginal Panel and Aptima BV), and the other three are

laboratory-developed tests.

The Max Vaginal Panel provides results by an algorithmic

analysis of molecular DNA detection of Lactobacillus species

(L. crispatus and L. jensenii) in addition to G. vaginalis,

A. vaginae, BVAB2, and Megasphaera type 1. This test has

90.5% sensitivity and 85.8% specificity for BV diagnosis,

compared with Amsel criteria and Nugent score. It also provides

results for Candida species and T. vaginalis. The Aptima BV

detects G. vaginalis, A. vaginae, and certain Lactobacillus species

including L. crispatus, L. jensenii, and L. gasseri, with sensitivity

and specificity ranging from 95.0% to 97.3% and 85.8% to

89.6%, respectively (using either clinician- or patient-collected

vaginal swabs). The three laboratory-developed tests (NuSwab

VG, OneSwab BV Panel PCR with Lactobacillus Profiling by

qPCR, and SureSwab BV) have to be internally validated before

use for patient care yet have good sensitivity and specificity,

similar to FDA-cleared assays. BV NAATs should be used

among symptomatic women only (e.g., women with vaginal

discharge, odor, or itch) because their accuracy is not well

defined for asymptomatic women. Despite the availability of

BV NAATs, traditional methods of BV diagnosis, including

the Amsel criteria, Nugent score, and the Affirm VP III assay,

remain useful for diagnosing symptomatic BV because of their

lower cost and ability to provide a rapid diagnosis. Culture of

G. vaginalis is not recommended as a diagnostic tool because

it is not specific. Cervical Pap tests have no clinical utility for

diagnosing BV because of their low sensitivity and specificity.

Treatment

Treatment for BV is recommended for women with

symptoms. Established benefits of therapy among nonpregnant

women are to relieve vaginal symptoms and signs of infection.

Other potential benefits of treatment include reduction

in the risk for acquiring C. trachomatis, N. gonorrhoeae,

T. vaginalis, M. genitalium, HIV, HPV, and HSV-2 (971,986–

988,990,1010). No data are available that directly compare

the efficacy of oral and topical medications for treating BV.

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Recommended Regimens for Bacterial Vaginosis

Metronidazole 500 mg orally 2 times/day for 7 days

Metronidazole gel 0.75% one full applicator (5 g) intravaginally, once

daily for 5 days

Clindamycin cream 2% one full applicator (5 g) intravaginally at

bedtime for 7 days

A review regarding alcohol consumption during

metronidazole treatment reported no in vitro studies, animal

models, reports of adverse effects, or clinical studies providing

convincing evidence of a disulfiram-like interaction between

alcohol and metronidazole (1011). The previous warning

against simultaneous use of alcohol and metronidazole was

based on laboratory experiments and individual case histories

in which the reported reactions were equally likely to have been

caused by alcohol alone or by adverse effects of metronidazole.

Metronidazole does not inhibit acetaldehyde dehydrogenase,

as occurs with disulfiram. Ethanol alone or ethanol-

independent side effects of metronidazole might explain the

suspicion of disulfiram-like effects. Thus, refraining from

alcohol use while taking metronidazole (or tinidazole) is

unnecessary. Clindamycin cream is oil based and might weaken

latex condoms and diaphragms for 5 days after use (refer to

clindamycin product labeling for additional information).

Women should be advised to refrain from sexual activity

or to use condoms consistently and correctly during the BV

treatment regimen. Douching might increase the risk for

relapse, and no data support use of douching for treatment

or symptom relief.

Alternative Regimens

Clindamycin 300 mg orally 2 times/day for 7 days

Clindamycin ovules 100 mg intravaginally once at bedtime for 3 days*

Secnidazole 2 g oral granules in a single dose

†

Tinidazole 2 g orally once daily for 2 days

Tinidazole 1 g orally once daily for 5 days

* Clindamycin ovules use an oleaginous base that might weaken latex or

rubber products (e.g., condoms and diaphragms). Use of such products

within 72 hours after treatment with clindamycin ovules is not

recommended.

†

Oral granules should be sprinkled onto unsweetened applesauce, yogurt,

or pudding before ingestion. A glass of water can be taken after

administration to aid in swallowing.

Alternative regimens include secnidazole oral granules

(1012–1014), multiple oral tinidazole regimens (1015), or

clindamycin (oral or intravaginal) (1016). In a phase 3 clinical

trial of secnidazole 2 g oral granules versus placebo, BV

clinical cure rates at days 21–30 were 53% in the secnidazole

arm compared with 19% in the placebo arm (p<0.001)

(1013). Secnidazole is listed as an alternative regimen, due

to its higher cost and lack of long-term outcomes compared

with recommended BV treatments. A patient savings card

for secnidazole is available at https://www.solosec.com/

savings-card.

Additional BV treatment regimens include metronidazole

1.3% vaginal gel in a single dose (1017,1018) and clindamycin

phosphate (Clindesse) 2% vaginal cream in a single dose

(1019). In a phase 3 clinical trial of metronidazole 1.3% vaginal

gel versus placebo, BV clinical cure rates at day 21 were 37.2%

in the metronidazole 1.3% vaginal gel arm, compared with

26.6% in the placebo arm (p = 0.01) (1018). A patient savings

card for metronidazole 1.3% vaginal gel is available at https://

nuvessa.com/nuvessa_files/19_Nuvessa_WEB_Card_032819.

pdf. In a multicenter, randomized, single-blind, parallel-

group study of Clindesse 2% vaginal cream single dose versus

clindamycin 2% vaginal cream at bedtime for 7 days among

540 women with BV, no statistically significant difference

existed between groups in clinical cure at days 21–30 (64.3%

versus 63.2%; p = 0.95) (1019); however, this study had

methodologic problems. A patient savings card for Clindesse

2% vaginal cream is available at https://www.clindesse.com/

pdf/CLINDESSE_SavingsCard.pdf.

BV biofilm disrupting agents (i.e., TOL-463) (1020) are

being investigated to determine their role in enhancing the

likelihood of BV cure relative to approved therapies. Studies

have evaluated the clinical and microbiologic efficacy of

intravaginal Lactobacillus and other probiotic formulations to

treat BV and restore normal vaginal microbiota (1021–1025);

overall, no studies support these products as an adjunctive or

replacement therapy for women with BV.

Other Management Considerations

All women with BV should be tested for HIV and other STIs.

Follow-Up

Follow-up visits are unnecessary if symptoms resolve. Because

persistent or recurrent BV is common, women should be advised

to return for evaluation if symptoms recur. Limited data are

available regarding optimal management strategies for women

with persistent or recurrent BV. Using a different recommended

treatment regimen can be considered for women who have a

recurrence; however, retreatment with the same recommended

regimen is an acceptable approach for treating persistent or

recurrent BV after the first occurrence (1026). For women with

multiple recurrences after completion of a recommended regimen,

either 0.75% metronidazole gel or 750 mg metronidazole vaginal

suppository twice weekly for >3 months has been reported to

reduce recurrences, although this benefit does not persist when

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suppressive therapy is discontinued (1027,1028). Limited data

indicate that for women with multiple recurrences, an oral

nitroimidazole (metronidazole or tinidazole 500 mg 2 times/

day for 7 days), followed by intravaginal boric acid 600 mg

daily for 21 days and suppressive 0.75% metronidazole gel

twice weekly for 4–6 months, might be an option for women

with recurrent BV (1029). Monthly oral metronidazole 2 g

administered with fluconazole 150 mg has also been evaluated

as suppressive therapy; this regimen reduced the BV incidence

and promoted colonization with normal vaginal microbiota

(1030). A randomized controlled trial of a dendrimer-based

microbicide 1% vaginal gel (Astodrimer) also reported favorable

results in prolonging the time to BV recurrence, compared with

placebo (1031). In addition, a clinical trial of L. crispatus CTV-05

(Lactin-V), administered vaginally in 4 consecutive daily doses

for 4 days in week 1 followed by twice weekly doses for 10 weeks

(after initial treatment with 5 days of 0.75% vaginal metronidazole

gel), reported a substantially lower incidence of BV recurrence at

12 weeks in the Lactin-V arm, compared with placebo (1032);

however this medication is not yet FDA cleared or commercially

available. High-dose Vitamin D supplementation has not been

determined to decrease BV recurrence in randomized controlled

trials (1033) and is not recommended.

Management of Sex Partners

Data from earlier clinical trials indicate that a woman’s

response to therapy and the likelihood of relapse or

recurrence are not affected by treatment of her sex partner

(998). Therefore, routine treatment of sex partners is not

recommended. However, a pilot study reported that male

partner treatment (i.e., metronidazole 400 mg orally 2 times/

day in conjunction with 2% clindamycin cream applied

topically to the penile skin 2 times/day for 7 days) of women

with recurrent BV had an immediate and sustained effect on

the composition of the vaginal microbiota, with an overall

decrease in bacterial diversity at day 28 (1034). Male partner

treatment also had an immediate effect on the composition of

the penile microbiota; however, this was not as pronounced

at day 28, compared with that among women. A phase 3

multicenter randomized double-blinded trial evaluating the

efficacy of a 7-day oral metronidazole regimen versus placebo

for treatment of male sex partners of women with recurrent

BV did not find that male partner treatment reduced BV

recurrence in female partners, although women whose male

partners adhered to multidose metronidazole were less likely

to experience treatment failure (1035).

Special Considerations

Drug Allergy, Intolerance, or Adverse Reactions

Intravaginal clindamycin cream is preferred in case of allergy

or intolerance to metronidazole or tinidazole. Intravaginal

metronidazole gel can be considered for women who are not

allergic to metronidazole but do not tolerate oral metronidazole.

Pregnancy

BV treatment is recommended for all symptomatic pregnant

women because symptomatic BV has been associated with

adverse pregnancy outcomes, including premature rupture

of membranes, preterm birth, intra-amniotic infection, and

postpartum endometritis (989,991,1036). Studies have been

undertaken to determine the efficacy of BV treatment among

this population, including two trials demonstrating that oral

metronidazole was efficacious during pregnancy by using

the 250 mg 3 times/day regimen (1037,1038); however, oral

metronidazole administered as a 500 mg 2 times/day regimen

can also be used. One trial involving a limited number of

participants revealed treatment with oral metronidazole

500 mg 2 times/day for 7 days to be equally effective as

metronidazole gel 0.75% for 5 days, with cure rates of 70%

by using Amsel criteria to define cure (1039). Another trial

demonstrated a cure rate of 85% by using Gram-stain criteria

after treatment with oral clindamycin 300 mg 2 times/day for

7 days (1040–1043).

Although older studies indicated a possible link between

using vaginal clindamycin during pregnancy and adverse

outcomes for the newborn, newer data demonstrate that

this treatment approach is safe for pregnant women (1044).

Although metronidazole crosses the placenta, no evidence of

teratogenicity or mutagenic effects among infants has been

reported in multiple cross-sectional, case-control, and cohort

studies of pregnant women (1041–1043). These data indicate

that metronidazole therapy poses low risk during pregnancy.

Data from human studies are limited regarding the use of

tinidazole in pregnancy; however, animal data demonstrate

that such therapy poses moderate risk. Thus, tinidazole should

be avoided during pregnancy (431). Data are insufficient

regarding efficacy and adverse effects of secnidazole, Clindesse

2% vaginal cream, metronidazole 1.3% vaginal gel, and

750-mg vaginal metronidazole tablets during pregnancy; thus,

their use should be avoided.

Oral therapy has not been reported to be superior to topical

therapy for treating symptomatic BV in effecting cure or

preventing adverse outcomes of pregnancy. Pregnant women

can be treated with any of the recommended regimens for

nonpregnant women, in addition to the alternative regimens

of oral clindamycin and clindamycin ovules.

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Treatment of asymptomatic BV among pregnant women

at high risk for preterm delivery (i.e., those with a previous

preterm birth or late miscarriage) has been evaluated by

multiple studies, which have yielded mixed results. Seven

trials have evaluated treatment of pregnant women with

asymptomatic BV at high risk for preterm delivery: one revealed

harm (1045), two reported no benefit (1046,1047), and four

demonstrated benefit (1037,1038,1048,1049).

Treatment of asymptomatic BV among pregnant women

at low risk for preterm delivery has not been reported to

reduce adverse outcomes of pregnancy in a large multicenter

randomized controlled trial (1050). Therefore, routine

screening for BV among asymptomatic pregnant women at

high or low risk for preterm delivery for preventing preterm

birth is not recommended.

Metronidazole is secreted in breast milk. With maternal

oral therapy, breastfed infants receive metronidazole in doses

that are less than those used to treat infections among infants,

although the active metabolite adds to the total infant exposure.

Plasma levels of the drug and metabolite are measurable

but remain less than maternal plasma levels (https://www.

ncbi.nlm.nih.gov/books/NBK501922/?report=classic).

Although multiple reported case series identified no evidence

of metronidazole-associated adverse effects for breastfed

infants, certain clinicians recommend deferring breastfeeding

for 12–24 hours after maternal treatment with a single 2-g

dose of metronidazole (1051). Lower doses produce a lower

concentration in breast milk and are considered compatible

with breastfeeding (1052,1053).

HIV Infection

BV appears to recur with higher frequency among women

who have HIV infection (1054). Women with HIV infection

and BV should receive the same treatment regimen as those

who do not have HIV.

Trichomoniasis

Trichomoniasis is estimated to be the most prevalent nonviral

STI worldwide, affecting approximately 3.7 million persons

in the United States (838,1055). Because trichomoniasis is

not a reportable disease (1056), and no recommendations are

available for general screening for T. vaginalis, the epidemiology

of trichomoniasis has largely come from population-based and

clinic-based surveillance studies. The U.S. population-based

T. vaginalis prevalence is 2.1% among females and 0.5% among

males, with the highest rates among Black females (9.6%)

and Black males (3.6%), compared with non-Hispanic White

women (0.8%) and Hispanic women (1.4%) (1057,1058).

Unlike chlamydia and gonorrhea, T. vaginalis prevalence

rates are as high among women aged >24 years as they are

for women aged <24 years (1057). Among persons attending

nine geographically diverse STD clinics, the trichomonas

prevalence was 14.6% among women (1059), and a study

of STD clinic attendees in Birmingham, Alabama, identified

a prevalence of 27% among women and 9.8% among men

(1060). Symptomatic women have a four times higher rate of

infection than asymptomatic women (26% versus 6.5%) (1061).

Rates are also high among incarcerated persons of both sexes at

9%–32% of incarcerated women (386,387,391,392,1062) and

3.2%–8% of incarcerated men (388). Women with a history of

incarceration are two to five times more likely to have T. vaginalis

(387,388,1063,1064). Other risk factors for T. vaginalis include

having two or more sex partners during the previous year, having

less than a high school education, and living below the national

poverty level (1065). Women with BV are at higher risk for

T. vaginalis (1066). Male partners of women with trichomoniasis

are likely to have infection (1067), although the prevalence of

trichomoniasis among MSM is low (179,1068).

The majority of persons who have trichomoniasis

(70%–85%) either have minimal or no genital symptoms,

and untreated infections might last from months to years

(137,1069,1070). Men with trichomoniasis sometimes have

symptoms of urethritis, epididymitis, or prostatitis, and women

with trichomoniasis sometimes have vaginal discharge, which

can be diffuse, malodorous, or yellow-green with or without

vulvar irritation, and might have a strawberry-appearing cervix,

which is observed more often on colposcopy than on physical

examination (1071). Although many persons might be unaware

of their infection, it is readily passed between sex partners

during penile-vaginal sex (1072) or through transmission of

infected vaginal fluids or fomites among women who have sex

with women (275,294).

Among persons who are sexually active, the best way to

prevent genital trichomoniasis is through consistent and correct

use of condoms (external or internal) (18). Partners of men

who have been circumcised might have a somewhat reduced

risk for T. vaginalis infection (1072,1073). Douching is not

recommended because it might increase the risk for vaginal

infections, including trichomoniasis (1074).

T. vaginalis causes reproductive morbidity and has been

reported to be associated with a 1.4-times greater likelihood

of preterm birth, premature rupture of membranes, and

infants who are small for gestational age (1075). T. vaginalis

was also determined to be associated with a 2.1-fold increased

risk for cervical cancer in a meta-analysis (1076). Another

meta-analysis of six studies reported a slightly elevated but

not statistically significant association between T. vaginalis and

prostate cancer (1077).

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T. vaginalis infection is associated with a 1.5-fold increased risk

for HIV acquisition and is associated with an increase in HIV

vaginal shedding, which is reduced with T. vaginalis treatment

among women without viral suppression (1078,1079). Among

women with HIV infection, T. vaginalis infection is associated

with increased risk for PID (1080–1082).

Diagnostic testing for T. vaginalis should be performed for

women seeking care for vaginal discharge. Annual screening

might be considered for persons receiving care in high-

prevalence settings (e.g., STD clinics and correctional facilities)

and for asymptomatic women at high risk for infection (e.g.,

multiple sex partners, transactional sex, drug misuse, or a

history of STIs or incarceration). However, data are lacking

regarding whether screening and treatment for asymptomatic

trichomoniasis in high-prevalence settings for women at high

risk can reduce any adverse health events and health disparities

or reduce community infection burden. Decisions about

screening can be guided by local epidemiology of T. vaginalis

infection. Routine annual screening for T. vaginalis among

asymptomatic women with HIV infection is recommended

because of these adverse events associated with trichomoniasis

and HIV infection.

Extragenital T. vaginalis is possible but highly uncommon

compared with genital infections. A study of 500 men in San

Francisco, California, reported a 0.6% rate of rectal T. vaginalis

(1083); however, this might reflect deposition of T. vaginalis

DNA and not necessarily active infection. Few studies of

extragenital T. vaginalis among women have been published.

The efficacy, benefit, and cost-effectiveness of extragenital

screening are unknown, and no tests are FDA cleared for

extragenital testing; therefore, rectal and oral testing for

T. vaginalis is not recommended.

Diagnostic Considerations

Wet-mount microscopy traditionally has been used as

the preferred diagnostic test for T. vaginalis among women

because it is inexpensive and can be performed at the POC;

however, it has low sensitivity (44%–68%) compared with

culture (1084–1086). To improve detection, clinicians using

wet mounts should attempt to evaluate slides immediately

after specimen collection because sensitivity decreases quickly

to 20% within 1 hour after collection (1087). More highly

sensitive and specific molecular diagnostic options are available,

which should be used in conjunction with a negative wet

mount when possible.

NAATs are highly sensitive, detecting more T. vaginalis

infections than wet-mount microscopy among women

(1060). The Aptima T. vaginalis assay (Beckton Dickinson) is

FDA cleared for detection of T. vaginalis from symptomatic

or asymptomatic women. Reliable samples include

clinician-collected endocervical swabs, clinician-collected

vaginal swabs, female urine specimens, and liquid Pap

smear specimens collected in PreservCyt Solution (Hologic)

(698,1088). This assay detects RNA by transcription-

mediated amplification with a sensitivity of 95.3%–100%

and specificity of 95.2%–100%, compared with wet mount

and culture (1088,1089). Among women, vaginal swabs and

urine specimens have <100% concordance (1084). This assay

has not been FDA cleared for use among men and should be

internally validated in accordance with CLIA regulations before

use with urine or urethral swabs from men. The Probe Tec TV

Amplified DNA Assay (Becton Dickinson) is FDA cleared

for detection of T. vaginalis from vaginal (patient-collected

or clinician-collected) swabs, endocervical swabs, or urine

specimens from women and has sensitivity of 98.3% and

specificity of 99.6%, compared with wet mount and culture

(1090). Similar to the Aptima T. vaginalis assay, this test is only

FDA cleared for use among women and should be internally

validated for use with men. The Max CTGCTV2 assay (Becton

Dickinson) is also FDA cleared for detection of T. vaginalis in

patient-collected or clinician-collected vaginal swab specimens

and male and female urine specimens, with sensitivity and

specificity of 96.2%–100% and 99.1%–100%, respectively,

depending on the specimen type, compared with wet mount

and culture (1091). GeneXpert TV (Cepheid) is a moderately

complex rapid test that can be performed in ≤1 hour and can be

used at the POC (1092). It has been FDA cleared for use with

female urine specimens, endocervical swabs, patient-collected

or clinician-collected vaginal specimens, and male urine

specimens, with sensitivity and specificity of 99.5%–100%

and 99.4%–99.9% (1007), respectively, compared with wet

mount and culture.

Multiple FDA-cleared rapid tests are available for detecting

T. vaginalis with improved sensitivities and specificities,

compared with wet mount. The Osom trichomonas rapid

test (Sekisui Diagnostics) is an antigen-detection test that uses

immunochromatographic capillary flow dipstick technology

that can be performed at the POC by using clinician-obtained

vaginal specimens. Results are available in approximately

10–15 minutes, with sensitivities of 82%–95% and specificity

of 97%–100%, compared with wet mount, culture, and

transcription-mediated amplification (1089,1093,1094). A

study of 209 women aged 14–22 years reported that >99%

could correctly perform and interpret a vaginal self-test by

using the Osom assay, with a high correlation with clinician

interpretation (96% agreement; κ=0.87) (1094). The Osom

test should not be used with men because of low sensitivity

(38% compared with Aptima) (1095). The Solana trichomonas

assay (Quidel) is another rapid test for the qualitative detection

of T. vaginalis DNA and can yield results <40 minutes after

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specimen collection. This assay is FDA cleared for diagnosing

T. vaginalis from female vaginal and urine specimens from

asymptomatic and symptomatic women with sensitivity >98%,

compared with NAAT for vaginal specimens, and >92% for

urine specimens (1096). The Amplivue trichomonas assay

(Quidel) is another rapid test providing qualitative detection

of T. vaginalis that has been FDA cleared for vaginal specimens

from symptomatic and asymptomatic women, with sensitivity

of 90.7% and specificity of 98.9%, compared with NAAT

(1097). Neither the Osom assay nor the Affirm VP III test is

FDA cleared for use with specimens from men.

Culture, such as the InPouch system (BioMed Diagnostics),

was considered the most sensitive method for diagnosing

T. vaginalis infection before molecular detection methods

became available. Culture has sensitivity of 44%–75% and

specificity of <100% (698,1086,1098). For women, vaginal

secretions are the preferred specimen type for culture because

urine culture is less sensitive (698,1099,1100). For men,

culture specimens require a urethral swab, urine sediment,

or semen. To improve diagnostic yield, multiple specimens

from men can be used to inoculate a single culture. Cultures

require an incubator and are necessary for T. vaginalis drug

susceptibility testing. The InPouch specimen should be

examined daily for 5 days over a 7-day period to reduce the

possibility of false negatives (1101).

Although T. vaginalis might be an incidental finding on a

Pap test, neither conventional nor liquid-based Pap smears

are considered diagnostic tests for trichomoniasis; however,

women with T. vaginalis identified on a Pap smear should be

retested with sensitive diagnostic tests and treated if infection

is confirmed (1102,1103).

Treatment

Treatment reduces symptoms and signs of T. vaginalis

infection and might reduce transmission. Treatment

recommendations for women are based on a meta-analysis

(1104) and a multicenter, randomized trial of mostly

symptomatic women without HIV infection (1105). The

study demonstrated that multidose metronidazole (500 mg

orally 2 times/day for 7 days) reduced the proportion of

women retesting positive at a 1-month test of cure visit by half,

compared with women who received the 2-g single dose.No

published randomized trials are available that compare these

doses among men.

Recommended Regimen for Trichomoniasis Among Women

Metronidazole 500 mg orally 2 times/day for 7 days

Recommended Regimen for Trichomoniasis Among Men

Metronidazole 2 g orally in a single dose

Alternative Regimen for Women and Men

Tinidazole 2 g orally in a single dose

The nitroimidazoles are the only class of medications with

clinically demonstrated efficacy against T. vaginalis infections.

Tinidazole is usually more expensive, reaches higher levels in

serum and the genitourinary tract, has a longer half-life than

metronidazole (12.5 hours versus 7.3 hours), and has fewer

gastrointestinal side effects (1106,1107). In randomized

clinical trials, recommended metronidazole regimens have

resulted in cure rates of approximately 84%–98% (1108),

and the recommended tinidazole regimen has resulted in cure

rates of approximately 92%–100% (1108–1112). Randomized

controlled trials comparing single 2-g doses of metronidazole

and tinidazole indicated that tinidazole is equivalent or superior

to metronidazole in achieving parasitologic cure and symptom

resolution (1110,1113,1114).

Metronidazole gel does not reach therapeutic levels in the

urethra and perivaginal glands. Because it is less efficacious

than oral metronidazole, it is not recommended.

Other Management Considerations

Providers should advise persons with T. vaginalis infections

to abstain from sex until they and their sex partners are treated

(i.e., when therapy has been completed and any symptoms

have resolved). Testing for other STIs, including HIV, syphilis,

gonorrhea, and chlamydia, should be performed for persons

with T. vaginalis.

Follow-Up

Because of the high rate of reinfection among women treated

for trichomoniasis, retesting for T. vaginalis is recommended

for all sexually active women <3 months after initial treatment

regardless of whether they believe their sex partners were

treated (137,1115). If retesting at 3 months is not possible,

clinicians should retest whenever persons next seek medical

care <12 months after initial treatment. Data are insufficient

to support retesting men after treatment.

Management of Sex Partners

Concurrent treatment of all sex partners is vital for

preventing reinfections. Current partners should be referred

for presumptive therapy. Partners also should be advised to

abstain from intercourse until they and their sex partners

have been treated and any symptoms have resolved. EPT

might have a role in partner management for trichomoniasis

(129,1116) and can be used in states where permissible by law

(https://www.cdc.gov/std/ept/legal/default.htm); however, no

partner management intervention has been demonstrated to

be superior in reducing reinfection rates (129,130). Although

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no definitive data exist to guide treatment for partners of

persons with persistent or recurrent trichomoniasis among

whom nonadherence and reinfection are unlikely, partners

might benefit from being evaluated and receiving treatment

(see Recurrent Trichomoniasis).

Recurrent Trichomoniasis

A recurrent infection can result from treatment failure

(antimicrobial-resistant T. vaginalis or host-related problems),

lack of adherence, or reinfection from an untreated sex partner.

In the case of a recurrent infection, the origin of the repeat

infection should be assessed because most recurrent infections

likely result from reinfection. Retesting can be considered in

cases of persistent or recurrent trichomoniasis with culture, the

preferred test. If NAAT is used, it should not be conducted before

3 weeks after treatment completion because of possible detection

of residual nucleic acid that is not clinically relevant (1117).

The nitroimidazoles are the only class of antimicrobials

known to be effective against trichomonas infection.

Metronidazole resistance occurs in 4%–10% of cases of

vaginal trichomoniasis (1116,1118). Tinidazole resistance

is less well studied but was present in 1% of infections in

one study (1116). Overall, more T. vaginalis isolates have

reported susceptibility to tinidazole than metronidazole (1119).

Multidose oral metronidazole is more effective than single-dose

treatment, particularly for women who are symptomatic or

have a history of T. vaginalis (1120).

Nitroimidazole-resistant trichomoniasis is concerning

because few alternatives to standard therapy exist. If treatment

failure occurs in a woman after completing a regimen of

metronidazole 500 mg 2 times/day for 7 days and she has been

reexposed to an untreated partner, a repeat course of the same

regimen is recommended. If no reexposure has occurred, she

should be treated with metronidazole or tinidazole 2 g once

daily for 7 days. If a man has persistent T. vaginalis after a

single 2-g dose of metronidazole and has been reexposed to

an untreated partner, he should be retreated with a single 2-g

dose of metronidazole. If he has not been reexposed, he should

be administered a course of metronidazole 500 mg 2 times/

day for 7 days.

For persons who are experiencing persistent infection

not attributable to reexposure, clinicians should request a

kit from CDC to perform drug-resistance testing (https://

www.cdc.gov/laboratory/specimen-submission/detail.

html?CDCTestCode=CDC-10239). CDC is experienced with

susceptibility testing for nitroimidazole-resistant T. vaginalis

and can provide guidance regarding treatment in cases of

drug resistance. On the basis of drug resistance testing, an

alternative treatment regimen might be recommended.

Treatments for infections demonstrating in vitro resistance

can include metronidazole or tinidazole 2 g daily for 7 days.

If a patient has treatment failure after the 7-day regimen of

high-dose oral metronidazole or tinidazole, two additional

treatment options have been determined to have successful

results for women. The first is high-dose oral tinidazole

2 g daily plus intravaginal tinidazole 500 mg 2 times/day for

14 days (1121). If this regimen fails, high-dose oral tinidazole

(1 g 3 times/day) plus intravaginal paromomycin (4 g of 6.25%

intravaginal paromomycin cream nightly) for 14 days should

be considered (1122).

Alternative regimens might be effective but have not been

systemically evaluated; therefore, consultation with an infectious

disease specialist is recommended. Clinical improvement has

been reported with intravaginal boric acid (1123,1124) but

not with nitazoxanide (1123–1125). The following topically

applied agents have minimal success (<50%) and are not

recommended: intravaginal betadine (povidone-iodine),

clotrimazole, acetic acid, furazolidone, GV, nonoxynol-9, and

potassium permanganate (1126). No other topical microbicide

has been reported to be effective against trichomoniasis.

Special Considerations

Drug Allergy, Intolerance, and Adverse Reactions

Metronidazole and tinidazole are both nitroimidazoles.

Patients with an IgE-mediated-type hypersensitivity reaction

to 5-nitroimidazole antimicrobials should be managed by

metronidazole desensitization according to published regimens

(1127,1128) and in consultation with an allergy specialist. The

optimal treatment for patients with T. vaginalis who are unable

to be desensitized has not been systematically investigated and is

based on case reports, some of which report using paromomycin

or boric acid for treating T. vaginalis (1123,1129).

Pregnancy

T. vaginalis infection among pregnant women is associated

with adverse pregnancy outcomes, particularly premature

rupture of membranes, preterm delivery, and delivery of infants

who are small for gestational age (1075). One randomized

trial of pregnant women with asymptomatic trichomoniasis

reported no substantial difference in preterm birth after

treatment with 2 g of metronidazole 48 hours apart during

16–23 and 24–29 weeks’ gestation, compared with placebo

(1130). However, that trial had multiple limitations, including

use of an atypical metronidazole regimen. Another multicenter

observational study of asymptomatic pregnant women in sub-

Sahara African, the majority with HIV infection, reported

neither trichomoniasis nor its treatment appeared to influence

the risk for preterm birth or a low-birthweight infant (1131).

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Although metronidazole crosses the placenta, data indicate

that it poses a low risk to the developing fetus (1040,1042,1132).

No evidence of teratogenicity or mutagenic effects among

infants has been found in multiple cross-sectional and cohort

studies among pregnant women examining single-dose (2 g)

and multidose metronidazole regimens (1040,1131–1135).

Symptomatic pregnant women, regardless of pregnancy stage,

should be tested and treated. Treatment of T. vaginalis infection

can relieve symptoms of vaginal discharge for pregnant women

and reduce sexual transmission to partners. Although perinatal

transmission of trichomoniasis is uncommon, treatment

might also prevent respiratory or genital infection in the

newborn (1136,1137). Clinicians should counsel symptomatic

pregnant women with trichomoniasis about the potential

risks and benefits of treatment and about the importance of

partner treatment and condom use in the prevention of sexual

transmission. The benefit of routine screening for T. vaginalis

in asymptomatic pregnant women has not been established.

Metronidazole is secreted in breast milk. With maternal oral

therapy, breastfed infants receive metronidazole in doses that

are lower than those used to treat infections among infants,

although the active metabolite adds to the total infant exposure.

Plasma levels of the drug and metabolite are measurable but

remain less than maternal plasma levels (https://www.ncbi.nlm.

nih.gov/books/NBK501922). Although multiple reported case

series studies demonstrated no evidence of adverse effects among

infants exposed to metronidazole in breast milk, clinicians

sometimes advise deferring breastfeeding for 12–24 hours after

maternal treatment with metronidazole (1051). In one study,

maternal treatment with metronidazole (400 mg 3 times/day

for 7 days) produced a lower concentration in breast milk and

was considered compatible with breastfeeding over longer

periods (1052).

Data from studies involving human subjects are limited

regarding tinidazole use during pregnancy; however, animal data

indicate this drug poses moderate risk. Thus, tinidazole should

be avoided for pregnant women, and breastfeeding should be

deferred for 72 hours after a single 2-g oral dose of tinidazole

(https://www.ncbi.nlm.nih.gov/books/NBK501922).

HIV Infection

Up to 53% of women with HIV have T. vaginalis infection

(1115,1138). T. vaginalis infection among these women is

substantially associated with pelvic inflammatory disease

(1082). Among women who are not virally suppressed,

treatment of trichomoniasis is associated with decreases in

genital tract HIV viral load and viral shedding (1079,1139);

however, no difference might occur among women who are

virally suppressed (1140). Because of the high prevalence

of T. vaginalis among women with HIV and the potential

for adverse reproductive health, poor birth outcomes, and

possibly amplified HIV transmission, routine screening and

prompt treatment are recommended for all women with HIV

infection; screening should occur at entry to care and then at

least annually thereafter.

A randomized clinical trial involving women with HIV

and T. vaginalis infection demonstrated that a single dose

of metronidazole 2 g orally was less effective than 500 mg

2 times/day for 7 days (1105). Factors that might interfere

with standard single-dose treatment for trichomoniasis among

women with HIV include high rates of asymptomatic BV

infection, ART use, changes in vaginal ecology, and impaired

immunity (1141). Thus, to improve cure rates, women with

HIV who receive a diagnosis of T. vaginalis infection should

be treated with metronidazole 500 mg orally 2 times/day

for 7 days. For pregnant women with HIV, screening at

the first prenatal visit and prompt treatment, as needed, are

recommended because T. vaginalis infection is a risk factor for

vertical transmission of HIV (1142).

Treatment

Treatment reduces symptoms and signs of T. vaginalis

infection, cures infection, and might reduce transmission.

Likelihood of adverse outcomes among women with HIV

infection is also reduced with T. vaginalis therapy.

Recommended Regimen for Trichomonas and HIV Infection

Among Women

Metronidazole 500 mg orally 2 times/day for 7 days

If a woman with HIV infection experiences treatment failure, the

protocol outlined is recommended (see Recurrent Trichomonas).

Other management considerations, follow-up, and management

of sex partners should be performed as for women without HIV

infection. Treatment of men with HIV infection should follow

the same guidelines as for men without HIV.

For women with HIV who receive a diagnosis of T. vaginalis

infection, retesting is recommended 3 months after treatment;

NAAT is encouraged because of higher sensitivity of these

tests. Data are insufficient to support retesting of men with

trichomonas and HIV infection.

Vulvovaginal Candidiasis

VVC usually is caused by Candida albicans but can

occasionally be caused by other Candida species or yeasts.

Typical symptoms of VVC include pruritus, vaginal soreness,

dyspareunia, external dysuria, and abnormal vaginal discharge.

None of these symptoms is specific for VVC. An estimated

75% of women will have at least one episode of VVC, and

40%–45% will have two or more episodes. On the basis of

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clinical presentation, microbiology, host factors, and response

to therapy, VVC can be classified as either uncomplicated or

complicated (Box 4). Approximately 10%–20% of women

will have complicated VVC, requiring special diagnostic and

therapeutic considerations.

Uncomplicated Vulvovaginal Candidiasis

Diagnostic Considerations

A diagnosis of Candida vaginitis is clinically indicated by the

presence of external dysuria and vulvar pruritus, pain, swelling,

and redness. Signs include vulvar edema, fissures, excoriations,

and thick curdy vaginal discharge. Most healthy women with

uncomplicated VVC have no identifiable precipitating factors.

The diagnosis can be made in a woman who has signs and

symptoms of vaginitis when either a wet preparation (saline,

10% KOH) of vaginal discharge demonstrates budding

yeasts, hyphae, or pseudohyphae, or a culture or other test

yields a positive result for a yeast species. Candida vaginitis is

associated with normal vaginal pH (<4.5). Use of 10% KOH

in wet preparations improves the visualization of yeast and

mycelia by disrupting cellular material that might obscure

the yeast or pseudohyphae. Examination of a wet mount with

KOH preparation should be performed for all women with

symptoms or signs of VVC, and women with a positive result

should be treated. For those with negative wet mounts but

existing signs or symptoms, vaginal cultures for Candida should

be considered. If Candida cultures cannot be performed for

these women, empiric treatment can be considered. Identifying

Candida by culture in the absence of symptoms or signs is not

an indication for treatment because approximately 10%–20%

of women harbor Candida species and other yeasts in the

vagina. The majority of PCR tests for yeast are not FDA

cleared, and providers who use these tests should be familiar

with the performance characteristics of the specific test used.

Yeast culture, which can identify a broad group of pathogenic

yeasts, remains the reference standard for diagnosis.

Treatment

Short-course topical formulations (i.e., single dose and

regimens of 1–3 days) effectively treat uncomplicated VVC.

Treatment with azoles results in relief of symptoms and negative

cultures in 80%–90% of patients who complete therapy.

Recommended Regimens for Vulvovaginal Candidiasis

Over-the-Counter Intravaginal Agents

Clotrimazole 1% cream 5 g intravaginally daily for 7–14 days

Clotrimazole 2% cream 5 g intravaginally daily for 3 days

Miconazole 2% cream 5 g intravaginally daily for 7 days

Miconazole 4% cream 5 g intravaginally daily for 3 days

Miconazole 100 mg vaginal suppository one suppository daily for 7 days

Miconazole 200 mg vaginal suppository one suppository for 3 days

Miconazole 1,200 mg vaginal suppository one suppository for 1 day

Tioconazole 6.5% ointment 5 g intravaginally in a single application

Prescription Intravaginal Agents

Butoconazole 2% cream (single-dose bioadhesive product) 5 g

intravaginally in a single application

Terconazole 0.4% cream 5 g intravaginally daily for 7 days

Terconazole 0.8% cream 5 g intravaginally daily for 3 days

Terconazole 80 mg vaginal suppository one suppository daily for 3 days

Oral Agent

Fluconazole 150 mg orally in a single dose

The creams and suppositories in these regimens are oil

based and might weaken latex condoms and diaphragms.

Patients should refer to condom product labeling for further

information. Even women who have previously received a

diagnosis of VVC by a clinician are not necessarily more

likely to be able to diagnose themselves; therefore, any woman

whose symptoms persist after using an over-the-counter

preparation or who has a recurrence of symptoms <2 months

BOX 4. Classification of vulvovaginal candidiasis

Uncomplicated vulvovaginal candidiasis (VVC)

• Sporadic or infrequent VVC

and

• Mild-to-moderate VVC

and

• Likely to be Candida albicans

and

• Nonimmunocompromised women

Complicated VVC

• Recurrent VVC (three or more episodes of

symptomatic VVC in <1 year)

• Severe VVC

• Non–albicans candidiasis

• Women with diabetes, immunocompromising

conditions (e.g., HIV infection), underlying

immunodeficiency, or immunosuppressive therapy

(e.g., corticosteroids)

Source: Sobel JD, Faro S, Force RW, et al. Vulvovaginal candidiasis:

epidemiologic, diagnostic, and therapeutic considerations.Am J Obstet Gynecol

1998;178:203–11.

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after treatment for VVC should be evaluated clinically and

tested. Unnecessary or unapproved use of over-the-counter

preparations is common and can lead to a delay in treatment

of other vulvovaginitis etiologies, which can result in adverse

outcomes. No substantial evidence exists to support using

probiotics or homeopathic medications for treating VVC.

Follow-Up

Follow-up typically is not required. However, women with

persistent or recurrent symptoms after treatment should be

instructed to return for follow-up visits.

Management of Sex Partners

Uncomplicated VVC is not usually acquired through sexual

intercourse, and data do not support treatment of sex partners.

A minority of male sex partners have balanitis, characterized

by erythematous areas on the glans of the penis in conjunction

with pruritus or irritation. These men benefit from treatment

with topical antifungal agents to relieve symptoms.

Special Considerations

Drug Allergy, Intolerance, and Adverse Reactions

Topical agents usually cause no systemic side effects, although

local burning or irritation might occur. Oral azoles occasionally

cause nausea, abdominal pain, and headache. Therapy with the

oral azoles has rarely been associated with abnormal elevations

of liver enzymes. Clinically important interactions can occur

when oral azoles are administered with other drugs (1141).

Complicated Vulvovaginal Candidiasis

Diagnostic Considerations

Vaginal culture or PCR should be obtained from women

with complicated VVC to confirm clinical diagnosis and

identify non–albicans Candida. Candida glabrata does not

form pseudohyphae or hyphae and is not easily recognized

on microscopy. C. albicans azole resistance is becoming more

common in vaginal isolates (1144,1145), and non–albicans

Candida is intrinsically resistant to azoles; therefore, culture

and susceptibility testing should be considered for patients

who remain symptomatic.

Recurrent Vulvovaginal Candidiasis

Recurrent VVC, usually defined as three or more episodes

of symptomatic VVC in <1 year, affects <5% of women but

carries a substantial economic burden (1146). Recurrent VVC

can be either idiopathic or secondary (related to frequent

antibiotic use, diabetes, or other underlying host factors). The

pathogenesis of recurrent VVC is poorly understood, and the

majority of women with recurrent VVC have no apparent

predisposing or underlying conditions. C. glabrata and other

non–albicans Candida species are observed in 10%–20%

of women with recurrent VVC. Conventional antimycotic

therapies are not as effective against these non–albicans yeasts

as against C. albicans.

Treatment

Most episodes of recurrent VVC caused by C. albicans

respond well to short-duration oral or topical azole therapy.

However, to maintain clinical and mycologic control, a longer

duration of initial therapy (e.g., 7–14 days of topical therapy

or a 100-mg, 150-mg, or 200-mg oral dose of fluconazole

every third day for a total of 3 doses [days 1, 4, and 7])

is recommended, to attempt mycologic remission, before

initiating a maintenance antifungal regimen.

Oral fluconazole (i.e., a 100-mg, 150-mg, or 200-mg dose)

weekly for 6 months is the indicated maintenance regimen.

If this regimen is not feasible, topical treatments used

intermittently can also be considered. Suppressive maintenance

therapies are effective at controlling recurrent VVC but are

rarely curative long-term (1147). Because C. albicans azole

resistance is becoming more common, susceptibility tests, if

available, should be obtained among symptomatic patients who

remain culture positive despite maintenance therapy. These

women should be managed in consultation with a specialist.

Severe Vulvovaginal Candidiasis

Severe VVC (i.e., extensive vulvar erythema, edema,

excoriation, and fissure formation) is associated with lower

clinical response rates among patients treated with short courses

of topical or oral therapy. Either 7–14 days of topical azole or

150 mg of fluconazole in two sequential oral doses (second dose

72 hours after initial dose) is recommended.

Non–albicans Vulvovaginal Candidiasis

Because approximately 50% of women with a positive culture

for non–albicans Candida might be minimally symptomatic or

have no symptoms, and because successful treatment is often

difficult, clinicians should make every effort to exclude other

causes of vaginal symptoms for women with non–albicans

yeast (1148). The optimal treatment of non–albicans VVC

remains unknown; however, a longer duration of therapy

(7–14 days) with a nonfluconazole azole regimen (oral or

topical) is recommended. If recurrence occurs, 600 mg of boric

acid in a gelatin capsule administered vaginally once daily for

3 weeks is indicated. This regimen has clinical and mycologic

eradication rates of approximately 70% (1149). If symptoms

recur, referral to a specialist is advised.

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Management of Sex Partners

No data exist to support treating sex partners of patients with

complicated VVC. Therefore, no recommendation can be made.

Special Considerations

Compromised Host

Women with underlying immunodeficiency, those with

poorly controlled diabetes or other immunocompromising

conditions (e.g., HIV), and those receiving immunosuppression

therapy (e.g., corticosteroid treatment) might not respond as

well to short-term therapies. Efforts to correct modifiable

conditions should be made, and more prolonged (i.e.,

7–14 days) conventional treatment is necessary.

Pregnancy

VVC occurs frequently during pregnancy. Only topical

azole therapies, applied for 7 days, are recommended for use

among pregnant women. Epidemiologic studies indicate a

single 150-mg dose of fluconazole might be associated with

spontaneous abortion (1150) and congenital anomalies;

therefore, it should not be used (1151).

HIV Infection

Vaginal Candida colonization rates among women with

HIV infection are higher than among women without HIV

with similar demographic and risk behavior characteristics,

and the colonization rates correlate with increasing severity of

immunosuppression (1152). Symptomatic VVC is also more

frequent among women with HIV infection and similarly

correlates with severity of immunodeficiency (1153). In

addition, among women with HIV, systemic azole exposure

is associated with isolation of non–albicans Candida species

from the vagina.

Treatment for uncomplicated and complicated VVC

among women with HIV infection should not differ from

that for women who do not have HIV. Although long-

term prophylactic therapy with fluconazole 200 mg weekly

has been effective in reducing C. albicans colonization and

symptomatic VVC (1154), this regimen is not recommended

for women with HIV infection in the absence of complicated

VVC (98). Although VVC is associated with increased HIV

seroconversion among HIV-negative women and increased

HIV cervicovaginal levels among women with HIV infection,

the effect of treatment for VVC on HIV acquisition and

transmission remains unknown.

Pelvic Inflammatory Disease

PID comprises a spectrum of inflammatory disorders of

the upper female genital tract, including any combination

of endometritis, salpingitis, tubo-ovarian abscess, and pelvic

peritonitis (1155–1157). Sexually transmitted organisms,

especially N. gonorrhoeae and C. trachomatis, often are

implicated. Recent studies report that the proportion of

PID cases attributable to N. gonorrhoeae or C. trachomatis is

decreasing; of women who received a diagnosis of acute PID,

approximately 50% have a positive test for either of those

organisms (1158–1160). Micro-organisms that comprise the

vaginal flora, such as strict and facultative anaerobes (1160)

and G. vaginalis, H. influenzae, enteric gram-negative rods, and

Streptococcus agalactiae, have been associated with PID (1161).

In addition, cytomegalovirus (CMV), T. vaginalis, M. hominis,

and U. urealyticum might be associated with certain PID cases

(1072). Data also indicate that M. genitalium might have a role

in PID pathogenesis (765,928) and might be associated with

milder symptoms (919,923,928), although one study failed

to demonstrate a substantial increase in PID after detection of

M. genitalium in the lower genital tract (925).

Screening and treating sexually active women for chlamydia

and gonorrhea reduces their risk for PID (1162,1163). Although

BV is associated with PID, whether PID incidence can be

reduced by identifying and treating women with BV is unclear

(1161). Whether screening young women for M. genitalium is

associated with a reduction in PID is unknown.

Diagnostic Considerations

Acute PID is difficult to diagnose because of the considerable

variation in symptoms and signs associated with this condition.

Women with PID often have subtle or nonspecific symptoms or

are asymptomatic. Delay in diagnosis and treatment probably

contributes to inflammatory sequelae in the upper genital tract.

Laparoscopy can be used to obtain a more accurate diagnosis

of salpingitis and a more complete bacteriologic diagnosis.

However, this diagnostic tool frequently is not readily available,

and its use is not easily justifiable when symptoms are mild or

vague. Moreover, laparoscopy will not detect endometritis and

might not detect subtle inflammation of the fallopian tubes.

Consequently, a PID diagnosis usually is based on imprecise

clinical findings (1164–1166).

Data indicate that a clinical diagnosis of symptomatic PID

has a positive predictive value for salpingitis of 65%–90%,

compared with laparoscopy (1167–1170). The positive

predictive value of a clinical diagnosis of acute PID depends on

the epidemiologic characteristics of the population, with higher

positive predictive values among sexually active young women

(particularly adolescents), women attending STD clinics, and

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those who live in communities with high rates of gonorrhea

or chlamydia. Regardless of positive predictive value, no single

historical, physical, or laboratory finding is both sensitive

and specific for the diagnosis of acute PID. Combinations of

diagnostic findings that improve either sensitivity (i.e., detect

more women who have PID) or specificity (i.e., exclude more

women who do not have PID) do so only at the expense of the

other. For example, requiring two or more findings excludes

more women who do not have PID and reduces the number

of women with PID who are identified.

Episodes of PID often go unrecognized. Although certain

cases are asymptomatic, others are not diagnosed because

the patient or the health care provider do not recognize the

implications of mild or nonspecific symptoms or signs (e.g.,

abnormal bleeding, dyspareunia, and vaginal discharge). Even

women with mild or asymptomatic PID might be at risk for

infertility (1157). Because of the difficulty of diagnosis and

the potential for damage to the reproductive health of women,

health care providers should maintain a low threshold for the

clinical diagnosis of PID (1158). The recommendations for

diagnosing PID are intended to assist health care providers to

recognize when PID should be suspected and when additional

information should be obtained to increase diagnostic certainty.

Diagnosis and management of other causes of lower abdominal

pain (e.g., ectopic pregnancy, acute appendicitis, ovarian cyst,

ovarian torsion, or functional pain) are unlikely to be impaired

by initiating antimicrobial therapy for PID. Presumptive

treatment for PID should be initiated for sexually active

young women and other women at risk for STIs if they are

experiencing pelvic or lower abdominal pain, if no cause for

the illness other than PID can be identified, or if one or more

of the following three minimum clinical criteria are present

on pelvic examination: cervical motion tenderness, uterine

tenderness, or adnexal tenderness.

More specific criteria for diagnosing PID include endometrial

biopsy with histopathologic evidence of endometritis;

transvaginal sonography or magnetic resonance imaging

techniques demonstrating thickened, fluid-filled tubes with or

without free pelvic fluid or tubo-ovarian complex, or Doppler

studies indicating pelvic infection (e.g., tubal hyperemia);

and laparoscopic findings consistent with PID. A diagnostic

evaluation that includes some of these more extensive

procedures might be warranted in certain cases. Endometrial

biopsy is warranted for women undergoing laparoscopy who

do not have visual evidence of salpingitis because endometritis

is the only sign of PID for certain women.

Requiring that all three minimum criteria be present

before the initiation of empiric treatment can result in

insufficient sensitivity for a PID diagnosis. After deciding

whether to initiate empiric treatment, clinicians should also

consider the risk profile for STIs. More elaborate diagnostic

evaluation frequently is needed because incorrect diagnosis

and management of PID might cause unnecessary morbidity.

For example, the presence of signs of lower genital tract

inflammation (predominance of leukocytes in vaginal

secretions, cervical discharge, or cervical friability), in addition

to one of the three minimum criteria, increases the specificity of

the diagnosis. One or more of the following additional criteria

can be used to enhance the specificity of the minimum clinical

criteria and support a PID diagnosis:

• Oral temperature >38.3°C (>101°F)

• Abnormal cervical mucopurulent discharge or cervical

friability

• Presence of abundant numbers of WBCs on saline

microscopy of vaginal fluid

• Elevated erythrocyte sedimentation rate

• Elevated C-reactive protein

• Laboratory documentation of cervical infection with

N. gonorrhoeae or C. trachomatis

The majority of women with PID have either mucopurulent

cervical discharge or evidence of WBCs on a microscopic

evaluation of a saline preparation of vaginal fluid (i.e., wet

prep). If the cervical discharge appears normal and no WBCs

are observed on the wet prep of vaginal fluid, a PID diagnosis

is unlikely, and alternative causes of pain should be considered.

A wet prep of vaginal fluid also can detect the presence of

concomitant infections (e.g., BV or trichomoniasis).

Treatment

PID treatment regimens should provide empiric, broad-

spectrum coverage of likely pathogens. Multiple parenteral and

oral antimicrobial regimens have been effective in achieving

clinical and microbiologic cure in randomized clinical trials

with short-term follow-up (1171–1173). However, only

a limited number of studies have assessed and compared

these regimens with regard to infection elimination in the

endometrium and fallopian tubes or determined the incidence

of long-term complications (e.g., tubal infertility and ectopic

pregnancy) after antimicrobial regimens (1159,1164,1174).

The optimal treatment regimen and long-term outcome of

early treatment of women with subclinical PID are unknown.

All regimens used to treat PID should also be effective against

N. gonorrhoeae and C. trachomatis because negative endocervical

screening for these organisms does not rule out upper genital

tract infection. Anaerobic bacteria have been isolated from the

upper genital tract of women who have PID, and data from in

vitro studies have revealed that some anaerobes (e.g., Bacteroides

fragilis) can cause tubal and epithelial destruction. BV is often

present among women who have PID (22,1160,1161,1175).

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Addition of metronidazole to IM or oral PID regimens more

effectively eradicates anaerobic organisms from the upper

genital tract (1160). Until treatment regimens that do not

cover anaerobic microbes have been demonstrated to prevent

long-term sequelae (e.g., infertility and ectopic pregnancy)

as successfully as the regimens that are effective against these

microbes, using regimens with anaerobic activity should

be considered. Treatment should be initiated as soon as the

presumptive diagnosis has been made because prevention of

long-term sequelae is dependent on early administration of

recommended antimicrobials. For women with PID of mild or

moderate clinical severity, parenteral and oral regimens appear

to have similar efficacy. The decision of whether hospitalization

is necessary should be based on provider judgment and whether

the woman meets any of the following criteria:

• Surgical emergencies (e.g., appendicitis) cannot be

excluded

• Tubo-ovarian abscess

• Pregnancy

• Severe illness, nausea and vomiting, or oral temperature

>38.5°C (101°F)

• Unable to follow or tolerate an outpatient oral regimen

• No clinical response to oral antimicrobial therapy

No evidence is available to indicate that adolescents have

improved outcomes from hospitalization for treatment of PID,

and the clinical response to outpatient treatment is similar

among younger and older women. The decision to hospitalize

adolescents with acute PID should be based on the same criteria

used for older women.

Parenteral Treatment

Randomized trials have demonstrated the efficacy of

parenteral regimens (1160,1171,1172,1176). Clinical

experience should guide decisions regarding transition to oral

therapy, which usually can be initiated within 24–48 hours of

clinical improvement. For women with tubo-ovarian abscesses,

>24 hours of inpatient observation is recommended.

Recommended Parenteral Regimens for Pelvic Inflammatory

Disease

Ceftriaxone 1 g by every 24 hours

plus

Doxycycline 100 mg orally or IV every 12 hours

plus

Metronidazole 500 mg orally or IV every 12 hours

Cefotetan 2 g IV every 12 hours

plus

Doxycycline 100 mg orally or IV every 12 hours

Cefoxitin 2 g IV every 6 hours

plus

Doxycycline 100 mg orally or IV every 12 hours

Because of the pain associated with IV infusion, doxycycline

should be administered orally when possible. Oral and IV

administration of doxycycline and metronidazole provide

similar bioavailability. Oral metronidazole is well absorbed

and can be considered instead of IV for women without severe

illness or tubo-ovarian abscess when possible. After clinical

improvement with parenteral therapy, transition to oral therapy

with doxycycline 100 mg 2 times/day and metronidazole

500 mg 2 times/day is recommended to complete 14 days of

antimicrobial therapy.

Alternative Parenteral Regimens

Only limited data are available to support using other

parenteral second- or third- generation cephalosporins (e.g.,

ceftizoxime or cefotaxime). Because these cephalosporins are

less active than cefotetan or cefoxitin against anaerobic bacteria,

the addition of metronidazole should be considered.

Ampicillin-sulbactam plus doxycycline has been investigated

in at least one clinical trial and has broad-spectrum coverage

(1177). Ampicillin-sulbactam plus doxycycline is effective

against C. trachomatis, N. gonorrhoeae, and anaerobes for

women with tubo-ovarian abscess. Another trial demonstrated

short-term clinical cure rates with azithromycin monotherapy

or combined with metronidazole (1178).

When using the clindamycin and gentamicin alternative

parenteral regimen, women with clinical improvement after

24–28 hours can be transitioned to clindamycin (450 mg orally

4 times/day) or doxycycline (100 mg orally 2 times/day) to

complete the 14-day therapy. However, when tubo-ovarian

abscess is present, clindamycin (450 mg orally 4 times/day) or

metronidazole (500 mg orally 2 times/day) should be used to

complete 14 days of therapy with oral doxycycline to provide

more effective anaerobic coverage.

Alternative Parenteral Regimens

Ampicillin-sulbactam 3 g IV every 6 hours

plus

Doxycycline 100 mg orally or IV every 12 hours

Clindamycin 900 mg IV every 8 hours

plus

Gentamicin loading dose IV or IM (2 mg/kg body weight), followed by a

maintenance dose (1.5 mg/kg body weight) every 8 hours; single daily

dosing (3–5 mg/kg body weight) can be substituted

Intramuscular or Oral Treatment

IM or oral therapy can be considered for women with mild-

to-moderate acute PID because the clinical outcomes among

women treated with these regimens are similar to those treated

with IV therapy (1158). Women who do not respond to IM or

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oral therapy within 72 hours should be reevaluated to confirm

the diagnosis and be administered therapy IV.

Recommended Intramuscular or Oral Regimens for Pelvic

Inflammatory Disease

Ceftriaxone 500 mg* IM in a single dose

plus

Doxycycline 100 mg orally 2 times/day for 14 days with metronidazole

500 mg orally 2 times/day for 14 days

Cefoxitin 2 g IM in a single dose and probenecid 1 g orally administered

concurrently in a single dose

plus

Doxycycline 100 mg orally 2 times/day for 14 days with metronidazole

500 mg orally 2 times/day for 14 days

Other parenteral third-generation cephalosporin (e.g., ceftizoxime or

cefotaxime)

plus

Doxycycline 100 mg orally 2 times/day for 14 days with metronidazole

500 mg orally 2 times/day for 14 days

* For persons weighing ≥150 kg, 1 g of ceftriaxone should be administered.

These regimens provide coverage against frequent etiologic

agents of PID; however, the optimal choice of a cephalosporin

is unclear. Cefoxitin, a second-generation cephalosporin, has

better anaerobic coverage than ceftriaxone, and, in combination

with probenecid and doxycycline, has been effective in short-

term clinical response among women with PID. Ceftriaxone

has better coverage against N. gonorrhoeae. The addition of

metronidazole to these regimens provides extended coverage

against anaerobic organisms and will also effectively treat BV,

which is frequently associated with PID.

Alternative Intramuscular or Oral Regimens

No data have been published regarding use of oral

cephalosporins for treating PID. As a result of the emergence

of quinolone-resistant N. gonorrhoeae, regimens that include

a quinolone agent are not recommended for PID treatment.

However, if the patient has cephalosporin allergy, the

community prevalence and individual risk for gonorrhea

are low, and follow-up is likely, alternative therapy can be

considered. Use of either levofloxacin 500 mg orally once daily

or moxifloxacin 400 mg orally once daily with metronidazole

500 mg orally 2 times/day for 14 days (1179–1181) or

azithromycin 500 mg IV daily for 1–2 doses, followed by

250 mg orally daily in combination with metronidazole

500 mg 2 times/day for 12–14 days (1178), can be considered.

Moxifloxacin is the preferred quinolone antimicrobial for

M. genitalium infections; however, the importance of providing

coverage for M. genitalium is unknown. Diagnostic tests for

gonorrhea should be obtained before starting therapy, and

persons should be managed as follows:

• If a culture for gonorrhea is positive, treatment should be

based on results of antimicrobial susceptibility testing.

• If the isolate is determined to be quinolone-resistant

N. gonorrhoeae or if antimicrobial susceptibility cannot be

assessed (e.g., if only NAAT testing is available), consultation

with an infectious disease specialist is recommended.

Other Management Considerations

To minimize disease transmission, women should be

instructed to abstain from sexual intercourse until therapy is

complete, symptoms have resolved, and sex partners have been

treated (see Chlamydial Infections; Gonococcal Infections).

All women who receive a diagnosis of PID should be tested

for gonorrhea, chlamydia, HIV, and syphilis. The value of

testing women with PID for M. genitalium is unknown (see

Mycoplasma genitalium). All contraceptive methods can be

continued during treatment.

Follow-Up

Women should demonstrate clinical improvement (e.g.,

defervescence; reduction in direct or rebound abdominal

tenderness; and reduction in uterine, adnexal, and cervical

motion tenderness) <3 days after therapy initiation. If no

clinical improvement has occurred <72 hours after outpatient

IM or oral therapy, then hospitalization, assessment of the

antimicrobial regimen, and additional diagnostics, including

consideration of diagnostic laparoscopy for alternative

diagnoses, are recommended. All women who have received a

diagnosis of chlamydial or gonococcal PID should be retested

3 months after treatment, regardless of whether their sex

partners have been treated (753). If retesting at 3 months is

not possible, these women should be retested whenever they

next seek medical care <12 months after treatment.

Management of Sex Partners

Persons who have had sexual contact with a partner with

PID during the 60 days preceding symptom onset should be

evaluated, tested, and presumptively treated for chlamydia

and gonorrhea, regardless of the PID etiology or pathogens

isolated. If the last sexual intercourse was >60 days before

symptom onset or diagnosis, the most recent sex partner should

be treated. Sex partners of persons who have PID caused by

C. trachomatis or N. gonorrhoeae frequently are asymptomatic.

Arrangements should be made to link sex partners to care. If

linkage is delayed or unlikely, EPT is an alternative approach

to treating sex partners who have chlamydial or gonococcal

infection (125,126) (see Partner Services). Partners should

be instructed to abstain from sexual intercourse until they

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and their sex partners have been treated (i.e., until therapy is

completed and symptoms have resolved, if originally present).

Special Considerations

Drug Allergy, Intolerance, and Adverse Reactions

The risk for penicillin cross-reactivity is highest with first-

generation cephalosporins but is negligible between the

majority of second-generation (e.g., cefoxitin) and all third-

generation (e.g., ceftriaxone) cephalosporins (619,631,653,656)

(see Management of Persons Who Have a History of

Penicillin Allergy).

Pregnancy

Pregnant women suspected of having PID are at high risk

for maternal morbidity and preterm delivery. These women

should be hospitalized and treated with IV antimicrobials in

consultation with an infectious disease specialist.

HIV Infection

Differences in PID clinical manifestations among women

with HIV infection and those without have not been well

delineated (1182). In early observational studies, women

with HIV infection and PID were more likely to require

surgical intervention. More comprehensive observational

and controlled studies have demonstrated that women with

HIV infection and PID coinfection have similar symptoms,

compared with women without HIV (1183–1185), except

they are more likely to have a tubo-ovarian abscess. Women

with HIV responded equally well to recommended parenteral

and IM or oral antibiotic regimens as women without HIV.

The microbiologic findings for women with HIV and women

without HIV were similar, except women with HIV had

higher rates of concomitant M. hominis and streptococcal

infections. These data are insufficient for determining whether

women with HIV infection and PID coinfection require

more aggressive management (e.g., hospitalization or IV

antimicrobial regimens).

Intrauterine Devices

IUDs are one of the most effective contraceptive methods.

Copper-containing and levonorgestrel-releasing IUDs are

available in the United States. The risk for PID associated with

IUD use is primarily confined to the first 3 weeks after insertion

(1186–1188). If an IUD user receives a diagnosis of PID,

the IUD does not need to be removed (59,1189). However,

the woman should receive treatment according to these

recommendations and should have close clinical follow-up.

If no clinical improvement occurs within 48–72 hours of

initiating treatment, providers should consider removing

the IUD. A systematic review of evidence demonstrated that

treatment outcomes did not differ between women with PID

who retained the IUD and those who had the IUD removed

(1190). These studies primarily included women using copper-

containing or other nonhormonal IUDs. No studies are

available regarding treatment outcomes among women using

levonorgestrel-releasing IUDs.

Epididymitis

Acute epididymitis is a clinical syndrome causing pain,

swelling, and inflammation of the epididymis and lasting

<6 weeks (1191). Sometimes a testicle is also involved, a

condition referred to as epididymo-orchitis. A high index

of suspicion for spermatic cord (testicular) torsion should

be maintained among men who have a sudden onset of

symptoms associated with epididymitis because this condition

is a surgical emergency.

Acute epididymitis can be caused by STIs (e.g., C. trachomatis,

N. gonorrhoeae, or M. genitalium) or enteric organisms (i.e.,

Escherichia coli) (1192). Acute epididymitis caused by an

STI is usually accompanied by urethritis, which is frequently

asymptomatic. Acute epididymitis caused by sexually

transmitted enteric organisms might also occur among men

who are the insertive partner during anal sex. Nonsexually

transmitted acute epididymitis caused by genitourinary

pathogens typically occurs with bacteriuria secondary to

bladder outlet obstruction (e.g., benign prostatic hyperplasia)

(1193). Among older men, nonsexually transmitted

acute epididymitis is also associated with prostate biopsy,

urinary tract instrumentation or surgery, systemic disease,

or immunosuppression. Uncommon infectious causes of

nonsexually transmitted acute epididymitis (e.g., Fournier’s

gangrene) should be managed in consultation with a urologist.

Chronic epididymitis is characterized by a ≥6-week history

of symptoms of discomfort or pain in the scrotum, testicle, or

epididymis. Chronic infectious epididymitis is most frequently

observed with conditions associated with a granulomatous

reaction. Mycobacterium tuberculosis (TB) is the most common

granulomatous disease affecting the epididymis and should be

suspected, especially among men with a known history of or recent

exposure to TB. The differential diagnosis of chronic noninfectious

epididymitis, sometimes termed orchialgia or epididymalgia, is

broad (e.g., trauma, cancer, autoimmune conditions, or idiopathic

conditions). Men with this diagnosis should be referred to a

urologist for clinical management (1191,1192).

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Diagnostic Considerations

Men who have acute epididymitis typically have unilateral

testicular pain and tenderness, hydrocele, and palpable swelling

of the epididymis. Although inflammation and swelling

usually begin in the tail of the epididymis, it can spread to

the rest of the epididymis and testicle. The spermatic cord

is usually tender and swollen. Spermatic cord (testicular)

torsion, a surgical emergency, should be considered in all cases;

however, it occurs more frequently among adolescents and

men without evidence of inflammation or infection. For men

with severe unilateral pain with sudden onset, those whose

test results do not support a diagnosis of urethritis or urinary

tract infection, or for whom diagnosis of acute epididymitis is

questionable, immediate referral to a urologist for evaluation

for testicular torsion is vital because testicular viability might

be compromised.

Bilateral symptoms should increase suspicion of other causes

of testicular pain. Radionuclide scanning of the scrotum is the

most accurate method for diagnosing epididymitis but it is

not routinely available. Ultrasound should be used primarily

for ruling out torsion of the spermatic cord in cases of acute,

unilateral, painful scrotal swelling. However, because partial

spermatic cord torsion can mimic epididymitis on scrotal

ultrasound, differentiation between spermatic cord torsion

and epididymitis when torsion is not ruled out by ultrasound

should be made on the basis of clinical evaluation. Although

ultrasound can demonstrate epididymal hyperemia and

swelling associated with epididymitis, it provides minimal

diagnostic usefulness for men with a clinical presentation

consistent with epididymitis. A negative ultrasound does

not rule out epididymitis and thus does not alter clinical

management. Ultrasound should be reserved for men if torsion

of the spermatic cord is suspected or for those with scrotal pain

who cannot receive an accurate diagnosis by history, physical

examination, and objective laboratory findings.

All suspected cases of acute epididymitis should be evaluated

for objective evidence of inflammation by one of the following

POC tests:

• Gram, MB, or GV stain of urethral secretions demonstrating

≥2 WBCs per oil immersion field (737) (see Urethritis).

These stains are preferred POC diagnostic tests for

evaluating urethritis because they are highly sensitive and

specific for documenting both urethral inflammation and

presence or absence of gonococcal infection. Gonococcal

infection is established by documenting the presence of

WBC-containing intracellular gram-negative or purple

diplococci on urethral Gram, MB, or GV stain, respectively.

• Positive leukocyte esterase test on first-void urine.

• Microscopic examination of sediment from a spun first-

void urine demonstrating ≥10 WBCs/HPF.

All suspected cases of acute epididymitis should be tested

for C. trachomatis and N. gonorrhoeae by NAAT. Urine is

the preferred specimen for NAAT for men (553). Urine

cultures for chlamydial and gonococcal epididymitis are

insensitive and are not recommended. Urine bacterial

cultures should also be performed for all men to evaluate for

the presence of genitourinary organisms and to determine

antibiotic susceptibility.

Treatment

To prevent complications and transmission of STIs,

presumptive therapy for all sexually active men is indicated

at the time of the visit before all laboratory test results are

available. Selection of presumptive therapy is based on risk for

chlamydial and gonococcal infections or enteric organisms.

Treatment goals for acute epididymitis are 1) microbiologic

infection cure, 2) improvement of signs and symptoms,

3) prevention of transmission of chlamydia and gonorrhea to

others, and 4) decreased potential for chlamydial or gonococcal

epididymitis complications (e.g., infertility or chronic pain).

Although the majority of men with acute epididymitis can

be treated on an outpatient basis, referral to a specialist and

hospitalization should be considered when severe pain or fever

indicates other diagnoses (e.g., torsion, testicular infarction,

abscess, or necrotizing fasciitis) or when men are unable to

comply with an antimicrobial regimen. Age, history of diabetes,

fever, and elevated C-reactive protein can indicate more severe

disease requiring hospitalization (1193).

Recommended Regimens for Epididymitis

For acute epididymitis most likely caused by chlamydia or gonorrhea:

Ceftriaxone 500 mg* IM in a single dose

plus

Doxycycline 100 mg orally 2 times/day for 10 days

For acute epididymitis most likely caused by chlamydia, gonorrhea,

or enteric organisms (men who practice insertive anal sex):

Ceftriaxone 500 mg* IM in a single dose

plus

Levofloxacin 500 mg orally once daily for 10 days

For acute epididymitis most likely caused by enteric organisms only:

Levofloxacin 500 mg orally once daily for 10 days

* For persons weighing ≥150 kg, 1 g of ceftriaxone should be administered.

Levofloxacin monotherapy should be considered if the

infection is most likely caused by enteric organisms only, and

gonorrhea has been ruled out by Gram, MB, or GV stain. This

includes men who have undergone prostate biopsy, vasectomy,

and other urinary tract instrumentation procedures. Treatment

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should be guided by bacterial cultures and antimicrobial

susceptibilities. As an adjunct to therapy, bed rest, scrotal

elevation, and nonsteroidal anti-inflammatory drugs are

recommended until fever and local inflammation have

subsided. Complete resolution of discomfort might not occur

for a few weeks after completion of the antibiotic regimen.

Other Management Considerations

Men who have acute epididymitis confirmed or suspected to

be caused by N. gonorrhoeae or C. trachomatis should be advised

to abstain from sexual intercourse until they and their partners

have been treated and symptoms have resolved. All men with

acute epididymitis should be tested for HIV and syphilis.

Follow-Up

Men should be instructed to return to their health care

providers if their symptoms do not improve <72 hours after

treatment. Signs and symptoms of epididymitis that do not

subside in <3 days require reevaluation of the diagnosis and

therapy. Men who experience swelling and tenderness that

persist after completion of antimicrobial therapy should be

evaluated for alternative diagnoses, including tumor, abscess,

infarction, testicular cancer, TB, and fungal epididymitis.

Management of Sex Partners

Men who have acute sexually transmitted epididymitis

confirmed or suspected to be caused by N. gonorrhoeae or

C. trachomatis should be instructed to refer all sex partners

during the previous 60 days before symptom onset for

evaluation, testing, and presumptive treatment (see Chlamydial

Infections; Gonococcal Infections). If the last sexual intercourse

was >60 days before onset of symptoms or diagnosis, the

most recent sex partner should be evaluated and treated.

Arrangements should be made to link sex partners to care. EPT

is an effective strategy for treating sex partners of men who

have or are suspected of having chlamydia or gonorrhea for

whom linkage to care is anticipated to be delayed (125,126)

(see Partner Services). Partners should be instructed to abstain

from sexual intercourse until they and their sex partners are

treated and symptoms have resolved.

Special Considerations

Drug Allergy, Intolerance, and Adverse Reactions

The risk for penicillin cross-reactivity is negligible between all

third-generation cephalosporins (e.g., ceftriaxone) (658,681)

(see Management of Persons Who Have a History of Penicillin

Allergy). Alternative regimens have not been studied; therefore,

clinicians should consult an infectious disease specialist if such

regimens are required.

HIV Infection

Men with HIV infection who have uncomplicated acute

epididymitis should receive the same treatment regimen as

those who do not have HIV. Other etiologic agents have

been implicated in acute epididymitis among men with HIV,

including CMV, salmonella, toxoplasmosis, U. urealyticum,

Corynebacterium species, Mycoplasma species, and Mima

polymorpha (1192).

Human Papillomavirus Infections

Approximately 150 types of HPV have been identified, at

least 40 of which infect the genital area (1194). The majority

of HPV infections are self-limited and are asymptomatic or

unrecognized. Sexually active persons are usually exposed to

HPV during their lifetime (838,1195,1196). Oncogenic,

high-risk HPV infection (e.g., HPV types 16 and 18) causes the

majority of cervical, penile, vulvar, vaginal, anal, and oropharyngeal

cancers and precancers (1197), whereas other HPV infection

(e.g., HPV types 6 and 11) causes genital warts and recurrent

respiratory papillomatosis. Persistent oncogenic HPV infection

is the strongest risk factor for development of HPV-attributable

precancers and cancers. A substantial proportion of cancers and

anogenital warts are attributable to HPV in the United States.

An estimated 34,800 new HPV-attributable cancers occurred

every year during 2012–2016 (1198). Before HPV vaccines were

introduced, approximately 355,000 new cases of anogenital warts

occurred every year (1199).

Prevention

HPV Vaccines

Three HPV vaccines are licensed in the United States:

Ceravrix, a 2-valent vaccine (2vHPV) that targets HPV types

16 and 18; Gardasil, a 4-valent vaccine (4vHPV) that targets

HPV types 6, 11, 16, and 18; and Gardasil 9, a 9-valent

vaccine (9vHPV) that targets HPV types 6, 11, 16, 18, 31,

33, 45, 52, and 58. Types 16 and 18 account for 66% of all

cervical cancers, whereas the five additional types targeted by

the 9-valent vaccine account for 15%. Types 6 and 11 cause

>90% of genital warts. Only 9vHPV vaccine is available in

the United States.

ACIP recommendations for HPV vaccination (https://www.

cdc.gov/vaccines/hcp/acip-recs/vacc-specific/hpv.html) include

the following:

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• Routine HPV vaccination for all adolescents at age 11 or

12 years.

• Administering vaccine starting at age 9 years.

• Catch-up vaccination through age 26 years for those not

vaccinated previously.

• Not using HPV vaccination for all adults aged >26 years.

Instead, shared clinical decision-making between a patient

and a provider regarding HPV vaccination is recommended

for certain adults aged 27–45 years not vaccinated previously.

• A 2-dose vaccine schedule (at 0- and 6–12-month

intervals) is recommended for persons who initiate

vaccination before their 15th birthday.

• A 3-dose vaccine schedule (at 0-, 1–2-, and 6-month

intervals) for immunocompromised persons regardless of

age of initiation.

HPV vaccines are not recommended for use in pregnant

women. HPV vaccines can be administered regardless of

history of anogenital warts, abnormal Pap test or HPV test, or

anogenital precancer. Women who have received HPV vaccine

should continue routine cervical cancer screening (see Cervical

Cancer). HPV vaccine is available for eligible children and

adolescents aged <19 years through the Vaccines for Children

(VFC) program (additional information is available at https://

www.cdc.gov/vaccines/programs/vfc/index.html or by calling

CDC INFO 800-232-4636). For uninsured persons aged

<19 years, patient assistance programs are available from the

vaccine manufacturers. Prelicensure and postlicensure safety

evaluations have determined that the vaccine is well tolerated.

With >120 million doses of HPV vaccines distributed in the

United States, robust data demonstrate that HPV vaccines are

safe (https://www.cdc.gov/vaccinesafety). Impact-monitoring

studies in the United States have demonstrated reductions

of genital warts as well as the HPV types contained within

the quadrivalent vaccine (1200–1203). Settings that provide

STI services should either administer the vaccine to eligible

clients within the routine and catch-up age groups through

age 26 years who have not started or completed the vaccine

series, or link these persons to another facility equipped to

provide the vaccine. Clinicians providing services to children,

adolescents, and young adults should be knowledgeable about

HPV and the vaccine (https://www.cdc.gov/vaccines/who/

teens/for-hcp/hpv-resources.html). HPV vaccination has not

been associated with initiation of sexual activity or sexual risk

behaviors (1204,1205).

Abstaining from sexual activity is the most reliable method

for preventing genital HPV infection. Persons can decrease

their chances of infection by practicing consistent and correct

condom use and limiting their number of sex partners. Although

these interventions might not fully protect against HPV, they

can decrease the chances of HPV acquisition and transmission.

Diagnostic Considerations

HPV tests are available for detecting oncogenic types of HPV

infection and are used in the context of cervical cancer screening

and management or follow-up of abnormal cervical cytology or

histology (see Cervical Cancer). These tests should not be used

for male partners of women with HPV or women aged <25 years,

for diagnosis of genital warts, or as a general STI test.

Application of 3%–5% acetic acid, which might cause

affected areas to turn white, has been used by certain providers

to detect genital mucosa infected with HPV. The routine use

of this procedure to detect mucosal changes attributed to

HPV infection is not recommended because the results do

not influence clinical management.

Treatment

Treatment is directed to the macroscopic (e.g., genital warts)

or pathologic precancerous lesions caused by HPV. Subclinical

genital HPV infection typically clears spontaneously; therefore,

specific antiviral therapy is not recommended to eradicate HPV

infection. Precancerous lesions are detected through cervical

cancer screening; HPV-related precancer should be managed

on the basis of existing guidance (see Cervical Cancer).

Counseling

Key Messages for Persons with Human

Papillomavirus Infection

When counseling persons with anogenital HPV infection,

the provider should discuss the following:

• Anogenital HPV infection is common. It usually infects

the anogenital area but can infect other areas, including

the mouth and throat. The majority of sexually active

persons get HPV at some time during their lifetime,

although most never know it.

• Partners tend to share HPV, and it is not possible to

determine which partner transmitted the original

infection. Having HPV does not mean that a person or

his or her partner is having sex outside the relationship.

• Persons who acquire HPV usually clear the infection

spontaneously, meaning that HPV becomes undetectable

with no associated health problems.

• If HPV infection persists, genital warts, precancers, and

cancers of the cervix, anus, penis, vulva, vagina, head, or

neck might develop.

• Discussion of tobacco use, and provision of cessation

counseling, is important because of its contribution to the

progression of precancer and cancer.

• The types of HPV that cause genital warts are different

from the types that can cause cancer.

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• Many types of HPV are sexually transmitted through

anogenital contact, mainly during vaginal and anal sex. HPV

also might be transmitted during oral sex and genital-to-genital

contact without penetration. In rare cases, a pregnant woman

can transmit HPV to an infant during delivery.

• Treatments are available for the conditions caused by HPV

but not for the virus itself.

• Having HPV does not make it harder for a woman to get

pregnant or carry a pregnancy to term. However, certain

precancers or cancers that HPV can cause, and the surgical

procedures needed to treat them, can affect a woman’s

ability to get pregnant or carry a pregnancy to term.

• No HPV test can determine which HPV infection will

become undetectable and which will persist or progress to

disease. However, in certain circumstances, HPV tests can

determine whether a woman is at increased risk for cervical

cancer. These tests are not for detecting other HPV-related

problems, nor are they useful for women aged<25 years

or men of any age.

Prevention

• Three HPV vaccines can prevent diseases and cancers

caused by HPV. The 2vHPV, 4vHPV, and 9vHPV vaccines

protect against the majority of cervical cancer cases,

although the 4vHPV and 9vHPV vaccines also protect

against the majority of genital warts. Only 9vHPV vaccine

is available in the United States. HPV vaccines are safe

and effective and are recommended routinely for

adolescents aged 11–12 years. Catch-up vaccination is also

recommended for older adolescents and young adults

through age 26 years (https://www.cdc.gov/hpv/hcp/

index.html). Shared clinical decision-making is

recommended regarding HPV vaccination for certain

adults aged 27–45 years who are not adequately vaccinated

per guidance (https://www.cdc.gov/mmwr/volumes/68/

wr/pdfs/mm6832a3-H.pdf).

• Condoms used consistently and correctly can lower the

chances of acquiring and transmitting HPV and

developing HPV-related diseases (e.g., genital warts or

cervical cancer). However, because HPV can infect areas

not covered by a condom, condoms might not fully protect

against HPV.

• Limiting the number of sex partners can reduce the risk

for HPV. However, even persons with only one lifetime

sex partner can get HPV.

• Abstaining from sexual activity is the most reliable method

for preventing genital HPV infection.

Anogenital Warts

Anogenital warts are a common disease, and 90% are caused

by nononcogenic HPV types 6 or 11. These types can be

commonly identified before or at the same time anogenital

warts are detected (1206). HPV types 16, 18, 31, 33, and 35

also are occasionally identified in anogenital warts (usually

as infections with HPV 6 or 11) and can be associated with

foci of high-grade squamous intraepithelial lesion (HSIL),

particularly among persons who have HIV infection. In

addition to anogenital warts, HPV types 6 and 11 have been

associated with conjunctival, nasal, oral, and laryngeal warts.

Anogenital warts are usually asymptomatic; however,

depending on the size and anatomic location, they can

be painful or pruritic. They are usually flat, papular, or

pedunculated growths on the genital mucosa. Anogenital warts

occur commonly at certain anatomic sites, including around

the vaginal introitus, under the foreskin of the uncircumcised

penis, and on the shaft of the circumcised penis. Warts can

also occur at multiple sites in the anogenital epithelium or

within the anogenital tract (e.g., cervix, vagina, urethra,

perineum, perianal skin, anus, or scrotum). Intra-anal warts

are observed predominantly in persons who have had receptive

anal intercourse; however, they also can occur among men and

women who have not had a history of anal sexual contact.

Prevention

Anogenital warts have decreased among adolescents,

young women, and heterosexual men with use of HPV

vaccination in multiple countries, including the United States

(1203,1207–1216).

Diagnostic Considerations

Diagnosis of anogenital warts is usually made by visual

inspection but can be confirmed by biopsy, which is indicated

if lesions are atypical (e.g., pigmented, indurated, affixed to

underlying tissue, bleeding, or ulcerated lesions). Biopsy might

also be indicated in the following circumstances, particularly

if the patient is immunocompromised (including those with

HIV infection): the diagnosis is uncertain, the lesions do not

respond to standard therapy, or the disease worsens during

therapy. HPV testing is not recommended for anogenital wart

diagnosis because test results are not confirmatory and do not

guide genital wart management. Some anogenital lesions can

resemble anogenital warts (condyloma accuminata), but do

not respond to anogenital wart treatment. Condyloma lata,

a manifestation of secondary syphilis, can be diagnosed by

serologic tests or through direct detection from serous fluid

from the lesions (see Syphilis, Diagnostic Considerations).

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Treatment

The aim of treatment is removal of the warts and amelioration

of symptoms, if present. The appearance of warts also can result

in considerable psychosocial distress, and removal can relieve

cosmetic concerns. For most patients, treatment results in

resolution of the warts. If left untreated, anogenital warts can

resolve spontaneously, remain unchanged, or increase in size or

number. Because warts might spontaneously resolve in <1 year,

an acceptable alternative for certain persons is to forego treatment

and wait for spontaneous resolution. Available therapies for

anogenital warts might reduce, but probably do not eradicate,

HPV infectivity. Whether reduction in HPV viral DNA resulting

from treatment reduces future transmission remains unknown.

Treatment of anogenital warts should be guided by wart size,

number, and anatomic site; patient preference; cost of treatment;

convenience; adverse effects; and provider experience. No

definitive evidence indicates that any one recommended treatment

is superior to another, and no single treatment is ideal for all

patients or all warts. Shared clinical decision-making between

a patient and a provider regarding treatment algorithms has

been associated with improved clinical outcomes and should be

encouraged. Because all available treatments have shortcomings,

clinicians sometimes use combination therapy (e.g., provider-

administered cryotherapy with patient-applied topical therapy

between visits to the provider). However, limited data exist

regarding the efficacy or risk for complications associated with

combination therapy. Treatment regimens are classified as either

patient-applied or provider-administered modalities. Patient-

applied modalities are preferred by certain persons because they

can be administered in the privacy of their home. To ensure

that patient-applied modalities are effective, instructions should

be provided to patients while in the clinic, and all anogenital

warts should be accessible and identified during the clinic visit.

Follow-up visits after weeks of therapy enable providers to answer

any questions about use of the medication, address any side effects

experienced, and facilitate assessment of the response to treatment.

Recommended Regimens for External Anogenital Warts (i.e.,

Penis, Groin, Scrotum, Vulva, Perineum, External Anus, or

Perianus)*

Patient-applied: Imiquimod 3.75% or 5% cream

†

Podofilox 0.5% solution or gel

Sinecatechins 15% ointment

†

Provider-administered: Cryotherapy with liquid nitrogen or cryoprobe

Surgical removal by tangential scissor excision, tangential shave

excision, curettage, laser, or electrosurgery

Trichloroacetic acid (TCA) or bichloroacetic acid (BCA)

80%–90% solution

* Persons with external anal or perianal warts might also have intra-anal

warts. Thus, persons with external anal warts might benefit from an

inspection of the anal canal by digital examination, standard anoscopy,

or high-resolution anoscopy.

†

Might weaken condoms and vaginal diaphragms.

Imiquimod is a patient-applied, topically active immune

enhancer that stimulates production of interferon and other

cytokines. Imiquimod 5% cream should be applied once

at bedtime, 3 times/week for <16 weeks (1217). Similarly,

imiquimod 3.75% cream should be applied once at bedtime

every night for <8 weeks (1218). With either formulation, the

treatment area should be washed with soap and water 6–10 hours

after the application. Local inflammatory reactions, including

redness, irritation, induration, ulceration or erosion, and vesicles

might occur with using imiquimod, and hypopigmentation has

also been described (1219). Limited case reports demonstrate

an association between treatment with imiquimod cream and

worsened inflammatory or autoimmune skin diseases (e.g.,

psoriasis, vitiligo, or lichenoid dermatoses) (1220–1222). Data

from studies of human participants are limited regarding use of

imiquimod during pregnancy; however, animal data indicate

that this therapy poses low risk (431).

Podofilox (podophyllotoxin) is a patient-applied antimitotic

drug that causes wart necrosis. Podofilox solution (using a

cotton swab) or podofilox gel (using a finger) should be applied

to anogenital warts 2 times/day for 3 days, followed by 4 days

of no therapy. This cycle can be repeated, as necessary, for up

to four cycles. The total wart area treated should not exceed

10 cm

, and the total volume of podofilox should be limited to

0.5 mL/day. If possible, the health care provider should apply the

initial treatment to demonstrate proper application technique

and identify which warts should be treated. Mild to moderate

pain or local irritation might develop after treatment. After each

treatment, the gel or solution should be allowed to dry. Patients

should wash their hands before and after each application.

Podofilox is contraindicated during pregnancy (431).

Sinecatechins is a patient-applied, green-tea extract with an

active product (catechins). Sinecatechins 15% ointment should

be applied 3 times/day (0.5-cm strand of ointment to each wart)

by using a finger to ensure coverage with a thin layer of ointment

until complete clearance of warts is achieved. This product should

not be continued for >16 weeks (1223–1225). The medication

should not be washed off after use. Genital, anal, and oral sexual

contact should be avoided while the ointment is on the skin. The

most common side effects of sinecatechins are erythema, pruritus

or burning, pain, ulceration, edema, induration, and vesicular

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rash. This medication is not recommended for persons with HIV

infection, other immunocompromised conditions, or genital herpes

because the safety and efficacy of therapy has not been evaluated.

The safety of sinecatechins during pregnancy is unknown.

Cryotherapy is a provider-administered therapy that destroys

warts by thermal-induced cytolysis. Health care providers

should be trained on the correct use of this therapy because

overtreatment or undertreatment can result in complications

or low efficacy. Pain during and after application of the liquid

nitrogen, followed by necrosis and sometimes blistering, is

common. Local anesthesia (topical or injected) might facilitate

therapy if warts are present in many areas or if the area of warts

is large. Surgical therapy has the advantage of eliminating the

majority of warts at a single visit, although recurrence can

occur. Surgical removal requires substantial clinical training,

additional equipment, and sometimes a longer office visit. After

local anesthesia is applied, anogenital warts can be physically

destroyed by electrocautery, in which case no additional

hemostasis is required. Care should be taken to control the

depth of electrocautery to prevent scarring. Alternatively, the

warts can be removed either by tangential excision with a pair of

fine scissors or a scalpel, by CO

laser, or by curettage. Because

most warts are exophytic, this procedure can be accomplished

with a resulting wound that only extends into the upper dermis.

Hemostasis can be achieved with an electrocautery unit or, in

cases of minor bleeding, a chemical styptic (e.g., an aluminum

chloride solution). Suturing is neither required nor indicated

in the majority of cases. For patients with large or extensive

warts, surgical therapy, including CO

laser, might be most

beneficial; such therapy might also be useful for intraurethral

warts, particularly for those persons whose warts have not

responded to other treatments. Treatment of anogenital and

oral warts should be performed in a ventilated room by using

standard precautions (https://www.cdc.gov/infectioncontrol/

guidelines/isolation/index.html/Isolation2007.pdf#page) and

local exhaust ventilation (e.g., a smoke evacuator) (1226).

Trichloroacetic acid (TCA) and bichloroacetic acid (BCA)

are provider-administered caustic agents that destroy warts by

chemical coagulation of proteins. Although these preparations

are widely used, they have not been investigated thoroughly.

TCA solution has a low viscosity, comparable with that of

water, and can spread rapidly and damage adjacent tissues if

applied excessively. A small amount should be applied only

to the warts and allowed to dry (i.e., develop white frost on

tissue) before the patient sits or stands. If pain is intense or an

excess amount of acid is applied, the area can be covered with

sodium bicarbonate (i.e., baking soda), washed with liquid

soap preparations, or be powdered with talc to neutralize the

acid or remove unreacted acid. TCA or BCA treatment can be

repeated weekly if necessary.

Alternative Regimens for External Genital Warts

Fewer data are available regarding the efficacy of alternative

regimens for treating anogenital warts, which include

podophyllin resin, intralesional interferon, photodynamic

therapy, and topical cidofovir. Shared clinical decision-

making between the patient and provider regarding benefits

and risks of these regimens should be provided. In addition,

alternative regimens might be associated with more side

effects. Podophyllin resin is no longer a recommended regimen

because of the number of safer regimens available, and severe

systemic toxicity has been reported when podophyllin resin

was applied to large areas of friable tissue and was not washed

off within 4 hours (1227–1229). Podophyllin resin 10%–25%

in a compound tincture of benzoin might be considered for

provider-administered treatment under conditions of strict

adherence to recommendations. Podophyllin should be applied

to each wart and then allowed to air dry before the treated area

comes into contact with clothing. Overapplication or failure

to air dry can result in local irritation caused by spread of the

compound to adjacent areas and possible systemic toxicity. The

treatment can be repeated weekly, if necessary. To avoid the

possibility of complications associated with systemic absorption

and toxicity, application should be limited to <0.5 mL of

podophyllin or an area of <10 cm

of warts per session; the

area to which treatment is administered should not contain

any open lesions, wounds, or friable tissue; and the preparation

should be thoroughly washed off 1–4 hours after application.

Podophyllin resin preparations differ in the concentration of

active components and contaminants. Shelf life and stability

of podophyllin preparations are unknown. The safety of

podophyllin during pregnancy has not been established.

Recommended Regimens for Urethral Meatus Warts

Cryotherapy with liquid nitrogen

Surgical removal

Recommended Regimens for Vaginal Warts

Cryotherapy with liquid nitrogen

The use of a cryoprobe in the vagina is not recommended because of

the risk for vaginal perforation and fistula formation.

Surgical removal

Trichloracetic acid (TCA) or bichloroacetic acid (BCA) 80%–90%

solution

Recommended Regimens for Cervical Warts

Cryotherapy with liquid nitrogen

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Surgical removal

Trichloracetic acid (TCA) or bichloroacetic acid (BCA) 80%–90%

solution

Management of cervical warts should include consultation with a specialist.

For women who have exophytic cervical warts, a biopsy evaluation to

exclude HSIL should be performed before treatment is initiated.

Recommended Regimens for Intra-Anal Warts

Cryotherapy with liquid nitrogen

Surgical removal

Trichloracetic acid (TCA) or bichloroacetic acid (BCA) 80%–90%

solution

Management of intra-anal warts should include consultation with a

colorectal specialist.

Follow-Up

Anogenital warts typically respond within 3 months of

therapy. Factors that might affect response to therapy include

immunosuppression and treatment compliance. Warts

located on moist surfaces or in intertriginous areas respond

best to topical treatment. A new treatment modality should

be selected when no substantial improvement is observed

after a complete course of treatment or in the event of severe

side effects; treatment response and therapy-associated side

effects should be evaluated throughout the therapy course.

Complications occur rarely when treatment is administered

correctly. Persistent hypopigmentation or hyperpigmentation

can occur with ablative modalities (e.g., cryotherapy and

electrocautery) and have been described with immune

modulating therapies (e.g., imiquimod cream). Depressed or

hypertrophic scars are uncommon but can occur, especially

if patients have insufficient time to heal between treatments.

Rarely, treatment can result in chronic pain syndromes (e.g.,

vulvodynia and hyperesthesia of the treatment site) or, in the

case of anal warts, painful defecation or fistulas.

Counseling

When counseling persons with anogenital warts, the provider

should discuss the following:

• If left untreated, genital warts might resolve, stay the same,

or increase in size or number. The types of HPV that cause

genital warts are different from the types that can cause cancer.

• Women with genital warts do not need Pap tests more

often than other women.

• Time of HPV acquisition cannot be definitively

determined. Genital warts can develop months or years

after acquiring HPV.

• HPV types that cause genital warts can be passed on to

another person, even without visible signs of warts. Sex

partners tend to share HPV, even though signs of HPV

(e.g., warts) might occur in only one or neither partner.

• Although genital warts are common and benign, certain

persons might experience considerable psychosocial impact

after receiving this diagnosis.

• Although genital warts can be treated, such treatment does

not cure the virus itself. For this reason, genital warts often

recur after treatment, especially during the first 3 months.

• Because genital warts can be sexually transmitted, persons

with genital warts benefit from testing for other STIs.

HPV might remain present and can still be transmitted

to partners even after the warts are gone.

• Condoms might lower the chances of transmitting genital

warts if used consistently and correctly; however, HPV

can infect areas that are not covered by a condom and

might not fully protect against HPV.

• A vaccine is available for males and females to prevent

genital warts (Gardasil 9) but it will not treat existing HPV

or genital warts. This vaccine can prevent the majority of

cases of genital warts among persons who have not yet

been exposed to wart-causing types of HPV.

Management of Sex Partners

Persons should inform current partners about having genital

warts because the types of HPV that cause warts can be passed

on to partners. Partners should be counseled that they might

already have HPV despite no visible signs of warts; therefore,

HPV testing of sex partners of persons with genital warts is

not recommended. Partners might benefit from a physical

examination to detect genital warts and tests for other STIs. No

recommendations can be made regarding informing future sex

partners about a diagnosis of genital warts because the duration

of viral persistence after warts have resolved is unknown.

Special Considerations

Pregnancy

Podofilox, podophyllin, and sinecatechins should not be

used during pregnancy. Imiquimod appears to pose low risk

but should be avoided until more data are available. Anogenital

warts can proliferate and become friable during pregnancy.

Although removal of warts during pregnancy can be considered,

resolution might be incomplete or poor until pregnancy is

complete. Rarely, HPV types 6 and 11 can cause respiratory

papillomatosis among infants and children, although the route

of transmission (i.e., transplacental, perinatal, or postnatal) is

not completely understood. Whether cesarean delivery prevents

respiratory papillomatosis among infants and children also

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is unclear (1230); therefore, cesarean delivery should not be

performed solely to prevent transmission of HPV infection to

the newborn. Cesarean delivery is indicated for women with

anogenital warts if the pelvic outlet is obstructed or if vaginal

delivery would result in excessive bleeding. Pregnant women

with anogenital warts should be counseled about the low risk

for warts on the larynx of their infants or children (recurrent

respiratory papillomatosis).

HIV and Other Causes of Immunosuppression

Persons with HIV infection or who are otherwise

immunosuppressed are more likely to develop anogenital

warts than those who do not have HIV (1231). Moreover,

such persons can have larger or more numerous lesions,

might not respond to therapy as well as those who are

immunocompetent, and might have more frequent recurrences

after treatment (1231,1232–1234). Despite these factors, data

do not support altered approaches to treatment for persons

with HIV infection. Squamous cell carcinomas arising in or

resembling anogenital warts might occur more frequently

among immunosuppressed persons, therefore requiring biopsy

for confirmation of diagnosis for suspicious cases (1235–1237).

High-Grade Squamous Intraepithelial Lesions

Biopsy of an atypical wart might reveal HSIL or cancer of

the anogenital tract. In this instance, referral to a specialist for

treatment is recommended.

Cancers and Precancers Associated with Human

Papillomavirus

Persistent infection with high-risk (oncogenic) types of HPV

has a causal role in approximately all cervical cancers and in

certain vulvar, vaginal, penile, anal, and oropharyngeal cancers

(1238). However, cervical cancer is the only HPV-associated

cancer for which routine screening is recommended.

Cervical Cancer

Screening Recommendations

Recommendations for cervical cancer screening in the

United States are based on systematic evidence reviews

by major medical and advocacy organizations, including

USPSTF (174), ACS (177), and ACOG (175). Over time,

general alignment across these organizations has emerged as

to when to start and end cervical cancer screening as well as

the periodicity of screening. Although no single guideline

universally guides screening practices in the United States, the

Patient Protection and Affordable Care Act required Medicaid

and new private health insurance plans to provide coverage for

preventive services graded A or B by USPSTF, which includes

cervical cancer screening. In addition, the National Center for

Quality Assurance provides a set of measures (the Healthcare

Effectiveness Data and Information Set [HEDIS]) for up-to-

date cervical cancer screening that aligns with USPSTF

recommendations (https://www.ncqa.org/hedis/measures/

cervical-cancer-screening). The Center for Medicaid and

Medicare Services uses the same measure as HEDIS to measure

cervical cancer screening performance.

USPSTF screening recommendations apply to persons with

a cervix at average risk, defined as those with no previous

cervical cancer or high-grade precancer, not currently

under close follow-up for a recent abnormal result, not

immunocompromised (e.g., persons with HIV), and who

had no exposure to diethylstilbestrol in utero. Among these

persons, screening should be performed starting at age 21 years

and continue through age 65 years. Testing can be performed

using either conventional or liquid-based cytologic tests (i.e.,

Pap tests). For persons aged ≥30 years, screening can include

FDA-cleared tests for high-risk, oncogenic types of HPV.

For cytopathologic testing, clinics should use CLIA-certified

laboratories using acceptable terminology (Bethesda 2001 or

LAST terminology) (1239).

Annual cervical cancer screening is not recommended for

persons at average risk. Instead, cytology testing is recommended

every 3 years for persons aged 21–29 years. For persons aged

30–65 years, a cytology test every 3 years, an HPV test alone

every 5 years, or a cytology test plus an HPV test (cotest) every

5 years is recommended. Cotesting can be done by either

collecting one sample for the cytology test and another for the

HPV test or by using the remaining liquid cytology material

for the HPV test. Cervical screening programs should screen

those who have received HPV vaccination in the same manner

as those that are unvaccinated. Screening is not recommended

before age 21 years among those at average risk. For those aged

30–65 years, cytology alone or primary HPV testing is preferred

by USPSTF; however, cotesting can be used as an alternative

approach. ACOG (1240), ACS (177), and USPSTF (174) each

have screening recommendations (1241) (Table 1).

Clinics should weigh the benefits of each screening strategy

as well as their resources, such as time and cost, in deciding on

which of the three possible screening strategies to implement.

Decision analytic models (1242) estimating the benefits, harms,

and costs (1243) of several different strategies might be useful

in making this determination (174,1244,1245). Adopting

recommended screening and follow-up procedures, including

screening methods, results provision, and follow-up, can lead to

success in implementing cervical cancer screening in clinics (1246).

Patients should be provided a copy of their test results;

those with normal results should be provided information

on follow-up visits and the importance of continued cervical

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TABLE 1. Cervical cancer screening and surveillance recommendations

Population Screening specifics

Guideline group, yr of recommendation

USPSTF, 2018 ACOG, 2016 ACS, 2020

Persons at average risk Age to start screening 21 yrs 21 yrs 25 yrs

Age to end screening 65 yrs 65 yrs 65 yrs

If three consecutive negative cytology tests or two negative cytology plus HPV tests or two

negative HPV tests (ACS) with the most recent within the previous 5 yrs and no abnormal tests

within the previous 10 yrs (ACS) and no CIN 2 or CIN 3 within the previous 25 yrs

Screening test options

and intervals

Aged 21–65 yrs: Cytology alone every 3 yrs

Aged 21–29 yrs: Cytology alone every 3 yrs

Aged 30–65 yrs: Cytology plus HPV testing every 5 yrs

Aged 21–29 yrs: Cytology alone every 3 yrs

Aged 30–65: HPV testing alone every 5 yrs*

HPV testing alone every 5 yrs

Cytology plus HPV testing every

5 yrs

Cytology alone every 3 yrs

Preferred strategies Cytology alone every 3 yrs

and HPV testing alone every

5 yrs (equally preferred)

Cytology plus HPV testing every

5 yrs

HPV testing alone every 5 yrs

Previous hysterectomy

with removal of cervix

Screening not recommended after hysterectomy for benign indications

Surveillance testing recommended for previous diagnosis of high-grade precancer, AIS, or cancer

Persons with an

immunocompromising medical

condition

†

(e.g., HIV infection or

solid organ transplantation)

Age to start screening No specific

recommendation

Within 1 yr of onset of sexual activity or, if already sexually active,

within the first year after HIV or other immunocompromising

medical condition diagnosis but no later than age 21 yrs

Age to end screening None; lifelong screening recommended

Screening test options

and intervals

Aged 21–65 yrs: Cytology every year; after three consecutive annual

normal cytology test results, screening can be every 3 yrs

Aged 21–29 yrs: Cytology every year

Aged 30–65 yrs: Cytology plus HPV testing every 3 yrs

Previous hysterectomy

with removal of cervix

Not specified

Persons with in utero exposure to

diethylstilbestrol

Age to start screening No specific

recommendation

Not specified No specific recommendation

Age to end screening Not specified

Screening test options

and intervals

Cytology alone annually

Previous hysterectomy

with removal of cervix

Not specified

Persons who have received HPV

vaccination

No changes to the screening approaches above

ASCCP, 2019, and ACOG, 2020

Persons with a diagnosis of CIN 2

or CIN 3 (histologic HSIL

)

within the previous 25 yrs

Age to start screening Not applicable

Age to end screening May end at age 65 yrs if CIN diagnosis ≥25 yrs ago and criteria for ending screening met, otherwise

continue screening past age 65 yrs

Continued screening for ≥25 yrs after diagnosis is acceptable if patient is in good health

Screening test options

and intervals

Initial surveillance:

HPV testing alone or cytology plus HPV testing at 6, 18, and 30 mos

Cytology at 6, 12, 18, 24, and 30 mos

Long-term surveillance:

HPV testing alone or cytology plus HPV testing every 3 yrs

Cytology alone annually

Continue for ≥25 yrs from the initial CIN diagnosis, even if extends past age 65 yrs

Routine screening can resume after the posttreatment surveillance period

Previous hysterectomy

with removal of cervix

HPV testing alone or cytology plus HPV testing every 3 yrs

Cytology alone annually

Continue for ≥25 yrs from the initial CIN diagnosis, even if extends past age 65 yrs

Source: Perkins R, Guido R, Saraiya M, et al. Summary of current guidelines for cervical cancer screening and management of abnormal test results: 2016–2020. J

Womens Health (Larchmt) 2021;30:5–13.

Abbreviations: ACS = American Cancer Society; ACOG = American College of Obstetricians and Gynecologists; AIS = adenocarcinoma in situ; ASCCP = American

Society for Colposcopy and Cervical Pathology; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus; HSIL = high-grade squamous intraepithelial

lesion; USPSTF = U.S. Preventive Services Task Force.

* Considered an alternative screening strategy by ACOG.

†

Panel for Opportunistic Infections, ACOG, 2016.

ACOG, 2016.

Either by cytology or by histology; includes a persistent cytologic diagnosis of atypical squamous cells, cannot rule out HSIL.

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cancer screening, if applicable. Those with abnormal screening

tests should be managed per published guidelines. National

consensus guidelines are available for the management of

abnormal cervical cancer screening tests (1247). HPV testing

or cotesting is preferred to cytology alone for surveillance

after an abnormal screening test result. These guidelines base

management recommendations on case-by-case assessment

of risk considering past screening history and current results

(see Follow-Up). Patients with abnormal cervical cancer

screening test results should be counseled about those results

(see Counseling Messages).

The following additional management considerations are

associated with performing Pap tests and HPV tests:

• Cytology (Pap tests) and HPV tests should not be

considered screening tests for STIs.

• All persons with a cervix should receive cervical cancer

screening, regardless of sexual orientation or gender

identity (i.e., those who identify as lesbian, bisexual,

heterosexual, or transgender).

• A conventional cytology test (in which the sample is

smeared onto a dry slide) should ideally be scheduled for

10–20 days after the first day of menses. Liquid-based

cytology can be performed at any time during the

menstrual cycle.

• If specific infections other than HPV (e.g., chlamydia or

gonorrhea) are identified at the visit, a repeat cytology test

after appropriate treatment for those infections might be

indicated. However, in most instances (even in the

presence of certain severe cervical infections), cytology

tests will be reported as satisfactory for evaluation, and

reliable final reports can be produced without the need to

repeat the cytology test after treatment.

• The presence of a mucopurulent discharge should not

postpone cytology testing. The test can be performed after

removal of the discharge with a saline-soaked cotton swab.

• HPV testing can be performed either as a separate test or

by using material from the liquid-based cytology specimen.

• In the absence of other indications, the presence of external

genital warts does not warrant more frequent cervical

cancer screening.

• The sequence of cytology testing in relation to collection

of other endocervical specimens does not influence Pap test

results or their interpretation (600). Typically, vaginal

specimens are preferred for chlamydia and gonorrhea

screening; however, during a pelvic examination, endocervical

specimens for STI testing can be collected first.

• Persons who have had a total hysterectomy with removal

of the cervix do not require screening unless cervical

intraepithelial neoplasia (CIN) 2, CIN 3, or adenocarcinoma

in situ was diagnosed within the previous 20 years

(175,1247). If the cervix remains intact after a supracervical

hysterectomy, regularly scheduled Pap tests should be

performed as indicated (1248–1250).

• Health care facilities that train providers on cytology test

collection and use simple quality assurance measures are

more likely to obtain satisfactory test results (as determined

by the laboratory).

• The use of instruments designed to sample the cervical

transformation zone (e.g., cytobrushes) improves the

accuracy of cytology tests (1251).

• Both liquid-based and conventional cytology are acceptable

because they have similar test-performance characteristics.

• At an initial visit, providers should ask patients about their

recent cytology test and HPV results and any history of

evaluation and treatment (e.g., loop electrosurgical

excision procedure and colposcopy) to assist with

management; effort should be made to obtain copies of

recent results. The importance and frequency of screening

should be reinforced.

Counseling

Persons might believe the cytology (Pap test) or HPV test

screens for conditions other than cervical cancer, or they

might be confused by abnormal results (1252–1254). Health

care providers, as trusted sources of information about HPV

infections and abnormal cytology test results, have an important

role in educating persons about HPV and can moderate the

psychosocial impact of abnormal results (1255,1256). Persons

should be counseled on the risks, uncertainties, and benefits

of screening (174,1257).

An abnormal cytology test or a positive HPV test can

cause short-term anxiety, stress, fear, and confusion, possibly

decreasing the patient’s ability to absorb and retain information

and acting as a barrier to follow-up care (1258–1261). A

positive HPV test might elicit concerns about partners, worries

about disclosure, and feelings of guilt, anger, and stigmatization

(1260). Providers should frame HPV positivity in a neutral,

nonstigmatizing context and emphasize its common,

asymptomatic, and transient nature. Providers also should

emphasize that HPV infections often are shared between

partners but it is often not possible to know the origin of an

HPV infection; HPV tests might become positive many years

after initial exposure due to reactivation of latent infections

in both male and female partners. Having an HPV infection

should not raise concerns about a male partner’s health (1262).

Providers should communicate the meaning of both the

cytology and HPV test results to patients at screening.

Providers also should screen for tobacco use and

perform cessation counseling (www.acog.org/clinical/

clinical-guidance/committee-opinion/articles/2011/09/

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tobacco-use-and-womens-health). Smoking contributes to

the progression of CIN, with both active and passive smoking

associated with squamous cell carcinoma of the cervix in

women with HPV 16 or 18 infection (1263–1266).

Promoting Cervical Cancer Screening

Clinics can use the evidence-based interventions in the

Community Preventive Services Task Force guidelines to

promote cervical cancer screening in their communities

(https://www.thecommunityguide.org/findings/cancer-

screening-multicomponent-interventions-cervical-cancer).

Implementing interventions that increase community demand

for screening (1266) (e.g., client reminders, client incentives,

media, group education, or one-on-one education) together

with those that increase community access to screening (e.g.,

reducing structural barriers and reducing client out-of-pocket

costs) is effective in increasing cervical cancer screening

coverage. These interventions are more effective if they are

implemented with interventions to increase provider delivery

of screening services (e.g., provider assessment and feedback,

provider incentives, and provider reminders). Print materials

and online resources are available at https://www.cdc.gov/

cancer/cervical/basic_info/screening.htm and https://www.

cdc.gov/std/hpv/facts-brochures.htm. Patient navigators can

be effective in improving both screening and follow-up after

abnormal results (1267).

Key Messages About Cervical Cancer Screening

When counseling persons about cervical cancer screening,

the provider should discuss the following:

• Cervical cancer can be prevented with regular screening tests,

like the Pap test (cytology) and HPV tests. Those at average

risk should start getting cytology tests at age 21 years.

• The cytology test can find abnormal cervical cells, which

could lead to cervical cancer over time, and an HPV test

detects HPV infection of the cervix. The HPV test can be

used alone for cervical cancer screening or at the same time

as the cytology test (known as cotesting) for those aged

≥30 years to 65 years. The HPV test is also used after a

cytology test result of atypical squamous cells of

undetermined significance (ASC-US) among persons aged

>25 years (known as reflex HPV testing).

• Positive cytology and HPV tests are markers of cervical

precancerous lesions, which often do not cause symptoms

until they become invasive. Appropriate follow-up is

essential to ensure that cervical cancer does not develop.

• HPV is a common infection and is often controlled by

the body without any medical interventions. A positive

HPV test does not mean that a person has cancer.

• Providers should emphasize that HPV infections often are

shared between partners, and it is often not possible to know

the origin of an HPV infection; HPV tests might become

positive many years after initial exposure due to reactivation

of latent infections in both male and female partners.

Management of Sex Partners

The benefit of disclosing a positive HPV test to current

and future sex partners is unclear. The following counseling

messages can be communicated to sex partners:

• Sex partners do not need to be tested for HPV.

• Sex partners tend to share HPV. Sex partners of persons

with HPV infection also are likely have an HPV infection.

• Female sex partners of men who disclose they had a previous

female partner with HPV should be screened at the same

intervals as women with average risk. No data are available

to suggest that more frequent screening is of benefit.

• When used correctly and consistently, condoms might

lower the risk for HPV infection and might decrease the

time to clear in those with HPV infection. However, HPV

can infect areas not covered by the condom, and condoms

might not fully protect against HPV (24,25).

Additional messages for partners include the messages for persons

with HPV (see Cervical Cancer Screening; Counseling Messages).

Screening Recommendations in Special

Populations

Pregnancy

Persons who are pregnant should be screened at the same

intervals as those who are not. A swab, Ayre’s spatula, or

cytobrush can be used for obtaining cytology test samples

during pregnancy (1268–1270).

HIV Infection

Several studies have documented an increased risk for cervical

precancers and cancers in individuals with HIV infection

(1271–1273). Adolescents with HIV should be screened 1 year

after onset of sexual activity but no later than age 21 years.

Sexually active persons should be screened at the time of the

initial HIV diagnosis. Conventional or liquid-based cytology

(Pap test) should be used as primary HPV testing and is not

recommended in individuals with HIV. Cotesting (cytology

and HPV test) can be done in individuals aged ≥30 years with

HIV. Annual screening is recommended for persons with HIV

infection; after 3 years of consecutive normal cytology results

or normal cotest (normal cytology and negative HPV test), the

screening interval can be increased to every 3 years. Lifelong

screening is recommended among persons with HIV infection.

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Providers should defer to existing Guidelines for the Prevention

and Treatment of Opportunistic Infections in Adults and

Adolescents with HIV for guidance on cervical cancer screening

and management of results in persons with HIV (98).

Adolescents

Prevalence of HPV infection is high among those aged

<21 years (174); however, HPV infections and squamous

intraepithelial lesions caused by HPV in adolescents are more

likely to regress than those in older persons. For these reasons,

cervical cancer screening and HPV testing are not recommended

in immunocompetent adolescents. However, for adolescents

with HIV infection, providers should screen 1 year after onset of

sexual activity, regardless of age or mode of HIV acquisition (e.g.,

perinatally acquired or sexually acquired) (98); such screening

is warranted because of the reported high rate of progression of

abnormal cytology in adolescents with HIV.

Human Papillomavirus Tests for Cervical

Cancer Screening

Clinical tests for HPV are used for the following: cervical

cancer screening as a primary test, cervical cancer screening

with a cytology test, triage of some abnormal cervical

cytology results, follow-up after abnormal screening test

results, follow-up after a colposcopy in which no CIN 2 or

CIN 3 is found, and follow-up after treatment of cervical

precancers. These tests are only FDA cleared for use with

cervical specimens, not oral or anal specimens. Testing

for nononcogenic HPV types (e.g., types 6 and 11) is not

recommended (https://www.asccp.org/guidelines).

FDA-cleared HPV tests detect viral DNA or messenger

RNA. Several FDA-cleared tests for HPV are available for

use in the United States. The Cobas 4800 HPV test (Roche

Molecular Diagnostics) and the Onclarity HPV test (Becton

Dickinson) can detect the presence of 14 oncogenic HPV types

(types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and

68), as well as individual types 16 and 18, and are cleared for

primary cervical cancer screening.

Other HPV tests are cleared for use in conjunction with

a cytology test or to triage some abnormal cervical cytology

results; they should not be used for primary HPV testing

because they are not cleared for this purpose. These tests

include the Hybrid Capture 2 High-Risk HPV DNA test

(Qiagen), the Cervista HPV High-Risk DNA and HPV 16/18

DNA tests (Hologics), and the APTIMA HR HPV (Gen

Probe) test. All HPV assays should be FDA cleared and used

only for the appropriate indications (https://www.fda.gov/

media/122799/download) (158).

HPV testing should not be performed in the following situations:

• Deciding whether to vaccinate against HPV

• Conducting HPV tests for low-risk (nononcogenic) HPV

types (e.g., types 6 and 11)

• Providing care to persons with genital warts or their partners

• Testing persons aged <25 years as part of routine cervical

cancer screening

• Testing oral or anal specimens

Unlike cytology, samples for HPV testing have the potential

to be collected by the patient and mailed to health programs

for analysis, thus self-collection might be one strategy for

increasing screening rates among populations where screening

rates are low. Self-collection for HPV testing is not cleared by

FDA or recommended by U.S. medical organizations (174).

Follow-Up of Abnormal Cytology and Human

Papillomavirus Test Results

If the result of the cytology (Pap test) is abnormal, follow-up

care should be provided according to the 2019 ASCCP Risk-

Based Management Consensus Guidelines for Abnormal Cervical

Cancer Screening Tests and Cancer Precursors (158). Clinics that

serve clients who might have difficulty adhering to follow-up

recommendations and for whom linkage to care is unlikely should

consider offering in-house colposcopy and biopsy services.

Consensus guidelines for management of abnormal

cervical cancer screening tests combine patient-level risk

data with clinical action thresholds to generate personalized

management recommendations (Table 2). This framework

allows management on the basis of risk for CIN 3, not specific

test results. The guidelines were designed to identify persons at

high risk who require colposcopy or expedited treatment and

persons at low risk who might be able to safely defer invasive

diagnostic procedures. The risk-based framework was designed

to easily incorporate future revisions, such as the inclusion of

new technologies for screening and management. Use of the

guidelines can be facilitated by electronic technology that is

continually updated, such as a smartphone application or the

website (https://www.asccp.org/Default.aspx).

The following are highlights of the new management guidelines:

• Colposcopy can be deferred for patients at low risk.

If a patient has a minimally abnormal test result (i.e.,

negative for intraepithelial lesion or malignancy HPV

positive, ASC-US HPV positive, LSIL, or HPV positive)

that was preceded by a negative screening HPV test or

cotest within the past 5 years, follow-up in 1 year instead

of colposcopy is recommended (a negative HPV test or

cotest performed during follow-up of abnormal results

would not similarly reduce risk).

Referral to colposcopy is recommended if cytology test

results are abnormal or the HPV test is positive at the

1-year follow-up visit.

• Treatment can be expedited for high-risk patients.

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If a patient has a high-grade cytology (Pap test) result

(i.e., HSIL) and an HPV test that is positive for HPV

type 16, then treatment with a loop electrosurgical

excision procedure (LEEP) is preferred. A colposcopy

with biopsy is not necessary to confirm the diagnosis first.

If a patient who has not been screened in more than

5 years (i.e., rarely screened) has an HSIL cytology result

and a positive HPV test (regardless of type), then

treatment with LEEP is preferred. A colposcopy with

biopsy is not necessary to confirm the diagnosis first.

When considering treatment without confirmatory

biopsy, shared decision-making with the patient is

important. Considerations include age, concern about

cancer, ability to follow up, financial concerns, and

concerns about the potential effect of treatment on a

future pregnancy.

• When primary HPV testing is used for screening, cytology

testing should be performed for all positive HPV test

results to help determine the next steps in management.

Ideally, cytology testing should be performed by the

laboratory as a reflex test from the same specimen so the

patient does not need to return to the clinic. Colposcopy

is recommended if HPV genotyping is positive for types

16 or 18, and it can be considered if it is infeasible for

the patient to return for cytology alone (1274).

HPV 16 is the highest-risk HPV type. Expedited

treatment should be considered for HSIL cytology

results, and colposcopy is recommended in all other

cases, even if the cytology test is normal.

TABLE 2. Comparison of 2012 and 2019 consensus recommendations for management of common abnormalities — American Society for

Colposcopy and Cervical Pathology

Current HPV result

Current Pap

test result Previous result

Management by 2012

guidelines

Management by 2019

guidelines

Negative ASC-US Unknown or HPV negative* Repeat Pap plus HPV testing

in 3 yrs

Repeat HPV test with or without

concurrent Pap test in 3 yrs

Negative LSIL Unknown or HPV negative* Repeat Pap plus HPV testing

in 1 yr preferred, colposcopy

acceptable

Repeat HPV test with or without

concurrent Pap test in 1 yr

Negative ASC-H Noncontributory Colposcopy Colposcopy

Noncontributory AGC Noncontributory Colposcopy Colposcopy

Positive NILM Unknown or HPV negative* Repeat Pap plus HPV testing

in 1 yr

Repeat HPV test with or without

concurrent Pap test in 1 yr

Positive NILM HPV positive

†

Colposcopy Colposcopy

Positive for genotype HPV 16,

HPV 18, or both

NILM Noncontributory Colposcopy Colposcopy

Positive for genotype HPV 16,

HPV 18, or both

ASC-US or LSIL Noncontributory Not applicable, genotyping

not recommended for

ASC-US or LSIL in 2012

Colposcopy

Positive ASC-US or LSIL Unknown or HPV positive Colposcopy Colposcopy

Positive ASC-US or LSIL Negative screening results with

HPV testing or HPV plus Pap

testing within the previous 5 yrs

Colposcopy Repeat HPV test with or without

concurrent Pap test in 1 yr

Positive ASC-US or LSIL Colposcopy confirming the absence

of high-grade lesion within the

past yr

Colposcopy Repeat HPV test with or without

concurrent Pap test in 1 yr

Positive ASC-H Noncontributory Colposcopy Colposcopy or expedited

treatment

Positive untyped, positive for

genotype other than HPV 16,

or negative

HSIL Noncontributory Colposcopy or expedited

treatment

Colposcopy or expedited

treatment

Positive for genotype HPV 16 HSIL Noncontributory Colposcopy or expedited

treatment

Expedited treatment

Sources: Massad LS, Einstein MH, Huh WK, et al.; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management of abnormal

cervical cancer screening tests and cancer precursors. Obstet Gynecol 2013;121:829–46; Perkins RB, Guido RS, Castle PE, et al; 2019 ASCCP Risk-Based Management

Consensus Guidelines Committee. 2019 ASCCP risk-based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.

J Low Genit Tract Dis 2020;24:102–31; Perkins R, Guido R, Saraiya M, et al. Summary of current guidelines for cervical cancer screening and management of abnormal

test results: 2016–2020. J Womens Health (Larchmt) 2021;30:5–13.

Abbreviations: AGC = atypical glandular cells; AIS = adenocarcinoma in situ; ASC-H = atypical squamous cells cannot exclude high-grade squamous intraepithelial

lesion; ASC-US = atypical squamous cells of undetermined significance; CIN = cervical intraepithelial neoplasia; HPV = human papillomavirus; HSIL = high-grade

squamous intraepithelial lesion; LSIL = low-grade squamous intraepithelial lesion; NILM = negative for intraepithelial lesion or malignancy; Pap = Papanicolaou.

* Colposcopy may be warranted for patients with a history of high-grade lesions (CIN 2 or CIN 3, histologic or cytologic HSIL, ASC-H, AGC, or AIS).

†

Previous Pap test results do not modify the recommendation; colposcopy is always recommended for two consecutive HPV-positive tests.

Negative HPV test or cotest (HPV plus Pap test) results only reduce risk sufficiently to defer colposcopy if performed for screening purposes within the last 5 years.

Colposcopy is still warranted if negative HPV test or cotest results occurred in the context of surveillance for a previous abnormal result.

Expedited treatment is preferred for nonpregnant patients aged ≥25 years. Colposcopy with biopsy is an acceptable option if desired by patient after shared

decision-making.

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HPV 18 has a relatively high association with cancer,

and colposcopy is recommended in all cases, even if the

cytology test is normal. Because of the association of

HPV 18 with adenocarcinoma, endocervical sampling

is acceptable at the time of colposcopy.

If the HPV type is not HPV 16 or 18, and the cytology test

is normal, return in 1 year is recommended in most cases.

• HPV testing or cotesting is preferred to cytology testing

alone for follow-up after an abnormal test result.

Negative HPV testing or cotesting is less likely to miss

disease than normal cytology testing alone. Therefore,

cytology testing is recommended more often than HPV

testing or cotesting for follow-up of abnormal results.

Specifically, cytology testing is recommended annually

when HPV testing or cotesting is recommended at

3-year intervals, and cytology testing is recommended

at 6-month intervals when HPV testing or cotesting is

recommended annually.

• After treatment for a high-grade precancer (moderate or

severe dysplasia), surveillance should continue for at least

25 years.

Initial testing includes an HPV test or cotest at 6, 18,

and 30 months. If cytology alone is used, testing should

occur at 6, 12, 18, 24, and 30 months.

After completing initial testing, long-term surveillance

includes testing at 3-year intervals if using HPV testing or

cotesting, or annual testing if using cytology testing alone.

Surveillance should continue for at least 25 years after

the initial treatment, even if this extends beyond age

65 years. If a woman undergoes hysterectomy during the

surveillance period, vaginal screening should continue.

Anal Cancer

Anal cancer is rare in the general population (1–2 cases per

100,000 person-years); however, incidence is substantially

higher among specific populations, including MSM with HIV

infection (80–131 cases per 100,000 person-years), men with

HIV infection (40–60 cases per 100,000 person-years), women

with HIV infection (20–30 cases per 100,000 person-years),

and MSM without HIV infection (14 cases per 100,000

person-years) (1275–1279). Incidence is variable among

women with previous HPV-related gynecologic dysplasia and

cancer (6–63 cases per 100,000 person-years) (1280,1281).

Persistent HPV infection might be a risk factor for preventable

HPV-associated second primary cancers among survivors of

HPV-associated cancers (1282).

Data are insufficient to recommend routine anal cancer

screening with anal cytology in persons with HIV infection,

MSM without HIV infection, and the general population. An

annual digital anorectal examination (DARE) might be useful

to detect masses on palpation in persons with HIV infection

and possibly in MSM without HIV with a history of receptive

anal intercourse (98). More evidence is needed concerning

the natural history of anal intraepithelial neoplasia, the best

screening methods and target populations, the safety and

response to treatments, and other programmatic considerations

before screening can be routinely recommended.

Populations at High Risk and Digital Anorectal

Examination

Providers should discuss anal cancer risk with their patients

among specific populations to guide management. According

to the HIV Opportunistic Infection guidelines and the

International Anal Neoplasia Society, a DARE should be

performed to detect early anal cancer in persons with HIV

infection and MSM without HIV with a history of receptive

anal intercourse (98,1283). DARE is acceptable to patients and

has a low risk for adverse outcomes (1284,1285).

Data are insufficient to guide initiation of DARE at a defined

age or optimal intervals for examination. Whereas anal HSIL

is observed among young adults, cancer incidence begins

to increase after the early 30s and continues to increase as a

function of age.

Populations at High Risk and Anal Cytology

Data are insufficient to recommend routine anal cancer

screening with anal cytology among populations at risk for

anal cancer. Certain clinical centers perform anal cytology to

screen for anal cancer among populations at high risk (e.g.,

persons with HIV infection, MSM, and those having receptive

anal intercourse), followed by high-resolution anoscopy (HRA)

for those with abnormal cytologic results (e.g., ACS-US, LSIL,

or HSIL). Sensitivity and specificity of anal cytology to detect

HSIL are limited (sensitivity 55%–89% and specificity 40%–

67%) (1286–1291). Health centers that initiate a cytology-

based screening program should only do so if referrals to HRA

and biopsy are available.

HRA can be used for diagnosis of HSIL, to monitor response

to therapy, or to conduct surveillance of HSIL for evidence of

progression. HRA is the primary method used for diagnosis of

superficially invasive squamous carcinoma, a very early form of

anal cancer that is not palpable on DARE. However, data are

insufficient to conclude whether use of HRA leads to reductions

in anal cancer incidence or improves anal cancer morbidity and

mortality. An ongoing clinical trial is investigating whether

treatment of HSIL is effective in reducing the incidence of anal

cancer among persons with HIV infection (NCT02135419).

Human Papillomavirus Testing

HPV tests (using high-risk HPV types) are not clinically

useful for anal cancer screening because of a high prevalence

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of anal HPV infection among populations at high risk,

particularly MSM (1278,1289,1290). No standard HPV-based

algorithms exist for anal cancer screening due to the high

prevalence of high-risk HPV infection among groups at risk.

Treatment of Anal High-Grade Squamous

Intraepithelial Lesion

Multiple office-based treatments exist for anal HSIL,

including ablative methods (e.g., laser, electrocautery, or

infrared coagulation) and topical patient-applied therapies

(e.g., imiquimod). Recurrence rates with both provider-

applied and patient-applied treatments are high, ranging

from approximately 50% at 1 year to 77% after 3 years

(1289,1292,1293). In addition, evidence exists that HSIL

might spontaneously regress without treatment (1294,1295).

Shared decision-making about treatment for anal HSIL is

recommended because of limited data on the natural history

of anal HSIL, including factors related to progression or

regression of lesions.

Viral Hepatitis

Hepatitis A Virus Infection

HAV infection has an incubation period of approximately

28 days (range: 15–50 days) (1296). HAV replicates in the liver

and is shed in high concentrations in feces from 2–3 weeks

before to 1 week after the onset of clinical illness. HAV infection

produces a self-limited disease that does not result in chronic

infection or chronic liver disease. However, approximately

10% of patients experience a relapse of symptoms during

the 6 months after acute illness. Acute liver failure from

hepatitis A is rare (overall case-fatality rate: 0.5%). The risk

for symptomatic infection is directly related to age, with

approximately 70% of adults having symptoms compatible

with acute viral hepatitis and the majority of children having

either asymptomatic or unrecognized infection. Antibody

produced in response to HAV infection persists for life and

confers protection against reinfection (1297).

HAV infection is primarily transmitted by the fecal-oral route,

by either person-to-person contact or through consumption

of contaminated food or water (1298). Transmission of HAV

during sexual activity probably results from fecal-oral contact.

Although viremia occurs early during infection and can persist

for weeks after symptom onset, bloodborne transmission of

HAV is uncommon (1299). Transmission by saliva has not

been demonstrated.

In the United States, of the hepatitis A cases accompanied by

risk information, a particular risk was identified among only

23.8% (13,372). Among cases with a risk factor identified, a

recognized foodborne or waterborne outbreak was the most

commonly identified risk (49.6%). Other infection sources

identified in the United States include MSM; persons who

use injecting drugs; sexual and household contacts; those

experiencing homelessness; international travelers; those with

children attending a nursery, childcare, or preschool; and

persons working in such settings (13,372).

Diagnostic Considerations

Diagnosis of HAV infection cannot be made on a clinical

basis alone but requires serologic testing. Presence of IgM

antibody to HAV is diagnostic of acute HAV infection. A

positive test for total anti-HAV indicates immunity to HAV

infection but does not differentiate current from previous HAV

infection. Although usually not sensitive enough to detect the

low level of protective antibody after vaccination, anti-HAV

tests also might be positive after hepatitis A vaccination.

Treatment

Patients with acute HAV infection usually require only

supportive care, with no restrictions in diet or activity.

Hospitalization might be necessary for patients who become

dehydrated because of nausea and vomiting and is crucial

for patients with signs or symptoms of acute liver failure.

Medications that might cause liver damage or are metabolized

by the liver should be used with caution among persons with

HAV infection.

Prevention

Vaccination is the most effective means of preventing HAV

transmission among persons at risk for infection (e.g., MSM,

injecting drug users, and persons with chronic liver disease)

who did not receive hepatitis A vaccination during childhood.

Hepatitis A vaccines are prepared from formalin-inactivated,

cell-culture–derived HAV. Two monovalent vaccines (Havrix

and Vaqta are approved by FDA for persons aged ≥12 months

(Table 3). These vaccines are available for eligible children

and adolescents aged <19 years through the VFC program

(https://www.cdc.gov/vaccines/programs/vfc/index.html).

Administered IM in a 2-dose series at 0 and 6–12 months,

hepatitis A vaccines induce protective antibody levels among

virtually all adults. By 1 month after the first dose, 94%–100%

of adults have protective antibody levels, and after a second

dose, 100% achieve protective levels (1297,1300,1301).

Kinetic models of antibody decrease among adults indicate that

protective levels persist for >40 years (1302–1304). A study of

Alaska Natives demonstrated that seropositivity for hepatitis

A persists for >20 years after completing 2-dose vaccination at

age 12–21 months (1302). Anti-HAV persistence of >20 years

was demonstrated among immunocompetent adults vaccinated

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with a 2-dose hepatitis A schedule as adults (1303,1305). A

combined hepatitis A and hepatitis B vaccine (Twinrix) has

been developed and licensed for use as a 3-dose series for

adults aged ≥18 years at risk for HAV or HBV infections.

When administered IM on a 0-, 1-, and 6-month schedule,

the vaccine has equivalent immunogenicity to that of the

monovalent hepatitis A vaccines.

Pre-Exposure Vaccination

Persons at risk for HAV infection (Box 5) (1297) should be

offered vaccine (Table 3). If persons are at risk for both HAV

and HBV, the combined vaccine can be considered.

Prevaccination Serologic Testing

Among U.S.-born adults aged >20 years, HAV susceptibility

prevalence (i.e., total antibody to HAV was negative) was

74.1% (95% CI:72.9%–75.3%) during 2007–2016 (1306).

Prevaccination serologic testing for HAV immunity before

vaccination is not routinely recommended; however, it can be

considered in specific settings to reduce costs by not vaccinating

persons who are already immune. Prevaccination serologic

testing should not be a barrier to vaccination of susceptible

persons, especially for populations that are difficult to access. If

prevaccination testing is performed, commercially available tests

for total anti-HAV or IgG anti-HAV should be used (1297).

BOX 5. Populations recommended for hepatitis A vaccination — Advisory Committee on Immunization Practices, 2020

Children

• All children aged 12–23 months

• Unvaccinated children and adolescents aged 2–18 years

Persons at increased risk for hepatitis A virus (HAV)

infection

• International travelers

• Men who have sex with men

• Persons who use injecting or noninjecting drugs (i.e.,

all those who use illegal drugs)

• Persons with occupational risk for exposure

• Persons who anticipate close personal contact with an

international adoptee

• Persons experiencing homelessness

Persons at increased risk for severe disease from

HAV infection

• Persons with chronic liver disease

• Persons with HIV infection

Other persons recommended for vaccination

• Pregnant women at risk for HAV infection or severe

outcome from HAV infection

• Any persons who requests a vaccine

Vaccination during outbreaks

• Unvaccinated persons in outbreak settings who are at

risk for HAV infection or at risk for severe disease from

HAV

Implementation strategies for settings providing

services to adults

• Persons in settings that provide services to adults where

a high proportion of those persons have risk factors for

HAV infection

Hepatitis A vaccination is no longer recommended by

the Advisory Committee on Immunization Practices

• Persons who receive blood products for clotting disorders

(e.g., hemophilia)

Source: Nelson NP, Weng MK, Hofmeister MG, et al. Prevention of hepatitis A virus infection in the United States: recommendations of the Advisory Committee

on Immunization Practices, 2020. MMWR Recomm Rep 2020;69(No. RR-5).

TABLE 3. Vaccines for preventing hepatitis A infection

Vaccine Trade name (manufacturer) Age group (yrs) Dose Route Schedule Booster

Hep A inactivated

(2 doses)

Havrix (GlaxoSmithKline) 1–18 0.5 mL (720 ELISA units inactivated HAV) IM 0, 6–12 mos None

≥19 1 mL (1,440 ELISA units inactivated HAV IM 0, 6–12 mos None

Hep A inactivated

(2 doses)

Vaqta (Merck) 1–18 0.5 mL (25 units HAV antigen) IM 0, 6–18 mos None

≥19 1 mL (50 units HAV antigen) IM 0, 6–18 mos None

Combined Hep A

and Hep B*

(3 doses)

Twinrix (GlaxoSmithKline) ≥18 (primary) 1 mL (720 ELISA units inactivated plus

20 µg HBsAg

IM 0, 1, 6 mos None

≥18 (accelerated) 1 mL (720 ELISA units inactivated plus

20 µg HBsAg

IM 0, 7, 21–30 days 12 mos

Source: Nelson NP, Weng MK, Hofmeister MG, et al. Prevention of hepatitis A virus infection in the United States: recommendations of the Advisory Committee on

Immunization Practices, 2020. MMWR Recomm Rep 2020;69(No. RR-5).

Abbreviations: ELISA = enzyme-linked immunosorbent assay; HAV = hepatitis A virus; HBsAg = hepatitis B surface antigen; Hep A = hepatitis A; Hep B = hepatitis B;

IM= intramuscular.

* Combined Hep A and Hep B vaccine (Twinrix) should not be used as postexposure prophylaxis.

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Persons for whom prevaccination testing will likely be most

cost-effective include adults who were either born in or lived for

extensive periods in geographic areas where HAV endemicity is

high or intermediate (1297). Prevaccination serologic testing

of children is not indicated because of the low prevalence of

infection among that age group.

For populations who are expected to have high rates of previous

HAV infection, vaccination history should be obtained when

feasible before testing or vaccination. Vaccination should not be

postponed if vaccination history cannot be obtained, records are

unavailable, or prevaccination testing is infeasible. Vaccinating

persons immune from natural infection carries no known risk, nor

does giving extra doses of hepatitis A vaccine (1307). Vaccination

of a person who is already immune is not harmful. Persons who

have a documented history of ≥2 doses of hepatitis A vaccine do

not need further vaccination or serologic testing.

Postvaccination Serologic Testing

Serologic testing for immunity is unnecessary after routine

vaccination of infants, children, or adults (1297). Testing

for anti-HAV antibody after vaccination is recommended

for persons whose subsequent clinical management depends

on knowledge of their immune status and persons for whom

revaccination might be indicated (e.g., persons with HIV

infection and other immunocompromising conditions).

Postexposure Prophylaxis

Persons who recently have been exposed to HAV and who

previously have not received hepatitis A vaccine should be

administered a single dose of monovalent hepatitis A vaccine

or immunoglobulin (IG) (0.1 mL/kg body weight) as soon as

possible, ideally <2 weeks after exposure because the efficacy

of vaccine or IG when administered >2 weeks after exposure

has not been established (1297). In most cases, monovalent

hepatitis A vaccine at the age-appropriate dose is preferred

over IG for PEP. Advantages of hepatitis A vaccine for PEP

include induction of active immunity, longer-term protection,

ease of administration, and better acceptability and availability.

Decisions to use vaccine versus IG should be guided by patient

characteristics associated with more severe manifestations

of HAV infection (e.g., older age, immunocompromising

conditions, and chronic liver disease) and the magnitude of the

risk for HAV transmission resulting from the exposure (1297).

IG should be used for children aged <6 months,

immunocompromised persons, persons with chronic liver

disease, and persons for whom vaccine is contraindicated. IG

can be administered to persons aged >40 years, in addition to

hepatitis A vaccine (1297).

IG administered IM can provide PEP against HAV (Table 4).

IG is a sterile solution of concentrated immunoglobulins prepared

TABLE 4. Recommendations for hepatitis A postexposure prophylaxis and pre-exposure protection, by age group and risk category — Advisory

Committee on Immunization Practices, 2020

Indication and age group Risk category and health status Hepatitis A vaccine IG*

Postexposure prophylaxis

0–11 mos Healthy No 0.1 mL/kg body weight

12 mos to 40 yrs Healthy 1 dose

†

None

>40 yrs Healthy 1 dose

†

0.1 mL/kg body weight

≥12 mos Immunocompromised or chronic liver disease 1 dose

†

0.1 mL/kg body weight

≥12 mos Vaccine contraindicated** No 0.1 mL/kg body weight

Pre-exposure protection (e.g., travel)

††

<6 mos Healthy No 0.1–0.2 mL/kg body weight

§§

6–11 mos Healthy 1 dose

¶¶

None

12 mos to 40 yrs Healthy 1 dose*** None

>40 yrs Healthy 1 dose*** 0.1–0.2 mL/kg body weight

§§,†††

>6 mos Immunocompromised or chronic liver disease 1 dose*** 0.1–0.2 mL/kg body weight

§§,†††

>6 mos Persons who elect not to receive vaccine or for whom

vaccine is contraindicated**

No 0.1–0.2 mL/kg body weight

§§

Source: Nelson NP, Weng MK, Hofmeister MG, et al. Prevention of hepatitis A virus infection in the United States: recommendations of the Advisory Committee on

Immunization Practices, 2020. MMWR Recomm Rep 2020;69(No. RR-5).

Abbreviations: HAV = hepatitis A virus; IG = immune globulin.

* Measles, mumps, and rubella vaccine should not be administered for ≥2 weeks before and 6 months after administration of IG.

†

A second dose of hepatitis A vaccine is not required for postexposure prophylaxis; however, for long-term immunity, the vaccination series should be completed

with a second dose ≥6 months after the first dose.

The provider’s risk assessment should determine the need for IG administration. If the provider’s risk assessment determines that both vaccine and IG are warranted,

hepatitis A vaccine and IG should be administered simultaneously at different anatomic sites (e.g., separate limbs).

Vaccine and IG should be administered simultaneously at different anatomic sites (e.g., separate limbs).

** Life-threatening allergic reaction to a previous dose of hepatitis A vaccine or allergy to any vaccine component.

††

IG should be considered before travel for persons with special risk factors for either HAV infection or severe disease from HAV infection.

§§

0.1 mL/kg body weight for travel ≤1 month; 0.2 mL/kg body weight for travel ≤2 months; 0.2 mL/kg every 2 months for travel of ≥2 months’ duration.

¶¶

This dose should not be counted toward the routine 2-dose series, which should be initiated at age 12 months.

*** For persons not previously vaccinated with hepatitis A vaccine, administer dose as soon as travel is considered and complete the series according to routine

schedule if the next dose is needed before travel.

†††

Can be administered on the basis of the provider’s risk assessment.

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from pooled human plasma processed by cold ethanol

fractionation. In the United States, IG is produced only from

plasma that has tested negative for HBsAg, antibodies to HIV

and HCV, and HIV and HCV RNA. In addition, the process

used to manufacture IG inactivates viruses (e.g., HBV, HCV,

and HIV). When administered IM <2 weeks after exposure to

HAV, IG is >85% effective in preventing HAV infection (1308).

If IG is administered to persons for whom hepatitis A vaccine

also is recommended, a dose of vaccine should be provided

simultaneously with IG in different anatomic sites (e.g.,

different limbs) as soon as possible, and the second vaccine dose

should be administered according to the licensed schedule to

complete the series. The combined vaccine can be considered

for persons among whom both hepatitis A and hepatitis B

vaccine is recommended (13,1297,1302–1304).

Special Considerations

For persons with HIV infection, antibody response can be

directly related to CD4

T-cell levels. Although persons with

HIV who have lower CD4

T-cell counts or percentages might

have a weaker response to the vaccine, vaccination should

not be delayed for the CD4

T-cell count to exceed a certain

threshold because of the prolonged risk for HAV exposure

created by missed opportunities to vaccinate.

Hepatitis B Virus Infection

The incubation period for HBV infection from time of

exposure to symptom onset ranges from 6 weeks to 6 months.

The highest concentrations of HBV are located in blood, with

lower concentrations in other body fluids including wound

exudates, semen, vaginal secretions, and saliva (1309,1310).

HBV is more infectious and more stable in the environment

than other bloodborne pathogens (e.g., HCV or HIV).

HBV infection can be either self-limited or chronic.

Among adults, approximately half of newly acquired HBV

infections are symptomatic, and approximately 1% of reported

cases result in acute liver failure and death (1311). Risk for

chronic infection is inversely related to age at acquisition;

approximately 90% of infected infants and 30% of infected

children aged <5 years become chronically infected, compared

with 2%–6% of persons who become infected as adults (1312).

Among persons with chronic HBV infection, the risk for

premature death from cirrhosis or hepatocellular carcinoma

is 15%–25% (1313).

HBV is efficiently transmitted by percutaneous or mucous

membrane exposure to HBV-infected blood or body fluids

that contain HBV. The primary risk factors associated with

infection among adolescents and adults are unprotected sex

with an infected partner, having multiple partners, men having

sex with men, having history of other STIs, and injecting drug

use (233). In addition, studies have demonstrated other modes

of HBV transmission, including premastication and lapses

in health care infection control procedures, as less common

sources of transmission (1314–1317).

CDC’s national strategy for eliminating transmission of HBV

infection includes prevention of perinatal infection through

routine screening of all pregnant women for HBsAg and

immunoprophylaxis of infants born to mothers with HBsAg

or mothers whose HBsAg status is unknown, routine infant

vaccination, vaccination of previously unvaccinated children

and adolescents through age 18 years, and vaccination of

previously unvaccinated adults at increased risk for infection

(12). High vaccination coverage rates with subsequent

decreases in acute HBV infection incidence have been achieved

among infants and adolescents (1318). The vaccination of

persons as children and adolescents likely has led to improved

vaccination coverage among adults aged <30 years (1319) and

corresponding lower rates of acute HBV infection among this

group. In contrast, vaccination coverage among the majority

of adult populations at high risk aged ≥30 years (e.g., persons

with multiple sex partners, MSM, and injecting drug users)

has remained low (1320,1321); these groups account for the

highest rates of preventable acute infections (12,1319,1322).

STD clinics and other health care settings providing STI

services to adults at high risk for infection should administer

hepatitis B vaccine to those who are unvaccinated.

Diagnosis

Diagnosis of acute or chronic HBV infection requires

serologic testing (Table 5). Because HBsAg is present in both

acute and chronic infection, presence of IgM antibody to

hepatitis B core antigen (IgM anti-HBc) is diagnostic of acute

or recently acquired HBV infection. Antibody to HBsAg

(anti-HBs) is produced after a resolved infection and is the

only HBV antibody marker present after vaccination. The

presence of HBsAg and anti-HBc, with a negative test for IgM

anti-HBc, indicates chronic HBV infection. The presence of

total anti-HBc alone might indicate acute, resolved, or chronic

infection or a false-positive result.

Treatment

No specific therapy is available for persons with acute HBV

infection; treatment is supportive. Persons with chronic

HBV infection should be referred for evaluation to a provider

experienced in managing such infections. Therapeutic agents

approved by FDA for treatment of chronic HBV infection

can achieve sustained suppression of HBV replication and

remission of liver disease (1323).

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Prevention

Two products have been approved for HBV prevention:

hepatitis B immune globulin (HBIG) for PEP and hepatitis

B vaccine (12). HBIG provides temporary (i.e., 3–6 months)

protection from HBV infection and is typically used as

PEP as an adjunct to hepatitis B vaccination for previously

unvaccinated persons or for persons who have not responded to

vaccination. HBIG is prepared from plasma known to contain

high concentrations of anti-HBs. The recommended dose of

HBIG is 0.06 mL/kg body weight.

Hepatitis B vaccine contains HBsAg produced in yeast by

recombinant DNA technology and provides protection from

HBV infection when used for both pre-exposure vaccination

and PEP. The three available monovalent hepatitis B vaccines

for use in the United States are Recombivax HB, Engerix-B,

and Heplisav-B. A combination hepatitis A and hepatitis B

vaccine for use among persons aged ≥18 years, Twinrix, also

is available.

When selecting a hepatitis B vaccination schedule, health care

providers should consider the need to achieve completion of

the vaccine series. The recommended HBV dose and schedule

varies by product and age of recipient (Table 6). Three different

3-dose schedules for adolescents and adults have been approved

for both monovalent hepatitis B vaccines (i.e., Engerix-B and

Recombivax HB); these vaccines can be administered at 0, 1,

and 6 months; 0, 1, and 4 months; or 0, 2, and 4 months.

A 4-dose schedule of Engerix-B at 0, 1, 2, and 12 months is

licensed for all age groups. A 2-dose schedule of Recombivax

HB adult formulation (10 µg) is licensed for adolescents

aged 11–15 years, with a 4-month minimal interval between

doses. When scheduled to receive the second dose, adolescents

aged 16–19 years should be switched to a 3-dose series, with

doses 2 and 3 consisting of the pediatric formulation (5 µg)

administered on a recommended schedule. Heplisav-B is a

new single-antigen recombinant hepatitis B vaccine with a

novel cytosine-phosphate-guanine 1018 oligodeoxynucleotide

adjuvant for prevention of HBV infection among persons

aged ≥18 years, administered as a 2-dose series at 0 and

1 month (>4 weeks apart) (156). Twinrix is a 3-dose schedule

administered at 0, 1, and 6 months to persons aged ≥18 years

at risk for both HAV and HBV infections.

Hepatitis B vaccine should be administered IM in the deltoid

muscle and can be administered simultaneously with other

vaccines. If the vaccine series is interrupted after the first or

second dose of vaccine, the missed dose should be administered

as soon as possible. The series does not need to be restarted after

a missed dose. HBV vaccination is available for eligible children

and adolescents aged <19 years through the VFC program

(https://www.cdc.gov/vaccines/programs/vfc/contacts-state.

html). When feasible, the same manufacturer’s vaccines should

be used to complete the series; however, vaccination should

not be deferred when the manufacturer of the previously

administered vaccine is unknown or when the vaccine from

the same manufacturer is unavailable (1324).

Among adolescents and healthy adults aged <40 years,

approximately 30%–55% achieve a protective antibody response

(i.e., anti-HBs ≥10 mIU/mL) after the first single-antigen

vaccine dose, 75% after the second, and >90% after the third.

Recent clinical trials reported a protective antibody response

achieved among approximately 90% of participants receiving

Heplisav-B, compared with 70.5%–90.2% of participants

receiving Engerix-B (12). Vaccine-induced immune memory

has been demonstrated to persist for >30 years (1325–1327).

TABLE 5. Interpretation of serologic test results* for hepatitis B virus infection

Serologic marker

InterpretationHBSAG Total anti-HBc IgM anti-HBc Anti-HBs

− − − − Never infected

†

− − − Early acute infection; transient (≤18 days) after vaccination

+ + + − Acute infection

− + + − Acute resolving infection

− + − + Recovered from past infection and immune

+ + − − Chronic infection

− + − − Past infection; low-level chronic infection

; passive transfer to infant born to HBsAg-

positive mother; false positive (no infection)

− − − + Immune if concentration is >10 mIU/mL after vaccination, passive transfer after HBIG

administration

Source: Adapted from Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus infection in the United States: recommendations of the Advisory Committee

on Immunization Practices. MMWR Recomm Rep 2018;67(No. RR-1).

Abbreviations: anti-HBc = antibody to hepatitis B core antigen; anti-HBs = antibody to hepatitis B surface antigen; HBIG = hepatitis B immune globulin; HBsAg =

hepatitis B surface antigen; IgM = immunoglobulin M.

* − = negative test result; + = positive test result.

†

To ensure that an HBsAg-positive test result is not false positive, samples with repeatedly reactive HBsAg results should be tested with a neutralizing confirmatory

test cleared by the Food and Drug Administration.

Persons positive for only anti-HBc are unlikely to be infectious, except under unusual circumstances involving direct percutaneous exposure to large quantities of

blood (e.g., blood transfusion or organ transplantation) or mutant HBsAg-related infection.

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Periodic testing to determine antibody levels after routine

vaccination among immunocompetent persons is unnecessary,

and booster doses of vaccine are not recommended.

Hepatitis B vaccination is usually well tolerated by the

majority of recipients. Pain at the injection site and low-grade

fever are reported by a minority of recipients. For children

and adolescents, a causal association exists between receipt of

hepatitis B vaccination and anaphylaxis. For each 1.1 million

doses of vaccine administered, approximately one recipient will

experience this type of reaction (1328); however, no deaths have

been reported among these patients (1318,1328). Vaccine is

contraindicated for persons with a history of anaphylaxis after a

previous dose of hepatitis B vaccine and persons with a known

anaphylactic reaction to any vaccine component (1329). No

other adverse events after administration of hepatitis B vaccine

have been demonstrated.

Pre-Exposure Vaccination

Hepatitis B vaccination is recommended for all unvaccinated

children and adolescents; all unvaccinated adults at risk for HBV

infection, especially injecting drug users; MSM; adults with

multiple sex partners; sex partners, needle-sharing contacts,

or household contacts of persons with chronic hepatitis B;

and persons with diabetes and all adults seeking protection

from HBV infection (1318). For adults, acknowledgment of

a specific risk factor is not a requirement for vaccination.

Hepatitis B vaccine should be routinely offered to all

unvaccinated persons attending STD clinics and to all

unvaccinated persons seeking evaluation or treatment for STIs

in other settings, especially correctional facilities, facilities

providing substance misuse treatment and prevention services,

Federally Qualified Health Centers, and settings serving MSM

(e.g., HIV infection care and prevention settings). If hepatitis

B vaccine is unavailable at a particular facility, persons should

be linked to a setting where they can receive vaccine. Persons

with a reliable vaccination history (i.e., a written, dated record

of each dose of a complete series) or reliable history of hepatitis

B infection (i.e., a written record of infection and serologic

results providing evidence of previous infection) do not require

vaccination. In all settings, vaccination should be initiated

at the initial visit, even if concerns about completion of the

vaccine series exist.

Prevaccination Serologic Testing

Conducting prevaccination serologic testing for susceptibility

just before the initial vaccine dose is administered can

be considered for identifying persons with chronic HBV

infection and, potentially, reducing the cost of completing the

vaccination series for adult populations that have an expected

high prevalence (20%–30%) of HBV infection (e.g., injecting

drug users and MSM, especially those among older age groups,

or persons born where HBV endemicity is moderate to

high). In addition, prevaccination testing for susceptibility is

TABLE 6. Recommended doses of licensed formulations of hepatitis B vaccines

Age group (yrs)

Single-antigen vaccine Combination vaccine

Recombivax HB Engerix-B Heplisav-B* Twinrix

†

Dose (μg)

Volume (mL) Dose (μg)

Volume (mL)

Infants (<1) 5 0.5 10 0.5 —

—

NA NA

Children (1–10) 5 0.5 10 0.5 —

—

NA NA

Adolescents (11–15) 10** 1.0 NA NA —

—

NA NA

Adolescents (11–19) 5 0.5 10 0.5 —

—

NA NA

Adults (≥18) —

††

—

††

—

††

—

††

20* 0.5 20

†

Adults (≥20) 10 1.0 20 1.0 20

†

0.5 20

†

Hemodialysis patients and other

immunocompromised persons (<20

§§

)

5 0.5 10 0.5 20 0.5 NA NA

Hemodialysis patients and other

immunocompromised persons (≥20)

¶¶

1.0 40*** 2.0 20 0.5 NA NA

Source: Adapted from Schillie S, Vellozzi C, Reingold A, et al. Prevention of hepatitis B virus infection in the United States: recommendations of the Advisory Committee

on Immunization Practices. MMWR Recomm Rep 2018;67(No. RR-1).

Abbreviation: NA = not applicable.

Administered on a 2-dose schedule.

†

Combined hepatitis A and B vaccines. This vaccine is recommended for persons aged ≥18 years who are at increased risk for both hepatitis B and hepatitis A virus

infections.

Recombinant hepatitis B surface antigen protein dose.

Heplisav-B should not be used for vaccination of infants, children, or adolescents because the safety and effectiveness of Heplisav-B has not been established in

persons aged <8 years and is not approved for use in these populations.

Adult formulation administered on a 2-dose schedule.

††

Engerix-B and Recombivax HB are approved for use in persons of all ages.

§§

Higher doses might be more immunogenic; however, no specific recommendations have been made.

¶¶

Dialysis formulation administered on a 3-dose schedule at 0, 1, and 6 months.

*** Two 1.0-mL doses administered at one site, on a 4-dose schedule at 0, 1, 2, and 6 months.

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recommended for unvaccinated household, sexual, and needle-

sharing contacts of HBsAg-positive persons (1318). Serologic

testing should not be a barrier to vaccination. The first vaccine

dose should be administered immediately after collection of the

blood sample for serologic testing. Vaccination of persons who

are immune to HBV infection because of current or previous

infection or vaccination is not harmful and does not increase

the risk for adverse events.

Prevaccination testing should be performed with HBsAg,

anti-HBs, and total anti-HBc to define patients’ HBV clinical

status and deliver recommended care (1330). Persons who

test HBsAg positive should receive prevention counseling and

evaluation for antiviral treatment (see Management of Persons

Who Are HBsAg Positive). Persons who test total anti-HBc

positive and anti-HBs positive should be counseled that they

have had previous HBV infection and are immune. Those

persons with isolated anti-HBc (i.e., negative HBsAg and

anti-HBs) need further assessment to rule out occult HBV

infection, and they are at higher risk for reactivation if exposed

to immunosuppressants. Persons who test negative to all three

HBV seromarkers should receive the complete vaccination

series, with the first vaccine dose administered immediately.

Postvaccination Serologic Testing for Response

Postvaccination serologic testing for immunity is unnecessary

after routine vaccination of adolescents or adults. However,

such testing is recommended for persons whose subsequent

clinical management depends on knowledge of their immune

status. Persons recommended to receive postvaccination

serologic testing include health care personnel and public safety

workers, persons with HIV infection, sex and needle-sharing

partners of HBsAg-positive persons, hemodialysis patients

and others who might require outpatient hemodialysis (e.g.,

predialysis, peritoneal dialysis, or home dialysis), and other

immunocompromised persons (e.g., hematopoietic stem-cell

transplant recipients or persons receiving chemotherapy) (1318).

If indicated, anti-HBs testing should be performed

1–2 months after administration of the last dose of the

vaccine series. Persons determined to have anti-HBs levels

of <10 mIU/mL after the primary vaccine series should be

revaccinated with a 3-dose series and tested again for anti-HBs

1–2 months after the third dose. Persons who do not respond to

revaccination should be tested for HBsAg and HBc. If HBsAg

positive, persons should receive recommended management

(see Management of Persons Who Are HBsAg Positive). If

HBsAg negative, persons should be considered susceptible to

HBV infection and counseled about precautions for preventing

HBV infection and the need for HBIG PEP for any known

exposure. If isolated anti-HBc positive (i.e., negative HBsAg

and anti-HBs), persons will need further assessment to rule out

occult HBV infection and are at higher risk for reactivation if

exposed to immunosuppressants.

Postexposure Prophylaxis

Both passive and active PEP (simultaneous administration of

HBIG [i.e., 0.06 mL/kg body weight] and hepatitis B vaccine

at separate anatomic sites) and active PEP (administration of

hepatitis B vaccination alone) have been demonstrated to be

highly effective in preventing transmission after exposure to

HBV (12). HBIG alone also has been demonstrated to be

effective in preventing HBV transmission; however, with the

availability of hepatitis B vaccine, HBIG typically is used as

an adjunct to vaccination.

Exposure to a Source Who Is HBsAg Positive

Unvaccinated persons or persons known not to have

responded to a complete hepatitis B vaccine series should

receive both HBIG and hepatitis vaccine as soon as possible

(preferably ≤24 hours) after a discrete, identifiable exposure

to blood or body fluids that contain blood from a person with

HBsAg (Table 7). Hepatitis B vaccine should be administered

simultaneously with HBIG at a separate anatomic site, and the

vaccine series should be completed by using the age-appropriate

vaccine dose and schedule (Table 6). Exposed persons who

are not fully vaccinated because they have not completed the

vaccine series should receive HBIG (i.e., 0.06 mL/kg body

weight) and complete the vaccine series. Persons who have

written documentation of a complete hepatitis B vaccine series

who did not receive postvaccination testing should receive a

single vaccine booster dose. Exposed persons who are known

to have responded to vaccination by postvaccination testing

are considered protected; therefore, they need no additional

doses of vaccine or HBIG. All persons with an occupational

exposure to blood or body fluids that contain HBV should be

managed according to guidelines (12).

Exposure to a Source with Unknown HBsAg Status

Unvaccinated persons and persons with previous nonresponse

to hepatitis B vaccination who have a discrete, identifiable

exposure to blood or body fluids containing blood from

a person with unknown HBsAg status should receive the

hepatitis B vaccine series, with the first dose initiated as soon

as possible after exposure (preferably <24 hours) and the series

completed according to the age-appropriate dose and schedule.

Exposed persons who are not fully vaccinated but started the

series should complete the vaccine series. Exposed persons

with written documentation of a complete hepatitis B vaccine

series who did not receive postvaccination testing require no

further treatment.

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Other Management Considerations

All persons with HBV infection should be tested for HIV,

syphilis, gonorrhea, and chlamydia.

Management of Persons Who Are HBsAg Positive

Recommendations for management of all persons with

HBsAg include the following:

• All persons with HBsAg documented on laboratory results

should be reported to the state or local health department.

• To verify the presence of chronic HBV infection, persons

with HBsAg should be retested. The absence of IgM anti-

HBc or the persistence of HBsAg for ≥6 months indicates

chronic HBV infection.

• Persons with chronic HBV infection should be referred

for evaluation to a specialist experienced in managing

chronic hepatitis B infection.

• Household, sexual, and needle-sharing contacts of persons

with chronic infection should be evaluated. Unvaccinated

sex partners and household and needle-sharing contacts

should be tested for susceptibility to HBV infection and

receive the first dose of hepatitis B vaccine immediately

after collection of the blood sample for serologic testing

(see Prevaccination Serologic Testing). Susceptible persons

should complete the vaccine series by using an age-

appropriate vaccine dose and schedule.

• Sex partners of persons with HBsAg should be counseled

to use latex condoms (1331) to protect themselves from

sexual exposure to infectious body fluids (e.g., semen and

vaginal secretions), unless they have been demonstrated

to be immune after vaccination (anti-HBs ≥10 mIU/mL)

or previously infected (anti-HBc positive).

• To prevent or reduce the risk for transmission to others in

addition to vaccination, persons with HBsAg also should

be advised to

use methods (e.g., condoms) to protect nonimmune sex

partners from acquiring HBV infection from sexual

activity until the partner can be vaccinated and

immunity documented;

cover cuts and skin lesions to prevent spread by

infectious secretions or blood;

refrain from donating blood, plasma, body organs, other

tissue, or semen; and

refrain from sharing household articles (e.g.,

toothbrushes, razors, or personal injecting equipment)

that could become contaminated with blood, and refrain

from premastication of food.

• To protect the liver from further harm, persons with

HBsAg should be advised to

TABLE 7. Guidelines for postexposure prophylaxis* of persons with nonoccupational exposure

†

to blood or body fluids that contain blood, by

exposure type and hepatitis B vaccination status

Source of exposure Unvaccinated person

Previously vaccinated person

HBsAg-positive source

Percutaneous (e.g., bite or needlestick) or mucosal

exposure to HBsAg-positive blood or body fluids

Sex or needle-sharing contact with an HBsAg-

positive person

Victim of sexual assault or abuse by an assailant

who is HBsAg positive

Administer hepatitis B vaccine series and HBIG Complete hepatitis B vaccine series and HBIG, if

vaccine series not completed

Administer hepatitis B vaccine booster dose, if

previous vaccination without testing**

Source with unknown HBsAg status

Percutaneous (e.g., bite or needlestick) or mucosal

exposure to potentially infectious blood or body

fluids from a source with unknown HBsAg status

Sex or needle-sharing contact with person with

unknown HBsAg status

Victim of sexual assault or abuse by a perpetrator

with unknown HBsAg status

Administer hepatitis B vaccine series Complete hepatitis B vaccine series

Sources: CDC. CDC guidance for evaluating health-care personnel for hepatitis B virus protection and for administering postexposure management. MMWR Recomm

Rep 2013;62(No. RR-10); CDC. Postexposure prophylaxis to prevent hepatitis B virus infection. MMWR Recomm Rep 2006;55(No. RR-16).

Abbreviations: HBIG = hepatitis B immune globulin; HBsAg = hepatitis B surface antigen.

* When indicated, immunoprophylaxis should be initiated as soon as possible, preferably within 24 hours. Studies are limited regarding the maximum interval after

exposure during which postexposure prophylaxis is effective, but the interval is unlikely to exceed 7 days for percutaneous exposures or 14 days for sexual exposures.

The hepatitis B vaccine series should be completed. These guidelines apply to nonoccupational exposures.

†

These guidelines apply to nonoccupational exposures.

A person who is in the process of being vaccinated but who has not completed the vaccine series should complete the series and receive treatment for hepatitis

B as indicated.

A person who has written documentation of a complete hepatitis B vaccine series and who did not receive postvaccination testing.

** No booster dose is needed for persons who have written documentation of hepatitis B vaccine series with serologic response.

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avoid or limit alcohol consumption because of the effects

of alcohol on the liver;

refrain from starting any new medicines, including over-

the-counter and herbal medicines, without checking

with their health care provider; and

obtain vaccination against hepatitis A.

When seeking medical or dental care, persons who are

HBsAg positive should be advised to inform their health care

providers of their HBsAg status so that they can be evaluated

and managed. The following are key counseling messages for

persons with HBsAg:

• HBV is not usually spread by hugging, coughing, food or water,

sharing eating utensils or drinking glasses, or casual contact.

• Persons should not be excluded from work, school, play,

childcare, or other settings because they are infected with HBV.

• Involvement with a support group might help patients

cope with chronic HBV infection.

• HBV infection is a chronic condition that can be treated,

and patients should receive prevention counseling and be

evaluated for antiviral treatment.

Special Considerations

Pregnancy

Regardless of whether they have been previously tested or

vaccinated, all pregnant women should be tested for HBsAg

at the first prenatal visit and again at delivery if at high

risk for HBV infection (see STI Detection Among Special

Populations). Pregnant women at risk for HBV infection and

without documentation of a complete hepatitis B vaccine series

should receive hepatitis B vaccination. All pregnant women

with HBsAg should be reported to state and local perinatal

hepatitis B prevention programs and referred to a specialist.

Information about management of pregnant women with

HBsAg and their infants is available at https://www.cdc.gov/

hepatitis/hbv/perinatalxmtn.htm.

HIV Infection

HIV infection can impair the response to hepatitis B

vaccination. Persons with HIV should be tested for anti-HBs

1–2 months after the third vaccine dose (see Postvaccination

Serologic Testing). Modified dosing regimens, including a

doubling of the standard antigen dose and administration of

additional doses, might increase the response rate and should be

managed in consultation with an infectious disease specialist.

Additional recommendations for management of persons with

HBsAg and HIV infection are available (98).

Hepatitis C Virus Infection

HCV infection is the most common chronic bloodborne

infection in the United States, with an estimated 2.4 million

persons living with chronic infection (1332). HCV is not

efficiently transmitted through sex (1333–1335). Studies of

HCV transmission between heterosexual couples and MSM

have yielded mixed results; however, studies have reported

either no or minimally increased rates of HCV infection

among partners of persons with HCV infection compared

with partners of those without HCV (1334,1336–1338).

However, data indicate that sexual transmission of HCV

can occur, especially among persons with HIV infection.

Increasing incidence of acute HCV infection among MSM

with HIV infection has been reported in multiple U.S.

(96,236,239,1339) and European cities (237,1340–1342). A

recent systematic review reported an HCV incidence of 6.35

per 1,000 person years among MSM with HIV infection

(1343). An association exists with high-risk and traumatic

sexual practices (e.g., condomless receptive anal intercourse

or receptive fisting) and concurrent genital ulcerative disease

or STI-related proctitis (237,1342). HCV transmission among

MSM with HIV infection has also been associated with group

sex and chemsex (i.e., using recreational drugs in a sexual

context) (1344–1348). Shedding of HCV in the semen and in

the rectum of men with HIV infection has been documented

(1349,1350). Certain studies have revealed that risk increases

commensurate with increasing numbers of sex partners among

heterosexual persons (1337,1338,1351–1353) and MSM with

HIV infection (1349,1354–1357), especially if their partners are

also coinfected with HIV (237,1340,1354–1356,1358). More

recently, acute HCV infections have been reported among MSM

on PrEP, increasing concerns that certain MSM might be at

increased risk for incident HCV infection through condomless

sexual intercourse with MSM with HCV infection (1359,1360).

Persons newly infected with HCV typically are either

asymptomatic or have a mild clinical illness. HCV RNA can

be detected in blood within 1–3 weeks after exposure. The

average time from exposure to antibody to HCV (anti-HCV)

seroconversion is 4−10 weeks, and anti-HCV can be detected

among approximately 97% of persons by 6 months after

exposure (1361–1364) (https://www.cdc.gov/hepatitis/hcv/

hcvfaq.htm#section3).

Chronic HCV infection develops among 75%–85% of

persons with HCV infection (1365,1366), and 10%–20% of

persons with chronic infection develop cirrhosis in 20–30 years

of active liver disease (1367). The majority of infected persons

remain unaware of their infection because they are not clinically

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ill. However, infected persons are a source of transmission to

others and are at risk for cirrhosis and hepatocellular carcinoma

decades after infection.

HCV is primarily transmitted parenterally, usually through

shared drug-injecting needles and paraphernalia. HCV also

can be transmitted through exposures in health care settings

as a consequence of inadequate infection control practices

(1314). Transmission after receipt of blood from donors and

from transplantation of tissues and organs with HCV infection

has occurred only rarely since 1992, when routine screening

of these donated products was mandated in the United

States (1367,1369). Tattoos applied in regulated settings

have not been associated with HCV transmission, although

those obtained in certain settings have been linked to such

transmission (1336). Occupational and perinatal exposures also

can result in transmission of HCV; however, such transmission

is uncommon.

Acute HCV infection is a reportable condition in 49 states.

Matching viral hepatitis and HIV surveillance registries, and

molecular epidemiologic assessments, can facilitate early

detection of social networks of HCV transmission among

MSM with HIV infection.

CDC recommends hepatitis C screening at least once in a

lifetime for all adults aged ≥18 years and for all women during

each pregnancy, except in settings where the prevalence of

HCV infection is <0.1% (156). One-time hepatitis C testing

is also recommended regardless of age, setting, or recognized

conditions or exposures (e.g., HIV infection, history of

injecting drug use, or children born to women with HCV

infection). Routine periodic HCV testing is recommended

for persons with ongoing risk factors (e.g., injecting drug use

or hemodialysis).

Diagnosis

Testing for HCV infection should include use of an FDA-

cleared test for antibody to HCV (i.e., immunoassay, EIA, or

enhanced CIA and, if recommended, a supplemental antibody

test) followed by NAAT to detect HCV RNA for those with a

positive antibody result (1370). Persons with HIV infection with

low CD4

T-cell count might require further testing by NAAT

because of the potential for a false-negative antibody assay.

Persons determined to have HCV infection (i.e., positive

for HCV RNA) should be evaluated for treatment. Antibody

to HCV remains positive after spontaneously resolving or

successful treatment; therefore, subsequent testing for HCV

reinfection among persons with ongoing risk factors should

be limited to HCV RNA. Persons who have spontaneous

resolution or who have undergone successful treatment are

not immune to reinfection.

Treatment

HCV infection is curable, and persons with diagnosed HCV

infection should be linked to care and treatment. Providers

should consult existing guidelines to learn about the latest

advances in treating HCV infection (https://www.hcvguidelines.

org) and with hepatitis specialists, as needed. Persons at high

risk for transmitting HCV to others should be treated both for

individual benefit and to prevent HCV transmission.

Management of Sex Partners

Because incident HCV has not been demonstrated to

occur among heterosexual couples followed over time

(1334,1371–1373), condom use might not be necessary in

such circumstances. Persons with HCV infection with one

long-term, steady sex partner do not need to change their

sexual practices. However, they should discuss the risk for

transmission with their partner and discuss the need for

testing (234) (https://www.cdc.gov/hepatitis/hcv/index.htm).

Heterosexual persons and MSM with HCV infection and

more than one partner, especially those with concurrent HIV

infection, should protect their partners against HCV and HIV

acquisition by using external latex condoms (237,1358,1374)

and HIV PrEP. Partners of persons with HCV and HIV should

be tested for both infections.

Other Management Considerations

All persons with HCV infection for whom HIV and

HBV infection status is unknown should be tested for these

infections. Those who have HIV or HBV infection should be

referred for or provided with recommended care and treatment.

Persons without previous exposure to HAV or HBV should

be vaccinated.

Prevention

Reducing the burden of HCV infection and disease in

the United States requires implementing both primary and

secondary prevention activities. Primary prevention reduces or

eliminates HCV transmission, whereas secondary prevention

identifies persons through screening and then provides

treatment to reduce chronic liver disease and other chronic

diseases and HCV transmission. No vaccine for hepatitis

C is available, and prophylaxis with IG is not effective in

preventing HCV infection after exposure. PEP using direct-

acting antivirals is not recommended.

Persons with HCV infection should be provided information

about how to protect their liver from further harm (i.e.,

hepatotoxic agents); for instance, persons with HCV infection

should be advised to avoid drinking alcohol and taking any new

medicines, including over-the-counter or herbal medications,

without checking with their clinician. In addition, a need for

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hepatitis A and B vaccination should be determined; persons

who are not immune should be vaccinated.

To reduce the risk for transmission to others, persons with HCV

infection should be advised not to donate blood, body organs,

other tissue, or semen; not to share any personal items that might

have blood on them (e.g., toothbrushes or razors); and to cover

cuts and sores on the skin to keep the virus from spreading by

blood or secretions. Women with HCV infection do not need

to avoid pregnancy or breastfeeding, although children born to

women with HCV also should be tested for HCV.

Persons who use or inject drugs should be counseled about

the importance of prevention and provided access to substance

misuse treatment, including medication-assisted treatment,

if indicated. Persons who inject drugs should be encouraged

to take the following additional steps to reduce personal and

public health risks:

• Never reuse or share syringes, water, or drug preparation

equipment.

• Only use syringes obtained from a reliable source (e.g., a

syringe services program or a pharmacy).

• Use a new, sterile syringe to prepare and inject drugs each time.

• If possible, use sterile water to prepare drugs; otherwise,

use clean water from a reliable source (e.g., fresh tap water).

• Use a new or disinfected container (i.e., cooker) and a new

filter (i.e., cotton) to prepare drugs.

• Clean the injection site with a new alcohol swab before

injection.

• Safely dispose of syringes after one use.

Postexposure Follow-Up

No PEP has been demonstrated to be effective against HCV

infection. Testing for HCV is recommended for health care

workers after percutaneous or perimucosal exposures to HCV-

positive blood. Prompt identification of acute infection is vital

because outcomes are improved when treatment is initiated

early during the illness course.

Special Considerations

Pregnancy

All pregnant women should be screened with each pregnancy

for HCV antibodies at the first prenatal visit in settings

where the HCV prevalence is >0.1% (https://www.cdc.gov/

hepatitis/hcv/index.htm) (154,155). Although the rate of

transmission is highly variable, more than six of every 100

infants born to women with HCV infection become infected;

this infection occurs predominantly during or near delivery,

and no treatment or delivery method (e.g., cesarean delivery)

has been demonstrated to decrease this risk (1375). However,

the risk is increased by the presence of maternal HCV viremia

at delivery and is twofold to threefold greater if the woman has

HIV infection. Although no recommendations are available

for HCV treatment during pregnancy, discussion about the

individual risks and benefits of postpartum treatment can be

considered in accordance with existing guidance (https://www.

hcvguidelines.org/unique-populations/pregnancy).

HCV has not been reported to be transmitted through breast

milk, although mothers with HCV infection should consider

abstaining from breastfeeding if their nipples are cracked or

bleeding. Infants born to mothers with HCV infection should

be tested for HCV infection; children should be tested for

anti-HCV no sooner than age 18 months because anti-HCV

from the mother might last until that age. If diagnosis is desired

before the child reaches age 18 months, testing for HCV

RNA can be performed at or after the infant’s first well-child

visit at age 1–2 months. HCV RNA testing can be repeated

at a subsequent visit, independent of the initial HCV RNA

test result (1376) (https://www.cdc.gov/hepatitis/hcv/hcvfaq.

htm#section3).

HIV Infection

All persons with HIV infection should undergo serologic

screening for HCV at initial evaluation (98) (https://www.

hcvguidelines.org). Providers should be aware of the likelihood

that MSM with HIV infection can acquire HCV after initial

screening. Because acute HCV infection acquisition among

persons with HIV infection can occur, especially among

MSM, and regular screening of those with HIV is cost-

effective (238,239,1377), periodic HCV screening should be

conducted (1378–1380). For persons with HIV infection,

hepatitis C screening with HCV antibody assays (followed

by HCV RNA if antibody positive) can be considered at least

yearly, for those at high risk for infection, and more frequently

depending on specific circumstances (e.g., community HCV

infection prevalence and incidence, high-risk sexual behavior,

and concomitant ulcerative STIs and proctitis). Antibody to

HCV remains positive after spontaneously resolved infection

or successful treatment; therefore, subsequent testing for

potential HCV reinfection among persons with ongoing risk

should be limited to HCV RNA testing only. Indirect testing

(e.g., alanine aminotransferase [ALT]) is not recommended

for detecting incident HCV infections because such testing,

especially if performed once a year, can miss persons who have

reverted after acute HCV infection to a normal ALT level at

the time of testing (239) (https://www.hcvguidelines.org).

Conversely, ALT can be elevated by antiretroviral and other

medications, alcohol, and toxins. If ALT levels are being

monitored, persons with HIV infection who experience new

or unexplained increases in ALT should be tested for acute

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HCV infection and evaluated for possible medication toxicity

or excessive alcohol use.

Continued unprotected sexual contact between partners

with HIV can facilitate spread of HCV infection because

the virus can be recovered from the semen of men with HIV

infection (1349,1381). Specific prevention practices (e.g.,

barrier precautions that limit contact with body fluids during

sexual contact with other MSM) should be discussed.

Because a minimal percentage of persons with HIV infection

do not develop HCV antibodies, HCV RNA testing should

be performed for persons with HIV infection and unexplained

liver disease who are anti-HCV negative. The course of liver

disease is more rapid among persons with HIV and HCV, and

the risk for cirrhosis is higher than that for persons with HCV

infection alone.

Proctitis, Proctocolitis, and Enteritis

Sexually transmitted gastrointestinal syndromes include

proctitis, proctocolitis, and enteritis. Evaluation for these

syndromes should include recommended diagnostic

procedures, including anoscopy or sigmoidoscopy, stool

examination for WBCs, and microbiologic workup (e.g.,

gonorrhea, chlamydia [LGV PCR if available], herpes simplex

NAAT, and syphilis serology). For those with enteritis, stool

culture or LGV PCR also is recommended.

Proctitis is inflammation of the rectum (i.e., the distal

10–12 cm) that can be associated with anorectal pain,

tenesmus, or rectal discharge. Fecal leukocytes are common.

Proctitis occurs predominantly among persons who have

receptive anal exposures (oral-anal, digital-anal, or genital-

anal). N. gonorrhoeae, C. trachomatis (including LGV serovars),

HSV, and T. pallidum are the most common STI pathogens.

Genital HSV and LGV proctitis are more prevalent among

persons with HIV infection (545,556,1382). M. genitalium

has been detected in certain cases of proctitis and might be

more common among persons with HIV infection (937,1382).

N. meningitidis has been identified as an etiology of proctitis

among MSM with HIV infection (1383).

Proctocolitis is associated with symptoms of proctitis,

diarrhea or abdominal cramps, and inflammation of the colonic

mucosa extending to 12 cm above the anus. Fecal leukocytes

might be detected on stool examination, depending on the

pathogen. Proctocolitis can be acquired through receptive anal

intercourse or by oral-anal contact, depending on the pathogen.

Pathogenic organisms include Campylobacter species,

Shigella species, E. histolytica, LGV serovars of C. trachomatis,

and T. pallidum. Among immunosuppressed persons with

HIV infection, CMV or other opportunistic agents should

be considered. The clinical presentation can be mistaken for

inflammatory bowel disease or malignancy, resulting in a

delayed diagnosis (1384,1385).

Enteritis usually results in diarrhea and abdominal cramping

without signs of proctitis or proctocolitis. Fecal leukocytes

might be detected on stool examination, depending on the

pathogen. When outbreaks of gastrointestinal illness occur

among social or sexual networks of MSM, clinicians should

consider sexual transmission as a mode of spread and provide

counseling accordingly. Sexual practices that can facilitate

transmission of enteric pathogens include oral-anal contact or,

in certain instances, direct genital-anal contact. G. lamblia is the

most frequently implicated parasite, and bacterial pathogens

include Shigella species, Salmonella, E. coli, Campylobacter

species, and Cryptosporidium. Outbreaks of Shigella species,

Campylobacter, Cryptosporidium, and microsporidiosis have

been reported among MSM (259,274,1386,1387). Multiple

enteric pathogens and concurrent STIs have also been reported.

Among immunosuppressed persons with HIV infection, CMV

or other opportunistic pathogens should be considered.

Diagnostic and Treatment Considerations

for Acute Proctitis

Diagnosis

Persons with symptoms of acute proctitis should be examined

by anoscopy. A Gram-stained smear of any anorectal exudate

from anoscopic or anal examination should be examined for

polymorphonuclear leukocytes. All persons should be evaluated

for herpes simplex (preferably by NAAT of rectal lesions),

N. gonorrhoeae (NAAT or culture), C. trachomatis (NAAT),

and T. pallidum (darkfield of lesion if available and serologic

testing). If the C. trachomatis NAAT test is positive on a rectal

swab and severe symptoms associated with LGV are present

(including rectal ulcers, anal discharge, bleeding, ≥10 WBCs

on Gram stain, and tenesmus), patients should be treated

empirically for LGV. Molecular testing for LGV is not widely

available or not FDA cleared, and results are not typically

available in time for clinical decision-making. However, if

available, molecular PCR testing for C. trachomatis serovars

L1, L2, or L3 can be considered for confirming LGV (553).

The pathogenic role of M. genitalium in proctitis is unclear.

For persons with persistent symptoms after standard treatment,

providers should consider testing for M. genitalium with NAAT

and treat if positive (see Mycoplasma genitalium).

Treatment

Acute proctitis among persons who have anal exposure

through oral, genital, or digital contact is usually sexually

acquired (1382,1388). Presumptive therapy should be

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initiated while awaiting results of laboratory tests for

persons with anorectal exudate detected on examination or

polymorphonuclear leukocytes detected on a Gram-stained

smear of anorectal exudate or secretions. Such therapy also

should be initiated when anoscopy or Gram stain is not

available and the clinical presentation is consistent with acute

proctitis for persons reporting receptive anal exposures.

Recommended Regimen for Acute Proctitis

Ceftriaxone 500 mg* IM in a single dose

plus

Doxycycline 100 mg orally 2 times/day for 7 days

†

* For persons weighing ≥150 kg, 1 g of ceftriaxone should be administered.

†

Doxycycline course should be extended to 100 mg orally 2 times/day for

21 days in the presence of bloody discharge, perianal or mucosal ulcers,

or tenesmus and a positive rectal chlamydia test.

Bloody discharge, perianal ulcers, or mucosal ulcers among

persons with acute proctitis and rectal chlamydia (NAAT)

should receive presumptive treatment for LGV with an

extended course of doxycycline 100 mg orally 2 times/day for

3 weeks (1389,1390) (see Lymphogranuloma Venereum). If

painful perianal ulcers are present or mucosal ulcers are

detected on anoscopy, presumptive therapy should also include

a regimen for genital herpes (see Genital Herpes).

Diagnostic and Treatment Considerations

for Proctocolitis or Enteritis

Treatment for proctocolitis or enteritis should be directed

to the specific enteric pathogen identified. Multiple stool

examinations might be necessary for detecting Giardia,

and special stool preparations are required for diagnosing

cryptosporidiosis and microsporidiosis. Diagnostic and

treatment recommendations for all enteric infections are beyond

the scope of these guidelines. Providers should be aware of the

potential for antimicrobial-resistant pathogens, particularly

during outbreaks of Shigella and Campylobacter among sexual

networks of MSM where increased resistance to azithromycin,

fluoroquinolones, and isolates resistant to multiple antibiotics

have been described (266,272,273,1391,1392).

Other Management Considerations

To minimize transmission and reinfection, patients treated

for acute proctitis should be instructed to abstain from sexual

intercourse until they and their partners have been treated

(i.e., until completion of a 7-day regimen and symptoms

have resolved). Studies have reported that behaviors that

facilitate enteric pathogen transmission might be associated

with acquisition of other STIs, including HIV infection.

All persons with acute proctitis and concern for sexually

transmitted proctocolitis or enteritis should be tested for HIV,

syphilis, gonorrhea, and chlamydia (at other exposed sites).

PEP should be considered for exposures that present a risk for

HIV acquisition. For ongoing risk for HIV acquisition, PrEP

should be considered.

Evidence-based interventions for preventing acquisition

of sexually transmitted enteric pathogens are not available.

However, extrapolating from general infection control practices

for communicable diseases and established STI prevention

practices, recommendations include avoiding contact with

feces during sex, using barriers, and washing hands after

handing materials that have been in contact with the anal

area (i.e., barriers and sex toys) and after touching the anus

or rectal area.

Follow-Up

Follow-up should be based on specific etiology and severity

of clinical symptoms. For proctitis associated with gonorrhea

or chlamydia, retesting for the respective pathogen should be

performed 3 months after treatment.

Management of Sex Partners

Partners who have had sexual contact with persons treated

for gonorrhea or chlamydia <60 days before the onset of

the persons symptoms should be evaluated, tested, and

presumptively treated for the respective infection. Partners

of persons with proctitis should be evaluated for any diseases

diagnosed in the index partner. Sex partners should abstain

from sexual contact until they and their partners are treated.

No specific recommendations are available for screening

or treating sex partners of persons with diagnosed sexually

transmitted enteric pathogens; however, partners should seek

care if symptomatic.

Special Considerations

Drug Allergy, Intolerance, and Adverse Reactions

Allergic reactions with third-generation cephalosporins (e.g.,

ceftriaxone) are uncommon among persons with a history of

penicillin allergy (620,631,658,896).

HIV Infection

Persons with HIV infection and acute proctitis might present

with bloody discharge, painful perianal ulcers, or mucosal

ulcers and LGV and herpes proctitis are more prevalent among

this population. Presumptive treatment in such cases should

include a regimen for genital herpes and LGV.

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Ectoparasitic Infections

Pediculosis Pubis

Persons who have pediculosis pubis (i.e., pubic lice) usually

seek medical attention because of pruritus or because they

notice lice or nits on their pubic hair. Pediculosis pubis is

caused by the parasite Phthirus pubis and is usually transmitted

by sexual contact (1393).

Diagnosis

The clinical diagnosis is based on typical symptoms of itching

in the pubic region. Lice and nits can be observed on pubic hair.

Treatment

Recommended Regimens for Pediculosis Pubis

Permethrin 1% cream rinse applied to affected areas and washed off

after 10 minutes

Pyrethrin with piperonyl butoxide applied to the affected area and

washed off after 10 minutes

Alternative Regimens

Malathion 0.5% lotion applied to affected areas and washed off after

8–12 hours

Ivermectin 250 µg/kg body weight orally, repeated in 7–14 days

Reported resistance to pediculcides (permethrin and

pyrethrin) has been increasing and is widespread (1394,1395).

Malathion can be used when treatment failure is believed to

have occurred as a result of resistance. The odor and longer

duration of application associated with malathion therapy

make it a less attractive alternative compared with the

recommended pediculicides. Ivermectin has limited ovicidal

activity (1396). Ivermectin might not prevent recurrences

from eggs at the time of treatment, and therefore treatment

should be repeated in 7–14 days (1397,1398). Ivermectin

should be taken with food because bioavailability is increased,

thus increasing penetration of the drug into the epidermis.

Adjustment of ivermectin dosage is not required for persons

with renal impairment; however, the safety of multiple doses

among persons with severe liver disease is unknown. Lindane

is not recommended for treatment of pediculosis because of

toxicity, contraindications for certain populations (pregnant

and breastfeeding women, children aged <10 years, and those

with extensive dermatitis), and complexity of administration.

Other Management Considerations

The recommended regimens should not be applied to the

eyes. Pediculosis of the eyelashes should be treated by applying

occlusive ophthalmic ointment or petroleum jelly to the eyelid

margins 2 times/day for 10 days. Bedding and clothing should

be decontaminated (i.e., machine washed and dried by using

the heat cycle or dry cleaned) or removed from body contact

for at least 72 hours. Fumigation of living areas is unnecessary.

Pubic hair removal has been associated with atypical patterns

of pubic lice infestation and decreasing incidence of infection

(537,1399). Persons with pediculosis pubis should be evaluated

for HIV, syphilis, chlamydia, and gonorrhea.

Follow-Up

Evaluation should be performed after 1 week if symptoms

persist. Retreatment might be necessary if lice are found or

if eggs are observed at the hair-skin junction. If no clinical

response is achieved to one of the recommended regimens,

retreatment with an alternative regimen is recommended.

Management of Sex Partners

Sex partners within the previous month should be treated.

Sexual contact should be avoided until patients and partners

have been treated, bedding and clothing decontaminated, and

reevaluation performed to rule out persistent infection.

Special Considerations

Pregnancy

Existing data from human participants demonstrate that

pregnant and lactating women should be treated with either

permethrin or pyrethrin with piperonyl butoxide. Because no

teratogenicity or toxicity attributable to ivermectin has been

observed during human pregnancy experience, ivermectin is

classified as “human data suggest low risk” during pregnancy

and probably compatible with breastfeeding (431).

HIV Infection

Persons who have pediculosis pubis and HIV infection

should receive the same treatment regimen as those who do

not have HIV.

Scabies

Scabies is a skin infestation caused by the mite Sarcoptes

scabiei, which causes pruritus. Sensitization to S. scabiei occurs

before pruritus begins. The first time a person is infested with

S. scabiei, sensitization takes weeks to develop. However,

pruritus might occur <24 hours after a subsequent reinfestation.

Scabies among adults frequently is sexually acquired, although

scabies among children usually is not (1400–1402).

Diagnosis

Scabies diagnosis is made by identifying burrows, mites, eggs,

or the mites’ feces from affected areas. Skin scrapings can be

examined under the microscope to identify organisms, although

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this method has low sensitivity and is time consuming (1403).

Alternatively, noninvasive examination of the affected skin by

using videodermatoscopy, videomicroscopy, or dermoscopy

can be used, each of which has high sensitivity and specificity,

particularly when performed by experienced operators (1404).

Low-technology strategies include the burrow ink test and the

adhesive tape test.

Treatment

Recommended Regimens for Scabies

Permethrin 5% cream applied to all areas of the body from the neck

down and washed off after 8–14 hours

Ivermectin 200 ug/kg body weight orally, repeated in 14 days*

Ivermectin 1% lotion applied to all areas of the body from the neck

down and washed off after 8–14 hours; repeat treatment in 1 week if

symptoms persist

* Oral ivermectin has limited ovicidal activity; a second dose is required

for eradication.

Alternative Regimen

Lindane 1% 1 oz of lotion or 30 g of cream applied in a thin layer to all

areas of the body from the neck down and thoroughly washed off after

8 hours*

Infants and children aged <10 years should not be treated with lindane.

Topical permethrin and oral and topical ivermectin have

similar efficacy for cure of scabies (1405–1410). Choice of

treatment might be based on patient preference for topical

versus oral therapy, drug interactions with ivermectin (e.g.,

azithromycin, trimethoprim/sulfamethoxazole [Bactrim], or

cetirizine [Zytrec]), and cost. Permethrin is safe and effective

with a single application (1411). Ivermectin has limited ovicidal

activity and might not prevent recurrences of eggs at the time

of treatment; therefore, a second dose of ivermectin should be

administered 14 days after the first dose (1412). Ivermectin

should be taken with food because bioavailability is increased,

thereby increasing penetration of the drug into the epidermis.

Adjustments to ivermectin dosing are not required for patients

with renal impairment; however, the safety of multiple doses

among patients with severe liver disease is unknown.

Lindane is an alternative regimen because it can cause toxicity

(1413); it should be used only if the patient cannot tolerate

the recommended therapies or if these therapies have failed

(1414–1416). Lindane is not recommended for pregnant and

breastfeeding women, children aged <10 years, and persons

with extensive dermatitis. Seizures have occurred when lindane

was applied after a bath or used by patients who had extensive

dermatitis. Aplastic anemia after lindane use also has been

reported (1413). Lindane resistance has been reported in some

areas of the world, including parts of the United States (1413).

Other Management Considerations

Bedding and clothing should be decontaminated (i.e.,

either machine washed and dried by using the heat cycle or

dry cleaned) or removed from body contact for >72 hours.

Fumigation of living areas is unnecessary. Persons with scabies

should be advised to keep fingernails closely trimmed to reduce

injury from excessive scratching (1417).

Crusted Scabies

Crusted scabies is an aggressive infestation that usually

occurs among immunodeficient, debilitated, or malnourished

persons, including persons receiving systemic or potent topical

glucocorticoids, organ transplant recipients, persons with HIV

infection or human T-lymphotrophic virus-1 infection, and

persons with hematologic malignancies. Crusted scabies is

transmitted more easily than scabies (1418). No controlled

therapeutic studies for crusted scabies have been conducted,

and a recommended treatment remains unclear. Substantial

treatment failure might occur with a single-dose topical

scabicide or with oral ivermectin treatment. Combination

treatment is recommended with a topical scabicide, either 5%

topical permethrin cream (full-body application to be repeated

daily for 7 days then 2 times/week until cure) or 25% topical

benzyl benzoate, and oral ivermectin 200 ug/kg body weight on

days 1, 2, 8, 9, and 15. Additional ivermectin treatment on days

22 and 29 might be required for severe cases (1419). Lindane

should be avoided because of the risks for neurotoxicity with

heavy applications on denuded skin.

Follow-Up

The rash and pruritus of scabies might persist for <2 weeks

after treatment. Symptoms or signs persisting for >2 weeks

can be attributed to multiple factors. Treatment failure

can occur as a result of resistance to medication or faulty

application of topical scabicides. These medications do not

easily penetrate into thick, scaly skin of persons with crusted

scabies, perpetuating the harboring of mites in these difficult-

to-penetrate layers. In the absence of recommended contact

treatment and decontamination of bedding and clothing,

persisting symptoms can be attributed to reinfection by family

members or fomites. Finally, other household mites can cause

symptoms to persist as a result of cross-reactivity between

antigens. Even when treatment is successful, reinfection is

avoided, and cross-reactivity does not occur, symptoms can

persist or worsen as a result of allergic dermatitis.

Retreatment 2 weeks after the initial treatment regimen can

be considered for those persons who are still symptomatic or

when live mites are observed. Use of an alternative regimen is

recommended for those persons who do not respond initially

to the recommended treatment.

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Management of Sex Partners and

Household Contacts

Persons who have had sexual, close personal, or household

contact with the patient within the month preceding scabies

infestation should be examined. Those identified as being

infested should be provided treatment.

Management of Outbreaks in Communities,

Nursing Homes, and Other Institutional Settings

Scabies epidemics frequently occur in nursing homes,

hospitals, residential facilities, and other communities

(1420,1421). Control of an epidemic can only be achieved

by treating the entire population at risk. Ivermectin can be

considered in these settings, especially if treatment with topical

scabicides fails. Mass treatment with oral ivermectin is highly

effective in decreasing prevalence in settings where scabies is

endemic (1422). Epidemics should be managed in consultation

with a specialist.

Special Considerations

Infants, Young Children, and Pregnant or

Lactating Women

Infants and young children should be treated with

permethrin; the safety of ivermectin for children weighing

<15 kg has not been determined. Infants and children aged

<10 years should not be treated with lindane. Ivermectin likely

poses a low risk to pregnant women and is likely compatible

with breastfeeding; however, because of limited data regarding

ivermectin use for pregnant and lactating women, permethrin

is the preferred treatment (431) (see Pediculosis Pubis).

HIV Infection

Persons with HIV infection who have uncomplicated scabies

should receive the same treatment regimens as those who do

not have HIV. Persons with HIV infection and others who are

immunosuppressed are at increased risk for crusted scabies and

should be managed in consultation with a specialist.

Sexual Assault and Abuse and STIs

Adolescents and Adults

These guidelines are primarily limited to the identification,

prophylaxis, and treatment of STIs and conditions among

adolescent and adult female sexual assault survivors. However,

some of the following guidelines might still apply to male

sexual assault survivors. Documentation of findings, collection

of nonmicrobiologic specimens for forensic purposes,

and management of potential pregnancy or physical and

psychological trauma are beyond the scope of these guidelines.

Examinations of survivors of sexual assault should be

conducted by an experienced clinician in a way that minimizes

further trauma to the person. The decision to obtain genital

or other specimens for STI diagnosis should be made on an

individual basis. Care systems for survivors should be designed

to ensure continuity, including timely review of test results,

support adherence, and monitoring for adverse reactions to

any prescribed therapeutic or prophylactic regimens. Laws in

all 50 states limit the evidentiary use of a survivor’s previous

sexual history, including evidence of previously acquired STIs,

as part of an effort to undermine the credibility of the survivor’s

testimony. Evidentiary privilege against revealing any aspect of

the examination or treatment also is enforced in most states.

Although it rarely occurs, STI diagnoses might later be accessed,

and the survivor and clinician might opt to defer testing for this

reason. Although collection of specimens at initial examination

for laboratory STI diagnosis gives the survivor and clinician

the option of deferring empiric prophylactic antimicrobial

treatment, compliance with follow-up visits is typically poor

(1423–1425). Among sexually active adults, identification

of an STI might represent an infection acquired before the

assault, and therefore might be more important for the medical

management of the patient than for legal purposes.

Trichomoniasis, BV, gonorrhea, and chlamydia are the

most frequently diagnosed infections among women who

have been sexually assaulted. Such conditions are prevalent

among the population, and detection of these infections

after an assault does not necessarily imply acquisition during

the assault. However, a postassault examination presents an

important opportunity for identifying or preventing an STI.

Chlamydial and gonococcal infections among women are

of particular concern because of the possibility of ascending

infection. In addition, HBV infection can be prevented

through postexposure vaccination (see Hepatitis B Virus

Infection). Because persons who have been sexually assaulted

also are at risk for acquiring HPV infection, and the efficacy

of the HPV vaccine is high (1426,1427), HPV vaccination is

also recommended for females and males through age 26 years

(https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/

hpv.html) (11). Reproductive-aged female survivors should be

evaluated for pregnancy and offered emergency contraception.

Evaluating Adolescents and Adults for STIs

Initial Examination

Decisions to perform the following tests should be made on

an individual basis. An initial examination after a sexual assault

might include the following:

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• NAATs for C. trachomatis and N. gonorrhoeae at the sites

of penetration or attempted penetration should be

performed (553). These tests are preferred for diagnostic

evaluation of adolescent or adult sexual assault survivors.

• Females should be offered NAAT testing for T. vaginalis

from a urine or vaginal specimen. POC or wet mount with

measurement of vaginal pH and KOH application for the

whiff test from vaginal secretions should be performed for

evidence of BV and candidiasis, especially if vaginal

discharge, malodor, or itching is present.

• MSM should be offered screening for C. trachomatis and

N. gonorrhoeae if they report receptive oral or anal sex

during the preceding year, regardless of whether sexual

contact occurred at these anatomic sites during the assault.

Anoscopy should be considered in instances of reported

anal penetration.

• A serum sample should be performed for HIV, HBV, and

syphilis infection.

Treatment

Compliance with follow-up visits is poor among survivors

of sexual assault (1423–1425). Consequently, the following

routine presumptive treatments after a sexual assault are

recommended:

• An empiric antimicrobial regimen for chlamydia,

gonorrhea, and trichomonas for women and chlamydia

and gonorrhea for men.

• Emergency contraception should be considered when the

assault could result in pregnancy (see Emergency

Contraception).

• Postexposure hepatitis B vaccination (without HBIG) if

the hepatitis status of the assailant is unknown and the

survivor has not been previously vaccinated. If the assailant

is known to be HBsAg positive, unvaccinated survivors

should receive both hepatitis B vaccine and HBIG. The

vaccine and HBIG, if indicated, should be administered

to sexual assault survivors at the time of the initial

examination, and follow-up doses of vaccine should be

administered 1–2 and 4–6 months after the first dose.

Survivors who were previously vaccinated but did not

receive postvaccination testing should receive a single

vaccine booster dose (see Hepatitis B Virus Infection).

• HPV vaccination for female and male survivors aged

9–26 years who have not been vaccinated or are

incompletely vaccinated (11) (https://www.cdc.gov/

vaccines/hcp/acip-recs/vacc-specific/hpv.html). The

vaccine should be administered to sexual assault survivors

at the time of the initial examination, and follow-up doses

should be administered at 1–2 months and 6 months after

the first dose. A 2-dose schedule (0 and 6–12 months) is

recommended for persons initiating vaccination before

age 15 years.

• Recommendations for HIV PEP are made on a case-by-

case basis according to risk (see Risk for Acquiring HIV

Infection; Recommendations for Postexposure HIV Risk

Assessment of Adolescents and Adults <72 Hours After

Sexual Assault).

Recommended Regimen for Adolescent and Adult Female

Sexual Assault Survivors

Ceftriaxone 500 mg* IM in a single dose

plus

Doxycycline 100 mg 2 times/day orally for 7 days

plus

Metronidazole 500 mg 2 times/day orally for 7 days

* For persons weighing ≥150 kg, 1 g of ceftriaxone should be administered.

Recommended Regimen for Adolescent and Adult Male Sexual

Assault Survivors

Ceftriaxone 500 mg* IM in a single dose

plus

Doxycycline 100 mg 2 times/day orally for 7 days

* For persons weighing ≥150 kg, 1 g of ceftriaxone should be administered.

Clinicians should counsel persons regarding the possible

benefits and toxicities associated with these treatment regimens;

gastrointestinal side effects can occur with this combination.

The efficacy of these regimens in preventing infections after

sexual assault has not been evaluated. For those requiring

alternative treatments, refer to the specific sections in this

report relevant to the specific organisms.

Other Management Considerations

At the initial examination and, if indicated, at follow-up

examinations, patients should be counseled regarding

symptoms of STIs and the need for immediate examination if

symptoms occur. Further, they should be instructed to abstain

from sexual intercourse until STI prophylactic treatment

is completed.

Follow-Up

After the initial postassault examination, follow-up

examinations provide an opportunity to detect new infections

acquired during or after the assault, complete hepatitis B

and HPV vaccinations, if indicated, complete counseling

and treatment for other STIs, and monitor side effects and

adherence to PEP, if prescribed. If initial testing was performed,

follow-up evaluation should be conducted in <1 week to ensure

that results of positive tests can be discussed promptly with

the survivor, treatment is provided if not administered at the

initial visit, and any follow-up for infections can be arranged.

If initial tests are negative and treatment was not provided,

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examination for STIs can be repeated 1–2 weeks after the

assault; repeat testing detects infectious organisms that might

not have reached sufficient concentrations to produce positive

test results at the time of initial examination. For survivors who

are treated during the initial visit, regardless of whether testing

was performed, posttreatment testing should be conducted

only if the person reports having symptoms. If initial test results

were negative and infection in the assailant cannot be ruled

out, serologic tests for syphilis can be repeated at 4–6 weeks

and 3 months; HIV testing can be repeated at 6 weeks and at

3 months by using methods to identify acute HIV infection.

Risk for Acquiring HIV Infection

HIV seroconversion has occurred among persons whose only

known risk factor was sexual assault or sexual abuse; however,

the frequency of this occurrence likely is low (1428,1429). In

consensual sex, the per-act risk for HIV transmission from

vaginal intercourse is 0.08%, and for receptive anal intercourse,

1.38% (192). The per-act risk for HIV transmission from

oral sex is substantially lower. Specific circumstances of an

assault (e.g., bleeding, which often accompanies trauma)

might increase risk for HIV transmission in cases involving

vaginal, anal, or oral penetration. Site of exposure to ejaculate,

viral load in ejaculate, and the presence of an STI or genital

lesions in the assailant or survivor also might increase risk for

HIV acquisition.

PEP with a 28-day course of zidovudine was associated with

an 81% reduction in risk for acquiring HIV in a study of health

care workers who had percutaneous exposures to HIV-infected

blood (1430). On the basis of these results and results from

animal studies, PEP has been recommended for health care

workers who have occupational exposures to HIV (1431).

These findings have been extrapolated to nonoccupational

injecting drug and sexual HIV exposures, including sexual

assault. The possibility of HIV exposure from the assault should

be assessed at the initial examination; survivors determined

to be at risk for acquiring HIV should be informed about the

possible benefit of PEP in preventing HIV infection. Initiation

of PEP as soon as possible after the exposure increases the

likelihood of prophylactic benefit.

Multiple factors affect the medical recommendation for

PEP and affect the assault survivor’s acceptance of that

recommendation. These factors include the likelihood of the

assailant having HIV, any exposure characteristics that might

increase the risk for HIV transmission, the time elapsed after

the event, and the potential benefits and risks associated

with PEP (1431). Determination of the assailant’s HIV

status at the time of the postassault examination is usually

not possible. Therefore, health care providers should assess

any available information concerning the characteristics and

HIV risk behaviors of the assailant (e.g., being an MSM or

using injecting drugs), local epidemiology of HIV/AIDS, and

exposure characteristics of the assault. When an assailant’s

HIV status is unknown, determinations about risk for HIV

transmission to the survivor should be based on whether vaginal

or anal penetration occurred; whether ejaculation occurred on

mucous membranes; whether multiple assailants were involved;

whether mucosal lesions were present in the assailant or

survivor; and any other characteristics of the assault, survivor,

or assailant that might increase risk for HIV transmission.

If PEP is offered, the following information should be

discussed with the survivor: the necessity of early initiation

of PEP to optimize potential benefits (i.e., as soon as possible

after and <72 hours after the assault), the importance of close

follow-up, the benefit of adherence to recommended dosing,

and potential adverse effects of antiretroviral medications.

Providers should emphasize that severe adverse effects are

rare from PEP (1431–1435). Clinical management of the

survivor should be implemented according to the HIV PEP

guidelines and in collaboration with specialists (1436). Health

care providers should provide an initial course of 3–7 days of

medication (i.e., a starter pack) with a prescription for the

remainder of the course, or, if starter packs are unavailable,

they should provide a prescription for an entire 28-day

course. Provision of the entire 28-day PEP medication supply

at the initial visit has been reported to increase likelihood of

adherence, especially when patients have difficulty returning

for multiple follow-up visits (1437). Routinely providing

starter packs or the entire 28-day course requires that health

care providers stock PEP drugs in their practice setting or have

an established agreement with a pharmacy to stock, package,

and urgently dispense PEP drugs with required administration

instructions. Uninsured patients or those with high copayments

can be enrolled in a patient-assistance program to ensure

access to PEP medications. An early follow-up visit should be

scheduled at which health care providers can discuss the results

of HIV and STI testing, provide additional counseling and

support, provide indicated vaccines not administered at the

initial evaluation, assess medication side effects and adherence,

or provide an altered PEP medication regimen if indicated by

side effects or laboratory test results.

Recommendations for Postexposure HIV Risk

Assessment of Adolescents and Adults <72 Hours

After Sexual Assault

Health care providers should do the following:

• Assess risk for HIV infection in the assailant, and test that

person for HIV whenever possible.

• Use the algorithm to evaluate the survivor for the need for

HIV PEP (Figure) (1436).

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• Consult with a specialist in HIV treatment if PEP is being

considered.

• If the survivor appears to be at risk for acquiring HIV from

the assault, discuss PEP, including benefits and risks.

• If the survivor chooses to start PEP, provide an initial

course of 3–7 days of medication (i.e., a starter pack) with

a prescription for the remainder of the course or provide

a prescription for an entire 28-day course. Schedule an

early follow-up visit to discuss test results and provide

additional counseling (1438).

• If PEP is started, obtain serum creatinine, AST, and alanine

aminotransferase at baseline.

• Perform an HIV antibody test at original assessment;

repeat at 6 weeks and 3 months.

• Counsel the survivor regarding ongoing risk for HIV

acquisition and about HIV PrEP, and provide referrals to

a PrEP provider.

Assistance with PEP-related decisions can be obtained by

calling the National Clinician’s Post Exposure Prophylaxis

Hotline (PEP Line) (telephone: 888-448-4911).

Sexual Assault or Abuse of Children

These guidelines are limited to the identification and

treatment of STIs in prepubertal children. Management of

the psychosocial or legal aspects of the sexual assault or abuse

of children is beyond the scope of these guidelines.

Identification of STIs in children past the neonatal period

strongly indicates sexual abuse (1438). The importance of

FIGURE. Algorithm to evaluate the need for nonoccupational HIV postexposure prophylaxis among adult and adolescent survivors of sexual assault

Substantial

exposure risk

<72 hours

since exposure

Source patient

known to be

HIV positive

PEP

recommended

Source patient

of unknown

HIV status

Case-by-case

determination

PEP not

recommended

≥72 hours

since exposure

Negligible

exposure risk

Substantial Risk for HIV Acquisition

Exposure of

vagina, rectum, eye, mouth, or other mucous membrane, nonintact skin, or

percutaneous contact

With

blood, semen, vaginal secretions, rectal secretions, breast milk, or any body

uid that is visibly contaminated with blood

When

the source is known to be HIV positive

Negligible Risk for HIV Acquisition

Exposure of

vagina, rectum, eye, mouth, or other mucous

membrane, intact or nonintact skin, or

percutaneous contact

With

urine, nasal secretions, saliva, sweat, or tears if

not visibly contaminated with blood

Regardless

of the known or suspected HIV status of

the source

Source: Adapted from Announcement: updated guidelines for antiretroviral postexposure prophylaxis after sexual, injection-drug use, or other nonoccupational

exposure to HIV—United States, 2016. MMWR Morb Mortal Wkly Rep 2016;65:458.

Abbreviation: PEP = postexposure prophylaxis.

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identifying a sexually transmitted organism for such children

as evidence of possible child sexual abuse varies by pathogen.

Postnatally acquired gonorrhea, syphilis, chlamydia, and

T. vaginalis infection and nontransfusion, nonperinatally

acquired HIV infection are indicative of sexual abuse.

Sexual abuse should be suspected when anogenital herpes or

anogenital warts are diagnosed. Investigation of sexual abuse

among children who have an infection that might have been

transmitted sexually should be conducted in compliance with

recommendations by clinicians who have experience and

training in all elements of the evaluation of child abuse, neglect,

and assault. The social significance of an infection that might

have been acquired sexually varies by the specific organism, as

does the threshold for reporting suspected child sexual abuse

(Table 8). When any STI has been diagnosed in a child, efforts

should be made in consultation with a specialist to evaluate

the possibility of sexual abuse, including conducting a history

and physical examination for evidence of abuse and diagnostic

testing for other commonly occurring STIs (1439–1441).

The general rule that STIs beyond the neonatal period are

evidence of sexual abuse has exceptions. For example, genital

infection with T. vaginalis (1442) or rectal or genital infection

with C. trachomatis among young children might be the result

of perinatally acquired infection and has, in certain cases

of chlamydial infection, persisted for as long as 2–3 years

(1443–1445), although perinatal chlamydial infection is now

uncommon because of prenatal screening and treatment of

pregnant women. Genital warts have been diagnosed among

children who have been sexually abused (1426) but also

among children who have no other evidence of sexual abuse

(1446,1447); lesions appearing for the first time in a child

aged >5 years are more likely to have been caused by sexual

transmission (1448). BV has been diagnosed among children

who have been abused but its presence alone does not prove

sexual abuse. The majority of HBV infections among children

result from household exposure to persons who have chronic

HBV infection rather than sexual abuse.

Reporting

All U.S. states and territories have laws that require reporting

of child abuse. Although the exact requirements differ by state

or territory, if a health care provider has reasonable cause to

suspect child abuse, a report must be made (1448). Health care

providers should contact their state or local child protection

service agency regarding child abuse reporting requirements.

Evaluating Children for STIs

Evaluating children for sexual assault or abuse should be

conducted in a manner designed to minimize pain and trauma

to the child. Examinations and collection of vaginal specimens

in prepubertal girls can be extremely uncomfortable and should

be performed by an experienced clinician to avoid psychological

and physical trauma to the child. The decision to obtain genital

or other specimens from a child to evaluate for STIs should be

made on an individual basis. However, children who received

a diagnosis of one STI should be screened for other STIs.

History and reported type of sexual contact might not be a

reliable indicator, and urogenital, pharyngeal, and rectal testing

should be considered for preverbal children and children who

cannot verbalize details of the assault (1438,1449). Factors that

should lead the physician to consider testing for STIs include

the following (1449):

• The child has experienced penetration or has evidence of

recent or healed penetrative injury to the genitals, anus,

or oropharynx.

• The child has been abused by a stranger.

TABLE 8. Implications of commonly encountered sexually transmitted or sexually associated infections for diagnosis and reporting of sexual

abuse among infants and prepubertal children

Infection Evidence for sexual abuse Recommended action

Gonorrhea* Diagnostic Report

†

Syphilis* Diagnostic Report

†

HIV

Diagnostic Report

†

Chlamydia trachomatis* Diagnostic Report

†

Trichomonas vaginalis* Diagnostic Report

†

Anogenital herpes Suspicious Consider report

†,¶

Condylomata acuminata (anogenital warts)* Suspicious Consider report

†,¶,

Anogenital molluscum contagiosum Inconclusive Medical follow-up

Bacterial vaginosis Inconclusive Medical follow-up

Sources: Adapted from Kellogg N; American Academy of Pediatrics Committee on Child Abuse and Neglect. The evaluation of child abuse in children. Pediatrics

2005;16:506–12; Adams JA, Farst KJ, Kellogg ND. Interpretation of medical findings in suspected child abuse: an update for 2018. J Pediatr Adolesc Gynecol

2018;31:225–31.

* If unlikely to have been perinatally acquired and vertical transmission, which is rare, is excluded.

†

Reports should be made to the local or state agency mandated to receive reports of suspected child abuse or neglect.

If unlikely to have been acquired perinatally or through transfusion.

Unless a clear history of autoinoculation exists.

** Report if evidence exists to suspect abuse, including history, physical examination, or other identified infections. Lesions appearing for the first time in a child aged

>5 years are more likely to have been caused by sexual transmission.

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• The child has been abused by an assailant known to be

infected with an STI or at high risk for STIs (e.g., injecting

drug user, MSM, person with multiple sex partners, or

person with a history of STIs).

• The child has a sibling, other relative, or another person

in the household with an STI.

• The child lives in an area with a high rate of STIs in the

community.

• The child has signs or symptoms of STIs (e.g., vaginal

discharge or pain, genital itching or odor, urinary

symptoms, or genital lesions or ulcers).

• The child or parent requests STI testing.

• The child is unable to verbalize details of the assault.

If a child has symptoms, signs, or evidence of an infection

that might be sexually transmitted, the child should be tested

for common STIs before initiation of any treatment that might

interfere with diagnosing other STIs. Because of the legal and

psychosocial consequences of a false-positive diagnosis, only

tests with high specificities should be used. The potential

benefit to the child of a reliable STI diagnosis justifies deferring

presumptive treatment until specimens for highly specific tests

are obtained by providers with experience in evaluating sexually

abused and assaulted children.

Evaluations should be performed on a case-by-case basis,

according to history of assault or abuse and in a manner

that minimizes the possibility for psychological trauma and

social stigma. If the initial exposure was recent, the infectious

organisms acquired through the exposure might not have

produced sufficient concentrations to result in positive test

results or examination findings (1450). Alternatively, positive

test results after a recent exposure might represent the assailant’s

secretions (but would nonetheless be an indication for

treatment of the child). A second visit approximately 2–6 weeks

after the most recent sexual exposure should be scheduled

to include a repeat physical examination and collection of

additional specimens to identify any infection that might not

have been detected at the time of initial evaluation. A single

evaluation might be sufficient if the child was abused for an

extended period and if a substantial amount of time elapsed

between the last suspected episode of abuse and the medical

evaluation. Compliance with follow-up appointments might be

improved when law enforcement personnel or child protective

services are involved.

Initial Examination

Visual inspection of the genital, perianal, and oral areas

for genital discharge, odor, bleeding, irritation, warts,

and ulcerative lesions should be performed during initial

examination. The clinical manifestations of certain STIs are

different for children than for adults. For example, typical

vesicular lesions might be absent even in the presence of HSV

infection. The following should be performed during the initial

examination, if STI testing is indicated:

• Testing for N. gonorrhoeae and C. trachomatis can be

performed from specimens collected from the pharynx

and rectum, as well as the vagina for girls and urine for

boys. Cervical specimens are not recommended for

prepubertal girls. For boys with a urethral discharge, a

meatal specimen discharge is an adequate substitute for

an intraurethral swab specimen. Culture or NAAT can be

used to test for N. gonorrhoeae and C. trachomatis.

Although data regarding NAAT for children are more

limited and performance is test dependent (553), no

evidence demonstrates that performance of NAAT for

detection of N. gonorrhoea or C. trachomatis among

children differs from that among adults. Only FDA-cleared

NAAT assays should be used. Consultation with an expert

is necessary before using NAAT in this context, both to

minimize the possibility of cross-reaction with

nongonococcal Neisseria species and other commensals

(e.g., N. meningitidis, N. sicca, N. lactamica, N. cinerea,

or M. catarrhalis) and to ensure correct interpretation of

results. Because of the implications of a diagnosis of

N. gonorrhoeae or C. trachomatis infection in a child, only

CLIA-validated, FDA-cleared NAATs should be used

(837). If culture for the isolation of N. gonorrhoeae or

C. trachomatis is performed, only standard culture

procedures should be followed. Specimens from the vagina,

urethra, pharynx, or rectum should be streaked onto

selective media for isolation of N. gonorrhoeae, and all

presumptive isolates of N. gonorrhoeae should be identified

definitively by at least two tests that involve different

approaches (e.g., biochemical, enzyme substrate, or

molecular probes). Gram stains are inadequate for

evaluating prepubertal children for gonorrhea and should

not be used to diagnose or exclude gonorrhea. Specimens

(either NAAT or culture, including any isolates) obtained

before treatment should be preserved for further validation

if needed. When a specimen is positive, the result should

be confirmed either by retesting the original specimen or

obtaining another. Because of the overall low prevalence

of N. gonorrhoeae and C. trachomatis among children,

false-positive results can occur, and all specimens that are

initially positive should be confirmed.

• Testing for T. vaginalis should not be limited to girls with

vaginal discharge if other indications for vaginal testing

exist because evidence indicates that asymptomatic sexually

abused children might be infected with T. vaginalis and

might benefit from treatment (1451,1452). NAAT can

be used as an alternative or in addition to culture and wet

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mount, especially in settings where culture and wet mount

of vaginal swab specimens are not obtainable. Data

regarding use of NAATs for detection of T. vaginalis among

children are limited; however, no evidence indicates that

performance of NAAT for detection of T. vaginalis for

children would differ from that for adults. Consultation

with an expert is necessary before using NAAT in this

context to ensure correct interpretation of results. Because

of the implications of a diagnosis of T. vaginalis infection in

a child, only CLIA-validated, FDA-cleared NAATs should

be used (837). POC tests for T. vaginalis have not been

validated for prepubertal children and should not be used.

In the case of a positive specimen, the result should be

confirmed either by retesting the original specimen or

obtaining another. Because of the overall low prevalence of

T. vaginalis among children, false-positive results can occur,

and all specimens that are initially positive should

be confirmed.

• HSV can be indicative of sexual abuse; therefore,

specimens should be obtained from all vesicular or

ulcerative genital or perianal lesions and sent for NAAT

or viral culture.

• Wet mount can be used for a vaginal swab specimen for

BV if discharge is present.

• Collection of serum samples should be evaluated, preserved

for subsequent analysis, and used as a baseline for

comparison with follow-up serologic tests. Sera can be tested

for antibodies to T. pallidum, HIV, and HBV. Decisions

regarding the infectious agents for which to perform

serologic tests should be made on a case-by-case basis.

Treatment

The risk for a child acquiring an STI as a result of sexual

abuse or assault has not been well studied. Presumptive

treatment for children who have been sexually assaulted or

abused is not recommended because the incidence of most

STIs among children is low after abuse or assault, prepubertal

girls appear to be at lower risk for ascending infection than

adolescent or adult women, and regular follow-up of children

usually can be ensured. However, certain children or their

parent or guardian might be concerned about the possibility

of infection with an STI, even if the health care provider

has perceived the risk to be low. Such concerns might be an

indication for presumptive treatment in certain settings and

might be considered after all relevant specimens for diagnostic

tests have been collected.

Other Management Considerations

Children who are survivors of sexual assault or abuse are at

increased risk for future unsafe sexual practices that have been

linked to higher risk for HPV acquisition (1426,1453) and

are more likely to engage in these behaviors at an earlier age;

therefore, ACIP recommends vaccination of these children

at age ≥9 years if they have not initiated or completed HPV

vaccination (see Human Papillomavirus Infections, Prevention)

(https://www.cdc.gov/vaccines/hcp/acip-recs/vacc-specific/

hpv.html). Although HPV vaccine will not protect against

progression of infection already acquired or promote clearance

of the infection, the vaccine protects against HPV types not

yet acquired.

Follow-Up

If no infections were identified at the initial examination

after the last suspected sexual exposure, and if this exposure

was recent, a follow-up evaluation approximately 2 weeks

after the last exposure can be considered. Likewise, if no

physical examination or diagnostic testing was performed

at the initial visit, a complete examination can be scheduled

approximately 2 weeks after the last exposure to identify any

evidence of STIs. In circumstances in which transmission of

syphilis, HIV, HBV, or HPV is a concern but baseline tests

for syphilis, HIV, and HBV are negative and examinations

for genital warts are negative, follow-up serologic testing and

examination approximately 6 weeks and <3 months after the

last suspected sexual exposure is recommended to allow time

for antibodies to develop and signs of infection to appear.

In addition, results of HBsAg testing should be interpreted

carefully because HBV can be transmitted nonsexually.

Decisions regarding which tests should be performed should

be made on a case-by-case basis.

Risk for Acquiring HIV Infection

HIV has been reported among children for whom sexual

abuse was the only known risk factor. Serologic testing for HIV

should be considered for sexually abused children. The decision

to test for HIV should involve the family, if possible, and be

made on a case-by-case basis depending on the likelihood

of infection in the assailant (1448,1454). Although data are

insufficient concerning the efficacy of PEP among children,

treatment is well tolerated by infants and children with and

without HIV, and children have a minimal risk for serious

adverse reactions because of the short period recommended

for prophylaxis (1455).

Recommendations for Postexposure HIV Risk

Assessment of Children <72 Hours After

Sexual Assault

Providers should do the following:

• Review local HIV epidemiology, assess risk for HIV in the

assailant, and test for HIV.

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• Evaluate the circumstances of the assault or abuse that

might affect risk for HIV transmission.

• Perform HIV antigen or antibody testing (or antibody

testing, if antigen or antibody testing is unavailable) during

the original assessment and again at follow-up visits, in

accordance with CDC guidelines (https://stacks.cdc.gov/

view/cdc/38856). In considering whether to offer PEP,

health care providers should consider whether the child

can be treated soon after the sexual exposure (i.e.,

<72 hours), the likelihood that the assailant has HIV

infection, and the likelihood of high compliance with the

prophylactic regimen (1436). Potential benefit of treating

a sexually abused child should be weighed against the risk

for adverse reactions.

• Consult with a provider specializing in evaluating or

treating children with HIV infection to determine age-

appropriate dosing and regimens and baseline laboratory

testing, if PEP is being considered.

• Discuss PEP with the caregivers, including its toxicity,

unknown efficacy, and possible benefits, for children

determined to be at risk for HIV transmission from the

assault or abuse.

• Provided adequate doses of medication, if PEP is begun,

to last until the follow-up visit 3–7 days after the initial

assessment, at which time the child should be reevaluated

and tolerance of medication assessed (139).

Conflicts of Interest

All authors have completed and submitted the International

Committee of Medical Journal Editors form for disclosure of

potential conflicts of interest. Christina Muzny reports other support

from CDC, during the conduct of the study; grants from the National

Institutes of Health/National Institute of Allergy and Infectious

Diseases and Lupin Pharmaceuticals; personal fees from Lupin

Pharmaceuticals, PhagoMed, Cepheid, and Beckton Dickinson; and

personal fees and other support from Roche Diagnostics, Abbott

Molecular, and BioFire Diagnostics, outside the submitted work.

Hilary Reno reports grants from Hologic, outside the submitted

work. Christine Johnston reports other support from CDC, during

the conduct of the study; received research funding from Sanofi-

Pasteur; royalties from UpToDate; and personal fees from MedPace,

Gilead, AbbVie, and UpToDate, outside the submitted work.

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and Human Services, National Institutes of Health, AIDSinfo; 2020.

https://aidsinfo.nih.gov/contentfiles/lvguidelines/pediatricguidelines.pdf

Recommendations and Reports

MMWR / July 23, 2021 / Vol. 70 / No. 4 185

US Department of Health and Human Services/Centers for Disease Control and Prevention

STI Treatment Guidelines, 2021, Work Group Members

Chairperson: Kimberly A. Workowski, MD, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC, and Emory University,

Atlanta, Georgia.

Work Group Members: Elizabeth Alderman, MD, The Children’s Hospital at Montefiore, The Pediatric Hospital for Albert Einstein College of Medicine,

Bronx, New York; Lindley Barbee, MD, University of Washington and Public Health Seattle and King County STD Clinic, Seattle, Washington; Luis

Barroso, MD, Wake Forest Baptist Health, Winston-Salem, North Carolina; Gale Burstein, MD, Erie County Department of Health, Buffalo, New York;

Virginia A. Caine, MD, Marion County Public Health Department, Indiana University, Indianapolis, Indiana; Carla Chibwesha, MD, University of North

Carolina at Chapel Hill, Chapel Hill, North Carolina; Stephanie Cohen, MD, San Francisco Department of Public Health, San Francisco, California; Susan

Cu-Uvin, MD, Brown University, Providence, Rhode Island; Jodie Dionne-Odom, MD, University of Alabama at Birmingham, Birmingham, Alabama; Julia

Dombrowski, MD, Public Health Seattle and King County, University of Washington, Seattle, Washington; Carolyn Gardella, MD, Veterans Affairs Puget

Sound University of Washington, Seattle, Washington; William M. Geisler, MD, University of Alabama at Birmingham, Birmingham, Alabama; Khalil G.

Ghanem, MD, PhD, Johns Hopkins University, Baltimore, Maryland; Matthew Golden, MD, Seattle and King County STD/HIV Program University of

Washington, Seattle, Washington; Margaret R. Hammerschlag, MD, SUNY Downstate Medical Center, Brooklyn, New York; H. Hunter Handsfield, MD,

University of Washington Center for AIDS and STD, Seattle, Washington; King K. Holmes, MD, PhD, University of Washington, Seattle, Washington;

Edward W. Hook, III, MD, University of Alabama at Birmingham, Birmingham, Alabama; Katherine Hsu, MD, Ratelle STD/HIV Prevention Training

Center, Massachusetts Department of Public Health, Boston, Massachusetts; Christine Johnston, MD, University of Washington, Seattle, Washington; Patricia

Kissinger, PhD, Tulane University School of Public Health and Tropical Medicine, New Orleans, Louisiana; Jeffrey D. Klausner, MD, University of California

Los Angeles, Los Angeles, California; Lisa E. Manhart, PhD, University of Washington, Seattle, Washington; Jeanne Marrazzo, MD, University of Alabama at

Birmingham, Birmingham, Alabama; David H. Martin, MD, Tulane University, Louisiana State University Health Sciences Center, New Orleans, Louisiana;

Leslie Massad, MD, Washington University, St. Louis, Missouri; Kenneth H. Mayer, MD, Fenway Health, The Fenway Institute, Harvard Medical School,

Beth Israel Deaconess Hospital, Boston, Massachusetts; Candice McNeil, MD, Wake Forest Baptist Health, Alabama/North Carolina HIV/STD Prevention

Training Center, Forsyth County Department of Public Health, Winston-Salem, North Carolina; Leandro Mena, MD, University of Mississippi Medical

Center, Jackson, Mississippi; Caroline Mitchell, MD, Vincent Center for Reproductive Biology, Boston, Massachusetts; Okeoma Mmeje, MD, University

of Michigan, Ann Arbor, Michigan; Anna-Barbara Moscicki, MD, University of California Los Angeles, Los Angeles, California; Christina A. Muzny, MD,

University of Alabama at Birmingham, Birmingham, Alabama; Natalie Neu, MD, Columbia University, New York, New York; Paul Nyirjesy, MD, Sidney

Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania; Jeff Peipert, MD, PhD, Indiana University, Indianapolis, Indiana;

Rebecca Perkins, MD, Boston University, Boston, Massachusetts; Susan Philip, MD, San Francisco Department of Public Health, San Francisco, California;

Asa Radix, MD, PhD, Callen-Lorde Community Health Center, New York, New York; Anne Rompalo, MD, Johns Hopkins University, Baltimore, Maryland;

Sarah Rudman, MD, County of Santa Clara Public Health Department, San Jose, California; Pablo J. Sanchez, MD, The Ohio State University Nationwide

Children’s Hospital, Columbus, Ohio; George Sawaya, MD, University of San Francisco, San Francisco, California; Arlene Seña, MD, University of North

Carolina at Chapel Hill and Durham County Department of Public Health, Durham, North Carolina; Jeanne Sheffield, MD, Johns Hopkins University,

Baltimore, Maryland; Jack Sobel, MD, Wayne State University, Detroit, Michigan; David Soper, MD, Medical University of South Carolina, Charleston, South

Carolina; Anne Spaulding, MD, Emory University, Atlanta, Georgia; Bradley Stoner, MD, PhD, Washington University, St. Louis, Missouri; Stephanie Taylor,

MD, Louisiana State University Crescent Care Sexual Health Center, New Orleans, Louisiana; Susan Tuddenham, MD, Johns Hopkins University School

of Medicine, Baltimore, Maryland; Karen Wendel, MD, Denver Public Health, Denver, Colorado; Harold C. Wiesenfeld, MD, University of Pittsburgh,

Pittsburgh, Pennsylvania; Jonathan Zenilman, MD, Johns Hopkins University, Baltimore, Maryland.

Moderators: Philip Chan, MD, Brown University, Providence, Rhode Island; Edward W. Hook, III, MD, University of Alabama at Birmingham, Birmingham,

Alabama; Christine Johnston, MD, University of Washington, Seattle, Washington; David H. Martin, MD, Tulane University, Louisiana State University

Health Sciences Center, New Orleans, Louisiana; Jeanne Marrazzo, MD, University of Alabama at Birmingham, Birmingham, Alabama; Christina A. Muzny,

MD, University of Alabama at Birmingham, Birmingham, Alabama; Ina Park, MD, University of California San Francisco, San Francisco, California; Hilary

Reno, MD, PhD, Washington University, St. Louis, Missouri; Jonathan Zenilman, MD, Johns Hopkins University, Baltimore, Maryland.

Rapporteurs: Philip Chan, MD, Brown University, Providence, Rhode Island; Hilary Reno, MD, PhD, Washington University, St. Louis, Missouri; Christine

Johnston, MD, University of Washington, Seattle, Washington; Christina A. Muzny, MD, University of Alabama at Birmingham, Birmingham, Alabama;

Ina Park, MD, University of California San Francisco, San Francisco, California; Jonathan Zenilman, MD, Johns Hopkins University, Baltimore, Maryland

Liaison Participants: Jean Anderson, MD, CDC/HRSA Advisory Committee on HIV, Viral Hepatitis and STD Prevention and Treatment, Johns Hopkins

University, Baltimore, Maryland; Kevin Ault, MD, American College of Obstetricians and Gynecologists, University of Kansas, Lawrence, Kansas; Himani

Bisht, PhD, Food and Drug Administration, Silver Spring, Maryland; J. Quentin Clemens, MD, American Urological Association, University of Michigan, Ann

Arbor, Michigan; Gina Coleman, MD, Public Health Agency of Canada, Ottawa, Ontario; Carolyn Deal, PhD, National Institute of Allergy and Infectious

Diseases, Bethesda, Maryland; Maeve B. Mello, PhD, Pan American Health Organization/World Health Organization, Washington, DC; Diane Foley, MD,

U.S. Department of Health and Human Services, Washington, DC; Michael Ganio, PharmD, American Society of Health-System Pharmacists, Bethesda,

Maryland; Eric Garges, MD, U.S. Department of Defense, Arlington, Virginia, and Uniformed Services University, Bethesda, Maryland; Brent Gibson, MD,

National Commission on Correctional Health Care, Chicago, Illinois; William A. Glover, II, PhD, Association of Public Health Laboratories, Silver Spring,

Maryland; W. David Hardy, MD, HIV Medical Association, Johns Hopkins University, Baltimore, Maryland; David Harvey, National Coalition of STD

Directors, Washington, DC; Letha Healey, MD, Health Resources and Services Administration (HIV/AIDS Bureau), Rockville, Maryland; Michael Huey,

MD, American College Health Association, Silver Spring, Maryland, and Emory University, Atlanta, Georgia; Gal Mayer, MD, GLMA: Health Professionals

Advancing LGBTQ Equality, Washington, DC; Sumathi Nambiar, MD, Food and Drug Administration, Silver Spring, Maryland; Seema Nayak, MD, National

Institutes of Health, Rockville, Maryland; Lori Newman, MD, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; Samantha Ritter,

MPH, National Association of County and City Health Officials, Washington, DC; Elizabeth Ruebush, Association of State and Territorial Health Officials,

Arlington, Virginia; Bisan Salhi, MD, PhD, American College of Emergency Physicians, Irving, Texas, Emory University, Atlanta, Georgia; Natasha Travis,

MD, National Medical Association, Silver Spring, Maryland, and Johns Hopkins University, Baltimore, Maryland; Maria Trent, MD, Society for Adolescent

Health and Medicine, Chicago, Illinois, and Johns Hopkins University, Baltimore, Maryland; Julie Vaishampayan, MD, Infectious Disease Society of America,

Arlington, Virginia; Barbara Van Der Pol, PhD, American Sexually Transmitted Diseases Association, Research Triangle Park, North Carolina, and University

of Alabama at Birmingham, Birmingham, Alabama; Teodora Elvira Wi, MD, Department of Global HIV, Hepatitis and STI Programmes, World Health

Organization, Geneva, Switzerland.

Recommendations and Reports

186 MMWR / July 23, 2021 / Vol. 70 / No. 4

US Department of Health and Human Services/Centers for Disease Control and Prevention

CDC and Outside CDC Consultants: Sevgi O. Aral, PhD; Laura H. Bachmann, MD; Kyle Bernstein, PhD; Gail Bolan, MD; John Brooks, MD; Philip Chan,

MD, Brown University, Providence, Rhode Island; Aaron Harris, MD; Matthew Hogben, PhD; Christine Johnston, MD, University of Washington, Seattle,

Washington; Sarah Kidd, MD; Kristen Kreisel, PhD; Lauri Markowitz, MD; Christina Muzny, MD, University of Alabama at Birmingham, Birmingham,

Alabama; Ina Park, MD, University of California San Francisco, San Francisco, California; Allan Pillay, PhD; Laura Quilter, MD; Hilary Reno, MD, PhD,

Washington University, St. Louis, Missouri; Sancta St. Cyr, MD; Mona Saraiya, MD; Julie Schillinger, MD; Virginia Senkomago, PhD; Philip Spradling,

MD; Phoebe Thorpe, MD; Mark Weng, MD; Jonathan Zenilman, MD, Johns Hopkins University, Baltimore, Maryland.

CDC, Division of Sexually Transmitted Disease Prevention Treatment Guidelines, 2021, Project Coordinator: Kimberly A. Workowski, MD, National

Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC, and Emory University, Atlanta, Georgia.

CDC Support Staff: Alexandra Coor, MPH; Catherine Carter; Quinn Haaga; Amber Herald; Patricia Jackson; Brenda Kelly.

Recommendations and Reports

MMWR / July 23, 2021 / Vol. 70 / No. 4 187

US Department of Health and Human Services/Centers for Disease Control and Prevention

Disclosure of Relationships

All STI Treatment Guidelines, 2021, Work Group members have completed and submitted the International Committee of Medical Journal Editors form for

disclosure of potential conflicts of interest. Lindley Barbee received research support from Hologic and SpeeDx and consults for Nabriva. Christine Johnston

received research funding from Sanofi-Pasteur; royalties from UpToDate; and personal fees from MedPace, Gilead, AbbVie, and UpToDate. Jeffrey Klausner

received research supplies from Hologic, Cepheid, and SpeeDx; advisory fees from Shield Diagnostics, Click Diagnostics, and SpeeDx; and research funding

from AbbVie and Gilead Sciences. Lisa Manhart received research supplies, honoraria, and research contracts from Hologic and served as a consultant to

diagnostic test manufacturers (SpeeDx, BioFire Diagnostics, Roche Diagnostics, and Click Diagnostics). Jeanne Marrazzo serves on expert advisory boards for

Becton Dickinson, BioFire Diagnostics, and Gilead Sciences and has research and grant support and supplies from Merck & Co. and Toltec. David Martin

served as a consultant in 2019 to Hologic, which recently gained Food and Drug Administration clearance for a Mycoplasma genitalium diagnostic test and

markets diagnostic tests for gonorrhea, chlamydia, and trichomonas. Kenneth Mayer serves on the scientific advisory boards for Gilead Sciences and Merck

& Co. Pharmaceuticals and receives grant funds from Gilead Sciences. Leandro Mena received research funding through his institution from Atlas Genetics,

Merck & Co., Becton Dickinson, Hologic, Biolytical, and Roche and received consulting honoraria from Roche Molecular, Merck & Co., Gilead Sciences, and

ViiV Healthcare and from speaker bureaus for Gilead Sciences and ViiV Healthcare. Caroline Mitchell served as a consultant for Lupin Pharmaceuticals and

Scynexis and received grant funding from Merck & Co. Christina A. Muzny served as a consultant and received research support from Lupin Pharmaceuticals

for a randomized controlled trial of secnidazole versus placebo for treatment of trichomoniasis and grants from the National Institutes of Health/National

Institute of Allergy and Infectious Diseases; was a speaker for Abbott Molecular, Cepheid, and Roche Diagnostics on topics related to STIs; received personal

fees from Lupin Pharmaceuticals, PhagoMed, Cepheid, and Beckton Dickinson; and served as a consultant for BioFire Diagnostics. Paul Nyirjesy received

research support from Mycovia Pharmaceuticals, Curatek Pharmaceuticals, Scynexis, and Hologic and served as a consultant for Mycovia Pharmaceuticals,

Hologic, Scynexis, Daré Bioscience, and Becton Dickinson. Jeffery Pepest serves on advisory boards for Cooper Surgical and Bayer and provides research support

to Merck & Co. Susan Philip is an unpaid public health advisor to GlaxoSmithKline. Anne Rompalo serves on the BioFire Diagnostics advisory board and

has financial ties to UpToDate. Hilary Reno is a site principle investigator on a project evaluating the prevalence of M. genitalium funded by Hologic (funds

are allocated via her institution). Arlene Seña serves on a speaker’s bureau and scientific advisory board for M. genitalium at Hologic, works with the Gilead

Focus grant for hepatitis C testing and linkage to care, and mentored Sancta St. Cyr, MD, at the University of North Carolina Division of Infectious Diseases

before employment at CDC. Anne Spaulding received consulting fees or honoraria (either directly or through third parties) from Gilead Sciences, Merck &

Co., and AbbVie and grants through her institution from Gilead Sciences and ViiV. Susan Tuddenham served as a consultant for Biofire Diagnostics and Roche

Molecular Diagnostics and received a speaker honorarium from Roche Molecular Diagnostics. Karen Wendel has stock ownership in Pfizer.

ISSN: 1057-5987 (Print)

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