auditory or ophthalmic abnormalities) warrant fur - cillin (Bicillin C-R) instead of the standard benza - ther investigation and treatment for neurosyphilis. thine penicillin product (Bicillin L-A) widely used Laboratory testing is helpful in supporting the diag - in the United States. Practitioners, pharmacists, and nosis of neurosyphilis; however, no single test can purchasing agents should be aware of the similar be used to diagnose neurosyphilis in all instances. names of these two products to avoid using the inap - Cerebrospinal fluid (CSF) laboratory abnormalities propriate combination therapy agent for treating are common in persons with early syphilis. The syphilis (206) . VDRL in cerebrospinal fluid (CSF-VDRL), which is highly specific but insensitive, is the standard The effectiveness of penicillin for the treatment of serologic test for CSF. When reactive in the absence syphilis was well established through clinical expe - of substantial contamination of CSF with blood, it is rience even before the value of randomized con - considered diagnostic of neurosyphilis; however in trolled clinical trials was recognized. Therefore, early syphilis, it can be of unknown prognostic sig - nearly all the recommendations for the treatment of nificance (203). Most other tests are both insensitive syphilis are based not only on clinical trials and and nonspecific and must be interpreted in relation observational studies, but approximately 50 years of to other test results and the clinical assessment. clinical experience. Therefore, the laboratory diagnosis of neurosyphilis usually depends on various combinations of reac - Parenteral penicillin G is the only therapy with doc - tive serologic test results, CSF cell count or protein, umented efficacy for syphilis during pregnancy. and a reactive CSF-VDRL with or without clinical Pregnant women with syphilis in any stage who manifestations. Among persons with HIV infection, report penicillin allergy should be desensitized and the CSF leukocyte count usually is elevated (>5 treated with penicillin (see Management of Patients 3 white blood cell count [WBC]/mm ); using a higher Who Have a History of Penicillin Allergy). 3 cutoff (>20 WBC/ mm ) might improve the speci - ficity of neurosyphilis diagnosis (204) . The CSF- The Jarisch-Herxheimer reaction is an acute febrile VDRL might be nonreactive even when neu - reaction frequently accompanied by headache, rosyphilis is present; therefore, additional evalua - myalgia, fever, and other symptoms that usually tion using FTA-ABS testing on CSF can be consid - occur within the first 24 hours after the initiation of ered. The CSF FTA-ABS test is less specific for any therapy for syphilis. Patients should be neurosyphilis than the CSF-VDRL but is highly informed about this possible adverse reaction. The sensitive; neurosyphilis is highly unlikely with a Jarisch-Herxheimer reaction occurs most frequently negative CSF FTA-ABS test (205) . among patients who have early syphilis, presum - Treatment ably because bacterial burdens are higher during these stages. Antipyretics can be used to manage symptoms, but they have not been proven to prevent Penicillin G, administered parenterally, is the pre - this reaction. The Jarisch-Herxheimer reaction ferred drug for treating all stages of syphilis. The might induce early labor or cause fetal distress in preparation used (i.e., benzathine, aqueous pro - pregnant women, but this should not prevent or caine, or aqueous crystalline), the dosage, and the delay therapy (see Syphilis During Pregnancy). length of treatment depend on the stage and clinical Management of Sex Partners manifestations of the disease. Selection of the appropriate penicillin preparation is important, because T. pallidum can reside in sequestered sites Sexual transmission of T. pallidum is thought to (e.g., the CNS and aqueous humor) that are poorly occur only when mucocutaneous syphilitic lesions accessed by some forms of penicillin. Combinations are present. Although such manifestations are of benzathine penicillin, procaine penicillin, and uncommon after the first year of infection, persons oral penicillin preparations are not considered exposed sexually to a patient who has syphilis in appropriate for the treatment of syphilis. Reports any stage should be evaluated clinically and sero - have indicated that practitioners have inadvertently logically and treated with a recommended regimen, prescribed combination benzathine-procaine peni - according to the following recommendations:

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 737 • Persons who were exposed within the 90 days pre - ceding the diagnosis of primary, secondary, or early latent syphilis in a sex partner might be infected even if seronegative; therefore, such per - sons should be treated presumptively. Available data demonstrate that additional doses of • Persons who were exposed >90 days before the benzathine penicillin G, amoxicillin, or other antibi - diagnosis of primary, secondary, or early latent otics in early syphilis (primary, secondary, and early syphilis in a sex partner should be treated pre - latent) do not enhance efficacy, regardless of HIV sumptively if serologic test results are not avail - status. able immediately and the opportunity for follow- Recommended Regimen for Infants and up is uncertain. Children • For purposes of partner notification and presump - tive treatment of exposed sex partners, patients Infants and children aged ≥1 month diagnosed with with syphilis of unknown duration who have high syphilis should have a CSF examination to detect nontreponemal serologic test titers (i.e., >1:32) asymptomatic neurosyphilis, and birth and maternal can be assumed to have early syphilis. For the pur - medical records should be reviewed to assess pose of determining a treatment regimen, however, whether such children have congenital or acquired serologic titers should not be used to differentiate syphilis (see Congenital Syphilis). Children with early from late latent syphilis (see Latent Syphilis, acquired primary or secondary syphilis should be Treatment). evaluated (e.g., through consultation with child-pro - tection services) (see Sexual Assault or Abuse of • Long-term sex partners of patients who have latent Children) and treated by using the following pedi - syphilis should be evaluated clinically and sero - atric regimen. logically for syphilis and treated on the basis of the evaluation findings.

Sexual partners of infected patients should be con - Other Management Considerations sidered at risk and provided treatment if they have had sexual contact with the patient within 3 months plus the duration of symptoms for patients diag - All persons who have syphilis should be tested for nosed with primary syphilis, 6 months plus duration HIV infection. In geographic areas in which the of symptoms for those with secondary syphilis, and prevalence of HIV is high, persons who have pri - 1 year for patients with early latent syphilis. mary syphilis should be retested for HIV after 3 Primary and Secondary Syphilis months if the first HIV test result was negative.

Treatment Patients who have syphilis and symptoms or signs suggesting neurologic disease (e.g., meningitis and hearing loss) or ophthalmic disease (e.g., uveitis, iri - Parenteral penicillin G has been used effectively for tis, neuroretinitis, and optic neuritis) should have an more than 50 years to achieve clinical resolution evaluation that includes CSF analysis, ocular slit- (i.e., the healing of lesions and prevention of sexual lamp ophthalmologic examination, and otologic transmission) and to prevent late sequelae. How - examination. Treatment should be guided by the ever, no comparative trials have been adequately results of this evaluation. conducted to guide the selection of an optimal peni - cillin regimen (i.e., the dose, duration, and prepara - Invasion of CSF by T. pallidum accompanied by tion). Substantially fewer data are available for non - CSF laboratory abnormalities is common among penicillin regimens. adults who have primary or secondary syphilis (203) . Therefore, in the absence of clinical neuro -

738 EDUCATIONAL REVIEW MANUAL IN URO LOGY logic findings, no evidence exists to support varia - unrecognized CNS infection, CSF examination can tion from the recommended treatment regimen for be considered in such situations. early syphilis. Symptomatic neurosyphilis develops in only a limited number of persons after treatment For retreatment, weekly injections of benzathine with the penicillin regimens recommended for pri - penicillin G 2.4 million units IM for 3 weeks is rec - mary and secondary syphilis. Therefore, unless clin - ommended, unless CSF examination indicates that ical signs or symptoms of neurologic or ophthalmic neurosyphilis is present (see Neurosyphilis). In rare involvement are present or treatment failure is doc - instances, serologic titers do not decline despite a umented, routine CSF analysis is not recommended negative CSF examination and a repeated course of for persons who have primary or secondary syphilis. therapy. In these circumstances, the need for addi - Follow-Up tional therapy or repeated CSF examinations is unclear, but is not generally recommended. Management of Sex Partners Treatment failure can occur with any regimen. However, assessing response to treatment fre - quently is difficult, and definitive criteria for cure or See General Principles, Management of Sex Part - failure have not been established. In addition, non - ners. treponemal test titers might decline more slowly for Special Considerations persons who previously have had syphilis (207). Clinical and serologic evaluation should be per - Penicillin Allergy formed 6 months and 12 months after treatment; more frequent evaluation might be prudent if fol - low-up is uncertain. Data to support the use of alternatives to penicillin in the treatment of early syphilis are limited. How - Patients who have signs or symptoms that persist or ever, several therapies might be effective in non - recur or who have a sustained fourfold increase in pregnant, penicillin-allergic patients who have pri - nontreponemal test titer (i.e., compared with the mary or secondary syphilis. Doxycycline 100 mg maximum or baseline titer at the time of treatment) orally twice daily for 14 days (209,210) and tetracy - probably failed treatment or were reinfected. These cline (500 mg four times daily for 14 days) are regi - patients should be retreated and reevaluated for HIV mens that have been used for many years. Compli - infection. Because treatment failure usually cannot ance is likely to be better with doxycycline than be reliably distinguished from reinfection with T. tetracycline, because tetracycline can cause gas - pallidum , a CSF analysis also should be performed. trointestinal side effects. Although limited clinical studies, along with biologic and pharmacologic evi - Although failure of nontreponemal test titers to dence, suggest that ceftriaxone (1 g daily either IM decline fourfold within 6–12 months after therapy or IV for 10–14 days) is effective for treating early for primary or secondary syphilis might be indica - syphilis, the optimal dose and duration of ceftriax - tive of treatment failure, clinical trial data have one therapy have not been defined (211) . demonstrated that >15% of patients with early Azithromycin as a single 2-g oral dose is effective syphilis treated with the recommended therapy will for treating early syphilis (212–214) . However, T. not achieve the two dilution decline in nontrepone - pallidum chromosomal mutations associated with mal titer used to define response at 1 year after treat - azithromycin resistance and treatment failures have ment (208) . Persons whose titers do not decline been documented in several geographical areas in should be reevaluated for HIV infection. Optimal the United States (215–217) . As such, the use of management of such patients is unclear. At a mini - azithromycin should be used with caution only mum, these patients should receive additional clini - when treatment with penicillin or doxycycline is not cal and serologic follow-up. If additional follow-up feasible. Azithromycin should not be used in MSM cannot be ensured, retreatment is recommended. or pregnant women. Close follow-up of persons Because treatment failure might be the result of receiving any alternative therapies is essential.

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 739 Persons with a penicillin allergy whose compliance who have syphilis should be tested for HIV infec - with therapy or follow-up cannot be ensured should tion. be desensitized and treated with benzathine peni - Treatment cillin. Skin testing for penicillin allergy might be useful in some circumstances in which the reagents and expertise are available to perform the test ade - Because latent syphilis is not transmitted sexually, quately (see Management of Patients Who Have a the objective of treating patients with this stage of History of Penicillin Allergy). disease is to prevent complications. Although clini - Pregnancy cal experience supports the effectiveness of peni - cillin in achieving this goal, limited evidence is available to guide choice of specific regimens. Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin The following regimens are recommended for peni - (see Management of Patients Who Have a History cillin nonallergic patients who have normal CSF of Penicillin Allergy and Syphilis During Preg - examinations (if performed). nancy). HIV Infection

See Syphilis Among HIV-Infected Persons. Latent Syphilis

Latent syphilis is defined as syphilis characterized by seroreactivity without other evidence of disease. Available data demonstrate no enhanced efficacy of Patients who have latent syphilis and who acquired additional doses of penicillin G, amoxicillin, or syphilis during the preceding year are classified as other antibiotics in early syphilis, regardless of HIV having early latent syphilis. Patients’ conditions can status. be diagnosed as early latent syphilis if, during the year preceding the evaluation, they had 1) a docu - Infants and children aged ≥1 month who have been mented seroconversion or fourfold or greater diagnosed with syphilis should have a CSF exami - increase in titer of a nontreponemal test; 2) unequiv - nation to exclude neurosyphilis. In addition, birth ocal symptoms of primary or secondary syphilis; or and maternal medical records should be reviewed to 3) a sex partner documented to have primary, sec - assess whether children have congenital or acquired ondary, or early latent syphilis. In addition, for per - syphilis (see Congenital Syphilis). Older children sons whose only possible exposure occurred during with acquired latent syphilis should be evaluated as the previous 12 months, reactive nontreponemal described for adults and treated using the following and treponemal tests are indicative of early latent pediatric regimens (see Sexual Assault or Abuse of syphilis. In the absence of these conditions, an Children). These regimens are for penicillin nonal - asymptomatic person should be considered to have lergic children who have acquired syphilis and who late latent syphilis or syphilis of unknown duration. have normal CSF examination results. 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

740 EDUCATIONAL REVIEW MANUAL IN URO LOGY Other Management Considerations Special Considerations

Penicillin Allergy Patients diagnosed with latent syphilis who demon - strate any of the following criteria should have a prompt CSF examination: The effectiveness of alternatives to penicillin in the treatment of latent syphilis has not been well docu - • Neurologic (e.g., auditory disease, cranial nerve mented. Nonpregnant patients allergic to penicillin dysfunction, acute or chronic meningitis, stroke, who have clearly defined early latent syphilis acute or chronic altered mental status, and loss of should respond to therapies recommended as alter - vibration sense) or ophthalmic signs or symptoms natives to penicillin for the treatment of primary and (e.g., iritis and uveitis); secondary syphilis (see Primary and Secondary Syphilis, Treatment). The only acceptable alterna - • evidence of active tertiary syphilis (e.g., aortitis tives for the treatment of late latent syphilis or latent and gumma); or syphilis of unknown duration are doxycycline (100 mg orally twice daily) or tetracycline (500 mg orally • serologic treatment failure. four times daily), both for 28 days. These therapies should be used only in conjunction with close sero - If a patient misses a dose of penicillin in a course of logic and clinical follow-up. Based on biologic weekly therapy for late syphilis, the appropriate plausibility and pharmacologic properties, ceftriax - course of action is unclear. Pharmacologic consider - one might be effective for treating late latent ations suggest that an interval of 10–14 days syphilis or syphilis of unknown duration. However, between doses of benzathine penicillin for late the optimal dose and duration of ceftriaxone therapy syphilis or latent syphilis of unknown duration have not been defined, and treatment decisions might be acceptable before restarting the sequence should be discussed in consultation with a special - of injections. Missed doses are not acceptable for ist. Some patients who are allergic to penicillin also pregnant patients receiving therapy for late latent might be allergic to ceftriaxone; in these circum - syphilis. Pregnant women who miss any dose of stances, use of an alternative agent might be therapy must repeat the full course of therapy. required. The efficacy of these alternative regimens Follow-Up in HIV-infected persons has not been well studied. Pregnancy Quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months. A CSF exami - Pregnant patients who are allergic to penicillin nation should be performed if 1) titers increase four - should be desensitized and treated with penicillin fold, 2) an initially high titer (≥1:32) fails to decline (see Management of Patients Who Have a History at least fourfold (i.e., two dilutions) within 12–24 of Penicillin Allergy and Syphilis During Preg - months of therapy, or 3) signs or symptoms nancy). attributable to syphilis develop. In such circum - HIV Infection stances, even if the CSF examination is negative, retreatment for latent syphilis should be initiated. In rare instances, despite a negative CSF examination See Syphilis Among HIV-Infected Persons. and a repeated course of therapy, serologic titers Tertiary Syphilis might fail to decline. In these circumstances, the need for additional therapy or repeated CSF exami - nations is unclear. Tertiary syphilis refers to gumma and cardiovascu - Management of Sex Partners lar 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 See General Principles, Management of Sex Part - regimen. ners.

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 741 Neurosyphilis

Treatment

Other Management Considerations CNS involvement can occur during any stage of syphilis. However, CSF laboratory abnormalities Patients who have symptomatic late syphilis should are common in persons with early syphilis, even in be given a CSF examination before therapy is initi - the absence of clinical neurological findings. No ated. Some providers treat all patients who have car - evidence exists to support variation from recom - diovascular syphilis with a neurosyphilis regimen. mended treatment for early syphilis for patients These patients should be managed in consultation found to have such abnormalities. If clinical evi - with an infectious disease specialist. dence of neurologic involvement is observed (e.g., Follow-Up cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis), a Limited information is available concerning clinical CSF examination should be performed. response and follow-up of patients who have ter - tiary syphilis. Syphilitic uveitis or other ocular manifestations fre - Management of Sex Partners quently are associated with neurosyphilis and should be managed according to the treatment rec - ommendations for neurosyphilis. Patients who have See General Principles, Management of Sex Part - neurosyphilis or syphilitic eye disease (e.g., uveitis, ners. neuroretinitis, and optic neuritis) should be treated Special Considerations with the recommended regimen for neurosyphilis; those with eye disease should be managed in collab - Penicillin Allergy oration with an ophthalmologist. A CSF examina - tion should be performed for all patients with syphilitic eye disease to identify those with abnor - Patients allergic to penicillin should be treated in malities; patients found to have abnormal CSF test consultation with an infectious disease specialist. results should be provided follow-up CSF examina - Pregnancy tions to assess treatment response.

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 Preg - The durations of the recommended and alternative nancy). regimens for neurosyphilis are shorter than the dura - HIV Infection tion 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 See Syphilis Among HIV-Infected Persons. to 3 weeks, can be considered after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy.

742 EDUCATIONAL REVIEW MANUAL IN URO LOGY Other Management Considerations patient with neurosyphilis, skin testing should be performed (if available) to confirm penicillin Other considerations in the management of patients allergy and, if necessary, desensitization in consul - who have neurosyphilis are as follows: tation with a specialist. Pregnancy • All persons who have syphilis should be tested for HIV. Pregnant patients who are allergic to penicillin • Although systemic steroids are used frequently as should be desensitized and treated with penicillin adjunctive therapy for otologic syphilis, such (see Syphilis During Pregnancy). drugs have not been proven to be beneficial. HIV Infection Follow-Up

See Syphilis Among HIV-Infected Persons. If CSF pleocytosis was present initially, a CSF Syphilis Among HIV-Infected Persons examination should be repeated every 6 months until the cell count is normal. Follow-up CSF exam - Diagnostic Considerations inations 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 Although they are uncommon, unusual serologic than cell counts, and persistent abnormalities might responses have been observed among HIV-infected be less important (219,220) . The leukocyte count is persons who have syphilis. Most reports have a sensitive measure of the effectiveness of therapy. involved serologic titers that were higher than If the cell count has not decreased after 6 months or expected, but false-negative serologic test results if the CSF cell count or protein is not normal after 2 and delayed appearance of seroreactivity also have years, retreatment should be considered. been reported (223) . Regardless, both treponemal and nontreponemal serologic tests for syphilis can Limited data suggest that in immunocompetent per - be interpreted in the usual manner for most patients sons and HIV-infected persons on highly active who are coinfected with T. pallidum and HIV. antiretroviral therapy, normalization of the serum RPR titer predicts normalization of CSF parameters When clinical findings are suggestive of syphilis (220) . but serologic tests are nonreactive or their interpre - Management of Sex Partners tation is unclear, alternative tests (e.g., biopsy of a lesion, darkfield examination, and PCR of lesion material) might be useful for diagnosis. Neu - See General Principles, Management of Sex Part - rosyphilis should be considered in the differential ners. diagnosis of neurologic disease in HIV-infected per - Special Considerations sons. Treatment Penicillin Allergy

Compared with HIV-negative patients, HIV-posi - Limited data suggest that ceftriaxone 2 g daily tive patients who have early syphilis might be at either IM or IV for 10–14 days can be used as an increased risk for neurologic complications (224) alternative treatment for patients with neurosyphilis and might have higher rates of serologic treatment (221,222) . However, the possibility of cross-reac - failure with currently recommended regimens. The tivity between ceftriaxone and penicillin exists. magnitude of these risks is not defined precisely, but Other regimens have not been adequately evaluated is likely small. No treatment regimens for syphilis for treatment of neurosyphilis. Therefore, if concern have been demonstrated to be more effective in pre - exists regarding the safety of ceftriaxone for a venting neurosyphilis in HIV-infected patients than

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 743 the syphilis regimens recommended for HIV-nega - HIV-infected persons who meet the criteria for treat - tive patients (208) . Careful follow-up after therapy ment failure (i.e., signs or symptoms that persist or is essential. recur or persons who have a sustained fourfold Primary and Secondary Syphilis Among increase in nontreponemal test titer) should be man - HIV-Infected Persons aged in the same manner as HIV-negative patients (i.e., a CSF examination and retreatment). CSF Treatment examination and retreatment also should be strongly considered for persons whose nontreponemal test titers do not decrease fourfold within 6–12 months of Treatment of primary and secondary syphilis among therapy. If CSF examination is normal, treatment HIV-infected persons is benzathine penicillin G, 2.4 with benzathine penicillin G administered as 2.4 mil - million units IM in a single dose. lion units IM each at weekly intervals for 3 weeks is recommended. Available data demonstrate that additional doses of Management of Sex Partners benzathine penicillin G, amoxicillin, or other antibi - otics in early syphilis do not result in enhanced effi - cacy, regardless of HIV status (208) . See General Principles, Management of Sex Part - Other Management Considerations ners. Special Considerations

Most HIV-infected persons respond appropriately to standard benzathine penicillin for primary and sec - Penicillin Allergy. HIV-infected, penicillin-allergic ondary syphilis. CSF abnormalities (e.g., mononu - patients who have primary or secondary syphilis clear pleocytosis and elevated protein levels) are should be managed according to the recommenda - common in HIV-infected persons, even in those tions for penicillin-allergic, HIV-negative patients. without neurologic symptoms, although the clinical Patients with penicillin allergy whose compliance and prognostic significance of such CSF abnormali - with therapy or follow-up cannot be ensured should ties with primary and secondary syphilis is be desensitized and treated with penicillin (see Man - unknown. Several studies have demonstrated that agement of Patients Who Have a History of Peni - among persons infected with both HIV and syphilis, cillin Allergy). The use of alternatives to penicillin clinical and CSF abnormalities consistent with neu - has not been well studied in HIV-infected patients. rosyphilis are associated with a CD4 count of ≤350 These therapies should be used only in conjunction cells/mL and/or an RPR titer of ≥1:32 with close serologic and clinical follow-up. (204,225,226) ; however, unless neurologic symp - Latent Syphilis Among HIV-Infected Persons toms are present, CSF examination in this setting has not been associated with improved clinical out - Treatment comes.

The use of antiretroviral therapy as per current HIV-infected persons with latent syphilis should be guidelines might improve clinical outcomes in HIV- treated according to the stage-specific recommenda - infected persons with syphilis (220,227,228) . tions for HIV-negative persons. Follow-Up • Treatment of early latent syphilis among HIV- infected persons is benzathine penicillin G, 2.4 mil - HIV-infected persons should be evaluated clinically lion units IM in a single dose. and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy. • Treatment of late latent syphilis or syphilis of unknown duration among HIV-infected persons is benzathine penicillin G, at weekly doses of 2.4 mil - lion units for 3 weeks.

744 EDUCATIONAL REVIEW MANUAL IN URO LOGY Other Management Considerations Neurosyphilis Among HIV-Infected Persons

Treatment All HIV-infected persons with syphilis and neuro - logic symptoms should undergo immediate CSF examination. Some studies have demonstrated that HIV-infected patients with neurosyphilis should be clinical and CSF abnormalities consistent with neu - treated according to the recommendations for HIV- rosyphilis are most likely in HIV-infected persons negative patients with neurosyphilis (see Neu - who have been diagnosed with syphilis and have a rosyphilis). CD4 count of ≤350 cells/ml and/or an RPR titer of Follow-Up ≥1:32 (204,225,226) ; however unless neurologic symptoms are present, CSF examination in this set - ting has not been associated with improved clinical If CSF pleocytosis was present initially, a CSF outcomes. examination should be repeated every 6 months until the cell count is normal. Follow-up CSF exam - Follow-Up inations also can be used to gauge response after therapy. Limited data suggest that changes in CSF Patients should be evaluated clinically and serologi - parameters might occur more slowly in HIV- cally at 6, 12, 18, and 24 months after therapy. If, at infected patients, especially those with more any time, clinical symptoms develop or nontrepone - advanced immunosuppression (219,227) . If the cell mal titers rise fourfold, a repeat CSF examination count has not decreased after 6 months or if the CSF should be performed and treatment administered is not normal after 2 years, retreatment should be accordingly. If during 12–24 months the nontre - considered. ponemal titer does not decline fourfold, CSF exami - Management of Sex Partners nation should be strongly considered and treatment administered accordingly. See General Principles, Management of Sex Part - Management of Sex Partners ners. Special Considerations See General Principles, Management of Sex Part - ners. Penicillin Allergy. HIV-infected, penicillin-allergic Special Considerations patients who have neurosyphilis should be managed according to the recommendations for penicillin- Penicillin Allergy. The efficacy of alternative non - allergic, HIV-negative patients with neurosyphilis. penicillin regimens in HIV-infected persons has not Several small observational studies conducted in been well studied. Patients with penicillin allergy HIV-infected patients with neurosyphilis suggest whose compliance with therapy or follow-up cannot that ceftriaxone 1–2 g IV daily for 10-14 days might be ensured should be desensitized and treated with be effective as an alternate agent (218,229,230) . penicillin (see Management of Patients Who Have a Syphilis During Pregnancy History of Penicillin Allergy). These therapies should be used only in conjunction with close sero - logic and clinical follow-up. Limited clinical stud - All women should be screened serologically for ies, along with biologic and pharmacologic evi - syphilis early in pregnancy. Most states mandate dence, suggest that ceftriaxone might be effective screening at the first prenatal visit for all women (229,230) . However, the optimal dose and duration (231) ; antepartum screening by nontreponemal anti - of ceftriaxone therapy have not been defined. body testing is typical, but in some settings, tre - ponemal antibody testing is being used. Pregnant women with reactive treponemal screening tests should have confirmatory testing with nontrepone - mal tests with titers. In populations in which use of

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 745 prenatal care is not optimal, RPR test screening and greater risk for fetal treatment failure (231) ; such treatment (if the RPR test is reactive) should be per - cases should be managed in consultation with formed at the time that pregnancy is confirmed obstetric specialists. Evidence is insufficient to rec - (232) . For communities and populations in which ommend specific regimens for these situations. the prevalence of syphilis is high and for patients at high risk, serologic testing should be performed Women treated for syphilis during the second half twice during the third trimester (ideally at 28–32 of pregnancy are at risk for premature labor and/or weeks’ gestation) and at delivery. Any woman who fetal distress if the treatment precipitates the delivers a stillborn infant after 20 weeks’ gestation Jarisch-Herxheimer reaction (236) . These women should be tested for syphilis. No infant should leave should be advised to seek obstetric attention after the hospital without the maternal serologic status treatment if they notice any fever, contractions, or having been determined at least once during preg - decrease in fetal movements. Stillbirth is a rare nancy. complication of treatment, but concern for this com - Diagnostic Considerations plication should not delay necessary treatment. All patients who have syphilis should be offered testing for HIV infection. Seropositive pregnant women should be considered Follow-Up infected unless an adequate treatment history is doc - umented clearly in the medical records and sequen - tial serologic antibody titers have declined. Serofast Coordinated prenatal care and treatment are vital. low antibody titers might not require treatment; Serologic titers should be repeated at 28–32 weeks’ however, persistent higher titer antibody tests might gestation and at delivery as recommended for the indicate reinfection, and treatment might be disease stage. Providers should ensure that the clini - required. cal and antibody responses are appropriate for the Treatment patient’s stage of disease, although most women will deliver before their serologic response to treat - ment can be assessed definitively. Inadequate Penicillin is effective for preventing maternal trans - maternal treatment is likely if delivery occurs mission to the fetus and for treating fetal infection within 30 days of therapy, if clinical signs of infec - (233) . Evidence is insufficient to determine optimal, tion are present at delivery, or if the maternal anti - recommended penicillin regimens (234) . body titer at delivery is fourfold higher than the pre - treatment 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 Other Management Considerations Management of Sex Partners

Some evidence suggests that additional therapy can See General Principles, Management of Sex Part - be beneficial for pregnant women in some settings ners. (e.g., a second dose of benzathine penicillin 2.4 mil - Special Considerations lion units IM administered 1 week after the initial dose for women who have primary, secondary, or Penicillin Allergy early latent syphilis) (235) . When syphilis is diag - nosed during the second half of pregnancy, manage - ment should include a sonographic fetal evaluation For treatment of syphilis during pregnancy, no for congenital syphilis, but this evaluation should proven alternatives to penicillin exist. Pregnant not delay therapy. Sonographic signs of fetal or pla - women who have a history of penicillin allergy cental syphilis (i.e., hepatomegaly, ascites, hydrops, should be desensitized and treated with penicillin. fetal anemia, or a thickened placenta) indicate a Oral step-wise penicillin dose challenge or skin test -

746 EDUCATIONAL REVIEW MANUAL IN URO LOGY B. Penicillin Allergy ing might be helpful in identifying women at risk for acute allergic reactions (see Management of Management of Persons Who Have a Patients Who Have a History of Penicillin Allergy). History of Penicillin Allergy

Tetracycline and doxycycline usually are not used during pregnancy. Erythromycin and azithromycin No proven alternatives to penicillin are available for should not be used, because neither reliably cures treating neurosyphilis, congenital syphilis, or maternal infection or treats an infected fetus (234). syphilis in pregnant women. Penicillin also is rec - Data are insufficient to recommend ceftriaxone for ommended for use, whenever possible, in HIV- treatment of maternal infection and prevention of infected patients. Of the adult U.S. population, congenital syphilis. 3%–10% have experienced an immunoglobulin E HIV Infection (IgE)-mediated allergic response to penicillin (238,239) , such as urticaria, angioedema, or ana - phylaxis (i.e., upper airway obstruction, bron - Placental inflammation from congenital infection chospasm, or hypotension). Readministration of might increase the risk for perinatal transmission of penicillin to these patients can cause severe, imme - HIV. All HIV-infected women should be evaluated diate reactions. Because anaphylactic reactions to for syphilis and receive treatment as recommended. penicillin can be fatal, every effort should be made Data are insufficient to recommend a specific regi - to avoid administering penicillin to penicillin-aller - men for HIV-infected pregnant women (see gic patients, unless they undergo acute desensitiza - Syphilis Among HIV-Infected Patients). tion to eliminate anaphylactic sensitivity.

Although an estimated 10% of persons who report a history of severe allergic reactions to penicillin con - tinue to remain allergic their entire lives, with the passage of time, most persons who have had a severe reaction to penicillin stop expressing peni - cillin-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 avail - able for more than 30 years, only benzylpenicilloyl poly-L-lysine (Pre-Pen [i.e., the major determi - nant]) and penicillin G have been available com - mercially. These two tests identify an estimated 90%–97% of the currently allergic patients. How - ever, because skin testing without the minor deter - minants 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 avail - ability of the Pre-Pen skin test reagent as well as an accompanying minor determinant mixture.

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 747 Recommendations Procedures

If the full battery of skin-test reagents is available, Dilute the antigens either 100-fold for preliminary including both major and minor determinants (see testing (if the patient has had a life-threatening reac - Penicillin Allergy Skin Testing), patients who report tion to penicillin) or 10-fold (if the patient has had a history of penicillin reaction and who are skin-test another type of immediate, generalized reaction to negative can receive conventional penicillin ther - penicillin within the preceding year). apy. Skin-test–positive patients should be desensi - Epicutaneous (Prick) Tests tized before initiating treatment.

If the full battery of skin-test reagents, including the Duplicate drops of skin-test reagent are placed on minor determinants, is not available, the patient the volar surface of the forearm. The underlying should be skin tested using benzylpenicilloyl poly- epidermis is pierced with a 26-gauge needle without L-lysine (i.e., the major determinant) and penicillin drawing blood. An epicutaneous test is positive if G. Patients who have positive test results should be the average wheal diameter after 15 minutes is ≥4 desensitized. One approach suggests that persons mm larger than that of negative controls; otherwise, with a history of allergy who have negative test the test is negative. The histamine controls should results should be regarded as possibly allergic and be positive to ensure that results are not falsely neg - desensitized. Another approach in those with nega - ative because of the effect of antihistaminic drugs. tive skin-test results involves test-dosing gradually Intradermal Test with oral penicillin in a monitored setting in which treatment for anaphylactic reaction can be provided. If epicutaneous tests are negative, duplicate 0.02- If the major determinant (Pre-Pen) is not available mL intradermal injections of negative control and for skin testing, all patients with a history suggest - antigen solutions are made into the volar surface of ing IgE-mediated reactions to penicillin (e.g., ana - the forearm by using a 26- or 27-gauge needle on a phylaxis, angioedema, bronchospasm, or urticaria) syringe. The margins of the wheals induced by the should be desensitized in a hospital setting. In injections should be marked with a ball point pen. patients with reactions not likely to be IgE-medi - An intradermal test is positive if the average wheal ated, outpatient-monitored test doses can be consid - diameter 15 minutes after injection is >2 mm larger ered. than the initial wheal size and also is >2 mm larger Penicillin Allergy Skin Testing than the negative controls. Otherwise, the tests are negative. Desensitization Patients at high risk for anaphylaxis, including those who 1) have a history of penicillin-related anaphy - laxis, asthma, or other diseases that would make Patients who have a positive skin test to one of the anaphylaxis more dangerous or 2) are being treated penicillin determinants can be desensitized (Table with beta-adrenergic blocking agents, should be 1). This is a straightforward, relatively safe proce - tested with 100-fold dilutions of the full-strength dure that can be performed orally or IV. Although skin-test reagents before being tested with full- the two approaches have not been compared, oral strength reagents. In these situations, patients desensitization is regarded as safer and easier to per - should be tested in a monitored setting in which form. Patients should be desensitized in a hospital treatment for an anaphylactic reaction is available. setting because serious IgE-mediated allergic reac - If possible, the patient should not have taken anti - tions can occur. Desensitization usually can be com - histamines recently (e.g., chlorpheniramine maleate pleted in approximately 4–12 hours, after which or fexafenadine during the preceding 24 hours, time the first dose of penicillin is administered. diphenhydramine HCl during the preceding 4 days, After desensitization, patients must be maintained or hydroxyzine or phenathiazines during the preced - on penicillin continuously for the duration of the ing 3 weeks). course of therapy.

748 EDUCATIONAL REVIEW MANUAL IN URO LOGY C. Urethritis

Diseases Characterized by Urethritis and Cervicitis

Urethritis

Urethritis, as characterized by urethral inflamma - tion, can result from infectious and noninfectious conditions. Symptoms, if present, include discharge of mucopurulent or purulent material, dysuria, or urethral pruritis. Asymptomatic infections are com - mon. Although N. gonorrhoeae and C. trachomatis are well established as clinically important infec - tious 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 test - ing to determine the specific etiology is recom - mended because both chlamydia and gonorrhea are reportable to health departments and a specific diag - nosis might improve partner notification and treat - ment. 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 speci - mens. 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 diplo - cocci (GNID) on urethral smear is indicative of gon - orrhea infection, which is frequently accompanied by chlamydial infection. Nongonoccocal urethritis (NGU), which is diagnosed when examination find - ings 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 epi - didymitis and Reiter’s syndrome. Documentation of

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 749 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 symp - toms 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 respon - sive to therapy. Enteric bacteria have been identified as an uncommon cause of NGU and might be associ - ated with insertive anal intercourse (244) . • Positive leukocyte esterase test on first-void urine or Confirmed Urethritis microscopic examination of first-void urine sedi - ment demonstrating ≥10 WBC per high-power field. Clinicians should attempt to obtain objective evi - If none of these criteria are present, testing for N. gon - dence of urethral inflammation. However, if clinic- orrhoeae and C. trachomatis using NAATs might based diagnostic tools (e.g., Gram-stain identify additional infections (248) . If the results microscopy) are not available, patients should be demonstrate infection with either of these pathogens, treated with drug regimens effective against both the appropriate treatment should be given and sex gonorrhea and chlamydia. partners referred for evaluation and treatment. If none of these criteria are present, empiric treatment of Urethritis can be documented on the basis of any of symptomatic males is recommended only for men at the following signs or laboratory tests: high risk for infection who are unlikely to return for a follow-up evaluation. Such patients should be treated • Mucopurulent or purulent discharge on examina - with drug regimens effective against gonorrhea and tion. chlamydia. Partners of patients treated empirically should be evaluated and treated, if indicated. • Gram stain of urethral secretions demonstrating ≥5 WBC per oil immersion field. The Gram stain is Nongonococcal Urethritis the preferred rapid diagnostic test for evaluating urethritis and is highly sensitive and specific for Diagnosis documenting both urethritis and the presence or absence of gonococcal infection. Gonococcal All patients who have confirmed or suspected urethri - infection is established by documenting the pres - tis should be tested for gonorrhea and chlamydia. ence of WBC containing GNID. 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.

750 EDUCATIONAL REVIEW MANUAL IN URO LOGY Treatment symptoms, pain during or after ejaculation, or new- onset premature ejaculation lasting for >3 months. Treatment should be initiated as soon as possible after diagnosis. Azithromycin and doxycycline are Unless a patient’s symptoms persist or therapeutic highly effective for chlamydial urethritis; however, noncompliance or reinfection is suspected by the infections with M. genitalium respond better to provider, a test-of-cure (i.e., repeat testing 3–4 azithromycin (249,250) . Single-dose regimens have weeks after completing therapy) is not recom - the advantage of improved compliance and directly mended for persons with documented chlamydia or observed treatment. To maximize compliance with gonococcal infections who have received treatment recommended therapies, medications should be dis - with recommended or alterative regimens. How - pensed on-site in the clinic, and the first dose should ever, because men with documented chlamydial or be directly observed. gonococcal infections have a high rate of reinfec - tion 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 To minimize transmission, men treated for NGU whether a specific etiology is identified. All sex should be instructed to abstain from sexual inter - partners within the preceding 60 days should be course for 7 days after single-dose therapy or until referred for evaluation, testing, and empiric treat - completion of a 7-day regimen, provided their ment with a drug regimen effective against chlamy - symptoms have resolved. To minimize the risk for dia. Expedited partner treatment and patient referral reinfection, men should be instructed to abstain are alternative approaches to treating partners (71) . from sexual intercourse until all of their sex partners are treated. Recurrent and Persistent Urethritis

Persons who have been diagnosed with a new STD Objective signs of urethritis should be present should receive testing for other infections, including before the initiation of antimicrobial therapy. In per - syphilis and HIV. sons who have persistent symptoms after treatment Follow-Up without objective signs of urethritis, the value of extending the duration of antimicrobials has not been demonstrated. Persons who have persistent or Patients should be instructed to return for evaluation recurrent urethritis can be retreated with the initial if symptoms persist or recur after completion of regimen if they did not comply with the treatment therapy. Symptoms alone, without documentation of regimen or if they were reexposed to an untreated signs or laboratory evidence of urethral inflamma - sex partner. Persistent urethritis after doxycycline tion, are not a sufficient basis for retreatment. treatment might be caused by doxycycline-resistant Providers should be alert to the possibility of U. urealyticum or M. genitalium . T. vaginalis is also chronic prostatitis/chronic pelvic pain syndrome in known to cause urethritis in men; a urethral swab, male patients experiencing persistent pain (perineal, first void urine, or semen for culture or a NAAT penile, or pelvic), discomfort, irritative voiding (PCR or TMA) on a urethral swab or urine can be

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 751 Special Considerations performed. If compliant with the initial regimen and re-exposure can be excluded, the following regimen HIV Infection is recommended while awaiting the results of the diagnostic tests. 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.

Studies involving a limited number of patients who experienced NGU treatment failures have demon - strated 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. vagi - nalis (e.g., MSM) are unlikely to benefit from the addition of metronidazole or tinidazole.

Urologic examinations usually do not reveal a spe - cific 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 pro - portion of men with chronic nonbacterial prostati - tis/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 regi - men for persistent urethritis and a sexually transmit - ted 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.

752 EDUCATIONAL REVIEW MANUAL IN URO LOGY D. Gonococcal Infections stain of endocervical specimens, pharyngeal, or rec - Gonococcal Infections in tal specimens also are not sufficient to detect infec - Adolescents and Adults tion, and therefore are not recommended. Specific testing for N. gonorrhoeae is recommended because of the increased utility and availability of highly In the United States, an estimated 700,000 new N. sensitive and specific testing methods and because a gonorrhoeae infections occur each year (93,293) . specific diagnosis might enhance partner notifica - Gonorrhea is the second most commonly reported tion. bacterial STD. The majority of urethral infections caused by N. gonorrhoeae among men produce Specific diagnosis of infection with N. gonorrhoeae symptoms that cause them to seek curative treat - can be performed by testing endocervical, vaginal, ment soon enough to prevent serious sequelae, but urethral (men only), or urine specimens. Culture, treatment might not be soon enough to prevent nucleic acid hybridization tests, and NAATs are transmission to others. Among women, gonococcal available for the detection of genitourinary infection infections might not produce recognizable symp - with N. gonorrhoeae (197) . Culture and nucleic toms until complications (e.g., PID) have occurred. acid hybridization tests require female endocervical PID can result in tubal scarring that can lead to or male urethral swab specimens. NAATs allow infertility or ectopic pregnancy. testing of the widest variety of specimen types including endocervical swabs, vaginal swabs, ure - The prevalence of gonorrhea varies widely among thral swabs (men), and urine (from both men and communities and populations; health-care providers women), and they are FDA-cleared for use. How - should consider local gonorrhea epidemiology ever, product inserts for each NAAT vendor must be when making screening decisions. Although carefully examined, because specimen types that widespread screening is not recommended because are FDA-cleared for use vary by test. NAAT tests gonococcal infections among women are frequently are not FDA-cleared for use in the rectum, pharynx, asymptomatic, targeted screening of young women and conjunctiva; however, some public and private (i.e., those aged <25 years) at increased risk for laboratories have established performance specifi - infection is a primary component of gonorrhea con - cations for using NAAT with rectal and pharyngeal trol in the United States. For sexually active women, swab specimens, thereby allowing results to be used including those who are pregnant, USPSTF (82) for clinical management. Laboratories that establish recommends that clinicians provide gonorrhea performance specifications for the use of NAATs screening only to those at increased risk for infec - with nongenital specimens must ensure that speci - tion (e.g., women with previous gonorrhea infec - ficity is not compromised by cross-reaction with tion, other STDs, new or multiple sex partners, and nongonococcal Neisseria species. The sensitivity of inconsistent condom use; those who engage in com - NAATs for the detection of N. gonorrhoeae in geni - mercial sex work and drug use; women in certain tal and nongenital anatomic sites is superior to cul - demographic groups; and those living in communi - ture but varies by NAAT type (197,278–281) . ties with a high prevalence of disease). USPSTF does not recommend screening for gonorrhea in Because nonculture tests cannot provide antimicro - men and women who are at low risk for infection bial susceptibility results, in cases of suspected or (82) . documented treatment failure, clinicians should per - form both culture and antimicrobial susceptibility Diagnostic Considerations testing.

Because of its high specificity (>99%) and sensitiv - All persons found to have who have gonorrhea also ity (>95%), a Gram stain of a male urethral speci - should be tested for other STDs, including chlamy - men that demonstrates polymorphonuclear leuko - dia, syphilis, and HIV. cytes 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

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 753 Dual Therapy for Gonococcal and Chlamydial Infections in Hawaii in 2001 (305) . To ensure appropriate antibiotic therapy, clinicians should ask patients testing positive for gonorrhea about recent travel to Patients infected with N. gonorrhoeae frequently and sexual activity in these countries. are coinfected with C. trachomatis ; this finding has led to the recommendation that patients treated for Decreased susceptibility of N. gonorrhoeae to gonococcal infection also be treated routinely with a cephalosporins and other antimicrobials is expected regimen that is effective against uncomplicated gen - to continue to spread; therefore, state and local ital C. trachomatis infection (294) . Because most surveillance for antimicrobial resistance is crucial gonococci in the United States are susceptible to for guiding local therapy recommendations (297) . doxycycline and azithromycin, routine cotreatment GISP, which samples approximately 3% of all U.S. might also hinder the development of antimicrobial- men who have gonococcal infections, is a mainstay resistant N. gonorrhoeae. Limited data suggest that of surveillance. However, surveillance by clinicians dual treatment with azithromycin might enhance also is critical. Clinicians who diagnose N. gonor - treatment efficacy for pharyngeal infection when rhoeae infection in a patient with suspected using oral cephalosporins (295,296) . cephalosporin treatment failure should perform cul - ture and susceptibility testing of relevant clinical Antimicrobial-Resistant N. gonorrhoeae specimens, consult a specialist for guidance in clin - ical management, and report the case to CDC Gonorrhea treatment is complicated by the ability of through state and local public health authorities. N. gonorrhoeae to develop resistance to antimicro - Health departments should prioritize partner notifi - bial therapies (297) . Quinolone-resistant N. gonor - cation and contact tracing of patients with N. gonor - rhoeae strains are now widely disseminated rhoeae infection thought to be associated with throughout the United States and the world (298) . cephalosporin treatment failure or associated with As of April 2007, quinolones are no longer recom - patients whose isolates demonstrate decreased sus - mended in the United States for the treatment of ceptibility to cephalosporin. gonorrhea and associated conditions, such as PID Uncomplicated Gonococcal Infections of (299) . Consequently, only one class of antimicro - the Cervix, Urethra, and Rectum bials, 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 informa - tion.

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 iso - lates had decreased susceptibility to cefixime. In To maximize compliance with recommended thera - 2008, no isolates demonstrated decreased suscepti - pies, medications for gonococcal infections should bility to ceftriaxone; cefixime was not part of test be dispensed on site. Ceftriaxone in a single injec - panel during that year (93) . Although only two tion of 250 mg provides sustained, high bactericidal cases of suspected treatment failure with ceftriax - levels in the blood. Extensive clinical experience one have been reported (300) , approximately 50 indicates that ceftriaxone is safe and effective for patients are thought to have failed oral the treatment of uncomplicated gonorrhea at all cephalosporin treatment (301–304) . anatomic sites, curing 99.2% of uncomplicated uro - genital and anorectal and 98.9% of pharyngeal Most of the treatment failures resulting from use of infections in published clinical trials (306,307) . A oral cephalosporins have been reported from Asian 250-mg dose of ceftriaxone is now recommended countries, although one possible case was reported over a 125-mg dose given the 1) increasingly wide

754 EDUCATIONAL REVIEW MANUAL IN URO LOGY geographic distribution of isolates demonstrating a urogenital and rectal cure rate of 96.6% (95% CI = decreased susceptibility to cephalosporins in vitro, 93.9%), but the efficacy of cefpodoxime 400 mg 2) reports of ceftriaxone treatment failures, 3) orally at the pharyngeal site was poor (70.3%, 95% improved efficacy of ceftriaxone 250 mg in pharyn - CI = 53.0%) (Hall, unpublished data, 2010). Gono - geal infection (which is often unrecognized), and 4) coccal strains with decreased susceptibility to oral the utility of having a simple and consistent recom - cephalosporins have been reported in the United mendation for treatment regardless of the anatomic States (308) . With a cure rate of 96.5% (95% CI = site involved. 93.6%–98.3%) for urogenital and rectal infection, cefpodoxime proxetil 200 mg orally meets the crite - A 400-mg oral dose of cefixime does not provide as ria for an alternative regimen; however, its use is not high, nor as sustained, a bactericidal level as that advised because of concerns about the pharmacody - provided by the 250-mg dose of ceftriaxone. In pub - namics of cefpodoxime using this dose. Efficacy in lished clinical trials, the 400-mg dose cured 97.5% treating pharyngeal infection with cefpodoxime 200 of uncomplicated urogenital and anorectal (95% CI mg is unsatisfactory (78.9%; 95% CI = = 95.4%–99.8%) and 92.3% of pharyngeal gono - 54.5%–94%), as with cefpodoxime at the 400-mg coccal infections (95% CI = 74.9%–99.1%) dose. (306,307) . Although cefixime can be administered orally, this advantage is offset by the limited effi - Treatment with cefuroxime axetil 1 g orally meets cacy of cefixime (as well as other oral the criteria for minimum efficacy as an alternative cephalosporins) for treating gonococcal infections regimen for urogenital and rectal infection (95.9%; of the pharynx. Providers should inquire about oral 95% CI = 94.3%–97.2%), but the pharmacodynam - sexual exposure and if reported, treat these patients ics of cefuroxime axetil 1 g orally are less favorable with ceftriaxone because of this drug’s well docu - than those of cefpodoxime 400 mg, cefixime 400 mented efficacy in treating pharyngeal infection. mg, or ceftriaxone 125 mg (309) . The efficacy of cefuroxime axetil 1 g orally in treating pharyngeal Single-dose injectible cephalosporin regimens infection is poor (56.9%; 95% CI = 42.2%–70.7%). (other than ceftriaxone 250 mg IM) that are safe and highly effective against uncomplicated urogenital Spectinomycin, which is useful in persons who can - and anorectal gonococcal infections include cefti - not tolerate cephalosporins, is expensive, must be zoxime (500 mg, administered IM), cefoxitin (2 g, injected, and is not available in the United States administered IM with probenecid 1 g orally), and (updates available at: www.cdc.gov/std/treatment) cefotaxime (500 mg, administered IM). None of the (310) . However, it has been effective in published injectible cephalosporins offer any advantage over clinical trials, curing 98.2% of uncomplicated uro - ceftriaxone for urogenital infection, and efficacy for genital and anorectal gonococcal infections. Specti - pharyngeal infection is less certain (306,307) . nomycin has poor efficacy against pharyngeal Alternative Regimens infection (51.8%; 95% CI = 38.7%–64.9%) (306) .

Azithromycin 2 g orally is effective against uncom - Several other antimicrobials are active against N. plicated gonococcal infection (99.2%; 95% CI = gonorrhoeae , but none have substantial advantages 97.3%–99.9%), but concerns over the ease with over the recommended regimens, and they should which N. gonorrhoeae can develop resistance to not be used if pharyngeal infection is suspected. macrolides should restrict its use to limited circum - Some evidence suggests that cefpodoxime 400-mg stances. Although azithromycin 1 g meets alterna - orally can be considered an alternative in the treat - tive regimen criteria (97.6%; 95% CI = ment of uncomplicated urogenital gonorrhea; this 95.7%–98.9%), it is not recommended because sev - regimen meets the minimum efficacy criteria for eral studies have documented treatment failures, alternative regimens for urogenital infection and concerns about possible rapid emergence of (demonstrated efficacy of ≥95% in clinical trials antimicrobial resistance with the 1-g dose of with lower 95% CI of >90%) (307) . In one clinical azithromycin are even greater than with the 2-g dose trial, cefpodoxime 400 mg orally was found to have (311–313). N. gonorrhoeae in the United States is

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 755 not adequately susceptible to penicillins, tetracy - gonorrhea to be retested 3 months after treatment. If clines, and older macrolides (e.g., erythromycin) for patients do not seek medical care for retesting in 3 these antimicrobials to be recommended. months, providers are encouraged to test these Uncomplicated Gonococcal Infections of patients whenever they next seek medical care the Pharynx within the following 12 months, regardless of whether the patients believe that their sex partners were treated. Retesting is distinct from test-of-cure Most gonococcal infections of the pharynx are to detect therapeutic failure, which is not recom - asymptomatic and can be relatively common in mended. some populations (103,278,279,314) . Gonococcal Management of Sex Partners infections of the pharynx are more difficult to eradi - cate than infections at urogenital and anorectal sites (315) . Few antimicrobial regimens, including those Effective clinical management of patients with involving oral cephalosporins, can reliably cure treatable STDs requires treatment of the patients’ >90% of gonococcal pharyngeal infections recent sex partners to prevent reinfection and curtail (306,307) . Providers should ask their patients about further transmission. Patients should be instructed oral sexual exposure; if reported, patients should be to refer their sex partners for evaluation and treat - treated with a regimen with acceptable efficacy ment. Sex partners of patients with N. gonorrhoeae against pharyngeal infection. Chlamydial coinfec - infection whose last sexual contact with the patient tion of the pharynx is unusual; however, because was within 60 days before onset of symptoms or coinfection at genital sites sometimes occurs, treat - diagnosis of infection in the patient should be evalu - ment for both gonorrhea and chlamydia is recom - ated and treated for N. gonorrhoeae and C. tra - mended. chomatis infections. If a patient’s last sexual inter - course was >60 days before onset of symptoms or diagnosis, the patient’s most recent sex partner should be treated. Patients should be instructed to abstain from sexual intercourse until therapy is completed and until they and their sex partners no longer have symptoms. Follow-Up For heterosexual patients with gonorrhea whose partners’ treatment cannot be ensured or is unlikely, Patients diagnosed with uncomplicated gonorrhea delivery of antibiotic therapy for gonorrhea (as well who are treated with any of the recommended or as for chlamydia) by the patients to their partners alternative regimens do not need a test-of-cure (i.e., can be considered (see Partner Management). Use repeat testing 3-4 weeks after completing therapy). of this approach (68,71) should always be accompa - Patients who have symptoms that persist after treat - nied by efforts to educate partners about symptoms ment should be evaluated by culture for N. gonor - and to encourage partners to seek clinical evalua - rhoeae , and any gonococci isolated should be tested tion. For male patients informing female partners, for antimicrobial susceptibility. Persistent urethritis, educational materials should include information cervicitis, or proctitis also might be caused by C. about the importance of seeking medical evaluation trachomatis or other organisms. for PID (especially if symptomatic). Possible under - treatment of PID in female partners and possible N. gonorrhoeae infection is prevalent among missed opportunities to diagnose other STDs are of patients who have been diagnosed with and treated concern and have not been evaluated in comparison for gonorrhea in the preceding several months with patient-delivered therapy and partner referral. (64,251,252,267) . Most infections result from rein - This approach should not be considered a routine fection rather than treatment failure, indicating a partner management strategy in MSM because of need for improved patient education and referral of sex partners. Clinicians should advise patients with

756 EDUCATIONAL REVIEW MANUAL IN URO LOGY Suspected Cephalosporin Treatment the high risk for coexisting undiagnosed STDs or Failure or Resistance HIV infection. Special Considerations Suspected treatment failure has been reported Allergy, Intolerance, and among persons receiving oral and injectable Adverse Reactions cephalosporins (300–304) . Therefore, clinicians of patients with suspected treatment failure or persons infected with a strain found to demonstrate in vitro Reactions to first generation cephalosporins occur resistance should consult an infectious disease spe - in approximately 5%–10% of persons with a history cialist, conduct culture and susceptibility testing of of penicillin allergy and occur less frequently with relevant clinical specimens, retreat with at least 250 third-generation cephalosporins (239) . In those per - mg of ceftriaxone IM or IV, ensure partner treat - sons with a history of penicillin allergy, the use of ment, and report the situation to CDC through state cephalosporins should be contraindicated only in and local public health authorities. those with a history of a severe reaction to penicillin Gonococcal Conjunctivitis (e.g., anaphylaxis, Stevens Johnson syndrome, and toxic epidermal necrolysis) (316) . In the only published study of the treatment of gono - Because data are limited regarding alternative regi - coccal conjunctivitis among U.S. adults, all 12 mens for treating gonorrhea among persons who study participants responded to a single 1-g IM have severe cephalosporin allergy, providers treat - injection of ceftriaxone (317) . ing such patients should consult infectious disease specialists. Azithromycin 2 g orally is effective against uncomplicated gonococcal infection, but because of concerns over emerging antimicrobial resistance to macrolides, its use should be limited. Consider lavage of the infected eye with saline solu - Cephalosporin treatment following desensitization tion once. Persons treated for gonococcal conjunc - is impractical in most clinical settings. tivitis should be treated presumptively for concur - Pregnancy rent C. trachomatis infection. Management of Sex Partners

As with other patients, pregnant women infected with N. gonorrhoeae should be treated with a rec - Patients should be instructed to refer their sex part - ommended or alternate cephalosporin. Because ners for evaluation and treatment (see Gonococcal spectinomycin is not available in the United States, Infections, Management of Sex Partners). azithromycin 2 g orally can be considered for Disseminated Gonococcal Infection (DGI) women who cannot tolerate a cephalosporin. Either azithromycin or amoxicillin is recommended for treatment of presumptive or diagnosed C. tra - DGI frequently results in petechial or pustular acral chomatis infection during pregnancy (see Chlamy - skin lesions, asymmetrical arthralgia, tenosynovitis, dial Infections). or septic arthritis. The infection is complicated HIV Infection occasionally by perihepatitis and rarely by endo - carditis or meningitis. Some strains of N. gonor - rhoeae that cause DGI can cause minimal genital Patients who have gonococcal infection and also are inflammation. No recent studies have been pub - infected with HIV should receive the same treat - lished on the treatment of DGI. ment regimen as those who are HIV negative.

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 757 Treatment Management of Sex Partners

Hospitalization is recommended for initial therapy, Patients should be instructed to refer their sex part - especially for patients who might not comply with ners for evaluation and treatment (see Gonococcal treatment, for those in whom diagnosis is uncertain, Infection, Management of Sex Partners). and for those who have purulent synovial effusions or other complications. Examination for clinical evidence of endocarditis and meningitis should be performed. Persons treated for DGI should be treated presumptively for concurrent C. trachomatis infection.

All of the preceding regimens should be continued for 24–48 hours after improvement begins, at which time therapy can be switched to cefixime 400 mg orally twice daily to complete at least 1 week of antimicrobial therapy. No treatment failures have been reported with the recommended regimens. Management of Sex Partners

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

Therapy for meningitis should be continued for 10–14 days; therapy for endocarditis should be con - tinued for at least 4 weeks. Treatment of compli - cated DGI should be undertaken in consultation with an infectious disease specialist.

758 EDUCATIONAL REVIEW MANUAL IN URO LOGY E. Epididymitis Diagnostic Considerations

Acute epididymitis is a clinical syndrome consisting Men who have acute epididymitis typically have of pain, swelling, and inflammation of the epi - unilateral testicular pain and tenderness; hydrocele didymis that lasts <6 weeks (402) . Chronic epi - and palpable swelling of the epididymis usually are didymitis is characterized by a ≥6 week history of present. Although the inflammation and swelling symptoms of discomfort and/or pain in the scrotum, usually begin in the tail of the epididymis, they can testicle, or epididymis. In most cases of acute epi - spread to involve the rest of the epididymis and tes - didymitis, the testis is also involved in the process ticle. The spermatic cord is usually tender and — a condition referred to as epididymo-orchitis. swollen. Testicular torsion, a surgical emergency, Chronic epididymitis has been subcategorized into should be considered in all cases, but it occurs more inflammatory chronic epididymitis, obstructive frequently among adolescents and in men without chronic epididymitis, and chronic epididymalgia evidence of inflammation or infection. Emergency (403) . testing for torsion might be indicated when the onset of pain is sudden, pain is severe, or the test results Among sexually active men aged <35 years, acute available during the initial examination do not sup - epididymitis is most frequently caused by C. tra - port a diagnosis of urethritis or urinary-tract infec - chomatis or N. gonorrhoeae . Acute epididymitis tion. If the diagnosis is questionable, a urologist caused by sexually transmitted enteric organisms should be consulted immediately because testicular (e.g., Escherichia coli and Pseudomonas spp.) also viability might be compromised. Radionuclide occurs among men who are the insertive partner scanning of the scrotum is the most accurate radio - during anal intercourse. Sexually transmitted acute logic method of diagnosis, but it is not routinely epididymitis usually is accompanied by urethritis, available. Although ultrasound is primarily used for which frequently is asymptomatic. ruling out torsion of the spermatic cord in cases of acute scrotum swelling, it will often demonstrate In men aged >35 years, sexually transmitted epi - epididymal hyperemia and swelling in men with didymitis is uncommon, whereas bacteriuria sec - epididymitis. However, differentiation between tes - ondary to obstructive urinary disease (e.g., benign ticular torsion and epididymitis must be made on the prostatic hyperplasia) is more common. In this older basis of clinical evaluation, because partial sper - population, nonsexually transmitted epididymitis is matic cord torsion can mimic epididymitis on scro - associated with urinary tract instrumentation or tal ultrasound. Ultrasound provides minimal utility surgery, systemic disease, and immunosuppression. for men with a clinical presentation consistent with epididymitis; a negative ultrasound does not alter Chronic infectious epididymitis is most frequently physician management of clinical epididymitis. seen in conditions associated with granulomatous Ultrasound, therefore, should be reserved for reaction; Mycobacterium tuberculosis (TB) is the patients with scrotal pain who cannot be diagnosed most common granulomatous disease affecting the accurately by physical examination, history, and epididymis. Up to 25% of patients can have bilateral objective laboratory findings. disease, with ultrasound demonstrating an enlarged hyperemic epididymis with multiple cysts and calci - fications. Tuberculous epididymitis should be sus - pected in all patients with a known history of or recent exposure to TB or in patients whose clinical status worsens despite appropriate antibiotic treat - ment.

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 759 The evaluation of men for epididymitis should (e.g., MSM who report insertive anal intercourse), include one of the following: ceftriaxone with a fluoroquinolone are recom - mended. • Gram stain of urethral secretions demonstrating ≥5 WBC per oil immersion field. Gram stain is the preferred rapid diagnostic test for evaluating ure - thritis because it is highly sensitive and specific for documenting both urethritis and the presence or absence of gonococcal infection. Gonococcal infection is established by documenting the pres - ence of WBC containing intracellular Gram-nega - tive diplococci on urethral Gram stain. Although most patients can be treated on an out- • Positive leukocyte esterase test on first-void urine patient basis, hospitalization should be considered or microscopic examination of first-void urine sed - when severe pain suggests other diagnoses (e.g., tor - iment demonstrating ≥10 WBC per high power sion, testicular infarction, or abscess) or when field. patients are unable or unlikely to comply with an antimicrobial regimen. Because high fever is uncom - Culture, nucleic acid hybridization tests, and NAATs mon and indicates a complicated infection, these are available for the detection of both N. gonor - patients should be admitted for further evaluation. rhoeae and C. trachomatis . Culture and nucleic acid Follow-Up hybridization tests require urethral swab specimens, whereas amplification tests can be performed on urine or urethral specimens. Because of their higher Patients should be instructed to return to their health- sensitivity, amplification tests are preferred for the care providers if their symptoms fail to improve detection of C. trachomatis . Depending on the risk, within 48 hours of the initiation of treatment. Signs patients whose conditions are associated with and symptoms of epididymitis that do not subside acquiring an STD should receive testing for other within 3 days requires re-evaluation of the diagnosis STDs. and therapy. Swelling and tenderness that persist Treatment after completion of antimicrobial therapy should be evaluated comprehensively. Differential diagnoses include tumor, abscess, infarction, testicular cancer, Empiric therapy is indicated before laboratory test TB, and fungal epididymitis. results are available. The goals of treatment of acute Management of Sex Partners epididymitis caused by C. trachomatis or N. gonor - rhoeae are 1) microbiologic cure of infection, 2) improvement of signs and symptoms, 3) prevention Patients who have acute epididymitis that is con - of transmission to others, and 4) a decrease in poten - firmed or suspected to be caused by N. gonorrhoeae tial complications (e.g., infertility or chronic pain). or C. trachomatis should be instructed to refer sex As an adjunct to therapy, bed rest, scrotal elevation, partners for evaluation and treatment if their contact and analgesics are recommended until fever and with the index patient was within the 60 days preced - local inflammation have subsided. Because empiric ing onset of their own symptoms. therapy is often initiated before laboratory tests are available, all patients should receive ceftriaxone plus Patients should be instructed to abstain from sexual doxycycline for the initial therapy of epididymitis. intercourse until they and their sex partners have Additional therapy can include a fluoroquinolone if been adequately treated (i.e., until therapy is com - acute epididymitis is not found to be caused by gon - pleted and patient and partners no longer have symp - orrhea by NAAT or if the infection is most likely toms). caused by enteric organisms. For men who are at risk for both sexually transmitted and enteric organisms

760 EDUCATIONAL REVIEW MANUAL IN URO LOGY Special Considerations Treatment

HIV Infection Treatment is directed to the macroscopic (i.e., genital warts) or pathologic (i.e, precancerous) lesions Patients who have uncomplicated acute epididymitis caused by infection. Subclinical genital HPV infec - and also are infected with HIV should receive the tion typically clears spontaneously, and therefore same treatment regimen as those who are HIV nega - specific antiviral therapy is not recommended to tive. Other etiologic agents have been implicated in eradicate HPV infection. In the absence of lesions, acute epididymitis in HIV infection including CMV, treatment is not recommended for subclinical genital salmonella, toxoplasmosis, Ureaplasma ure - HPV infection whether it is diagnosed by col - alyticum, Corynebacterium sp., Mycoplasma sp., and poscopy, acetic acid application, or by laboratory Mima polymorpha . Fungi and mycobacteria are also tests for HPV DNA. Treatment also is not recom - more likely to cause acute epididymitis in immuno - mended for cervical intraepithelial neoplasia 1 suppressed men than in immunocompetent men. (CIN1). Human Papillomavirus (HPV) Infection Prevention

More than 100 types of HPV exist, more than 40 of Two HPV vaccines are licensed in the United States: which can infect the genital area. Most HPV infec - a bivalent vaccine (Cervarix) containing HPV types tions are asymptomatic, unrecognized, or subclini - 16 and 18 and a quadrivalent vaccine (Gardasil) vac - cal. Oncogenic, or high-risk HPV types (e.g., HPV cine containing HPV types 6, 11, 16, and 18. Both types 16 and 18), are the cause of cervical cancers. vaccines offer protection against the HPV types that These HPV types are also associated with other cause 70% of cervical cancers (i.e., types 16 and 18), anogenital cancers in men and women, including and the quadrivalent HPV vaccine also protects penile, vulvar, vaginal, and anal cancer, as well a against the types that cause 90% of genital warts subset of oropharyngeal cancers (404) . Nononco - (i.e., types 6 and 11). Either vaccine can be adminis - genic, or low-risk HPV types (e.g., HPV types 6 and tered to girls aged 11–12 years and can be adminis - 11), are the cause of genital warts and recurrent res - tered to those as young as 9 years of age (15,16) ; girls piratory papillomatosis. Asymptomatic genital HPV and women ages 13–26 years who have not started or infection is common and usually self-limited; it is completed the vaccine series also should receive the estimated that more than 50% of sexually active per - vaccine. HPV vaccine is indicated for girls in this sons become infected at least once in their lifetime age group, because benefit is greatest if it is adminis - (405) . Persistent oncogenic HPV infection is the tered before the onset of sexual activity. The quadri - strongest risk factor for development of precancers valent (Gardasil) HPV vaccine can also be used in and cancers. males aged 9–26 years to prevent genital warts (17) . Administering the vaccine to boys before the onset HPV Tests of sexual activity is optimal. Both HPV vaccines are administered as a 3-dose series of IM injections over HPV tests are available for women aged >30 years a 6-month period, with the second and third doses undergoing cervical cancer screening. These tests given 1–2 and then 6 months after the first dose. Ide - should not be used for men, for women <20 years of ally, the same vaccine product should be used for the age, or as a general test for STDs. These HPV tests entire 3-dose series. HPV vaccine is available for eli - detect viral nucleic acid (i.e., DNA or RNA) or cap - gible children and adolescents aged <19 years sid protein. Four tests have been approved by the through the Vaccines for Children (VFC) program FDA for use in the United States: the HC II High- (available by calling CDC INFO [800-232-4636]). Risk HPV test (Qiagen), HC II Low-Risk HPV test (Qiagen), Cervista HPV 16/18 test, and Cervista Women who have received HPV vaccine should con - HPV High-Risk test (Hologics). tinue routine cervical cancer screening because 30% of cervical cancers are caused by HPV types other than 16 or 18. In the United States, the vaccines are

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 761 F. Genital Warts not licensed or recommended for use in women >26 years of age. No published data are available on the effectiveness, programmatic requirements, or cost- Of genital warts, 90% are caused by HPV 6 or 11. effectiveness of administering the HPV vaccine in HPV types 6 or 11 are commonly found before, or at STD clinic settings. the time of, detection of genital warts (406) . HPV types 16, 18, 31, 33, and 35 are found occasionally in visible genital warts (usually as coinfections with HPV 6 or 11) and can be associated with foci of high- grade intraepithelial neoplasia, particularly in per - sons who are infected with HIV infection. In addition to warts on genital areas, HPV types 6 and 11 have been associated with conjunctival, nasal, oral, and laryngeal warts.

Genital warts are usually asymptomatic, but depend - ing on the size and anatomic location, they can be painful or pruritic. Genital warts are usually flat, papular, or pedunculated growths on the genital mucosa. Genital warts occur commonly at certain anatomic sites, including around the introitus in women, under the foreskin of the uncircumcised penis, and on the shaft of the circumcised penis. Gen - ital warts can also occur at multiple sites in the anogenital epithelium or within the anogenital tract (e.g., cervix, vagina, urethra, perineum, perianal skin, and scrotum). Intra-anal warts are observed pre - dominantly in persons who have had receptive anal intercourse, but they can also occur in men and women who do not have a history of anal sexual con - tact.

Diagnosis of genital warts is usually clinical, made by visual inspection. Genital warts can be confirmed by biopsy, which might be indicated if 1) the diagno - sis is uncertain; 2) the lesions do not respond to stan - dard therapy; 3) the disease worsens during therapy; 4) the lesion is atypical; 5) the patient has comprised immunity; or 6) the warts are pigmented, indurated, fixed, bleeding, or ulcerated. Genital warts are usu - ally asymptomatic, but depending on the size and anatomic location, they might be painful or pruritic. The use of HPV DNA testing for genital wart diagno - sis is not recommended, because test results would not alter clinical management of the condition.

The application of 3%–5% acetic acid, which causes skin color to turn white, has been used by some providers to detect HPV-infected genital mucosa. However, acetic acid application is not a specific test for HPV infection. Therefore, the routine use of this

762 EDUCATIONAL REVIEW MANUAL IN URO LOGY procedure for screening to detect mucosal changes apy. The response to treatment and any side effects attributed to HPV infection is not recommended. should be evaluated throughout the course of therapy. Treatment Complications occur rarely when treatment is admin - istered properly. Patients should be warned that per - The primary reason for treating genital warts is the sistent hypopigmentation or hyperpigmentation amelioration of symptoms (including relieving cos - occurs commonly with ablative modalities and has metic concerns) and ultimately, removal of the warts. also been described with immune modulating thera - In most patients, treatment can induce wart-free peri - pies (imiquimod). Depressed or hypertrophic scars ods. If left untreated, visible genital warts can resolve are uncommon but can occur, especially if the patient on their own, remain unchanged, or increase in size has had insufficient time to heal between treatments. or number. Available therapies for genital warts Rarely, treatment can result in disabling chronic pain likely reduce, but probably do not eradicate, HPV syndromes (e.g., vulvodynia and hyperesthesia of the infectivity. Whether the reduction in HPV viral DNA treatment site) or, in the case of anal warts, painful resulting from treatment reduces future transmission defecation or fistulas. A limited number of case remains unclear. No evidence indicates that the pres - reports of severe systemic effects resulting from ence of genital warts or their treatment is associated treatment with podophyllin resin and interferon have with the development of cervical cancer. been documented. Regimens Treatment regimens are classified into patient- applied and provider-applied modalities. Patient- Treatment of genital warts should be guided by the applied modalities are preferred by some patients preference of the patient, available resources, and the because they can be administered in the privacy of experience of the health-care provider. No definitive the patient’s home. To ensure that patient-applied evidence suggests that any of the available treat - modalities are effective, patients must comply with ments are superior to any other, and no single treat - the treatment regimen and must be capable of identi - ment is ideal for all patients or all warts. The use of fying and reaching all genital warts. Follow-up visits locally developed and monitored treatment algo - are not required for persons using patient-applied rithms has been associated with improved clinical therapy. However, follow-up visits after several outcomes and should be encouraged. Because of weeks of therapy enable providers to answer any uncertainty regarding the effect of treatment on questions patients might have about the use of the future transmission of HPV and the possibility of medication and any side effects they have experi - spontaneous resolution, an acceptable alternative for enced; follow-up visits also facilitate the assessment some persons is to forego treatment and wait for of a patient’s response to treatment. spontaneous resolution.

Factors that influence selection of treatment include wart size, wart number, anatomic site of the wart, wart morphology, patient preference, cost of treat - ment, convenience, adverse effects, and provider experience. Factors that might affect response to therapy include the presence of immunosuppression and compliance with therapy, which can consist of either a single treatment or complete course of treat - ment. In general, warts located on moist surfaces or in intertriginous areas respond best to topical treat - ment. The treatment modality should be changed if a patient has not improved substantially after a com - plete course of treatment or if side effects are severe. Most genital warts respond within 3 months of ther -

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 763 Podofilox is an antimitotic drug that destroys warts, not been established. The safety of sinecatechins dur - is relatively inexpensive, easy to use, safe, and self- ing pregnancy also is unknown. applied. Podofilox solution should be applied with a cotton swab, or podofilox gel with a finger, to visible Cryotherapy destroys warts by thermal-induced genital warts twice a day for 3 days, followed by 4 cytolysis. Health-care providers must be trained on days of no therapy. This cycle can be repeated, as the proper use of this therapy because over- and necessary, for up to four cycles. The total wart area undertreatment can result in complications or low 2 treated should not exceed 10 cm , and the total vol - efficacy. Pain after application of the liquid nitrogen, ume of podofilox should be limited to 0.5 mL per day. followed by necrosis and sometimes blistering, is If possible, the health-care provider should apply the common. Local anesthesia (topical or injected) might initial treatment to demonstrate the proper applica - facilitate therapy if warts are present in many areas or tion technique and identify which warts should be if the area of warts is large. treated. Mild to moderate pain or local irritation might develop after treatment. The safety of pod - Pedophyllin resin 10%–25% should be applied to ofilox during pregnancy has not been established. each wart and allowed to air-dry before the treated area comes into contact with clothing; overapplica - Imiquimod is a topically active immune enhancer tion or failure to air dry can result in local irritation that stimulates production of interferon and other caused by spread of the compound to adjacent areas. cytokines. Imiquimod cream should be applied once The treatment can be repeated weekly, if necessary. daily at bedtime, three times a week for up to 16 To avoid the possibility of complications associated weeks (407) . The treatment area should be washed with systemic absorption and toxicity, two guidelines with soap and water 6–10 hours after the application. should be followed: 1) application should be limited Local inflammatory reactions, including redness, to <0.5 mL of podophyllin or an area of <10 cm2 of irritation, induration, ulceration/erosions, and vesi - warts per session and 2) the area to which treatment is cles, are common with the use of imiquimod, and administered should not contain any open lesions or hypopigmentation has also been described (408) . wounds. The preparation should be thoroughly Imiquimod might weaken condoms and vaginal washed off 1–4 hours after application to reduce local diaphragms. The safety of imiquimod during preg - irritation. The safety of podophyllin during preg - nancy has not been established. nancy has not been established. Podophyllin resin preparations differ in the concentration of active Sinecatechin ointment, a green-tea extract with an components and contaminants. The shelf life and sta - active product (catechins), should be applied three bility of podophyllin preparations are unknown. times daily (0.5-cm strand of ointment to each wart) using a finger to ensure coverage with a thin layer of Both TCA and BCA are caustic agents that destroy ointment until complete clearance of warts. This warts by chemical coagulation of proteins. Although product should not be continued for longer than 16 these preparations are widely used, they have not weeks (409–411) . The medication should not be been investigated thoroughly. TCA solutions have a washed off after use. Sexual (i.e., genital, anal, or low viscosity comparable with that of water and can oral) contact should be avoided while the ointment is spread rapidly if applied excessively; therefore, they on the skin. The most common side effects of sinecat - can damage adjacent tissues. A small amount should echins 15% are erythema, pruritis/burning, pain, be applied only to the warts and allowed to dry before ulceration, edema, induration, and vesicular rash. the patient sits or stands, at which time a white frost - This medication may weaken condoms and ing develops. If pain is intense, the acid can be neu - diaphragms. No clinical data are available regarding tralized with soap or sodium bicarbonate. If an excess the efficacy or safety of sinecatechins compared with amount of acid is applied, the treated area should be other available anogenital wart treatment modalities. powdered with talc, sodium bicarbonate (i.e., baking The medication is not recommended for HIV- soda), or liquid soap preparations to remove unre - infected persons, immunocompromised persons, or acted acid. This treatment can be repeated weekly, if persons with clinical genital herpes because the necessary. safety and efficacy of therapy in these settings has

764 EDUCATIONAL REVIEW MANUAL IN URO LOGY Surgical therapy has the advantage of usually elimi - nating warts at a single visit. However, such therapy requires substantial clinical training, additional equipment, and a longer office visit. After local anes - thesia is applied, the visible genital warts can be physically destroyed by electrocautery, in which case no additional hemostasis is required. Care must be taken to control the depth of electrocautery to prevent scarring. Alternatively, the warts can be removed either by tangential excision with a pair of fine scis - sors or a scalpel, by laser, or by curettage. Because most warts are exophytic, this procedure can be accomplished with a resulting wound that only extends into the upper dermis. Hemostasis can be achieved with an electrocautery unit or a chemical styptic (e.g., an aluminum chloride solution). Sutur - ing is neither required nor indicated in most cases if surgical removal is performed properly. Surgical therapy is most beneficial for patients who have a large number or area of genital warts. Both carbon dioxide laser and surgery might be useful in the man - agement of extensive warts or intraurethral warts, particularly for those persons who have not responded to other treatments.

Because all available treatments have shortcomings, some clinics employ combination therapy (simulta - Intra-anal warts should be managed in consultation neous use of two or more modalities on the same wart with a specialist. Many persons with warts on the at the same time). Data are limited regarding the effi - anal mucosa also have warts on the rectal mucosa, so cacy or risk of complications associated with use of persons with anal and/or intra-anal warts might bene - such combinations. fit from an inspection of the rectal mucosa by digital Alternative Regimens examination, standard anoscopy, or high-resolution anoscopy. Counseling Alternative regimens include treatment options that might be associated with more side effects and/or less data on efficacy. Alternative regimens include The following key counseling messages should be intralesional interferon, photodynamic therapy, and conveyed to all patients diagnosed with HPV infec - topical cidofovir. tion:

• Genital HPV infection is very common. Many types of HPV are passed on through genital contact, most often during vaginal and anal sexual contact. HPV can also be spread by oral sexual contact.

• Most sexually active adults will get HPV at some point in their lives, though most will never know it because HPV infection usually has no signs or symptoms.

CHAPTER 23A: SEXUALLY TRANSMITTED DISEASES 765 • In most cases, HPV infection clears spontaneously, – adolescent females; or without causing any health problems. Nevertheless, some infections do progress to genital warts, pre - – for health conditions other than cervical cancers, and cancers. cancer.

• The types of HPV that cause genital warts are dif - • Two HPV vaccines are available, both of which ferent from the types that can cause anogenital can - offer protection against the HPV types that cause cers. 70% of cervical cancers (i.e., types 16 and 18); the quadrivalent vaccine (Gardasil) also protects • Within an ongoing sexual relationship, both part - against the types that cause 90% of genital warts ners are usually infected at the time one person is (i.e., types 6 and 11). These vaccines are most effec - diagnosed with HPV infection, even though signs of tive when all doses are administered before sexual infection might not be apparent. contact. Either vaccine is recommended for 11- and 12-year-old girls and for females aged 13–26 years • A diagnosis of HPV in one sex partner is not indica - who did not receive or complete the vaccine series tive of sexual infidelity in the other partner. when they were younger. The quadrivalent HPV vaccine can be used in males aged 9–26 years to • Treatments are available for the conditions caused prevent genital warts. by HPV (e.g., genital warts), but not for the virus itself. The following are specific counseling messages for those persons diagnosed with genital warts and their • HPV does not affect a woman’s fertility or ability to partners: carry a pregnancy to term. • Genital warts are not life threatening. If left • Correct and consistent male condom use might untreated, genital warts might go away, stay the lower the chances of giving or getting genital HPV, same, or grow in size or number. Except in very rare but such use is not fully protective, because HPV and unusual cases, genital warts will not turn into can infect areas that are not covered by a condom. cancer.

• Sexually active persons can lower their chances of • It is difficult to determine how or when a person getting HPV by limiting their number of partners. became infected with HPV; genital warts can be However, HPV is common and often goes unrecog - transmitted to others even when no visible signs of nized; persons with only one lifetime sex partner warts are present, even after warts are treated. can have the infection. For this reason, the only definitive method to avoid giving and getting HPV • It is not known how long a person remains conta - infection and genital warts is to abstain from sexual gious after warts are treated. It is also unclear activity. whether informing subsequent sex partners about a past diagnosis of genital warts is beneficial to the • Tests for HPV are now available to help providers health of those partners. screen for cervical cancer in certain women. These tests are not useful for screening adolescent females • Genital warts commonly recur after treatment, for cervical cancer, nor are they useful for screening especially in the first 3 months. for other HPV-related cancers or genital warts in men or women. HPV tests should not be used to • Women should get regular Pap tests as recom - screen: mended, regardless of vaccination or genital wart history. Women with genital warts do not need to – men; get Pap tests more often than recommended.

– partners of women with HPV; • HPV testing is unnecessary in sexual partners of persons with genital warts.

766 EDUCATIONAL REVIEW MANUAL IN URO LOGY