MMWR May 10, 2002 / 51(RR06);1-80
Sexually Transmitted Diseases Treatment Guidelines --- 2002
Prepared by Kimberly A. Workowski, M.D., William C. Levine, M.D., M.Sc.
The information in this report updates the 1998 Guidelines for Treatment of Sexually Transmitted Diseases (MMWR 1998;47[No. RR-1]). Included in these updated guidelines are new alternative regimens for scabies, bacterial vaginosis, early syphilis, and granuloma inguinale; an expanded section on the diagnosis of genital herpes (including type-specific serologic tests); new recommendations for treatment of recurrent genital herpes among persons infected with human immunodeficiency virus (HIV); a revised approach to the management of victims of sexual assault; expanded regimens for the treatment of urethral meatal warts; and inclusion of hepatitis C as a sexually transmitted infection. In addition, these guidelines emphasize education and counseling for persons infected with human papillomavirus, clarify the diagnostic evaluation of congenital syphilis, and present information regarding the emergence of quinolone-resistant Neisseria gonorrhoeae and implications for treatment. Recommendations also are provided for vaccine-preventable STDs, including hepatitis A and hepatitis B.
Clinical Prevention Guidelines
The prevention and control of STDs is based on the following five major concepts:
Prevention messages should be tailored to the patient, with consideration given to the patient's specific risk factors for STDs. Messages should include a description of specific actions that the patient can take to avoid acquiring or transmitting STDs (e.g., abstinence from sexual activity if STD-related symptoms develop).
If risk factors are identified, providers should encourage patients to adopt safer sexual behaviors.
Many patients seeking treatment or screening for STDs expect evaluation for all common STDs; all patients should be specifically informed if testing for a common STD (e.g., genital herpes and human papillomavirus [HPV]) is not performed.
The most reliable way to avoid transmission of STDs is to abstain from sexual intercourse (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 wish to avoid the possible consequences of sexual intercourse (e.g., STD/HIV and unintended pregnancy). A more comprehensive discussion of abstinence and the range of sexual expression is available in Contraceptive Technology, 17th edition (4).
Both partners should get tested for STDs, including HIV, before initiating sexual intercourse.
If a person chooses to have sexual intercourse with a partner whose infection status is unknown or who is infected with HIV or another STD, a new condom should be used for each act of insertive intercourse.
Preexposure vaccination is one of the most effective methods for preventing transmission of certain STDs. For example, because hepatitis B virus infection frequently is sexually transmitted, hepatitis B vaccination is recommended for all unvaccinated persons being evaluated for an STD. In addition, hepatitis A vaccine is currently licensed and is recommended for men who have sex with men (MSM) and illegal drug users (both injection and non-injection). Vaccine trials for other STDs are being conducted, and additional vaccines may become available in the next several years.
When used consistently and correctly, male latex condoms are effective in preventing the sexual transmission of HIV infection and can reduce the risk for other STDs (i.e., gonorrhea, chlamydia, and trichomonas). However, because condoms do not cover all exposed areas, they are likely to be more effective in preventing infections transmitted by fluids from mucosal surfaces (e.g., gonorrhea, chlamydia, trichomoniasis, and HIV) than in preventing those transmitted by skin-to-skin contact (e.g., herpes simplex virus [HSV], HPV, syphilis, and chancroid). 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 low in the United States (i.e., approximately two broken condoms per 100 condoms used). Condom failure 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, the pregnancy rates among women whose partners use these condoms are similar. Non-latex condoms (i.e., those made of polyurethane or other synthetic material) can be substituted for persons with latex allergy.
Patients should be advised that condoms must be used consistently and correctly to be highly effective in preventing STDs. Patients 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 act of sexual intercourse (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 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 intercourse, possibly requiring the use of exogenous lubricants.
Hold the condom firmly against the base of the penis during withdrawal, and withdraw while the penis is still erect to prevent slippage.
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 (5). With the exception of one investigation of recurrent trichomoniasis, no clinical studies have been completed to evaluate the efficacy of female condoms in providing protection from STDs, including HIV. If used consistently and correctly, the female condom may substantially reduce the risk for STDs. When a male condom cannot be used properly, sex partners should consider using a female condom.
Vaginal Spermicides, Sponges, and Diaphragms
Recent evidence has indicated that vaginal spermicides containing nonoxynol-9 (N-9) are not effective in preventing cervical gonorrhea, chlamydia, or HIV infection (6). Thus, spermicides alone are not recommended for STD/HIV prevention. Frequent use of spermicides containing N-9 has been associated with genital lesions, which may be associated with an increased risk of HIV transmission. The vaginal contraceptive sponge appears to protect against cervical gonorrhea and chlamydia, but its use increases the risk for candidiasis. In case-control and cross-sectional studies, diaphragm use has been demonstrated to protect against cervical gonorrhea, chlamydia, and trichomoniasis; however, no cohort studies have been conducted (7). Neither vaginal sponges nor diaphragms should be relied on to protect women against HIV infection. The role of spermicides, sponges, and diaphragms for preventing transmission of HIV to men has not been evaluated. Diaphragm and spermicide use has been associated with an increased risk of bacterial urinary tract infection 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. Distribution of previously purchased condoms lubricated with N-9 spermicide should continue provided the condoms have not passed their expiration date. However, purchase of any additional condoms lubricated with the spermicide N-9 is not recommended 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 data indicate that N-9 may increase the risk for HIV transmission during vaginal intercourse (6). 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, thus providing 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
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 or chemical 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 (IUDs), have been surgically sterilized, or have had hysterectomies should be counseled regarding the use of condoms and the risk for STDs, including HIV infection.
STD/HIV Prevention Counseling
Interactive counseling approaches directed at a patient's personal risk, the situations in which risk occurs, and use of goal-setting strategies are effective in STD prevention (8). One such approach --- "client-centered" HIV prevention counseling --- involves two sessions, each lasting 15--20 minutes, and has been recommended for STD clinic patients who receive HIV testing. In addition to prevention counseling, certain videos and large group presentations that provide explicit information about how to use condoms correctly have been effective in reducing the occurrence of additional STDs among persons at high risk, including STD clinic patients and adolescents. Results from randomized controlled trials demonstrate that compared with traditional approaches to providing information, certain brief risk reduction counseling approaches can reduce the occurrence of new sexually transmitted infections by 25%--40% among STD clinic patients (9).
Interactive counseling strategies can be effectively used by most health-care providers, regardless of educational background or demographic profile. High-quality counseling is best ensured when clinicians are provided basic training in prevention counseling methods and skills building approaches, periodic supervisor observation of counseling with immediate feedback to counselors, periodic counselor and/or patient satisfaction evaluations, and regularly scheduled meetings of counselors and supervisors to discuss difficult situations. Prevention counseling is believed to be more effective if provided in a non-judgmental manner appropriate to the patient's culture, language, sex, sexual orientation, age, and developmental level.
Partner notification, once referred to as "contact tracing" but more recently included in the broader category of partner services, is the process of learning from persons with STDs about their sexual partners and helping to arrange for evaluation and treatment of those partners. Providers can furnish this service directly or with assistance from state and local health departments. The intensity of services and the specific conditions for which such services are offered by health agencies vary from area to area. Such services usually are accompanied by health counseling and may include referral of patients and their partners for other services.
Many persons benefit from partner notification; thus, providers should encourage their patients to make partners aware of potential STD risk and urge them to seek diagnosis and treatment, regardless of assistance from local health agencies. However, whether the process of partner notification effectively decreases exposure to STDs from a person's sexual environment or whether it changes the incidence and prevalence of disease is uncertain. The paucity of supporting evidence regarding the consequences of partner notification has spurred the exploration of alternative approaches. One such approach is to place partner notification in the larger context of the sexual and social networks in which people are exposed to STDs. The underlying hypotheses are that networks have an influence on disease transmission that is independent of personal behaviors, that network structure is related directly to prevalence and to underlying disease transmission dynamics, and that network approaches provide a more powerful tool for identifying exposed persons and other persons at risk. A second such approach for which supporting data are being collected is the use of patient delivered therapy for treatment of contacts and others at risk, a technique that can considerably expand the role of practitioners in the control of STDs. The combination of these approaches has the potential to provide both an intervention and its evaluative tool.
These approaches have not yet been sufficiently assessed to warrant definitive recommendations. However, practitioners and public health professionals should be aware of the current potential use of these nontraditional modalities in the prevention and control of STDs.
Reporting and Confidentiality
The accurate identification and timely reporting of STDs are integral components of successful disease control efforts. Timely reporting is important for assessing morbidity trends, targeting limited resources, and assisting local health authorities in identifying sex partners who may be infected. STD/HIV and acquired immunodeficiency syndrome (AIDS) cases should be reported in accordance with local statutory requirements.
Syphilis, gonorrhea, chlamydia, and AIDS are reportable diseases in every state. HIV infection and chancroid are reportable in many states. The requirements for reporting other STDs differ by state, and clinicians should be familiar with local reporting requirements. Reporting can be provider- and/or laboratory-based. Clinicians who are unsure of local reporting requirements should seek advice from local health departments or state STD programs.
STD and HIV reports are kept strictly confidential. In most 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.
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 should be offered voluntary HIV testing at the first prenatal visit. Reasons for refusal of testing should be explored, and testing should be reoffered to pregnant women who initially declined testing. Retesting in the third trimester (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). In addition, women who have not received prenatal counseling should be encouraged to be tested for HIV infection at delivery.
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. Patients who are at high risk for syphilis, are living in areas of excess 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.
A serologic test for hepatitis B surface antigen (HBsAg) should be performed on all pregnant women at the first prenatal visit. HBsAg testing should be repeated late in pregnancy for women who are HBsAg negative but who are at high risk for HBV infection (e.g., injection-drug users and women who have concomitant STDs).
A test for Chlamydia trachomatis should be performed 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 tested during the third trimester to prevent maternal postnatal complications and chlamydial infection in the infant. Screening during the first trimester might enable prevention of adverse effects of chlamydia during pregnancy. However, evidence for preventing adverse effects during pregnancy is lacking. If screening is performed only during the first trimester, a longer period exists for acquiring infection before delivery.
A test for Neisseria gonorrhoeae should be performed at the first prenatal visit for women at risk or for women living in an area in which the prevalence of N. gonorrhoeae is high. A repeat test should be performed during the third trimester for those at continued risk.
A test for hepatitis C antibodies (anti-HCV) should be performed at the first prenatal visit for pregnant women at high risk for exposure. Women at high risk include those with a history of injection-drug use, repeated exposure to blood products, prior blood transfusion, or organ transplants.
Evaluation for bacterial vaginosis (BV) may be conducted at 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). Current 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 STD-related concerns are as follows.
HBsAg-positive women should be reported to the local and/or state health department to ensure that they are entered into a case-management system and that appropriate prophylaxis is provided for their infants. In addition, household and sex contacts of HBsAg-positive women should be vaccinated.
No treatment is available for anti-HCV-positive pregnant women. However, all women found to be anti-HCV-positive should receive appropriate counseling (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.
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 these guidelines, as well as infections not transmitted sexually, refer to the following references: Guide to Clinical Preventive Services (10), Guidelines for Perinatal Care (11), American College of Obstetricians and Gynecologists (ACOG) Educational Bulletin: Antimicrobial Therapy for Obstetric Patients (12), ACOG Committee Opinion: Primary and Preventive Care: Periodic Assessments (13), Recommendations for the Prevention and Management of Chlamydia trachomatis Infections (14), Hepatitis B Virus: A Comprehensive Strategy for Eliminating Transmission in the United States through Universal Childhood Vaccination --- Recommendations of the Immunization Practices Advisory Committee (ACIP) (1), Mother-to-infant transmission of hepatitis C virus (15), Hepatitis C: Screening in pregnancy (16), American College of Obstetricians and Gynecologists (ACOG) Educational Bulletin: Viral hepatitis in pregnancy (17), Human Immunodeficiency Virus Screening: Joint statement of the AAP and ACOG (18), Preventing Perinatal Transmission of HIV (19), and the Revised Public Health Service Recommendations for HIV Screening of Pregnant Women (20).
These sources are not entirely consistent in their recommendations. 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 recommend 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 more extensive (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.
Health professionals who provide care for adolescents should be aware of several issues that relate specifically to persons within this age group. 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 young adults are also at highest risk for HPV infection. In addition, surveillance data indicate that 9% of adolescents who have acute HBV infection either have had sexual contact with a chronically infected person or with multiple sex partners or report 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 be administered hepatitis B vaccine (1).
Younger adolescents (i.e., persons aged <15 years) who are sexually active are at particular risk for infection. Adolescents at especially high risk for STDs include youth in detention facilities, STD clinic patients, male homosexuals, and injection-drug users. Adolescents are at greater risk for STDs because they frequently have unprotected intercourse, are biologically more susceptible to infection, are engaged in partnerships often of limited duration, and face multiple obstacles to utilization of health care. Several of these issues can be addressed by clinicians who provide services to adolescents. Clinicians can address the lack of knowledge and awareness about the risks and consequences of STDs and offer guidance, constituting true primary prevention, to help adolescents develop healthy sexual behaviors and thus prevent the establishment of patterns of behavior that can undermine sexual health.
With a few exceptions, all adolescents in the United States can consent to the confidential diagnosis and treatment of STDs. Medical care for STDs can be provided to adolescents without parental consent or knowledge. Furthermore, in many 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. Health-care providers should acknowledge the importance of confidentiality for adolescents and should strive to follow policies that comply with state laws to ensure the confidentiality of STD-related services.
Despite the prevalence of STDs among adolescents, providers frequently fail to inquire about sexual behavior, assess risk for STDs, counsel about risk reduction, and screen for asymptomatic infection during clinical encounters. When addressing these sensitive areas with young people, the style and content of counseling and health education should be adapted for adolescents. Discussions should be appropriate for the patient's developmental level and should identify risky behaviors (e.g., sex and drug-use behaviors). Careful counseling and thorough discussions are particularly important for adolescents who may not acknowledge that they engage in high-risk behaviors. Care and counseling should be direct and nonjudgmental.
Management of children who have STDs requires close cooperation between clinicians, laboratorians, and child-protection authorities. Investigations, when indicated, should be initiated promptly. Some diseases (e.g., gonorrhea, syphilis, and chlamydia), if acquired after the neonatal period, are almost 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).
Men Who Have Sex with Men
Some MSM are at high risk for HIV infection and other viral and bacterial STDs. Although the frequency of unsafe sexual practices and reported rates of bacterial STDs and incident HIV infection has declined substantially in MSM during the last several decades, increased rates of infectious syphilis, gonorrhea, and chlamydial infection, largely among HIV-infected MSM, have been recently reported in many cities in the United States and other industrialized countries. Preliminary data also indicate higher frequencies of unsafe sex and suggest that the incidence of HIV infection may be rising among MSM in some cities. The underlying behavioral changes likely are related to effects of improved HIV/AIDS therapy on quality of life and survival, "safer sex burnout," and in some cities, adverse trends in substance abuse.
Clinicians should assess sexual risk for all male patients, which includes routinely inquiring about the sex of patients' sex partners. MSM, including those with HIV infection, should routinely undergo straightforward, nonjudgmental STD/HIV risk assessment and client-centered prevention counseling to reduce the likelihood of acquisition or transmission of HIV and other STDs. In addition, screening for STDs should be considered for many MSM.
The following screening recommendations are based on preliminary data; these tests should be performed at least annually for sexually active MSM:
In addition, vaccination against hepatitis is the most effective means of preventing sexual transmission of hepatitis A and B. Prevaccination serologic testing may be cost-effective in MSM, among whom the prevalence of hepatitis A and B infection is likely to be high.
More frequent STD screening (e.g., at 3--6-month intervals) may be indicated for MSM at highest risk (e.g., those who acknowledge having multiple anonymous partners or having sex in conjunction with illicit drug use and patients whose sex partners participate in these activities). Screening tests usually are indicated regardless of a patient's history of consistent use of condoms for insertive or receptive anal intercourse. Providers also should be knowledgeable about the common manifestations of symptomatic STDs in MSM (e.g., urethral discharge, dysuria, anorectal symptoms [such as pain, pruritis, discharge, and bleeding], genital or anorectal ulcers, other mucocutaneous lesions, lymphadenopathy, and skin rash). If these symptoms are present, providers should perform appropriate diagnostic tests.
HIV Infection: Detection, Counseling, and Referral
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). Most adults and adolescents infected with HIV remain symptom-free for extended periods, but viral replication is active during all stages of infection, increasing substantially as the immune system deteriorates. In the absence of treatment, AIDS eventually develops in almost all HIV-infected persons; in one study of HIV-infected adults, AIDS developed in 87% within 17 years of infection. Additional cases are expected to occur among those who have remained AIDS-free for longer periods of time.
Greater awareness among both patients and health-care providers of the risk factors associated with HIV transmission has led to increased testing for HIV and earlier diagnosis of the infection, often before symptoms develop. Prompt diagnosis of HIV infection is important for several 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 carinii pneumonia [PCP], toxoplasmic 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 many other diseases and may affect the efficacy of antimicrobial therapy for some STDs. Finally, the early diagnosis of HIV enables health-care providers to counsel such patients, refer them to various support services, and help prevent HIV transmission to others.
Proper management of HIV infection involves a complex array of behavioral, psychosocial, and medical services. Although some of these services may be available in the STD treatment facility, many services are often unavailable in this setting. Therefore, referral to a health-care provider or facility experienced in caring for HIV-infected patients is advised. Staff in STD treatment facilities should be knowledgeable about the options for referral available in their communities. While in STD treatment facilities, HIV-infected patients should be educated about HIV infection and the various options for available support services and HIV care.
Because multiple, complex services are required for management of HIV infection, detailed information (particularly regarding medical care) is beyond the scope of this section and can be found elsewhere (8,21). This report provides information regarding diagnostic testing for HIV infection, counseling patients who have HIV infection, and referral of patients to support services (including medical care). Information also is provided regarding the management of sex partners, because such services can and should be provided in STD treatment facilities. In addition, the topics of HIV infection during pregnancy and in infants and children are addressed.
Detection of HIV Infection: Diagnostic Testing
Testing for HIV is recommended and should be offered to all persons who seek evaluation and treatment for STDs. Counseling before and after testing (i.e., pretest and posttest counseling) is an integral part of the testing procedure (see HIV Prevention Counseling). Informed consent must be obtained before an HIV test is performed. Some states require written consent.
HIV infection usually is diagnosed by tests for antibodies against HIV-1 and HIV-2 (HIV-1/2). Antibody testing begins with a sensitive screening test (e.g., the enzyme immunoassay [EIA]). Reactive screening tests must be confirmed by 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.
Most HIV infections in the United States are caused by HIV-1; <100 cases of HIV-2 infection have been documented (22). However, HIV-2 infection should be suspected in persons who have epidemiologic risk factors for HIV-2. Examples of these risk factors include persons with sex partners from West Africa (where HIV-2 is endemic), those with sex partners known to be infected with HIV-2, and persons who received a blood transfusion or a non-sterile injection in a West African country. HIV-2 testing is also indicated when clinical evidence of HIV exists but tests for antibodies to HIV-1 are not positive, or when HIV-1 Western blot results include the unusual indeterminate pattern of gag plus pol bands in the absence of env bands (22).
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 RNA [i.e., viral load]) to detect the presence of HIV, although this test is not approved for diagnostic purposes; a positive test should be confirmed by another HIV test. Current guidelines suggest that persons with recently acquired HIV infection might benefit from antiretroviral drugs, and such patients may be candidates for clinical trials (23,24). Therefore, patients with acute HIV infection should be referred immediately to an HIV clinical care provider.
Detection 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 likely constitute a risk factor for HIV transmission.
The following are specific recommendations for diagnostic testing for HIV infection.
HIV testing is recommended and should be offered to all persons who seek evaluation and treatment for STDs.
Informed consent must be obtained before an HIV test is performed; some states require written consent.
Positive screening tests for HIV antibody must be confirmed by a more specific confirmatory test (either WB or IFA) before being considered diagnostic of HIV infection.
Patients who have positive HIV test results must receive initial counseling on-site and should either a) receive behavioral, psychosocial, and medical evaluation and monitoring services or b) 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
Patients can be expected to be distressed when first informed of a positive HIV test result. Such patients face several major adaptive challenges, including a) accepting the possibility of a shortened life span, b) coping with others' reactions to a stigmatizing illness, c) developing and adopting strategies for maintaining physical and emotional health, and d) initiating changes in behavior to prevent HIV transmission to others. Many patients also require assistance with making reproductive choices, gaining access to health services, and confronting possible employment or housing discrimination. Therefore, in addition to medical care, behavioral and psychosocial services are an integral part of health care for HIV-infected patients. 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 (8).
Practice settings for offering HIV care differ depending on local resources and needs. Primary-care providers and outpatient facilities must 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 often 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.
Recently identified HIV infection may not have been recently acquired. Persons newly diagnosed with HIV may 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 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 (25). Providers should be able to refer patients for prevention counseling and risk reduction support concerning high risk behaviors (e.g., substance abuse and high risk sexual behavior).
HIV-infected patients in the STD treatment setting should be educated about what to expect as they enter medical care for HIV infection. In non-emergent situations, the initial evaluation of HIV-positive patients usually includes a) a detailed medical history, including sexual and substance-abuse history, previous STDs, and specific HIV-related symptoms or diagnoses; b) a physical examination (including a gynecologic examination for women); c) testing for N. gonorrhoeae and C. trachomatis (and for women, a Pap test and wet mount examination of vaginal secretions); d) complete blood and platelet counts and blood chemistry profile; e) toxoplasma antibody test; f) tests for hepatitis B, C, and for MSM, hepatitis A; g) syphilis serology; h) a CD4+ T-lymphocyte analysis and determination of HIV plasma RNA (i.e., HIV viral load); i) a tuberculin skin test (TST) (sometimes referred to as a purified protein derivative [PPD]); j) a urinalysis; and k) a chest radiograph (21).
In subsequent visits, once the results of laboratory and skin tests are available, the patient may be offered antiretroviral therapy (23,24), if indicated, as well as specific medications to reduce the incidence of opportunistic infections (e.g., PCP, TE, disseminated MAC infection, and TB) (21,26). Hepatitis B vaccination should be offered to patients who lack hepatitis B serologic markers. Hepatitis A vaccination should be given to persons at increased risk for hepatitis A infection (e.g., MSM and illegal drug users) and to patients with chronic hepatitis B or hepatitis C who lack antibodies to hepatitis A. Influenza vaccination should be offered annually, and pneumococcal vaccination should be administered if not given in the previous 5 years (21).
Providers must be alert to the possibility of new or recurrent STDs and treat such conditions aggressively. 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. More frequent screening may 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.
Patients should receive, or be referred for, a thorough psychosocial evaluation, including ascertainment of behavioral factors indicating risk for transmitting HIV. Patients may require referral for specific behavioral intervention (e.g., a substance abuse program), for mental health disorders (e.g., depression), or for emotional distress. They may 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 may be candidates for prevention case management (27).
The following are specific recommendations for counseling and referral.
Persons who test positive for HIV antibody should be counseled, either on site or through referral, about 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 persons for immediate care and support needs and link them to services in which health-care personnel are experienced in providing care for HIV-infected patients, including services for medical care, substance abuse, mental health disorders, emotional distress, reproductive counseling, risk-reduction counseling, and prevention management. HIV-infected persons should be referred to these services as needed and followed up to ensure that referrals have been completed.
Patients should be educated about what to expect in follow-up medical care.
Management of Sex Partners and Injection-Drug Partners
Clinicians evaluating HIV-infected persons should collect information to determine whether any partners should be notified about possible exposure to HIV (8). When referring to persons who are infected with HIV, the term "partner" includes not only sex partners but also injection-drug users 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 possibly reduces morbidity and provides the opportunity to encourage risk-reducing behaviors. Partner notification for HIV infection must be confidential and depends on the voluntary cooperation of the patient.
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 health departments provide assistance, if requested, with provider-referral partner notification.
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 procedures to notify partners.
Voluntary counseling and HIV testing should be offered routinely to all pregnant women as early in pregnancy as possible (20). For women who decline these services, providers should continue to strongly encourage testing and to address concerns that pose obstacles to testing. Providing pregnant women with counseling and testing is particularly important not only to maintain the health of the patient, but also because interventions (antiretroviral and obstetrical) are available that can reduce perinatal transmission of HIV.
Once identified as being HIV-infected, pregnant women should be informed specifically about the risk for perinatal infection. Current 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% are infected during breastfeeding in resource-limited settings where HIV-infected women breastfeed their infants into the second year of life (28). However, the risk of HIV transmission can be reduced substantially to <2% through antiretroviral regimens and obstetrical interventions (i.e., AZT or nevirapine and elective c-section at 38 weeks of pregnancy) and by avoiding breastfeeding (29). Pregnant women who are HIV-infected should be counseled about their options (either on-site or by referral), given appropriate antenatal treatment, and (for women living in the United States, where infant formula is readily available and can be safely prepared) advised not to breastfeed their infants.
HIV Infection Among Infants and Children
Diagnosis of HIV infection in a pregnant woman indicates the need to consider whether additional children are 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 should be based on laboratory evidence of HIV in blood or tissues by culture, nucleic acid, or antigen detection. 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 (21,30).
Diseases Characterized by Genital Ulcers
Management of Patients Who Have Genital Ulcers
In the United States, most young, sexually active patients who have genital ulcers have either genital herpes, syphilis, or chancroid. The relative frequency of each differs by geographic area and patient population; however, genital herpes is the most prevalent of these diseases. More than one of these diseases sometimes is present in a patient who has genital ulcers. Each disease 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 often is inaccurate. Therefore, evaluation of all patients who have genital ulcers should include 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
No FDA-approved PCR test for these organisms is available in the United States, but such testing can be performed by commercial laboratories that have developed their own PCR tests. Type-specific serology for HSV type 2 may be helpful in identifying persons with genital herpes (see Genital Herpes). Biopsy of ulcers may be helpful in identifying the cause of unusual ulcers or ulcers that do not respond to initial therapy.
HIV testing should be performed in the management of patients who have genital ulcers caused by T. pallidum or H. ducreyi. Such testing should be considered for those who have ulcers caused by HSV (see sections on Syphilis, Chancroid, and Genital Herpes).
Health-care providers often 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 upon prompt initiation of therapy. In this circumstance, the clinician should treat for the diagnosis considered most likely on the basis of clinical presentation and epidemiologic circumstances. Sometimes 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.
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; high rates of HIV infection among patients who have chancroid occur in the United States and other countries. About 10% of persons who have chancroid acquired in the United States are coinfected with T. pallidum or HSV; this percentage is higher in persons acquiring chancroid outside the United States.
A definitive diagnosis of chancroid requires identification of H. ducreyi on special culture media that is not widely available from commercial sources; even using these media, sensitivity is <80%. No FDA-approved PCR test for H. ducreyi is available in the United States, but such testing can be performed by commercial laboratories that have developed their own PCR test. A probable diagnosis, for both clinical and surveillance purposes, can be made if all the following criteria are met: a) the patient has one or more painful genital ulcers; b) 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; c) the clinical presentation, appearance of genital ulcers and, if present, regional lymphadenopathy are typical for chancroid; and d) a test for HSV performed on the ulcer exudate is negative. The combination of a painful ulcer and tender inguinal adenopathy, symptoms occurring in one third of patients, suggests a diagnosis of chancroid; when accompanied by suppurative inguinal adenopathy, these signs are almost pathognomonic.
Treatment of Chancroid Infection
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.
NOTE: 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
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.
Patients should be re-examined 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 a) the diagnosis is correct, b) the patient is coinfected with another STD, c) the patient is infected with HIV, d) the treatment was not used as instructed, or e) 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 may 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 that of ulcers and may require needle aspiration or incision and drainage, despite otherwise successful therapy. Although needle aspiration of buboes is a simpler procedure, incision and drainage may be preferred because of reduced need for subsequent 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.
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-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 may require longer courses of therapy than those recommended for HIV-negative patients, and treatment failures can occur with any regimen. Because data are 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 suggest using the erythromycin 7-day regimen for treating HIV-infected persons.
Genital Herpes Simplex Virus Infections
Genital herpes is a recurrent, life-long viral infection. Two serotypes of HSV have been identified: HSV-1 and HSV-2. Most cases of recurrent genital herpes are caused by HSV-2. At least 50 million persons in the United States have genital HSV infection.
Most persons infected with HSV-2 have not been diagnosed. Many such persons have mild or unrecognized infections but shed virus intermittently in the genital tract. Most genital herpes infections are transmitted by persons unaware that they have the infection or who are asymptomatic when transmission occurs. Rarely, first-episode genital herpes is manifested by severe disease that may require hospitalization.
Diagnosis of HSV Infection
The clinical diagnosis of genital herpes is both insensitive and nonspecific. The typical painful multiple vesicular or ulcerative lesions are absent in many infected persons. Up to 30% of first-episode cases of genital herpes are caused by HSV-1, but recurrences are much less frequent for genital HSV-1 infection than genital HSV-2 infection. Therefore, the distinction between HSV serotypes influences prognosis and counseling. For these reasons, the clinical diagnosis of genital herpes should be confirmed by laboratory testing. Both virologic tests 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.
Isolation of HSV in cell culture is the preferred virologic test in patients who present with genital ulcers or other mucocutaneous lesions. The sensitivity of culture declines rapidly as lesions begin to heal, usually within a few days of onset. Some HSV antigen detection tests, unlike culture and the direct fluorescent antibody test, do not distinguish HSV-1 from HSV-2. Polymerase chain reaction (PCR) assays for HSV DNA are highly sensitive, but their role in the diagnosis of genital ulcer disease has not been well-defined. However, PCR is available in some laboratories and is the test of choice for detecting HSV in spinal fluid for diagnosis of HSV-infection of the central nervous system (CNS). Cytologic detection of cellular changes of herpes virus infection is insensitive and nonspecific, both in genital lesions (Tzanck preparation) and cervical Pap smears, and should not be relied on for diagnosis of HSV infection.
Type-specific Serologic Tests
Both type-specific and nonspecific antibodies to HSV develop during the first several weeks following infection and persist indefinitely. Because almost all HSV-2 infections are sexually acquired, type-specific HSV-2 antibody indicates anogenital infection, but the presence of HSV-1 antibody does not distinguish anogenital from orolabial infection. Accurate type-specific assays for HSV antibodies must be based on the HSV-specific glycoprotein G2 for the diagnosis of infection with HSV-2 and glycoprotein G1 for diagnosis of infection with 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 gG-based assays should be specifically requested when serology is performed.
Currently, the FDA-approved, gG-based type-specific assays include POCkitHSV-2 (manufactured by Diagnology); HerpeSelect-1 ELISA IgG or HerpeSelect-2 ELISA IgG (manufactured by Focus Technology, Inc.); and HerpeSelect 1 and 2 Immunoblot IgG (manufactured by Focus Technology, Inc.). The POCkit-HSV-2 assay is a point-of-care test that provides results for HSV-2 antibodies from capillary blood or serum during a clinic visit. The Focus Technology assays are laboratory-based. The sensitivities of these tests for detection of HSV-2 antibody vary from 80% to 98%, and false-negative results may occur, especially at early stages of infection. The specificities of these assays are >96%. False-positive results can occur, especially in patients with low likelihood of HSV infection. Therefore, repeat testing or a confirmatory test (e.g., an immunoblot assay if the initial test was an ELISA) may be indicated in some settings.
Because false-negative HSV cultures are common, especially in patients with recurrent infection or with healing lesions, type-specific serologic tests are useful in confirming a clinical diagnosis of genital herpes. Additionally, such tests can be used to diagnose persons with unrecognized infection and to manage sex partners of persons with genital herpes. Although serologic assays for HSV-2 should be available for persons who request them, screening for HSV-1 or HSV-2 infection in the general population is not indicated.
Principles of Management of Genital Herpes
Antiviral chemotherapy offers clinical benefits to most symptomatic patients and is the mainstay of management. In addition, 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 partially control the symptoms and signs of herpes episodes when used to treat first clinical episodes 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 indicate that three antiviral medications provide clinical benefit for genital herpes: acyclovir, valacyclovir, and famciclovir (31--41). Valacyclovir is the valine ester of acyclovir and has enhanced absorption after oral administration. Famciclovir, a pro-drug of penciclovir, also has high oral bioavailability. Topical therapy with antiviral drugs offers minimal clinical benefit, and its use is not recommended.
First Clinical Episode of Genital Herpes
Many patients with first-episode herpes present with mild clinical manifestations but later develop severe or prolonged symptoms. Therefore, most patients with initial genital herpes should receive antiviral therapy.
NOTE: Treatment may be extended if healing is incomplete after 10 days of therapy.
Higher dosages of acyclovir (i.e., 400 mg orally five times a day) were used in treatment studies of first-episode herpes proctitis and first-episode oral infection. However, no comparative studies have been conducted, and whether these forms of HSV infection require higher doses of antiviral drugs than used for genital herpes is unknown. Valacyclovir and famciclovir probably are also effective for acute HSV proctitis or oral infection, but clinical experience is lacking.
Recurrent Episodes of HSV Disease
Most patients with symptomatic, first-episode genital HSV-2 infection subsequently experience recurrent episodes of genital lesions; recurrences are much less frequent following initial genital HSV-1 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 patients, including those with mild or infrequent recurrent outbreaks, benefit from antiviral therapy; therefore, options for treatment should be discussed with all patients.
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 self-initiate treatment immediately when symptoms begin.
For episodic therapy, a randomized controlled trial indicated that a 3-day course of valacyclovir 500 mg twice daily is as effective as a 5-day course. Similar studies have not been done with acyclovir and famciclovir.
Suppressive Therapy for Recurrent Genital Herpes
Suppressive therapy reduces the frequency of genital herpes recurrences by 70%--80% among patients who have frequent recurrences (i.e., >6 recurrences per year), and many patients report no symptomatic outbreaks. Treatment probably is also effective in patients with less frequent recurrences, although definitive data are lacking. 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 often is improved in patients with frequent recurrences who receive suppressive compared with episodic treatment.
The frequency of recurrent outbreaks diminishes over time in many patients, and the patient's psychological adjustment to the disease may change. Therefore, periodically during suppressive treatment (e.g., once a year), discontinuation of therapy should be discussed with the patient to reassess the need for continued therapy.
Suppressive antiviral therapy reduces but does not eliminate subclinical viral shedding. Therefore, the extent to which suppressive therapy prevents HSV transmission is unknown.
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). Few comparative studies of valacyclovir or famciclovir with acyclovir have been conducted. The results of these studies suggest that valacyclovir and famciclovir are comparable to acyclovir in clinical outcome (35--39). Ease of administration and cost also are important considerations for prolonged treatment.
Severe Disease - Genital Herpes Simplex Virus Infections
IV acyclovir therapy should be provided for patients who have severe disease or complications that necessitate hospitalization, such as disseminated infection, pneumonitis, hepatitis, or complications of the central nervous system (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 total therapy.
Counseling of infected persons and their sex partners is critical to management of genital herpes. Counseling has two main goals: to help patients cope with the infection and to prevent sexual and perinatal transmission. 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. Numerous resources, including the CDC National STD/HIV Hotline (tel: 800-227-8922), web sites (http://www.ashastd.org), and printed materials are available to assist patients and clinicians in counseling.
HSV-infected persons may express anxiety about genital herpes that does not reflect the actual clinical severity of their disease; the psychological impact of infection often is substantial. Common concerns about genital herpes include the severity of initial clinical manifestations, recurrent episodes, sexual relationships and transmission to sex partners, and ability to bear healthy children. The misconception that HSV causes cancer should be dispelled, because the role of HSV-2 in cervical cancer is at most that of a cofactor, not a primary etiologic agent.
Specific counseling messages should include the following information.
Management of Sex Partners
The sex partners of patients who have genital herpes likely 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, educated to recognize symptoms of herpes, and offered type-specific serologic testing for HSV infection.
Allergy, Intolerance, and Adverse Reactions
Allergic and other adverse reactions to acyclovir, valacyclovir, and famciclovir are rare. Desensitization to acyclovir has been described (42).
Immunocompromised patients may have prolonged or severe episodes of genital, perianal, or oral herpes. Lesions caused by HSV are common among HIV-infected patients and may be severe, painful, and atypical. Episodic or suppressive therapy with oral antiviral agents is often beneficial.
Recommended Regimens for Episodic Infection in Persons Infected with HIV
Recommended Regimens for Daily Suppressive Therapy in Persons Infected with HIV
In the doses recommended for treatment of genital herpes, acyclovir, valacyclovir, and famciclovir are safe for use in immunocompromised patients. For severe cases, initiating therapy with acyclovir 5--10 mg/kg body weight IV every 8 hours may be necessary.
If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected and a viral isolate obtained for sensitivity testing. Such patients should be managed in consultation with a specialist, and alternate therapy should be administered. All acyclovir-resistant strains are resistant to valacyclovir and most are resistant to famciclovir. Foscarnet, 40 mg/kg body weight IV every 8 hours until clinical resolution is attained, is often 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
Most 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 remains high. 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 cunnilingus during the third trimester with partners known or suspected to have orolabial herpes. Some specialists believe type-specific serologic tests are useful to identify pregnant women at risk for HSV infection and to guide counseling with regard to the risk of acquiring genital herpes during pregnancy. Such testing and counseling may be especially important when a woman's sex partner has HSV infection.
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 prodrome, and all women should be examined carefully for herpetic lesions. Women without symptoms or signs of genital herpes or its prodrome can deliver vaginally. Most specialists recommend that women with recurrent genital herpetic lesions at the onset of labor deliver by cesarean section to prevent neonatal herpes. However, abdominal delivery does not completely eliminate the risk for HSV transmission to the infant. The results of viral cultures during pregnancy in women with or without visible herpetic lesions do not predict viral shedding at the time of delivery, and therefore routine viral cultures of pregnant women with recurrent genital herpes are not recommended.
The safety of systemic acyclovir, valacyclovir, and famciclovir therapy in pregnant women has not been 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 (43). These findings provide some assurance to women who have had prenatal exposure to acyclovir. However, available data are insufficient to reach definitive conclusions regarding the risks to the newborn associated with acyclovir treatment during pregnancy. 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. Preliminary data suggest that acyclovir treatment late in pregnancy might reduce the frequency of cesarean sections among women who have recurrent genital herpes by diminishing the frequency of recurrences at term (44,45), and some specialists recommend such treatment. The risk for herpes is high in infants of women who acquire genital HSV in late pregnancy; such women should be managed in consultation with an HSV 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.
Infants exposed to HSV during birth, as documented by virologic testing or presumed by observation of 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. 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 evidence of 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 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 Calymmatobacterium granulomatis. The disease occurs rarely in the United States, although it is endemic in certain tropical and developing areas, including India; Papua, New Guinea; central Australia; and southern Africa. Clinically, the disease commonly presents as painless, progressive ulcerative lesions without regional lymphadenopathy. The lesions are highly vascular ("beefy red appearance") and bleed easily on contact. However, the clinical presentation can also 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. The lesions may develop secondary bacterial infection or may be coinfected with another sexually transmitted pathogen.
Treatment Granuloma Inguinale (Donovanosis)
Treatment halts progression of lesions, although prolonged therapy may be required to permit granulation and reepithelialization of the ulcers. Relapse can occur 6--18 months after apparently effective therapy. Several antimicrobial regimens have been effective, but few controlled trials have been published.
Therapy should be continued at least 3 weeks or until all lesions have completely healed. Some specialists recommend addition of an aminoglycoside (e.g., gentamicin 1 mg/kg IV every 8 hours) to the above regimens if improvement is not evident within the first few days of therapy.
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.
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 may prove useful for treating granuloma inguinale in pregnancy, but published data are lacking. Doxycycline and ciprofloxacin are contraindicated in pregnant women.
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 (LGV) is caused by C. trachomatis serovars L1, L2, or L3. The disease occurs rarely in the United States. The most common clinical manifestation of LGV among heterosexuals is tender inguinal and/or femoral lymphadenopathy that is most commonly unilateral. Women and homosexually active men may have proctocolitis or inflammatory involvement of perirectal or perianal lymphatic tissues resulting in fistulas and strictures. A self-limited genital ulcer sometimes occurs at the site of inoculation. However, by the time patients seek care, the ulcer usually has disappeared. The diagnosis of LGV is usually made serologically and by exclusion of other causes of inguinal lymphadenopathy or genital ulcers. Complement fixation titers >1:64 are consistent with the diagnosis of LGV. The diagnostic utility of serologic methods other than complement fixation is unknown.
Treatment cures infection and prevents ongoing tissue damage, although tissue reaction can result in scarring. Buboes may require aspiration through intact skin or incision and drainage to prevent the formation of inguinal/femoral ulcerations. Doxycycline is the preferred treatment.
Some STD specialists believe azithromycin 1.0 g orally once weekly for 3 weeks is likely effective, although clinical data are lacking.
Management of Sex Partners
Persons who have had sexual contact with a patient who has LGV within the 30 days before onset of the patient's symptoms should be examined, tested for urethral or cervical chlamydial infection, and treated.
Pregnant and lactating women should be treated with erythromycin. Azithromycin may 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.
Persons with both LGV and HIV infection should receive the same regimens as those who are HIV-negative. Prolonged therapy may be required, and delay in resolution of symptoms may occur.
Syphilis is a systemic disease caused by T. pallidum. Patients who have syphilis may 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, ophthalmic, auditory abnormalities, and 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 may 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 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 for syphilis: a) nontreponemal tests (e.g., Venereal Disease Research Laboratory [VDRL] and Rapid Plasma Reagin [RPR]) and b) 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 may occur secondary to various medical conditions.
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 to 1:4 or from 1:8 to 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 often 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."
Most 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. Treponemal test antibody titers correlate poorly with disease activity and should not be used to assess treatment response.
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 and clinical syndromes suggestive of early syphilis do not correspond with one another, use of other tests (e.g., biopsy and direct microscopy) should be considered. However, for most HIV-infected patients, serologic tests are accurate and reliable for the diagnosis of syphilis and for following the response to treatment.
No test can be used alone to diagnose neurosyphilis. The VDRL-CSF is highly specific, but it is insensitive. Most 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, abnormalities of cerebrospinal fluid (CSF) cell count or protein, or a reactive VDRL-CSF with or without clinical manifestations. The CSF leukocyte count usually is elevated (>5 WBCs/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 may be nonreactive 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 of Syphilis
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 disease. However, neither combinations of benzathine penicillin and procaine penicillin nor oral penicillin preparations are considered appropriate for the treatment of syphilis.
The efficacy of penicillin for the treatment of syphilis was well established through clinical experience before the value of randomized controlled clinical trials was recognized. Therefore, almost 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 may 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 occurs 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 often among patients who have early syphilis. Antipyretics may be used, but they have not been proven to prevent this reaction. The Jarisch-Herxheimer reaction may induce early labor or cause fetal distress in pregnant women. This concern 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 according to the following recommendations.
For identification of at-risk partners, the time periods before treatment are a) 3 months plus duration of symptoms for primary syphilis, b) 6 months plus duration of symptoms for secondary syphilis, and c) 1 year for early latent syphilis.
Primary and Secondary Syphilis
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
NOTE: Recommendations for treating pregnant women and HIV-infected patients for syphilis are discussed in separate sections.
Recommended Regimen for Children
After the newborn period, 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.
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 who also have symptoms or signs suggesting neurologic disease (e.g., meningitis) or ophthalmic disease (e.g., uveitis) 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.
Treatment failure can occur with any regimen. However, assessing response to treatment often is difficult, and definitive criteria for cure or failure have not been established. Nontreponemal test titers may decline more slowly for patients who previously had syphilis. Patients should be reexamined clinically and serologically 6 months and 12 months following treatment; more frequent evaluation may 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 re-treated 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. A recent clinical trial 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 following treatment.
Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis is 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 have 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 may be the result of unrecognized CNS infection, some specialists recommend CSF examination in such situations.
When patients are re-treated, most 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.
Penicillin Allergy. Data to support the use of alternatives to penicillin in the treatment of early syphilis are limited. However, several therapies might be considered 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. However, some specialists recommend 1 gram daily either IM or IV for 8--10 days. Preliminary data suggest that azithromycin may be effective as a single oral dose of 2 grams. Because the efficacy of these therapies is not well documented, close follow-up of persons receiving these therapies is essential. The use of any of these therapies in HIV-infected persons has not been studied; 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 may 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 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 can be diagnosed as having early latent syphilis if, within the year preceding the evaluation, they had a) a documented seroconversion, b) unequivocal symptoms of primary or secondary syphilis, or c) a sex partner documented to have primary, secondary, or early latent syphilis. Patients who have latent syphilis of unknown duration should be managed as if they have late latent syphilis. 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 underneath the foreskin in uncircumcised men) to evaluate for internal mucosal lesions. All patients who have syphilis should be tested for HIV infection.
Treatment of Latent Syphilis
Treatment of latent syphilis usually does not affect transmission and is intended to prevent occurrence or progression of late complications. Although clinical experience supports the effectiveness of penicillin in achieving these goals, limited evidence is available for guidance in choosing specific regimens.
The following regimens are recommended for nonallergic patients who have normal CSF examinations (if performed).
Recommended Regimens for Adults
Early Latent Syphilis
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 non-allergic children who have acquired syphilis and who have normal CSF examination results.
Recommended Regimens for Children
Early Latent Syphilis
Late Latent Syphilis or Latent Syphilis of Unknown Duration
Other Management Considerations
All patients who have latent syphilis should be evaluated clinically for evidence of tertiary disease (e.g., aortitis, gumma, and iritis). Patients who have syphilis and who demonstrate any of the following criteria should have a prompt CSF examination:
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. The risk 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 the 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 should not be considered 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 a) titers increase fourfold, b) an initially high titer (>1:32) fails to decline at least fourfold (i.e., two dilutions) within 12--24 months of therapy, or c) signs or symptoms attributable to syphilis develop. In rare instances, despite a negative CSF examination and a repeated course of therapy, serologic titers may 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.
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 Treatment of Primary and Secondary Syphilis). 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. The efficacy of these alternative regimens in HIV-infected persons has not been studied, and thus 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 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.
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.
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.
Treatment of Neurosyphilis
CNS disease 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 who should have 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.
If compliance with therapy can be ensured, patients may be treated with the following alternative regimen.
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 are slower, and persistent abnormalities may 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.
Management of Sex Partners. See General Principles, Management of Sex Partners.
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 grams 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
Unusual serologic responses have been observed among HIV-infected persons who have syphilis. Most 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, aberrant serologic responses are uncommon, and most specialists believe that both treponemal and non-treponemal serologic tests for syphilis can be interpreted in the usual manner for most patients who are coinfected with T. pallidum and HIV.
When clinical findings are suggestive of syphilis, but serologic tests are nonreactive or the interpretation is unclear, alternative tests (e.g., biopsy of a lesion, darkfield examination, or direct fluorescent antibody staining of lesion material) may be useful for diagnosis.
Neurosyphilis should be considered in the differential diagnosis of neurologic disease in HIV-infected persons.
Compared with HIV-negative patients, HIV-positive patients who have early syphilis may be at increased risk for neurologic complications and may have higher rates of treatment failure with currently recommended regimens. The magnitude of these risks, although not defined precisely, 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. Careful follow-up after therapy is essential.
Primary and Secondary Syphilis Among HIV-Infected Persons
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 most 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 following treatment in persons with initial abnormalities.
Follow-Up. HIV-infected patients 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 patients who meet the criteria for treatment failure 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 patients whose nontreponemal test titers do not decrease fourfold within 6--12 months of therapy. Most specialists would re-treat patients with benzathine penicillin G administered as three doses of 2.4 million units IM each at weekly intervals, if CSF examinations are normal.
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
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.
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 in 12--24 months the nontreponemal titer does not decline fourfold, the CSF examination should be repeated and treatment administered accordingly.
Penicillin Allergy. 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). The efficacy of alternative non-penicillin regimens in HIV-infected persons has not been studied.
Syphilis During Pregnancy
All women should be screened serologically for syphilis at the first prenatal visit. In populations in which prenatal care is not optimal, RPR-card test screening and treatment (if the RPR-card test is reactive) should be performed at the time a pregnancy is confirmed. 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 weeks' gestation, and at delivery in addition to routine early screening. Some states mandate screening at delivery for all women. Any woman who delivers a stillborn infant after 20 weeks' gestation should be tested for syphilis. No infant should leave the hospital if maternal serologic status has not been determined at least once during pregnancy and preferably again at delivery.
Seropositive pregnant women should be considered infected unless an adequate treatment history is documented in the medical records and sequential serologic antibody titers have declined.
Penicillin is effective for preventing maternal transmission to the fetus and for treating fetal infection. Evidence is insufficient to determine whether the specific, recommended penicillin regimens are optimal.
Other Management Considerations
Some specialists recommend additional therapy in some patients. A second dose of benzathine penicillin 2.4 million units IM may be administered 1 week after the initial dose for women who have primary, secondary, or early latent syphilis. In the second half of pregnancy, management and counseling may be facilitated by a sonographic fetal evaluation for congenital syphilis, but this should not delay therapy. Sonographic signs of fetal syphilis (i.e., hepatomegaly, ascites, and hydrops) 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. Although stillbirth is a rare complication of treatment, concern about this complication should not delay necessary treatment. All patients who have syphilis should be offered testing for HIV infection.
Follow-Up. Coordinated prenatal care, treatment follow-up, and syphilis case management are important in the management of pregnant women with syphilis. Serologic titers should be repeated in the third trimester and at delivery. Serologic titers may 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. Most women will deliver before their serologic response to treatment can be assessed definitively.
Management of Sex Partners. See General Principles, Management of Sex Partners.
Penicillin Allergy. No alternatives to penicillin have been proved effective for treatment of syphilis during pregnancy. Pregnant women who have a history of penicillin allergy should be desensitized and treated with penicillin. Skin testing may be helpful (see Management of Patients Who Have a History of Penicillin Allergy).
Tetracycline and doxycycline should 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.
HIV Infection. 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. Serologic testing and a sexual history also should be obtained at 28 weeks of gestation and at delivery in communities and populations in which the risk for congenital syphilis is high. 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 over testing infant serum, because the serologic tests performed on infant serum can be nonreactive if the mother's serologic test result is of low titer or if the mother was infected late in pregnancy. No infant or mother should leave the hospital unless the maternal serologic status has been documented at least once during pregnancy and preferably again at delivery.
Evaluation and Treatment of Infants in the First Month of Life
The diagnosis of congenital syphilis is complicated by the transplacental transfer of maternal nontreponemal and treponemal immunoglobulin G (IgG) antibodies to the fetus. This transfer of antibodies makes the interpretation of reactive serologic tests for syphilis in infants difficult. Treatment decisions often must be made on the basis of a) identification of syphilis in the mother; b) adequacy of maternal treatment; c) presence of clinical, laboratory, or radiographic evidence of syphilis in the infant; and d) comparison of maternal (at delivery) and infant nontreponemal serologic titers utilizing 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. Currently, no commercially available 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 using specific fluorescent antitreponemal antibody staining is suggested. Darkfield microscopic examination or direct fluorescent antibody 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
If more than 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 quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the
A complete evaluation is not necessary if 10 days of parenteral therapy is administered. However, such evaluation may be useful; a lumbar puncture may 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.¶
NOTE: 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
No evaluation is required.
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
No evaluation is required.
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., at >1 month of age) should have maternal serology and records reviewed to assess whether the child has congenital or acquired syphilis (for acquired syphilis, see Primary and Secondary Syphilis and Latent Syphilis). Any child at risk for congenital syphilis should receive a full evaluation and testing for HIV infection.
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 following the 10-day course of IV aqueous penicillin.
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 3 months of age and should be nonreactive by 6 months of age 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 may be slower for infants treated after the neonatal period. If these titers are stable or increase after 6--12 months of age, 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.
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.
Data are insufficient regarding 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.
Management of Patients Who Have a History of Penicillin Allergy
No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women. Penicillin is also recommended for use, whenever possible, in HIV-infected patients. Of the adult U.S. population, 3%--10% have experienced urticaria, angioedema, or anaphylaxis (i.e., upper airway obstruction, bronchospasm, or hypotension) after penicillin therapy. 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 after an allergic reaction to penicillin, most persons who have had a severe reaction stop expressing penicillin-specific immunoglobulin E (IgE). These persons can be treated safely with penicillin. The results of many investigations indicate that skin testing with the major and minor determinants 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 are 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).
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 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.
Penicillin Allergy Skin Testing
Patients at high risk for anaphylaxis, including those who a) have a history of penicillin-related anaphylaxis, asthma, or other diseases that would make anaphylaxis more dangerous and b) 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).
Dilute the antigens either a) 100-fold for preliminary testing if the patient has had a life-threatening reaction to penicillin or b) 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.
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 using a 26- or 27-gauge needle on a syringe. The crossed 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.
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 done orally or IV. Although the two approaches have not been compared, oral desensitization is regarded as safer to use and easier to perform. Patients should be desensitized in a hospital setting because serious IgE-mediated allergic reactions rarely 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.
Diseases Characterized by Urethritis and Cervicitis
Management of Male Patients Who Have Urethritis
Urethritis is caused by an infection characterized by urethral discharge of mucopurulent or purulent material and sometimes by dysuria or urethral pruritis. Asymptomatic infections are common. The principal bacterial pathogens of proven clinical importance in men who have urethritis are N. gonorrhoeae and C. trachomatis. Testing to determine the specific etiology is recommended because both chlamydia and gonorrhea are conditions that are reportable to state health departments, and a specific diagnosis may enhance partner notification and improve compliance with treatment, especially in the exposed partner. If diagnostic tools (e.g., a Gram stain and microscope) are unavailable, patients should be treated for both infections. The additional antibiotic exposure and expense of treating a person who has nongonococcal urethritis (NGU) for both infections also should encourage the health-care provider to make a specific diagnosis. Nucleic acid amplification tests enable detection of N. gonorrhoeae and C. trachomatis on all specimens. These tests are more sensitive than traditional culture techniques for C. trachomatis and are the preferred method for the detection of this organism.
NGU is diagnosed if Gram-negative intracellular diplococci cannot be identified on urethral smears. C. trachomatis is a frequent cause (i.e., 15%--55% of cases); however, the prevalence differs by age group, with lower prevalence of this organism 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 and Reiter's syndrome. Documentation of chlamydia infection is important because of the need for partner referral for evaluation and treatment.
The etiology of most cases of nonchlamydial NGU is unknown. Ureaplasma urealyticum and Mycoplasma genitalium have been implicated as causes of NGU in some studies. Specific diagnostic tests for these organisms are not indicated, because the detection of these organisms is often difficult and would not alter therapy.
T. vaginalis and HSV sometimes 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 suggestive of genital herpes) or when NGU is not responsive to therapy.
Clinicians should document that urethritis is present. Urethritis can be documented on the basis of any of the following signs.
If none of these criteria is present, then 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
All patients who have urethritis should be evaluated for the presence of gonococcal and chlamydial infection. 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 may enhance partner notification and improve compliance with treatment, especially in the exposed partner.
Treatment should be initiated as soon as possible after diagnosis. Single-dose regimens have the advantage of improved compliance and of DOT. To improve compliance, the medication should be provided in the clinic or health-care provider's office.
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.
Patients should refer for evaluation and treatment all sex partners within the preceding 60 days. Because a specific diagnosis may 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. Effective regimens have not been identified for treating patients who do not have objective signs of urethritis but who have persistent symptoms after treatment. Patients who have persistent or recurrent urethritis should 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 culture of an intra-urethral swab specimen and a first-void urine specimen for T. vaginalis should be performed. Some cases of recurrent urethritis following doxycycline treatment may be caused by tetracycline-resistant U. urealyticum. Urologic examinations usually do not reveal a specific etiology. If the patient was compliant with the initial regimen and re-exposure can be excluded, the following regimen is recommended.
Gonococcal urethritis, chlamydial urethritis, and nongoncoccal, nonchlamydial urethritis may 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 Mucopurulent Cervicitis (MPC)
MPC is characterized by a purulent or mucopurulent endocervical exudate visible in the endocervical canal or in an endocervical swab specimen. Some specialists also diagnose MPC on the basis of easily induced cervical bleeding. Although some specialists consider an increased number of polymorphonuclear leukocytes on endocervical Gram stain as being useful in the diagnosis of MPC, this criterion has not been standardized, has a low positive-predictive value (PPV), and is not available in some settings. MPC often is asymptomatic, but some women have an abnormal vaginal discharge and vaginal bleeding (e.g., after sexual intercourse). MPC can be caused by C. trachomatis or N. gonorrhoeae; however, in most cases neither organism can be isolated. MPC can persist despite repeated courses of antimicrobial therapy. Because relapse or reinfection with C. trachomatis or N. gonorrhoeae usually does not occur in persons with persistent cases of MPC, other non-microbiologic determinants (e.g., inflammation in the zone of ectopy) might be involved.
Patients who have MPC should be tested for C. trachomatis and for N. gonorrhoeae with the most sensitive and specific test available. However, MPC is not a sensitive predictor of infection with these organisms; most women who have C. trachomatis or N. gonorrhoeae do not have MPC.
The results of sensitive tests for C. trachomatis or N. gonorrhoeae (e.g., culture or nucleic acid amplification tests) should determine the need for treatment, unless the likelihood of infection with either organism is high or the patient is unlikely to return for treatment. Empiric treatment should be considered for a patient who is suspected of having gonorrhea and/or chlamydia if a) the prevalences of these infections are high in the patient population and b) the patient might be difficult to locate for treatment. If relapse and reinfection have been excluded, management options of persistent MPC are undefined. For such persons, additional antimicrobial therapy may be of minimal benefit.
Follow-up should be conducted as recommended for the infections for which a woman is being treated. If symptoms persist, women should be instructed to return for reevaluation and to abstain from sexual intercourse, even if they have completed the prescribed therapy.
Management of Sex Partners
Management of sex partners of women treated for MPC should be appropriate for the identified or suspected STD. Partners should be notified, examined, and treated for the STD identified or suspected in the index patient.
Because a microbiologic test of cure usually is not recommended, 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).
Patients who have MPC and also are infected with HIV should receive the same treatment regimen as those who are HIV-negative.
In the United States, chlamydial genital infection occurs frequently among sexually active adolescents and young adults. Asymptomatic infection is common among both men and women. Sexually active adolescent women should be screened for chlamydial infection at least annually, even if symptoms are not present. Annual screening of all sexually active women aged 20--25 years is also recommended, as is screening of older women with risk factors (e.g., those who have a new sex partner and those with multiple sex partners). An appropriate sexual risk assessment should always be conducted and may indicate more frequent screening for some women.
Several important sequelae can result from C. trachomatis infection in women; the most serious of these include pelvic inflammatory disease (PID), ectopic pregnancy, and infertility. Some women who have apparently uncomplicated cervical infection already have subclinical upper-reproductive--tract infection. A recent investigation of patients in a health maintenance organization demonstrated that screening and treatment of cervical infection can reduce the likelihood of PID.
Treating infected patients prevents transmission to sex partners. In addition, treatment of chlamydia in 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 often 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.
The results of clinical trials indicate that azithromycin and doxycycline are equally efficacious (46,47). These investigations were conducted primarily in populations in which follow-up was encouraged and adherence to a 7-day regimen was good. Azithromycin should always be available to health-care providers to treat patients for whom compliance is in question.
In populations that have erratic health-care-seeking behavior, poor compliance with treatment, or unpredictable follow-up, azithromycin may be more cost-effective because it enables the provision of single-dose DOT. Doxycycline costs less than azithromycin, and it has been used extensively for a longer period. Erythromycin is less efficacious than either azithromycin or doxycycline, and gastrointestinal side effects frequently discourage patients from complying with this regimen. Ofloxacin is similar in efficacy to doxycycline and azithromycin, but it is more expensive to use and offers no advantage with regard to the dosage regimen. Levofloxacin has not been evaluated for treatment of C. trachomatis infection in clinical trials, but because its pharmacology and in vitro microbiologic activity are similar to that of ofloxacin, levofloxacin may be substituted in doses of 500 mg once a day for 7 days. Other quinolones either are not reliably effective against chlamydial infection or have not been adequately evaluated.
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 further transmission of infection, patients 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.
Patients do not need to be retested for chlamydia after completing treatment with doxycycline or azithromycin unless symptoms persist or reinfection is suspected. A test of cure may be considered 3 weeks after completion of treatment with erythromycin. The validity of chlamydial culture testing at <3 weeks after completion of therapy to identify patients who did not respond to therapy has not been established. False-negative results can occur resulting from infections involving small numbers of chlamydial organisms. In addition, nonculture tests conducted at <3 weeks after completion of therapy for patients who were treated successfully could yield false-positive results because of continued excretion of dead organisms.
A high prevalence of C. trachomatis infection is found in women who have had chlamydial infection in the preceding several months. Most post-treatment infections result from reinfection, often occurring because patient's sex partners were not treated or because the patient resumed sex among a network of persons with a high prevalence of infection. Repeat infection confers an elevated risk of PID and other complications when compared with initial infection. Therefore, recently infected women are a high priority for repeat testing for C. trachomatis. For these reasons, clinicians and health-care agencies should consider advising all women with chlamydial infection to be rescreened 3--4 months after treatment. Some specialists believe rescreening is an especially high priority for adolescents. Providers are also strongly encouraged to rescreen all women treated for chlamydial infection whenever they next present for care within the following 12 months, regardless of whether the patient believes that her sex partners were treated.
Rescreening is distinct from early retesting to detect therapeutic failure (test-of-cure). Except in pregnant women, test-of-cure is not recommended for persons treated with the recommended regimens, unless therapeutic compliance is in question.
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.
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.
Pregnancy. Doxycycline and ofloxacin are contraindicated in pregnant women. However, clinical experience and preliminary data suggest that azithromycin is safe and effective (48,49). Repeat testing (preferably by culture) 3 weeks after completion of therapy with the following regimens is recommended for all pregnant women, because these regimens may not be highly efficacious and the frequent side effects of erythromycin might discourage patient compliance with this regimen.
NOTE: Erythromycin estolate is contraindicated during pregnancy because of drug-related hepatotoxicity.
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 validity of using these recommendations in particular settings.
C. trachomatis infection of neonates results from perinatal exposure to the mother's infected cervix. The prevalence of C. trachomatis infection among pregnant women does not vary by race/ethnicity or socioeconomic status. 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 mucous membranes of the eye, oropharynx, urogenital tract, and rectum. C. trachomatis infection in neonates is most often recognized by conjunctivitis that develops 5--12 days after birth. Chlamydia is the most frequent identifiable infectious cause of ophthalmia neonatorum. C. trachomatis also is a common cause of subacute, afebrile pneumonia with onset from 1--3 months of age. Asymptomatic infections also can occur in the oropharynx, genital tract, and rectum of neonates.
A chlamydial etiology should be considered for all infants aged <30 days who have conjunctivitis.
Sensitive and specific methods used to diagnose chlamydial ophthalmia in the neonate include both tissue culture and nonculture tests (e.g., direct fluorescent antibody tests, enzyme immunoassays, and nucleic acid amplification tests). 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 should also be tested for N. gonorrhoeae.
Topical antibiotic therapy alone is inadequate for treatment of chlamydial infection and is unnecessary when systemic treatment is administered.
The efficacy of erythromycin treatment is approximately 80%; a second course of therapy may be required, and follow-up of infants to determine whether treatment was effective is recommended. 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 a) a repetitive staccato cough with tachypnea and b) hyperinflation and bilateral diffuse infiltrates on a chest radiograph. Wheezing is rare, and infants are typically afebrile. Peripheral eosinophilia sometimes occurs in infants who have chlamydial pneumonia. Because clinical presentations differ, initial treatment and diagnostic tests should encompass C. trachomatis for all infants aged 1--3 months who possibly have pneumonia.
Specimens for chlamydial testing should be collected from the nasopharynx. Tissue culture is the definitive standard for chlamydial pneumonia. Nonculture tests (e.g., EIA, direct flourescent antibody [DFA], and nucleic acid amplification [NAATs]) can be used, although nonculture tests of nasopharyngeal specimens produce lower sensitivity and specificity than nonculture tests of ocular 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 include an agent in the antibiotic regimen that is active against C. trachomatis 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).
The effectiveness of erythromycin in treating pneumonia caused by C. trachomatis is approximately 80%; a second course of therapy may 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 chlamydial infection 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 infection develops.
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 may persist for >1 year (see Sexual Assault or Abuse of Children).
Nonculture tests for chlamydia (e.g., non-amplified probes [EIA and 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 Chlamydia pneumoniae; with genital and anal specimens, false-positive results occur because of cross-reaction with fecal flora.
Other Management Considerations
Follow-Up. Follow-up cultures are necessary to ensure that treatment has been effective.
Minor Determinant Precursors
* Adapted from Saxon A, Beall GN, Rohr AS, Adelman DC. Immediate hypersensitivity reactions to beta-lactam antibiotics. Ann Intern Med 1987;107:20415. Reprinted with permission from G.N. Beall and Annals of Internal Medicine.
Aged penicillin is not an adequate source of minor determinants. Penicillin G should be freshly prepared or should come from a fresh-frozen source.
Box 2. Classification of vulvovaginal candidiasis (VVC)
This page last reviewed 5/3/2002
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