Sexually Transmitted Diseases Treatment Guidelines

The term sexually transmitted diseases (STDs) is used to refer to a variety of clinical syndromes caused by pathogens that can be acquired and transmitted through sexual activity. Physicians and other health-care providers play a critical role in preventing and treating STDs. These guidelines for the treatment of STDs are intended to assist with that effort. Although these guidelines emphasize treatment, prevention strategies, and diagnostic recommendations also are discussed.

These recommendations should be regarded as a source of clinical guidance and not prescriptive standards; health-care providers should always consider the clinical circumstances of each person in the context of local disease prevalence. They are applicable to various patient-care settings, including family-planning clinics, private physicians’ offices, managed care organizations, and other primary-care facilities. These guidelines focus on the treatment and counseling of individual patients and do not address other community services and interventions that are essential to STD/human immunodeficiency virus (HIV) prevention efforts.

Abstinence and Reduction of Number of Sex Partners

A reliable way to avoid transmission of STDs is to abstain from oral, vaginal, and anal sex or to be in a long-term, mutually monogamous relationship with an uninfected partner. For persons who are being treated for an STD (or whose partners are undergoing treatment), counseling that encourages abstinence from sexual intercourse until completion of the entire course of medication is crucial. A more comprehensive discussion of abstinence and other sexual practices than can help persons reduce their risk for STDs is available in Contraceptive Technology, 19th Edition (7). For persons embarking on a mutually monogamous relationship, screening for common STDs before initiating sex might reduce the risk for future disease transmission.

Pre-exposure Vaccination

Pre-exposure vaccination is one of the most effective methods for preventing the transmission of some STDs. Two human papillomaviruses (HPV) vaccines are available for females aged 9–26 years to prevent cervical precancer and cancer (15,16): the quadrivalent HPV vaccine (Gardasil) and the bivalent HPV vaccine (Cervarix). Gardasil also prevents genital warts. Routine vaccination of females aged 11 or 12 years is recommended with either vaccine, as is catch-up vaccination for females aged 13–26 years. Gardasil can be administered to males aged 9–26 years to prevent genital warts (17). Details regarding HPV vaccination are available at www.cdc.gov/std/hpv.

Hepatitis B vaccination is recommended for all unvaccinated, uninfected persons being evaluated for an STD (3,4). In addition, hepatitis A and B vaccines are recommended for men who have sex with men (MSM) and injection-drug users (IDUs) (2—4); each of these vaccines should also be administered to HIV-infected persons who have not yet been infected with one or both types of hepatitis virus. Details regarding hepatitis A and B vaccination are available at http://www.cdc.gov/hepatitis.

Male Condoms

When used consistently and correctly, male latex condoms are highly effective in preventing the sexual transmission of HIV infection. In heterosexual serodiscordant relationships (i.e., those involving one infected and one uninfected partner) in which condoms were consistently used, HIV-negative partners were 80% less likely to become HIV-infected compared with persons in similar relationships in which condoms were not used (18).

Moreover, studies show condoms can reduce the risk for other STDs, including chlamydia, gonorrhea, and trichomoniasis; by limiting lower genital tract infections, condoms also might reduce the risk for women developing pelvic inflammatory disease (PID) (19,20). In addition, consistent and correct use of latex condoms also reduces the risk for genital herpes, syphilis, and chancroid when the infected area or site of potential exposure is covered, although data for this effect are more limited (21–24). Additional information is available at www.cdc.gov/condomeffectiveness/latex.htm.

Cohort studies have demonstrated that condoms protect against the acquisition of genital HPV infection. A prospective study among newly sexually active women who were attending college demonstrated that consistent and correct condom use was associated with a 70% reduction in risk for HPV transmission (25). Use of condoms also appears to reduce the risk for HPV-associated diseases (e.g., genital warts and cervical cancer) and mitigate the adverse consequences of infection with HPV. Condom use has been associated with higher rates of regression of cervical intraepithelial neoplasia (CIN) and clearance of HPV infection in women (26) and with regression of HPV-associated penile lesions in men (27).

Condoms are regulated as medical devices and are subject to random sampling and testing by the U.S. Food and Drug Administration (FDA). Each latex condom manufactured in the United States is tested electronically for holes before packaging. Rates of condom breakage during sexual intercourse and withdrawal are approximately two broken condoms per 100 condoms used in the United States. The failure of condoms to protect against STD transmission or unintended pregnancy usually results from inconsistent or incorrect use rather than condom breakage (28).

Male condoms made of materials other than latex are available in the United States. Two general categories of nonlatex condoms exist. The first type is made of polyurethane or other synthetic material and provides protection against STDs/HIV and pregnancy equal to that of latex condoms (29). These can be substituted for latex condoms by persons with latex allergy. Although they have had higher breakage and slippage rates when compared with latex condoms and are usually more costly, the pregnancy rates among women whose partners use these condoms are similar to those asociated with use of latex condoms (30).

The second type is natural membrane condoms (frequently called “natural” condoms or, incorrectly, “lambskin” condoms). These condoms are usually made from lamb cecum and can have pores up to 1,500 nm in diameter. Although these pores do not allow the passage of sperm, they are more than 10 times the diameter of HIV and more than 25 times that of HBV (29). Moreover, laboratory studies demonstrate that viral STD transmission can occur with natural membrane condoms (29). Use of natural membrane condoms for prevention of STDs is not recommended.

Providers should advise their patients that condoms must be used consistently and correctly to be effective in preventing STDs; providing instructions about the correct use of condoms can be useful. Communicating the following recommendations can help ensure that patients use male condoms correctly:

• Use a new condom with each sex act (i.e., oral, vaginal, and anal).
• Carefully handle the condom to avoid damaging it with fingernails, teeth, or other sharp objects.
• Put the condom on after the penis is erect and before any genital, oral, or anal contact with the partner.
• Use only water-based 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 and should not be used.
• Ensure adequate lubrication during vaginal and anal sex, which might require the use of exogenous water-based lubricants.
• To prevent the condom from slipping off, hold the condom firmly against the base of the penis during withdrawal, and withdraw while the penis is still erect.

Female Condoms

Laboratory studies indicate that the female condom (Reality) is an effective mechanical barrier to viruses, including HIV, and to semen. The first female condom approved for use in the United States consisted of a lubricated polyurethane sheath with a ring on each end that is inserted into the vagina. A newer version made from nitrile is now available in the United States.

A limited number of clinical studies have evaluated the efficacy of female condoms in providing protection from STDs, including HIV (31,32). Although female condoms are costly compared with male condoms, sex partners should consider using a female condom when a male condom cannot be used properly. The female condom also has been used for STDs/HIV protection during receptive anal intercourse (33); although it might provide some protection in this setting, its efficacy remains unknown.

Cervical Diaphragms

In observational studies, diaphragm use has been demonstrated to protect against cervical gonorrhea, chlamydia, and trichomoniasis (34). A recent trial examined the effect of use of a diaphragm plus polycarbophil (Replens) lubricant on HIV acquisition in women in Africa relative to male condom use alone. The study revealed that neither the diaphragm nor the lubricant gel provided additional protective effects when compared with the use of condoms alone (35). Likewise, no difference by study arm in the rate of acquisition of chlamydia or gonorrhea occurred; however, data from participants who reported following the protocol for the use of these products suggested that consistent use of the diaphragm plus gel might reduce acquisition of gonorrhea (36). Diaphragms should not be relied on as the sole source of protection against HIV infection. Diaphragm and nonoxynol-9 (N-9) spermicide use has been associated with an increased risk for bacterial urinary tract infections in women (37).

Topical Microbicides and Spermicides

Studies examining nonspecific topical microbicides for the prevention of HIV and STD have demonstrated that these products are ineffective (38,39). Studies of spermicides containing N-9 have demonstrated that they should not be recommended for STDs/HIV prevention (40), and more recent randomized controlled trials have failed to show a protective effect against HIV acquisition for BufferGel (a vaginal buffering agent), Carraguard (a carrageenan derivative) (41), cellulose sulfate (an HIV entry inhibitor), (42) and SAVVY (1.0% C31G, a surfactant) (43,44).

Initial results from a study in which participants used 0.5% PRO2000 vaginal gel (a synthetic polyanion polymer that blocks cellular entry of HIV) on a daily basis appeared promising, reducing the rate of HIV acquisition by 30% relative to no gel (45). However, a recent randomized trial of approximately 9,000 women failed to show any protective effect (46).

Topical antiretroviral agents for the prevention of HIV appear more promising. Use of tenofovir gel during sexual intercourse significantly reduced the rate of HIV acquisition (i.e., by 39%) in a study of South African women (47). Additional studies are being undertaken to elucidate the optimal dosing regimens for this drug.

Other products remain under study, including VivaGel, a topical vaginal microbicide. A list of products under development is maintained by the Alliance for Microbicide Development at www.microbicide.org.

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 (www.cdc.gov/condomeffectiveness/latex.htm). Furthermore, frequent use of spermicides containing N-9 has been associated with disruption of the genital epithelium, which might be associated with an increased risk for HIV transmission (40). Therefore, use of condoms lubricated with N-9 is not recommended for STD/HIV prevention; in addition, 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 (37).

Rectal Use of N-9 Spermicides

N-9 can damage the cells lining the rectum, which might provide a portal of entry for HIV and other sexually transmissible agents. Therefore, it should not be used as a microbicide or lubricant during anal intercourse by MSM or by women.

No barrier Contraception, Surgical Sterilization, and Hysterectomy

Contraceptive methods that are not mechanical barriers offer no protection against HIV or other STDs. Sexually active women who use hormonal contraception (i.e., 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 because these women might incorrectly perceive that they are not at risk for these diseases. Women who take oral contraceptives and are prescribed certain antibiotics should be counseled about potential interactions (7).

Male Circumcision

Although male circumcision should not be substituted for other HIV risk-reduction strategies, it has been shown to reduce the risk for HIV and some STDs in heterosexual men. Three randomized, controlled trials performed in regions of sub-Saharan Africa where generalized HIV epidemics involving predominantly heterosexual transmission were occurring demonstrated that male circumcision reduced the risk for HIV acquisition among men by 50%–60% (48–50). In these trials, circumcision was also protective against other STDs, including high-risk genital HPV infection and genital herpes (51–54). Despite these data, male circumcision has not been demonstrated to reduce the risk for HIV or other STDs among MSM (55). The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have recommended that male circumcision be scaled up as an effective intervention for the prevention of heterosexually acquired HIV infection (56). These organizations also recommend that countries with hyperendemic and generalized HIV epidemics and low prevalence of male circumcision expand access to safe male circumcision services within the context of ensuring universal access to comprehensive HIV prevention, treatment, care, and support. Similar recommendations have not been made in the United States, although evidence regarding the role of male circumcision in the prevention of HIV/AIDS is under review (57).

Emergency Contraception (EC)

Women who might have been exposed to STDs during a recent act of unprotected intercourse also are at risk for pregnancy. Providers managing such women should offer to counsel about the option of EC if pregnancy is not desired. In the United States, EC products are available over-the-counter to women aged ≥17 years and by prescription to younger women. If these EC pill products are not readily accessible, many commonly available brands of oral contraceptive pills can effectively provide EC, but women must be instructed to take an appropriate and specified number of tablets at one time. All oral EC regimens are efficacious when initiated as soon as possible after unprotected sex, but have some efficacy as long as 5 days later. EC is ineffective (but is also not harmful) if the woman is already pregnant (58). More information about EC is available in the 19th edition of Contraceptive Technology (7) or http://ec.princeton.edu/emergency-contraception.html.

Insertion of an IUD up to 7 days after unprotected sex can reduce pregnancy risk by more than 99% (7). However, this method is not advisable for a woman who may have untreated cervical gonorrhea or chlamydia, who is already pregnant, or who has other contraindications to IUD use.

Postexposure Prophylaxis (PEP) for HIV and STD

Guidelines for the use of PEP aimed at preventing HIV infection as a result of sexual exposure are available and are discussed in this report (see Sexual Assault and STDs). Genital hygiene methods (e.g., vaginal washing and douching) after sexual exposure are ineffective in protecting against HIV and STD and might increase the risk for bacterial vaginosis, some STDs, and HIV (59).

Pre-exposure Prophylaxis (PrEP) for HIV and STD

Antiretroviral therapy (ART) has the potential to impact transmission and acquisition of HIV. In HIV-infected persons, ART reduces viral load and presumably reduces infectiousness (60). In HIV-uninfected persons, ART might reduce susceptibility to infection, a concept supported both by animal studies and by a study of safety and acceptability involving West African women (61,62). A randomized, placebo-controlled trial involving South African women recently demonstrated that use of tenofovir gel associated with sexual intercourse significantly reduced the rate of HIV and herpes simplex virus type 2 (HSV-2) acquisition by 39% and 51%, respectively (47,63).

Several large randomized controlled trials of PrEP are either underway or planned. These involve the oral use of non-nucleoside reverse transcriptase inhibitors (tenofovir or tenofovir-emtricitabine) or vaginal use of 1% tenofovir gel.

Retesting to Detect Repeat Infections

Retesting several months after a diagnosis of chlamydia or gonorrhea can detect repeat infection and potentially can be used to enhance population-based prevention (64). Further details on retesting can be found in the specific sections on chlamydia and gonorrhea within this report.

Partner Management

Partner management refers to a continuum of activities designed to increase the number of infected persons brought to treatment and disrupt transmission networks. Part of this continuum is partner notification — the process by which providers or public health authorities learn about the sex- and needle-sharing partners of infected patients and help to arrange for partner evaluation and treatment. Clinical-care providers can obtain this information and help to arrange for evaluation and treatment of sex partners directly or by cooperating with state and local health departments. The types and comprehensiveness of existing partner services and the specific STDs for which they are offered vary by provider, public health agency, and geographic area. Ideally, persons referred to such services should also receive health counseling and should be referred for other health services as appropriate.

Data are limited regarding whether partner notification effectively decreases exposure to STDs and whether it reduces the incidence and prevalence of these infections in a community. Nevertheless, evaluations of partner notification interventions have documented the important contribution this approach can make to case-finding in clinical and community contexts (65). When partners are treated, index patients have reduced risk for reinfection. Therefore, providers should encourage persons with STDs to notify their sex partners and urge them to seek medical evaluation and treatment. Further, providers can ask patients to bring partners with them when returning for treatment. Time spent with index patients to counsel them on the importance of notifying partners is associated with improved notification outcomes (66).

When patients diagnosed with chlamydia or gonorrhea indicate that their partners are unlikely to seek evaluation and treatment, providers can offer patient-delivered partner therapy (PDPT), a form of expedited partner therapy (EPT) in which partners of infected persons are treated without previous medical evaluation or prevention counseling. Because EPT might be prohibited in some states and is the topic of ongoing legislation in others (67), providers should visit www.cdc.gov/std/ept to obtain updated information for their individual jurisdiction. Any medication or prescription provided for PDPT should be accompanied by treatment instructions, appropriate warnings about taking medications (if the partner is pregnant or has an allergy to the medication), general health counseling, and a statement advising that partners seek personal medical evaluation, particularly women with symptoms of STDs or PID.

The evidence supporting PDPT is based on three clinical trials that included heterosexual men and women with chlamydia or gonorrhea. The trials and meta-analyses revealed that the magnitude of reduction in reinfection of index case-patients compared with patient referral differed according to the STD and the sex of the index case-patient (68–71). However, across trials, reductions in chlamydia prevalence at follow-up were approximately 20%; reductions in gonorrhea at follow-up were approximately 50%. Rates of notification increased in some trials and were equivalent to patient referral without PDPT in others. Existing data suggest that PDPT also might have a role in partner management for trichomoniasis; however, no single partner management intervention has been shown to be more effective than any other in reducing reinfection rates (72,73). No data support the use of PDPT in the routine management of patients with syphilis. No studies have been published involving PDPT for gonorrhea or chlamydia among MSM.

Public health program involvement with partner notification services varies by locale and by STD. Some programs have considered partner notification in a broader context, developing interventions to address sexual and social networks in which persons are exposed to STDs. Prospective evaluations incorporating the assessment of venues, community structure, and social and sexual contacts in conjunction with partner notification efforts have improved case-finding and illustrated transmission networks (74,75). While such efforts are beyond the scope of individual clinicians, support of and collaboration with STD programs by clinicians are critical to the success of social network-based interventions.

Certain evidence supports the use of the internet to facilitate partner notification (76), especially among MSM and in cases where no other identifying information is available, and many health departments now conduct formal internet partner notification (IPN) (http://www.ncsddc.org/upload/wysiwyg/documents/NGuidelinesforInternet.htm). Clinical providers are unlikely to participate directly in IPN. However, when discussing partner notification approaches with patients, they should be aware of the value of the internet in this type of communication and should know where to refer patients who are interested in using the internet to notify partners about their diagnosis.

Reporting and Confidentiality

The accurate and timely reporting of STDs is integral to efforts to assess morbidity trends, allocate limited resources, and assist local health authorities in partner notification and treatment. STD/HIV and acquired immunodeficiency syndrome (AIDS) cases should be reported in accordance with state and local statutory requirements. Syphilis, gonorrhea, chlamydia, chancroid, HIV infection, and AIDS are reportable diseases in every state. Because the requirements for reporting other STDs differ by state, clinicians should be familiar with the reporting requirements applicable within their jurisdictions.

Reporting can be provider- or laboratory-based. Clinicians who are unsure of state and local reporting requirements should seek advice from state or local health departments or STD programs. STDs and HIV reports are kept strictly confidential. In most jurisdictions, such reports are protected by statute from subpoena. Before conducting a follow-up of a positive STD-test result, public health professionals should consult the patient’s health-care provider to verify the diagnosis and to determine the treatments being received.

Special Populations

Pregnant Women

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

Recommended Screening Tests

• All pregnant women in the United States should be screened for HIV infection as early in pregnancy as possible (77). Screening should be conducted after the woman is notified that she will be screened for HIV as part of the routine panel of prenatal tests, unless she declines (i.e., opt-out screening). For women who decline HIV testing, providers should address their objections, and when appropriate, continue to encourage testing strongly. Women who decline testing because they have had a previous negative HIV test should be informed of the importance of retesting during each pregnancy. Testing pregnant women and treating those who are infected are vital not only to maintain the health of the patient, but to reduce perinatal transmission of HIV through available antiretroviral and obstetrical interventions. Retesting in the third trimester (preferably before 36 weeks’ gestation) is recommended for women at high risk for acquiring HIV infection (e.g., women who use illicit drugs, have STDs during pregnancy, have multiple sex partners during pregnancy, live in areas with high HIV prevalence, or have HIV-infected partners). Rapid HIV screening should be performed on any woman in labor who has an undocumented HIV status unless she declines. If a rapid HIV test result is positive in these women, antiretroviral prophylaxis should be administered without waiting for the results of the confirmatory test (78).

• A serologic test for syphilis should be performed on all pregnant women at the first prenatal visit (79). In populations in which the amount of prenatal care delivered is not optimal, rapid plasma reagin (RPR) card test screening (and treatment, if that test is reactive) should be performed at the time that a pregnancy is confirmed. Women who are at high risk for syphilis, live in areas of high syphilis morbidity, or are previously untested should be screened again early in the third trimester (at approximately 28 weeks’ gestation) and at delivery. Some states require all women to be screened at delivery. Infants should not be discharged from the hospital unless the syphilis serologic status of the mother has been determined at least one time during pregnancy and preferably again at delivery. Any woman who delivers a stillborn infant should be tested for syphilis.

• All pregnant women should be routinely tested for hepatitis B surface antigen (HBsAg) during an early prenatal visit (i.e., a visit during the first trimester), even if they have been previously vaccinated or tested (80). Women who were not screened prenatally, those who engage in behaviors that put them at high risk for infection (e.g., having had more than one sex partner in the previous 6 months, evaluation or treatment for an STD, recent or current injection-drug use, and an HBsAg-positive sex partner) and those with clinical hepatitis should be retested at the time of admission to the hospital for delivery. Pregnant women at risk for HBV infection also should be vaccinated. To avoid misinterpreting a transient positive HBsAg result during the 21 days after vaccination, HBsAg testing should be performed before vaccine administration. All laboratories that conduct HBsAg tests should use an FDA-cleared HBsAg test and perform testing according to the manufacturer’s labeling, including testing of initially reactive specimens with a licensed neutralizing confirmatory test. When pregnant women are tested for HBsAg at the time of admission for delivery, shortened testing protocols can be used, and initially reactive results should prompt expedited administration of immunoprophylaxis to infants (80).

• All pregnant women should be routinely screened for Chlamydia trachomatis (see Chlamydia Infections, Diagnostic Considerations) during the first prenatal visit (81). Women aged ≤25 years and those at increased risk for chlamydia (e.g., women who have a new or more than one sex partner) also should be retested during the third trimester to prevent maternal postnatal complications and chlamydial infection in the infant. Women found to have chlamydial infection during the first trimester should be retested within approximately 3–6 months, preferably in the third trimester. Screening during the first trimester might prevent the adverse effects of chlamydia during pregnancy, but supportive evidence for such screening is lacking.

• All pregnant women at risk for gonorrhea or living in an area in which the prevalence of Neisseria gonorrhoeae is high should be screened at the first prenatal visit for N. gonorrhoeae (82). Women aged <25 years are at highest risk for gonorrhea infection. Other risk factors for gonorrhea include a previous gonorrhea infection, other STDs, new or multiple sex partners, inconsistent condom use, commercial sex work, and drug use. Pregnant women found to have gonococcal infection during the first trimester should be retested within approximately 3–6 months, preferably in the third trimester. Uninfected pregnant women who remain at high risk for gonococcal infection also should be retested during the third trimester.

• All pregnant women at high risk for hepatitis C infection should be screened for hepatitis C antibodies (see Hepatitis C, Diagnostic Considerations) at the first prenatal visit. Women at high risk include those with a history of injection-drug use and those with a history of blood transfusion or organ transplantion before 1992.

• Pregnant women should undergo a Papanicolau (Pap) test at the same frequency as nonpregnant women, although recommendations for their management differ (83,84).

Other Tests

• Evidence does not support routine testing for bacterial vaginosis (BV) in pregnancy. For asymptomatic pregnant women at high risk for preterm delivery, evidence is insufficient to assess the balance of benefits and harms of screening for BV (85). Symptomatic women should be evaluated and treated (see Bacterial Vaginosis).

• Evidence does not support routine screening for Trichomonas vaginalis in asymptomatic pregnant women. Women who report symptoms should be evaluated and treated appropriately (see Trichomonas).

• Evidence does not support routine HSV-2 serologic screening among previously undiagnosed women during pregnancy.

Other Concerns

• Pregnant women who are HBsAg positive should be reported to the local or state health department to ensure that they are entered into a case-management system and that timely and appropriate prophylaxis is provided for their infants. Information concerning the pregnant woman’s HBsAg status should be provided to the hospital in which delivery is planned and to the health-care provider who will care for the newborn. In addition, household and sex contacts of women who are HBsAg positive should be vaccinated.

• Women who are HBsAg positive should be provided with, or referred for, appropriate counseling and medical management. Pregnant women who are HBsAg positive should receive information regarding hepatitis B that addresses:
  — modes of transmission;
  — perinatal concerns (e.g., breastfeeding is not contraindicated);
  — prevention of HBV transmission, including the importance of postexposure prophylaxis for the newborn infant and hepatitis B vaccination for household contacts and sex partners; and
  — evaluation for and treatment of chronic HBV infection.

• No treatment is available for pregnant women infected with hepatitis C virus (HCV). However, all women with HCV infection should receive appropriate counseling and supportive care as needed (see Hepatitis C, Prevention). No vaccine is available to prevent HCV transmission.

• In the absence of lesions during the third trimester, routine serial cultures for herpes simplex virus (HSV) are not indicated for women who have a history of recurrent genital herpes. Prophylactic cesarean delivery 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 delivery.

For a more detailed discussion of STD testing and treatment among pregnant women, refer to the following references: Prenatal screening for HIV: A Review of the evidence for the U.S. Preventive Services Task Force (86); Revised Recommendations for HIV Testing of Adults, Adolescents, and Pregnant Women in Health-Care Setting (77); Guidelines for Perinatal Care (87); Rapid HIV Antibody Testing During Labor and Delivery for Women of Unknown HIV Status: A Practical Guide and Model Protocol (88); Viral Hepatitis in Pregnancy (89); Hepatitis B Virus: A Comprehensive Strategy for Eliminating Transmission in the United States — Recommendations of the Immunization Practices Advisory Committee (ACIP) (4); Screening for Chlamydial Infection: U.S. Preventive Services Task Force Recommendation Statement (81); Canadian guidelines on sexually transmitted infections (90); USPSTF recommendations for STI screening (91); and Screening for Bacterial Vaginosis in Pregnancy to Prevent Preterm Delivery: U.S. Preventive Services Task Force Recommendation Statement (85).

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 generally broader (i.e., if followed, more women will be screened for more STDs than would by following other screening recommendations) and are also consistent with other CDC guidelines.

Adolescents

In the United States, prevalence rates of many sexually acquired infections are highest among adolescents (92,93). For example, the reported rates of chlamydia and gonorrhea are highest among females aged 15–19 years, and many persons acquire HPV infection during their adolescent years.

Persons who initiate sex early in adolescence are at higher risk for STDs, along with persons residing in detention facilities, attending STD clinics, young men having sex with men (YMSM), and youth who use injection drugs. Factors contributing to this increased risk during adolescence include having multiple sexual partners concurrently, having sequential sexual partnerships of limited duration, failing to use barrier protection consistently and correctly, having increased biologic susceptibility to infection, and experiencing multiple obstacles to accessing health care (92).

All 50 states and the District of Columbia explicitly allow minors to consent for their own health services for STDs. No state requires parental consent for STD care or requires that providers notify parents that an adolescent minor has received STD services, except in limited or unusual circumstances.

Protecting confidentiality for such care, particularly for adolescents enrolled in private health insurance plans, presents multiple problems. After a claim has been reported, many states mandate that health plans provide a written statement to a beneficiary indicating the benefits and charges covered or not covered by the health plan (i.e., explanation of benefit [EOB]). In addition, federal laws obligate notices to beneficiaries when claims are denied, including alerting consumers who need to pay for care until the allowable deductable is reached. For STD detection- and treatment-related care, an EOB or medical bill that is received by a parent might disclose services provided and list any laboratory tests performed. This type of mandated notification breeches confidentiality, and at a minimum, could prompt parents and guardians to question the costs and reasons for service provision.

Despite the high rates of infections documented in the adolescent population, providers frequently fail to inquire about sexual behaviors, assess STD risks, provide risk reduction counseling, and ultimately, fail to screen for asymptomatic infections during clinical encounters. Sexual health discussions should be appropriate for the patient’s developmental level and should be aimed at identifying risk behaviors (e.g., unprotected oral, anal, or vaginal sex and drug-use behaviors). Careful, nonjudgmental, and thorough counseling is particularly vital for adolescents who might not feel comfortable acknowledging their engagement in behaviors that place them at high risk for STDs.

Screening Recommendations

Routine laboratory screening for common STDs is indicated for sexually active adolescents. The following screening recommendations summarize published federal agency and medical professional organizations’ clinical guidelines for sexually active adolescents:

• Routine screening for C. trachomatis of all sexually active females aged ≤25 years is recommended annually (81).Evidence is insufficient to recommend routine screening for C. trachomatis in sexually active young men based on feasibility, efficacy, and cost-effectiveness. However, screening of sexually active young men should be considered in clinical settings associated with high prevalence of chlamydia (e.g., adolescent clinics, correctional facilities, and STD clinics) (81,94).

• Routine screening for N. gonorrhoeae in all sexually active women at risk for infection is recommended annually (82). Women aged <25 years are at highest risk for gonorrhea infection. Other risk factors that place women at increased risk include a previous gonorrhea infection, the presence of other STDs, new or multiple sex partners, inconsistent condom use, commercial sex work, and drug use.

• HIV screening should be discussed with all adolescents and encouraged for those who are sexually active and those who use injection drugs (77,95).

• The routine screening of adolescents who are asymptomatic for certain STDs (e.g., syphilis, trichomoniasis, BV, HSV, HPV, HAV, and HBV) is not recommended. However, YMSM and pregnant adolescent females might require more thorough evaluation.

• Guidelines from USPSTF and ACOG recommend that cervical cancer screening begin at age 21 years (96,97), a recommendation based on the low incidence of cervical cancer and limited utility of screening for younger adolescents (98). However, the American Cancer Society (ACS) recommends that women start cervical screening with Pap tests 3 years after initiating sexual activity, but by no later than age 21 years (99).

Primary Prevention Recommendations

Primary prevention and anticipatory guidance to recognize symptoms and behaviors associated with STDs are strategies that can be incorporated into any or all types of health-care visits. The following recommendations for primary prevention of STDs (i.e., vaccination and counseling) are based on published federal agency and medical professional organizations’ clinical guidelines for sexually active adolescents:

• The HPV vaccine, either Cervarix or Gardasil, is recommended for 11 and 12 year-old females. The vaccine series can be started at 9 years of age. Catch-up vaccination is recommended for females aged 13–26 years who have not yet received or completed the vaccine series (16). The quadrivalent (Gardasil) HPV vaccine can also be used in males and females aged 9–26 years to prevent genital warts (17).

• The HBV vaccination series is recommended for all adolescents. Adolescents who have not previously received hepatitis B vaccine should be vaccinated routinely at any age with an appropriate dose and schedule (3,4).

• The HAV vaccination series for children and adolescents aged 2–18 years should be offered in areas with existing hepatitis A vaccination programs. In areas without existing hepatitis A vaccination programs, catch-up vaccination of unvaccinated children aged 2–18 years can be considered (2).

• Information regarding HIV infection, testing, transmission, and implications of infection should be regarded as an essential component of the anticipatory guidance provided to all adolescents as part of health care (77).

• Health-care providers who care for children and adolescents should integrate sexuality education into clinical practice. Providers should counsel adolescents about the sexual behaviors that are associated with risk for acquiring STDs and should educate patients using evidence-based prevention strategies, all of which include a discussion about abstinence and other risk-reduction behaviors (e.g., consistent and correct condom use). USPSTF recommends high-intensity behavioral counseling to prevent STIs* for all sexually active adolescents (6).

Children

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

Persons in Correctional Facilities

Multiple studies have demonstrated that persons entering correctional facilities have high rates of STDs (including HIV) and viral hepatitis, especially those aged ≤35 years (93). Incarcerated persons are more likely to have low socioeconomic status, live in urban areas, and be ethnic and racial minorities. Risk behaviors for contracting STDs (e.g., having unprotected sex; having multiple sexual partners; using drugs and alcohol; and engaging in commercial, survival [prostitution to earn money for food, shelter, or drugs], or coerced sex) are common among incarcerated populations. Before incarceration, many have had limited access to medical care, especially to community-based clinical prevention services.

Although no comprehensive national guidelines regarding STD care and management have been developed for correctional populations, the utility of expanded STD services in correctional settings has been reported (100). Capacity to provide STD care also varies by type of correctional facility. For example, local juvenile detention facilities and jails are short-term facilities (often housing entrants for ≤1 year) where up to half of all entrants are released back to the community within 48 hours of arrest, thereby complicating efforts to provide comprehensive STD services. These services are likely more conducive to prisons and state juvenile confinement facilities, which are long-term, secure facilities where entrants are held for a longer period of time.

Most institutions, especially those for adults, do not routinely screen for STDs. Diagnostic testing of inmates with symptoms indicative of an STD is the more common practice in juvenile detention and jail facilities. However, screening for asymptomatic infections facilitates the identification and treatment of persons with otherwise undetected infections, which not only eliminates complications for the individual, but reduces the prevalence of infection among detainees who are released back into the local community.

Females in juvenile detention facilities and young women ≤35 years of age have been reported to have high rates of chlamydia (101) and gonorrhea (93). Syphilis seroprevalence rates, which can indicate previous infection, are considerably higher among adult men and women than in adolescents, consistent with the overall national syphilis trends (102).

Chlamydia and Gonorrhea Screening

Universal screening of adolescent females for chlamydia and gonorrhea should be conducted at intake in juvenile detention or jail facilities. Universal screening of adult females should be conducted at intake among adult females up to 35 years of age (or on the basis of local institutional prevalence data).

Syphilis Screening

Universal screening should be conducted on the basis of the local area and institutional prevalence of early (primary, secondary, and early latent) infectious syphilis.

MSM

Subgroups of MSM are at high risk for HIV infection and other viral and bacterial STDs. The frequency of unsafe sexual practices and the reported rates of bacterial STDs and incident HIV infection declined substantially in MSM from the 1980s through the mid-1990s. However, since that time, increased rates of early syphilis (primary, secondary, or early latent), gonorrhea, and chlamydial infection and higher rates of unsafe sexual behaviors have been documented among MSM in the United States and virtually all industrialized countries (103,104). The effect of these behavioral changes on HIV transmission has not been ascertained, but preliminary data suggest that the incidence of HIV infection is increasing among MSM in some urban centers, particularly among MSM from racial and ethnic minority groups (105) and among those who use nonprescription drugs during sex, particularly methamphetamine and volatile nitrites (also known as “poppers”). These adverse trends likely reflect the 1) changing attitudes concerning HIV infection that have accompanied advances in HIV therapy, resulting in improved quality of life and survival for HIV-infected persons; 2) changing patterns of substance abuse; 3) demographic shifts in MSM populations; and 4) changes in sex partner networks resulting from new venues for partner acquisition (e.g., the internet). Increases in bacterial STDs are not necessarily accompanied by increases in HIV incidence; for example, oral sex may permit efficient spread of bacterial STDs but not HIV, as does serosorting (preferential selection of sex partners of the same serostatus) among HIV-infected MSM (106,107).

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

Routine laboratory screening for common STDs is indicated for all sexually active MSM. The following screening tests should be performed at least annually for sexually active MSM:

• HIV serology, if HIV negative or not tested within the previous year;

• syphilis serology, with a confirmatory testing to establish whether persons with reactive serologies have incident untreated syphilis, have partially treated syphilis, or are manifesting a slow serologic response to appropriate prior therapy;

• a test for urethral infection with N. gonorrhoeae and C. trachomatis in men who have had insertive intercourse† during the preceding year; testing of the urine using nucleic acid amplification testing (NAAT) is the preferred approach;

• a test for rectal infection§ with N. gonorrhoeae and C. trachomatis in men who have had receptive anal intercourse* during the preceding year (NAAT of a rectal swab is the preferred approach); and

• a test for pharyngeal infection§ with N. gonorrhoeae in men who have had receptive oral intercourse† during the preceding year (NAAT is the preferred approach). Testing for C. trachomatis pharyngeal infection is not recommended.

Evaluation for HSV-2 infection with type-specific serologic tests also can be considered if infection status is unknown; knowledge of HSV-2 serostatus might be helpful in identifying persons with previously undiagnosed genital tract infection. Because of the increased incidence of anal cancer in HIV-infected MSM, screening for anal cytologic abnormalities can be considered; however, evidence is limited concerning the natural history of anal intraepithelial neoplasias, the reliability of screening methods, the safety and response to treatments, and the programmatic support needed for such a screening activity.

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

All MSM should be tested for HBsAg to detect HBV infection. Prompt identification of chronic infection with HBV is essential to ensure necessary care and services to prevent transmission to others (108). HBsAg testing should be made available in STD treatment settings. In addition, screening among past or current drug users should include HCV and HBV testing.

Vaccination against hepatitis A and B is recommended for all MSM in whom previous infection or vaccination cannot be documented (2,3). Preimmunization serologic testing might be considered to reduce the cost of vaccinating MSM who are already immune to these infections, but this testing should not delay vaccination. Vaccinating persons who are immune to HAV or HBV infection because of previous infection or vaccination does not increase the risk for vaccine-related adverse events (see Hepatitis B, Prevaccination Antibody Screening). Sexual transmission of hepatitis C virus infection can occur, especially among HIV-infected MSM. Serologic screening for hepatitis C infection is recommended at initial evaluation of newly diagnosed HIV-infected persons. HIV-infected MSM can also acquire HCV after initial screening; therefore, men with new and unexplained increases in alanine aminotransferase (ALT) should be tested for acute HCV infection. To detect acute HCV infection among HIV-infected MSM with high-risk sexual behaviors or concomitant ulcerative STDs, routine HCV testing of HIV-infected MSM should be considered.

Women Who Have Sex with Women

Women who have sex with women (WSW) are a diverse group with variations in sexual identity, sexual behaviors, sexual practices, and risk behaviors. Recent studies indicate that some WSW, particularly adolescents, young women, and women with both male and female partners, might be at increased risk for STDs and HIV as a result of certain reported risk behaviors (109–112). WSW are at risk for acquiring bacterial, viral, and protozoal infections from current and prior partners, both male and female. WSW should not be presumed to be at low or no risk for STDs based on sexual orientation. Effective screening requires that providers and their female clients engage in a comprehensive and open discussion not only about sexual identify, but sexual and behavioral risks.

Few data are available on the risk for STDs transmitted by sex between women, but risk probably varies by the specific STD and sexual practice (e.g., oral-genital sex; vaginal or anal sex using hands, fingers, or penetrative sex items; and oral-anal sex [113,114]). Practices involving digital-vaginal or digital-anal contact, particularly with shared penetrative sex items, present a possible means for transmission of infected cervicovaginal secretions. This possibility is most directly supported by reports of metronidazole-resistant trichomoniasis (115) and genotype-concordant HIV transmitted sexually between women who reported these behaviors (116) and by the high prevalence of BV among monogamous WSW (117).

Transmission of HPV can occur with skin-to-skin or skin-to-mucosa contact, which can occur during sex between women. HPV DNA has been detected through polymerase chain reaction (PCR)-based methods from the cervix, vagina, and vulva in 13%–30% of WSW, and high- and low-grade squamous intraepithelial lesions (SIL) have been detected on Pap tests in WSW who reported no previous sex with men (118). However, most self-identified WSW (53%–99%) report having had sex with men and indicate that they might continue this practice in the future (119). Therefore, routine cervical cancer screening should be offered to all women, regardless of sexual preference or sexual practices, and women should be offered HPV vaccine in accordance with current guidelines.

Limited data demonstrate that HSV-2 genital transmission between female sex partners is probably inefficient but can occur. The relatively frequent practice of orogenital sex among WSW might place them at higher risk for genital infection with herpes simplex virus type 1 (HSV-1), a hypothesis supported by the recognized association between HSV-1 seropositivity and number of female partners among WSW (120).

Although the rate of transmission of C. trachomatis between women remains largely unknown, infection also can be acquired from past or current male partners. Recent data suggest that C. trachomatis infection among WSW might be more common than previously thought (121); transmission of syphilis between female sex partners (likely through oral sex) also has been reported. Therefore, report of same-sex behavior in women should not deter providers from screening these women for STDs, including chlamydia and syphilis, as recommended.

BV is common among women in general and even more so among women with female partners. Sexual behaviors that facilitate the transfer of vaginal fluid and/or bacteria between partners might be involved in the pathogenesis of BV. A recent study demonstrated that female sex partners frequently share identical genital Lactobacillus strains (122). Although BV is common in WSW, routine screening for BV is not recommended, nor is the treatment of partners of women with BV. Encouraging awareness of signs and symptoms of BV in women and encouraging healthy sexual practices (e.g., cleaning shared sex toys between uses) might be helpful.

HIV Infection: Detection, Counseling, and Referral

HIV infection represents a spectrum of disease that can begin with a brief acute retroviral syndrome that typically transitions to a multiyear chronic and clinically latent illness. Without treatment, this illness eventually progresses to a symptomatic, life-threatening immunodeficiency disease known as AIDS. In untreated patients, the time between HIV infection and the development of AIDS varies, ranging from a few months to many years with an estimated median time of approximately 11 years (123). HIV replication is present during all stages of the infection and progressively depletes CD4 lymphocytes, which are critical for maintenance of effective immune function. When the CD4 cell count falls below 200 cells/µL, patients are at high risk for life-threatening AIDS-defining opportunistic infections (e.g., Pneumocystis pneumonia, Toxoplasma gondii encephalitis, disseminated Mycobacterium avium complex disease, tuberculosis, and bacterial pneumonia). In the absence of treatment, virtually all HIV-infected persons will die of AIDS.

Early diagnosis of HIV infection is essential to ensuring that patients are referred promptly for evaluation, provided treatment (if indicated), and linked into counseling and related support services to help them reduce their risk for transmitting HIV to others. Diagnosing persons during acute infection is particularly important. It is during this phase that HIV-infected persons are most infectious (124–126), but test negative for HIV antibodies and therefore unknowingly continue to engage in those high-risk behaviors associated with HIV transmission. Providers are in a particularly good position to diagnose persons during acute HIV infection because such persons might present for assessment and treatment of a concomitantly acquired STD during this phase of the disease. Knowing that a patient is infected with HIV has important clinical implications because HIV infection alters the immune system and thereby affects the diagnosis, evaluation, treatment, and follow-up of other STDs.

Even in the era of highly effective antiretroviral therapy (HAART), HIV infection is often diagnosed in persons with advanced infection (i.e., persons with low CD4 cell counts). Nationally, the proportion of patients diagnosed with AIDS at or within 12 months of their HIV diagnosis in 2007 was 32% (127). Since 2006, CDC has endorsed efforts to increase HIV testing by streamlining the consent process and expanding opt-out testing to all health-care settings, especially STD clinics (77). However, rates of testing remain unacceptably low: in 2006, only 40% of surveyed adults had ever been tested, and <25% of high-risk adults had been tested during the preceding 12 months (128).

Proper management of HIV infection requires medical therapy, which for many patients should be coupled with behavioral and psychosocial services. Comprehensive HIV treatment services are usually not available in facilities focusing primarily on STD treatment (e.g., STD clinics); therefore, patients diagnosed in these settings ideally should be referred to a health-care provider or facility experienced in caring for HIV-infected patients. Nonetheless, providers working in STD-treatment facilities should be knowledgeable about the treatment options available in their communities, educate persons who test positive for HIV about the illness, and know where to refer their patients for support services and HIV care.

A detailed discussion of the complex issues required for the management of HIV infection is beyond the scope of this report; however this information is available in other published resources (129–131). In subsequent sections of this report, additional types of HIV-related information about the diagnosis of HIV infection, counseling of HIV-infected patients, referral of patients for support services (including medical care), and management of sex and injection-drug partners in STD-treatment facilities is provided. In addition, this report discusses HIV infection during pregnancy and among infants and children.

Detection of HIV Infection: Screening and Establishing a Diagnosis

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

Consent and Pretest Information

CDC recommends HIV screening for patients aged 13–64 years in all health-care settings (77). Patients should be notified that testing will be performed, but given the option to decline or defer testing (i.e., provided with opt-out testing) (128). Assent is inferred unless the patient verbally declines testing. Separate written consent for HIV testing should not be required; in most facilities, general consent for medical care is considered sufficient to encompass consent for HIV testing. Providing prevention counseling along with HIV diagnostic testing or as part of HIV screening programs is not a requirement within health-care settings. In addition, routine opt-out testing (instead of traditional written informed consent with pre-and post-test counseling) might be precluded in some jurisdictions by local laws and regulations, although many state and local authorities have updated laws and regulations to facilitate adoption of routine opt-out testing. Information about regulations in specific jurisdictions is available through the National Clinicians Consultation Center at www.nccc.ucsf.edu.

Prevention Counseling

Prevention counseling should be offered and encouraged in all health-care facilities that serve patients at high risk (e.g., STD clinics), because these facilities routinely elicit information about the behaviors that place persons at high risk for HIV. Prevention counseling need not be explicitly linked to HIV testing. However, some patients might be more likely to think about HIV and consider their risk-related behavior when undergoing an HIV test. HIV testing presents an excellent opportunity to provide or arrange for prevention counseling to assist with behavior changes that can reduce risk for acquiring HIV infection.

Establishing the Diagnosis of HIV Infection

HIV infection can be diagnosed by serologic tests that detect antibodies against HIV-1 and HIV-2 and by virologic tests that can detect HIV antigens or ribonucleic acid (RNA). Antibody testing begins with a sensitive screening test (e.g., the conventional or rapid enzyme immunoassay [EIA]). Currently available serologic tests are both highly sensitive and specific and can detect all known subtypes of HIV-1. Most can also detect HIV-2 and uncommon variants of HIV-1 (e.g., Group O and Group N). The advent of HIV rapid serologic testing has enabled clinicians to make an accurate presumptive diagnosis of HIV infection within half an hour, which could potentially facilitate the identification of the approximately 250,000 persons estimated to be living with undiagnosed HIV in the United States (127).

Reactive screening tests must be confirmed by a supplemental antibody test (i.e., Western blot [WB] and indirect immunofluorescence assay [IFA]) or virologic test (i.e., the HIV-1 RNA assay) (132). A confirmed positive antibody test result indicates that a person is infected with HIV and 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. Virologic tests for HIV-1 RNA can also be used to identify acute infection in persons who are negative for HIV antibodies.

The majority of HIV infections in the United States are caused by HIV-1. However, HIV-2 infection should be suspected in persons who have epidemiologic risk factors or an unusual clinical presentation. Epidemiologic factors associated with HIV-2 infection include having lived in or having a sex partner from an HIV-2 endemic area (e.g., West Africa and some European countries such as Portugal, where HIV-2 prevalence is increasing), having a sex partner known to be infected with HIV-2, or having received a blood transfusion or nonsterile injection in an HIV-2-endemic area. Specific testing for HIV-2 is also indicated when clinical evidence of HIV infection exists but tests for HIV-1 antibodies or HIV-1 viral load are negative, or when HIV-1 WB results exhibit the unusual indeterminate pattern of gag (p55, p24, p17) plus pol (p66, p51, p31) bands in the absence of env (gp160, gp120, gp41) bands.

Health-care providers should be knowledgeable about acute HIV infection and the symptoms and signs of acute retroviral syndrome, which develops in 50%–80% of acutely infected patients. Acute retroviral syndrome is characterized by non-specific symptoms, including fever, malaise, lymphadenopathy, and skin rash. It frequently occurs in the first few weeks after HIV infection, before antibody test results become positive. Suspicion of acute retroviral syndrome should result in prompt nucleic acid testing (HIV plasma RNA) in addition to an HIV antibody test to detect the presence of HIV. A positive HIV nucleic acid test should be confirmed by subsequent antibody testing to document seroconversion. Acutely infected patients are highly contagious during this stage of infection because the concentration of virus in plasma and genital secretions is extremely elevated (125,133). Antiretroviral therapy might benefit the health of persons with recently acquired HIV infection and reduce their infectiousness to others, but evidence to support this recommendation is still inconclusive and awaits the outcomes of several clinical trials currently underway (129). Notwithstanding, patients with acute HIV infection should be referred immediately to an HIV clinical-care provider. Diagnosis of HIV infection should prompt efforts to reduce behaviors that could transmit HIV to others (134).

The following are specific recommendations that apply to testing for HIV infection:

• HIV screening is recommended for all persons who seek evaluation and treatment for STDs.

• HIV testing must be voluntary and free from coercion. Patients must not be tested without their knowledge.

• HIV screening after notifying the patient that an HIV test will be performed (unless the patient declines) is recommended in all health-care settings.

• Specific signed consent for HIV testing should not be required. In most settings, general informed consent for medical care is considered sufficient to encompass informed consent for HIV testing.

• Use of rapid HIV tests should be considered, especially in clinics where a high proportion of patients do not return for HIV test results.

• Positive screening tests for HIV antibody must be confirmed by a supplemental test before the diagnosis of HIV infection can be established.

• Providers should be alert to the possibility of acute HIV infection and perform a nucleic acid test in addition to an antibody test for HIV, if indicated. Persons suspected of recently acquired HIV infection should be referred for immediate consultation with an infectious disease specialist.

Persons with newly diagnosed HIV infection who receive care in the STD treatment setting should be informed of the importance of promptly initiating medical care, the effectiveness of HIV treatments, and about what to expect as they enter medical care for HIV infection (131). In nonemergent situations, the initial evaluation of HIV-positive patients usually includes the following:

• Detailed medical history, including sexual and substance abuse history; vaccination history; previous STDs; travel history; and assessment for specific HIV-related symptoms or diagnoses;

• physical examination, including a gynecologic examination for women;

• testing for N. gonorrhoeae and C. trachomatis (in women perform Pap test and wet mount examination or culture of vaginal secretions for Trichomonas vaginalis);

• complete blood and platelet counts, blood chemistry profile, and lipid profile;

• toxoplasma antibody test;

• testing for antibodies to hepatitis C virus;

• testing for previous or present infections with HAV or HBV infection (recommended if determined to be cost-effective before considering vaccination) (see Hepatitis A and Hepatitis B);

• syphilis serology;

• CD4 T-lymphocyte analysis and determination of HIV plasma viral load;

• HIV genotypic resistance testing;

• tuberculin skin test (sometimes referred to as a purified protein derivative);

• urinalysis; and

• chest radiograph.

Type-specific testing for HSV-2 infection can be considered if herpes infection status is unknown. A first dose of hepatitis A and hepatitis B vaccine should be administered at this first visit for previously unvaccinated persons for whom vaccine is recommended (see Hepatitis A and Hepatitis B). In subsequent visits, when the results of laboratory tests are available, antiretroviral therapy can be offered based on existing guidance (129). Recommendations for the prophylaxis of opportunistic infections and vaccinations in HIV-infected adults and adolescents are available (130,131).

Providers should be alert to the possibility of new or recurrent STDs and should treat such conditions aggressively. Diagnosis of an STD in an HIV-infected person indicates on-going or recurrent 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 annually for all sexually active, HIV-positive persons. Women should be screened annually for cervical cancer precursor lesions by cervical Pap tests. More frequent STD screening might be appropriate depending on individual risk behaviors, the local epidemiology of STDs, and whether incident STDs are detected by screening or by the presence of symptoms.

Recently identified HIV infection might not have been recently acquired; persons newly diagnosed with HIV might be at any stage of infection. Therefore, health-care providers should be alert for symptoms or signs that suggest advanced HIV infection (e.g., fever, weight loss, diarrhea, cough, shortness of breath, and oral candidiasis). The presence of any of these symptoms should prompt urgent referral to an infectious diseases provider. Similarly, providers should be alert for signs of psychological distress and be prepared to refer patients accordingly (see Counseling for Patients with HIV Infection and Referral to Support Services).

Counseling for Patients with HIV Infection and Referral to Support Services

Those persons who test positive for HIV should receive prevention counseling before leaving the testing site. Such persons should receive or be referred for a medical evaluation and, if indicated, be provided with behavioral and psychological services as determined by a thorough psychosocial evaluation, which can also be used to identify high-risk behaviors. Providers who refer their HIV-positive patients to other professionals should establish means to ensure that these patients are linked successfully to such services, especially to on-going medical care.

Providers should expect persons to be distressed when first informed of a positive HIV test result. Such persons face multiple major adaptive challenges, including coping with the reactions of others to a stigmatizing illness, developing and adopting strategies for maintaining physical and emotional health, initiating changes in behavior to prevent HIV transmission to others, and reducing the risk for acquiring additional STDs. Many persons will require assistance with making reproductive choices, gaining access to health services, and coping with changes in personal relationships. Therefore, behavioral and psychosocial services are an integral part of health care for HIV-infected persons.

Patients testing positive for HIV have unique needs. Some patients require referral for specific behavioral interventions (e.g., a substance abuse program), mental health disorders (e.g., depression), or emotional distress. Others might require assistance with securing and maintaining employment and housing. Women should be counseled or appropriately referred regarding reproductive choices and contraceptive options, and patients with multiple psychosocial problems might be candidates for comprehensive risk-reduction counseling and services.

The following are specific recommendations for HIV counseling and referral:

• Persons who test positive for HIV antibody should be counseled, either on site or through referral, concerning the behavioral, psychosocial, and medical implications of HIV infection.

• Health-care providers should be alert for medical or psychosocial conditions that require immediate attention.

• Providers should assess the needs of newly diagnosed persons for immediate medical care or support and should link them to services provided by health-care personnel experienced in providing care for HIV-infected persons. Such persons might need medical care or services for substance abuse, mental health disorders, emotional distress, reproductive counseling, risk-reduction counseling, and case management. Providers should follow up to ensure that patients have received the needed services.

• Patients should be educated about the importance of follow-up medical care as well as what to expect.

Several successful, innovative interventions for HIV prevention have been developed for diverse at-risk populations, and these can be locally replicated or adapted (11–14,135,136). Involvement of nongovernment organizations and community-based organizations might complement such efforts in the clinical setting.

Management of Sex Partners and Injection-Drug Partners

Clinicians evaluating HIV-infected persons should determine whether any partners should be notified concerning possible exposure to HIV (77,137). In the context of HIV management, the term “partner” includes not only sex partners, but persons who share syringes or other injection equipment. Partner notification is an important component of disease management, because early diagnosis and treatment of HIV infection might reduce morbidity and provide the opportunity to encourage risk-reduction behaviors. Partner notification for HIV infection should be confidential. Specific guidance regarding spousal notification varies by jurisdiction. Detailed recommendations concerning identification, notification, diagnosis, and treatment of exposed partners are available in Recommendations for Partner Services Programs for HIV Infection, Syphilis, Gonorrhea, and Chlamydial Infections (137).

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, whereas with provider referral, trained health department personnel locate partners on the basis of information provided by the patient. During the provider referral notification process, the confidentiality of patients is protected; their names are not revealed to partners who are notified. Many state and local health departments provide these services.

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

• HIV-infected patients should be encouraged to notify their partners and to refer them for counseling and testing. If requested by the patient, health-care providers should assist in this process, either directly or by referral to health department partner-notification programs.

• If patients are unwilling to notify their partners or if they cannot ensure that their partners will seek counseling, physicians or health department personnel should use confidential partner notification procedures.

• Partners who have been reached and were exposed to genital secretions and/or blood of an HIV-infected partner though sex or injection-drug use within the preceding 72 hours should be offered postexposure prophylaxis with combination antiretrovirals (78).

Special Considerations

Pregnancy

All pregnant women in the United States should be tested for HIV infection as early during pregnancy as possible. A second test during the third trimester, preferably at <36 weeks’ gestation, should be considered for all pregnant women and is recommended for women known to be at high risk for acquiring HIV, those who receive health care in jurisdictions with elevated incidence of HIV or AIDS among women, and women living in facilities in which prenatal screening identifies at least one HIV-infected pregnant women per 1,000 women screened (77). An RNA test should be used in conjunction with an HIV antibody test for women who have signs or symptoms consistent with acute HIV infection. The patient should first be informed that she will be tested for HIV as part of the panel of prenatal tests, unless she declines, or opts-out, of screening (77,86). For women who decline, providers should continue to strongly encourage testing and address concerns that pose obstacles to testing. Women who decline testing because they have had a previous negative HIV test should be informed about the importance of retesting during each pregnancy. Testing pregnant women is particularly important not only to maintain the health of the patient, but because interventions (i.e., antiretroviral and obstetrical) can reduce the risk for perinatal transmission of HIV.

After a pregnant woman has been identified as being HIV-infected, she should be educated about the risk for perinatal infection. Evidence indicates that, in the absence of antiretroviral and other interventions, 15%–25% of infants born to HIV-infected mothers will become infected with HIV; such evidence also indicates that an additional 12%–14% of infants born to infected mothers who breastfeed into the second year of life will become infected (138,139).

The risk for perinatal HIV transmission can be reduced to <2% through the use of antiretroviral regimens and obstetrical interventions (i.e., zidovudine or nevirapine and elective cesarean section at 38 weeks of pregnancy) and by avoiding breastfeeding (138,140). Pregnant women who are HIV-infected should be counseled concerning their options (either on-site or by referral), given appropriate antenatal treatment, and advised not to breastfeed their infants.

HIV Infection Among Infants and Children

Diagnosis of HIV infection in a pregnant woman indicates the need to consider whether the woman’s other children might be infected. Infants and young children with HIV infection differ from adults and adolescents with respect to the diagnosis, clinical presentation, and management of HIV disease. For example, because maternal HIV antibody passes through the placenta, antibody tests for HIV are expected to be positive in the sera of both infected and uninfected infants born to seropositive mothers. A definitive determination of HIV infection for an infant aged <18 months is usually based on HIV nucleic acid testing (141). 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 (142,143).

Diseases Characterized by Genital, Anal, or Perianal Ulcers

In the United States, most young, sexually active patients who have genital, anal, or perianal ulcers have either genital herpes or syphilis. The frequency of each condition differs by geographic area and population; however, genital herpes is the most prevalent of these diseases. More than one etiologic agent (e.g., herpes and syphilis) can be present in a genital, anal, or perianal ulcer. Less common infectious causes of genital, anal, or perianal ulcers include chancroid and donovanosis. HSV, syphilis, and chancroid have been associated with an increased risk for HIV transmission, and genital, anal, or perianal lesions might be associated with conditions that are not sexually transmitted (e.g., yeast, trauma, carcinoma, aphthae, fixed drug eruption, and psoriasis).

A diagnosis based only on the patient’s medical history and physical examination frequently is inaccurate. Therefore, all patients who have genital, anal, or perianal ulcers should be evaluated with a serologic test for syphilis and a diagnostic evaluation for genital herpes; in settings where chancroid is prevalent, a test for Haemophilus ducreyi should also be performed. Specific tests for evaluation of genital, anal, or perianal ulcers include 1) syphilis serology and darkfield examination; 2) culture for HSV or PCR testing for HSV; and 3) serologic testing for type-specific HSV antibody.

No FDA-cleared PCR test to diagnose either herpes or syphilis is available in the United States; however, such testing can be performed by clinical laboratories that have developed their own tests and have conducted a Clinical Laboratory Improvement Amendment (CLIA) verification study. Type-specific serology for HSV-2 might be helpful in identifying persons with genital herpes (see Genital Herpes, Type-Specific Serologic Tests). In addition, biopsy of genital, anal, or perianal ulcers can help identify the cause of ulcers that are unusual or that do not respond to initial therapy. HIV testing should be performed on all persons with genital, anal, or perianal ulcers who are not known to have HIV infection (see Diagnostic Considerations, sections on Syphilis, Chancroid, and Genital Herpes Simplex Virus).

Health-care providers frequently must treat patients before test results are available, because early treatment decreases the possibility of ongoing transmission and because successful treatment of genital herpes depends on prompt initiation of therapy. The clinician should empirically treat for the diagnosis considered most likely on the basis of clinical presentation and epidemiologic circumstances (including travel history); even after complete diagnostic evaluation, at least 25% of patients who have genital ulcers have no laboratory-confirmed diagnosis.

Chancroid

The prevalence of chancroid has declined in the United States (93). When infection does occur, it is usually associated with sporadic outbreaks. Worldwide, chancroid appears to have declined as well, although infection might still occur in some regions of Africa and the Caribbean. Chancroid, as well as genital herpes and syphilis, is a risk factor in the transmission of HIV infection (144).

A definitive diagnosis of chancroid requires the identification of H. ducreyi on special culture media that is not widely available from commercial sources; even when these media are used, sensitivity is <80% (145). No FDA-cleared PCR test for H. ducreyi is available in the United States, but such testing can be performed by clinical laboratories that have developed their own PCR test and have conducted a CLIA verification study.

The combination of a painful genital ulcer and tender suppurative inguinal adenopathy suggests the diagnosis of chancroid (146). A probable diagnosis of chancroid, for both clinical and surveillance purposes, can be made if all of the following criteria are met: 1) the patient has one or more painful genital ulcers; 2) the patient has no evidence of T. pallidum infection by darkfield examination of ulcer exudate or by a serologic test for syphilis performed at least 7 days after onset of ulcers; 3) the clinical presentation, appearance of genital ulcers and, if present, regional lymphadenopathy are typical for chancroid; and 4) a test for HSV performed on the ulcer exudate is negative.

Treatment

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

Recommended Regimens

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

* Ciprofloxacin is contraindicated for pregnant and lactating women.

Azithromycin and ceftriaxone offer the advantage of single-dose therapy. Worldwide, several isolates with intermediate resistance to either ciprofloxacin or erythromycin have been reported. However, because cultures are not routinely performed, data are limited regarding the current prevalence of antimicrobial resistance.

Other Management Considerations

Men who are uncircumcised and patients with HIV infection do not respond as well to treatment as persons who are circumcised or HIV-negative. Patients should be tested for HIV infection at the time chancroid is diagnosed. If the initial test results were negative, a serologic test for syphilis and HIV infection should be performed 3 months after the diagnosis of chancroid.

Follow-Up

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 1) the diagnosis is correct, 2) the patient is coinfected with another STD, 3) the patient is infected with HIV, 4) the treatment was not used as instructed, or 5) the H. ducreyi strain causing the infection is resistant to the prescribed antimicrobial. The time required for complete healing depends on the size of the ulcer; large ulcers might require >2 weeks. In addition, healing is slower for some uncircumcised men who have ulcers under the foreskin. Clinical resolution of fluctuant lymphadenopathy is slower than that of ulcers and might require needle aspiration or incision and drainage, despite otherwise successful therapy. Although needle aspiration of buboes is a simpler procedure, incision and drainage might be preferred because of reduced need for subsequent drainage procedures.

Management of Sex Partners

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

Special Considerations

Pregnancy

Ciprofloxacin is contraindicated during pregnancy and lactation. No adverse effects of chancroid on pregnancy outcome have been reported.

HIV Infection

HIV-infected patients who have chancroid should be monitored closely because, as a group, they are more likely to experience treatment failure and to have ulcers that heal more slowly. HIV-infected patients might require repeated or 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.

Genital HSV Infections

Genital herpes is a chronic, life-long viral infection. Two types of HSV have been identified as causing genital herpes: HSV-1 and HSV-2. Most cases of recurrent genital herpes are caused by HSV-2, and at least 50 million persons in the United States are infected with this type of genital herpes (147). However, an increasing proportion of anogenital herpetic infections in some populations has been attributed to HSV-1 infection.

Most persons infected with HSV-2 have not been diagnosed with genital herpes. Many such persons have mild or unrecognized infections but shed virus intermittently in the genital tract. As a result, the majority of genital herpes infections are transmitted by persons unaware that they have the infection or who are asymptomatic when transmission occurs. Management of genital HSV should address the chronic nature of the disease and go beyond the treatment of acute episodes of genital ulcers.

Diagnosis of HSV Infection

The clinical diagnosis of genital herpes is both nonsensitive and nonspecific. The classical painful multiple vesicular or ulcerative lesions are absent in many infected persons. HSV-1 is causing an increasing proportion of first episodes of anogenital herpes in some populations (e.g., young women and MSM) and might now account for most of these infections (148,149). Recurrences and subclinical shedding are much less frequent for genital HSV-1 infection than for genital HSV-2 infection (150,151). A patient’s prognosis and the type of counseling needed depends on the type of genital herpes (HSV-1 or HSV-2) causing the infection; therefore, the clinical diagnosis of genital herpes should be confirmed by laboratory testing (152). Both virologic and type-specific serologic tests for HSV should be available in clinical settings that provide care for persons diagnosed with or at risk for STDs.

Virologic Tests

Cell culture and PCR are the preferred HSV tests for persons who seek medical treatment for genital ulcers or other mucocutaneous lesions. The sensitivity of viral culture is low, especially for recurrent lesions, and declines rapidly as lesions begin to heal. PCR assays for HSV DNA are more sensitive and are increasingly used in many settings (153,154). PCR is the test of choice for detecting HSV in spinal fluid for diagnosis of HSV infection of the central nervous system (CNS). Viral culture isolates should be typed to determine which type of HSV is causing the infection. Failure to detect HSV by culture or PCR does not indicate an absence of HSV infection, because viral shedding is intermittent. The use of cytologic detection of cellular changes of HSV infection is an insensitive and nonspecific method of diagnosis, both for genital lesions (i.e., Tzanck preparation) and for cervical Pap smears and therefore should not be relied upon.

Type-Specific Serologic Tests

Both type-specific and nontype-specific antibodies to HSV develop during the first several weeks after infection and persist indefinitely. Accurate type-specific HSV serologic assays are based on the HSV-specific glycoprotein G2 (HSV-2) and glycoprotein G1 (HSV-1). Such assays first became commercially available in 1999, but older assays that do not accurately distinguish HSV-1 from HSV-2 antibody (despite claims to the contrary) remain on the market (155); providers should specifically request serologic type-specific glycoprotein G (gG)-based assays when serology is performed for their patients (156–158).

Both laboratory-based assays and point-of-care tests that provide results for HSV-2 antibodies from capillary blood or serum during a clinic visit are available. The sensitivities of these glycoprotein G type-specific tests for the detection of HSV-2 antibody vary from 80%–98%, and false-negative results might be more frequent at early stages of infection. The specificities of these assays are ≥96%. False-positive results can occur, especially in patients with a low likelihood of HSV infection. Repeat or confirmatory testing might be indicated in some settings, especially if recent acquisition of genital herpes is suspected. IgM testing for HSV is not useful, because the IgM tests are not type-specific and might be positive during recurrent episodes of herpes (159).

Because nearly all HSV-2 infections are sexually acquired, the presence of type-specific HSV-2 antibody implies anogenital infection. In this instance, education and counseling appropriate for persons with genital herpes should be provided. The presence of HSV-1 antibody alone is more difficult to interpret. Most persons with HSV-1 antibody have oral HSV infection acquired during childhood, which might be asymptomatic. However, acquisition of genital HSV-1 appears to be increasing, and genital HSV-1 also can be asymptomatic (147–149). Lack of symptoms in an HSV-1 seropositive person does not distinguish anogenital from orolabial or cutaneous infection, and regardless of site of infection, these persons remain at risk for acquiring HSV-2.

Type-specific HSV serologic assays might be useful in the following scenarios: 1) recurrent genital symptoms or atypical symptoms with negative HSV cultures; 2) a clinical diagnosis of genital herpes without laboratory confirmation; or 3) a partner with genital herpes. HSV serologic testing should be considered for persons presenting for an STD evaluation (especially for those persons with multiple sex partners), persons with HIV infection, and MSM at increased risk for HIV acquisition. Screening for HSV-1 and HSV-2 in the general population is not indicated.

Management of Genital Herpes

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

Systemic antiviral drugs can partially control the signs and symptoms of herpes episodes when used to treat first clinical and recurrent episodes, or when used as daily suppressive therapy. However, these drugs neither eradicate latent virus nor affect the risk, frequency, or severity of recurrences after the drug is discontinued. Randomized trials have indicated that three antiviral medications provide clinical benefit for genital herpes: acyclovir, valacyclovir, and famciclovir (160–168). Valacyclovir is the valine ester of acyclovir and has enhanced absorption after oral administration. Famciclovir also has high oral bioavailability. Topical therapy with antiviral drugs offers minimal clinical benefit, and its use is discouraged.

First Clinical Episode of Genital Herpes

Newly acquired genital herpes can cause a prolonged clinical illness with severe genital ulcerations and neurologic involvement. Even persons with first-episode herpes who have mild clinical manifestations initially can develop severe or prolonged symptoms. Therefore, all patients with first episodes of genital herpes should receive antiviral therapy.

Recommended Regimens*

Acyclovir 400 mg orally three times a day for 7–10 days OR Acyclovir 200 mg orally five times a day for 7–10 days OR Famciclovir 250 mg orally three times a day for 7–10 days OR Valacyclovir 1 g orally twice a day for 7–10 days

*Treatment can be extended if healing is incomplete after 10 days of therapy.

Established HSV-2 Infection

Almost all persons with symptomatic first-episode genital HSV-2 infection subsequently experience recurrent episodes of genital lesions; recurrences are less frequent after initial genital HSV-1 infection. Intermittent asymptomatic shedding occurs in persons with genital HSV-2 infection, even in those with longstanding or clinically silent infection. Antiviral therapy for recurrent genital herpes can be administered either as suppressive therapy to reduce the frequency of recurrences or episodically to ameliorate or shorten the duration of lesions. Some persons, including those with mild or infrequent recurrent outbreaks, benefit from antiviral therapy; therefore, options for treatment should be discussed. Many persons might prefer suppressive therapy, which has the additional advantage of decreasing the risk for genital HSV-2 transmission to susceptible partners (169,170).

Suppressive Therapy for Recurrent Genital Herpes

Suppressive therapy reduces the frequency of genital herpes recurrences by 70%–80% in patients who have frequent recurrences (166–169); many persons receiving such therapy report having experienced no symptomatic outbreaks. Treatment also is effective in patients with less frequent recurrences. Safety and efficacy have been documented among patients receiving daily therapy with acyclovir for as long as 6 years and with valacyclovir or famciclovir for 1 year (171,172). Quality of life is improved in many patients with frequent recurrences who receive suppressive therapy rather than episodic treatment.

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

Treatment with valacyclovir 500 mg daily decreases the rate of HSV-2 transmission in discordant, heterosexual couples in which the source partner has a history of genital HSV-2 infection (170). Such couples should be encouraged to consider suppressive antiviral therapy as part of a strategy to prevent transmission, in addition to consistent condom use and avoidance of sexual activity during recurrences. Suppressive antiviral therapy also is likely to reduce transmission when used by persons who have multiple partners (including MSM) and by those who are HSV-2 seropositive without a history of genital herpes.

Recommended Regimens

Acyclovir 400 mg orally twice a day OR Famiciclovir 250 mg orally twice a day OR Valacyclovir 500 mg orally once a day* OR Valacyclovir 1 g orally once a day

* Valacyclovir 500 mg once a day might be less effective than other valacyclovir or acyclovir dosing regimens in patients who have very frequent recurrences (i.e., ≥10 episodes per year).

Acyclovir, famciclovir, and valacyclovir appear equally effective for episodic treatment of genital herpes, but famciclovir appears somewhat less effective for suppression of viral shedding (163–167,173). Ease of administration and cost also are important considerations for prolonged treatment.

Episodic Therapy for Recurrent Genital Herpes

Effective episodic treatment of recurrent herpes requires initiation of therapy within 1 day of lesion onset or during the prodrome that precedes some outbreaks. The patient should be provided with a supply of drug or a prescription for the medication with instructions to initiate treatment immediately when symptoms begin.

Recommended Regimens

Acyclovir 400 mg orally three times a day for 5 days OR Acyclovir 800 mg orally twice a day for 5 days OR Acyclovir 800 mg orally three times a day for 2 days OR Famciclovir 125 mg orally twice daily for 5 days OR Famciclovir 1000 mg orally twice daily for 1 day OR Famciclovir 500 mg once, followed by 250 mg twice daily for 2 days OR Valacyclovir 500 mg orally twice a day for 3 days OR Valacyclovir 1 g orally once a day for 5 days

Severe Disease

Intravenous (IV) acyclovir therapy should be provided for patients who have severe HSV disease or complications that necessitate hospitalization (e.g., disseminated infection, pneumonitis, or hepatitis) or CNS complications (e.g., meningoencephalitis). The recommended regimen is acyclovir 5–10 mg/kg IV every 8 hours for 2–7 days or until clinical improvement is observed, followed by oral antiviral therapy to complete at least 10 days of total therapy. Acyclovir dose adjustment is recommended for impaired renal function.

Counseling

Counseling of infected persons and their sex partners is critical to the management of genital herpes. The goals of counseling include 1) helping patients cope with the infection and 2) preventing sexual and perinatal transmission (174,175). Although initial counseling can be provided at the first visit, many patients benefit from learning about the chronic aspects of the disease after the acute illness subsides. Multiple resources, including websites (http://www.ashastd.org) and printed materials, are available to assist patients, their partners, and clinicians who become involved in counseling.

Although the psychological effect of a serologic diagnosis of HSV-2 infection in a person with asymptomatic or unrecognized genital herpes appears minimal and transient (176), some HSV-infected persons might express anxiety concerning genital herpes that does not reflect the actual clinical severity of their disease; the psychological effect of HSV infection frequently is substantial. Common concerns regarding genital herpes include the severity of initial clinical manifestations, recurrent episodes, sexual relationships and transmission to sex partners, and ability to bear healthy children. The misconception that HSV causes cancer should be dispelled.

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

• Persons who have genital herpes should be educated concerning the natural history of the disease, with emphasis on the potential for recurrent episodes, asymptomatic viral shedding, and the attendant risks of sexual transmission.

• Persons experiencing a first episode of genital herpes should be advised that suppressive therapy is available and effective in preventing symptomatic recurrent episodes and that episodic therapy often is useful in shortening the duration of recurrent episodes.

• All persons with genital HSV infection should be encouraged to inform their current sex partners that they have genital herpes and to inform future partners before initiating a sexual relationship.

• Sexual transmission of HSV can occur during asymptomatic periods. Asymptomatic viral shedding is more frequent in genital HSV-2 infection than genital HSV-1 infection and is most frequent during the first 12 months after acquiring HSV-2.

• All persons with genital herpes should remain abstinent from sexual activity with uninfected partners when lesions or prodromal symptoms are present.

• The risk for HSV-2 sexual transmission can be decreased by the daily use of valacyclovir by the infected person. Episodic therapy does not reduce the risk for transmission and its use should be discouraged for this purpose among persons whose partners might be at risk for HSV-2 acquisition.

• Infected persons should be informed that male latex condoms, when used consistently and correctly, might reduce the risk for genital herpes transmission (21–23).

• Sex partners of infected persons should be advised that they might be infected even if they have no symptoms. Type-specific serologic testing of the asymptomatic partners of persons with genital herpes is recommended to determine whether such partners are already HSV seropositive or whether risk for acquiring HSV exists.

• The risk for neonatal HSV infection should be explained to all persons, including men. Pregnant women and women of childbearing age who have genital herpes should inform their providers who care for them during pregnancy and those who will care for their newborn infant about their infection. Pregnant women who are not known to be infected with HSV-2 should be advised to abstain from intercourse with men who have genital herpes during the third trimester of pregnancy. Similarly, pregnant women who are not known to be infected with HSV-1 should be counseled to avoid genital exposure to HSV-1 during the third trimester (e.g., oral sex with a partner with oral herpes and vaginal intercourse with a partner with genital HSV-1 infection).

• Asymptomatic persons diagnosed with HSV-2 infection by type-specific serologic testing should receive the same counseling messages as persons with symptomatic infection. In addition, such persons should be educated about the clinical manifestations of genital herpes.

• When exposed to HIV, HSV-2 seropositive persons are at increased risk for HIV acquisition. Patients should be informed that suppressive antiviral therapy does not reduce the increased risk for HIV acquisition associated with HSV-2 infection (177,178).

Management of Sex Partners

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

Special Considerations

Allergy, Intolerance, and Adverse Reactions

Allergic and other adverse reactions to acyclovir, valacyclovir, and famciclovir are rare. Desensitization to acyclovir has been described (179).

HIV Infection

Immunocompromised patients can have prolonged or severe episodes of genital, perianal, or oral herpes. Lesions caused by HSV are common among HIV-infected patients and might be severe, painful, and atypical. HSV shedding is increased in HIV-infected persons. Whereas antiretroviral therapy reduces the severity and frequency of symptomatic genital herpes, frequent subclinical shedding still occurs (180). Clinical manifestations of genital herpes might worsen during immune reconstitution after initiation of antiretroviral therapy.

Suppressive or episodic therapy with oral antiviral agents is effective in decreasing the clinical manifestations of HSV among HIV-positive persons (181–183). The extent to which suppressive antiviral therapy will decrease HSV transmission from this population is unknown. HSV type-specific serologies can be offered to HIV-positive persons during their initial evaluation if infection status is unknown, and suppressive antiviral therapy can be considered in those who have HSV-2 infection.

Recommended Regimens for Daily Suppressive Therapy in Persons with HIV

Acyclovir 400–800 mg orally twice to three times a day OR Famciclovir 500 mg orally twice a day OR Valacyclovir 500 mg orally twice a day

Recommended Regimens for Episodic Infection in Persons with HIV

Acyclovir 400 mg orally three times a day for 5–10 days OR Famciclovir 500 mg orally twice a day for 5–10 days OR Valacyclovir 1 g orally twice a day for 5–10 days

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

If lesions persist or recur in a patient receiving antiviral treatment, HSV resistance should be suspected and a viral isolate should be obtained for sensitivity testing (184). Such persons should be managed in consultation with an HIV specialist, and alternate therapy should be administered. All acyclovir-resistant strains are resistant to valacyclovir, and the majority are resistant to famciclovir. Foscarnet, 40 mg/kg IV every 8 hours until clinical resolution is attained, is frequently effective for treatment of acyclovir-resistant genital herpes. Intravenous cidofovir 5 mg/kg once weekly might also be effective. Imiquimod is a topical alternative, as is topical cidofovir gel 1%, which is not commercially available and must be compounded at a pharmacy. These topical preparations should be applied to the lesions once daily for 5 consecutive days.

Clinical management of antiviral resistance remains challenging among HIV-infected patients, and other preventative approaches might be necessary. However, experience with another group of immunocompromised persons (hematopoietic stem-cell recipients) demonstrated that persons receiving daily suppressive antiviral therapy were less likely to develop acyclovir-resistant HSV compared with those who received episodic therapy with outbreaks (185).

Genital Herpes in Pregnancy

Most mothers of infants who acquire neonatal herpes lack histories of clinically evident genital herpes (186). The risk for transmission to the neonate from an infected mother is high (30%–50%) among women who acquire genital herpes near the time of delivery and low (<1%) among women with histories of recurrent herpes at term or who acquire genital HSV during the first half of pregnancy (187). However, because recurrent genital herpes is much more common than initial HSV infection during pregnancy, the proportion of neonatal HSV infections acquired from mothers with recurrent herpes is substantial. Prevention of neonatal herpes depends both on preventing acquisition of genital HSV infection during late pregnancy and avoiding exposure of the infant to herpetic lesions during delivery. Because the risk for herpes is high in infants of women who acquire genital HSV during late pregnancy, these women should be managed in consultation with an infectious disease specialist.

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

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

The safety of systemic acyclovir, valacyclovir, and famciclovir therapy in pregnant women has not been definitively established. Available data do not indicate an increased risk for major birth defects compared with the general population in women treated with acyclovir during the first trimester (188) — findings that provide assurance to women who have had prenatal exposure to acyclovir. However, data regarding prenatal exposure to valacyclovir and famciclovir are too limited to provide useful information on pregnancy outcomes. Acyclovir can be administered orally to pregnant women with first episode genital herpes or severe recurrent herpes and should be administered IV to pregnant women with severe HSV infection. Acyclovir treatment late in pregnancy reduces the frequency of cesarean sections among women who have recurrent genital herpes by diminishing the frequency of recurrences at term (189–191); the effect of antiviral therapy late in pregnancy on the incidence of neonatal herpes is not known. No data support the use of antiviral therapy among HSV seropositive women without a history of genital herpes.

Neonatal Herpes

Infants exposed to HSV during birth, as documented by maternal virologic testing or presumed by observation of maternal lesions, should be followed carefully in consultation with a pediatric infectious disease specialist. Surveillance cultures of mucosal surfaces to detect HSV infection might be considered before the development of clinical signs of neonatal herpes. In addition, administration of acyclovir might be considered for infants born to women who acquired HSV near term because the risk for neonatal herpes is high for these infants. All infants who have neonatal herpes should be promptly evaluated and treated with systemic acyclovir. The recommended regimen for infants treated for known or suspected neonatal herpes is acyclovir 20 mg/kg IV every 8 hours for 21 days for disseminated and CNS disease or for 14 days for disease limited to the skin and mucous membranes.

Granuloma Inguinale (Donovanosis)

Granuloma inguinale is a genital ulcerative disease caused by the intracellular gram-negative bacterium Klebsiella granulomatis (formerly known as Calymmatobacterium granulomatis). The disease occurs rarely in the United States, although it is endemic in some tropical and developing areas, including India; Papua, New Guinea; the Caribbean; central Australia; and southern Africa (192,193). Clinically, the disease is commonly characterized as painless, slowly progressive ulcerative lesions on the genitals or perineum without regional lymphadenopathy; subcutaneous granulomas (pseudoboboes) might also occur. The lesions are highly vascular (i.e., beefy red appearance) and bleed easily on contact. The clinical presentation also can include hypertrophic, necrotic, or sclerotic variants. Extragenital infection can occur with extension of infection to the pelvis, or it can disseminate to intraabdominal organs, bones, or the mouth. The lesions also can develop secondary bacterial infection and can coexist with other sexually transmitted pathogens.

The causative organism is difficult to culture, and diagnosis requires visualization of dark-staining Donovan bodies on tissue crush preparation or biopsy. No FDA-cleared molecular tests for the detection of K. granulomatis DNA exist, but such an assay might be useful when undertaken by laboratories that have conducted a CLIA verification study.

Treatment

Several antimicrobial regimens have been effective, but only a limited number of controlled trials have been published (192). Treatment has been shown to halt progression of lesions, and healing typically proceeds inward from the ulcer margins; prolonged therapy is usually required to permit granulation and reepithelialization of the ulcers. Relapse can occur 6–18 months after apparently effective therapy.

Recommended Regimen

Doxycycline 100 mg orally twice a day for at least 3 weeks and until all lesions have completely healed

Alternative Regimens

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

The addition of an aminoglycoside (e.g., gentamicin 1 mg/kg IV every 8 hours) to these regimens can be considered if improvement is not evident within the first few days of therapy.

Follow-Up

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

Management of Sex Partners

Persons who have had sexual contact with a patient who has granuloma inguinale within the 60 days before onset of the patient’s symptoms should be examined and offered therapy. However, the value of empiric therapy in the absence of clinical signs and symptoms has not been established.

Special Considerations

Pregnancy

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

HIV Infection

Persons with both granuloma inguinale and HIV infection should receive the same regimens as those who are HIV negative; however, the addition of a parenteral aminoglycoside (e.g., gentamicin) can also be considered.

Lymphogranuloma Venereum

Lymphogranuloma venereum (LGV) is caused by C. trachomatis serovars L1, L2, or L3 (194). The most common clinical manifestation of LGV among heterosexuals is tender inguinal and/or femoral lymphadenopathy that is typically unilateral. A self-limited genital ulcer or papule sometimes occurs at the site of inoculation. However, by the time patients seek care, the lesions have often disappeared. Rectal exposure in women or MSM can result in proctocolitis, including mucoid and/or hemorrhagic rectal discharge, anal pain, constipation, fever, and/or tenesmus (195,196). LGV is an invasive, systemic infection, and if it is not treated early, LGV proctocolitis can lead to chronic, colorectal fistulas and strictures. Genital and colorectal LGV lesions can also develop secondary bacterial infection or can be coinfected with other sexually and nonsexually transmitted pathogens.

Diagnosis is based on clinical suspicion, epidemiologic information, and the exclusion of other etiologies for proctocolitis, inguinal lymphadenopathy, or genital or rectal ulcers. C. trachomatis testing also should be conducted, if available.

Genital and lymph node specimens (i.e., lesion swab or bubo aspirate) can be tested for C. trachomatis by culture, direct immunofluorescence, or nucleic acid detection. NAATs for C. trachomatis are not FDA-cleared for testing rectal specimens, although some laboratories have performed the CLIA validation studies that are needed to provide results for clinical management. Additional molecular procedures (e.g., PCR-based genotyping) can be used to differentiate LGV from non-LGV C. trachomatis, but these are not widely available.

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

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

Treatment

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

Recommended Regimen

Doxycycline 100 mg orally twice a day for 21 days

Alternative Regimen

Erythromycin base 500 mg orally four times a day for 21 days

Although clinical data are lacking, azithromycin 1 g orally once weekly for 3 weeks is probably effective based on its chlamydial antimicrobial activity. Fluoroquinolone-based treatments might also be effective, but extended treatment intervals are likely required.

Follow-Up

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

Management of Sex Partners

Persons who have had sexual contact with a patient who has LGV within the 60 days before onset of the patient’s symptoms should be examined, tested for urethral or cervical chlamydial infection, and treated with a chlamydia regimen (azithromycin 1 gm orally single dose or doxycycline 100 mg orally twice a day for 7 days).

Special Considerations

Pregnancy

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

HIV Infection

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

Syphilis

Syphilis is a systemic disease caused by Treponema pallidum. On the basis of clinical findings, the disease has been divided into a series of overlapping stages, which are used to help guide treatment and follow-up. Persons who have syphilis might seek treatment for signs or symptoms of primary infection (i.e., ulcer or chancre at the infection site), secondary infection (i.e., manifestations that include, but are not limited to, skin rash, mucocutaneous lesions, and lymphadenopathy), neurologic infection (i.e., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, and auditory or ophthalmic abnormalities, which might occur through the natural history of untreated infection), or tertiary infection (i.e., cardiac or gummatous lesions). Latent infections (i.e., those lacking clinical manifestations) are detected by serologic testing. Latent syphilis acquired within the preceding year is referred to as early latent syphilis; all other cases of latent syphilis are either late latent syphilis or latent syphilis of unknown duration. Treatment for both late latent syphilis and tertiary syphilis might require a longer duration of therapy because organisms might be dividing more slowly; however, the validity of this concept has not been assessed.

Diagnostic Considerations

Darkfield examinations and tests to detect T. pallidum in lesion exudate or tissue are the definitive methods for diagnosing early syphilis (197). Although no T. pallidum detection tests are commercially available, some laboratories provide locally developed PCR tests for the detection of T. pallidum. A presumptive diagnosis of syphilis is possible with the use of two types of serologic tests: 1) nontreponemal tests (e.g., Venereal Disease Research Laboratory [VDRL] and RPR) and 2) treponemal tests (e.g., fluorescent treponemal antibody absorbed [FTA-ABS] tests, the T. pallidum passive particle agglutination [TP-PA] assay, various EIAs, and chemiluminescence immunoassays). The use of only one type of serologic test is insufficient for diagnosis, because each type of test has limitations, including the possibility of false-positive test results in persons without syphilis. False-positive nontreponemal test results can be associated with various medical conditions unrelated to syphilis, including autoimmune conditions, older age, and injection-drug use (198,199); therefore, persons with a reactive nontreponemal test should receive a treponemal test to confirm the diagnosis of syphilis.

Nontreponemal test antibody titers may 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 using the same testing method (e.g., VDRL or RPR), preferably by the same laboratory. The VDRL and RPR are equally valid assays, but quantitative results from the two tests cannot be compared directly because RPR titers frequently are slightly higher than VDRL titers. Nontreponemal test titers usually decline after treatment and might become nonreactive with time; however, in some persons, nontreponemal antibodies can persist for a long period of time — a response 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 (200). Treponemal test antibody titers should not be used to assess treatment response.

Some clinical laboratories and blood banks have begun to screen samples using treponemal tests, typically by EIA or chemiluminescence immunoassays (201,202). This strategy will identify both persons with previous treatment for syphilis and persons with untreated or incompletely treated syphilis. The positive predictive value for syphilis associated with a treponemal screening test result might be lower among populations with a low prevalence of syphilis.

Persons with a positive treponemal screening test should have a standard nontreponemal test with titer performed reflexively by the laboratory to guide patient management decisions. If the nontreponemal test is negative, then the laboratory should perform a different treponemal test (preferably one based on different antigens than the original test) to confirm the results of the initial test. If a second treponemal test is positive, persons with a history of previous treatment will require no further management unless sexual history suggests likelihood of re-exposure. Those without a history of treatment for syphilis should be offered treatment. Unless history or results of a physical examination suggest a recent infection, previously untreated persons should be treated for late latent syphilis. If the second treponemal test is negative, further evaluation or treatment is not indicated.

For most HIV-infected persons, serologic tests are accurate and reliable for the diagnosis of syphilis and for following a patient’s response to treatment. However, atypical syphilis serologic test results (i.e., unusually high, unusually low, or fluctuating titers) can occur in HIV-infected persons. When serologic tests do not correspond with clinical findings suggestive of early syphilis, use of other tests (e.g., biopsy and darkfield microscopy) should be considered.

Clinical signs of neurosyphilis (i.e., cranial nerve dysfunction, meningitis, stroke, acute or chronic altered mental status, loss of vibration sense, and auditory or ophthalmic abnormalities) warrant further investigation and treatment for neurosyphilis. Laboratory testing is helpful in supporting the diagnosis of neurosyphilis; however, no single test can be used to diagnose neurosyphilis in all instances. Cerebrospinal fluid (CSF) laboratory abnormalities are common in persons with early syphilis. The VDRL in cerebrospinal fluid (CSF-VDRL), which is highly specific but insensitive, is the standard serologic test for CSF. When reactive in the absence of substantial contamination of CSF with blood, it is considered diagnostic of neurosyphilis; however in early syphilis, it can be of unknown prognostic significance (203). Most other tests are both insensitive and nonspecific and must be interpreted in relation to other test results and the clinical assessment. Therefore, the laboratory diagnosis of neurosyphilis usually depends on various combinations of reactive serologic test results, CSF cell count or protein, and a reactive CSF-VDRL with or without clinical manifestations. Among persons with HIV infection, the CSF leukocyte count usually is elevated (>5 white blood cell count [WBC]/mm3); using a higher cutoff (>20 WBC/ mm3) might improve the specificity of neurosyphilis diagnosis (204). The CSF-VDRL might be nonreactive even when neurosyphilis is present; therefore, additional evaluation using FTA-ABS testing on CSF can be considered. The CSF FTA-ABS test is less specific for neurosyphilis than the CSF-VDRL but is highly sensitive; neurosyphilis is highly unlikely with a negative CSF FTA-ABS test (205).

Treatment

Penicillin G, administered parenterally, is the preferred drug for treating all stages of syphilis. The preparation used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of the disease. Selection of the appropriate penicillin preparation is important, because T. pallidum can reside in sequestered sites (e.g., the CNS and aqueous humor) that are poorly accessed by some forms of penicillin. Combinations of benzathine penicillin, procaine penicillin, and oral penicillin preparations are not considered appropriate for the treatment of syphilis. Reports have indicated that practitioners have inadvertently prescribed combination benzathine-procaine penicillin (Bicillin C-R) instead of the standard benzathine penicillin product (Bicillin L-A) widely used in the United States. Practitioners, pharmacists, and purchasing agents should be aware of the similar names of these two products to avoid using the inappropriate combination therapy agent for treating syphilis (206).

The effectiveness of penicillin for the treatment of syphilis was well established through clinical experience even before the value of randomized controlled clinical trials was recognized. Therefore, nearly all the recommendations for the treatment of syphilis are based not only on clinical trials and observational studies, but approximately 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 (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, fever, and other symptoms that usually occur within the first 24 hours after the initiation of any therapy for syphilis. Patients should be informed about this possible adverse reaction. The Jarisch-Herxheimer reaction occurs most frequently among patients who have early syphilis, presumably because bacterial burdens are higher during these stages. Antipyretics can be used to manage symptoms, but they have not been proven to prevent this reaction. The Jarisch-Herxheimer reaction might induce early labor or cause fetal distress in pregnant women, but this should not prevent or delay therapy (see Syphilis During Pregnancy).

Management of Sex Partners

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

• Persons who were exposed within the 90 days preceding the diagnosis of primary, secondary, or early latent syphilis in a sex partner might be infected even if seronegative; therefore, such persons should be treated presumptively.

• Persons who were exposed >90 days before the diagnosis of primary, secondary, or early latent syphilis in a sex partner should be treated presumptively if serologic test results are not available immediately and the opportunity for follow-up is uncertain.

• For purposes of partner notification and presumptive treatment of exposed sex partners, patients with syphilis of unknown duration who have high nontreponemal serologic test titers (i.e., >1:32) can be assumed to have early syphilis. For the purpose of determining a treatment regimen, however, serologic titers should not be used to differentiate early from late latent syphilis (see Latent Syphilis, Treatment).

• Long-term sex partners of patients who have latent syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of the evaluation findings.

Sexual partners of infected patients should be considered at risk and provided treatment if they have had sexual contact with the patient within 3 months plus the duration of symptoms for patients diagnosed with primary syphilis, 6 months plus duration of symptoms for those with secondary syphilis, and 1 year for patients with early latent syphilis.

Primary and Secondary Syphilis

Treatment

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

Recommended Regimen for Adults*

Benzathine penicillin G 2.4 million units IM in a single dose

* Recommendations for treating syphilis in HIV-infected persons and pregnant women are discussed later in this report (see Syphilis among HIV–Infected Persons and Syphilis in Pregnancy).

Available data demonstrate that additional doses of benzathine penicillin G, amoxicillin, or other antibiotics in early syphilis (primary, secondary, and early latent) do not enhance efficacy, regardless of HIV status.

Recommended Regimen for Infants and Children

Infants and children aged ≥1 month diagnosed 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.

Recommended Regimen for Infants and Children

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

Other Management Considerations

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

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

Invasion of CSF by T. pallidum accompanied by CSF laboratory abnormalities is common among adults who have primary or secondary syphilis (203). Therefore, in the absence of clinical neurologic findings, no evidence exists to support variation from the recommended treatment regimen for early syphilis. Symptomatic neurosyphilis develops in only a limited number of persons 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 or treatment failure is documented, routine CSF analysis is not recommended for persons who have primary or secondary syphilis.

Follow-Up

Treatment failure can occur with any regimen. However, assessing response to treatment frequently is difficult, and definitive criteria for cure or failure have not been established. In addition, nontreponemal test titers might decline more slowly for persons who previously have had syphilis (207). Clinical and serologic evaluation should be performed 6 months and 12 months after treatment; more frequent evaluation might be prudent if follow-up is uncertain.

Patients who have signs or symptoms that persist or recur or who have a sustained fourfold increase in nontreponemal test titer (i.e., compared with the maximum or baseline titer at the time of treatment) probably failed treatment or were reinfected. These patients should be retreated and reevaluated for HIV infection. Because treatment failure usually cannot be reliably distinguished from reinfection with T. pallidum, a CSF analysis also should be performed.

Although failure of nontreponemal test titers to decline fourfold within 6–12 months after therapy for primary or secondary syphilis might be indicative of treatment failure, clinical trial data have demonstrated that >15% of patients with early syphilis treated with the recommended therapy will not achieve the two dilution decline in nontreponemal titer used to define response at 1 year after treatment (208). Persons whose titers do not decline should be reevaluated for HIV infection. Optimal management of such patients is unclear. At a minimum, these patients should receive additional clinical and serologic follow-up. If additional follow-up cannot be ensured, retreatment is recommended. Because treatment failure might be the result of unrecognized CNS infection, CSF examination can be considered in such situations.

For retreatment, weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks is recommended, unless CSF examination indicates that neurosyphilis is present (see Neurosyphilis). In rare instances, serologic titers do not decline despite a negative CSF examination and a repeated course of therapy. In these circumstances, the need for additional therapy or repeated CSF examinations is unclear, but is not generally recommended.

Management of Sex Partners

See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Data to support the use of alternatives to penicillin in the treatment of early syphilis are limited. However, several therapies might be effective in nonpregnant, penicillin-allergic patients who have primary or secondary syphilis. Doxycycline 100 mg orally twice daily for 14 days (209,210) 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 (1 g daily either IM or IV for 10–14 days) is effective for treating early syphilis, the optimal dose and duration of ceftriaxone therapy have not been defined (211). Azithromycin as a single 2-g oral dose is effective for treating early syphilis (212–214). However, T. pallidum chromosomal mutations associated with azithromycin resistance and treatment failures have been documented in several geographical areas in the United States (215–217). As such, the use of azithromycin should be used with caution only when treatment with penicillin or doxycycline is not feasible. Azithromycin should not be used in MSM or pregnant women. Close follow-up of persons receiving any alternative therapies is essential.

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

Pregnancy

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

HIV Infection

See Syphilis Among HIV-Infected Persons.

Latent Syphilis

Latent syphilis is defined as syphilis characterized by seroreactivity without other evidence of disease. Patients who have latent syphilis and who acquired syphilis during the preceding year are classified as having early latent syphilis. Patients’ conditions can be diagnosed as early latent syphilis if, during the year preceding the evaluation, they had 1) a documented seroconversion or fourfold or greater increase in titer of a nontreponemal test; 2) unequivocal symptoms of primary or secondary syphilis; or 3) a sex partner documented to have primary, secondary, or early latent syphilis. In addition, for persons whose only possible exposure occurred during the previous 12 months, reactive nontreponemal and treponemal tests are indicative of early latent syphilis. In the absence of these conditions, an asymptomatic person should be considered to have late latent syphilis or syphilis of unknown duration. 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, perianal area, perineum and vagina 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

Because latent syphilis is not transmitted sexually, the objective of treating patients with this stage of disease is to prevent complications. Although clinical experience supports the effectiveness of penicillin in achieving this goal, limited evidence is available to guide choice of specific regimens.

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

Recommended Regimens for Adults*

Early Latent Syphilis Benzathine penicillin G 2.4 million units IM in a single dose

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

* Recommendations for treating syphilis in HIV-infected persons and pregnant women are discussed later in this report (see Syphilis among HIV-Infected Persons and Syphilis in Pregnancy).

Available data demonstrate no enhanced efficacy of additional doses of penicillin G, amoxicillin, or other antibiotics in early syphilis, regardless of HIV status.

Infants and children aged ≥1 month who have been diagnosed with syphilis should have a CSF examination to exclude neurosyphilis. In addition, birth and maternal medical records should be reviewed to assess whether children have congenital or acquired syphilis (see Congenital Syphilis). Older children with acquired latent syphilis should be evaluated as described for adults and treated using the following pediatric regimens (see Sexual Assault or Abuse of Children). These regimens are for penicillin nonallergic children who have acquired syphilis and who have normal CSF examination results.

Recommended Regimens for Children

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

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

Other Management Considerations

Patients diagnosed with latent syphilis who demonstrate any of the following criteria should have a prompt CSF examination:

• Neurologic (e.g., auditory disease, cranial nerve dysfunction, acute or chronic meningitis, stroke, acute or chronic altered mental status, and loss of vibration sense) or ophthalmic signs or symptoms (e.g., iritis and uveitis);

• evidence of active tertiary syphilis (e.g., aortitis and gumma); or

• serologic treatment failure.

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

Follow-Up

Quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months. A CSF examination should be performed if 1) titers increase fourfold, 2) an initially high titer (≥1:32) fails to decline at least fourfold (i.e., two dilutions) within 12–24 months of therapy, or 3) signs or symptoms attributable to syphilis develop. In such circumstances, even if the CSF examination is negative, retreatment for latent syphilis should be initiated. In rare instances, despite a negative CSF examination and a repeated course of therapy, serologic titers might fail to decline. In these circumstances, the need for additional therapy or repeated CSF examinations is unclear.

Management of Sex Partners

See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy

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

Pregnancy

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

HIV Infection

See Syphilis Among HIV-Infected Persons.

Tertiary Syphilis

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

Recommended Regimen

Benzathine penicillin G 7.2 million units total, administered as 3 doses of 2.4 million units IM each at 1-week intervals

Other Management Considerations

Patients who have symptomatic late syphilis should be given a CSF examination before therapy is initiated. Some providers treat all patients who have cardiovascular syphilis with a neurosyphilis regimen. These patients should be managed in consultation with an infectious disease specialist.

Follow-Up

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

Management of Sex Partners

See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Patients allergic to penicillin should be treated in consultation with an infectious disease specialist.

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.

Neurosyphilis

Treatment

CNS involvement can occur during any stage of syphilis. However, CSF laboratory abnormalities are common in persons with early syphilis, even in the absence of clinical neurological findings. No evidence exists to support variation from recommended treatment for early syphilis for patients found to have such abnormalities. If clinical evidence of neurologic involvement is observed (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis), a CSF examination should be performed.

Syphilitic uveitis or other ocular manifestations frequently are associated with neurosyphilis and should be managed according to the treatment recommendations for neurosyphilis. Patients who have neurosyphilis or syphilitic eye disease (e.g., uveitis, neuroretinitis, and optic neuritis) should be treated with the recommended regimen for neurosyphilis; those with eye disease should be managed in collaboration with an ophthalmologist. A CSF examination should be performed for all patients with syphilitic eye disease to identify those with abnormalities; patients found to have abnormal CSF test results should be provided follow-up CSF examinations to assess treatment response.

Recommended Regimen

Aqueous crystalline penicillin G 18–24 million units per day, administered as 3–4 million units IV every 4 hours or continuous infusion, for 10–14 days

If compliance with therapy can be ensured, the following alternative regimen might be considered.

Alternative Regimen

Procaine penicillin 2.4 million units IM once daily PLUS Probenecid 500 mg orally four times a day, both for 10–14 days

The durations of the recommended and alternative regimens for neurosyphilis are shorter than the duration of the regimen used for late syphilis in the absence of neurosyphilis. Therefore, benzathine penicillin, 2.4 million units IM once per week for up to 3 weeks, can be considered 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 persons who have syphilis should be tested for HIV.

• Although systemic steroids are used frequently as adjunctive therapy for otologic syphilis, such drugs have not been proven to be 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 CSF-VDRL or CSF protein after therapy; however, changes in these two parameters occur more slowly than cell counts, and persistent abnormalities might be less important (219,220). The leukocyte count is a sensitive measure of the effectiveness of therapy. If the cell count has not decreased after 6 months or if the CSF cell count or protein is not normal after 2 years, retreatment should be considered. Limited data suggest that in immunocompetent persons and HIV-infected persons on highly active antiretroviral therapy, normalization of the serum RPR titer predicts normalization of CSF parameters (220).

Management of Sex Partners

See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy

Limited data suggest that ceftriaxone 2 g daily either IM or IV for 10–14 days can be used as an alternative treatment for patients with neurosyphilis (221,222). However, the possibility of cross-reactivity between ceftriaxone and penicillin exists. 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, skin testing should be performed (if available) to confirm penicillin allergy and, if necessary, desensitization in consultation with a specialist.

Pregnancy

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

HIV Infection

See Syphilis Among HIV-Infected Persons.

Syphilis Among HIV-Infected Persons

Diagnostic Considerations

Although they are uncommon, 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 (223). Regardless, both treponemal and nontreponemal 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 their interpretation is unclear, alternative tests (e.g., biopsy of a lesion, darkfield examination, and PCR of lesion material) might be useful for diagnosis. Neurosyphilis should be considered in the differential diagnosis of neurologic disease in HIV-infected persons.

Treatment

Compared with HIV-negative patients, HIV-positive patients who have early syphilis might be at increased risk for neurologic complications (224) and might have higher rates of serologic treatment failure with currently recommended regimens. The magnitude of these risks is not defined precisely, but is likely small. 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 (208). Careful follow-up after therapy is essential.

Primary and Secondary Syphilis Among HIV-Infected Persons

Treatment

Treatment of primary and secondary syphilis among HIV-infected persons is benzathine penicillin G, 2.4 million units IM in a single dose.

Available data demonstrate that additional doses of benzathine penicillin G, amoxicillin, or other antibiotics in early syphilis do not result in enhanced efficacy, regardless of HIV status (208).

Other Management Considerations

Most HIV-infected persons respond appropriately to standard benzathine penicillin for primary and secondary syphilis. CSF abnormalities (e.g., mononuclear pleocytosis and elevated protein levels) are common in HIV-infected persons, even in those without neurologic symptoms, although the clinical and prognostic significance of such CSF abnormalities with primary and secondary syphilis is unknown. Several studies have demonstrated that among persons infected with both HIV and syphilis, clinical and CSF abnormalities consistent with neurosyphilis are associated with a CD4 count of ≤350 cells/mL and/or an RPR titer of ≥1:32 (204,225,226); however, unless neurologic symptoms are present, CSF examination in this setting has not been associated with improved clinical outcomes.

The use of antiretroviral therapy as per current guidelines might improve clinical outcomes in HIV-infected persons with syphilis (220,227,228).

Follow-Up

HIV-infected persons should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy.

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

Management of Sex Partners

See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy. HIV-infected, penicillin-allergic patients who have primary or secondary syphilis should be managed according to the recommendations for penicillin-allergic, HIV-negative patients. 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 use of alternatives to penicillin has not been well studied in HIV-infected patients. These therapies should be used only in conjunction with close serologic and clinical follow-up.

Latent Syphilis Among HIV-Infected Persons

Treatment

HIV-infected persons with latent syphilis should be treated according to the stage-specific recommendations for HIV-negative persons.

• Treatment of early latent syphilis among HIV-infected persons is benzathine penicillin G, 2.4 million units IM in a single dose.

• Treatment of late latent syphilis or syphilis of unknown duration among HIV-infected persons is benzathine penicillin G, at weekly doses of 2.4 million units for 3 weeks.

Other Management Considerations

All HIV-infected persons with syphilis and neurologic symptoms should undergo immediate CSF examination. Some studies have demonstrated that clinical and CSF abnormalities consistent with neurosyphilis are most likely in HIV-infected persons who have been diagnosed with syphilis and have a CD4 count of ≤350 cells/ml and/or an RPR titer of ≥1:32 (204,225,226); however unless neurologic symptoms are present, CSF examination in this setting has not been associated with improved clinical outcomes.

Follow-Up

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

Management of Sex Partners

See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy. The efficacy of alternative nonpenicillin regimens in HIV-infected persons has not been well studied. Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin (see Management of Patients Who Have a History of Penicillin Allergy). These therapies should be used only in conjunction with close serologic and clinical follow-up. Limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone might be effective (229,230). However, the optimal dose and duration of ceftriaxone therapy have not been defined.

Neurosyphilis Among HIV-Infected Persons

Treatment

HIV-infected patients with neurosyphilis should be treated according to the recommendations for HIV-negative patients with neurosyphilis (see Neurosyphilis).

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 gauge response after therapy. Limited data suggest that changes in CSF parameters might occur more slowly in HIV-infected patients, especially those with more advanced immunosuppression (219,227). If the cell count has not decreased after 6 months or if the CSF is not normal after 2 years, retreatment should be considered.

Management of Sex Partners

See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy. HIV-infected, penicillin-allergic patients who have neurosyphilis should be managed according to the recommendations for penicillin-allergic, HIV-negative patients with neurosyphilis. Several small observational studies conducted in HIV-infected patients with neurosyphilis suggest that ceftriaxone 1–2 g IV daily for 10-14 days might be effective as an alternate agent (218,229,230).

Syphilis During Pregnancy

All women should be screened serologically for syphilis early in pregnancy. Most states mandate screening at the first prenatal visit for all women (231); antepartum screening by nontreponemal antibody testing is typical, but in some settings, treponemal antibody testing is being used. Pregnant women with reactive treponemal screening tests should have confirmatory testing with nontreponemal tests with titers. In populations in which use of prenatal care is not optimal, RPR test screening and treatment (if the RPR test is reactive) should be performed at the time that pregnancy is confirmed (232). For communities and populations in which the prevalence of syphilis is high and for patients at high risk, serologic testing should be performed twice during the third trimester (ideally at 28–32 weeks’ gestation) and at delivery. Any woman who delivers a stillborn infant after 20 weeks’ gestation should be tested for syphilis. No infant should leave the hospital without the maternal serologic status having been determined at least once during pregnancy.

Diagnostic Considerations

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

Treatment

Penicillin is effective for preventing maternal transmission to the fetus and for treating fetal infection (233). Evidence is insufficient to determine optimal, recommended penicillin regimens (234).

Recommended Regimen

Pregnant women should be treated with the penicillin regimen appropriate for their stage of infection.

Other Management Considerations

Some evidence suggests that additional therapy can be beneficial for pregnant women in some settings (e.g., a second dose of benzathine penicillin 2.4 million units IM administered 1 week after the initial dose for women who have primary, secondary, or early latent syphilis) (235). When syphilis is diagnosed during the second half of pregnancy, management should include a sonographic fetal evaluation for congenital syphilis, but this evaluation should not delay therapy. Sonographic signs of fetal or placental syphilis (i.e., hepatomegaly, ascites, hydrops, fetal anemia, or a thickened placenta) indicate a greater risk for fetal treatment failure (231); 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 (236). These women should be advised to seek obstetric attention after treatment if they notice any fever, contractions, or decrease in fetal movements. Stillbirth is a rare complication of treatment, but concern for this complication should not delay necessary treatment. All patients who have syphilis should be offered testing for HIV infection.

Follow-Up

Coordinated prenatal care and treatment are vital. Serologic titers should be repeated at 28–32 weeks’ gestation and at delivery as recommended for the disease stage. Providers should ensure that the clinical and antibody responses are appropriate for the patient’s stage of disease, although most women will deliver before their serologic response to treatment can be assessed definitively. Inadequate maternal treatment is likely if delivery occurs within 30 days of therapy, if clinical signs of infection are present at delivery, or if the maternal antibody titer at delivery is fourfold higher than the pretreatment titer. Serologic titers can be checked monthly in women at high risk for reinfection or in geographic areas in which the prevalence of syphilis is high

Management of Sex Partners

See General Principles, Management of Sex Partners.

Special Considerations

Penicillin Allergy

For treatment of syphilis during pregnancy, no proven alternatives to penicillin exist. Pregnant women who have a history of penicillin allergy should be desensitized and treated with penicillin. Oral step-wise penicillin dose challenge or skin testing might be helpful in identifying women at risk for acute allergic reactions (see Management of Patients Who Have a History of Penicillin Allergy).

Tetracycline and doxycycline usually are not used during pregnancy. Erythromycin and azithromycin should not be used, because neither reliably cures maternal infection or treats an infected fetus (234). Data are insufficient to recommend ceftriaxone for treatment of maternal infection and prevention of congenital syphilis.

HIV Infection

Placental inflammation from congenital infection might increase the risk for perinatal transmission of HIV. All HIV-infected women should be evaluated for syphilis and receive treatment as recommended. Data are insufficient to recommend a specific regimen for HIV-infected pregnant women (see Syphilis Among HIV-Infected Patients).

Congenital Syphilis

Effective prevention and detection of congenital syphilis depends on the identification of syphilis in pregnant women and, therefore, on the routine serologic screening of pregnant women during the first prenatal visit. In communities and populations in which the risk for congenital syphilis is high, serologic testing and a sexual history also should be obtained at 28 weeks’ gestation and at delivery. Moreover, as part of the management of pregnant women who have syphilis, information concerning the treatment of sex partners should be obtained to assess the risk for reinfection.

Routine screening of newborn sera or umbilical cord blood is not recommended. Serologic testing of the mother’s serum is preferred rather than testing of the infant’s serum because the serologic tests performed on infant serum can be nonreactive if the mother’s serologic test result is of low titer or the mother was infected late in pregnancy (see Diagnostic Considerations and Use of Serologic Tests). Screening can be performed using either a nontreponemal or treponemal test. If either screening test is positive, testing must be performed immediately using the other complimentary test (i.e., nontreponemal test followed by treponemal test or vice-versa). No infant or mother should leave the hospital unless maternal serologic status has been documented at least once during pregnancy; in communities and populations in which the risk for congenital syphilis is high, documentation should also occur at delivery.

Evaluation and Treatment of Infants During the First Month of Life

The diagnosis of congenital syphilis is complicated by the transplacental transfer of maternal nontreponemal and treponemal IgG antibodies to the fetus, which can complicate the interpretation of reactive serologic tests for syphilis in infants. Therefore, treatment decisions frequently must be made on the basis of 1) identification of syphilis in the mother; 2) adequacy of maternal treatment; 3) presence of clinical, laboratory, or radiographic evidence of syphilis in the infant; and 4) comparison of maternal (at delivery) and infant nontreponemal serologic titers using the same test conducted preferably by 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 yield a false-positive result. Conducting a treponemal test (i.e., TP-PA, FTA-ABS, EIA, or chemiluminescence assay) on a newborn’s serum is not necessary. No commercially available immunoglobulin (IgM) test can be recommended.

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

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

Scenario 1

Infants with proven or highly probable disease and

1. an abnormal physical examination that is consistent with congenital syphilis;

2. a serum quantitative nontreponemal serologic titer that is fourfold higher than the mother’s titer;¶ or

3. a positive darkfield test of body fluid(s).

Recommended Evaluation

• CSF analysis for VDRL, cell count, and protein**

• Complete blood count (CBC) and differential and platelet count

• Other tests as clinically indicated (e.g., long-bone radiographs, chest radiograph, liver-function tests, cranial ultrasound, ophthalmologic examination, and auditory brain stem response)

Recommended Regimens

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

If 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 quantitive nontreponemal serologic titer the same or less than fourfold the maternal titer and the

1. mother was not treated, inadequately treated, or has no documentation of having received treatment;

2. mother was treated with erythromycin or another nonpenicillin regimen;†† or

3. mother received treatment <4 weeks before delivery.

Recommended Evaluation

• CSF analysis for VDRL, cell count, and protein

• CBC, differential, and platelet count

• Long-bone radiographs

A complete evaluation is not necessary if 10 days of parenteral therapy is administered, although such evaluations might be useful. For instance, a lumbar puncture might document CSF abnormalities that would prompt close follow-up. Other tests (e.g., CBC, platelet count, and bone radiographs) can 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., by CSF examination, long-bone radiographs, and CBC with platelets), the full evaluation must be normal, and follow-up must be certain. If any part of the infant’s evaluation is abnormal or not performed or if the CSF analysis is rendered uninterpretable because of contamination with blood, then a 10-day course of penicillin is required.§§

Recommended Regimens

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

If the mother has untreated early syphilis at delivery, 10 days of parenteral therapy can be considered.

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

1. mother was treated during pregnancy, treatment was appropriate for the stage of infection, and treatment was administered >4 weeks before delivery and

2. mother has no evidence of reinfection or relapse.

Recommended Evaluation

No evaluation is required.

Recommended Regimen

Benzathine penicillin G 50,000 units/kg/dose IM in a single dose*

* Another approach involves not treating the infant, but rather providing close serologic follow-up in those whose mother’s nontreponemal titers decreased fourfold after appropriate therapy for early syphilis or remained stable or low for late syphilis.

Scenario 4

Infants who have a normal physical examination and a serum quantitative nontreponemal serologic titer the same or less than fourfold the maternal titer and the

1. mother’s treatment was adequate before pregnancy and

2. mother’s nontreponemal serologic titer remained low and stable before and during pregnancy and at delivery (VDRL <1:2; RPR <1:4).

Recommended Evaluation

No evaluation is required.

Recommended Regimen

No treatment is required; however, benzathine penicillin G 50,000 units/kg as a single IM injection might be considered, particularly if follow-up is uncertain.

Evaluation and Treatment of Older Infants and Children

Older infants and children aged ≥1 month who are identified as having reactive serologic tests for syphilis should have maternal serology and records reviewed to assess whether they have congenital or acquired syphilis (see Primary and Secondary Syphilis and Latent Syphilis, Sexual Assault or Abuse of Children). Any child at risk for congenital syphilis should receive a full evaluation and testing for HIV infection.

Recommended Evaluation

• CSF analysis for VDRL, cell count, and protein

• CBC, differential, and platelet count

• Other tests as clinically indicated (e.g., long-bone radiographs, chest radiograph, liver function tests, abdominal ultrasound, ophthalmologic examination, and auditory brain stem response)

Recommended Regimen

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

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

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

Follow-Up

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

Treponemal tests should not be used to evaluate treatment response, because the results for an infected child can remain positive despite effective therapy. Passively transferred maternal treponemal antibodies can be present in an infant until age 15 months; therefore, 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 retreatment for possible neurosyphilis.

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

Special Considerations

Penicillin Allergy

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

Penicillin Shortage

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

1. For infants with clinical evidence of congenital syphilis (Scenario 1), check local sources for aqueous crystalline penicillin G (potassium or sodium). If IV penicillin G is limited, substitute some or all daily doses with procaine penicillin G (50,000 U/kg/dose IM a day in a single daily dose for 10 days).

   If aqueous or procaine penicillin G is not available, ceftriaxone (in doses appropriate for age and weight) can be considered with careful clinical and serologic follow-up. Ceftriaxone must be used with caution in infants with jaundice. For infants aged ≥30 days, use 75 mg/kg IV/IM a day in a single daily dose for 10–14 days; however, dose adjustment might be necessary based on current weight. For older infants, the dose should be 100 mg/kg a day in a single daily dose. Evidence is insufficient to support the use of ceftriaxone for the treatment of congenital syphilis. Therefore, ceftriaxone should be used in consultation with a specialist in the treatment of infants with congenital syphilis. Management may include a repeat CSF examination at age 6 months if the initial examination was abnormal.

2. For infants without any clinical evidence of infection (Scenario 2 and Scenario 3), use
   a. procaine penicillin G, 50,000 U/kg/dose IM a day in a single dose for 10 days;
   or
   b. benzathine penicillin G, 50,000 U/kg IM as a single dose.

   If any part of the evaluation for congenital syphilis is abnormal, CSF examination is not interpretable, CSF examination was not performed, or follow-up is uncertain, procaine penicillin G is recommended. A single dose of ceftriaxone is inadequate therapy.

3. For premature infants who have no other clinical evidence of infection (Scenario 2 and Scenario 3) and might not tolerate IM injections because of decreased muscle mass, IV ceftriaxone can be considered with careful clinical and serologic follow-up (see Penicillin Shortage, Number 1). Ceftriaxone dosing must be adjusted according to age and birth weight.

HIV Infection

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

Management of Persons 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 also is recommended for use, whenever possible, in HIV-infected patients. Of the adult U.S. population, 3%–10% have experienced an immunoglobulin E (IgE)-mediated allergic response to penicillin (238,239), such as urticaria, angioedema, or anaphylaxis (i.e., upper airway obstruction, bronchospasm, or hypotension). Readministration 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.

Although an estimated 10% of persons who report a history of severe allergic reactions to penicillin continue to remain allergic their entire lives, with the passage of time, most persons who have had a severe reaction to penicillin stop expressing penicillin-specific IgE (238,239). These persons can then be treated safely with penicillin. Penicillin skin testing with the major and minor determinants of penicillin can reliably identify persons at high risk for penicillin reactions (238,239). Although these reagents are easily generated and have been available for more than 30 years, only benzylpenicilloyl poly-L-lysine (Pre-Pen [i.e., the major determinant]) and penicillin G have been available commercially. These two tests identify 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, caution should be exercised when the full battery of skin-test reagents is not available (Box 2). Manufacturers are working to ensure better availability of the Pre-Pen skin test reagent as well as an accompanying minor determinant mixture.

Recommendations

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

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. One approach suggests that persons with a history of allergy who have negative test results should be regarded as possibly allergic and desensitized. Another approach in those with negative skin-test results involves test-dosing gradually with oral penicillin in a monitored setting in which treatment for anaphylactic reaction can be provided.

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

Penicillin Allergy Skin Testing

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

Procedures

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

Epicutaneous (Prick) Tests

Duplicate drops of skin-test reagent are placed on the volar surface of the forearm. The underlying epidermis is pierced with a 26-gauge needle without drawing blood. An epicutaneous test is positive if the average wheal diameter after 15 minutes is ≥4 mm larger than that of negative controls; otherwise, the test is negative. The histamine controls should be positive to ensure that results are not falsely negative because of the effect of antihistaminic drugs.

Intradermal Test

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

Desensitization

Patients who have a positive skin test to one of the penicillin determinants can be desensitized (Table 1). This is a straightforward, relatively safe procedure that can be performed orally or IV. Although the two approaches have not been compared, oral desensitization is regarded as safer and easier to perform. Patients should be desensitized in a hospital setting because serious IgE-mediated allergic reactions can occur. Desensitization usually can be completed in approximately 4–12 hours, after which time 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

Urethritis

Urethritis, as characterized by urethral inflammation, can result from infectious and noninfectious conditions. Symptoms, if present, include discharge of mucopurulent or purulent material, dysuria, or urethral pruritis. Asymptomatic infections are common. Although N. gonorrhoeae and C. trachomatis are well established as clinically important infectious causes of urethritis, Mycoplasma genitalium has also been associated with urethritis (240–243). If clinic-based diagnostic tools (e.g., Gram-stain microscopy, first void urine with microscopy, and leukocyte esterase) are not available, patients should be treated with drug regimens effective against both gonorrhea and chlamydia. Further testing to determine the specific etiology is recommended because both chlamydia and gonorrhea are reportable to health departments and a specific diagnosis might improve partner notification and treatment. Culture, nucleic acid hybridization tests, and NAATs are available for the detection of both N. gonorrhoeae and C. trachomatis. Culture and hybridization tests require urethral swab specimens, whereas NAATs can be performed on urine specimens. Because of their higher sensitivity, NAATs are preferred for the detection of C. trachomatis (197).

Etiology

Several organisms can cause infectious urethritis. The presence of Gram-negative intracellular diplococci (GNID) on urethral smear is indicative of gonorrhea infection, which is frequently accompanied by chlamydial infection. Nongonoccocal urethritis (NGU), which is diagnosed when examination findings or microscopy indicate inflammation without GNID, is caused by C. trachomatis in 15%–40% of cases; however, prevalence varies by age group, with a lower burden of disease occurring among older men (244). Complications of NGU among males infected with C. trachomatis include epididymitis and Reiter’s syndrome. Documentation of chlamydial infection is essential because of the need for partner referral for evaluation and treatment.

In most cases of nonchlamydial NGU, no pathogen can be detected. M. genitalium, which appears to be sexually transmitted, is associated with both symptoms of urethritis and urethral inflammation and accounts for 15%–25% of NGU cases in the United States (240–243). T. vaginalis, HSV, and adenovirus also can cause NGU, but data supporting other Mycoplasma species and Ureaplasma as etiologic agents are inconsistent (244–247). Diagnostic and treatment procedures for these organisms are reserved for situations in which these infections are suspected (e.g., contact with trichomoniasis, genital lesions, or severe dysuria and meatitis, which might suggest genital herpes) or when NGU is not responsive to therapy. Enteric bacteria have been identified as an uncommon cause of NGU and might be associated with insertive anal intercourse (244).

Confirmed Urethritis

Clinicians should attempt to obtain objective evidence of urethral inflammation. However, if clinic-based diagnostic tools (e.g., Gram-stain microscopy) are not available, patients should be treated with drug regimens effective against both gonorrhea and chlamydia.

Urethritis can be documented on the basis of any of the following signs or laboratory tests:

• Mucopurulent or purulent discharge on examination.

• Gram stain of urethral secretions demonstrating ≥5 WBC per oil immersion field. The Gram stain is the preferred rapid diagnostic test for evaluating urethritis and is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. Gonococcal infection is established by documenting the presence of WBC containing GNID.

• Positive leukocyte esterase test on first-void urine or microscopic examination of first-void urine sediment demonstrating ≥10 WBC per high-power field.

If none of these criteria are present, testing for N. gonorrhoeae and C. trachomatis using NAATs might identify additional infections (248). If the results demonstrate infection with either of these pathogens, the appropriate treatment should be given and sex partners referred for evaluation and treatment. If none of these criteria are present, empiric treatment of symptomatic males is recommended only for men at high risk for infection who are unlikely to return for a follow-up evaluation. Such patients should be treated with drug regimens effective against gonorrhea and chlamydia. Partners of patients treated empirically should be evaluated and treated, if indicated.

Nongonococcal Urethritis

Diagnosis

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

Treatment

Treatment should be initiated as soon as possible after diagnosis. Azithromycin and doxycycline are highly effective for chlamydial urethritis; however, infections with M. genitalium respond better to azithromycin (249,250). Single-dose regimens have the advantage of improved compliance and directly observed treatment. To maximize compliance with recommended therapies, medications should be dispensed on-site in the clinic, and the first dose should be directly observed.

Recommended Regimens

Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days

Alternative Regimens

Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Levofloxacin 500 mg orally once daily for 7 days OR Ofloxacin 300 mg orally twice a day for 7 days

To minimize transmission, men treated for NGU should be instructed to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen, provided their symptoms have resolved. To minimize the risk for reinfection, men should be instructed to abstain from sexual intercourse until all of their sex partners are treated.

Persons who have been diagnosed with a new STD should receive testing for other infections, including syphilis and HIV.

Follow-Up

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 retreatment. Providers should be alert to the possibility of chronic prostatitis/chronic pelvic pain syndrome in male patients experiencing persistent pain (perineal, penile, or pelvic), discomfort, irritative voiding symptoms, pain during or after ejaculation, or new-onset premature ejaculation lasting for >3 months.

Unless a patient’s symptoms persist or therapeutic noncompliance or reinfection is suspected by the provider, a test-of-cure (i.e., repeat testing 3–4 weeks after completing therapy) is not recommended for persons with documented chlamydia or gonococcal infections who have received treatment with recommended or alterative regimens. However, because men with documented chlamydial or gonococcal infections have a high rate of reinfection within 6 months after treatment (251,252), repeat testing of all men diagnosed with chlamydia or gonorrhea is recommended 3–6 months after treatment, regardless of whether patients believe that their sex partners were treated (251).

Partner Referral

A specific diagnosis might facilitate partner referral. Therefore, testing for gonorrhea and chlamydia is encouraged. Because a substantial proportion of female partners of males with nonchlamydial NGU are infected with chlamydia, partner management is recommended for males with NGU regardless of whether a specific etiology is identified. All sex partners within the preceding 60 days should be referred for evaluation, testing, and empiric treatment with a drug regimen effective against chlamydia. Expedited partner treatment and patient referral are alternative approaches to treating partners (71).

Recurrent and Persistent Urethritis

Objective signs of urethritis should be present before the initiation of antimicrobial therapy. In persons who have persistent symptoms after treatment without objective signs of urethritis, the value of extending the duration of antimicrobials has not been demonstrated. Persons who have persistent or recurrent urethritis can be retreated with the initial regimen if they did not comply with the treatment regimen or if they were reexposed to an untreated sex partner. Persistent urethritis after doxycycline treatment might be caused by doxycycline-resistant U. urealyticum or M. genitalium. T. vaginalis is also known to cause urethritis in men; a urethral swab, first void urine, or semen for culture or a NAAT (PCR or TMA) on a urethral swab or urine can be performed. If compliant with the initial regimen and re-exposure can be excluded, the following regimen is recommended while awaiting the results of the diagnostic tests.

Recommended Regimens

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

Studies involving a limited number of patients who experienced NGU treatment failures have demonstrated that Moxifloxacin 400 mg orally once daily for 7 days is highly effective against M. genitalium (253,254). Men with a low probability of T. vaginalis (e.g., MSM) are unlikely to benefit from the addition of metronidazole or tinidazole.

Urologic examinations usually do not reveal a specific etiology for urethritis. A four-glass Meares-Stamey lower-urinary-tract localization procedure (or four-glass test) might be helpful in localizing pathogens to the prostate (255). A substantial proportion of men with chronic nonbacterial prostatitis/chronic pelvic pain syndrome have evidence of urethral inflammation without any identifiable microbial pathogens. Estimates vary considerably depending on the source and sensitivity of the assay, but one study demonstrated that in 50% of men with this syndrome, ≥5 WBCs per high-power field were detected in expressed prostatic secretions (256). Referral to a urologist should be considered for men who experience pain for more than 3 months within a 6-month period.

If men require treatment with a new antibiotic regimen for persistent urethritis and a sexually transmitted agent is the suspected cause, all partners in the past 60 days before the initial diagnosis and any interim partners should be referred for evaluation and appropriate treatment.

Special Considerations

HIV Infection

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

Cervicitis

Two major diagnostic signs characterize cervicitis: 1) a purulent or mucopurulent endocervical exudate visible in the endocervical canal or on an endocervical swab specimen (commonly referred to as mucopurulent cervicitis or cervicitis) and 2) sustained endocervical bleeding easily induced by gentle passage of a cotton swab through the cervical os. Either or both signs might be present. Cervicitis frequently is asymptomatic, but some women complain of an abnormal vaginal discharge and intermenstrual vaginal bleeding (e.g., after sexual intercourse). A finding of leukorrhea (>10 WBC per high-power field on microscopic examination of vaginal fluid) has been associated with chlamydial and gonococcal infection of the cervix. In the absence of inflammatory vaginitis, leukorrhea might be a sensitive indicator of cervical inflammation with a high negative predictive value (257,258). Although some specialists consider an increased number of polymorphonuclear leukocytes on endocervical Gram stain as being useful in the diagnosis of cervicitis, this criterion has not been standardized. In addition, it has a low positive-predictive value (PPV) for infection with C. trachomatis and N. gonorrhoeae and is not available in most clinical settings. Finally, although the presence of GNID on Gram stain of endocervical fluid is specific for the diagnosis of gonococcal cervical infection, it is not a sensitive indicator, because it is observed in only 50% of women with this infection.

Etiology

When an etiologic organism is isolated in the presence of cervicitis, it is typically C. trachomatis or N. gonorrhoeae. Cervicitis also can accompany trichomoniasis and genital herpes (especially primary HSV-2 infection). However, in most cases of cervicitis, no organism is isolated, especially in women at relatively low risk for recent acquisition of these STDs (e.g., women aged >30 years). Limited data indicate that infection with M. genitalium and BV and frequent douching might cause cervicitis (259–263). For reasons that are unclear, cervicitis can persist despite repeated courses of antimicrobial therapy. Because most persistent cases of cervicitis are not caused by relapse or reinfection with C. trachomatis or N. gonorrhoeae, other factors (e.g., persistent abnormality of vaginal flora, douching [or exposure to other types of chemical irritants], or idiopathic inflammation in the zone of ectopy) might be involved.

Diagnosis

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

As discussed, NAAT should be used for diagnosing C. trachomatis and N. gonorrhoeae in women with cervicitis; this testing can be performed on either vaginal, cervical, or urine samples (197). A finding of >10 WBC in vaginal fluid, in the absence of trichomoniasis, might indicate endocervical inflammation caused specifically by C. trachomatis or N. gonorrhoeae (264,265).

Treatment

Several factors should affect the decision to provide presumptive therapy for cervicitis or to await the results of diagnostic tests. Treatment with antibiotics for C. trachomatis should be provided for those women at increased risk for this common STD (e.g., those aged ≤25 years, those with new or multiple sex partners, and those who engage in unprotected sex), especially if follow-up cannot be ensured and if a relatively insensitive diagnostic test is used in place of NAAT. Concurrent therapy for N. gonorrhoeae is indicated if the prevalence of this infection is >5% (those in younger age groups and those living in certain facilities).

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

Recommended Regimens for Presumptive Treatment*

Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days

* Consider concurrent treatment for gonococcal infection if prevalence of gonorrhea is high in the patient population under assessment.

Recurrent and Persistent Cervicitis

Women with persistent cervicitis should be reevaluated for possible reexposure to an STD. If relapse and/or reinfection with a specific STD has been excluded, BV is not present, and sex partners have been evaluated and treated, management options for persistent cervicitis are undefined; in addition, the utility of repeated or prolonged administration of antibiotic therapy for persistent symptomatic cervicitis remains unknown. Women who receive such therapy should return after treatment so that a determination can be made regarding whether cervicitis has resolved. Research is needed on the etiology of persistent cervicitis including the potential role of M. genitalium (266). In women with persistent symptoms that are clearly attributable to cervicitis, referral to a gynecologic specialist can be considered.

Follow-Up

Follow-up should be conducted as recommended for the infections for which a woman is treated. If symptoms persist, women should be instructed to return for re-evaluation because women with documented chlamydial or gonococcal infections have a high rate of reinfection within 6 months after treatment. Therefore, repeat testing of all women with chlamydia or gonorrhea is recommended 3-6 months after treatment, regardless of whether their sex partners were treated (267).

Management of Sex Partners

Management of sex partners of women treated for cervicitis should be appropriate for the identified or suspected STD. Partners should be notified and examined if chlamydia, gonorrhea, or trichomoniasis was identified or suspected in the index patient; these partners should then be treated for the STDs for which the index patient received treatment. To avoid reinfection, 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). Expedited partner treatment and patient referral (see Partner Management) are alternative approaches to treating male partners of women that have chlamydia or gonococcal infections (68,69,71).

Special Considerations

HIV Infection

Patients who have cervicitis and also are infected with HIV should receive the same treatment regimen as those who are HIV negative. Treatment of cervicitis in HIV-infected women is vital because cervicitis increases cervical HIV shedding. Treatment of cervicitis in HIV-infected women reduces HIV shedding from the cervix and might reduce HIV transmission to susceptible sex partners (268–270).

Chlamydial Infections

Chlamydial Infections in Adolescents and Adults

Chlamydial genital infection is the most frequently reported infectious disease in the United States, and prevalence is highest in persons aged ≤25 years (93). Several important sequelae can result from C. trachomatis infection in women, the most serious of which include PID, ectopic pregnancy, and infertility. Some women who have uncomplicated cervical infection already have subclinical upper-reproductive–tract infection upon diagnosis.

Asymptomatic infection is common among both men and women. To detect chlamydial infections, health-care providers frequently rely on screening tests. Annual screening of all sexually active women aged ≤25 years is recommended, as is screening of older women with risk factors (e.g., those who have a new sex partner or multiple sex partners). In June 2007, USPSTF reviewed and updated their chlamydia screening guidance and found that the epidemiology of chlamydial infection in the United States had not changed since the last review (81,271). In issuing recommendations, USPSTF made the decision to alter the age groups used to demonstrate disease incidence (i.e., from persons aged ≤25 years to those aged ≤24 years). CDC has not changed its age cutoff, and thus continues to recommend annual chlamydia screening of sexually active women aged ≤25 years.

Screening programs have been demonstrated to reduce both the prevalence of C. trachomatis infection and rates of PID in women (272,273). Although evidence is insufficient to recommend routine screening for C. trachomatis in sexually active young men because of several factors (including feasibility, efficacy, and cost-effectiveness) (94), the screening of sexually active young men should be considered in clinical settings with a high prevalence of chlamydia (e.g., adolescent clinics, correctional facilities, and STD clinics). Among women, the primary focus of chlamydia screening efforts should be to detect chlamydia and prevent complications, whereas targeted chlamydia screening in men should only be considered when resources permit and do not hinder chlamydia screening efforts in women (274 275). An appropriate sexual risk assessment should be conducted for all persons and might indicate more frequent screening for some women or certain men (see MSM).

Diagnostic Considerations

C. trachomatis urogenital infection in women can be diagnosed by testing urine or by collecting swab specimens from the endocervix or vagina. Diagnosis of C. trachomatis urethral infection in men can be made by testing a urethral swab or urine specimen. Rectal C. trachomatis infections in persons that engage in receptive anal intercourse can be diagnosed by testing a rectal swab specimen. NAATs, cell culture, direct immunofluorescence, EIA, and nucleic acid hybridization tests are available for the detection of C. trachomatis on endocervical specimens and urethral swab specimens from men (197). NAATs are the most sensitive tests for these specimens and are FDA-cleared for use with urine. Some NAATs are cleared for use with vaginal swab specimens, which can be collected by a provider or self-collected by a patient. Self-collected vaginal swab specimens perform at least as well as with other approved specimens using NAATs (276,277), and women find this screening strategy highly acceptable. Rectal and oropharyngeal C. trachomatis infection in persons engaging in receptive anal or oral intercourse can be diagnosed by testing at the anatomic site of exposure. Most tests, including NAAT and nucleic acid hybridization tests, are not FDA-cleared for use with rectal or oropharyngeal swab specimens, and chlamydia culture is not widely available for this purpose. However, NAATs have demonstrated improved sensitivity and specificity compared with culture for the detection of C. trachomatis at rectal sites (278–280) and at oropharyngeal sites among men (278–281). Some laboratories have met CLIA requirements and have validated NAAT testing on rectal swab specimens for C. trachomatis. Recent evidence suggests that the liquid-based cytology specimens collected for Pap smears might be acceptable specimens for NAAT testing, although test sensitivity using these specimens might be lower than those resulting from the use of cervical swab specimens (282); regardless, certain NAATs have been FDA-cleared for use on liquid-based cytology specimens. Persons who undergo testing and are diagnosed with chlamydia should be tested for other STDs.

Treatment

Treating infected patients prevents sexual transmission of the disease, and treating all sex partners of those testing positive for chlamydia can prevent reinfection of the index patient and infection of other partners. Treating pregnant women usually prevents transmission of C. trachomatis to infants during birth. Chlamydia treatment should be provided promptly for all persons testing positive for infection; delays in receiving chlamydia treatment have been associated with complications (e.g., PID) in a limited proportion of chlamydia-infected subjects (283). Coinfection with C. trachomatis frequently occurs among patients who have gonococcal infection; therefore, presumptive treatment of such patients for chlamydia is appropriate (see Gonococcal Infection, Dual Therapy for Gonococcal and Chlamydial Infections). The following recommended treatment regimens and alternative regimens cure infection and usually relieve symptoms.

Recommended Regimens

Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days

Alternative Regimens

Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Levofloxacin 500 mg orally once daily for 7 days OR Ofloxacin 300 mg orally twice a day for 7 days

A meta-analysis of 12 randomized clinical trials of azithromycin versus doxycycline for the treatment of genital chlamydial infection demonstrated that the treatments were equally efficacious, with microbial cure rates of 97% and 98%, respectively (284). These studies were conducted primarily in populations in which follow-up was encouraged, adherence to a 7-day regimen was effective, and culture or EIA (rather than the more sensitive NAAT) was used for determining microbiological outcome. Azithromycin should always be available to treat patients for whom compliance with multiday dosing is uncertain. The clinical significance and transmissibility of C. trachomatis detected at oropharyngeal sites is unclear (285), and the efficacy of different antibiotic regimens in resolving oropharyngeal chlamydia remains unknown.

In patients who have erratic health-care–seeking behavior, poor treatment compliance, or unpredictable follow-up, azithromycin might be more cost-effective in treating chlamydia because it enables the provision of a single-dose of directly observed therapy (284). Erythromycin might be less efficacious than either azithromycin or doxycycline, mainly because of the frequent occurrence of gastrointestinal side effects that can lead to noncompliance. Levofloxacin and ofloxacin are effective treatment alternatives but are more expensive and offer no advantage in the dosage regimen. Other quinolones either are not reliably effective against chlamydial infection or have not been evaluated adequately.

To maximize compliance with recommended therapies, medications for chlamydial infections should be dispensed on site, and the first dose should be directly observed. To minimize disease transmission to sex partners, persons treated for chlamydia should be instructed to abstain from sexual intercourse for 7 days after single-dose therapy or until completion of a 7-day regimen. To minimize the risk for reinfection, patients also should be instructed to abstain from sexual intercourse until all of their sex partners are treated.

Follow-Up

Except in pregnant women, test-of-cure (i.e., repeat testing 3–4 weeks after completing therapy) is not advised for persons treated with the recommended or alterative regimens, unless therapeutic compliance is in question, symptoms persist, or reinfection is suspected. Moreover, the validity of chlamydial diagnostic testing at <3 weeks after completion of therapy (to identify patients who did not respond to therapy) has not been established. False-negative results might occur in the presence of persistent infections involving limited numbers of chlamydial organisms. In addition, NAAT conducted at <3 weeks after completion of therapy in persons who were treated successfully could yield false-positive results because of the continued presence of nonviable organisms (197).

A high prevalence of C. trachomatis infection has been observed in women and men who were treated for chlamydial infection during the preceding several months (251,267,286—288). Most post-treatment infections result from reinfection caused by failure of sex partners to receive treatment or the initiation of sexual activity with a new infected partner. Repeat infections confer an elevated risk for PID and other complications. Unlike the test-of-cure, which is not recommended, repeat C. trachomatis testing of recently infected women or men should be a priority for providers. Chlamydia-infected women and men should be retested approximately 3 months after treatment, regardless of whether they believe that their sex partners were treated (251,267). If retesting at 3 months is not possible, clinicians should retest whenever persons next present for medical care in the 12 months following initial treatment.

Management of Sex Partners

Patients should be instructed to refer their sex partners for evaluation, testing, and treatment if they had sexual contact with the patient during the 60 days preceding onset of the patient’s symptoms or chlamydia diagnosis. Although the exposure intervals defined for the identification of at-risk sex partners are based on limited evaluation, 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.

Among heterosexual patients, if concerns exist that sex partners who are referred to evaluation and treatment will not seek these services (or if other management strategies are impractical or unsuccessful), patient delivery of antibiotic therapy to their partners can be considered (see Partner Management). Compared with standard partner referral, this approach, which involves delivering a prescription or the medication itself, has been associated with a trend toward a decrease in rates of persistent or recurrent chlamydia (68,69,71). Patients must also inform their partners of their infection and provide them with written materials about the importance of seeking evaluation for any symptoms suggestive of complications (e.g., testicular pain in men and pelvic or abdominal pain in women). Patient-delivered partner therapy is not routinely recommended for MSM because of a high risk for coexisting infections, especially undiagnosed HIV infection, in their partners.

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

Special Considerations

Pregnancy

Doxycycline, ofloxacin, and levofloxacin are contraindicated in pregnant women. However, clinical experience and published studies suggest that azithromycin is safe and effective (289—291). Repeat testing to document chlamydial eradication (preferably by NAAT) 3 weeks after completion of therapy with the following regimens is recommended for all pregnant women to ensure therapeutic cure, considering the severe sequelae that might occur in mothers and neonates if the infection persists. Women aged <25 years and those at increased risk for chlamydia (i.e., women who have a new or more than one sex partner) also should be retested during the third trimester to prevent maternal postnatal complications and chlamydial infection in the infant (81). Pregnant women diagnosed with a chlamydial infection during the first trimester should not only receive a test to document chlamydial eradication, but be retested 3 months after treatment.

Recommended Regimens

Azithromycin 1 g orally in a single dose OR Amoxicillin 500 mg orally three times a day for 7 days

Alternative Regimens

Erythromycin base 500 mg orally four times a day for 7 days OR Erythromycin base 250 mg orally four times a day for 14 days OR Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days OR Erythromycin ethylsuccinate 400 mg orally four times a day for 14 days

The frequent gastrointestinal side effects associated with erythromycin can result in noncompliance with the alternative regimens. Although erythromycin estolate is contraindicated during pregnancy because of drug-related hepatotoxicity, the lower dose 14-day erythromycin regimens can be considered if gastrointestinal tolerance is a concern.

HIV Infection

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

Chlamydial Infections Among Infants

Prenatal screening and treatment of pregnant women can prevent chlamydial infection among neonates. Pregnant women aged <25 years are at high risk for infection.

C. trachomatis infection of neonates results from perinatal exposure to the mother’s infected cervix. Although neonatal ocular prophylaxis with silver nitrate solution or antibiotic ointments does not prevent perinatal transmission of C. trachomatis from mother to infant, ocular prophylaxis with these agents does prevent gonococcal ophthalmia and therefore should be administered (see Ophthalmia Neonatorum Prophylaxis).

Initial C. trachomatis perinatal infection involves the mucous membranes of the eye, oropharynx, urogenital tract, and rectum, although infection might be asymptomatic in these locations. Instead, C. trachomatis infection in neonates is most frequently recognized by conjunctivitis that develops 5–12 days after birth. C. trachomatis also can cause a subacute, afebrile pneumonia with onset at ages 1–3 months. Although C. trachomatis has been the most frequent identifiable infectious cause of ophthalmia neonatorum, perinatal chlamydial infections (including ophthalmia and pneumonia) have occurred less frequently because of the institution of widespread prenatal screening and treatment of pregnant women.

Ophthalmia Neonatorum Caused by C. trachomatis

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

Diagnostic Considerations

Sensitive and specific methods used to diagnose chlamydial ophthalmia in the neonate include both tissue culture and nonculture tests (e.g., direct fluorescence antibody [DFA] tests, EIA, and NAAT). Most nonculture tests are not FDA-cleared for the detection of chlamydia from conjunctival swabs, and clinical laboratories must verify the procedure according to CLIA regulations. Specimens 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, and they must contain conjunctival cells, not exudate alone. 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 specimens from infants being evaluated for chlamydial conjunctivitis also should be tested for N. gonorrhoeae.

Recommended Regimen

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

* An association between oral erythromycin and infantile hypertrophic pyloric stenosis (IHIS) has been reported in infants aged <6 weeks who were treated with this drug. Infants treated with erythromycin should be followed for signs and symptoms of IHPS. † Data on use of other macrolides (e.g., azithromycin and clarithromycin) for the treatment of neonatal chlamydia infection are limited. The results of one study involving a limited number of patients suggest that a short course of azithromycin, 20 mg/kg/day orally, 1 dose daily for 3 days, might be effective (292).

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

Follow–Up

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

Management of Mothers and Their Sex Partners

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

Infant Pneumonia Caused by C. trachomatis

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

Diagnostic Considerations

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

Because test results for chlamydia often are not available in a timely manner, the decision to provide treatment for C. trachomatis pneumonia must frequently be based on clinical and radiologic findings. The results of tests for chlamydial infection assist in the management of an infant’s illness and can help determine the need for treating the mother and her sex partner(s).

Recommended Regimen

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

Follow-Up

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

Management of Mothers and Their Sex Partners

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

Infants Born to Mothers Who Have Chlamydial Infection

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

Chlamydial Infections Among Children

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

Diagnostic Considerations

Nonculture, nonamplified probe tests for chlamydia (EIA 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 C. pneumoniae; with genital and anal specimens, false-positive results might occur as a result of cross-reaction with fecal flora.

Recommended Regimen for Children Who Weigh <45 kg

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

Recommended Regimen for Children Who Weigh ≥45 kg but Who Are Aged <8 Years

Azithromycin 1 g orally in a single dose

Recommended Regimens for Children Aged ≥8 years

Azithromycin 1 g orally in a single dose OR Doxycycline 100 mg orally twice a day for 7 days

Other Management Considerations

See Sexual Assault or Abuse of Children.

Follow-Up

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

Gonococcal Infections

Gonococcal Infections in Adolescents and Adults

In the United States, an estimated 700,000 new N. gonorrhoeae infections occur each year (93,293). Gonorrhea is the second most commonly reported bacterial STD. The majority of urethral infections caused by N. gonorrhoeae among men produce symptoms that cause them to seek curative treatment soon enough to prevent serious sequelae, but treatment might not be soon enough to prevent transmission to others. Among women, gonococcal infections might not produce recognizable symptoms until complications (e.g., PID) have occurred. PID can result in tubal scarring that can lead to infertility or ectopic pregnancy.

The prevalence of gonorrhea varies widely among communities and populations; health-care providers should consider local gonorrhea epidemiology when making screening decisions. Although widespread screening is not recommended because gonococcal infections among women are frequently asymptomatic, targeted screening of young women (i.e., those aged <25 years) at increased risk for infection is a primary component of gonorrhea control in the United States. For sexually active women, including those who are pregnant, USPSTF (82) recommends that clinicians provide gonorrhea screening only to those at increased risk for infection (e.g., women with previous gonorrhea infection, other STDs, new or multiple sex partners, and inconsistent condom use; those who engage in commercial sex work and drug use; women in certain demographic groups; and those living in communities with a high prevalence of disease). USPSTF does not recommend screening for gonorrhea in men and women who are at low risk for infection (82).

Diagnostic Considerations

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

Specific diagnosis of infection with N. gonorrhoeae can be performed by testing endocervical, vaginal, urethral (men only), or urine specimens. Culture, nucleic acid hybridization tests, and NAATs are available for the detection of genitourinary infection with N. gonorrhoeae (197). Culture and nucleic acid hybridization tests require female endocervical or male urethral swab specimens. NAATs allow testing of the widest variety of specimen types including endocervical swabs, vaginal swabs, urethral swabs (men), and urine (from both men and women), and they are FDA-cleared for use. However, product inserts for each NAAT vendor must be carefully examined, because specimen types that are FDA-cleared for use vary by test. NAAT tests are not FDA-cleared for use in the rectum, pharynx, and conjunctiva; however, some public and private laboratories have established performance specifications for using NAAT with rectal and pharyngeal swab specimens, thereby allowing results to be used for clinical management. Laboratories that establish performance specifications for the use of NAATs with nongenital specimens must ensure that specificity is not compromised by cross-reaction with nongonococcal Neisseria species. The sensitivity of NAATs for the detection of N. gonorrhoeae in genital and nongenital anatomic sites is superior to culture but varies by NAAT type (197,278—281).

Because nonculture tests cannot provide antimicrobial susceptibility results, in cases of suspected or documented treatment failure, clinicians should perform both culture and antimicrobial susceptibility testing.

All persons found to have who have gonorrhea also should be tested for other STDs, including chlamydia, syphilis, and HIV.

Dual Therapy for Gonococcal and Chlamydial Infections

Patients infected with N. gonorrhoeae frequently are coinfected with C. trachomatis; this finding has led to the recommendation that patients treated for gonococcal infection also be treated routinely with a regimen that is effective against uncomplicated genital C. trachomatis infection (294). Because most gonococci in the United States are susceptible to doxycycline and azithromycin, routine cotreatment might also hinder the development of antimicrobial-resistant N. gonorrhoeae. Limited data suggest that dual treatment with azithromycin might enhance treatment efficacy for pharyngeal infection when using oral cephalosporins (295,296).

Antimicrobial-Resistant N. gonorrhoeae

Gonorrhea treatment is complicated by the ability of N. gonorrhoeae to develop resistance to antimicrobial therapies (297). Quinolone-resistant N. gonorrhoeae strains are now widely disseminated throughout the United States and the world (298). As of April 2007, quinolones are no longer recommended in the United States for the treatment of gonorrhea and associated conditions, such as PID (299). Consequently, only one class of antimicrobials, the cephalosporins, is recommended and available for the treatment of gonorrhea in the United States. The CDC website (http://www.cdc.gov/std/gisp) and state health departments can provide the most current information.

The proportion of isolates in CDC’s Gonococcal Isolate Surveillance Project (GISP) demonstrating decreased susceptibility to ceftriaxone or cefixime has remained very low over time; during 1987–2008, only four isolates were found to have decreased susceptibility to ceftriaxone, and 48 isolates had decreased susceptibility to cefixime. In 2008, no isolates demonstrated decreased susceptibility to ceftriaxone; cefixime was not part of test panel during that year (93). Although only two cases of suspected treatment failure with ceftriaxone have been reported (300), approximately 50 patients are thought to have failed oral cephalosporin treatment (301—304).

Most of the treatment failures resulting from use of oral cephalosporins have been reported from Asian countries, although one possible case was reported in Hawaii in 2001 (305). To ensure appropriate antibiotic therapy, clinicians should ask patients testing positive for gonorrhea about recent travel to and sexual activity in these countries.

Decreased susceptibility of N. gonorrhoeae to cephalosporins and other antimicrobials is expected to continue to spread; therefore, state and local surveillance for antimicrobial resistance is crucial for guiding local therapy recommendations (297). GISP, which samples approximately 3% of all U.S. men who have gonococcal infections, is a mainstay of surveillance. However, surveillance by clinicians also is critical. Clinicians who diagnose N. gonorrhoeae infection in a patient with suspected cephalosporin treatment failure should perform culture and susceptibility testing of relevant clinical specimens, consult a specialist for guidance in clinical management, and report the case to CDC through state and local public health authorities. Health departments should prioritize partner notification and contact tracing of patients with N. gonorrhoeae infection thought to be associated with cephalosporin treatment failure or associated with patients whose isolates demonstrate decreased susceptibility to cephalosporin.

Uncomplicated Gonococcal Infections of the Cervix, Urethra, and Rectum

Recommended Regimens

Ceftriaxone 250 mg IM in a single dose OR, IF NOT AN OPTION Cefixime 400 mg orally in a single dose OR Single-dose injectible cephalosporin regimens PLUS Azithromycin 1g orally in a single dose OR Doxycycline 100 mg a day for 7 days

To maximize compliance with recommended therapies, medications for gonococcal infections should be dispensed on site. Ceftriaxone in a single injection of 250 mg provides sustained, high bactericidal levels in the blood. Extensive clinical experience indicates that ceftriaxone is safe and effective for the treatment of uncomplicated gonorrhea at all anatomic sites, curing 99.2% of uncomplicated urogenital and anorectal and 98.9% of pharyngeal infections in published clinical trials (306,307). A 250-mg dose of ceftriaxone is now recommended over a 125-mg dose given the 1) increasingly wide geographic distribution of isolates demonstrating decreased susceptibility to cephalosporins in vitro, 2) reports of ceftriaxone treatment failures, 3) improved efficacy of ceftriaxone 250 mg in pharyngeal infection (which is often unrecognized), and 4) the utility of having a simple and consistent recommendation for treatment regardless of the anatomic site involved.

A 400-mg oral dose of cefixime does not provide as high, nor as sustained, a bactericidal level as that provided by the 250-mg dose of ceftriaxone. In published clinical trials, the 400-mg dose cured 97.5% of uncomplicated urogenital and anorectal (95% CI = 95.4%–99.8%) and 92.3% of pharyngeal gonococcal infections (95% CI = 74.9%–99.1%) (306,307). Although cefixime can be administered orally, this advantage is offset by the limited efficacy of cefixime (as well as other oral cephalosporins) for treating gonococcal infections of the pharynx. Providers should inquire about oral sexual exposure and if reported, treat these patients with ceftriaxone because of this drug’s well documented efficacy in treating pharyngeal infection.

Single-dose injectible cephalosporin regimens (other than ceftriaxone 250 mg IM) that are safe and highly effective against uncomplicated urogenital and anorectal gonococcal infections include ceftizoxime (500 mg, administered IM), cefoxitin (2 g, administered IM with probenecid 1 g orally), and cefotaxime (500 mg, administered IM). None of the injectible cephalosporins offer any advantage over ceftriaxone for urogenital infection, and efficacy for pharyngeal infection is less certain (306,307).

Alternative Regimens

Several other antimicrobials are active against N. gonorrhoeae, but none have substantial advantages over the recommended regimens, and they should not be used if pharyngeal infection is suspected. Some evidence suggests that cefpodoxime 400-mg orally can be considered an alternative in the treatment of uncomplicated urogenital gonorrhea; this regimen meets the minimum efficacy criteria for alternative regimens for urogenital infection (demonstrated efficacy of ≥95% in clinical trials with lower 95% CI of >90%) (307). In one clinical trial, cefpodoxime 400 mg orally was found to have a urogenital and rectal cure rate of 96.6% (95% CI = 93.9%), but the efficacy of cefpodoxime 400 mg orally at the pharyngeal site was poor (70.3%, 95% CI = 53.0%) (Hall, unpublished data, 2010). Gonococcal strains with decreased susceptibility to oral cephalosporins have been reported in the United States (308). With a cure rate of 96.5% (95% CI = 93.6%–98.3%) for urogenital and rectal infection, cefpodoxime proxetil 200 mg orally meets the criteria for an alternative regimen; however, its use is not advised because of concerns about the pharmacodynamics of cefpodoxime using this dose. Efficacy in treating pharyngeal infection with cefpodoxime 200 mg is unsatisfactory (78.9%; 95% CI = 54.5%–94%), as with cefpodoxime at the 400-mg dose.

Treatment with cefuroxime axetil 1 g orally meets the criteria for minimum efficacy as an alternative regimen for urogenital and rectal infection (95.9%; 95% CI = 94.3%–97.2%), but the pharmacodynamics of cefuroxime axetil 1 g orally are less favorable than those of cefpodoxime 400 mg, cefixime 400 mg, or ceftriaxone 125 mg (309). The efficacy of cefuroxime axetil 1 g orally in treating pharyngeal infection is poor (56.9%; 95% CI = 42.2%–70.7%).

Spectinomycin, which is useful in persons who cannot tolerate cephalosporins, is expensive, must be injected, and is not available in the United States (updates available at: www.cdc.gov/std/treatment) (310). However, it has been effective in published clinical trials, curing 98.2% of uncomplicated urogenital and anorectal gonococcal infections. Spectinomycin has poor efficacy against pharyngeal infection (51.8%; 95% CI = 38.7%–64.9%) (306).

Azithromycin 2 g orally is effective against uncomplicated gonococcal infection (99.2%; 95% CI = 97.3%–99.9%), but concerns over the ease with which N. gonorrhoeae can develop resistance to macrolides should restrict its use to limited circumstances. Although azithromycin 1 g meets alternative regimen criteria (97.6%; 95% CI = 95.7%–98.9%), it is not recommended because several studies have documented treatment failures, and concerns about possible rapid emergence of antimicrobial resistance with the 1-g dose of azithromycin are even greater than with the 2-g dose (311—313). N. gonorrhoeae in the United States is not adequately susceptible to penicillins, tetracyclines, and older macrolides (e.g., erythromycin) for these antimicrobials to be recommended.

Uncomplicated Gonococcal Infections of the Pharynx

Most gonococcal infections of the pharynx are asymptomatic and can be relatively common in some populations (103,278,279,314). Gonococcal infections of the pharynx are more difficult to eradicate than infections at urogenital and anorectal sites (315). Few antimicrobial regimens, including those involving oral cephalosporins, can reliably cure >90% of gonococcal pharyngeal infections (306,307). Providers should ask their patients about oral sexual exposure; if reported, patients should be treated with a regimen with acceptable efficacy against pharyngeal infection. Chlamydial coinfection of the pharynx is unusual; however, because coinfection at genital sites sometimes occurs, treatment for both gonorrhea and chlamydia is recommended.

Recommended Regimens

Ceftriaxone 250 mg IM in a single dose PLUS Azithromycin 1g orally in a single dose OR Doxycycline 100 mg a day for 7 days

Follow-Up

Patients diagnosed with uncomplicated gonorrhea who are treated with any of the recommended or alternative regimens do not need a test-of-cure (i.e., repeat testing 3-4 weeks after completing therapy). Patients who have symptoms that persist after treatment should be evaluated by culture for N. gonorrhoeae, and any gonococci isolated should be tested for antimicrobial susceptibility. Persistent urethritis, cervicitis, or proctitis also might be caused by C. trachomatis or other organisms.

N. gonorrhoeae infection is prevalent among patients who have been diagnosed with and treated for gonorrhea in the preceding several months (64,251,252,267). Most infections result from reinfection rather than treatment failure, indicating a need for improved patient education and referral of sex partners. Clinicians should advise patients with gonorrhea to be retested 3 months after treatment. If patients do not seek medical care for retesting in 3 months, providers are encouraged to test these patients whenever they next seek medical care within the following 12 months, regardless of whether the patients believe that their sex partners were treated. Retesting is distinct from test-of-cure to detect therapeutic failure, which is not recommended.

References

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