Upon successful completion of this course, you will be able to:

• Identify and discuss the five major strategies for the prevention and control of STDs
• Explain what is meant by “special populations” and explain the special prevention-control issues they face
• Identify and explain the key elements of HIV Infection: Detection, Counseling, and Referral
• List and discuss the major STDs that health care professionals have to deal with today

These guidelines for the treatment of persons who have sexually transmitted diseases (STDs) were developed by CDC after consultation with a group of professionals knowledgeable in the field of STDs who met in Atlanta, Georgia, during April 19--21, 2005. The information in this report updates the Sexually Transmitted Diseases Treatment Guidelines, 2002 (MMWR 2002;51[No. RR-6]). Included in these updated guidelines are an expanded diagnostic evaluation for cervicitis and trichomoniasis; new antimicrobial recommendations for trichomoniasis; additional data on the clinical efficacy of azithromycin for chlamydial infections in pregnancy; discussion of the role of Mycoplasma genitalium and trichomoniasis in urethritis/cervicitis and treatment-related implications; emergence of lymphogranuloma venereum protocolitis among men who have sex with men (MSM); expanded discussion of the criteria for spinal fluid examination to evaluate for neurosyphilis; the emergence of azithromycin- resistant Treponema pallidum; increasing prevalence of quinolone-resistant Neisseria gonorrhoeae in MSM; revised discussion concerning the sexual transmission of hepatitis C; postexposure prophylaxis after sexual assault; and an expanded discussion of STD prevention approaches. The material in this report originated in National Center for HIV, Viral Hepatitis, STDs, and Tuberculosis Prevention (proposed), Kevin A. Fenton, MD, PhD, Director; and the Division of STD Prevention, John M. Douglas, MD, Director.

Physicians and other health-care providers play a critical role in preventing and treating sexually transmitted diseases (STDs). These guidelines for the treatment of STDs are intended to assist with that effort. Although these guidelines emphasize treatment, prevention strategies and diagnostic recommendations also are discussed.

Methods

This report was produced through a multistage process. Beginning in 2004, CDC personnel and professionals knowledgeable in the field of STDs systematically reviewed evidence, including published abstracts and peer-reviewed journal articles concerning each of the major STDs, focusing on information that had become available since publication of the Sexually Transmitted Diseases Treatment Guidelines, 2002. Background papers were written and tables of evidence were constructed 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. A draft document was developed on the basis of the reviews.

In April 2005, CDC staff members and invited consultants assembled in Atlanta, Georgia, for a 3-day meeting to present the key questions regarding STD treatment that emerged from the evidence-based reviews and the information available to answer those questions. When relevant, the questions focused on four principal outcomes of STD therapy for each individual disease:
1) microbiologic cure,
2) alleviation of signs and symptoms,
3) prevention of sequelae, and
4) prevention of transmission.

Cost-effectiveness and other advantages (e.g., single-dose formulations and directly observed therapy of specific regimens) also were discussed. The consultants then assessed whether the questions identified were relevant, ranked them in order of priority, and attempted to arrive at answers using the available evidence. In addition, the consultants evaluated the quality of evidence supporting the answers on the basis of the number, type, and quality of the studies.

In several areas, the process diverged from that previously described. The sections on hepatitis B virus (HBV) and hepatitis A virus (HAV) infections are based on previously or recently approved recommendations of the Advisory Committee on Immunization Practices. The recommendations for STD screening during pregnancy were developed after CDC staff reviewed the recommendations from other knowledgeable groups.

Throughout this report, the evidence used as the basis for specific recommendations is discussed briefly. More comprehensive, annotated discussions of such evidence will appear in background papers that will be published in a supplement issue of Clinical Infectious Diseases. When more than one therapeutic regimen is recommended, the sequence is in alphabetical order unless the choices for therapy are prioritized based on efficacy, convenience, or cost. For STDs with more than one recommended treatment regimen, it can be assumed that all regimens have similar efficacy and similar rates of intolerance or toxicity, unless otherwise specified. Persons treating STDs should use recommended regimens primarily; alternative regimens can be considered in instances of substantial drug allergy or other contraindications to the recommended regimens.
These recommendations were developed in consultation with public and private sector professionals knowledgeable in the treatment of persons with STDs. The recommendations are applicable to various patient-care settings, including family planning clinics, private physicians' offices, managed care organizations, and other primary-care facilities.

These recommendations are meant to serve as a source of clinical guidance: health-care providers should always consider the individual clinical circumstances of each person in the context of local disease prevalence. These guidelines focus on the treatment and counseling of individual persons and do not address other community services and interventions that are important in STD/human immunodeficiency virus (HIV) prevention.

The prevention and control of STDs are based on the following five major strategies:
1) education and counseling of persons at risk on ways to avoid STDs through changes in sexual behaviors;
2) identification of asymptomatically infected persons and of symptomatic persons unlikely to seek diagnostic and treatment services;
3) effective diagnosis and treatment of infected persons;
4) evaluation, treatment, and counseling of sex partners of persons who are infected with an STD; and
5) preexposure vaccination of persons at risk for vaccine-preventable STD.

Primary prevention of STD begins with changing the sexual behaviors that place persons at risk for infection. Health-care providers have a unique opportunity to provide education and counseling to their patients. As part of the clinical interview, health-care providers should routinely and regularly obtain sexual histories from their patients and address management of risk reduction as indicated in this report. Guidance in obtaining a sexual history is available in Contraceptive Technology, 18th edition (5) and in the curriculum provided by CDC's STD/HIV Prevention Training Centers (http://www.stdhivpreventiontraining.org).

Counseling skills, characterized by respect, compassion, and a nonjudgmental attitude toward all patients, are essential to obtaining a thorough sexual history and to delivering prevention messages effectively. Key techniques that can be effective in facilitating rapport with patients include the use of 1) open-ended questions (e.g., "Tell me about any new sex partners you've had since your last visit" and "what's your experience with using condoms been like?"), 2) understandable language ("have you ever had a sore or scab on your penis?"), and 3) normalizing language ("some of my patients have difficulty using a condom with every sex act. How is it for you?"). One approach to eliciting information concerning five key areas of interest has been summarized.

The Five Ps: Partners, Prevention of Pregnancy, Protection from STDs, Practices, Past History of STDs

1. Partners

• "Do you have sex with men, women, or both?"
• "In the past 2 months, how many partners have you had sex with?"
• "In the past 12 months, how many partners have you had sex with?"

2. Prevention of pregnancy

• "Are you or your partner trying to get pregnant?" If no, "What are you doing to prevent pregnancy?"

3. Protection from STDs

1. "What do you do to protect yourself from STDs and HIV?"

4. Practices

• "To understand your risks for STDs, I need to understand the kind of sex you have had recently."
• "Have you had vaginal sex, meaning `penis in vagina sex'"?
• If yes, "Do you use condoms: never, sometimes, or always?"
• "Have you had anal sex, meaning `penis in rectum/anus sex'"?
• If yes, "Do you use condoms: never, sometimes, or always?"
• "Have you had oral sex, meaning `mouth on penis/vagina'"?

For condom answers

• If "never:" "Why don't you use condoms?"
• If "sometimes": "In what situations or with whom, do you not use condoms?"

5. Past history of STDs

• "Have you ever had an STD?"
• "Have any of your partners had an STD?"

Additional questions to identify HIV and hepatitis risk

• "Have you or any of your partners ever injected drugs?
• "Have any of your partners exchanged money or drugs for sex?"
• "Is there anything else about your sexual practices that I need to know about?"

Patients should be reassured that treatment will be provided regardless of individual circumstances (e.g., ability to pay, citizenship or immigration status, language spoken, or specific sex practices). Many patients seeking treatment or screening for a particular STD should be evaluated for all common STDs; even so, all patients should be informed concerning all the STDs for which they are being tested and if testing for a common STD (e.g., genital herpes) is not being performed.

STD/HIV Prevention Counseling

Effective delivery of prevention messages requires that providers integrate communication of general risk reduction messages that are relevant to the client (i.e., client-centered counseling) and education regarding specific actions that can reduce the risk for STD/HIV transmission (e.g., abstinence, condom use, limiting the number of sex partners, modifying sexual behaviors, and vaccination). Each of these specific actions is discussed separately in this report.

• Interactive counseling approaches directed at a patient's personal risk, the situations in which risk occurs, and the use of goal-setting strategies are effective in STD/HIV prevention. One such approach, client-centered STD/HIV prevention counseling, involves tailoring a discussion of risk reduction to the patient's individual situation. Client-centered counseling can have a beneficial effect on the likelihood of patients using risk-reduction practices and can reduce the risk for future acquisition of an STD. One effective client-centered approach is Project RESPECT, which demonstrated that a brief counseling intervention was associated with a reduced frequency of STD/HIV risk-related behaviors and with a lowered acquisition of STDs. Practice models based on Project RESPECT have been successfully implemented in clinic-based settings. Other approaches use motivational interviewing to move clients toward achievable risk reduction goals. CDC provides additional information on these and other effective behavioral interventions at http://effectiveinterventions.org.
  
  
• Interactive counseling can be used effectively by all health-care providers or can be conducted by specially trained counselors. The quality of counseling is best ensured when providers receive basic training in prevention counseling methods and skill-building approaches, periodic observation of counseling with immediate feedback by persons with expertise in the counseling approach, periodic counselor and/or patient satisfaction evaluations, and availability of expert assistance or referral for challenging situations. Training in client-centered counseling is available through the CDC STD/HIV Prevention Training Centers (http://www.stdhivpreventiontraining.org). Prevention counseling is most effective if provided in a nonjudgmental manner appropriate to the patient's culture, language, sex, sexual orientation, age, and developmental level.

In addition to individual prevention counseling, some videos and large group presentations provide explicit information concerning how to use condoms correctly. These have been effective in reducing the occurrence of additional STDs among persons at high risk, including STD clinic patients and adolescents.

Because the incidence of some STDs, notably syphilis, has increased in HIV-infected persons, the use of client-centered STD counseling for HIV-infected persons has received strong emphasis from public health agencies and organizations. Consensus guidelines issued by CDC, the Health Resources and Services Administration, the HIV Medicine Association of the Infectious Diseases Society of America, and the National Institutes of Health emphasize that STD/HIV risk assessment, STD screening, and client-centered risk reduction counseling should be provided routinely to HIV-infected persons. Several specific methods have been designed for the HIV care setting. Additional information regarding these approaches is available at http://effectiveinterventions.org.

Prevention Methods

Client-Initiated Interventions to Reduce Sexual Transmission of STD/HIV and Unintended Pregnancy

Abstinence and Reduction of Number of Sex Partners

The most reliable way to avoid transmission of STDs is to abstain from sex (i.e., oral, vaginal, or anal sex) or to be in a long-term, mutually monogamous relationship with an uninfected partner. Counseling that encourages abstinence from sexual intercourse is crucial for persons who are being treated for an STD (or whose partners are undergoing treatment) and for persons who want to avoid the possible consequences of sex completely (e.g., STD/HIV and unintended pregnancy). A more comprehensive discussion of abstinence is available in Contraceptive Technology, 18th edition. For persons embarking on a mutually monogamous relationship, screening for common STDs before initiating sex might reduce the risk for future transmission of asymptomatic STDs.

Preexposure Vaccination

Preexposure vaccination is one of the most effective methods for preventing transmission of some STDs. For example, because HBV infection is frequently sexually transmitted, hepatitis B vaccination is recommended for all unvaccinated, uninfected persons being evaluated for an STD. In addition, hepatitis A vaccine is licensed and is recommended for men who have sex with men (MSM) and illicit drug users (i.e., both injecting and noninjecting). Specific details regarding hepatitis A and B vaccination are available at http://cdc.gov/hepatitis. A quadrivalent vaccine against human papillomavirus (HPV types 6, 11, 16, 18) is now available and licensed for females aged 9--26 years. Vaccine trials for other STDs are being conducted.

Male Condoms

When used consistently and correctly, male latex condoms are highly effective in preventing the sexual transmission of HIV infection (i.e., HIV-negative partners in heterosexual serodiscordant relationships in which condoms were consistently used were 80% less likely to become HIV-infected compared with persons in similar relationships in which condoms were not used) and can reduce the risk for other STDs, including chlamydia, gonorrhea, and trichomoniasis, and might reduce the risk of women developing pelvic inflammatory disease (PID). Condom use might reduce the risk for transmission of herpes simplex virus-2 (HSV-2), although data for this effect are more limited. Condom use might reduce the risk for HPV-associated diseases (e.g., genital warts and cervical cancer) and mitigate the adverse consequences of infection with HPV, as their use has been associated with higher rates of regression of cervical intraepithelial neoplasia (CIN) and clearance of HPV infection in women, and with regression of HPV-associated penile lesions in men. A limited number of prospective studies have demonstrated a protective effect of condoms on the acquisition of genital HPV; one recent prospective study among newly sexually active college women demonstrated that consistent condom use was associated with a 70% reduction in risk for HPV transmission.

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. Rates of condom breakage during sexual intercourse and withdrawal are approximately two broken condoms per 100 condoms used in the United States. The failure of condoms to protect against STD transmission or unintended pregnancy usually results from inconsistent or incorrect use rather than condom breakage.

Male condoms made of materials other than latex are available in the United States. Although they have had higher breakage and slippage rates when compared with latex condoms and are usually more costly, the pregnancy rates among women whose partners use these condoms are similar to latex condoms. Two general categories of nonlatex condoms exist. The first type is made of polyurethane or other synthetic material and provides protection against STD/HIV and pregnancy equal to that of latex condoms. These can be substituted for persons with latex allergy. The second type is natural membrane condoms (frequently called "natural" condoms or, incorrectly, lambskin condoms). These condoms are usually made from lamb cecum and can have pores up to 1500 nm in diameter. Whereas 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 viral STD transmission can occur with natural membrane condoms. Using natural membrane condoms for protection against STDs is not recommended.

Patients should be advised that condoms must be used consistently and correctly to be effective in preventing STDs, and they should be instructed in the correct use of condoms. The following recommendations ensure the proper use of male condoms:

• Use a new condom with each sex act (e.g., 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 lubricants (e.g., K-Y Jelly™, Astroglide™, AquaLube™, and glycerin) with latex condoms. Oil-based lubricants (e.g., petroleum jelly, shortening, mineral oil, massage oils, body lotions, and cooking oil) can weaken latex.
• Ensure adequate lubrication during vaginal and anal sex, which might require the use of exogenous water-based lubricants.
• To prevent the condom from slipping off, hold the condom firmly against the base of the penis during withdrawal, and withdraw while the penis is still erect.

Female Condoms

Laboratory studies indicate that the female condom (Reality™), which consists of a lubricated polyurethane sheath with a ring on each end that is inserted into the vagina, is an effective mechanical barrier to viruses, including HIV, and to semen. A limited number of clinical studies have evaluated the efficacy of female condoms in providing protection from STDs, including HI. If used consistently and correctly, the female condom might substantially reduce the risk for STDs. When a male condom cannot be used properly, sex partners should consider using a female condom. Female condoms are costly compared with male condoms. The female condom also has been used for STD/HIV protection during receptive anal intercourse. Whereas it might provide some protection in this setting, its efficacy is undefined.

Vaginal Spermicides and Diaphragms

Vaginal spermicides containing nonoxynol-9 (N-9) are not effective in preventing cervical gonorrhea, chlamydia, or HIV infection. Furthermore, frequent use of spermicides containing N-9 has been associated with disruption of the genital epithelium, which might be associated with an increased risk for HIV transmission. Therefore, N-9 is not recommended for STD/HIV prevention. In case-control and cross-sectional studies, diaphragm use has been demonstrated to protect against cervical gonorrhea, chlamydia, and trichomoniasis; a randomized controlled trial will be conducted. On the basis of all available evidence, diaphragms should not be relied on as the sole source of protection against HIV infection. Diaphragm and spermicide use have been associated with an increased risk for bacterial urinary tract infections in women.

Condoms and N-9 Vaginal Spermicides

Condoms lubricated with spermicides are no more effective than other lubricated condoms in protecting against the transmission of HIV and other STDs, and those that are lubricated with N-9 pose the concerns that have been previously discussed. Use of condoms lubricated with N-9 is not recommended for STD/HIV prevention because spermicide-coated condoms cost more, have a shorter shelf-life than other lubricated condoms, and have been associated with urinary tract infection in young women.

Rectal Use of N-9 Spermicides

Recent studies indicate that N-9 might increase the risk for HIV transmission during vaginal intercourse. Although similar studies have not been conducted among men who use N-9 spermicide during anal intercourse with other men, N-9 can damage the cells lining the rectum, which might provide a portal of entry for HIV and other sexually transmissible agents. Therefore, N-9 should not be used as a microbicide or lubricant during anal intercourse.

Nonbarrier Contraception, Surgical Sterilization, and Hysterectomy

Sexually active women who are not at risk for pregnancy might incorrectly perceive themselves to be at no risk for STDs, including HIV infection. Contraceptive methods that are not mechanical barriers offer no protection against HIV or other STDs. Women who use hormonal contraception (e.g., oral contraceptives, Norplant™, and Depo-Provera™), have intrauterine devices (IUD), have been surgically sterilized, or have had hysterectomies should be counseled regarding the use of condoms and the risk for STDs, including HIV infection.

Emergency Contraception (EC)

Emergency use of oral contraceptive pills containing levonorgesterol alone reduces the risk for pregnancy after unprotected intercourse by 89%. Pills containing a combination of ethinyl estradiol and either norgestrel or levonorgestrel can be used and reduce the risk for pregnancy by 75%. Emergency insertion of a copper IUD also is highly effective, reducing the risk by as much as 99%. EC with oral contraceptive pills should be initiated as soon as possible after unprotected intercourse and definitely within 120 hours (i.e., 5 days). The only medical contraindication to provision of EC is current pregnancy.

Providers who manage persons at risk for STDs should counsel women concerning the option for EC, if indicated, and provide it in a timely fashion if desired by the woman. Plan B (two 750 mcg levonorgestrel tablets) has been approved by FDA and is available in the United States for the prevention of unintended pregnancy. Additional information on EC is available in Contraceptive Technology, 18th edition, or at http://www.arhp.org/healthcareproviders/resources/contraceptionresources.

Postexposure Prophylaxis (PEP) for HIV

Guidelines for the use of PEP aimed at preventing HIV acquisition as a result of sexual exposure are available and are discussed in this report (see Sexual Assault and STDs).

Partner Management

Partner notification, previously referred to as "contact tracing" but recently included in the broader category of partner services, is the process by which providers or public health authorities learn from persons with STDs about their sex partners and help to arrange for the evaluation and treatment of sex partners. Providers can seek this information and help to arrange for evaluation and treatment of sex partners, either directly or with assistance from state and local health departments. The intensity of partner services and the specific STDs for which they are offered vary among providers, agencies, and geographic areas. Ideally, such services should be accompanied by health counseling and might include referral of patients and their partners for other services, whenever appropriate.

In general, whether partner notification effectively decreases exposure to STDs and whether it changes the incidence and prevalence of STDs in a community are uncertain. The paucity of supporting evidence regarding the effectiveness of partner notification has spurred the exploration of alternative approaches. One such approach is to place partner notification in a larger context by making interventions in the sexual and social networks in which persons are exposed to STDs. Prospective evaluations incorporating assessment of venues, community structure, and social and sexual, contacts in conjunction with partner notification of efforts are promising in terms of increasing case-finding and warrant further exploration. The scope of such efforts probably precludes individual clinician efforts to use network-based approaches, but STD-control programs might find them useful.

Many persons individually benefit from partner notification. When partners are treated, index patients have reduced risk for reinfection. At a population level, partner notification can disrupt networks of STD transmission and reduce disease incidence. Therefore, providers should encourage their patients with STDs to notify their sex partners and urge them to seek medical evaluation and treatment, regardless of whether assistance is available from health agencies. When medical evaluation, counseling, and treatment of partners cannot be done because of the particular circumstances of a patient or partner or because of resource limitations, other partner management options can be considered. One option is patient-delivered therapy, a form of expedited partner therapy (EPT) in which partners of infected patients are treated without previous medical evaluation or prevention counseling (http://www.cdc.gov/std/treatment/EPTFinalReport2006.pdf).

The evidence supporting patient-delivered therapy is based on three clinical trials that included heterosexual men and women with chlamydia or gonorrhea. The strength of the supporting evidence differed by STD and by the sex of the index case when reinfection of the index case was the measured outcome. Despite this variation, patient-delivered therapy (i.e., via medications or prescriptions) can prevent reinfection of index case and has been associated with a higher likelihood of partner notification, compared with unassisted patient referral of partners. Medications and prescriptions for patient-delivered therapy should be accompanied by treatment instructions, appropriate warnings about taking medications if pregnant, general health counseling, and advice that partners should seek personal medical evaluations, particularly women with symptoms of STDs or PID. Existing data suggest that EPT has a limited role in partner management for trichomoniasis. No data support its use in the routine management of syphilis. There is no experience with expedited partner therapy for gonorrhea or chlamydia infection among MSM. Currently, EPT is not feasible in many settings because of operational barriers, including the lack of clear legal status of EPT in some states.

Reporting and Confidentiality

The accurate and timely reporting of STDs is integrally important for assessing morbidity trends, targeting limited resources, and assisting local health authorities in partner notification and treatment. STD/HIV and acquired immunodeficiency syndrome (AIDS) cases should be reported in accordance with state and local statutory requirements. Syphilis, gonorrhea, chlamydia, chanroid, HIV infection, and AIDS are reportable diseases in every state. The requirements for reporting other STDs differ by state, and clinicians should be familiar with state and local reporting requirements.
Reporting can be provider- and/or laboratory-based. Clinicians who are unsure of state and local reporting requirements should seek advice from state or local health departments or STD programs. STD and HIV reports are kept strictly confidential. In the majority of jurisdictions, such reports are protected by statute from subpoena. Before public health representatives conduct a follow-up of a positive STD-test result, they should consult the patient's health-care provider to verify the diagnosis and treatment.

Pregnant Women

Intrauterine or perinatally transmitted STDs can have severely debilitating effects on pregnant women, their partners, and their fetuses. All pregnant women and their sex partners should be asked about STDs, counseled about the possibility of perinatal infections, and ensured access to treatment, if needed.

Recommended Screening Tests

• All pregnant women in the United States should be tested for HIV infection as early in pregnancy as possible. Testing should be conducted after the woman is notified that she will be tested for HIV as part of the routine panel of prenatal tests, unless she declines the test (i.e., opt-out screening). For women who decline HIV testing, providers should address their objections, and where appropriate, continue to strongly encourage testing. Women who decline testing because they have had a previous negative HIV test should be informed of the importance of retesting during each pregnancy. Testing pregnant women is vital not only to maintain the health of the patient but also because interventions (i.e., antiretroviral and obstetrical) are available that can reduce perinatal transmission of HIV. Retesting in the third trimester (i.e., preferably before 36 weeks' gestation) is recommended for women at high risk for acquiring HIV infection (i.e., women who use illicit drugs, have STDs during pregnancy, have multiple sex partners during pregnancy, or have HIV-infected partners). Rapid HIV testing should be performed on women in labor with undocumented HIV status. If a rapid HIV test result is positive, antiretroviral prophylaxis (with consent) should be administered without waiting for the results of the confirmatory test.
  
  
• A serologic test for syphilis should be performed on all pregnant women at the first prenatal visit. In populations in which use of prenatal care is not optimal, rapid plasma reagin (RPR) card test screening (and treatment, if that test is reactive) should be performed at the time a pregnancy is confirmed. Women who are at high risk for syphilis, live in areas of high syphilis morbidity, are previously untested, or have positive serology in the first trimester should be screened again early in the third trimester (28 weeks' gestation) and at delivery. Some states require all women to be screened at delivery. Infants should not be discharged from the hospital unless the syphilis serologic status of the mother has been determined at least one time during pregnancy and preferably again at delivery. Any woman who delivers a stillborn infant should be tested for syphilis.
  
  
• All pregnant women should be routinely tested for hepatitis B surface antigen (HBsAg) during an early prenatal visit (e.g., first trimester) in each pregnancy, even if they have been previously vaccinated or tested. Women who were not screened prenatally, those who engage in behaviors that put them at high risk for infection (e.g., more than one sex partner in the previous 6 months, evaluation or treatment for an STD, recent or current injecting-drug use, and HBsAg-positive sex partner), and those with clinical hepatitis should be retested at the time of admission to the hospital for delivery. Women at risk for HBV infection also should be vaccinated. To avoid misinterpreting a transient positive HBsAg result during the 21 days after vaccination, HBsAg testing should be performed before the vaccination.
  
  
• All laboratories that conduct HBsAg tests should use an HBsAg test that is FDA-cleared and should perform testing according to the manufacturer's labeling, including testing of 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 may be used, and initially reactive results should prompt expedited administration of immunoprophylaxis to infants.
  
  
• All pregnant women should be routinely tested for Chlamydia trachomatis (see Chlamydia Infections, Diagnostic Considerations) at the first prenatal visit. Women aged <25 years and those at increased risk for chlamydia (i.e., women who have a new or more than one sex partner) also should be retested during the third trimester to prevent maternal postnatal complications and chlamydial infection in the infant. Screening during the first trimester might prevent the adverse effects of chlamydia during pregnancy, but supportive evidence for this is lacking. If screening is performed only during the first trimester, a longer period exists for acquiring infection before delivery.
  
  
• All pregnant women at risk for gonorrhea or living in an area in which the prevalence of Neisseria gonorrhoeae is high should be tested at the first prenatal visit for N. gonorrhoeae. (See Gonococcal Infections, Diagnostic Considerations). A repeat test should be performed during the third trimester for those at continued risk.
  
  
• All pregnant women at high risk for hepatitis C infection should be tested for hepatitis C antibodies (see Hepatitis C, Diagnostic Considerations) at the first prenatal visit. Women at high risk include those with a history of injecting-drug use and those with a history of blood transfusion or organ transplantion before 1992.
  
  
• Evaluation for bacterial vaginosis (BV) might be conducted during the first prenatal visit for asymptomatic patients who are at high risk for preterm labor (e.g., those who have a history of a previous preterm delivery). Evidence does not support routine testing for BV.
  
  
• A Papanicolaou (Pap) smear should be obtained at the first prenatal visit if none has been documented during the preceding year.

Other Concerns

• Women who are HBsAg positive should be reported to the local and/or state health department to ensure that they are entered into a case-management system and that timely and appropriate prophylaxis is provided for their infants. Information concerning the pregnant woman's HBsAg status should be provided to the hospital in which delivery is planned and to the health-care provider who will care for the newborn. In addition, household and sex contacts of women who are HBsAg positive should be vaccinated.
  
  
• Women who are HBsAg positive should be provided with, or referred for, appropriate counseling and medical management. Pregnant women who are HBsAg positive pregnant women should receive information regarding hepatitis B that addresses
  --- modes of transmission;
  --- perinatal concerns (e.g., breastfeeding is not contraindicated);
  --- prevention of HBV transmission, including the importance of postexposure prophylaxis for the newborn infant and hepatitis B vaccination for household contacts and sex partners; and
  --- evaluation for and treatment of chronic HBV infection.
  
  
• No treatment is available for HCV-infected pregnant women. However, all women with HCV infection should receive appropriate counseling and supportive care as needed (see Hepatitis C, Prevention). No vaccine is available to prevent HCV transmission.
  
  
• In the absence of lesions during the third trimester, routine serial cultures for HSV are not indicated for women who have a history of recurrent genital herpes. Prophylactic cesarean section is not indicated for women who do not have active genital lesions at the time of delivery. In addition, insufficient evidence exists to recommend routine HSV-2 serologic screening among previously undiagnosed women during pregnancy, nor does sufficient evidence exist to recommend routine antiviral suppressive therapy late in gestation for all HSV-2 positive women.
  
  
• The presence of genital warts is not an indication for cesarean section.
  
  
• Not enough evidence exists to recommend routine screening for Trichomonas vaginalis in asymptomatic pregnant women.

For a more detailed discussion of STD testing and treatment among pregnant women and other infections not transmitted sexually, refer to the following references: Guide to Clinical Preventive Services; Guidelines for Perinatal Care; ACOG Practice Bulletin: Prophylatic Antibiotics in Labor and Delivery; ACOG Committee Opinion: Primary and Preventive Care: Periodic Assessments; Recommendations for the Prevention and Management of Chlamydia trachomatis Infections; Hepatitis B Virus: A Comprehensive Strategy for Eliminating Transmission in the United States---Recommendations of the Immunization Practices Advisory Committee (ACIP); Mother-To-Infant Transmission of Hepatitis C Virus; Hepatitis C: Screening in Pregnancy; American College of Obstetricians and Gynecologists (ACOG) Educational Bulletin: Viral Hepatitis in Pregnancy; Revised Public Health Service Recommendations for HIV Screening of Pregnant Women; Prenatal and Perinatal Human Immunodeficiency Virus Testing: Expanded Recommendations; US Preventative Task Force HIV Screening Guidelines; Rapid HIV Antibody Testing During Labor and Delivery for Women of Unknown HIV Status: A Practical Guide and Model Protocol; and Sexually Transmitted Diseases in Adolescents.

These sources are not entirely consistent in their recommendations. For example, the Guide to Clinical Preventive Services recommends screening of patients at high risk for chlamydia but indicates that the optimal timing for screening is uncertain. The Guidelines for Perinatal Care recommends that pregnant women at high risk for chlamydia be screened for infection during the first prenatal care visit and during the third trimester. Recommendations to screen pregnant women for STDs are based on disease severity and sequelae, prevalence in the population, costs, medicolegal considerations (e.g., state laws), and other factors. The screening recommendations in this report are broader (i.e., if followed, more women will be screened for more STDs than would be screened by following other recommendations) and are compatible with other CDC guidelines.

Adolescents

The rates of many STDs are highest among adolescents. For example, the reported rates of chlamydia and gonorrhea are highest among females aged 15--19 years, and many persons acquire HPV infection during their adolescent years. Among adolescents with acute HBV infection, the most commonly reported risk factors are having sexual contact with a chronically infected person or with multiple sex partners, or reporting their sexual preference as homosexual. As part of a comprehensive strategy to eliminate HBV transmission in the United States, ACIP has recommended that all children and adolescents be administered HBV vaccine.

Younger adolescents (i.e., persons aged <15 years) who are sexually active are at particular risk for STDs, especially youth in detention facilities, STD clinic patients, male homosexuals, and injecting-drug users (IDUs). Adolescents are at higher risk for STDs because they frequently have unprotected intercourse, are biologically more susceptible to infection, are engaged in sexual partnerships frequently of limited duration, and face multiple obstacles to using health care. Several of these issues can be addressed by clinicians who provide services to adolescents. Clinicians can address adolescents' lack of knowledge and awareness regarding the risks and consequences of STDs by offering guidance concerning healthy sexual behavior and, therefore, prevent the establishment of patterns of behavior that can undermine sexual health.

With a few exceptions, all adolescents in the United States can legally consent to the confidential diagnosis and treatment of STDs. In all 50 states and the District of Columbia, medical care for STDs can be provided to adolescents without parental consent or knowledge. In addition, in the majority of states, adolescents can consent to HIV counseling and testing. Consent laws for vaccination of adolescents differ by state. Several states consider provision of vaccine similar to treatment of STDs and provide vaccination services without parental consent. Because of the crucial importance of confidentially, health-care providers should follow policies that provide confidentiality and comply with state laws for STD services.

Despite the prevalence of STDs among adolescents, providers frequently fail to inquire about sexual behavior, assess risk for STDs, provide counseling on risk reduction, and screen for asymptomatic infection during clinical encounters. The style and content of counseling and health education on these sensitive subjects should be adapted for adolescents. Discussions should be appropriate for the patient's developmental level and should be aimed at identifying risky behaviors (e.g., sex and drug-use behaviors). Careful, nonjudgmental, and thorough counseling are particularly vital for adolescents who might not acknowledge that they engage in high-risk behaviors.

Children

Management of children who have STDs requires close cooperation between clinicians, laboratorians, and child-protection authorities. Official investigations, when indicated, should be initiated promptly. Some diseases (e.g., gonorrhea, syphilis, and chlamydia), if acquired after the neonatal period, are virtually 100% indicative of sexual contact. For other diseases (e.g., HPV infection and vaginitis), the association with sexual contact is not as clear (see Sexual Assault and STDs).

MSM

Some MSM are at high risk for HIV infection and other viral and bacterial STDs. The frequency of unsafe sexual practices and the reported rates of bacterial STDs and incident HIV infection have declined substantially in MSM from the 1980s through the mid-1990s. However, during the previous 10 years, increased rates of infectious syphilis, gonorrhea, and chlamydial infection and of higher rates of unsafe sexual behaviors have been documented among MSM in the United States and virtually all industrialized countries. The effect of these behavioral changes on HIV transmission has not been ascertained, but preliminary data suggest that the incidence of HIV infection might be increasing among some MSM. These adverse trends probably are related to changing attitudes concerning HIV infection because of the effects of improved HIV/AIDS therapy on quality of life and survival, changing patterns of substance abuse, demographic shifts in MSM populations, and changes in sex partner networks resulting from new venues for partner acquisition.

Clinicians should assess the risks of STDs for all male patients, including a routine inquiry about the sex of patients' sex partners. MSM, including those with HIV infection, should routinely undergo nonjudgmental STD/HIV risk assessment and client-centered prevention counseling to reduce the likelihood of acquiring or transmitting HIV or other STDs. Clinicians should be familiar with local community resources available to assist MSM at high risk in facilitating behavioral change. Clinicians also should routinely ask sexually active MSM about symptoms consistent with common STDs, including urethral discharge, dysuria, genital and perianal ulcers, regional lymphadenopathy, skin rash, and anorectal symptoms consistent with proctitis. Clinicians also should maintain a low threshold for diagnostic testing of symptomatic patients.

Routine laboratory screening for common STDs is indicated for all sexually active MSM. The following screening recommendations are based on preliminary data. These tests should be performed at least annually for sexually active MSM, including men with or without established HIV infection:

• HIV serology, if HIV negative or not tested within the previous year;
• syphilis serology;
• a test for urethral infection with N. gonorrhoeae and C. trachomatis in men who have had insertive intercourse* during the preceding year;
• a test for rectal infection† with N. gonorrhoeae and C. trachomatis in men who have had receptive anal intercourse* during the preceding year;
• a test for pharyngeal infection† with N. gonorrhoeae in men who have acknowledged participation in receptive oral intercourse* during the preceding year; testing for C. trachomatis pharyngeal infection is not recommended.

In addition, some specialists would consider type-specific serologic tests for HSV-2, if infection status is unknown. Routine testing for anal cytologic abnormalities or anal HPV infection is not recommended until more data are available on the reliability of screening methods, the safety of and response to treatment, and programmatic considerations.

More frequent STD screening (i.e., at 3--6 month intervals) is indicated for MSM who have multiple or anonymous partners, have sex in conjunction with illicit drug use, use methamphetamine, or whose sex partners participate in these activities.

Vaccination against hepatitis A and B is recommended for all MSM in whom previous infection or immunization cannot be documented. Preimmunization serologic testing might be considered to reduce the cost of vaccinating MSM who are already immune to these infections, but this testing should not be delay vaccination. Vaccinating persons who are immune to HAV or HBV infection because of previous infection or vaccination does not increase the risk for vaccine-related adverse events (see Hepatitis B, Prevaccination Antibody Screening).

Women Who Have Sex with Women (WSW)

Few data are available on the risk of STDs conferred by sex between women, but transmission risk probably varies by the specific STD and sexual practice (e.g., oral-genital sex, vaginal or anal sex using hands, fingers, or penetrative sex items, and oral-anal sex). Practices involving digital-vaginal or digital-anal contact, particularly with shared penetrative sex items, present a possible means for transmission of infected cervicovaginal secretions. This possibility is most directly supported by reports of metronidazole-resistant trichomoniasis and genotype-concordant HIV transmitted sexually between women who reported these behaviors and by the high prevalence of BV among monogamous WSW. Transmission of HPV can occur with skin-to-skin or skin-to-mucosa contact, which can occur during sex between women. HPV deoxyribonucleic acid (DNA) has been detected through polymerase chain reaction (PCR)-based methods from the cervix, vagina, and vulva in 13%--30% of WSW, and high- and low-grade squamous intraepithelial lesions (SIL) have been detected on Pap tests in WSW who reported no previous sex with men. However, the majority of self-identified WSW (53%--99%) have had sex with men and might continue this practice. Therefore, all women should undergo Pap test screening using current national guidelines, regardless of sexual preference or sexual practices.

HSV-2 genital transmission between female sex partners is probably inefficient, but the relatively frequent practice of orogenital sex among WSW might place them at higher risk for genital infection with HSV-1. This hypothesis is supported by the recognized association between HSV-1 seropositivity and previous number of female partners among WSW. Transmission of syphilis between female sex partners, probably through oral sex, has been reported. Although the rate of transmission of C. trachomatis between women is unknown, WSW who also have sex with men are at risk and should undergo routine screening according to guidelines.

Infection with HIV produces a spectrum of disease that progresses from a clinically latent or asymptomatic state to AIDS as a late manifestation. The pace of disease progression varies. In untreated patients, the time between infection with HIV and the development of AIDS ranges from a few months to as long as 17 years (median: 10 years). The majority of adults and adolescents infected with HIV remain symptom-free for extended periods, but viral replication is active during all stages of infection and increases substantially as the immune system deteriorates. In the absence of treatment, AIDS will develop eventually in nearly all HIV-infected persons.

Improvements in antiretroviral therapy and increasing awareness among both patients and health-care providers of the risk factors associated with HIV transmission have led to more testing for HIV and earlier diagnosis, frequently before symptoms develop. However, the conditions of nearly 40% of persons who acquire HIV infection continue to be diagnosed late, within 1 year of acquiring AIDS. Prompt diagnosis of HIV infection is essential for multiple reasons. Treatments are available that slow the decline of immune system function; use of these therapies has been associated with substantial declines in HIV-associated morbidity and mortality in recent years. HIV-infected persons who have altered immune function are at increased risk for infections for which preventive measures are available (e.g., Pneumocystis jiroveci pneumonia, toxoplasma encephalitis [TE], disseminated Mycobacterium avium complex [MAC] disease, tuberculosis [TB], and bacterial pneumonia). Because of its effect on the immune system, HIV affects the diagnosis, evaluation, treatment, and follow-up of multiple other diseases and might affect the efficacy of antimicrobial therapy for some STDs. Finally, the early diagnosis of HIV enables health-care providers to counsel infected patients, refer them to various support services, and help prevent HIV transmission to others. Acutely infected persons might have elevated HIV viral loads and, therefore, might be more likely to transmit HIV to their partners.

Proper management of HIV infection involves a complex array of behavioral, psychosocial, and medical services. Although some services might not be available in STD treatment facilities. Therefore, referral to a health-care provider or facility experienced in caring for HIV-infected patients is advised. Providers working in STD-treatment facilities should be knowledgeable about the options for referral available in their communities. While receiving care in STD-treatment facilities, HIV-infected patients should be educated about HIV infection and the various options available for support services and HIV care.

A detailed discussion of the multiple, complex services required for management of HIV infection is beyond the scope of this section; however, this information is available in other published resources. In subsequent sections, this report provides information regarding diagnostic testing for HIV infection, counseling patients who have HIV infection, referral of patients for support services, including medical care, and the management of sex and injecting-drug partners in STD-treatment facilities. In addition, the report discusses HIV infection during pregnancy and in infants and children.

Detection of HIV Infection: Screening and Diagnostic Testing

All persons who seek evaluation and treatment for STDs should be screened for HIV infection. Screening should be routine, regardless of whether the patient is known or suspected to have specific behavioral risks for HIV infection.

Consent and Pretest Information

HIV screening should be voluntary and conducted only with the patient's knowledge and understanding that testing is planned. Persons should be informed orally or in writing that HIV testing will be performed unless they decline (i.e., opt-out screening). Oral or written communications should include an explanation of positive and negative test results, and patients should be offered an opportunity to ask questions and to decline testing.

Prevention Counseling

Prevention counseling does not need to be explicitly linked to the HIV-testing process. However, some patients might be more likely to think about HIV and consider their risks when undergoing an HIV test. HIV testing might present an ideal opportunity to provide or arrange for prevention counseling to assist with behavior changes that can reduce risk for acquiring HIV infection. Prevention counseling should be offered and encouraged in all health-care facilities serving patients at high risk and in those (e.g., STD clinics) where information on HIV-risk behaviors is routinely elicited.

Diagnostic Testing

HIV infection usually is diagnosed by tests for antibodies against HIV-1. Some combination tests also detect antibodies against HIV-2 (i.e., HIV-1/2). Antibody testing begins with a sensitive screening test (e.g., the enzyme immunoassay [EIA] or rapid test). The advent of HIV rapid testing has enabled clinicians to make a substantially accurate presumptive diagnosis of HIV-1 infection within half an hour. This testing can facilitate the identification of the more than 250,000 persons living with undiagnosed HIV in the United States. Reactive screening tests must be confirmed by a supplemental test (e.g., the Western blot [WB]) or an immunofluorescence assay (IFA). If confirmed by a supplemental test, a positive antibody test result indicates that a person is infected with HIV and is capable of transmitting the virus to others. HIV antibody is detectable in at least 95% of patients within 3 months after infection. Although a negative antibody test result usually indicates that a person is not infected, antibody tests cannot exclude recent infection.

The majority of HIV infections in the United States are caused by HIV-1. However, HIV-2 infection should be suspected in persons who have epidemiologic risk factors, including being from West Africa (where HIV-2 is endemic) or have sex partners from endemic areas, have sex partners known to be infected with HIV-2, or have received a blood transfusion or nonsterile injection in a West African country. HIV-2 testing also is indicated when clinical evidence of HIV exists but tests for HIV-1 antibodies or HIV-1 viral load are not positive, or when HIV-1 WB results include the unusual indeterminate pattern of gag plus pol bands in the absence of env bands.

Health-care providers should be knowledgeable about the symptoms and signs of acute retroviral syndrome, which is characterized by fever, malaise, lymphadenopathy, and skin rash. This syndrome frequently occurs in the first few weeks after HIV infection, before antibody test results become positive. Suspicion of acute retroviral syndrome should prompt nucleic acid testing (HIV plasma ribonucleic acid [RNA]) to detect the presence of HIV, although not all nucleic acid tests are approved for diagnostic purposes; a positive HIV nucleic acid test should be confirmed by subsequent antibody testing to document seroconversion (using standard methods, EIA, and WB). Acutely infected patients might be highly contagious because of increased plasma and genital HIV RNA concentrations and might be continuing to engage in risky behaviors. Current guidelines suggest that persons with recently acquired HIV infection might benefit from antiretroviral drugs and be candidates for clinical trials. Therefore, patients with acute HIV infection should be referred immediately to an HIV clinical care provider.

Diagnosis of HIV infection should prompt efforts to reduce the risk behavior that resulted in HIV infection and could result in transmission of HIV to others. Early counseling and education are particularly important for persons with recently acquired infection because HIV plasma RNA levels are characteristically high during this phase of infection and probably constitute an increased risk for HIV transmission. The following are specific recommendations for diagnostic testing for HIV infection:

• HIV screening is recommended for all persons who seek evaluation and treatment for STDs.
• HIV testing must be voluntary.
• Consent for HIV testing should be incorporated into the general consent for care (verbally or in writing) with an opportunity to decline (opt-out screening).
• HIV rapid testing must be considered, especially in clinics where a high proportion of patients do not return for HIV test results.
• Positive screening tests for HIV antibody must be confirmed by a supplemental test (e.g., WB or IFA) before being considered diagnostic of HIV infection.
• Persons who have positive HIV test results (screening and confirmatory) must receive initial HIV prevention counseling before leaving the testing site. Such persons should 1) receive a medical evaluation and, if indicated, behavioral and psychological services, or 2) be referred for these services.
• Providers should be alert to the possibility of acute retroviral syndrome and should perform nucleic acid testing for HIV, if indicated. Patients suspected of having recently acquired HIV infection should be referred for immediate consultation with a specialist.
  

Counseling for Patients with HIV Infection and Referral to Support Services

Persons can be expected to be distressed when first informed of a positive HIV test result. Such persons face multiple major adaptive challenges, including
1) accepting the possibility of a shortened life span,
2) coping with the reactions of others to a stigmatizing illness,
3) developing and adopting strategies for maintaining physical and emotional health, and
4) initiating changes in behavior to prevent HIV transmission to others.

Many persons will require assistance with making reproductive choices, gaining access to health services, confronting possible employment or housing discrimination, and coping with changes in personal relationships. Therefore, behavioral and psychosocial services are an integral part of health care for HIV-infected persons. Such services should be available on site or through referral when HIV infection is diagnosed. A comprehensive discussion of specific recommendations is available in the Guidelines for HIV Counseling, Testing, and Referral and Revised Recommendations for HIV Screening of Pregnant Women. Innovative and successful interventions to decrease risk taking by HIV-infected patients have been developed for diverse populations.

Practice settings for offering HIV care differ depending on local resources and needs. Primary care providers and outpatient facilities should ensure that appropriate resources are available for each patient to avoid fragmentation of care. Although a single source that is capable of providing comprehensive care for all stages of HIV infection is preferred, the limited availability of such resources frequently results in the need to coordinate care among medical and social service providers in different locations. Providers should avoid long delays between diagnosis of HIV infection and access to additional medical and psychosocial services. The use of HIV rapid testing can help avoid unnecessary delays.

Recently identified HIV infection might not have been recently acquired. Persons newly diagnosed with HIV might be at any stage of infection. Therefore, health-care providers should be alert for symptoms or signs that suggest advanced HIV infection (e.g., fever, weight loss, diarrhea, cough, shortness of breath, and oral candidiasis). The presence of any of these symptoms should prompt urgent referral for specialty medical care. Similarly, providers should be alert for signs of psychologic distress and be prepared to refer patients accordingly.

Diagnosis of HIV infection reinforces the need to counsel patients regarding high-risk behaviors because the consequences of such behaviors include the risk for acquiring additional STDs and for transmitting HIV (and other STDs) to other persons. Such attention to behaviors in HIV-infected persons is consistent with national strategies for HIV prevention. Providers should refer patients for prevention counseling and risk-reduction support concerning high-risk behaviors (e.g., substance abuse and high-risk sexual behaviors). In multiple recent studies, researchers have developed successful prevention interventions for different HIV-infected populations that can be adapted to individuals.

Persons with newly diagnosed HIV infection who receive care in the STD treatment setting should be educated concerning what to expect as they enter medical care for HIV infection. In nonemergent situations, the initial evaluation of HIV-positive patients usually includes the following:

• a detailed medical history, including sexual and substance abuse history; vaccination history; previous STDs; and specific HIV-related symptoms or diagnoses;
• a physical examination, including a gynecologic examination for women;
• testing for N. gonorrhoeae and C. trachomatis (and for women, a Pap test and wet mount examination of vaginal secretions);
• complete blood and platelet counts and blood chemistry profile;
• toxoplasma antibody test;
• tests for antibodies to HCV; testing for previous or present HAV or HBV infection is recommended if determined to be cost-effective before considering vaccination (see Hepatitis A and Hepatitis B);
• syphilis serology;
• a CD4 T-lymphocyte analysis and determination of HIV plasma viral load;
• a tuberculin skin test (sometimes referred to as a purified protein derivative);
• a urinalysis; and
• a chest radiograph.

Some specialists recommend type-specific testing for HSV-2 if herpes infection status is unknown. A first dose of hepatitis A and/or hepatitis B vaccination for previously unvaccinated persons for whom vaccine is recommended (see Hepatitis A and Hepatitis B) should be administered at this first visit.

In subsequent visits, when the results of laboratory and skin tests are available, antiretroviral therapy may be offered, if indicated, after initial antiretroviral resistance testing is performed and specific prophylactic medications are administered to reduce the incidence of opportunistic infections (e.g., Pneumocystis jiroveci pneumonia, TE, disseminated MAC infection, and TB). The vaccination series for hepatitis A and/or B should be offered for those in whom vaccination is recommended. Influenza vaccination should be offered annually, and pneumococcal vaccination should be given if it has not been administered in the previous 5 years.

Providers should be alert to the possibility of new or recurrent STDs and should treat such conditions aggressively. The occurrence of an STD in an HIV-infected person is an indication of high-risk behavior and should prompt referral for counseling. Because many STDs are asymptomatic, routine screening for curable STDs (e.g., syphilis, gonorrhea, and chlamydia) should be performed at least yearly for sexually active persons. Women should be screened for cervical cancer precursor lesions by annual Pap smears. More frequent STD screening might be appropriate depending on individual risk behaviors, the local epidemiology of STDs, and whether incident STDs are detected by screening or by the presence of symptoms.

Newly diagnosed HIV-infected persons should receive or be referred for a thorough psychosocial evaluation, including ascertainment of behavioral factors indicating risk for transmitting HIV. Patients might require referral for specific behavioral intervention (e.g., a substance abuse program), mental health disorders (e.g., depression), or emotional distress. They might require assistance with securing and maintaining employment and housing. Women should be counseled or appropriately referred regarding reproductive choices and contraceptive options. Patients with multiple psychosocial problems might be candidates for comprehensive risk-reduction counseling and services.

The following are specific recommendations for HIV counseling and referral:

• Persons who test positive for HIV antibody should be counseled, either on site or through referral, concerning the behavioral, psychosocial, and medical implications of HIV infection.
• Health-care providers should be alert for medical or psychosocial conditions that require immediate attention.
• Providers should assess whether newly diagnosed patients' need for immediate medical care or support should and link them to services in which health-care personnel are experienced in providing care for HIV-infected persons. Such persons might need medical care or services for substance abuse, mental health disorders, emotional distress, reproductive counseling, risk-reduction counseling, and case management. Providers should follow-up to ensure that patients have received the needed services.
• Patients should be educated regarding what to expect in follow-up medical care.

Several innovative interventions for HIV prevention have been developed for diverse at-risk populations, and these can be locally replicated or adapted. Involvement of nongovernment organizations and community-based organizations might complement such efforts in the clinical setting.

Management of Sex Partners and Injecting-Drug Partners

Clinicians evaluating HIV-infected persons should collect information to determine whether any partners should be notified concerning possible exposure to HIV. When referring to persons who are infected with HIV, the term "partner" includes not only sex partners but also IDUs who share syringes or other injection equipment. The rationale for partner notification is that the early diagnosis and treatment of HIV infection in these partners might reduce morbidity and provides the opportunity to encourage risk-reducing behaviors. Partner notification for HIV infection should be confidential and depends on the voluntary cooperation of the patient. Specific guidance regarding spousal notification may vary by jurisdiction.

Two complementary notification processes, patient referral and provider referral, can be used to identify partners. With patient referral, patients directly inform their partners of their exposure to HIV infection. With provider referral, trained health department personnel locate partners on the basis of the names, descriptions, and addresses provided by the patient. During the notification process, the confidentiality of patients is protected; their names are not revealed to partners who are notified. Many state and local health departments provide these services.

The following are specific recommendations for implementing partner-notification procedures:

• HIV-infected patients should be encouraged to notify their partners and to refer them for counseling and testing. If requested by the patient, health-care providers should assist in this process, either directly or by referral to health department partner-notification programs.
• If patients are unwilling to notify their partners or if they cannot ensure that their partners will seek counseling, physicians or health department personnel should use confidential partner notification procedures.
• Partners who are contacted within 72 hours of a high-risk sexual or injecting-drug exposure to an HIV-infected partner, which involves exposure to genital secretions and/or blood, should be offered PEP with combination antiretroviral therapy to complete a 28-day course

Special Considerations

Pregnancy. All pregnant women in the United States should be tested for HIV infection as early during pregnancy as possible. Testing should occur after the patient is notified that she will be tested for HIV as part of the routine panel of prenatal tests, unless she declines (i.e., opt-out screening). For women who decline, providers should continue to strongly encourage testing and address concerns that pose obstacles to testing. Women who decline testing because they have had a previous negative HIV test should be informed of the importance of retesting during each pregnancy. Testing pregnant women is particularly important, not only to maintain the health of the patient, but also because interventions (i.e., antiretroviral and obstetrical) can reduce the risk of perinatal transmission of HIV.

After pregnant women have been identified as being HIV-infected, they should be educated about the risk of perinatal infection. Evidence indicates that, in the absence of antiretroviral and other interventions, 15%--25% of infants born to HIV-infected mothers will become infected with HIV; such evidence also indicates that an additional 12%--14% will become infected during breastfeeding where HIV-infected women breastfeed their infants into the second year of life.

The risk of perinatal HIV transmission can be reduced substantially to <2% through the use of antiretroviral regimens and obstetrical interventions (i.e., zidovudine or nevirapine and elective cesarean section at 38 weeks of pregnancy) and by avoiding breastfeeding. Pregnant women who are HIV infected should be counseled concerning their options (either on-site or by referral), given appropriate antenatal treatment, and advised not to breastfeed their infants (for women living in the United States, where infant formula is readily available and can be safely prepared).

HIV Infection Among Infants and Children

Diagnosis of HIV infection in a pregnant woman indicates the need to consider whether other children of the woman might be infected. Infants and young children with HIV infection differ from adults and adolescents with respect to the diagnosis, clinical presentation, and management of HIV disease. For example, because maternal HIV antibody passes through the placenta, antibody tests for HIV are expected to be positive in the sera of both infected and uninfected infants born to seropositive mothers. A definitive determination of HIV infection for an infant aged <18 months is usually based on HIV nucleic acid testing. Management of infants, children, and adolescents who are known or suspected to be infected with HIV requires referral to physicians familiar with the manifestations and treatment of pediatric HIV infection.

Management of Patients Who Have Genital Ulcers

In the United States, the majority of young, sexually active patients who have genital ulcers have either genital herpes, syphilis, or chancroid. The frequency of each condition differs by geographic area and patient population; however, genital herpes is the most prevalent of these diseases. More than one of these diseases can be present in a patient who has genital ulcers. All three of these diseases has been associated with an increased risk for HIV infection. Not all genital ulcers are caused by sexually transmitted infections.

A diagnosis based only on the patient's medical history and physical examination frequently is inaccurate. Therefore, all patients who have genital ulcers should be evaluated with a serologic test for syphilis and a diagnostic evaluation for genital herpes; in settings where chancroid is prevalent, a test for Haemophilus ducreyi should also be performed. Specific tests for evaluation of genital ulcers include
1) syphilis serology and either darkfield examination or direct immunofluorescence test for T. pallidum;
2) culture or antigen test for HSV; and
3) culture for H. ducreyi.

No FDA-cleared PCR test for these organisms is available in the United States; however, such testing can be performed by clinical laboratories that have developed their own tests and conducted a Clinical Laboratory Improvement Amendment (CLIA) verification study. Type-specific serology for HSV-2 might be helpful in identifying persons with genital herpes (see Genital Herpes, Type-Specific Serologic Tests). Biopsy of genital ulcers might be helpful in identifying the cause of ulcers that are unusual or that do not respond to initial therapy. HIV testing should be performed on all patients who have genital ulcers caused by T. pallidum or H. ducreyi, and should be strongly considered for those who have genital ulcers caused by HSV (see Diagnostic Considerations, sections, Syphilis, Chancroid, and Genital Herpes Simplex Virus).

Health-care providers frequently must treat patients before test results are available because early treatment decreases the possibility of ongoing transmission and because successful treatment of genital herpes depends on prompt initiation of therapy. The clinician should treat for the diagnosis considered most likely, on the basis of clinical presentation and epidemiologic circumstances. In some instances, treatment must be initiated for additional conditions because of diagnostic uncertainty. Even after complete diagnostic evaluation, at least 25% of patients who have genital ulcers have no laboratory-confirmed diagnosis.

Chancroid

In the United States, chancroid usually occurs in discrete outbreaks, although the disease is endemic in some areas. Chancroid is a cofactor for HIV transmission, as are genital herpes and syphilis; high rates of HIV infection among patients who have chancroid occur in the United States and other countries. Approximately 10% of persons who have chancroid that was acquired in the United States are coinfected with T. pallidum or HSV; this percentage is higher in persons who have acquired chancroid outside the United States.

A definitive diagnosis of chancroid requires the identification of H. ducreyi on special culture media that is not widely available from commercial sources; even when these media are used, sensitivity is <80%. No FDA-cleared PCR test for H. ducreyi is available in the United States, but such testing can be performed by clinical laboratories that have developed their own PCR test and conducted a CLIA verification study.

The combination of a painful genital ulcer and tender suppurative inguinal adenopathy suggests the diagnosis of chancroid. A probable diagnosis of chancroid, for both clinical and surveillance purposes, can be made if all of the following criteria are met:
1) the patient has one or more painful genital ulcers;
2) the patient has no evidence of T. pallidum infection by darkfield examination of ulcer exudate or by a serologic test for syphilis
    performed at least 7 days after onset of ulcers;
3) the clinical presentation, appearance of genital ulcers and, if present, regional lymphadenopathy are typical for chancroid; and
4) a test for HSV performed on the ulcer exudate is negative.

Treatment

Successful treatment for chancroid cures the infection, resolves the clinical symptoms, and prevents transmission to others. In advanced cases, scarring can result, despite successful therapy.

Recommended Regimens*
Azithromycin 1 g orally in a single dose
OR
Ceftriaxone 250 mg intramuscularly (IM) in a single dose
OR
Ciprofloxacin 500 mg orally twice a day for 3 days
OR
Erythromycin base 500 mg orally three times a day for 7 days

* Ciprofloxacin is contraindicated for pregnant and lactating women. Azithromycin and ceftriaxone offer the advantage of single-dose therapy. Worldwide, several isolates with intermediate resistance to either ciprofloxacin or erythromycin have been reported.

Other Management Considerations

Male patients who are uncircumcised and patients with HIV infection do not respond as well to treatment as those who are circumcised or HIV negative. Patients should be tested for HIV infection at the time chancroid is diagnosed. Patients should be retested for syphilis and HIV 3 months after the diagnosis of chancroid, if the initial test results were negative.

Follow-Up

Patients should be reexamined 3--7 days after initiation of therapy. 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 must consider whether
1) the diagnosis is correct,
2) the patient is coinfected with another STD,
3) the patient is infected with HIV,
4) the treatment was not used as instructed, or
5) 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 is slower for some uncircumcised men who have ulcers under the foreskin. Clinical resolution of fluctuant lymphadenopathy is slower than resolution for ulcers and might require needle aspiration or incision and drainage. Although needle aspiration of chancroid buboes is a simple procedure, incision and drainage might be preferred because of a reduced need for repeat drainage procedures.

Management of Sex Partners

Sex partners of patients who have chancroid should be examined and treated, regardless of whether symptoms of the disease are present, if they had sexual contact with the patient during the 10 days preceding the patient's onset of symptoms.

Special Considerations

Pregnancy

The safety and efficacy of azithromycin for pregnant and lactating women have not been established. Ciprofloxacin is contraindicated during pregnancy and lactation. No adverse effects of chancroid on pregnancy outcome have been reported.

HIV Infection

HIV-infected patients who have chancroid should be monitored closely because, as a group, these patients are more likely to experience treatment failure and to have ulcers that heal more slowly. HIV-infected patients might require longer courses of therapy than those recommended for HIV-negative patients, and treatment failures can occur with any regimen. Because evidence is limited concerning the therapeutic efficacy of the recommended ceftriaxone and azithromycin regimens in HIV-infected patients, these regimens should be used for such patients only if follow-up can be ensured. Some specialists prefer the erythromycin 7-day regimen for treating HIV-infected persons.

Genital HSV Infections

Genital herpes is a chronic, life-long viral infection. Two types of HSV have been identified, HSV-1 and HSV-2. The majority of cases of recurrent genital herpes are caused by HSV-2 although HSV-1 might become more common as a cause of first episode genital herpes. At least 50 million persons in the United States have genital HSV infection.

The majority of persons infected with HSV-2 have not been diagnosed with genital herpes. Many such persons have mild or unrecognized infections but shed virus intermittently in the genital tract. The majority of genital herpes infections are transmitted by persons unaware that they have the infection or who are asymptomatic when transmission occurs.

Diagnosis of HSV Infection

The clinical diagnosis of genital herpes is both insensitive and nonspecific. The classical painful multiple vesicular or ulcerative lesions are absent in many infected persons. Up to 50% of first-episode cases of genital herpes are caused by HSV-1, but recurrences and subclinical shedding are much less frequent for genital HSV-1 infection than genital HSV-2 infection. Therefore, whether genital herpes is caused by HSV-1 or HSV-2 influences prognosis and counseling. Therefore, the clinical diagnosis of genital herpes should be confirmed by laboratory testing (66). Both virologic and type-specific serologic tests for HSV should be available in clinical settings that provide care for patients with STDs or those at risk for STDs.

Virologic Tests

Isolation of HSV in cell culture is the preferred virologic test for patients who seek medical treatment for genital ulcers or other mucocutaneous lesions. However, the sensitivity of culture is low, especially for recurrent lesions, and declines rapidly as lesions begin to heal. PCR assays for HSV DNA are more sensitive and have been used instead of viral culture; however, PCR tests are not FDA-cleared for testing of genital specimens. PCR is the test of choice for detecting HSV in spinal fluid for diagnosis of HSV infection of the central nervous system (CNS). Viral culture isolates should be typed to determine if HSV-1 or HSV-2 is the cause of the infection. Lack of HSV detection (i.e., culture or PCR) does not indicate a lack of HSV infection, as viral shedding is intermittent. The use of cytologic detection of cellular changes of HSV infection is an insensitive and nonspecific method of diagnosis, both for genital lesions (i.e., Tzanck preparation) and for cervical Pap smears and should not be relied upon.

Type-Specific Serologic Tests

Both type-specific and nontype-specific antibodies to HSV develop during the first several weeks after infection and persist indefinitely. Accurate type-specific HSV serologic assays are based on the HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1). Such assays first became commercially available in 1999, but older assays that do not accurately distinguish HSV-1 from HSV-2 antibody (despite claims to the contrary) remain on the market. Therefore, the serologic type-specific glycoprotein G (gG)-based assays should be specifically requested when serology is performed.

The FDA-cleared glycoprotein G-based type-specific assays include the laboratory-based assays HerpeSelect™-1 enzyme-linked immunosorbent assay (ELISA) immunoglobulin G (IgG) or HerpeSelect™-2 ELISA IgG and HerpeSelect™ 1 and 2 Immunoblot IgG (Focus Technology, Inc., Herndon, Virginia), and HSV-2 ELISA (Trinity Biotech USA, Berkeley Heights, New Jersey). Two other assays, Biokit HSV-2 and SureVue HSV-2 (Biokit USA, Lexington, Massachusetts, and Fisher Scientific, Pittsburgh, Pennsylvania, respectively), are point-of-care tests that provide results for HSV-2 antibodies from capillary blood or serum during a clinic visit. The sensitivities of these glycoprotein G type-specific tests for the detection of HSV-2 antibody vary from 80%--98%, and false-negative results might be more frequent at early stages of infection. The specificities of these assays are >96%. False-positive results can occur, especially in patients with a low likelihood of HSV infection. Repeat or confirmatory testing might be indicated in some settings, especially if recent acquisition of genital herpes is suspected.

Because nearly all HSV-2 infections are sexually acquired, the presence of type-specific HSV-2 antibody implies anogenital infection and education and counseling appropriate for persons with genital herpes should be provided. The presence of HSV-1 antibody alone is more difficult to interpret. The majority of persons with HSV-1 antibody have oral HSV infection acquired during childhood, which might be asymptomatic. However, acquisition of genital HSV-1 appears to be increasing, and genital HSV-1 also might be asymptomatic. Lack of symptoms in an HSV-1 seropositive person does not distinguish anogenital from orolabial or cutaneous infection. Persons with HSV-1 infection, regardless of site of infection, remain at risk for HSV-2 acquisition.

Type-specific HSV serologic assays might be useful in the following scenarios:
1) recurrent genital symptoms or atypical symptoms with negative HSV cultures;
2) a clinical diagnosis of genital herpes without laboratory confirmation; and
3) a partner with genital herpes.

Some specialists believe that HSV serologic testing should be included in a comprehensive evaluation for STDs among persons with multiple sex partners, HIV infection, and among MSM at increased risk for HIV acquisition. Screening for HSV-1 or HSV-2 in the general population is not indicated.

Principles of Management of Genital Herpes

Antiviral chemotherapy offers clinical benefits to the majority of symptomatic patients and is the mainstay of management. Counseling regarding the natural history of genital herpes, sexual and perinatal transmission, and methods to reduce transmission is integral to clinical management.

Systemic antiviral drugs can partially control the signs and symptoms of herpes episodes 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 antiviral medications provide clinical benefit for genital herpes: acyclovir, valacyclovir, and famciclovir (72--80). Valacyclovir is the valine ester of acyclovir and has enhanced absorption after oral administration. Famciclovir also has high oral bioavailability. Topical therapy with antiviral drugs offers minimal clinical benefit, and its use is discouraged.

First Clinical Episode of Genital Herpes

Many persons with first-episode herpes have mild clinical manifestations but later develop severe or prolonged symptoms. Therefore, patients with initial genital herpes should receive antiviral therapy.

Recommended Regimens*
Acyclovir 400 mg orally three times a day for 7--10 days
OR
Acyclovir 200 mg orally five times a day for 7--10 days
OR
Famciclovir 250 mg orally three times a day for 7--10 days
OR
Valacyclovir 1 g orally twice a day for 7--10 days
· Treatment might be extended if healing is incomplete after 10 days of therapy.

Established HSV-2 infection

The majority of patients with symptomatic, first-episode genital HSV-2 infection subsequently experience recurrent episodes of genital lesions; recurrences are less frequent after initial genital HSV-1 infection. Intermittent asymptomatic shedding occurs in persons with genital HSV-2 infection, even in those with longstanding or clinically silent infection. Antiviral therapy for recurrent genital herpes can be administered either episodically to ameliorate or shorten the duration of lesions or continuously as suppressive therapy to reduce the frequency of recurrences. Many persons, including those with mild or infrequent recurrent outbreaks, benefit from antiviral therapy; therefore, options for treatment should be discussed. Some persons might prefer suppressive therapy, which has the additional advantage of decreasing the risk of genital HSV-2 transmission to susceptible partners.

Suppressive Therapy for Recurrent Genital Herpes

Suppressive therapy reduces the frequency of genital herpes recurrences by 70%--80% in patients who have frequent recurrences (i.e., >6 recurrences per year), and many patients report no symptomatic outbreaks. Treatment also is effective in patients with less frequent recurrences. Safety and efficacy have been documented among patients receiving daily therapy with acyclovir for as long as 6 years and with valacyclovir or famciclovir for 1 year. Quality of life frequently is improved in patients with frequent recurrences who receive suppressive therapy, compared with episodic treatment.

The frequency of recurrent genital herpes outbreaks diminishes over time in many patients, and the patient's psychological adjustment to the disease might change. Therefore, periodically during suppressive treatment (e.g., once a year), providers should discuss the need to continue therapy with the patient.

Daily treatment with valacyclovir 500 mg daily decreases the rate of HSV-2 transmission in discordant, heterosexual couples in which the source partner has a history of genital HSV-2 infection (82). Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences. Suppressive antiviral therapy probably reduces transmission when used by persons who have multiple partners (including MSM) and by those who are HSV-2 seropositive without a history of genital herpes.

Recommended Regimens
Acyclovir 400 mg orally twice a day
OR
Famiciclovir 250 mg orally twice a day
OR
Valacyclovir 500 mg orally once a day
OR
Valacyclovir 1.0 g orally once a day

Valacyclovir 500 mg once a day might be less effective than other valacyclovir or acyclovir dosing regimens in patients who have very frequent recurrences (i.e., >10 episodes per year). Several studies have compared valacyclovir or famciclovir with acyclovir. The results of these studies suggest that valacyclovir and famciclovir are comparable to acyclovir in clinical outcome. Ease of administration and cost also are important considerations for prolonged treatment.

Episodic Therapy for Recurrent Genital Herpes

Effective episodic treatment of recurrent herpes requires initiation of therapy 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.

Recommended Regimens
Acyclovir 400 mg orally three times a day for 5 days
OR
Acyclovir 800 mg orally twice a day for 5 days
OR
Acyclovir 800 mg orally three times a day for 2 days
OR
Famciclovir 125 mg orally twice daily for 5 days
OR
Famciclovir 1000 mg orally twice daily for 1 day
OR
Valacyclovir 500 mg orally twice a day for 3 days
OR
Valacyclovir 1.0 g orally once a day for 5 days

Severe Disease

Intravenous (IV) acyclovir therapy 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). The recommended regimen is acyclovir 5--10 mg/kg body weight IV every 8 hours for 2--7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days of total therapy.

Counseling

Counseling of infected persons and their sex partners is critical to the management of genital herpes. The goal of counseling is to
1) help patients cope with the infection and
2) prevent sexual and perinatal transmission (8).

Although initial counseling can be provided at the first visit, many patients benefit from learning about the chronic aspects of the disease after the acute illness subsides. Multiple resources, including websites (http://www.ashastd.org and http://www.ihmf.org) and printed materials are available to assist patients, their partners, and clinicians in counseling.

HSV-infected persons might express anxiety concerning genital herpes that does not reflect the actual clinical severity of their disease; the psychological effect of HSV infection frequently is substantial. Common concerns regarding genital herpes include the severity of initial clinical manifestations, recurrent episodes, sexual relationships and transmission to sex partners, and ability to bear healthy children. The misconception that HSV causes cancer should be dispelled. The psychological effect of a serologic diagnosis of HSV-2 infection in a person with asymptomatic or unrecognized genital herpes appears small and transient.

The following recommendations apply to counseling of persons with HSV infection:

• Persons who have genital herpes should be educated concerning the natural history of the disease, with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and the attendant risks of sexual transmission.
• Persons experiencing a first episode of genital herpes should be advised that suppressive therapy is available and is effective in preventing symptomatic recurrent episodes and that episodic therapy sometimes is useful in shortening the duration of recurrent episodes.
• All persons with genital HSV infection should be encouraged to inform their current sex partners that they have genital herpes and to inform future partners before initiating a sexual relationship.
• Sexual transmission of HSV can occur during asymptomatic periods. Asymptomatic viral shedding is more frequent in genital HSV-2 infection than genital HSV-1 infection and is most frequent during the first 12 months after acquiring HSV-2.
• All persons with genital herpes should remain abstinent from sexual activity with uninfected partners when lesions or prodromal symptoms are present.
• The risk of HSV-2 sexual transmission can be decreased by the daily use of valacyclovir by the infected person.
• Recent studies indicate that latex condoms, when used consistently and correctly, might reduce the risk for genital herpes transmission.
• Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of asymptomatic partners of persons with genital herpes is recommended to determine whether risk for HSV acquisition exists.
• The risk for neonatal HSV infection should be explained to all persons, including men. Pregnant women and women of childbearing age who have genital herpes should inform their providers who care for them during pregnancy and those who will care for their newborn infant. Pregnant women who are not infected with HSV-2 should be advised to avoid intercourse during the third trimester with men who have genital herpes. Similarly, pregnant women who are not infected with HSV-1 should be counseled to avoid genital exposure to HSV-1 during the third trimester (e.g., oral sex with a partner with oral herpes and vaginal intercourse with a partner with genital HSV-1 infection).
• Asymptomatic persons diagnosed with HSV-2 infection by type-specific serologic testing should receive the same counseling messages as persons with symptomatic infection. In addition, such persons should be taught about the clinical manifestations of genital herpes.

Management of Sex Partners

The sex partners of patients who have genital herpes can benefit from evaluation and counseling. Symptomatic sex partners should be evaluated and treated in the same manner as patients who have genital lesions. Asymptomatic sex partners of patients who have genital herpes should be questioned concerning histories of genital lesions and offered type-specific serologic testing for HSV infection.

Special Considerations

Allergy, Intolerance, and Adverse Reactions

Allergic and other adverse reactions to acyclovir, valacyclovir, and famciclovir are rare. Desensitization to acyclovir has been described (85).
HIV Infection

Immunocompromised patients might have prolonged or severe episodes of genital, perianal, or oral herpes. Lesions caused by HSV are common among HIV-infected patients and might be severe, painful, and atypical. HSV shedding is increased in HIV-infected persons. Whereas antiretroviral therapy reduces the severity and frequency of symptomatic genital herpes, frequent subclinical shedding still occurs. Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV among HIV-positive persons. HIV-infected persons are likely to be more contagious for HSV; the extent to which suppressive antiviral therapy will decrease HSV transmission from this population is unknown. Some specialists suggest that HSV type-specific serologies be offered to HIV-positive persons during their initial evaluation, and that suppressive antiviral therapy be considered in those who have HSV-2 infection.

Recommended Regimens for Daily Suppressive Therapy in Persons Infected with HIV
Acyclovir 400--800 mg orally twice to three times a day
OR
Famciclovir 500 mg orally twice a day
OR
Valacyclovir 500 mg orally twice a day

Recommended Regimens for Episodic Infection in Persons Infected with HIV
Acyclovir 400 mg orally three times a day for 5--10 days
OR
Famiciclovir 500 mg orally twice a day for 5--10 days
OR
Valacyclovir 1.0 grams orally twice a day for 5--10 days

Acyclovir, valacyclovir, and famciclovir are safe for use in immunocompromised patients in the doses recommended for treatment of genital herpes. For severe HSV disease, initiating therapy with acyclovir 5--10 mg/kg body weight IV every 8 hours might be necessary.

If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected and a viral isolate should be obtained for sensitivity testing (90). Such patients should be managed in consultation with an HIV specialist, and alternate therapy should be administered. All acyclovir-resistant strains are resistant to valacyclovir, and the majority are resistant to famciclovir. Foscarnet, 40 mg/kg body weight IV every 8 hours until clinical resolution is attained, is frequently effective for treatment of acyclovir-resistant genital herpes. Topical cidofovir gel 1% applied to the lesions once daily for 5 consecutive days also might be effective. This preparation is not commercially available and must be compounded at a pharmacy.

Genital Herpes in Pregnancy

The majority of mothers of infants who acquire neonatal herpes lack histories of clinically evident genital herpes. 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 is low (<1%) among women with histories of recurrent herpes at term or who acquire genital HSV during the first half of pregnancy. However, because recurrent genital herpes is much more common than initial HSV infection during pregnancy, the proportion of neonatal HSV infections acquired from mothers with recurrent herpes is substantial. Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery.

Women without known genital herpes should be counseled to avoid intercourse during the third trimester with partners known or suspected of having genital herpes. In addition, pregnant women without known orolabial herpes should be advised to avoid receptive oral sex during the third trimester with partners known or suspected to have orolabial herpes. Some specialists believe that type-specific serologic tests are useful to identify pregnant women at risk for HSV infection and to guide counseling regarding the risk for acquiring genital herpes during pregnancy. Such testing should be offered to women without genital herpes whose sex partner has HSV infection. The effectiveness of antiviral therapy to decrease the risk for HSV transmission to pregnant women has not been studied.

All pregnant women should be asked whether they have a history of genital herpes. At the onset of labor, all women should be questioned carefully about symptoms of genital herpes, including prodromal symptoms, and all women should be examined carefully for herpetic lesions. Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally. The majority of specialists recommend that women with recurrent genital herpetic lesions at the onset of labor deliver by cesarean section to prevent neonatal herpes. However, cesarean section does not completely eliminate the risk for HSV transmission to the infant.

The safety of systemic acyclovir, valacyclovir, and famciclovir therapy in pregnant women has not been definitively established. Available data do not indicate an increased risk for major birth defects compared with the general population in women treated with acyclovir during the first trimester (91). These findings provide some assurance to women who have had prenatal exposure to acyclovir. The experience with prenatal exposure to valacyclovir and famciclovir is too limited to provide useful information on pregnancy outcomes. Acyclovir may be administered orally to pregnant women with first episode genital herpes or severe recurrent herpes and should be administered IV to pregnant women with severe HSV infection. Acyclovir treatment late in pregnancy reduces the frequency of cesarean sections among women who have recurrent genital herpes by diminishing the frequency of recurrences at term, and many specialists recommend such treatment. No data support the use of antiviral therapy among HSV seropositive women without a history of genital herpes. The risk for herpes is high in infants of women who acquire genital HSV during late pregnancy; such women should be managed in consultation with an infectious diseases specialist. Some specialists recommend acyclovir therapy in this circumstance, some recommend routine cesarean section to reduce the risk for neonatal herpes, and others recommend both.

Neonatal Herpes

Infants exposed to HSV during birth, as documented by maternal virologic testing or presumed by observation of maternal lesions, should be followed carefully in consultation with a specialist. Some specialists recommend that such infants undergo surveillance cultures of mucosal surfaces to detect HSV infection before development of clinical signs of neonatal herpes. In addition, some specialists recommend the use of acyclovir for infants born to women who acquired HSV near term because the risk for neonatal herpes is high for these infants. All 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 21 days for disseminated and CNS disease or for 14 days for disease limited to the skin and mucous membranes.

Granuloma Inguinale (Donovanosis)

Granuloma inguinale 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, although it is endemic in some tropical and developing areas, including India; Papua, New Guinea; central Australia; and southern Africa. Clinically, the disease is commonly characterized as painless, progressive ulcerative lesions without regional lymphadenopathy. The lesions are highly vascular (i.e., beefy red appearance) and bleed easily on contact. However, the clinical presentation also can include hypertrophic, necrotic, or sclerotic variants. The causative organism is difficult to culture, and diagnosis requires visualization of dark-staining Donovan bodies on tissue crush preparation or biopsy. No FDA-cleared PCR tests for the detection of K. granulomatis DNA exist, but such an assay might be useful if a CLIA verification study has been conducted. The lesions might develop secondary bacterial infection or can coexist with other sexually transmitted pathogens.

Treatment

A limited number of studies on Donovanosis treatment have been published. Treatment halts progression of lesions, although prolonged therapy is usually required to permit granulation and reepithelialization of the ulcers. Healing typically proceeds inward from the ulcer margins. Relapse can occur 6--18 months after apparently effective therapy. Several antimicrobial regimens have been effective, but a limited number of controlled trials have been published.

Recommended Regimen
Doxycycline 100 mg orally twice a day for at least 3 weeks and until all lesions have completely healed
Alternative Regimens
Azithromycin 1 g orally once per week for at least 3 weeks and until all lesions have completely healed
OR
Ciprofloxacin 750 mg orally twice a day for at least 3 weeks and until all lesions have completely healed
OR
Erythromycin base 500 mg orally four times a day for at least 3 weeks and until all lesions have completely healed
OR
Trimethoprim-sulfamethoxazole one double-strength (160 mg/800 mg) tablet orally twice a day for at least 3 weeks and until all lesions have completely healed

Therapy should be continued at least 3 weeks and until all lesions have completely healed. Some specialists recommend the addition of an aminoglycoside (e.g., gentamicin 1 mg/kg IV every 8 hours) to these regimens if improvement is not evident within the first few days of therapy.

Follow-Up

Patients should be followed clinically until signs and symptoms have resolved.

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

Pregnancy is a relative contraindication to the use of sulfonamides. Pregnant and lactating women should be treated with the erythromycin regimen, and consideration should be given to the addition of a parenteral aminoglycoside (e.g., gentamicin). Azithromycin might prove useful for treating granuloma inguinale during pregnancy, but published data are lacking. Doxycycline and ciprofloxacin are contraindicated in pregnant

Persons with both granuloma inguinale and HIV infection should receive the same regimens as those who are HIV negative. Consideration should be given to the addition of a parenteral aminoglycoside (e.g., gentamicin).

Lymphogranuloma Venereum

Lymphogranuloma venereum (LGV) is caused by C. trachomatis serovars L1, L2, or L3 (96). The most common clinical manifestation of LGV among heterosexuals is tender inguinal and/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 patients seek care, the lesions might have disappeared. Rectal exposure in women or MSM might result in proctocolitis (including mucoid and/or hemorrhagic rectal discharge, anal pain, constipation, fever, and/or tenesmus). LGV is an invasive, systemic infection, and if it is not treated early, LGV proctocolitis might lead to chronic, colorectal fistulas and strictures. Genital and colorectal LGV lesions might also develop secondary bacterial infection or might be coinfected with other sexually and nonsexually transmitted pathogens.
Diagnosis is based on clinical suspicion, epidemiologic information, and the exclusion of other etiologies (of proctocolitis, inguinal lymphadenopathy, or genital or rectal ulcers), along with C. trachomatis testing, if available.

Genital and lymph node specimens (i.e., lesion swab or bubo aspirate) may be tested for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection. Nucleic acid amplification tests (NAAT) for C. trachomatis are not FDA-cleared for testing rectal specimens. Additional procedures (e.g., genotyping) are required for differentiating LGV from non-LGV C. trachomatis but are not widely available.

Chlamydia serology (complement fixation titers >1:64) can support the diagnosis in the appropriate clinical context. Comparative data between types of serologic tests are lacking, and the diagnostic utility of serologic methods other than complement fixation and some microimmunofluorescence procedures has not been established. Serologic test interpretation for LGV is not standardized, tests have not been validated for clinical proctitis presentations, and C. trachomatis serovar-specific serologic tests are not widely available.

In the absence of specific LGV diagnostic testing, patients with a clinical syndrome consistent with LGV, including proctocolitis or genital ulcer disease with lymphadenopathy, should be treated for LGV as described in this report.

Treatment

Treatment cures infection and prevents ongoing tissue damage, although tissue reaction to the injection can result in scarring. Buboes might require aspiration through intact skin or incision and drainage to prevent the formation of inguinal/femoral ulcerations. Doxycycline is the preferred treatment.

Recommended Regimen
Doxycycline 100 mg orally twice a day for 21 days
Alternative Regimen
Erythromycin base 500 mg orally four times a day for 21 days

Some STD specialists believe that azithromycin 1.0 g orally once weekly for 3 weeks is probably effective, although clinical data are lacking.

Follow-Up

Patients should be followed clinically until signs and symptoms have resolved.

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 examined, tested for urethral or cervical chlamydial infection, and treated with a standard chlamydia regimen (azithromycin 1 gm orally x 1 or doxycycline 100 mg orally twice a day for 7 days). The optimum contact interval is unknown; some specialists use longer contact intervals.

Special Considerations

Pregnancy

Pregnant and lactating women should be treated with erythromycin. Azithromycin might prove useful for treatment of LGV in pregnancy, but no published data are available regarding its safety and efficacy. Doxycycline is contraindicated in pregnant women.

HIV Infection

Persons with both LGV and HIV infection should receive the same regimens as those who are HIV negative. Prolonged therapy might be required, and delay in resolution of symptoms might occur.

General Principles

Background

Syphilis is a systemic disease caused by T. pallidum. Patients who have syphilis might seek treatment for signs or symptoms of primary infection (i.e., ulcer or chancre at the infection site), secondary infection (i.e., manifestations that include, but are not limited to, skin rash, mucocutaneous lesions, and lymphadenopathy), or tertiary infection (e.g., cardiac or ophthalmic manifestations, auditory abnormalities, or gummatous lesions). 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 either late latent syphilis or latent syphilis of unknown duration. Treatment for both late latent syphilis and tertiary syphilis theoretically might require a longer duration of therapy because organisms are dividing more slowly; however, the validity of this concept has not been assessed.

Diagnostic Considerations and Use of Serologic Tests

Darkfield examinations and direct fluorescent antibody (DFA) tests of lesion exudate or tissue are the definitive methods for diagnosing early syphilis. A presumptive diagnosis is possible with the use of two types of serologic tests:
1) nontreponemal tests (e.g., Venereal Disease Research Laboratory [VDRL] and RPR) and
2) treponemal tests (e.g., fluorescent treponemal antibody absorbed [FTA-ABS] and T. pallidum particle agglutination [TP-PA]).
    The use of only one type of serologic test is insufficient for diagnosis because false-positive nontreponemal test results are sometimes
    associated with various medical conditions unrelated to syphilis.

Nontreponemal test antibody titers usually correlate with disease activity, and results should be reported quantitatively. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16--1:4 or from 1:8--1:32), is considered necessary to demonstrate a clinically significant difference between two nontreponemal test results that were obtained using the same serologic test. Sequential serologic tests in individual patients should be performed by using the same testing method (e.g., VDRL or RPR), preferably by the same laboratory. The VDRL and RPR are equally valid assays, but quantitative results from the two tests cannot be compared directly because RPR titers frequently are slightly higher than VDRL titers. Nontreponemal tests usually become nonreactive with time after treatment; however, in some patients, nontreponemal antibodies can persist at a low titer for a long period of time, sometimes for the life of the patient. This response is referred to as the serofast reaction.
The majority of patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. However, 15%--25% of patients treated during the primary stage revert to being serologically nonreactive after 2--3 years (97). Treponemal test antibody titers do not correlate with disease activity and should not be used to assess treatment response.
Some clinical laboratories and blood banks have begun to screen samples using treponemal EIA tests (98). This strategy will identify both persons with previous treatment and persons with untreated or incompletely treated syphilis. False-positive results can occur, particularly among populations with a low prevalence of syphilis.

Persons with a positive treponemal screening test should have a standard nontreponemal test with titer to guide patient management decisions. If the nontreponemal test is negative, then a different treponemal test should be performed to confirm the results of the initial test. If a second trepomenal test is positive, treatment decisions should be discussed in consultation with a specialist. Some HIV-infected patients can have atypical serologic test results (i.e., unusually high, unusually low, or fluctuating titers). For such patients, when serologic tests do not correspond with clinical syndromes suggestive of early syphilis, use of other tests (e.g., biopsy and direct microscopy) should be considered. However, for the majority of HIV-infected patients, serologic tests are accurate and reliable for the diagnosis of syphilis and for following the response to treatment.
No single test can be used to diagnose neurosyphilis. The VDRL-cerebrospinal fluid (CSF) is highly specific, but it is insensitive. The majority of other tests are both insensitive and nonspecific and must be interpreted in relation to other test results and the clinical assessment. Therefore, the diagnosis of neurosyphilis usually depends on various combinations of reactive serologic test results, CSF cell count or protein, or a reactive VDRL-CSF with or without clinical manifestations. The CSF leukocyte count usually is elevated (>5 white blood cell count [WBC]/mm3) in patients with neurosyphilis; this count also is a sensitive measure of the effectiveness of therapy. The VDRL-CSF is the standard serologic test for CSF, and when reactive in the absence of substantial contamination of CSF with blood, it is considered diagnostic of neurosyphilis. However, the VDRL-CSF might be nonreactive even when neurosyphilis is present. Some specialists recommend performing an FTA-ABS test on CSF. The CSF FTA-ABS is less specific (i.e., yields more false-positive results) for neurosyphilis than the VDRL-CSF, but the test is highly sensitive. Therefore, some specialists believe that a negative CSF FTA-ABS test excludes neurosyphilis.

Treatment

Penicillin G, administered parenterally, is the preferred drug for treatment of all stages of syphilis. The preparation(s) used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of the disease. However, neither combinations of benzathine penicillin and procaine penicillin nor oral penicillin preparations are considered appropriate for the treatment of syphilis. Reports have indicated that inappropriate use of combination benzathine-procaine penicillin (Bicillin C-R®) instead of the standard benzathine penicillin product widely used in the United States (Bicillin L-A®) has occurred. Practitioners, pharmacists, and purchasing agents should be aware of the similar names of these two products and avoid use of the inappropriate combination therapy agent for treating syphilis.

The efficacy of penicillin for the treatment of syphilis was well established through clinical experience even before the value of randomized controlled clinical trials was recognized. Therefore, nearly all the recommendations for the treatment of syphilis are based on the opinions of persons knowledgeable about STDs and are reinforced by case series, clinical trials, and 50 years of clinical experience.

Parenteral penicillin G is the only therapy with documented efficacy for syphilis during pregnancy. Pregnant women with syphilis in any stage who report penicillin allergy should be desensitized and treated with penicillin. Skin testing for penicillin allergy might be useful in pregnant women; such testing also is useful in other patients (see Management of Patients Who Have a History of Penicillin Allergy).

The Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache, myalgia, and other symptoms that usually occur within the first 24 hours after any therapy for syphilis. Patients should be informed about this possible adverse reaction. The Jarisch-Herxheimer reaction occurs most frequently among patients who have early syphilis. Antipyretics may be used, but they have not been proven to prevent this reaction. The Jarisch-Herxheimer reaction might induce early labor or cause fetal distress in pregnant women, but this possibly should not prevent or delay therapy (see Syphilis During Pregnancy).

Management of Sex Partners

Sexual transmission of T. pallidum occurs only when mucocutaneous syphilitic lesions are present; such manifestations are uncommon after the first year of infection. However, persons exposed sexually to a patient who has syphilis in any stage should be evaluated clinically and serologically and treated with a recommended regimen, according to the following recommendations:

• Persons who were exposed within the 90 days preceding the diagnosis of primary, secondary, or early latent syphilis in a sex partner might be infected even if seronegative; therefore, such persons should be treated presumptively.
• Persons who were exposed >90 days before the diagnosis of primary, secondary, or early latent syphilis in a sex partner should be treated presumptively if serologic test results are not available immediately and the opportunity for follow-up is uncertain.
• For purposes of partner notification and presumptive treatment of exposed sex partners, patients with syphilis of unknown duration who have high nontreponemal serologic test titers (i.e., >1:32) can be assumed to have early syphilis. However, serologic titers should not be used to differentiate early from late latent syphilis for the purpose of determining treatment (see Latent Syphilis, Treatment).
• Long-term sex partners of patients who have latent syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of the evaluation findings.

For identification of at-risk sexual partners, the periods before treatment are
1) 3 months plus duration of symptoms for primary syphilis,
2) 6 months plus duration of symptoms for secondary syphilis, and
3) 1 year for early latent syphilis.

Primary and Secondary Syphilis

Treatment

Parenteral penicillin G has been used effectively for more than 50 years to achieve clinical resolution (i.e., healing of lesions and prevention of sexual transmission) and to prevent late sequelae. However, no comparative trials have been adequately conducted to guide the selection of an optimal penicillin regimen (i.e., the dose, duration, and preparation). Substantially fewer data are available for nonpenicillin regimens.

Recommended Regimen for Adults*
Benzathine penicillin G 2.4 million units IM in a single dose
* Recommendations for treating HIV-infected persons and pregnant women for syphilis have been discussed in this report (see Syphilis, Special considerations and Syphilis in Pregnancy).

Recommended Regimen for Children

After the newborn period (aged >1 month), children with syphilis should have a CSF examination to detect asymptomatic neurosyphilis, and birth and maternal medical records should be reviewed to assess whether such children have congenital or acquired syphilis (see Congenital Syphilis). Children with acquired primary or secondary syphilis should be evaluated (e.g., through consultation with child-protection services) (see Sexual Assault or Abuse of Children) and treated by using the following pediatric regimen.

Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose

Other Management Considerations

All patients who have syphilis should be tested for HIV infection. In geographic areas in which the prevalence of HIV is high, patients who have primary syphilis should be retested for HIV after 3 months if the first HIV test result was negative.

Patients who have syphilis and symptoms or signs suggesting neurologic disease (e.g., meningitis) or ophthalmic disease (e.g., uveitis, iritis, neuroretinitis, or optic neuritis) should have an evaluation that includes CSF analysis and ocular slit-lamp examination. Treatment should be guided by the results of this evaluation.

Invasion of CSF by T. pallidum accompanied by CSF abnormalities is common among adults who have primary or secondary syphilis. However, neurosyphilis develops in only a limited number of patients after treatment with the penicillin regimens recommended for primary and secondary syphilis. Therefore, unless clinical signs or symptoms of neurologic or ophthalmic involvement are present, CSF analysis is not recommended for routine evaluation of patients who have primary or secondary syphilis.

Follow-Up

Treatment failure can occur with any regimen. However, assessing response to treatment frequently is difficult, and definitive criteria for cure or failure have not been established. Nontreponemal test titers might decline more slowly for persons who previously had syphilis. Patients should be reexamined clinically and serologically 6 months and 12 months after treatment; more frequent evaluation might be prudent if follow-up is uncertain.

Patients who have signs or symptoms that persist or recur or who have a sustained fourfold increase in nontreponemal test titer (i.e., compared with the maximum or baseline titer at the time of treatment) probably failed treatment or were reinfected. These patients should be retreated and reevaluated for HIV infection. Because treatment failure usually cannot be reliably distinguished from reinfection with T. pallidum, a CSF analysis also should be performed. Clinical trial data have demonstrated that 15% of patients with early syphilis treated with the recommended therapy will not achieve a two dilution decline in nontreponemal titer used to define response at 1 year after treatment.

Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis might be indicative of probable treatment failure. Persons for whom titers remain serofast should be reevaluated for HIV infection. Optimal management of such patients is unclear. At a minimum, these patients should receive additional clinical and serologic follow-up. HIV-infected patients should be evaluated more frequently (i.e., at 3-month intervals instead of 6-month intervals). If additional follow-up cannot be ensured, re-treatment is recommended. Because treatment failure might be the result of unrecognized CNS infection, many specialists recommend CSF examination in such situations.
For retreatment, the majority of STD specialists recommend administering weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks, unless CSF examination indicates that neurosyphilis is present. In rare instances, serologic titers do not decline despite a negative CSF examination and a repeated course of therapy. Additional therapy or repeated CSF examinations are not warranted in these circumstances.

Management of Sex Partners

See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy. Data to support the use of alternatives to penicillin in the treatment of early syphilis are limited. However, several therapies might be effective in nonpregnant, penicillin-allergic patients who have primary or secondary syphilis. Doxycycline (100 mg orally twice daily for 14 days) and tetracycline (500 mg four times daily for 14 days) are regimens that have been used for many years. Compliance is likely to be better with doxycycline than tetracycline because tetracycline can cause gastrointestinal side effects. Although limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone is effective for treating early syphilis, the optimal dose and duration of ceftriaxone therapy have not been defined. Some specialists recommend 1 g daily either IM or IV for 8--10 days. Some patients who are allergic to penicillin also might be allergic to ceftriaxone; in these circumstances, use of an alternative agent might be required. Preliminary data suggest that azithromycin might be effective as a single oral dose of 2 g. However, several cases of azithromycin treatment failure have been reported, and resistance to azithromycin has been documented in several geographic areas. Close follow-up of persons receiving alternative therapies is essential. The use of any of these therapies in HIV-infected persons has not been well-studied; therefore, the use of doxycycline, ceftriaxone, and azithromycin among such persons must be undertaken with caution.

Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin. Skin testing for penicillin allergy might be useful in some circumstances in which the reagents and expertise are available to perform the test adequately (see Management of Patients Who Have a History of Penicillin Allergy).

Pregnancy. Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy).

HIV Infection. See Syphilis Among HIV-Infected Persons.

Latent Syphilis

Latent syphilis is defined as syphilis characterized by seroreactivity without other evidence of disease. Patients who have latent syphilis and who acquired syphilis within the preceding year are classified as having early latent syphilis. Patients' conditions can be diagnosed as early latent syphilis if, within the year preceding the evaluation, they had

1) a documented seroconversion or fourfold or greater increase in titer of a nontreponemal test;
2) unequivocal symptoms of primary or secondary syphilis;
3) a sex partner documented to have primary, secondary, or early latent syphilis; or
4) reactive nontreponemal and treponemal tests from a person whose only possible exposure occurred within the previous 12 months.

Nontreponemal serologic titers usually are higher during early latent syphilis than late latent syphilis. However, early latent syphilis cannot be reliably distinguished from late latent syphilis solely on the basis of nontreponemal titers. All patients with latent syphilis should have careful examination of all accessible mucosal surfaces (i.e., the oral cavity, the perineum in women, and perianal area, underneath the foreskin in uncircumcised men) to evaluate for internal mucosal lesions. All patients who have syphilis should be tested for HIV infection.

Treatment

Treatment of latent syphilis usually does not affect transmission and is intended to prevent late complications. Although clinical experience supports the effectiveness of penicillin in achieving this goal, limited evidence is available for guidance in choosing specific regimens.

The following regimens are recommended for penicillin nonallergic patients who have normal CSF examinations (if performed).

Recommended Regimens for Adults
Early Latent Syphilis
Benzathine penicillin G 2.4 million units IM in a single dose

Late Latent Syphilis or Latent Syphilis of Unknown Duration
Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals

After the newborn period, children with syphilis should have a CSF examination to exclude neurosyphilis. In addition, birth and maternal medical records should be reviewed to assess whether children have congenital or acquired syphilis (see Congenital Syphilis). Older children with acquired latent syphilis should be evaluated as described for adults and treated using the following pediatric regimens (see Sexual Assault or Abuse of Children). These regimens are for penicillin nonallergic children who have acquired syphilis and who have normal CSF examination results.

Recommended Regimens for Children
Early Latent Syphilis
Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose
Late Latent Syphilis or Latent Syphilis of Unknown Duration
Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, administered as 3 doses at 1-week intervals (total 150,000 units/kg up to the adult total dose of 7.2 million units)

Other Management Considerations

All persons who have latent syphilis should be evaluated clinically for evidence of tertiary disease (e.g., aortitis and gumma) and syphilitic ocular disease (e.g., iritis and uveitis). Patients who have syphilis and who demonstrate any of the following criteria should have a prompt CSF examination:

• neurologic or ophthalmic signs or symptoms,
• evidence of active tertiary syphilis (e.g., aortitis and gumma),
• treatment failure, or
• HIV infection with late latent syphilis or syphilis of unknown duration.

If dictated by circumstances and patient preferences, a CSF examination may be performed for patients who do not meet these criteria. Some specialists recommend performing a CSF examination on all patients who have latent syphilis and a nontreponemal serologic test of >1:32 or if the patient is HIV-infected with a serum CD4 count <350. However, the likelihood of neurosyphilis in this circumstance is unknown. If a CSF examination is performed and the results indicate abnormalities consistent with neurosyphilis, the patient should be treated for neurosyphilis (see Neurosyphilis).

If a patient misses a dose of penicillin in a course of weekly therapy for late syphilis, the appropriate course of action is unclear. Pharmacologic considerations suggest that an interval of 10--14 days between doses of benzathine penicillin for late syphilis or latent syphilis of unknown duration might be acceptable before restarting the sequence of injections. Missed doses are not acceptable for pregnant patients receiving therapy for late latent syphilis; pregnant women who miss any dose of therapy must repeat the full course of therapy.

Follow-Up

Quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months. Patients with a normal CSF examination should be re-treated for latent syphilis if

1) titers increase fourfold,
2) an initially high titer (>1:32) fails to decline at least fourfold (i.e., two dilutions) within 12--24 months of therapy, or
3) signs or symptoms attributable to syphilis develop. In rare instances, despite a negative CSF examination and a repeated course of therapy,     serologic titers might still not decline. In these circumstances, the need for additional therapy or repeated CSF examinations is unclear.

Management of Sex Partners. See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy. The effectiveness of alternatives to penicillin in the treatment of latent syphilis has not been well-documented. Nonpregnant patients allergic to penicillin who have clearly defined early latent syphilis should respond to therapies recommended as alternatives to penicillin for the treatment of primary and secondary syphilis (see Primary and Secondary Syphilis, Treatment). The only acceptable alternatives for the treatment of late latent syphilis or latent syphilis of unknown duration are doxycycline (100 mg orally twice daily) or tetracycline (500 mg orally four times daily), both for 28 days. These therapies should be used only in conjunction with close serologic and clinical follow-up. Limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone might be effective for treating late latent syphilis or syphilis of unknown duration. However, the optimal dose and duration of ceftriaxone therapy have not been defined, and treatment decisions should be discussed in consultation with a specialist. Some patients who are allergic to penicillin also might be allergic to ceftriaxone; in these circumstances, use of an alternative agent might be required. The efficacy of these alternative regimens in HIV-infected persons has not been well-studied and, therefore, must be considered with caution.

Pregnancy

Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy).

HIV Infection. See Syphilis Among HIV-Infected Persons.

Tertiary Syphilis

Tertiary syphilis refers to gumma and cardiovascular syphilis but not to all neurosyphilis. Patients who are not allergic to penicillin and have no evidence of neurosyphilis should be treated with the following regimen.

Recommended Regimen
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

Patients who have symptomatic late syphilis should be given a CSF examination before therapy is initiated. Some providers treat all patients who have cardiovascular syphilis with a neurosyphilis regimen. The complete management of patients who have cardiovascular or gummatous syphilis is beyond the scope of these guidelines. These patients should be managed in consultation with an infectious diseases specialist.

Follow-Up

Limited information is available concerning clinical response and follow-up of patients who have tertiary syphilis.

Management of Sex Partners. See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy. Patients allergic to penicillin should be treated according to treatment regimens recommended for late latent syphilis.

Pregnancy. Pregnant patients who are allergic to penicillin should be desensitized, if necessary, and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy and Syphilis During Pregnancy).

HIV Infection. See Syphilis Among HIV-Infected Persons.

Neurosyphilis

Treatment

CNS involvement can occur during any stage of syphilis. A patient who has clinical evidence of neurologic involvement with syphilis (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis) should have a CSF examination.

Syphilitic uveitis or other ocular manifestations frequently are associated with neurosyphilis; patients with these symptoms should be treated according to the recommendations for patients with neurosyphilis. A CSF examination should be performed for all such patients to identify those with abnormalities that require follow-up CSF examinations to assess treatment response.

Patients who have neurosyphilis or syphilitic eye disease (e.g., uveitis, neuroretinitis, and optic neuritis) should be treated with the following regimen.

Recommended Regimen
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, patients may be treated with the following alternative regimen.
Alternative Regimen
Procaine penicillin 2.4 million units IM once daily
PLUS
Probenecid 500 mg orally four times a day, both for 10--14 days

The durations of the recommended and alternative regimens for neurosyphilis are shorter than that of the regimen used for late syphilis in the absence of neurosyphilis. Therefore, some specialists administer benzathine penicillin, 2.4 million units IM once per week for up to 3 weeks after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy.

Other Management Considerations

Other considerations in the management of patients who have neurosyphilis are as follows:

• All patients who have syphilis should be tested for HIV.
• Many specialists recommend treating patients who have evidence of auditory disease caused by syphilis in the same manner as patients who have neurosyphilis, regardless of CSF examination results. Although systemic steroids are used frequently as adjunctive therapy for otologic syphilis, such drugs have not been proven beneficial.

Follow-Up

If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. Follow-up CSF examinations also can be used to evaluate changes in the VDRL-CSF or CSF protein after therapy; however, changes in these two parameters occur more slowly than cell counts, and persistent abnormalities might be less important. If the cell count has not decreased after 6 months or if the CSF is not normal after 2 years, re-treatment should be considered. Recent data on HIV-infected persons with neurosyphilis suggest that CSF abnormalities might persist for extended periods in these persons, and close clinical follow-up is warranted (105,106).

Management of Sex Partners. See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy. Ceftriaxone can be used as an alternative treatment for patients with neurosyphilis, although the possibility of cross-reactivity between this agent and penicillin exists. Some specialists recommend ceftriaxone 2 g daily either IM or IV for 10--14 days. Other regimens have not been adequately evaluated for treatment of neurosyphilis. Therefore, if concern exists regarding the safety of ceftriaxone for a patient with neurosyphilis, the patient should obtain skin testing to confirm penicillin allergy and, if necessary, be desensitized and managed in consultation with a specialist.

Pregnancy. Pregnant patients who are allergic to penicillin should be desensitized, if necessary, and treated with penicillin (see Syphilis During Pregnancy).

HIV Infection. See Syphilis Among HIV-Infected Patients.

Syphilis Among HIV-Infected Persons

Diagnostic Considerations

Unusual serologic responses have been observed among HIV-infected persons who have syphilis. The majority of reports have involved serologic titers that were higher than expected, but false-negative serologic test results and delayed appearance of seroreactivity also have been reported. However, unusual serologic responses are uncommon, and the majority of specialists believe that both treponemal and nontreponemal serologic tests for syphilis can be interpreted in the usual manner for the majority of patients who are coinfected with T. pallidum and HIV.

When clinical findings are suggestive of syphilis but serologic tests are nonreactive or their interpretation is unclear, alternative tests (e.g., biopsy of a lesion, darkfield examination, or DFA staining of lesion material) might be useful for diagnosis. Neurosyphilis should be considered in the differential diagnosis of neurologic disease in HIV-infected persons.

Treatment

Compared with HIV-negative patients, HIV-positive patients who have early syphilis might be at increased risk for neurologic complications and might have higher rates of treatment failure with currently recommended regimens. The magnitude of these risks is not defined precisely but is likely minimal. No treatment regimens for syphilis have been demonstrated to be more effective in preventing neurosyphilis in HIV-infected patients than the syphilis regimens recommended for HIV-negative patients (100). Careful follow-up after therapy is essential.

Primary and Secondary Syphilis Among HIV-Infected Persons

Treatment

Treatment with benzathine penicillin G, 2.4 million units IM in a single dose is recommended. Some specialists recommend additional treatments (e.g., benzathine penicillin G administered at 1-week intervals for 3 weeks, as recommended for late syphilis) in addition to benzathine penicillin G 2.4 million units IM.

Other Management Considerations

Because CSF abnormalities (e.g., mononuclear pleocytosis and elevated protein levels) are common in patients with early syphilis and in persons with HIV infection, the clinical and prognostic significance of such CSF abnormalities in HIV-infected persons with primary or secondary syphilis is unknown. Although the majority of HIV-infected persons respond appropriately to standard benzathine penicillin therapy, some specialists recommend intensified therapy when CNS syphilis is suspected in these persons. Therefore, some specialists recommend CSF examination before treatment of HIV-infected persons with early syphilis, with follow-up CSF examination conducted after treatment in persons with initial abnormalities.

Follow-Up. HIV-infected persons should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy. Although of unproven benefit, some specialists recommend a CSF examination 6 months after therapy.

HIV-infected persons who meet the criteria for treatment failure (i.e., signs or symptoms that persist or recur or persons who have fourfold increase in nontreponemal test titer) should be managed in the same manner as HIV-negative patients (i.e., a CSF examination and re-treatment). CSF examination and re-treatment also should be strongly considered for persons whose nontreponemal test titers do not decrease fourfold within 6--12 months of therapy. The majority of specialists would re-treat patients with benzathine penicillin G administered as 3 doses of 2.4 million units IM each at weekly intervals, if CSF examinations are normal.

Special Considerations

Penicillin Allergy. Penicillin-allergic patients who have primary or secondary syphilis and HIV infection should be managed according to the recommendations for penicillin-allergic, HIV-negative patients. The use of alternatives to penicillin has not been well studied in HIV-infected patients.

Latent Syphilis Among HIV-Infected Persons

Diagnostic Considerations

HIV-infected patients who have early latent syphilis should be managed and treated according to the recommendations for HIV-negative patients who have primary and secondary syphilis. HIV-infected patients who have either late latent syphilis or syphilis of unknown duration should have a CSF examination before treatment.

Treatment

Patients with late latent syphilis or syphilis of unknown duration and a normal CSF examination can be treated with benzathine penicillin G, at weekly doses of 2.4 million units for 3 weeks. Patients who have CSF consistent with neurosyphilis should be treated and managed as patients who have neurosyphilis (see Neurosyphilis).

Follow-Up

Patients should be evaluated clinically and serologically at 6, 12, 18, and 24 months after therapy. If, at any time, clinical symptoms develop or nontreponemal titers rise fourfold, a repeat CSF examination should be performed and treatment administered accordingly. If during 12--24 months the nontreponemal titer does not decline fourfold, the CSF examination should be repeated and treatment administered accordingly.

Special Considerations

Penicillin Allergy. The efficacy of alternative nonpenicillin regimens in HIV-infected persons has not been well studied. Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy). These therapies should be used only in conjunction with close serologic and clinical follow-up. Limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone might be effective. However, optimal dose and duration of ceftriaxone therapy have not been defined.

Syphilis During Pregnancy

All women should be screened serologiclly for syphilis during the early stages of pregnancy. The majority of states mandate screening at the first prenatal visit for all women. Antepartum screening by nontreponemal antibody testing is typical, but in some settings, treponemal antibody testing is being used. Pregnant women with reactive treponemal screening tests should have confirmatory testing with nontreponemal tests with titers. In populations in which use of prenatal care is not optimal, RPR-card test screening and treatment (i.e., if the RPR-card test is reactive) should be performed at the time a pregnancy is diagnosed. For communities and populations in which the prevalence of syphilis is high or for patients at high risk, serologic testing should be performed twice during the third trimester, at 28 to 32 weeks' gestation and at delivery. Any woman who delivers a stillborn infant after 20 weeks' gestation should be tested for syphilis. No infant should leave the hospital without the maternal serologic status having been determined at least once during pregnancy.

Diagnostic Considerations

Seropositive pregnant women should be considered infected unless an adequate treatment history is documented clearly in the medical records and sequential serologic antibody titers have declined. Serofast low antibody titers might not require treatment; however, persistent higher titer antibody tests might indicate reinfection and require treatment.

Treatment

Penicillin is effective for preventing maternal transmission to the fetus and for treating fetal infection. Evidence is insufficient to determine specific, recommended penicillin regimens that are optimal (107).

Recommended Regimen
Treatment during pregnancy should be the penicillin regimen appropriate for the stage of syphilis.

Other Management Considerations

Some specialists recommend additional therapy for pregnant women in some settings (e.g., a second dose of benzathine penicillin 2.4 million units IM administered 1 week after the initial dose for women who have primary, secondary, or early latent syphilis). During the second half of pregnancy, syphilis management may be facilitated by a sonographic fetal evaluation for congenital syphilis, but this evaluation should not delay therapy. Sonographic signs of fetal or placental syphilis (i.e., hepatomegaly, ascites, hydrops, or a thickened placenta) indicate a greater risk for fetal treatment failure; such cases should be managed in consultation with obstetric specialists. Evidence is insufficient to recommend specific regimens for these situations.

Women treated for syphilis during the second half of pregnancy are at risk for premature labor and/or fetal distress, if the treatment precipitates the Jarisch-Herxheimer reaction. These women should be advised to seek obstetric attention after treatment, if they notice any contractions or decrease in fetal movements. Stillbirth is a rare complication of treatment, but concern for this complication should not delay necessary treatment. All patients who have syphilis should be offered testing for HIV infection.

Follow-Up. Coordinated prenatal care and treatment follow-up are vital. Serologic titers should be repeated at 28--32 weeks' gestation, at delivery, and following the recommendations for the stage of disease. Serologic titers can be checked monthly in women at high risk for reinfection or in geographic areas in which the prevalence of syphilis is high. The clinical and antibody response should be appropriate for the stage of disease. The majority of women will deliver before their serologic response to treatment can be assessed definitively. Inadequate maternal treatment is likely if delivery occurs within 30 days of therapy, if clinical signs of infection are present at delivery, or if the maternal antibody titer is fourfold higher than the pretreatment titer.

Management of Sex Partners. See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy. For treatment of syphilis during pregnancy, no proven alternatives to penicillin exist. Pregnant women who have a history of penicillin allergy should be desensitized and treated with penicillin. Skin testing might be helpful (see Management of Patients Who Have a History of Penicillin Allergy).

Tetracycline and doxycycline usually are not used during pregnancy. Erythromycin should not be used because it does not reliably cure an infected fetus. Data are insufficient to recommend azithromycin or ceftriaxone for treatment of maternal infection and prevention of congenital syphilis.
HIV Infection. Placental inflammation from congenital infection might increase the risk for perinatal transmission of HIV. All HIV-infected women should be evaluated for infectious syphilis and treated. Data are insufficient to recommend a specific regimen (see Syphilis Among HIV-Infected Patients).

Effective prevention and detection of congenital syphilis depends on the identification of syphilis in pregnant women and, therefore, on the routine serologic screening of pregnant women during the first prenatal visit. In communities and populations in which the risk for congenital syphilis is high, serologic testing and a sexual history also should be obtained at 28 weeks' gestation and at delivery. Moreover, as part of the management of pregnant women who have syphilis, information concerning treatment of sex partners should be obtained to assess the risk for reinfection. All pregnant women who have syphilis should be tested for HIV infection. Routine screening of newborn sera or umbilical cord blood is not recommended. Serologic testing of the mother's serum is preferred rather than testing of the infant's serum because the serologic tests performed on infant serum can be nonreactive if the mother's serologic test result is of low titer or was infected late in pregnancy (see Diagnostic Considerations and Use of Serologic Tests). No infant or mother should leave the hospital unless the maternal serologic status has been documented at least once during pregnancy, and at delivery in communities and populations in which the risk for congenital syphilis is high.

Evaluation and Treatment of Infants During the First Month of Life

The diagnosis of congenital syphilis is complicated by the transplacental transfer of maternal nontreponemal and treponemal IgG antibodies to the fetus. This transfer of antibodies makes the interpretation of reactive serologic tests for syphilis in infants difficult. Treatment decisions frequently must be made on the basis of
1) identification of syphilis in the mother;
2) adequacy of maternal treatment;
3) presence of clinical, laboratory, or radiographic evidence of syphilis in the infant; and
4) comparison of maternal (at delivery) and infant nontreponemal serologic titers by using the same test and preferably the same laboratory.

All infants 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 infant serum because umbilical cord blood can become contaminated with maternal blood and could yield a false-positive result. Conducting a treponemal test (i.e., TP-PA or FTA-ABS) on a newborn's serum is not necessary. No commercially available immunoglobulin (IgM) test can be recommended.

All infants born to women who have reactive serologic tests for syphilis should be examined thoroughly for evidence of congenital syphilis (e.g., nonimmune hydrops, jaundice, hepatosplenomegaly, rhinitis, skin rash, and/or pseudoparalysis of an extremity). Pathologic examination of the placenta or umbilical cord by using specific fluorescent antitreponemal antibody staining is suggested. Darkfield microscopic examination or DFA staining of suspicious lesions or body fluids (e.g., nasal discharge) also should be performed.

The following scenarios describe the evaluation and treatment of infants for congenital syphilis:

Scenario 1. Infants with proven or highly probable disease and
1. an abnormal physical examination that is consistent with congenital syphilis,
2. a serum quantitative nontreponemal serologic titer that is fourfold higher than the mother's titer,§ or
3. a positive darkfield or fluorescent antibody test of body fluid(s).

Recommended Evaluation

• CSF analysis for VDRL, cell count, and protein
• Complete blood count (CBC) and differential and platelet count
• Other tests as clinically indicated (e.g., long-bone radiographs, chest radiograph, liver-function tests, cranial ultrasound, ophthalmologic examination, and auditory brainstem response)

Recommended Regimens
Aqueous crystalline penicillin G 100,000--150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days OR
Procaine penicillin G 50,000 units/kg/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 the 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. The use of agents other than penicillin requires close serologic follow-up to assess adequacy of therapy. In all other situations, the maternal history of infection with T. pallidum and treatment for syphilis must be considered when evaluating and treating the infant.

Scenario 2. Infants who have a normal physical examination and a serum quantitive nontreponemal serologic titer the same or less than fourfold the maternal titer and the
1. mother was not treated, inadequately treated, or has no documentation of having received treatment;
2. mother was treated with erythromycin or other nonpenicillin regimen;** or
3. mother received treatment <4 weeks before delivery.

Recommended Evaluation

• CSF analysis for VDRL, cell count, and protein
• CBC and differential and platelet count
• Long-bone radiographs

A complete evaluation is not necessary if 10 days of parenteral therapy is administered. However, such evaluations might be useful; a lumbar puncture might document CSF abnormalities that would prompt close follow-up. Other tests (e.g., CBC, platelet count, and bone radiographs) may be performed to further support a diagnosis of congenital syphilis. If a single dose of benzathine penicillin G is used, then the infant must be fully evaluated (i.e., through CSF examination, long-bone radiographs, and CBC with platelets), the full evaluation must be normal, and follow-up must be certain. If any part of the infant's evaluation is abnormal or not performed or if the CSF analysis is rendered uninterpretable because of contamination with blood, then a 10-day course of penicillin is required.††

Recommended Regimens
Aqueous crystalline penicillin G 100,000--150,000 units/kg/day, administered as 50,000 units/kg/dose IV every 12 hours during the first 7 days of life and every 8 hours thereafter for a total of 10 days
OR
Procaine penicillin G 50,000 units/kg/dose IM in a single daily dose for 10 days
OR
Benzathine penicillin G 50,000 units/kg/dose IM in a single dose

Some specialists prefer the 10 days of parenteral therapy if the mother has untreated early syphilis at delivery.
Scenario 3. Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the

• mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered >4 weeks before delivery; and
• mother has no evidence of reinfection or relapse.

Recommended Evaluation

No evaluation is required.

Recommended Regimen
Benzathine penicillin G 50,000 units/kg/dose IM in a single dose§§

Scenario 4. Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the
1. mother's treatment was adequate before pregnancy, and
2. mother's nontreponemal serologic titer remained low and stable before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4).

Recommended Evaluation

No evaluation is required.

Recommended Regimen
No treatment is required; however, some specialists would treat with benzathine penicillin G 50,000 units/kg as a single IM injection, particularly if follow-up is uncertain.
Evaluation and Treatment of Older Infants and Children

Children who are identified as having reactive serologic tests for syphilis after the neonatal period (i.e., aged >1 month) should have maternal serology and records reviewed to assess whether the child has congenital or acquired syphilis (see Primary and Secondary Syphilis and Latent Syphilis, Sexual Assault or Abuse of Children). Any child at risk for congenital syphilis should receive a full evaluation and testing for HIV infection.

Recommended Evaluation

• 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, and auditory brain stem response)

Recommended Regimen
Aqueous crystalline penicillin G 200,000--300,000 units/kg/day IV, administered as 50,000 units/kg every 4--6 hours for 10 days

If the child has no clinical manifestations of disease, the CSF examination is normal, and the CSF VDRL test result is negative, some specialists would treat with up to 3 weekly doses of benzathine penicillin G, 50,000 U/kg IM.

Any child who is suspected of having congenital syphilis or who has neurologic involvement should be treated with aqueous penicillin G. Some specialists also suggest giving these patients a single dose of benzathine penicillin G, 50,000 units/kg IM after the 10-day course of IV aqueous penicillin. This treatment also would be adequate for children who might have other treponemal infections.

Follow-Up

All seroreactive infants (or infants whose mothers were seroreactive at delivery) should receive careful follow-up examinations and serologic testing (i.e., a nontreponemal test) every 2--3 months until the test becomes nonreactive or the titer has decreased fourfold. Nontreponemal antibody titers should decline by age 3 months and should be nonreactive by age 6 months if the infant was not infected (i.e., if the reactive test result was caused by passive transfer of maternal IgG antibody) or was infected but adequately treated. The serologic response after therapy might be slower for infants treated after the neonatal period. If these titers are stable or increase after age 6--12 months, the child should be evaluated (e.g., given a CSF examination) and treated with a 10-day course of parenteral penicillin G.

Treponemal tests should not be used to evaluate treatment response because the results for an infected child can remain positive despite effective therapy. Passively transferred maternal treponemal antibodies can be present in an infant until age 15 months. A reactive treponemal test after age 18 months is diagnostic of congenital syphilis. If the nontreponemal test is nonreactive at this time, no further evaluation or treatment is necessary. If the nontreponemal test is reactive at age 18 months, the infant should be fully (re)evaluated and treated for congenital syphilis.

Infants whose initial CSF evaluations are abnormal should undergo a repeat lumbar puncture approximately every 6 months until the results are normal. A reactive CSF VDRL test or abnormal CSF indices that cannot be attributed to other ongoing illness requires re-treatment for possible neurosyphilis.

Follow-up of children treated for congenital syphilis after the newborn period should be conducted as is recommended for neonates.

Special Considerations

Penicillin Allergy

Infants and children who require treatment for syphilis but who have a history of penicillin allergy or develop an allergic reaction presumed secondary to penicillin should be desensitized, if necessary, and then treated with penicillin (see Management of Patients With a History of Penicillin Allergy). Data are insufficient regarding the use of other antimicrobial agents (e.g., ceftriaxone); if a nonpenicillin agent is used, close serologic and CSF follow-up are indicated.

HIV Infection

Evidence is insufficient to determine whether infants who have congenital syphilis and whose mothers are coinfected with HIV require different evaluation, therapy, or follow-up for syphilis than is recommended for all infants.

Penicillin Shortage

During periods when the availability of penicillin is compromised, the following is recommended (see http://www.cdc.gov/nchstp/dstd/penicillinG.htm):

1. For infants with clinical evidence of congenital syphilis (Scenario 1), check local sources for aqueous crystalline penicillin G (potassium or sodium). If IV penicillin G is limited, substitute some or all daily doses with procaine penicillin G (50,000 U/kg/dose IM a day in a single daily dose for 10 days).
   
   If aqueous or procaine penicillin G is not available, ceftriaxone (in doses according to age and weight) may be considered with careful clinical and serologic follow-up. Ceftriaxone must be used with caution in infants with jaundice. For infants aged >30 days, use 75 mg/kg IV/IM a day in a single daily dose for 10--14 days; however, dose adjustment might be necessary based on birthweight. For older infants, the dose should be 100 mg/kg a day in a single daily dose. Studies that strongly support ceftriaxone for the treatment of congenital syphilis have not been conducted. Therefore, ceftriaxone should be used in consultation with a specialist in the treatment of infants with congenital syphilis. Management may include a repeat CSF examination at age 6 months if the initial examination was abnormal.
   
   
2. For infants at risk for congenital syphilis without any clinical evidence of infection (Scenarios 2 and 3), use
   a. procaine penicillin G, 50,000 U/kg/dose IM a day in a single dose for 10 days;
   OR
   b. benzathine penicillin G, 50,000 U/kg IM as a single dose.
   If any part of the evaluation for congenital syphilis is abnormal, CSF examination is not interpretable, CSF examination was not performed, or follow-up is uncertain, Procaine penicillin G is recommended. A single dose of ceftriaxone is inadequate therapy.
   
   
3. For premature infants at risk for congenital syphilis but who have no other clinical evidence of infection (Scenarios 2 and 3) and who might not tolerate IM injections because of decreased muscle
   mass, IV ceftriaxone may be considered with careful clinical and serologic follow-up (see Penicillin Shortage, Number 1). Ceftriaxone dosing must be adjusted to age and birthweight.

No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women. Penicillin also is recommended for use, whenever possible, in HIV-infected patients. Of the adult U.S. population, 3%--10% have experienced an immunoglobulin E (IgE) mediated allergic response to penicillin such as urticaria, angioedema, or anaphylaxis (i.e., upper airway obstruction, bronchospasm, or hypotension). Re-administration of penicillin to these patients can cause severe, immediate reactions. Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic patients, unless they undergo acute desensitization to eliminate anaphylactic sensitivity.

An estimated 10% of persons who report a history of severe allergic reactions to penicillin remain allergic. With the passage of time, the majority of persons who have had a severe reaction to penicillin stop expressing penicillin-specific IgE. These persons can be treated safely with penicillin. The results of many investigations indicate that skin testing with the major and minor determinants of penicillin can reliably identify persons at high risk for penicillin reactions. Although these reagents are easily generated and have been available for >30 years, only benzylpenicilloyl poly-L-lysine (Pre-Pen® [i.e., the major determinant]) and penicillin G have been available commercially. Testing with only the major determinant and penicillin G identifies an estimated 90%--97% of the currently allergic patients. However, because skin testing without the minor determinants would still miss 3%--10% of allergic patients and because serious or fatal reactions can occur among these minor-determinant--positive patients, specialists suggest exercising caution when the full battery of skin-test reagents is not available (Box 1). An additional challenge has occurred with the recent unavailability of Pre-Pen®; however, plans for future availability of this product have been made, as well as a companion minor determinant mixture.

Recommendations

If the full battery of skin-test reagents is available, including the major and minor determinants (see Penicillin Allergy Skin Testing), patients who report a history of penicillin reaction and who are skin-test negative can receive conventional penicillin therapy. Skin-test--positive patients should be desensitized.

If the full battery of skin-test reagents, including the minor determinants, is not available, the patient should be skin tested using benzylpenicilloyl poly-L-lysine (i.e., the major determinant) and penicillin G. Patients who have positive test results should be desensitized. Some specialists suggest that persons who have negative test results should be regarded as probably allergic and should be desensitized. Others suggest that those with negative skin-test results can be test-dosed gradually with oral penicillin in a monitored setting in which treatment for anaphylactic reaction can be provided.

If the major determinant (Pre-Pen®) is not available for skin testing, all patients with a history suggesting IgE mediated reactions (anaphylaxis, angioedema, bronchospasm, or urticaria) to penicillin should be desensitized in a hospital setting. In patients with reactions not likely to be IgE mediated, outpatient oral desensitization or monitored test doses may be considered.

Penicillin Allergy Skin Testing

Patients at high risk for anaphylaxis, including those who 1) have a history of penicillin-related anaphylaxis, asthma, or other diseases that would make anaphylaxis more dangerous or 2) are being treated with beta-adrenergic blocking agents should be tested with 100-fold dilutions of the full-strength skin-test reagents before being tested with full-strength reagents. In these situations, patients should be tested in a monitored setting in which treatment for an anaphylactic reaction is available. If possible, the patient should not have taken antihistamines recently (e.g., chlorpheniramine maleate or terfenadine during the preceding 24 hours, diphenhydramine HCl or hydroxyzine during the preceding 4 days, or astemizole during the preceding 3 weeks).

Procedures

Dilute the antigens either 1) 100-fold for preliminary testing if the patient has had a life-threatening reaction to penicillin or 2) 10-fold if the patient has had another type of immediate, generalized reaction to penicillin within the preceding year.

Epicutaneous (Prick) Tests

Duplicate drops of skin-test reagent are placed on the volar surface of the forearm. The underlying epidermis is pierced with a 26-gauge needle without drawing blood.

An epicutaneous test is positive if the average wheal diameter after 15 minutes is 4 mm larger than that of negative controls; otherwise, the test is negative. The histamine controls should be positive to ensure that results are not falsely negative because of the effect of antihistaminic drugs.

Intradermal Test

If epicutaneous tests are negative, duplicate 0.02-mL intradermal injections of negative control and antigen solutions are made into the volar surface of the forearm by using a 26- or 27-gauge needle on a syringe. The diameters of the wheals induced by the injections should be recorded.
An intradermal test is positive if the average wheal diameter 15 minutes after injection is >2 mm larger than the initial wheal size and also is >2 mm larger than the negative controls. Otherwise, the tests are negative.

Desensitization

Patients who have a positive skin test to one of the penicillin determinants can be desensitized (Table 1). This is a straightforward, relatively safe procedure that can be performed orally or IV. Although the two approaches have not been compared, oral desensitization is regarded as safer and easier to perform. Patients should be desensitized in a hospital setting because serious IgE-mediated allergic reactions can occur. Desensitization usually can be completed in approximately 4 hours, after which the first dose of penicillin is administered. After desensitization, patients must be maintained on penicillin continuously for the duration of the course of therapy.

Management of Male Patients Who Have Urethritis

Urethritis, as characterized by urethral inflammation, can result from infectious and noninfectious conditions. Symptoms, if present, include discharge of mucopurulent or purulent material, dysuria, or urethral pruritis. Asymptomatic infections are common. N. gonorrhoeae and C. trachomatis are clinically important infectious causes of urethritis. If clinic-based diagnostic tools (Gram stain microscopy) are not available, patients should be treated for both gonorrhea and chlamydia. Further testing to determine the specific etiology is recommended because both chlamydia and gonorrhea are reportable to state health departments, and a specific diagnosis might enhance partner notification and improve compliance with treatment, especially in exposed partners. Culture, nucleic acid hybridization tests, and nucleic acid amplification tests are available for the detection of both N. gonorrhoeae and C. trachomatis. Culture and hybridization tests require urethral swab specimens, whereas amplification tests can be performed on urine specimens. Because of their higher sensitivity, amplification tests are preferred for the detection of C. trachomatis.

Etiology

Several organisms can cause infectious urethritis. The presence of Gram-negative intracellular diplococci (GNID) on urethral smear is indicative of gonorrhea infection, which is frequently accompanied by chlamydial infection. Nongonoccocal urethritis (NGU) is diagnosed when microscopy indicates inflammation without GNID. C. trachomatis is a frequent cause of NGU (i.e., 15%--55% of cases); however, the prevalence varies by age group, with lower prevalence among older men. The proportion of NGU cases caused by chlamydia has been declining gradually. Complications of NGU among men infected with C. trachomatis include epididymitis, prostatitis, and Reiter's syndrome. Documentation of chlamydia infection is essential because of the need for partner referral for evaluation and treatment.

The etiology of the majority of cases of nonchlamydial NGU is unknown. Ureaplasma urealyticum and Mycoplasma genitalium have been implicated as etiologic agents of NGU in some studies; however, detection of these organisms is frequently difficult. T. vaginalis, HSV, and adenovirus might also cause NGU. Diagnostic and treatment procedures for these organisms are reserved for situations in which these infections are suspected (e.g., contact with trichomoniasis and genital lesions or severe dysuria and meatitis, which might suggest genital herpes) or when NGU is not responsive to therapy. Enteric bacteria have been identified as an uncommon cause of NGU and might be associated with insertive anal sex.

Confirmed Urethritis

Clinicians should document that urethritis is present. Urethritis can be documented on the basis of any of the following signs or laboratory tests:

• Mucopurulent or purulent discharge.
• Gram stain of urethral secretions demonstrating >5 WBC per oil immersion field. The Gram stain is the preferred rapid diagnostic test for evaluating urethritis. It is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. Gonococcal infection is established by documenting the presence of WBC containing GNID, or
• Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment demonstrating >10 WBC per high power field.

If none of these criteria are present, treatment should be deferred, and the patient should be tested for N. gonorrhoeae and C. trachomatis and followed closely if test results are negative. If the results demonstrate infection with either N. gonorrhoeae or C. trachomatis, the appropriate treatment should be given and sex partners referred for evaluation and treatment.

Empiric treatment of symptoms without documentation of urethritis is recommended only for patients at high risk for infection who are unlikely to return for a follow-up evaluation. Such patients should be treated for gonorrhea and chlamydia. Partners of patients treated empirically should be evaluated and treated.

Management of Patients Who Have Nongonococcal Urethritis

Diagnosis

All patients who have confirmed or suspected urethritis should be tested for gonorrhea and chlamydia. Testing for chlamydia is strongly recommended because of the increased utility and availability of highly sensitive and specific testing methods and because a specific diagnosis might enhance partner notification and improve compliance with treatment, especially in the exposed partner.

Treatment

Treatment should be initiated as soon as possible after diagnosis. Azithromycin and doxycycline are highly effective for chlamydial urethritis; however, infections with M. genitalium may respond better to azithromycin. Single-dose regimens have the advantage of improved compliance and directly observed treatment. To improve compliance, ideally the medication should be provided in the clinic or health-care provider's office.

Recommended Regimens
Azithromycin 1 g orally in a single dose
OR
Doxycycline 100 mg orally twice a day for 7 days
Alternative Regimens
Erythromycin base 500 mg orally four times a day for 7 days
OR
Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days
OR
Ofloxacin 300 mg orally twice a day for 7 days
OR
Levofloxacin 500 mg orally once daily for 7 days

Follow-Up for Patients Who Have Urethritis

Patients should be instructed to return for evaluation if symptoms persist or recur after completion of therapy. Symptoms alone, without documentation of signs or laboratory evidence of urethral inflammation, are not a sufficient basis for re-treatment. Patients should be instructed to abstain from sexual intercourse until 7 days after therapy is initiated, provided their symptoms have resolved and their sex partners have been adequately treated. Persistence of pain, discomfort, and irritative voiding symptoms beyond 3 months should alert the clinician to the possibility of chronic prostatitis/chronic pelvic pain syndrome in men. Persons whose conditions have been diagnosed as a new STD should receive testing for other STDs, including syphilis and HIV.

Partner Referral

Persons with NGU should refer for evaluation and treatment all sex partners within the preceding 60 days. Because a specific diagnosis might facilitate partner referral, testing for gonorrhea and chlamydia is encouraged.

Recurrent and Persistent Urethritis

Objective signs of urethritis should be present before initiation of antimicrobial therapy. In persons who have persistent symptoms after treatment without objective signs of urethritis, the value of extending the duration of antimicrobials has not been demonstrated. Persons who have persistent or recurrent urethritis can be re-treated with the initial regimen if they did not comply with the treatment regimen or if they were reexposed to an untreated sex partner. Otherwise, a T. vaginalis culture should be performed using an intraurethral swab or a first-void urine specimen. Some cases of recurrent urethritis after doxycycline treatment might be caused by tetracycline-resistant U. urealyticum. Urologic examinations usually do not reveal a specific etiology. Approximately 50% of men with chronic nonbacterial prostatitis/chronic pelvic pain syndrome have evidence of urethral inflammation without any identifiable microbial pathogens. If the patient was compliant with the initial regimen and reexposure can be excluded, the following regimen is recommended.

Recommended Regimens
Metronidazole 2 g orally in a single dose
OR
Tinidazole 2 g orally in a single dose
PLUS
Azithromycin 1 g orally in a single dose (if not used for initial episode)

Special Considerations

HIV Infection

Gonococcal urethritis, chlamydial urethritis, and nongonococcal, nonchlamydial urethritis might facilitate HIV transmission. Patients who have NGU and also are infected with HIV should receive the same treatment regimen as those who are HIV negative.

Management of Patients Who Have 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" or cervicitis), and 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, but some women complain of an abnormal vaginal discharge and intermenstrual vaginal bleeding (e.g., after sexual intercourse). A finding of leukorrhea (>10 WBC per high power field on microscopic examination of vaginal fluid) has been associated with chlamydial and gonococcal infection of the cervix. In the absence of inflammatory vaginitis, leukorrhea might be a sensitive indicator of cervical inflammation with a high negative predictive value. Although some specialists consider an increased number of polymorphonuclear leukocytes on endocervical Gram stain as being useful in the diagnosis of cervicitis, this criterion has not been standardized. In addition, it has a low positive-predictive value (PPV) for infection with C. trachomatis and N. gonorrhoeae and is not available in the majority of clinical settings. Finally, although the presence of GNID on Gram stain of endocervical fluid is specific for the diagnosis of gonococcal cervical infection, it is insensitive because it is observed in only 50% of women with this infection.

Etiology

When an etiologic organism is isolated in the setting of cervicitis, it is typically C. trachomatis or N. gonorrhoeae. Cervicitis also can accompany trichomoniasis and genital herpes (especially primary HSV-2 infection). However, in the majority of cases of cervicitis, no organism is isolated, especially in women at relatively low risk for recent acquisition of these STDs (for example, women aged >30 years). Limited data indicate that infection with M. genitalium and BV as well as frequent douching might cause cervicitis. For reasons that are unclear, cervicitis can persist despite repeated courses of antimicrobial therapy. Because the majority of persistent cases of cervicitis are not caused by relapse or reinfection with C. trachomatis or N. gonorrhoeae, other determinants (e.g., persistent abnormality of vaginal flora, douching or exposure to chemical irritants, or idiopathic inflammation in the zone of ectopy) might be involved.

Diagnosis

Because cervicitis might be a sign of upper genital tract infection (endometritis), women who seek medical treatment for a new episode of cervicitis should be assessed for signs of PID and should be tested for C. trachomatis and for N. gonorrhoeae with the most sensitive and specific test available, NAAT. Women with cervicitis also should be evaluated for the presence of BV and trichomoniasis, and these conditions should be treated, if present. Because the sensitivity of microscopy to detect T. vaginalis is relatively low (approximately 50%), symptomatic women with cervicitis and negative microscopy for trichomonads should receive further testing (i.e., culture or antigen-based detection). Although HSV-2 infection has been associated with cervicitis, the utility of specific testing (i.e., culture or serologic testing) for HSV-2 in this setting is unclear. Standardized diagnostic tests for M. genitalium are not commercially available.

NAAT for C. trachomatis and N. gonorrhoeae are preferred for the diagnostic evaluation of cervicitis and can be performed on either cervical or urine samples. A finding of >10 WBC in vaginal fluid, in the absence of trichomoniasis, might indicate endocervical inflammation caused specifically by C. trachomatis or N. gonorrhoeae.

Treatment

Several factors should affect the decision to provide presumptive therapy for cervicitis or to await the results of diagnostic tests. Treatment with antibiotics for C. trachomatis should be provided in women at increased risk for this common STD (age <25 years, new or multiple sex partners, and unprotected sex), especially if follow-up cannot be ensured and if a relatively insensitive diagnostic test (not a NAAT) is used. Concurrent therapy for N. gonorrhoeae is indicated if the prevalence of this infection is high (>5%) in the patient population (young age and facility prevalence).

Concomitant trichomoniasis or symptomatic BV should also be treated if detected. For women in whom any component of (or all) presumptive therapy is deferred, the results of sensitive tests for C. trachomatis and N. gonorrhoeae (e.g., nucleic acid amplification tests) should determine the need for treatment subsequent to the initial evaluation.

Recommended Regimens for Presumptive Treatment*
Azithromycin 1 g orally in a single dose
OR
Doxycycline 100 mg orally twice a day for 7 days
* Consider concurrent treatment for gonococcal infection if prevalence of gonorrhea is high in the patient population under assessment.

Recurrent and Persistent Cervicitis

Women with persistent cervicitis should be reevaluated for possible reexposure to an STD, and her vaginal flora should be reassessed. If relapse and/or reinfection with a specific STD has been excluded, BV is not present, and sex partners have been evaluated and treated, management options for persistent cervicitis are undefined. For such women, the value of repeated or prolonged administration of antibiotic therapy for persistent symptomatic cervicitis is unknown. Women who receive such a course should return after treatment so that a determination can be made regarding whether cervicitis has resolved. In women with persistent symptoms that are clearly attributable to cervicitis, ablative therapy may be considered by a gynecologic specialist.

Follow-Up

Follow-up should be conducted as recommended for the infections for which a woman is treated. If symptoms persist, women should be instructed to return for reevaluation.

Management of Sex Partners

Management of sex partners of women treated for cervicitis should be appropriate for the identified or suspected STD. Partners should be notified and examined if chlamydia, gonorrhea, or trichomoniasis was identified or suspected in the index patient and treated for the STDs for which the index patient received treatment. To avoid re-infection, patients and their sex partners should abstain from sexual intercourse until therapy is completed (i.e., 7 days after a single-dose regimen or after completion of a 7-day regimen).

Special Considerations

HIV Infection

Patients who have cervicitis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. Treatment of cervicitis in HIV-infected women is vital because cervicitis increases cervical HIV shedding. Treatment of cervicitis in HIV-infected women reduces HIV shedding from the cervix and might reduce HIV transmission to susceptible sex partners.

Chlamydial Infections

Chlamydial Infections in Adolescents and Adults

In the United States, chlamydial genital infection is the most frequently reported infectious disease, and the prevalence is highest in persons aged <25 years. Several important sequelae can result from C. trachomatis infection in women; the most serious of these include PID, ectopic pregnancy, and infertility. Some women who have uncomplicated cervical infection already have subclinical upper reproductive tract infection.

Asymptomatic infection is common among both men and women, and to detect chlamydial infections 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 with risk factors (e.g., those who have a new sex partner or multiple sex partners). The benefits of C. trachomatis screening in women have been demonstrated in areas where screening programs have reduced both the prevalence of infection and rates of PID. Evidence is insufficient to recommend routine screening for C. trachomatis in sexually active young men, based on feasibility, efficacy, and cost-effectiveness. However, screening of sexually active young men should be considered in clinical settings with a high prevalence of chlamydia (e.g., adolescent clinics, correctional facilities, and STD clinics). An appropriate sexual risk assessment should be conducted for all persons and might indicate more frequent screening for some women or certain men.

Diagnostic Considerations

C. trachomatis urogenital infection in women can be diagnosed by testing urine or swab specimens collected from the endocervix or vagina. Diagnosis of C. trachomatis urethral infection in men can be made by testing a urethral swab or urine specimen. Rectal C. trachomatis infections in persons that engage in receptive anal intercourse can be diagnosed by testing a rectal swab specimen. Culture, direct immunofluorescence, EIA, nucleic acid hybridization tests, and NAATs are available for the detection of C. trachomatis on endocervical and male urethral swab specimens. NAATs are the most sensitive tests for these specimens and are FDA-cleared for use with urine, and some tests are cleared for use with vaginal swab specimens. The majority of tests, including NAAT and nucleic acid hybridization tests, are not FDA-cleared for use with rectal swab specimens, and chlamydia culture is not widely available for this purpose. Some noncommercial laboratories have initiated NAAT of rectal swab specimens after establishing the performance of the test to meet CLIA requirements. Patients' whose condition has been diagnosed as chlamydia also should be tested for other STDs.

Treatment

Treating infected patients prevents transmission to sex partners. In addition, treating pregnant women usually prevents transmission of C. trachomatis to infants during birth. Treatment of sex partners helps to prevent reinfection of the index patient and infection of other partners.

Coinfection with C. trachomatis frequently occurs among patients who have gonococcal infection; therefore, presumptive treatment of such patients for chlamydia is appropriate (see Gonococcal Infection, Dual Therapy for Gonococcal and Chlamydial Infections). The following recommended treatment regimens and alternative regimens cure infection and usually relieve symptoms.

Recommended Regimens
Azithromycin 1 g orally in a single dose
OR
Doxycycline 100 mg orally twice a day for 7 days
Alternative Regimens
Erythromycin base 500 mg orally four times a day for 7 days
OR
Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days
OR
Ofloxacin 300 mg orally twice a day for 7 days
OR
Levofloxacin 500 mg orally once daily for 7 days

A recent meta-analysis of 12 randomized clinical trials of azithromycin versus doxycycline for the treatment of genital chlamydial infection demonstrated that the treatments were equally efficacious, with microbial cure rates of 97% and 98%, respectively. These studies were conducted primarily in populations in which follow-up was encouraged, adherence to a 7-day regimen was effective, and culture or EIA (rather than the more sensitive NAAT was used for determining microbiological outcome. Azithromycin should always be available to treat patients for whom compliance with multiday dosing is in question.

In populations that have erratic health-care--seeking behavior, poor treatment compliance, or unpredictable follow-up, azithromycin might be more cost-effective because it enables the provision of a single-dose of directly observed therapy. However, doxycycline costs less than azithromycin and has no higher risk for adverse events. Erythromycin might be less efficacious than either azithromycin or doxycycline, mainly because of the frequent occurrence of gastrointestinal side effects that discourage compliance. Ofloxacin and levofloxacin are effective treatment alternatives but are more expensive and offer no advantage in the dosage regimen. Other quinolones either are not reliably effective against chlamydial infection or have not been evaluated adequately.

To maximize compliance with recommended therapies, medications for chlamydial infections should be dispensed on site, and the first dose should be directly observed. To minimize transmission, 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. To minimize the risk for reinfection, patients also should be instructed to abstain from sexual intercourse until all of their sex partners are treated.

Follow-up

Except in pregnant women, test-of-cure (repeat testing 3--4 weeks after completing therapy) is not recommended for persons treated with the recommended or alterative regimens, unless therapeutic compliance is in question, symptoms persist, or reinfection is suspected. Moreover, the validity of chlamydial diagnostic testing at <3 weeks after completion of therapy (to identify patients who did not respond to therapy) has not been established. False-negative results might occur because of persistent infections involving limited numbers of chlamydial organisms. In addition, NAAT conducted at <3 weeks after completion of therapy in persons who were treated successfully could yield false-positive results because of the continued presence of dead organisms.

A high prevalence of C. trachomatis infection is observed in women who were treated for chlamydial infection in the preceding several months . The majority of posttreatment infections result from reinfection, frequently occurring because the patient's sex partners were not treated or because the patient resumed sex with a new partner infected with C. trachomatis. Repeat infections confer an elevated risk for PID and other complications when compared with the initial infection. Therefore, recently infected women are a major priority for repeat testing for C. trachomatis. Clinicians and health-care agencies should consider advising all women with chlamydial infection to be retested approximately 3 months after treatment. Providers also are strongly encouraged to retest all women treated for chlamydial infection whenever they next seek medical care within the following 3--12 months, regardless of whether the patient believes that her sex partners were treated. Recognizing that retesting is distinct from a test-of-cure, as discussed in this report, is vital. Limited evidence is available on the benefit of retesting for chlamydia in men previously infected; however, some specialists suggest retesting men approximately 3 months after treatment.

Management of Sex Partners

Patients should be instructed to refer their sex partners for evaluation, testing, and treatment. The following recommendations on exposure intervals are based on limited evaluation. Sex partners should be evaluated, tested, and treated if they had sexual contact with the patient during the 60 days preceding onset of symptoms in the patient or diagnosis of chlamydia. 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 concerns exist that sex partners will not seek evaluation and treatment, or if other management strategies are impractical or unsuccessful, then delivery of antibiotic therapy (either a prescription or medication) by heterosexual male or female patients to their partners might be an option (see Partner Notification). Limited studies to date have demonstrated a trend toward a decrease in rates of persistent or recurrent chlamydia with this approach compared with standard partner referral. Male patients must inform female partners of their infection and be given accompanying written materials about the importance of seeking evaluation for PID (especially if symptomatic). Patient-delivered partner therapy is not routinely recommended for MSM because of a high risk for coexisting infections, especially undiagnosed HIV infection, in their partners.

Patients should be instructed to abstain from sexual intercourse until they and their sex partners have completed treatment. Abstinence should be continued until 7 days after a single-dose regimen or after completion of a 7-day regimen. Timely treatment of sex partners is essential for decreasing the risk for reinfecting the index patient.

Special Considerations

Pregnancy. Doxycycline, ofloxacin, and levofloxacin are contraindicated in pregnant women. However, clinical experience and studies suggest that azithromycin is safe and effective. Repeat testing (preferably by NAAT) 3 weeks after completion of therapy with the following regimens is recommended for all pregnant women to ensure therapeutic cure, considering the sequelae that might occur in the mother and neonate if the infection persists. The frequent gastrointestinal side effects associated with erythromycin might discourage patient compliance with the alternative regimens.

Recommended Regimens
Azithromycin 1 g orally in a single dose
OR
Amoxicillin 500 mg orally three times a day for 7 days
Alternative Regimens
Erythromycin base 500 mg orally four times a day for 7 days
OR
Erythromycin base 250 mg orally four times a day for 14 days
OR
Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days
OR
Erythromycin ethylsuccinate 400 mg orally four times a day for 14 days

Erythromycin estolate is contraindicated during pregnancy because of drug-related hepatotoxicity. The lower dose 14-day erythromycin regimens may be considered if gastrointestinal tolerance is a concern.

HIV Infection. Patients who have chlamydial infection and also are infected with HIV should receive the same treatment regimen as those who are HIV negative.

Chlamydial Infections Among Infants

Prenatal screening of pregnant women can prevent chlamydial infection among neonates. Pregnant women aged <25 years are at high risk for infection. Local or regional prevalence surveys of chlamydial infection can be conducted to confirm the utility of using these recommendations in particular settings.

C. trachomatis infection of neonates results from perinatal exposure to the mother's infected cervix. Neonatal ocular prophylaxis with silver nitrate solution or antibiotic ointments does not prevent perinatal transmission of C. trachomatis from mother to infant. However, ocular prophylaxis with those agents does prevent gonococcal ophthalmia and, therefore, should be continued (see Prevention of Ophthalmia Neonatorum).
Initial C. trachomatis perinatal infection involves the mucous membranes of the eye, oropharynx, urogenital tract, and rectum and might be asymptomatic in these locations. C. trachomatis infection in 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. C. trachomatis has been the most frequent identifiable infectious cause of ophthalmia neonatorum, but perinatal chlamydial infections, including opthalmia and pneumonia, are detected less frequently because of the institution of widespread prenatal screening and treatment of pregnant women.

Ophthalmia Neonatorum Caused by C. trachomatis

A chlamydial etiology should be considered for all infants aged <30 days who have conjunctivitis, especially if the mother has a history of untreated chlamydia infection.

Diagnostic Considerations

Sensitive and specific methods used to diagnose chlamydial ophthalmia in the neonate include both tissue culture and nonculture tests (e.g., DFA tests, EIA, and NAAT). The majority of nonculture tests are not FDA-cleared for the detection of chlamydia from conjunctival swabs, and clinical laboratories must verify the procedure according to CLIA regulations. Specimens must contain conjunctival cells, not exudate alone. Specimens for culture isolation and nonculture tests should be obtained from the everted eyelid using a dacron-tipped swab or the swab specified by the manufacturer's test kit. A specific diagnosis of C. trachomatis infection confirms the need for treatment not only for the neonate but also for the mother and her sex partner(s). Ocular exudate from infants being evaluated for chlamydial conjunctivitis also should be tested for N. gonorrhoeae.

Recommended Regimen
Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days,***

Topical antibiotic therapy alone is inadequate for treatment of chlamydial infection and is unnecessary when systemic treatment is administered.

Follow-Up

The efficacy of erythromycin treatment is approximately 80%; a second course of therapy might be required and, therefore, follow-up of infants is recommended to determine whether initial treatment was effective. The possibility of concomitant chlamydial pneumonia should be considered.

Management of Mothers and Their Sex Partners

The mothers of infants who have chlamydial infection and the sex partners of these women should be evaluated and treated (see Chlamydial Infection in Adolescents and Adults).

Infant Pneumonia Caused by C. trachomatis

Characteristic signs of chlamydial pneumonia in infants include 1) a repetitive staccato cough with tachypnea and 2) hyperinflation and bilateral diffuse infiltrates on a chest radiograph. Wheezing is rare, and infants are typically afebrile. Peripheral eosinophilia (>400 cells/mm3) occurs frequently. Because clinical presentations differ, initial treatment and diagnostic tests should include C. trachomatis for all infants aged 1--3 months who possibly have pneumonia (especially with untreated maternal chlamydial infection).

Diagnostic Considerations

Specimens for chlamydial testing should be collected from the nasopharynx. Tissue culture is the definitive standard for chlamydial pneumonia. Nonculture tests (e.g., EIA, DFA, and NAAT) can be used, although nonculture tests of nasopharyngeal specimens have a lower sensitivity and specificity than nonculture tests of ocular specimens. DFA is the only FDA-cleared test for the detection of C. trachomatis from nasopharyngeal specimens. Tracheal aspirates and lung biopsy specimens, if collected, should be tested for C. trachomatis.

Because of the delay in obtaining test results for chlamydia, the decision to provide treatment for C. trachomatis pneumonia must frequently be based on clinical and radiologic findings. The results of tests for chlamydial infection assist in the management of an infant's illness and determine the need for treating the mother and her sex partner(s).

Recommended Regimen
Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days

Follow-Up

The effectiveness of erythromycin in treating pneumonia caused by C. trachomatis is approximately 80%; a second course of therapy might be required. Follow-up of infants is recommended to determine whether the pneumonia has resolved. Some infants with chlamydial pneumonia have abnormal pulmonary function tests later in childhood.

Management of Mothers and Their Sex Partners

Mothers of infants who have chlamydia pneumonia and the sex partners of these women should be evaluated and treated according to the recommended treatment of adults for chlamydial infections (see Chlamydial Infection in Adolescents and Adults).

Infants Born to Mothers Who Have Chlamydial Infection

Infants born to mothers who have untreated chlamydia are at high risk for infection; however, prophylatic antibiotic treatment is not indicated, and the efficacy of such treatment is unknown. Infants should be monitored to ensure appropriate treatment if symptoms develop.

Chlamydial Infections Among Children

Sexual abuse must be considered a cause of chlamydial infection in preadolescent children, although perinatally transmitted C. trachomatis infection of the nasopharynx, urogenital tract, and rectum might persist for >1 year (see Sexual Assault or Abuse of Children).

Diagnostic Considerations

Nonculture, nonamplified probe tests for chlamydia (EIA, DFA) should not be used because of the possibility of false-positive test results. With respiratory tract specimens, false-positive results can occur because of cross-reaction of test reagents with C. pneumoniae; with genital and anal specimens, false-positive results might occur because of cross-reaction with fecal flora.

Recommended Regimens for Children Who Weigh <45 kg
Erythromycin base or ethylsuccinate 50 mg/kg/day orally divided into 4 doses daily for 14 days

Recommended Regimen for Children Who Weigh >45 kg but Who Are Aged >8 Years
Azithromycin 1 g orally in a single dose

Recommended Regimens for Children Aged >8 years
Azithromycin 1 g orally in a single dose
OR
Doxycycline 100 mg orally twice a day for 7 days

Other Management Considerations

See Sexual Assault or Abuse of Children.

Follow-Up. Follow-up cultures are necessary to ensure that treatment has been effective.

Gonococcal Infections in Adolescents and Adults

In the United States, an estimated 600,000 new N. gonorrhoeae infections occur each year (123). Gonorrhea is the second most commonly reported bacterial STD. The majority of urethral infections caused by N. gonorrhoeae among men produce symptoms that cause them to seek curative treatment soon enough to prevent serious sequelae, but treatment might not be soon enough to prevent transmission to others. Among women, several infections do not produce recognizable symptoms until complications (e.g., PID) have occurred. Both symptomatic and asymptomatic cases of PID can result in tubal scarring that can lead to infertility or ectopic pregnancy.

Because gonococcal infections among women frequently are asymptomatic, an essential component of gonorrhea control in the United States continues to be the screening of women at high risk for STDs. The U.S. Preventive Services Task Force (USPSTF) recommends that clinicians screen all sexually active women, including those who are pregnant, for gonorrhea infection if they are at increased risk. Women aged <25 years are at highest risk for gonorrhea infection. Other risk factors for gonorrhea include a previous gonorrhea infection, other sexually transmitted infections, new or multiple sex partners, inconsistent condom use, commercial sex work, and drug use. The prevalence of gonorrhea infection varies widely among communities and patient populations. The USPSTF does not recommend screening for gonorrhea in men and women who are at low risk for infection.

Diagnostic Considerations

Because of high specificity (>99%) and sensitivity (>95%), a Gram stain of a male urethral specimen that demonstrates polymorphonuclear leukocytes with intracellular Gram-negative diplococci can be considered diagnostic for infection with N. gonorrhoeae in symptomatic men. However, because of lower sensitivity, a negative Gram stain should not be considered sufficient for ruling out infection in asymptomatic men. In addition, Gram stain of endocervical specimens, pharyngeal, or rectal specimens also are not sufficient to detect infection and, therefore, are not recommended. Specific testing for N. gonorrhoeae is recommended because of the increased utility and availability of highly sensitive and specific testing methods and because a specific diagnosis might enhance partner notification.

Specific diagnosis of infection with N. gonorrhoeae may be performed by testing endocervical, vaginal, male urethral, or urine specimens. Culture, nucleic acid hybridization tests, and NAAT are available for the detection of genitourinary infection with N. gonorrhoeae. Culture and nucleic acid hybridization tests require female endocervical or male urethral swab specimens. NAAT offer the widest range of testing specimen types because they are FDA-cleared for use with endocervical swabs, vaginal swabs, male urethral swabs, and female and male urine. However, product inserts for each NAAT vendor must be carefully examined to assess current indications because FDA-cleared specimen types might vary. In general, culture is the most widely available option for the diagnosis of infection with N. gonorrhoeae in nongenital sites (e.g., rectum and pharynx). Nonculture tests are not FDA-cleared for use in the rectum and pharynx. Some NAATs have the potential to cross-react with nongonococcal Neisseria and related organisms that are commonly found in the throat. Some noncommercial laboratories have initiated NAAT of rectal and pharyngeal swab specimens after establishing the performance of the test to meet CLIA requirements.

Because nonculture tests cannot provide antimicrobial susceptibility results, in cases of persistent gonococcal infection after treatment, clinicians should perform both culture and antimicrobial susceptibility testing.

All patients tested for gonorrhea should be tested for other STDs, including chlamydia, syphilis, and HIV.

Dual Therapy for Gonococcal and Chlamydial Infections

Patients infected with N. gonorrhoeae frequently are coinfected with C. trachomatis; this finding has led to the recommendation that patients treated for gonococcal infection also be treated routinely with a regimen that is effective against uncomplicated genital C. trachomatis infection (135). Because the majority of gonococci in the United States are susceptible to doxycycline and azithromycin, routine cotreatment might also hinder the development of antimicrobial-resistant N. gonorrhoeae.

Because of the high sensitivity of NAATs for chlamydial infection, patients with a negative chlamydial NAAT result at the time of treatment for gonorrhea do not need to be treated for chlamydia as well. However, if chlamydial test results are not available or if a non-NAAT was negative for chlamydia, patients should be treated for both gonorrhea and chlamydia.

Quinolone-Resistant N. gonorrhoeae (QRNG)

QRNG continues to spread, making the treatment of gonorrhea with quinolones such as ciprofloxacin inadvisable in many areas and populations. Resistance to ciprofloxacin usually indicates resistance to other quinolones as well. QRNG is common in parts of Europe, the Middle East, Asia, and the Pacific. In the United States, QRNG is becoming increasingly common. Previously, CDC had advised that quinolones not be used in California and Hawaii because of the high prevalence of QRNG in these areas. The prevalence of QRNG has increased in other areas of the United States, which has resulted in changes in recommended treatment regimens by other states and local areas. QRNG prevalence will continue to increase, and quinolones will eventually not be advisable for the treatment of gonorrhea. The CDC website (http://www.cdc.gov/std/gisp) or state health departments can provide the most current information. In 2004, of 6,322 isolates collected by CDC's Gonococcal Isolate Surveillance Project (GISP), 6.8% were resistant to ciprofloxacin (minimum inhibitory concentrations [MICs] >1.0 µg/mL). Excluding isolates from California and Hawaii, 3.6% of isolates were QRNG. QRNG was more common among MSM than among heterosexual men (23.9% versus 2.9%). In 2004, QRNG among heterosexual men outside of California and Hawaii was 1.4%.

Quinolones should not be used for the treatment of gonorrhea among MSM or in areas with increased QRNG prevalence in the United States (e.g., California and Hawaii) or for infections acquired while traveling abroad. Because oral alternatives to quinolones are limited, quinolones may continue to be used for heterosexual men and women in areas and populations not known to have elevated levels of resistance. Clinicians should obtain information on the sexual behavior and recent travel history (including histories from sex partners) of persons to be treated for gonorrhea to ensure appropriate antibiotic therapy.

Resistance of N. gonorrhoeae to fluoroquinolones and other antimicrobials is expected to continue to spread; therefore, state and local surveillance for antimicrobial resistance is crucial for guiding local therapy recommendations. GISP, which samples approximately 3% of all U.S. men who have gonococcal infections, is a mainstay of surveillance. However, surveillance by clinicians also is critical. Clinicians who have diagnosed N. gonorrhoeae infection in a person who was previously treated with a recommended regimen and who probably has not been reexposed should perform culture and susceptibility testing of relevant clinical specimens and report the case to the local health department.

Uncomplicated Gonococcal Infections of the Cervix, Urethra, and Rectum

Recommended Regimens*
Ceftriaxone 125 mg IM in a single dose
OR
Cefixime 400 mg orally in a single dose
OR
Ciprofloxacin 500 mg orally in a single dose*
OR
Ofloxacin 400 mg orally in a single dose*
OR
Levofloxacin 250 mg orally in a single dose*
PLUS
TREATMENT FOR CHLAMYDIA IF CHLAMYDIAL INFECTION IS NOT RULED OUT

* Quinolones should not be used for infections in MSM or in those with a history of recent foreign travel or partners' travel, infections acquired in California or Hawaii, or infections acquired in other areas with increased QRNG prevalence.

Recommended Regimens for MSM or Heterosexuals with a History of Recent Travel*
Ceftriaxone 125 mg IM in a single dose
OR
Cefixime 400 mg orally in a single dose
PLUS
TREATMENT FOR CHLAMYDIA IF CHLAMYDIAL INFECTION IS NOT RULED OUT

* Quinolones should not be used for infections in MSM or in those with a history of recent foreign travel or partners' travel, infections acquired in California or Hawaii, or infections acquired in other areas with increased QRNG prevalence.

To maximize compliance with recommended therapies, medications for gonococcal infections should be dispensed on site.

Ceftriaxone in a single injection of 125 mg provides sustained, high bactericidal levels in the blood. Extensive clinical experience indicates that ceftriaxone is safe and effective for the treatment of uncomplicated gonorrhea at all anatomic sites, curing 98.9% of uncomplicated urogenital and anorectal infections in published clinical trials.

Cefixime has an antimicrobial spectrum similar to that of ceftriaxone, but the 400 mg oral dose does not provide as high, nor as sustained, a bactericidal level as that provided by the 125 mg dose of ceftriaxone. In published clinical trials, the 400 mg dose cured 97.4% of uncomplicated urogenital and anorectal gonococcal infections. The advantage of cefixime is that it can be administered orally. Updates on the availability of cefixime are available from CDC or state health departments.

Ciprofloxacin is no longer universally effective against N. gonorrhoeae in the United States. However, ciprofloxacin is safe, inexpensive, and can be administered orally. In published clinical trials of uncomplicated urogenital and anorectal infections in the absence of QRNG, a dose of 500 mg of ciprofloxacin provides sustained bactericidal levels with cure rates of 99.8%. If QRNG is suspected, ceftriaxone IM or cefixime PO (by mouth) should be used. If neither of these regimens are feasible options, then one of the alternative nonquinolone regimens in this report should be considered.
Similar to ciprofloxacin, ofloxacin is no longer universally effective against N. gonorrhoeae in the United States. The 400 mg oral dose of ofloxacin has been effective for treatment of uncomplicated urogenital and anorectal infections; in clinical trials, 98.6% of infections were cured. Levofloxacin, the active l-isomer of ofloxacin, can be used in place of ofloxacin as a single dose of 250 mg.

Alternative Regimens
Spectinomycin 2 g in a single IM dose
OR
Single-dose cephalosporin regimens
OR
Single-dose quinolone regimens

Several other antimicrobials are active against N. gonorrhoeae, but none have substantial advantages over the recommended regimens. Spectinomycin is expensive and must be injected; however, it has been effective in published clinical trials, curing 98.2% of uncomplicated urogenital and anorectal gonococcal infections. Spectinomycin is useful for the treatment of patients who cannot tolerate cephalosporins and quinolones.

Single-dose cephalosporin regimens (other than ceftriaxone 125 mg IM and cefixime 400 mg orally) that are safe and highly effective against uncomplicated urogenital and anorectal gonococcal infections include ceftizoxime (500 mg, administered IM), cefoxitin (2 g, administered IM with probenecid 1 g orally), and cefotaxime (500 mg, administered IM). None of the injectable cephalosporins offer any advantage over ceftriaxone.

Single-dose quinolone regimens include gatifloxacin 400 mg orally, norfloxacin 800 mg orally, and lomefloxacin 400 mg orally. These regimens appear to be safe and effective for the treatment of uncomplicated gonorrhea, but data regarding their use are limited. None of the regimens appear to offer any advantage over ciprofloxacin, ofloxacin, or levofloxacin, and they are not effective against QRNG.

Some evidence suggests that cefpodoxime and cefuroxime axetil 1 g orally might be additional oral alternatives in the treatment of uncomplicated urogenital gonorrhea; additional information on alternative oral regimens are available at http://www.cdc.gov/std. Cefpodoxime proxetil 200 mg PO is less active against N. gonorrhoeae than cefixime and also does not quite meet the minimum efficacy criteria (demonstrated efficacy with lower 95% confidence interval [CI] of >95% in summed clinical trials) with cure rates, 96.5% (CI = 94.8%--98.9%) for urogenital and rectal infection; efficacy in treating pharyngeal infection is unsatisfactory, 78.9% (CI = 54.5%--94%). Clinical studies are being conducted to assess whether cefpodoxime 400 mg PO is an acceptable oral alternative. Treatment with cefuroxime axetil 1 g PO does not quite meet the minimum efficacy criteria for urogenital and rectal infection (95.9%; CI = 94.5%--97.3%) and, its efficacy in treating pharyngeal infection is unacceptable (56.9%; CI = 42.2%--70.7%).

Azithromycin 2 g orally is effective against uncomplicated gonococcal infection but is expensive and causes gastrointestinal distress and is not recommended for treatment of gonorrhea. Although azithromycin 1 g theoretically meets alternative regimen criteria, it is not recommended because of concerns regarding the possible rapid emergence of antimicrobial resistance. N. gonorrhoeae in the United States is not adequately susceptible to penicillins, tetracyclines, and macrolides (e.g., erythromycin) for these antimicrobials to be recommended.

Uncomplicated Gonococcal Infections of the Pharynx

Gonococcal infections of the pharynx are more difficult to eradicate than infections at urogenital and anorectal sites. Few antimicrobial regimens can reliably cure >90% of gonococcal pharyngeal infections. Although chlamydial coinfection of the pharynx is unusual, coinfection at genital sites sometimes occurs. Therefore, treatment for both gonorrhea and chlamydia is recommended.

Recommended Regimens*
Ceftriaxone 125 mg IM in a single dose
OR
Ciprofloxacin 500 mg orally in a single dose
PLUS
TREATMENT FOR CHLAMYDIA IF CHLAMYDIAL INFECTION IS NOT RULED OUT

* Quinolones should not be used for infections in MSM or in those with a history of recent foreign travel or partners' travel, infections acquired in California or Hawaii, or infections acquired in other areas with increased QRNG prevalence.

Recommended Regimens for MSM or Heterosexuals with a History of Recent Travel
Ceftriaxone 125 mg IM in a single dose
PLUS
TREATMENT FOR CHLAMYDIA IN CHLAMYDIAL INFECTION IS NOT RULED OUT

Follow-Up

Patients who have uncomplicated gonorrhea and who are treated with any of the recommended or alternative regimens do not need a test of cure. Patients who have symptoms that persist after treatment should be evaluated by culture for N. gonorrhoeae, and any gonococci isolated should be tested for antimicrobial susceptibility. Persistent urethritis, cervicitis, or proctitis also might be caused by C. trachomatis or other organisms.

A high prevalence of N. gonorrhoeae infection is observed in patients who have had gonorrhea in the preceding several months. The majority of infections identified after treatment with one of the recommended regimens result from reinfection rather than treatment failure, indicating a need for improved patient education and referral of sex partners. Repeat infection might confer an elevated risk for PID and other complications, when compared with initial infection. Clinicians should consider advising all patients with gonorrhea to be retested 3 months after treatment. If patients do not seek medical care for retesting in 3 months, providers are encouraged to test these patients whenever they next seek medical care within the following 12 months, regardless of whether the patient believes that their sex partners were treated. Retesting is distinct from test of cure to detect therapeutic failure, which is not recommended.

Management of Sex Partners

Effective clinical management of patients with treatable STDs requires treatment of the patients' recent sex partners to prevent reinfection and curtail further transmission. Patients should be instructed to refer their sex partners for evaluation and treatment. Sex partners of patients with N. gonorrhoeae infection whose last sexual contact with the patient was within 60 days before onset of symptoms or diagnosis of infection in the patient should be evaluated and treated for N. gonorrhoeae and C. trachomatis infections. If a patient's last sexual intercourse was >60 days before onset of symptoms or diagnosis, the patient's most recent sex partner should be treated. Patients should be instructed to avoid sexual intercourse until therapy is completed and until they and their sex partners no longer have symptoms.

For patients with gonorrhea whose partners' treatment cannot be ensured or is unlikely, delivery of antibiotic therapy (i.e., either a prescription or medication) by heterosexual male or female patients to their partners is an option (see Partner Notification). Use of this approach should always be accompanied by efforts to educate partners about symptoms and to encourage partners to seek clinical evaluation. Male patients must inform female partners of their infection and be given accompanying materials about the importance of seeking medical evaluation for PID (especially if symptomatic). Possible undertreatment of PID in female partners and possible missed opportunities to diagnose other STDs are of concern and have not been evaluated in comparisons with patient-delivered therapy and partner referral. Patient-delivered therapy for patients with gonorrhea should routinely include treatment for chlamydia. This approach should not be considered a routine partner management strategy in MSM because of the high risk of coexisting undiagnosed STDs or HIV infection.

Special Considerations

Allergy, Intolerance, and Adverse Reactions
Persons who cannot tolerate cephalosporins or quinolones should be treated with spectinomycin. Because spectinomycin is unreliable (52% effective) against pharyngeal infections, patients who have suspected or known pharyngeal infection should have a pharyngeal culture 3--5 days after treatment to verify eradication of infection.

Pregnancy

Pregnant women should not be treated with quinolones or tetracyclines. Those infected with N. gonorrhoeae should be treated with a recommended or alternate cephalosporin. Women who cannot tolerate a cephalosporin should be administered a single 2-g dose of spectinomycin IM. Either azithromycin or amoxicillin is recommended for treatment of presumptive or diagnosed C. trachomatis infection during pregnancy (see Chlamydial Infections).

Administration of Quinolones to Adolescents

Fluoroquinolones have not been recommended for persons aged <18 years because studies have indicated that they can damage articular cartilage in some young animals. However, no joint damage attributable to quinolone therapy has been observed in children treated with prolonged ciprofloxacin regimens (143). Therefore, children who weigh >45 kg can be treated with any regimen recommended for adults (See Gonococcal Infections).

HIV Infection

Patients who have gonococcal infection and also are infected with HIV should receive the same treatment regimen as those who are HIV negative.

Gonococcal Conjunctivitis

In the only published study of the treatment of gonococcal conjunctivitis among U.S. adults, all 12 study participants responded to a single 1-g IM injection of ceftriaxone. The following recommendation reflects the opinions of consultants knowledgeable in the field of STDs.

Recommended Regimen
Ceftriaxone 1 g IM in a single dose

Consider lavage of the infected eye with saline solution once.

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 (DGI)

DGI results from gonococcal bacteremia. DGI frequently results in petechial or pustular acral skin lesions, asymmetrical arthralgia, tenosynovitis, or septic arthritis. The infection is complicated occasionally by perihepatitis and rarely by endocarditis or meningitis. Some strains of N. gonorrhoeae that cause DGI may cause minimal genital inflammation.

No studies on the treatment of DGI among adults have been published since publication of the last CDC STD treatment guidelines publication. DGI treatment recommendations reflect the opinions of consultants. No treatment failures have been reported with the recommended regimens.

Treatment

Hospitalization is recommended for initial therapy, especially for patients who might not comply with treatment, for those in whom diagnosis is uncertain, and for those who have purulent synovial effusions or other complications. Patients should be examined for clinical evidence of endocarditis and meningitis. Patients treated for DGI should be treated presumptively for concurrent C. trachomatis infection, unless appropriate testing excludes this infection.

Recommended Regimen
Ceftriaxone 1 g IM or IV every 24 hours
Alternative Regimens
Cefotaxime 1 g IV every 8 hours
OR
Ceftizoxime 1 g IV every 8 hours
OR
Ciprofloxacin 400 mg IV every 12 hours*
OR
Ofloxacin 400 mg IV every 12 hours*
OR
Levofloxacin 250 mg IV daily*
OR
Spectinomycin 2 g IM every 12 hours

* Quinolones should not be used for infections in MSM or in those with a history of recent foreign travel or partners' travel, infections acquired in California or Hawaii, or infections acquired in other areas with increased QRNG prevalence.

All of the preceding regimens should be continued for 24--48 hours after improvement begins, at which time therapy may be switched to one of the following regimens to complete at least 1 week of antimicrobial therapy.

Cefixime 400 mg orally twice daily
OR
Ciprofloxacin 500 mg orally twice daily*
OR
Ofloxacin 400 mg orally twice daily*
OR
Levofloxacin 500 mg orally once daily*

* Quinolones should not be used for infections in MSM or in those with a history of recent foreign travel or partners' travel, infections acquired in California or Hawaii, or infections acquired in other areas with increased QRNG prevalence.

Management of Sex Partners

Gonococcal infection frequently is asymptomatic in sex partners of patients who have DGI. As with uncomplicated gonococcal infections, patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infection, Management of Sex Partners).

Gonococcal Meningitis and Endocarditis

Recommended Regimen
Ceftriaxone 1--2 g IV every 12 hours

Therapy for meningitis should be continued for 10--14 days; therapy for endocarditis should be continued for at least 4 weeks. Treatment of complicated DGI should be undertaken in consultation with a specialist.

Management of Sex Partners

Patients should be instructed to refer their sex partners for evaluation and treatment (see Gonococcal Infection, Management of Sex Partners).

Gonococcal Infections Among Infants

Gonococcal infection among infants usually results from exposure to infected cervical exudate at birth. It is usually an acute illness that manifests 2--5 days after birth. The prevalence of infection among infants depends on the prevalence of infection among pregnant women, whether pregnant women are screened for gonorrhea, and whether newborns receive ophthalmia prophylaxis. The most severe manifestations of N. gonorrhoeae infection in newborns are ophthalmia neonatorum and sepsis, which can include arthritis and meningitis. Less severe manifestations include rhinitis, vaginitis, urethritis, and reinfection at sites of fetal monitoring.

Ophthalmia Neonatorum Caused by N. gonorrhoeae

In the United States, although N. gonorrhoeae causes ophthalmia neonatorum less frequently than C. trachomatis and nonsexually transmitted agents, identifying and treating this infection is especially important because ophthalmia neonatorum can result in perforation of the globe of the eye and blindness.

Diagnostic Considerations

Infants at increased risk for gonococcal ophthalmia are those who do not receive ophthalmia prophylaxis and those whose mothers have had no prenatal care or whose mothers have a history of STDs or substance abuse. Gonococcal ophthalmia is strongly suspected when intracellular gram-negative diplococci are identified in conjunctival exudate, justifying presumptive treatment for gonorrhea after appropriate cultures for N. gonorrhoeae are obtained. Appropriate chlamydial testing should be done simultaneously. Presumptive treatment for N. gonorrhoeae might be indicated for newborns who are at increased risk for gonococcal ophthalmia and who have conjunctivitis but do not have gonococci in a Gram-stained smear of conjunctival exudate.

In all cases of neonatal conjunctivitis, conjunctival exudates should be cultured for N. gonorrhoeae and tested for antibiotic susceptibility before a definitive diagnosis is made. A definitive diagnosis is vital because of the public health and social consequences of a diagnosis of gonorrhea. Nongonococcal causes of neonatal ophthalmia include Moraxella catarrhalis and other Neisseria species that are indistinguishable from N. gonorrhoeae on Gram-stained smear but can be differentiated in the microbiology laboratory.

Recommended Regimen
Ceftriaxone 25--50 mg/kg IV or IM in a single dose, not to exceed 125 mg

Topical antibiotic therapy alone is inadequate and is unnecessary if systemic treatment is administered.

Other Management Considerations

Simultaneous infection with C. trachomatis should be considered when a patient does not improve after treatment. Both mother and infant should be tested for chlamydial infection at the same time that gonorrhea testing is conducted (see Ophthalmia Neonatorum Caused by C. trachomatis). Ceftriaxone should be administered cautiously to hyperbilirubinemic infants, especially those born prematurely.

Follow-Up

Infants who have gonococcal ophthalmia should be hospitalized and evaluated for signs of disseminated infection (e.g., sepsis, arthritis, and meningitis). One dose of ceftriaxone is adequate therapy for gonococcal conjunctivitis.

Management of Mothers and Their Sex Partners

The mothers of infants who have gonococcal infection and the mothers' sex partners should be evaluated and treated according to the recommendations for treating gonococcal infections in adults (see Gonococcal Infections in Adolescents and Adults).

DGI and Gonococcal Scalp Abscesses in Newborns

Sepsis, arthritis, and meningitis (or any combination of these conditions) are rare complications of neonatal gonococcal infection. Localized gonococcal infection of the scalp can result from fetal monitoring through scalp electrodes. Detection of gonococcal infection in neonates who have sepsis, arthritis, meningitis, or scalp abscesses requires cultures of blood, CSF, and joint aspirate on chocolate agar. Specimens obtained from the conjunctiva, vagina, oropharynx, and rectum that are cultured on gonococcal selective medium are useful for identifying the primary site(s) of infection, especially if inflammation is present. Positive Gram-stained smears of exudate, CSF, or joint aspirate provide a presumptive basis for initiating treatment for N. gonorrhoeae. Diagnoses based on Gram-stained smears or presumptive identification of cultures should be confirmed with definitive tests on culture isolates.

Recommended Regimens
Ceftriaxone 25--50 mg/kg/day IV or IM in a single daily dose for 7 days, with a duration of 10--14 days, if meningitis is documented
OR
Cefotaxime 25 mg/kg IV or IM every 12 hours for 7 days, with a duration of 10--14 days, if meningitis is documented

Prophylactic Treatment for Infants Whose Mothers Have Gonococcal Infection

Infants born to mothers who have untreated gonorrhea are at high risk for infection.

Recommended Regimen in the Absence of Signs of Gonococcal Infection
Ceftriaxone 25--50 mg/kg IV or IM, not to exceed 125 mg, in a single dose

Other Management Considerations

Both mother and infant should be tested for chlamydial infection.

Follow-Up

Follow-up examination is not required.

Management of Mothers and Their Sex Partners

The mothers of infants who have gonococcal infection and the mothers' sex partners should be evaluated and treated according to the recommendations for treatment of gonococcal infections in adults (see Gonococcal Infections).

Gonococcal Infections Among Children

Sexual abuse is the most frequent cause of gonococcal infection in pre-adolescent children (see Sexual Assault or Abuse of Children). Vaginitis is the most common manifestation of gonococcal infection in preadolescent girls. PID after vaginal infection is probably less common in children than among adults. Among sexually abused children, anorectal and pharyngeal infections with N. gonorrhoeae are common and frequently asymptomatic.

Diagnostic Considerations

Because of the legal implications of a diagnosis of N. gonorrhoeae infection in a child, only standard culture procedures for the isolation of N. gonorrhoeae should be used for children. Nonculture gonococcal tests for gonococci (e.g., Gram-stained smear, nucleic acid hybridization tests, EIA, and NAAT) should not be used without standard culture; none of these tests have been approved by FDA for use with specimens obtained from the oropharynx, rectum, or genital tract of children. 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 principles (e.g., biochemical, enzyme substrate, or serologic). Isolates should be preserved to enable additional or repeated testing.

Recommended Regimens for Children Who Weigh >45 kg
Treat with one of the regimens recommended for adults (see Gonococcal Infections)

Fluoroquinolones have not been recommended for persons aged <18 years because they have damaged articular cartilage in young animals. However, no such joint damage clearly attributable to quinolone therapy has been observed in children, even in those receiving multiple-dose regimens.

Recommended Regimens for Children Who Weigh <45 kg and Who Have Uncomplicated Gonococcal Vulvovaginitis,
Cervicitis, Urethritis, Pharyngitis, or Proctitis
Ceftriaxone 125 mg IM in a single dose

Alternative Regimen
Spectinomycin 40 mg/kg (maximum dose: 2 g) IM in a single dose may be used, but this therapy is unreliable for treatment of pharyngeal infections. Some specialists use cefixime to treat gonococcal infections in children because it can be administered orally; however, no reports have been published concerning the safety or effectiveness of cefixime used for this purpose.

Recommended Regimen for Children Who Weigh <45 kg and Who Have Bacteremia or Arthritis
Ceftriaxone 50 mg/kg (maximum dose: 1 g) IM or IV in a single dose daily for 7 days

Recommended Regimen for Children Who Weigh >45 kg and Who Have Bacteremia or Arthritis
Ceftriaxone 50 mg/kg IM or IV in a single dose daily for 7 days

Follow-Up

Follow-up cultures are unnecessary if ceftriaxone is used. If spectinomycin is used to treat pharyngitis, a follow-up culture is necessary to ensure that treatment was effective.

Other Management Considerations

Only parenteral cephalosporins are recommended for use in children. Ceftriaxone is approved for all gonococcal infections in children; cefotaxime is approved for gonococcal ophthalmia only. Oral cephalosporins used for treatment of gonococcal infections in children have not been adequately evaluated.

All children who have gonococcal infections should be evaluated for coinfection with syphilis and C. trachomatis. (For a discussion of concerns regarding sexual assault, refer to Sexual Assault or Abuse of Children).

Ophthalmia Neonatorum Prophylaxis

To prevent gonococcal ophthalmia neonatorum, a prophylactic agent should be instilled into the eyes of all newborn infants; this procedure is required by law in the majority of states. All of the recommended prophylactic regimens in this section prevent gonococcal ophthalmia. However, the efficacy of these preparations in preventing chlamydial ophthalmia is less clear, and they do not eliminate nasopharyngeal colonization by C. trachomatis. The diagnosis and treatment of gonococcal and chlamydial infections in pregnant women is the best method for preventing neonatal gonococcal and chlamydial disease. Not all women, however, receive prenatal care. Ocular prophylaxis is warranted because it can prevent sight-threatening gonococcal ophthalmia and because it is safe, easy to administer, and inexpensive.

Prophylaxis

Recommended Regimens
Erythromycin (0.5%) ophthalmic ointment in a single application
OR
Tetracycline ophthalmic ointment (1%) in a single application

One of these recommended preparations should be instilled into both eyes of every neonate as soon as possible after delivery. If prophylaxis is delayed (i.e., not administered in the delivery room), a monitoring system should be established to ensure that all infants receive prophylaxis. All infants should be administered ocular prophylaxis, regardless of whether they are delivered vaginally or by cesarean section. Single-use tubes or ampules are preferable to multiple-use tubes. Bacitracin is not effective. Use of povidone iodine has not been studied adequately.

Management of Patients Who Have Vaginal Infections

Vaginitis is usually characterized by a vaginal discharge and/or vulvar itching and irritation, and a vaginal odor might be present. The three diseases most frequently associated with vaginal discharge are BV (replacement of the normal vaginal flora by an overgrowth of anaerobic microorganisms, mycoplasmas, and Gardnerella vaginalis), trichomoniasis (T. vaginalis), and candidiasis (usually caused by Candida albicans). Cervicitis can sometimes cause a vaginal discharge. Although vulvovaginal candidiasis (VVC) usually is not transmitted sexually, it is included in this section because it is frequently diagnosed in women being evaluated for STDs.

Various diagnostic methods are available to identify the etiology of an abnormal vaginal discharge. Laboratory testing fails to identify the cause of vaginitis in a minority of women. The cause of vaginal symptoms usually can be determined by pH and microscopic examination of fresh samples of the discharge. The pH of the vaginal secretions can be determined by narrow-range pH paper; an elevated pH (i.e., >4.5) is common with BV or trichomoniasis but might not be highly specific. Discharge can be further examined by diluting one sample in one to two drops of 0.9% normal saline solution on one slide and a second sample in 10% potassium hydroxide (KOH) solution. An amine odor detected immediately after applying KOH suggests BV.

Cover slips are placed on the slides, and they are examined under a microscope at low- and high-dry power. Motile T. vaginalis or clue cells (epithelial cells with borders obscured by small bacteria), which are characteristic of BV, usually are identified easily in the saline specimen. WBCs without evidence of trichomonads or yeast are usually suggestive of cervicitis (see Cervicitis). The yeast or pseudohyphae of Candida species are more easily identified in the KOH specimen. However, the absence of trichomonads or pseudohyphae does not rule out these infections because several studies have demonstrated the presence of these pathogens by culture or PCR after a negative microscopic examination. The presence of objective signs of vulvar inflammation in the absence of vaginal pathogens, along with a minimal amount of discharge, suggests the possibility of mechanical, chemical, allergic, or other noninfectious irritation of the vulva. Culture for T. vaginalis is more sensitive than microscopic examination. In settings where microscopy is not available, alternative point-of-care tests may be used to diagnose vaginitis.

Bacterial Vaginosis

BV is a polymicrobial clinical syndrome resulting from replacement of the normal H2O2--producing Lactobacillus sp. in the vagina with high concentrations of anaerobic bacteria (e.g., Prevotella sp. and Mobiluncus sp.), G. vaginalis, and Mycoplasma hominis. BV is the most prevalent cause of vaginal discharge or malodor; however, more than 50% of women with BV are asymptomatic. The cause of the microbial alteration is not fully understood. BV is associated with having multiple sex partners, a new sex partner, douching, and lack of vaginal lactobacilli; whether BV results from acquisition of a sexually transmitted pathogen is unclear. Women who have never been sexually active are rarely affected. Treatment of male sex partners has not been beneficial in preventing the recurrence of BV.

Diagnostic Considerations

BV can be diagnosed by the use of clinical criteria or Gram stain. Clinical criteria require three of the following symptoms or signs:

• homogeneous, thin, white discharge that smoothly coats the vaginal walls;
• presence of clue cells on microscopic examination;
• pH of vaginal fluid >4.5; and
• a fishy odor of vaginal discharge before or after addition of 10% KOH (i.e., the whiff test).

When a Gram stain is used, determining the relative concentration of lactobacilli (long Gram-positive rods), Gram-negative and Gram-variable rods and cocci (i.e., G. vaginalis, Prevotella, Porphyromonas, and peptostreptococci), and curved Gram-negative rods (Mobiluncus) characteristic of BV is considered the gold standard laboratory method for diagnosing BV. Culture of G. vaginalis is not recommended as a diagnostic tool because it is not specific. However, a DNA probe-based test for high concentrations of G. vaginalis (AffirmTM VP III, Becton Dickinson, Sparks, Maryland) might have clinical utility. Cervical Pap tests have no clinical utility for the diagnosis of BV because of low sensitivity. Other commercially available tests that might be useful for the diagnosis of BV include a card test for the detection of elevated pH and trimethylamine (QuickVue Advance Quidel, San Diego, California) and prolineaminopeptidase (Pip Activity TestCardTM, Quidel, San Diego, California).

Treatment

The established benefits of therapy for BV in nonpregnant women are to 1) relieve vaginal symptoms and signs of infection and 2) reduce the risk for infectious complications after abortion or hysterectomy. Other potential benefits might include a reduction in risk for other infections (e.g., HIV and other STDs). All women who have symptomatic disease require treatment.

BV during pregnancy is associated with adverse pregnancy outcomes, including premature rupture of the membranes, preterm labor, preterm birth, intraamniotic infection, and postpartum endometritis. The established benefit of therapy for BV in pregnant women is to relieve vaginal symptoms and signs of infection. Additional potential benefits of therapy include 1) reducing the risk for infectious complications associated with BV during pregnancy and 2) reducing the risk for other infections (e.g., other STDs or HIV). The results of several investigations indicate that treatment of pregnant women with BV who are at high risk for preterm delivery (i.e., those who previously delivered a premature infant) might reduce the risk for prematurity. Therefore, clinicians should consider evaluation and treatment of high-risk pregnant women with asymptomatic BV.

The bacterial flora that characterizes BV have been recovered from the endometria and salpinges of women who have PID. BV has been associated with endometritis, PID, and vaginal cuff cellulitis after invasive procedures, including endometrial biopsy, hysterectomy, hysterosalpingography, placement of an IUD, cesarean section, and uterine curettage. The results of two randomized controlled trials have indicated that treatment of BV with metronidazole substantially reduced postabortion.

Three trials that evaluated the use of anaerobic antimicrobial coverage (i.e., metronidazole) for routine operative prophylaxis before abortion and seven trials that evaluated this additional coverage for women undergoing hysterectomy demonstrated a substantial reduction in postoperative infectious complications. Because of the increased risk for postoperative infectious complications associated with BV, some specialists recommend that before performing surgical abortion or hysterectomy, providers should screen and treat women with BV in addition to providing routine prophylaxis. However, more information is needed before recommending treatment of asymptomatic BV before other invasive procedures.

Recommended Regimens
Metronidazole 500 mg orally twice a day for 7 days
OR
Metronidazole gel, 0.75%, one full applicator (5g) intravaginally, once a day for 5 days
OR
Clindamycin cream, 2%, one full applicator (5g) intravaginally at bedtime for 7 days

Patients should be advised to avoid consuming alcohol during treatment with metronidazole and for 24 hours thereafter. 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. Topical clindamycin preparations should not be used in the second half of pregnancy.

The recommended metronidazole regimens are equally efficacious. The recommended intravaginal clindamycin regimen might be less efficacious than the metronidazole regimens. One randomized trial evaluated the clinical equivalency of intravaginal metronidazole gel 0.75% once daily versus twice daily and demonstrated similar cure rates 1 month after therapy.

Alternative Regimens
Clindamycin 300 mg orally twice a day for 7 days
OR
Clindamycin ovules 100 g intravaginally once at bedtime for 3 days

Metronidazole 2 g single-dose therapy has the lowest efficacy for BV and is no longer a recommended or alternative regimen. FDA has cleared metronidazole 750 mg extended release tablets once daily for 7 days and a single dose of clindamycin intravaginal cream. No data have been published that compares the clinical or microbiologic equivalencies of these regimens with other regimens. Cure rates do not differ between intravaginal clindamycin cream and ovules.

Several studies have evaluated the clinical and microbiologic efficacy of using lactobacillus intravaginal suppositories to restore normal flora and treat BV. However, no currently available lactobacillus suppository was determined to be better than placebo 1 month after therapy for either clinical or microbiologic cure. No data support the use of douching for treatment or relief of symptoms.

Follow-Up

Follow-up visits are unnecessary if symptoms resolve. Because recurrence of BV is not unusual, women should be advised to return for additional therapy if symptoms recur. A treatment regimen different from the original regimen may be used to treat recurrent disease. However, women with multiple recurrences should be managed in consultation with a specialist. One randomized trial for persistent BV indicated that metronidazole gel 0.75% twice per week for 6 months after completion of a recommended regimen was effective in maintaining a clinical cure for 6 months.

Management of Sex Partners

The results of 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(s). Therefore, routine treatment of sex partners is not recommended.

Special Considerations

Allergy or Intolerance to the Recommended Therapy

Intravaginal clindamycin cream is preferred in case of allergy or intolerance to metronidazole. Intravaginal metronidazole gel can be considered for patients who do not tolerate systemic metronidazole, but patients allergic to oral metronidazole should not be administered intravaginal metronidazole.

Pregnancy

All pregnant women who have symptomatic disease require treatment. BV has been associated with adverse pregnancy outcomes (e.g., premature rupture of the membranes, chorioamnionitis, preterm labor, preterm birth, intraamniotic infection, postpartum endometritis, and postcesarean wound infection). Some specialists prefer using systemic therapy to treat possible subclinical upper genital tract infections.

Treatment of BV in asymptomatic pregnant women at high risk for preterm delivery (i.e., those who have previously delivered a premature infant) with a recommended oral regimen has reduced preterm delivery in three of four randomized controlled trials; some specialists recommend screening and oral treatment of these women. However, the optimal treatment regimens have not been established. Screening (if conducted) and treatment should be performed during the first prenatal visit.

Two trials that evaluated the efficacy of metronidazole during pregnancy used the 250-mg regimen. However, some specialists suggest using a regimen of 500 mg twice daily in pregnant women. One small trial demonstrated that treatment with oral metronidazole 500 mg twice daily was equally effective as metronidazole gel, with cure rates of 70%. These regimens were not effective in reducing preterm birth in any group of women. Multiple studies and meta-analyses have not demonstrated an association between metronidazole use during pregnancy and teratogenic or mutagenic effects in newborns.

Recommended Regimens for Pregnant Women
Metronidazole 500 mg orally twice a day for 7 days
OR
Metronidazole 250 mg orally three times a day for 7 days
OR
Clindamycin 300 mg orally twice a day for 7 days

Whether treatment of asymptomatic pregnant women with BV who are at low risk for preterm delivery reduces adverse outcomes of pregnancy is unclear. One trial in which oral clindamycin was used demonstrated a reduction in spontaneous preterm birth. Several trials have evaluated the use of intravaginal clindamycin during pregnancy to reduce preterm birth and treat asymptomatic BV. One trial in which women were treated before 20 weeks' gestation demonstrated a reduction in preterm birth. In three other trials, intravaginal clindamycin cream was administered at 16--32 weeks' gestation, and an increase in adverse events (e.g., low birthweight and neonatal infections) was observed in newborns. Therefore, intravaginal clindamycin cream should only be used during the first half of pregnancy.

Follow-Up of Pregnant Women

Treatment of BV in asymptomatic pregnant women who are at high risk for preterm delivery might prevent adverse pregnancy outcomes. Therefore, a follow-up evaluation 1 month after completion of treatment should be considered to evaluate whether therapy was effective.

HIV Infection

Patients who have BV and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. BV appears to be more persistent in HIV-positive women.

Trichomoniasis

Trichomoniasis is caused by the protozoan T. vaginalis. Some men who are infected with T. vaginalis might not have symptoms; others have NGU. Many infected women have symptoms characterized by a diffuse, malodorous, yellow-green vaginal discharge with vulvar irritation. However, some women have minimal or no symptoms.

Diagnosis of vaginal trichomoniasis is usually performed by microscopy of vaginal secretions, but this method has a sensitivity of only approximately 60%--70% and requires immediate evaluation of wet preparation slide for optimal results. Other FDA-cleared tests for trichomoniasis in women include OSOM Trichomonas Rapid Test (Genzyme Diagnostics, Cambridge, Massachusetts), an immunochromatographic capillary flow dipstick technology, and the Affirm™ VP III (Becton Dickenson, San Jose, California), a nucleic acid probe test that evaluates for T. vaginalis, G. vaginalis, and C. albicans. These tests are both performed on vaginal secretions and have a sensitivity >83% and a specificity >97%. Both tests are point-of-care diagnostics. The results of the OSOM Trichomonas Rapid Test are available in approximately 10 minutes, and results of the Affirm™ VP III are available within 45 minutes. Although these tests tend to be more sensitive than vaginal wet preparation, false positives might occur especially in low prevalence populations. Culture is the most sensitive and specific commercially available method of diagnosis. In women in whom trichomoniasis is suspected but not confirmed by microscopy, vaginal secretions should be cultured for T. vaginalis.

In men, wet preparation is insensitive, and culture testing of urethral swab, urine, and semen is required for optimal sensitivity. No FDA-cleared PCR test for T. vaginalis is available in the United States, but such testing might be available from commercial laboratories that have developed their own PCR tests.

Recommended Regimens
Metronidazole 2 g orally in a single dose
OR
Tinidazole 2 g orally in a single dose

Alternative Regimen
Metronidazole 500 mg orally twice a day for 7 days

Patients should be advised to avoid consuming alcohol during treatment with metronidazole or tinidazole. Abstinence from alcohol use should continue for 24 hours after completion of metronidazole or 72 hours after completion of tinidazole.

The nitroimidazoles comprise the only class of drugs useful for the oral or parenteral therapy of trichomoniasis. Of these drugs, metronidazole and tinidazole are available in the United States and are cleared by the FDA for the treatment of trichomoniasis. In randomized clinical trials, the recommended metronidazole regimens have resulted in cure rates of approximately 90%--95%, and the recommended tinidazole regimen has resulted in cure rates of approximately 86%--100%. The appropriate treatment of sex partners might increase these reported rates. Randomized controlled trials comparing single 2 g doses of metronidazole and tinidazole suggest that tinidazole is equivalent to, or superior to, metronidazole in achieving parasitologic cure and resolution of symptoms. Treatment of patients and sex partners results in relief of symptoms, microbiologic cure, and reduction of transmission.

Metronidazole gel is considerably less efficacious for the treatment of trichomoniasis (<50%) than oral preparations of metronidazole. Topically applied antimicrobials (e.g., metronidazole gel) are unlikely to achieve therapeutic levels in the urethra or perivaginal glands; therefore, use of the gel is not recommended. Several other topically applied antimicrobials occasionally have been used for treatment of trichomoniasis; however, these preparations probably do not have greater efficacy than metronidazole gel.

Follow-Up

Follow-up is unnecessary for men and women who become asymptomatic after treatment or who are initially asymptomatic. Some strains of T. vaginalis can have diminished susceptibility to metronidazole; however, infections caused by the majority of these organisms respond to tinidazole or higher doses of metronidazole. Low-level metronidazole resistance has been identified in 2%--5% of cases of vaginal trichomoniasis. High-level resistance is rare. Tinidazole has a longer serum half-life and reaches higher levels in genitourinary tissues than metronidazole. In addition, many T. vaginalis isolates have lower minimum inhibitory concentrations (MICs) to tinidazole than metronidazole.

If treatment failure occurs with metronidazole 2 g single dose and reinfection is excluded, the patient can be treated with metronidazole 500 mg orally twice daily for 7 days or tinidazole 2 g single dose. For patients failing either of these regimens, clinicians should consider treatment with tinidazole or metronidazole at 2 g orally for 5 days. If these therapies are not effective, further management should be discussed with a specialist. The consultation should ideally include determination of the susceptibility of T. vaginalis to metronidazole and tinidazole. Consultation and T. vaginalis susceptibility testing is available from CDC (telephone: 770-488-4115; website: http://www.cdc.gov/std).

Management of Sex Partners

Sex partners of patients with T. vaginalis should be treated. Patients should be instructed to avoid sex until they and their sex partners are cured (i.e., when therapy has been completed and patient and partner(s) are asymptomatic).

Special Considerations

Allergy, Intolerance, and Adverse Reactions

Metronidazole and tinidazole are both nitroimidazoles. Patients with an immediate-type allergy to a nitroimidazole can be managed by metronidazole desensitization in consultation with a specialist (171,172). Topical therapy with drugs other than nitroimidazoles can be attempted, but cure rates are low (<50%).

Pregnancy

Vaginal trichomoniasis has been associated with adverse pregnancy outcomes, particularly premature rupture of membranes, preterm delivery, and low birthweight. However, data do not suggest that metronidazole treatment results in a reduction in perinatal morbidity. Although some trials suggest the possibility of increased prematurity or low birthweight after metronidazole treatment, limitations of the studies prevent definitive conclusions regarding risks of treatment. Treatment of T. vaginalis might relieve symptoms of vaginal discharge in pregnant women and might prevent respiratory or genital infection of the newborn and further sexual transmission. Clinicians should counsel patients regarding the potential risks and benefits of treatment. Some specialists would defer therapy in asymptomatic pregnant women until after 37 weeks' gestation. In addition, these pregnant women should be provided careful counseling regarding condom use and the continued risk of sexual transmission.

Women may be treated with 2 g of metronidazole in a single dose. Metronidazole is pregnancy category B (animal studies have revealed no evidence of harm to the fetus, but no adequate, well-controlled studies among pregnant women have been conducted). Multiple studies and meta-analyses have not demonstrated a consistent association between metronidazole use during pregnancy and teratogenic or mutagenic effects in infants. Tinidazole is pregnancy category C (animal studies have demonstrated an adverse event, and no adequate, well-controlled studies in pregnant women have been conducted), and its safety in pregnant women has not been well-evaluated.

In lactating women who are administered metronidazole, withholding breastfeeding during treatment and for 12--24 hours after the last dose will reduce the exposure of metronidazole to the infant. While using tinidazole, interruption of breastfeeding is recommended during treatment and for 3 days after the last dose.

HIV Infection

Patients who have trichomoniasis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. The incidence, persistence, and recurrence of trichomoniasis in HIV-infected women are not correlated with immune status.

Vulvovaginal Candidiasis

VVC usually is caused by C. albicans but occasionally is caused by other Candida sp. 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 clinical presentation, microbiology, host factors, and response to therapy, VVC can be classified as either uncomplicated or complicated (Box 2). Approximately 10%--20% of women will have complicated VVC, suggesting diagnostic and therapeutic considerations.

Uncomplicated VVC

Diagnostic Considerations in Uncomplicated VVC

A diagnosis of Candida vaginitis is suggested clinically by the presence of external dysuria and vulvar pruritis, pain, swelling, and redness. Signs include vulvar edema, fissures, excoriations, or thick curdy vaginal discharge. The diagnosis can be made in a woman who has signs and symptoms of vaginitis when either 1) a wet preparation (saline, 10% KOH) or Gram stain of vaginal discharge demonstrates yeasts or pseudohyphae or 2) a culture or other test yields a positive result for a yeast species. Candida vaginitis is associated with a 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 receive treatment. For those with negative wet mounts, vaginal cultures for Candida should be considered for those with any sign or multiple symptoms. If Candida cultures cannot be done, empiric treatment can be considered for symptomatic women with any sign of VVC on examination when the wet mount is negative. 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 sp. and other yeasts in the vagina. VVC can occur concomitantly with STDs. The majority of healthy women with uncomplicated VVC have no identifiable precipitating factors.

Treatment

Short-course topical formulations (i.e., single dose and regimens of 1--3 days) effectively treat uncomplicated VVC. The topically applied azole drugs are more effective than nystatin. Treatment with azoles results in relief of symptoms and negative cultures in 80%--90% of patients who complete therapy.

Recommended Regimens
Intravaginal Agents:
Butoconazole 2% cream 5 g intravaginally for 3 days*
OR
Butoconazole 2% cream 5 g (Butaconazole1-sustained release), single intravaginal application
OR
Clotrimazole 1% cream 5 g intravaginally for 7--14 days*
OR
Clotrimazole 100 mg vaginal tablet for 7 days
OR
Clotrimazole 100 mg vaginal tablet, two tablets for 3 days
OR
Miconazole 2% cream 5 g intravaginally for 7 days*
OR
Miconazole 100 mg vaginal suppository, one suppository for 7 days*
OR
Miconazole 200 mg vaginal suppository, one suppository for 3 days*
OR
Miconazole 1,200 mg vaginal suppository, one suppository for 1 day*
OR
Nystatin 100,000-unit vaginal tablet, one tablet for 14 days
OR
Tioconazole 6.5% ointment 5 g intravaginally in a single application*
OR
Terconazole 0.4% cream 5 g intravaginally for 7 days
OR
Terconazole 0.8% cream 5 g intravaginally for 3 days
OR
Terconazole 80 mg vaginal suppository, one suppository for 3 days
Oral Agent:
Fluconazole 150 mg oral tablet, one tablet in single dose

* Over-the-counter preparations.

The creams and suppositories in this regimen are oil-based and might weaken latex condoms and diaphragms. Refer to condom product labeling for further information.

Intravaginal preparations of butaconazole, clotrimazole, miconazole, and tioconazole are available over-the-counter (OTC). Women whose condition has previously been diagnosed with VVC are not necessarily more likely to be able to diagnose themselves; therefore, any woman whose symptoms persist after using an OTC preparation, or who has a recurrence of symptoms within 2 months, should be evaluated with office-based testing. Unnecessary or inappropriate use of OTC preparations is common and can lead to a delay in the treatment of other vulvovaginitis etiologies, which can result in adverse clinical outcomes.

Follow-Up

Patients should be instructed to return for follow-up visits only if symptoms persist or recur within 2 months of onset of initial symptoms.
Management of Sex Partners

VVC is not usually acquired through sexual intercourse; treatment of sex partners is not recommended but may be considered in women who have recurrent infection. A minority of male sex partners might have balanitis, which is 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

Allergy, Intolerance, and Adverse Reactions

Topical agents usually cause no systemic side effects, although local burning or irritation might occur. Oral agents occasionally cause nausea, abdominal pain, and headache. Therapy with the oral azoles has been associated rarely with abnormal elevations of liver enzymes. Clinically important interactions can occur when these oral agents are administered with other drugs, including astemizole, calcium channel antagonists, cisapride, coumadin, cyclosporin A, oral hypoglycemic agents, phenytoin, protease inhibitors, tacrolimus, terfenadine, theophylline, trimetrexate, and rifampin.

Complicated VVC

Recurrent Vulvovaginal Candidiasis (RVVC)

RVVC, usually defined as four or more episodes of symptomatic VVC in 1 year, affects a small percentage of women (<5%). The pathogenesis of RVVC is poorly understood, and the majority of women with RVVC have no apparent predisposing or underlying conditions. Vaginal cultures should be obtained from patients with RVVC to confirm the clinical diagnosis and to identify unusual species, including nonalbicans species, particularly Candida glabrata (C. glabrata does not form pseudohyphae or hyphae and is not easily recognized on microscopy). C. glabrata and other nonalbicans Candidia species are observed in 10%--20% of patients with RVVC. Conventional antimycotic therapies are not as effective against these species as against C. albicans.

Treatment

Each individual episode of RVVC cause