Updating the CDC's treatment guidelines: Syphilis

STD GUIDELINES Updating the CDC's STD treatment guidelines Part 4: Syphilis (Editor's note: The following article is the fourth excerpt taken from Sexually Transmitted Diseases Treatment Guidelines. MMWR Recommendations and Reports. 2002;51(RR-6):1-79.) General principles Background Syphilis is a systemic disease caused by Treponema pallidum. Patients who have syphilis may seek treatment for signs or symptoms of primary infection (i.e., ulcer or chancre at the infection site), secondary infection (i.e., manifestations that include but are not limited to skin rash, mucocutaneous lesions, and lymphadenopathy), or tertiary infection (e.g., cardiac, ophthalmic, auditory abnormalities, and gummatous lesions). Latent infections (i.e., those lacking clinical manifestations) are detected by serologic testing. Latent syphilis acquired within the preceding year is referred to as early latent syphilis; all other cases of latent syphilis are either late latent syphilis or latent syphilis of unknown duration. Treatment for both late latent syphilis and tertiary syphilis theoretically may require a longer duration of therapy because organisms are dividing more slowly; however, the validity of this concept has not been assessed. Diagnostic considerations and use of serologic tests Darkfield examinations and direct fluorescent antibody tests of lesion exudate or tissue are the definitive methods for diagnosing early syphilis. A presumptive diagnosis is possible with the use of two types of serologic tests for syphilis: (a) nontreponemal tests (e.g., Venereal Disease Research Laboratory [VDRL] and Rapid Plasma Reagin [RPR]) and (b) treponemal tests (e.g., fluorescent trepone- mal antibody absorbed [FTA-ABS] and T pallidum particle agglutination [TP-PA]). The use of only one type of serologic test is insufficient for diagnosis, because false-positive nontreponemal test results may occur secondary to various medical conditions. Nontreponemal test antibody titers usually correlate with disease activity, and results should be reported quantitatively. A fourfold change in titer, equivalent to a change of two dilutions (e.g., from 1:16 to 1:4 or from 1:8 to 1:32), is considered necessary to demonstrate a clinically significant difference between two nontreponemal test results that were obtained using the same serologic test. Sequential serologic tests in individual patients should be performed by using the same testing method (e.g., VDRL or RPR), preferably by the same laboratory. The VDRL and RPR are equally valid assays, but quantitative results from the two tests cannot be compared directly because RPR titers often are slightly higher than VDRL titers. Nontreponemal tests usually become nonreactive with time after treatment; however, in some patients, nontreponemal antibodies can persist at a low titer for a long period of time, sometimes for the life of the patient. This response is referred to as the "serofast reaction." Most patients who have reactive treponemal tests will have reactive tests for the remainder of their lives, regardless of treatment or disease activity. However, 15% to 25% of patients treated during the primary stage revert to being serologically nonreactive after 2 to 3 years. Treponemal test antibody titers correlate poorly with disease activity and should not be used to assess treatment response. Some HIV-infected patients can have atypical serologic test results (i.e., unusually high, unusually low, or fluctuating titers). For such patients, when serologic tests and clinical syndromes suggestive of early syphilis do not correspond with one another, use of other tests (e.g., biopsy and direct microscopy) should be considered. However, for most HIV-infected patients, serologic tests are accurate and reliable for the diagnosis of syphilis and for following the response to treatment. No test can be used alone to diagnose neurosyphilis. The VDRL-CSF is highly specific, but it is insensitive. Most other tests are both insensitive and nonspecific and must be interpreted in relation to other test results and the clinical assessment. Therefore, the diagnosis of neurosyphilis usually depends on various combinations of reactive serologic test results, abnormalities of cerebrospinal fluid (CSF) cell count or protein, or a reactive VDRL-CSF with or without clinical manifestations. The CSF leukocyte count usually is elevated (>5 WBCs/mm3) in patients with neurosyphilis; this count also is a sensitive measure of the effectiveness of therapy. The VDRL-CSF is the standard serologic test for CSF, and when reactive in the absence of substantial contamination of CSF with blood, it is considered diagnostic of neurosyphilis. However, the VDRL-CSF may be nonreactive when neurosyphilis is present. Some specialists recommend performing an FTA-ABS test on CSF. The CSF FTA-ABS is less specific (i.e., yields more false-positive results) for neurosyphilis than the VDRL-CSF, but the test is highly sensitive. Therefore, some specialists believe that a negative CSF FTA-ABS test excludes neurosyphilis. Treatment Penicillin G, administered parenterally, is the preferred drug for treatment of all stages of syphilis. The preparation(s) used (i.e., benzathine, aqueous procaine, or aqueous crystalline), the dosage, and the length of treatment depend on the stage and clinical manifestations of disease. However, neither combinations of benzathine penicillin and procaine penicillin nor oral penicillin preparations are considered appropriate for the treatment of syphilis. The efficacy of penicillin for the treatment of syphilis was well established through clinical experience before the value of randomized controlled clinical trials was recognized. Therefore, almost all the recommendations for the treatment of syphilis are based on the opinions of persons knowledgeable about STDs and are reinforced by case series, clinical trials, and 50 years of clinical experience. Parenteral penicillin G is the only therapy with documented efficacy for syphilis during pregnancy. Pregnant women with syphilis in any stage who report penicillin allergy should be desensitized and treated with penicillin. Skin testing for penicillin allergy may be useful in pregnant women; such testing also is useful in other patients (see "Management of patients who have a history of penicillin allergy"). The Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache, myalgia, and other symptoms that usually occurs within the first 24 hours after any therapy for syphilis. Patients should be informed about this possible adverse reaction. The Jarisch-Herxheimer reaction occurs most often among patients who have early syphilis. Antipyretics may be used, but they have not been proven to prevent this reaction. The Jarisch-Herxheimer reaction may induce early labor or cause fetal distress in pregnant women. This concern should not prevent or delay therapy (see "Syphilis during pregnancy"). Management of sex partners Sexual transmission of T pallidum occurs only when mucocutaneous syphilitic lesions are present; such manifestations are uncommon after the first year of infection. However, persons exposed sexually to a patient who has syphilis in any stage should be evaluated clinically and serologically according to the following recommendations. Persons who were exposed within the 90 days preceding the diagnosis of primary, secondary, or early latent syphilis in a sex partner might be infected even if seronegative; therefore, such persons should be treated presumptively. Persons who were exposed more than 90 days before the diagnosis of primary, secondary, or early latent syphilis in a sex partner should be treated presumptively if serologic test results are not available immediately and the opportunity for follow-up is uncertain. For purposes of partner notification and presumptive treatment of exposed sex partners, patients with syphilis of unknown duration who have high nontreponemal serologic test titers (i.e., >1:32) can be assumed to have early syphilis. However, serologic titers should not be used to differentiate early from late latent syphilis for the purpose of determining treatment (see "Latent syphilis, treatment"). Long-term sex partners of patients who have latent syphilis should be evaluated clinically and serologically for syphilis and treated on the basis of the evaluation findings. For identification of at-risk partners, the time periods before treatment are (a) 3 months plus duration of symptoms for primary syphilis, (b) 6 months plus duration of symptoms for secondary syphilis, and (c) 1 year for early latent syphilis. Primary and secondary syphilis Treatment Parenteral penicillin G has been used effectively for more than 50 years to achieve clinical resolution (i.e., healing of lesions and prevention of sexual transmission) and to prevent late sequelae. However, no comparative trials have been adequately conducted to guide the selection of an optimal penicillin regimen (i.e., the dose, duration, and preparation). Substantially fewer data are available for nonpenicillin regimens. Recommended regimen for adults Benzathine penicillin G 2.4 million units IM in a single dose. (NOTE: Recommendations for treating pregnant women and HIV-infected patients for syphilis are discussed in separate sections.) Recommended regimen for children After the newborn period, children with syphilis should have a CSF examination to detect asymptomatic neurosyphilis, and birth and maternal medical records should be reviewed to assess whether such children have congenital or acquired syphilis (see "Congenital syphilis"). Children with acquired primary or secondary syphilis should be evaluated (e.g., through consultation with child-protection services) (see "Sexual assault or abuse of children" in original MMWR report) and treated by using the following pediatric regimen. Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose. Other management considerations All patients who have syphilis should be tested for HIV infection. In geographic areas in which the prevalence of HIV is high, patients who have primary syphilis should be retested for HIV after 3 months if the first HIV test result was negative. Patients who have syphilis and who also have symptoms or signs suggesting neurologic disease (e.g., meningitis) or ophthalmic disease (e.g., uveitis) should have an evaluation that includes CSF analysis and ocular slit-lamp examination. Treatment should be guided by the results of this evaluation. Invasion of CSF by T pallidum accompanied by CSF abnormalities is common among adults who have primary or secondary syphilis. However, neurosyphilis develops in only a limited number of patients after treatment with the penicillin regimens recommended for primary and secondary syphilis. Therefore, unless clinical signs or symptoms of neurologic or ophthalmic involvement are present, CSF analysis is not recommended for routine evaluation of patients who have primary or secondary syphilis. Follow-up Treatment failure can occur with any regimen. However, assessing response to treatment often is difficult, and definitive criteria for cure or failure have not been established. Nontreponemal test titers may decline more slowly for patients who previously had syphilis. Patients should be reexamined clinically and serologically 6 months and 12 months following treatment; more frequent evaluation may be prudent if follow-up is uncertain. Patients who have signs or symptoms that persist or recur or who have a sustained fourfold increase in nontreponemal test titer (i.e., compared with the maximum or baseline titer at the time of treatment) probably failed treatment or were reinfected. These patients should be re-treated and reevaluated for HIV infection. Because treatment failure usually cannot be reliably distinguished from reinfection with T pallidum, a CSF analysis also should be performed. A recent clinical trial demonstrated that 15% of patients with early syphilis treated with the recommended therapy will not achieve a two dilution decline in nontreponemal titer used to define response at 1 year following treatment. Failure of nontreponemal test titers to decline fourfold within 6 months after therapy for primary or secondary syphilis is indicative of probable treatment failure. Persons for whom titers remain serofast should be reevaluated for HIV infection. Optimal management of such patients is unclear. At a minimum, these patients should have additional clinical and serologic follow-up. HIV-infected patients should be evaluated more frequently (i.e., at 3-month intervals instead of 6-month intervals). If additional follow-up cannot be ensured, re-treatment is recommended. Because treatment failure may be the result of unrecognized CNS infection, some specialists recommend CSF examination in such situations. When patients are re-treated, most STD specialists recommend administering weekly injections of benzathine penicillin G 2.4 million units IM for 3 weeks, unless CSF examination indicates that neurosyphilis is present. In rare instances, serologic titers do not decline despite a negative CSF examination and a repeated course of therapy. Additional therapy or repeated CSF examinations are not warranted in these circumstances. Management of sex partners See "General principles, management of sex partners." Special considerations Penicillin allergy. Data to support the use of alternatives to penicillin in the treatment of early syphilis are limited. However, several therapies might be considered effective in nonpregnant, penicillin-allergic patients who have primary or secondary syphilis. Doxycycline (100 mg orally twice daily for 14 days) and tetracycline (500 mg four times daily for 14 days) are regimens that have been used for many years. Compliance is likely to be better with doxycycline than tetracycline, because tetracycline can cause gastrointestinal side effects. Although limited clinical studies, along with biologic and pharmacologic evidence, suggest that ceftriaxone is effective for treating early syphilis, the optimal dose and duration of ceftriaxone therapy have not been defined. However, some specialists recommend 1 g daily either IM or IV for 8 to 10 days. Preliminary data suggest that azithromycin may be effective as a single oral dose of 2 g. Because the efficacy of these therapies is not well documented, close follow-up of persons receiving these therapies is essential. The use of any of these therapies in HIV-infected persons has not been studied; the use of doxycycline, ceftriaxone, and azithromycin among such persons must be undertaken with caution. Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin. Skin testing for penicillin allergy may be useful in some circumstances in which the reagents and expertise are available to perform the test adequately (see "Management of patients who have a history of penicillin allergy"). Pregnancy. Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see "Management of patients who have a history of penicillin allergy and syphilis during pregnancy"). HIV infection. See "Syphilis among HIV-infected persons." Latent syphilis Latent syphilis is defined as syphilis characterized by seroreactivity without other evidence of disease. Patients who have latent syphilis and who acquired syphilis within the preceding year are classified as having early latent syphilis. Patients can be diagnosed as having early latent syphilis if, within the year preceding the evaluation, they had (a) a documented seroconversion, (b) unequivocal symptoms of primary or secondary syphilis, or (c) a sex partner documented to have primary, secondary, or early latent syphilis. Patients who have latent syphilis of unknown duration should be managed as if they have late latent syphilis. Nontreponemal serologic titers usually are higher during early latent syphilis than late latent syphilis. However, early latent syphilis cannot be reliably distinguished from late latent syphilis solely on the basis of nontreponemal titers. All patients with latent syphilis should have careful examination of all accessible mucosal surfaces (i.e., the oral cavity, the perineum in women, and underneath the foreskin in uncircumcised men) to evaluate for internal mucosal lesions. All patients who have syphilis should be tested for HIV infection. Treatment Treatment of latent syphilis usually does not affect transmission and is intended to prevent occurrence or progression of late complications. Although clinical experience supports the effectiveness of penicillin in achieving these goals, limited evidence is available for guidance in choosing specific regimens. The following regimens are recommended for nonallergic patients who have normal CSF examinations (if performed). Recommended regimens for adults Early latent syphilis Benzathine penicillin G 2.4 million units IM in a single dose. Late latent syphilis or latent syphilis of unknown duration Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM each at 1-week intervals. After the newborn period, children with syphilis should have a CSF examination to exclude neurosyphilis. In addition, birth and maternal medical records should be reviewed to assess whether children have congenital or acquired syphilis (see "Congenital syphilis"). Older children with acquired latent syphilis should be evaluated as described for adults and treated using the following pediatric regimens (see "Sexual assault or abuse of children" in original MMWR report). These regimens are for nonallergic children who have acquired syphilis and who have normal CSF examination results. Recommended regimens for children Early latent syphilis Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units in a single dose. Late latent syphilis or latent syphilis of unknown duration Benzathine penicillin G 50,000 units/kg IM, up to the adult dose of 2.4 million units, administered as three doses at 1-week intervals (total 150,000 units/kg up to the adult total dose of 7.2 million units). Other management considerations All patients who have latent syphilis should be evaluated clinically for evidence of tertiary disease (e.g., aortitis, gumma, and iritis). Patients who have syphilis and who demonstrate any of the following criteria should have a prompt CSF examination: neurologic or ophthalmic signs or symptoms; evidence of active tertiary syphilis (e.g., aortitis, gumma, and iritis); treatment failure; or HIV infection with late latent syphilis or syphilis of unknown duration. If dictated by circumstances and patient preferences, a CSF examination may be performed for patients who do not meet these criteria. Some specialists recommend performing a CSF examination on all patients who have latent syphilis and a nontreponemal serologic test of 1:32 or more. The risk of neurosyphilis in this circumstance is unknown. If a CSF examination is performed and the results indicate abnormalities consistent with neurosyphilis, the patient should be treated for neurosyphilis (see "Neurosyphilis"). If a patient misses a dose of penicillin in the course of weekly therapy for late syphilis, the appropriate course of action is unclear. Pharmacologic considerations suggest that an interval of 10 to 14 days between doses of benzathine penicillin for late syphilis or latent syphilis of unknown duration might be acceptable before restarting the sequence of injections. Missed doses should not be considered acceptable for pregnant patients receiving therapy for late latent syphilis; pregnant women who miss any dose of therapy must repeat the full course of therapy. Follow-up. Quantitative nontreponemal serologic tests should be repeated at 6, 12, and 24 months. Patients with a normal CSF examination should be re-treated for latent syphilis if (a) titers increase fourfold, (b) an initially high titer (>1:32) fails to decline at least fourfold (i.e., two dilutions) within 12 to 24 months of therapy, or (c) signs or symptoms attributable to syphilis develop. In rare instances, despite a negative CSF examination and a repeated course of therapy, serologic titers may still not decline. In these circumstances, the need for additional therapy or repeated CSF examinations is unclear. Management of sex partners. See "General principles, management of sex partners." Special considerations Penicillin allergy. The effectiveness of alternatives to penicillin in the treatment of latent syphilis has not been well documented. Nonpregnant patients allergic to penicillin who have clearly defined early latent syphilis should respond to therapies recommended as alternatives to penicillin for the treatment of primary and secondary syphilis (see "Treatment of primary and secondary syphilis"). The only acceptable alternatives for the treatment of late latent syphilis or latent syphilis of unknown duration are doxycycline (100 mg orally twice daily) or tetracycline (500 mg orally four times daily) both for 28 days. These therapies should be used only in conjunction with close serologic and clinical follow-up. The efficacy of these alternative regimens in HIV-infected persons has not been studied, and thus must be considered with caution. Pregnancy. Pregnant patients who are allergic to penicillin should be desensitized and treated with penicillin (see "Management of patients who have a history of penicillin allergy and syphilis during pregnancy"). HIV infection. See "Syphilis among HIV-infected persons." Tertiary syphilis Tertiary syphilis refers to gumma and cardiovascular syphilis, but not to all neurosyphilis. Patients who are not allergic to penicillin and have no evidence of neurosyphilis should be treated with the following regimen. Recommended regimen Benzathine penicillin G 7.2 million units total, administered as three doses of 2.4 million units IM each at 1-week intervals. Other management considerations Patients who have symptomatic late syphilis should be given a CSF examination before therapy is initiated. Some providers treat all patients who have cardiovascular syphilis with a neurosyphilis regimen. The complete management of patients who have cardiovascular or gummatous syphilis is beyond the scope of these guidelines. These patients should be managed in consultation with an infectious diseases specialist. Follow-up. Limited information is available concerning clinical response and follow-up of patients who have tertiary syphilis. Management of sex partners. See "General principles, management of sex partners." Special considerations Penicillin allergy. Patients allergic to penicillin should be treated according to treatment regimens recommended for late latent syphilis. Pregnancy. Pregnant patients who are allergic to penicillin should be desensitized, if necessary, and treated with penicillin (see "Management of patients who have a history of penicillin allergy and syphilis during pregnancy"). HIV infection. See "Syphilis among HIV-infected persons." Neurosyphilis Treatment CNS disease can occur during any stage of syphilis. A patient who has clinical evidence of neurologic involvement with syphilis (e.g., cognitive dysfunction, motor or sensory deficits, ophthalmic or auditory symptoms, cranial nerve palsies, and symptoms or signs of meningitis) should have a CSF examination. Syphilitic uveitis or other ocular manifestations frequently are associated with neurosyphilis; patients with these symptoms should be treated according to the recommendations for patients with neurosyphilis. A CSF examination should be performed for all such patients to identify those with abnormalities who should have follow-up CSF examinations to assess treatment response. Patients who have neurosyphilis or syphilitic eye disease (e.g., uveitis, neuroretinitis, and optic neuritis) should be treated with the following regimen. Recommended regimen Aqueous crystalline penicillin G 18 to 24 million units per day, administered as 3 to 4 million units IV every 4 hours or continuous infusion, for 10 to 14 days. If compliance with therapy can be ensured, patients may be treated with the following alternative regimen. Alternative regimen Procaine penicillin 2.4 million units IM once daily PLUS Probenecid 500 mg orally four times a day, both for 10 to 14 days. The durations of the recommended and alternative regimens for neurosyphilis are shorter than that of the regimen used for late syphilis in the absence of neurosyphilis. Therefore, some specialists administer benzathine penicillin, 2.4 million units IM once per week for up to 3 weeks after completion of these neurosyphilis treatment regimens to provide a comparable total duration of therapy. Other management considerations Other considerations in the management of patients who have neurosyphilis are as follows. All patients who have syphilis should be tested for HIV. Many specialists recommend treating patients who have evidence of auditory disease caused by syphilis in the same manner as patients who have neurosyphilis, regardless of CSF examination results. Although systemic steroids are used frequently as adjunctive therapy for otologic syphilis, such drugs have not been proven beneficial. Follow-up. If CSF pleocytosis was present initially, a CSF examination should be repeated every 6 months until the cell count is normal. Follow-up CSF examinations also can be used to evaluate changes in the VDRL-CSF or CSF protein after therapy; however, changes in these two parameters are slower, and persistent abnormalities may be less important. If the cell count has not decreased after 6 months, or if the CSF is not normal after 2 years, re-treatment should be considered. Management of sex partners. See "General principles, management of sex partners." Special considerations Penicillin allergy. Ceftriaxone can be used as an alternative treatment for patients with neurosyphilis, although the possibility of cross-reactivity between this agent and penicillin exists. Some specialists recommend ceftriaxone 2 g daily either IM or IV for 10 to 14 days. Other regimens have not been adequately evaluated for treatment of neurosyphilis. Therefore, if concern exists regarding the safety of ceftriaxone for a patient with neurosyphilis, the patient should obtain skin testing to confirm penicillin allergy and, if necessary, be desensitized and managed in consultation with a specialist. Pregnancy. Pregnant patients who are allergic to penicillin should be desensitized, if necessary, and treated with penicillin (see "Syphilis during pregnancy"). HIV infection. See "Syphilis among HIV-infected patients." Syphilis among HIV-infected persons Diagnostic considerations Unusual serologic responses have been observed among HIV-infected persons who have syphilis. Most reports have involved serologic titers that were higher than expected, but false-negative serologic test results and delayed appearance of seroreactivity also have been reported. However, aberrant serologic responses are uncommon, and most specialists believe that both treponemal and nontreponemal serologic tests for syphilis can be interpreted in the usual manner for most patients who are co-infected with T pallidum and HIV. When clinical findings are suggestive of syphilis, but serologic tests are nonreactive or the interpretation is unclear, alternative tests (e.g., biopsy of a lesion, darkfield examination, or direct fluorescent antibody staining of lesion material) may be useful for diagnosis. Neurosyphilis should be considered in the differential diagnosis of neurologic disease in HIV-infected persons. Treatment Compared with HIV-negative patients, HIV-positive patients who have early syphilis may be at increased risk for neurologic complications and may have higher rates of treatment failure with currently recommended regimens. The magnitude of these risks, although not defined precisely, is likely minimal. No treatment regimens for syphilis have been demonstrated to be more effective in preventing neurosyphilis in HIV-infected patients than the syphilis regimens recommended for HIV-negative patients. Careful follow-up after therapy is essential. Primary and secondary syphilis among HIV-infected persons Treatment Treatment with benzathine penicillin G, 2.4 million units IM in a single dose is recommended. Some specialists recommend additional treatments (e.g., benzathine penicillin G administered at 1-week intervals for 3 weeks, as recommended for late syphilis) in addition to benzathine penicillin G 2.4 million units IM. Other management considerations Because CSF abnormalities (e.g., mononuclear pleocytosis and elevated protein levels) are common in patients with early syphilis and in persons with HIV infection, the clinical and prognostic significance of such CSF abnormalities in HIV-infected persons with primary or secondary syphilis is unknown. Although most HIV-infected persons respond appropriately to standard benzathine penicillin therapy, some specialists recommend intensified therapy when CNS syphilis is suspected in these persons. Therefore, some specialists recommend CSF examination before treatment of HIV-infected persons with early syphilis, with follow-up CSF examination following treatment in persons with initial abnormalities. Follow-up. HIV-infected patients should be evaluated clinically and serologically for treatment failure at 3, 6, 9, 12, and 24 months after therapy. Although of unproven benefit, some specialists recommend a CSF examination 6 months after therapy. HIV-infected patients who meet the criteria for treatment failure should be managed in the same manner as HIV-negative patients (i.e., a CSF examination and re-treatment). CSF examination and re-treatment also should be strongly considered for patients whose nontreponemal test titers do not decrease fourfold within 6 to 12 months of therapy. Most specialists would re-treat patients with benzathine penicillin G administered as three doses of 2.4 million units IM each at weekly intervals, if CSF examinations are normal. Special considerations Penicillin allergy. Penicillin-allergic patients who have primary or secondary syphilis and HIV infection should be managed according to the recommendations for penicillin-allergic, HIV-negative patients. The use of alternatives to penicillin has not been well studied in HIV-infected patients. Latent syphilis among HIV-infected persons Diagnostic considerations HIV-infected patients who have early latent syphilis should be managed and treated according to the recommendations for HIV-negative patients who have primary and secondary syphilis. HIV-infected patients who have either late latent syphilis or syphilis of unknown duration should have a CSF examination before treatment. Treatment Patients with late latent syphilis or syphilis of unknown duration and a normal CSF examination can be treated with benzathine penicillin G, at weekly doses of 2.4 million units for 3 weeks. Patients who have CSF consistent with neurosyphilis should be treated and managed as patients who have neurosyphilis (see "Neurosyphilis"). Follow-up. Patients should be evaluated clinically and serologically at 6, 12, 18, and 24 months after therapy. If, at any time, clinical symptoms develop or nontreponemal titers rise fourfold, a repeat CSF examination should be performed and treatment administered accordingly. If in 12 to 24 months the nontreponemal titer does not decline fourfold, the CSF examination should be repeated and treatment administered accordingly. Special considerations Penicillin allergy. Patients with penicillin allergy whose compliance with therapy or follow-up cannot be ensured should be desensitized and treated with penicillin (see "Management of patients who have a history of penicillin allergy"). The efficacy of alternative non-penicillin regimens in HIV-infected persons has not been studied. Syphilis during pregnancy All women should be screened serologically for syphilis at the first prenatal visit. In populations in which prenatal care is not optimal, RPR-card test screening and treatment (if the RPR-card test is reactive) should be performed at the time a pregnancy is confirmed. For communities and populations in which the prevalence of syphilis is high or for patients at high risk, serologic testing should be performed twice during the third trimester, at 28 weeks' gestation, and at delivery in addition to routine early screening. Some states mandate screening at delivery for all women. Any woman who delivers a stillborn infant after 20 weeks' gestation should be tested for syphilis. No infant should leave the hospital if maternal serologic status has not been determined at least once during pregnancy and preferably again at delivery. Diagnostic considerations Seropositive pregnant women should be considered infected unless an adequate treatment history is documented in the medical records and sequential serologic antibody titers have declined. Treatment Penicillin is effective for preventing maternal transmission to the fetus and for treating fetal infection. Evidence is insufficient to determine whether the specific, recommended penicillin regimens are optimal. Recommended regimen Treatment during pregnancy should consist of the penicillin regimen appropriate for the stage of syphilis. Other management considerations Some specialists recommend additional therapy in some patients. A second dose of benzathine penicillin 2.4 million units IM may be administered 1 week after the initial dose for women who have primary, secondary, or early latent syphilis. In the second half of pregnancy, management and counseling may be facilitated by a sonographic fetal evaluation for congenital syphilis, but this should not delay therapy. Sonographic signs of fetal syphilis (i.e., hepatomegaly, ascites, and hydrops) indicate a greater risk for fetal treatment failure; such cases should be managed in consultation with obstetric specialists. Evidence is insufficient to recommend specific regimens for these situations. Women treated for syphilis during the second half of pregnancy are at risk for premature labor and/or fetal distress if the treatment precipitates the Jarisch-Herxheimer reaction. These women should be advised to seek obstetric attention after treatment if they notice any contractions or decrease in fetal movements. Although stillbirth is a rare complication of treatment, concern about this complication should not delay necessary treatment. All patients who have syphilis should be offered testing for HIV infection. Follow-up. Coordinated prenatal care, treatment follow-up, and syphilis case management are important in the management of pregnant women with syphilis. Serologic titers should be repeated in the third trimester and at delivery. Serologic titers may be checked monthly in women at high risk for reinfection or in geographic areas in which the prevalence of syphilis is high. The clinical and antibody response should be appropriate for the stage of disease. Most women will deliver before their serologic response to treatment can be assessed definitively. Management of sex partners. See "General principles, management of sex partners." Special considerations Penicillin allergy. No alternatives to penicillin have been proved effective for treatment of syphilis during pregnancy. Pregnant women who have a history of penicillin allergy should be desensitized and treated with penicillin. Skin testing may be helpful (see "Management of patients who have a history of penicillin allergy"). Tetracycline and doxycycline should not used during pregnancy. Erythromycin should not be used, because it does not reliably cure an infected fetus. Data are insufficient to recommend azithromycin or ceftriaxone. HIV infection. See "Syphilis among HIV-infected patients." Congenital syphilis Effective prevention and detection of congenital syphilis depends on the identification of syphilis in pregnant women and, therefore, on the routine serologic screening of pregnant women during the first prenatal visit. Serologic testing and a sexual history also should be obtained at 28 weeks' gestation and at delivery in communities and populations in which the risk for congenital syphilis is high. Moreover, as part of the management of pregnant women who have syphilis, information concerning treatment of sex partners should be obtained to assess the risk for reinfection. All pregnant women who have syphilis should be tested for HIV infection. Routine screening of newborn sera or umbilical cord blood is not recommended. Serologic testing of the mother's serum is preferred over testing infant serum, because the serologic tests performed on infant serum can be nonreactive if the mother's serologic test result is of low titer or if the mother was infected late in pregnancy. No infant or mother should leave the hospital unless the maternal serologic status has been documented at least once during pregnancy and preferably again at delivery. (Editor's note: For discussion of the evaluation and treatment of infants in the first month of life and older infants and children, see original MMWR report.) Management of patients who have a history of penicillin allergy No proven alternatives to penicillin are available for treating neurosyphilis, congenital syphilis, or syphilis in pregnant women. Penicillin is also recommended for use, whenever possible, in HIV-infected patients. Of the adult US population, 3% to 10% have experienced urticaria, angioedema, or anaphylaxis (i.e., upper airway obstruction, bronchospasm, or hypotension) after penicillin therapy. Re-administration of penicillin to these patients can cause severe, immediate reactions. Because anaphylactic reactions to penicillin can be fatal, every effort should be made to avoid administering penicillin to penicillin-allergic patients, unless they undergo acute desensitization to eliminate anaphylactic sensitivity. An estimated 10% of persons who report a history of severe allergic reactions to penicillin remain allergic. With the passage of time after an allergic reaction to penicillin, most persons who have had a severe reaction stop expressing penicillin-specific immunoglobulin E (IgE). These persons can be treated safely with penicillin. The results of many investigations indicate that skin testing with the major and minor determinants can reliably identify persons at high risk for penicillin reactions. Although these reagents are easily generated and have been available for over 30 years, only benzylpenicilloyl poly-L-lysine (Pre-Pen [i.e., the major determinant]) and penicillin G are available commercially. Testing with only the major determinant and penicillin G identifies an estimated 90% to 97% of the currently allergic patients. However, because skin testing without the minor determinants would still miss 3% to 10% of allergic patients and because serious or fatal reactions can occur among these minor-determinant-positive patients, specialists suggest exercising caution when the full battery of skin-test reagents is not available (see Box 1 in original MMWR report for details). Recommendations If the full battery of skin-test reagents is available, including the major and minor determinants (see "Penicillin allergy skin testing"), patients who report a history of penicillin reaction and are skin-test negative can receive conventional penicillin therapy. Skin-test-positive patients should be desensitized. If the full battery of skin-test reagents, including the minor determinants, is not available, the patient should be skin tested using benzylpenicilloyl poly-L-lysine (i.e., the major determinant) and penicillin G. Patients who have positive test results should be desensitized. Some specialists suggest that persons who have negative test results should be regarded as probably allergic and should be desensitized. Others suggest that those with negative skin-test results can be test-dosed gradually with oral penicillin in a monitored setting in which treatment for anaphylactic reaction can be provided. Penicillin allergy skin testing Patients at high risk for anaphylaxis, including those who (a) have a history of penicillin-related anaphylaxis, asthma, or other diseases that would make anaphylaxis more dangerous and (b) are being treated with beta-adrenergic blocking agents, should be tested with one hundred-fold dilutions of the full-strength skin-test reagents before being tested with full-strength reagents. In these situations, patients should be tested in a monitored setting in which treatment for an anaphylactic reaction is available. If possible, the patient should not have taken antihistamines recently (e.g., chlorpheniramine maleate or terfenadine during the preceding 24 hours, diphenhydramine HCl or hydroxyzine during the preceding 4 days, or astemizole during the preceding 3 weeks). Procedures Dilute the antigens either (a) one hundred-fold for preliminary testing if the patient has had a life-threatening reaction to penicillin or (b) tenfold if the patient has had another type of immediate, generalized reaction to penicillin within the preceding year. Epicutaneous (prick) tests Duplicate drops of skin-test reagent are placed on the volar surface of the forearm. The underlying epidermis is pierced with a 26-gauge needle without drawing blood. An epicutaneous test is positive if the average wheal diameter after 15 minutes is 4 mm larger than that of negative controls; otherwise, the test is negative. The histamine controls should be positive to ensure that results are not falsely negative because of the effect of antihistaminic drugs. Intradermal test If epicutaneous tests are negative, duplicate 0.02 mL intradermal injections of negative control and antigen solutions are made into the volar surface of the forearm using a 26- or 27-gauge needle on a syringe. The crossed diameters of the wheals induced by the injections should be recorded. An intradermal test is positive if the average wheal diameter 15 minutes after injection is more than 2 mm larger than the initial wheal size and also is more than 2 mm larger than the negative controls. Otherwise, the tests are negative. Desensitization Patients who have a positive skin test to one of the penicillin determinants can be desensitized (see Table 1 in original MMWR report for details). This is a straightforward, relatively safe procedure that can be done orally or IV. Although the two approaches have not been compared, oral desensitization is regarded as safer to use and easier to perform. Patients should be desensitized in a hospital setting because serious IgE-mediated allergic reactions rarely can occur. Desensitization usually can be completed in approximately 4 hours, after which the first dose of penicillin is administered. After desensitization, patients must be maintained on penicillin continuously for the duration of the course of therapy. The material in this report was prepared for publication by the National Center for HIV, STD, and TB Prevention, Harold W. Jaffe, MD, Acting Director; and the Division of Sexually Transmitted Diseases Prevention. Paul Cerrato. Updating the CDC's treatment guidelines: Syphilis. Contemporary Ob/Gyn 2003;3:82-104.