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Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents


(Last updated: May 7, 2013; last reviewed: May 7, 2013)


Syphilis is associated with increased risk of sexual acquisition and transmission of HIV.1,2 In recent years, there has been a resurgence of the disease in men in several U.S. cities and in Western Europe ( Although coexistent HIV infection, particularly in the advanced stages, may modify the diagnosis, natural history, or management of Treponema pallidum infection, the principles of syphilis management are the same for persons with and without coexistent HIV infection.9-13

Clinical Manifestations

The effect of coexistent HIV on the protean manifestations of syphilis have been documented in multiple case reports and small case series, but in only a limited number of large studies. Some studies suggest that HIV infection may shift the clinical manifestations of syphilis, making clinical lesions more apparent, and may accelerate progression of syphilitic disease.10,11,14,15 Early syphilis in HIV-infected patients also may cause a transient decrease in CD4 T-lymphocyte (CD4) count and increase in HIV viral load that improves with recommended syphilis treatment regimens.16-20

Primary syphilis commonly manifests as a single painless nodule at the site of contact that rapidly ulcerates to form a classic chancre; in HIV-infected patients, however, multiple or atypical chancres occur and primary lesions may be absent or missed.10,21

Progression to secondary syphilis typically follows 2 to 8 weeks after primary inoculation. Although more rapid progression or severe disease can occur in HIV-infected patients with advanced immunosuppression, the clinical manifestations are similar to those in HIV-uninfected individuals. The manifestations of secondary syphilis involve virtually all organ systems. The most common manifestations—macular, maculopapular, papulosquamous, or pustular skin lesions—can involve the palms and soles and be accompanied by generalized lymphadenopathy, fever, malaise, anorexia, arthralgias, and headache.11,12,19 Condyloma lata (moist, flat, papular lesions in warm intertrigenous regions) can occur and may resemble human papillomavirus infection. Lues maligna is a rare manifestation of secondary syphilis, characterized by papulopustular skin lesions that evolve into ulcerative lesions with sharp borders and a dark central crust.22 Secondary syphilis, especially when associated with symptomatic early neurosyphilis, can resemble acute primary HIV infection. Constitutional symptoms, along with nonfocal central nervous system (CNS) symptoms and cerebrospinal fluid (CSF) abnormalities such as lymphocytic pleocytosis with a mildly elevated CSF protein, are common to both secondary syphilis and acute primary HIV infection.14,15,21,23-26 Signs and symptoms of secondary syphilis can persist from a few days to several weeks before resolving and evolving to latent or later stages. 

Latent syphilis lacks overt clinical signs and symptoms, but relapse of manifestations of secondary syphilis can occur, most commonly during the first year after infection. Manifestations of tertiary syphilis generally include cardiovascular syphilis and gummatous syphilis or a slowly progressive disease that can affect any organ system. Neurosyphilis can occur at any stage of syphilis and manifest in varied clinical presentations, such as cranial nerve dysfunction, stroke, meningitis, acute or chronic change in mental status, loss of vibration sense, and auditory or ophthalmic abnormalities. Manifestations of symptomatic neurosyphilis in HIV-infected patients are similar to those in individuals who are not HIV infected. However, clinical manifestations of neurosyphilis, such as concomitant uveitis and meningitis, may be more common in HIV-infected persons.14,15,26-28


Darkfield microscopy and tests to detect T. pallidum in lesion exudates or tissue (biopsy with silver stain) are definitive for diagnosing early syphilis, although no T. pallidum direct detection tests are commercially available. A presumptive serologic diagnosis of syphilis is possible based upon non-treponemal tests (i.e., Venereal Disease Research Laboratory [VDRL] and rapid plasma reagin [RPR]) and treponemal tests (i.e., fluorescent treponemal antibody absorbed [FTA-ABS], T. pallidum particle agglutination [TP-PA], enzyme immunoassays [EIAs], and chemiluminescence immunoassays [CIA]). 

Serologic diagnosis of syphilis traditionally has involved screening for non-treponemal antibodies with confirmation of reactive tests by treponemal-based assays.19,29 Recently, some laboratories have initiated a testing algorithm using EIA or CIA as a screening test, followed by a reflex-quantitative, non-treponemal test if the EIA or CIA is positive. This latter strategy may identify those with previously treated syphilis infection more often than those with untreated infection.30

In persons with a positive treponemal screening test and a negative reflex-quantitative, non-treponemal test, the laboratory should perform a second treponemal test (based on different antigens from the initial test) to confirm the results of the positive initial treponemal test. If a second treponemal test is positive, an assessment is needed of current sexual risk factors and prior syphilis treatment. Physical examination should be performed to assess for evidence of syphilis, especially primary disease. Patients with suspected primary syphilis should be empirically treated and retested with a non-treponemal test in several weeks (if initial non-treponemal test was non-reactive) to confirm the diagnosis. Persons with discordant sera (reactive EIA/CIA and non-reactive, non-treponemal test) and a reactive TP-PA assay should be treated for late-latent syphilis if past treatment cannot be confirmed. If the second treponemal test is negative, no treatment is indicated.19,31 In the absence of neurologic signs or symptoms, risk of neurosyphilis is low in patients with a reactive treponemal test and a non-reactive, non-treponemal test;32 examination of CSF is not recommended. 

Early-stage disease (i.e., primary, secondary, and early-latent syphilis) in HIV-infected patients is confirmed with the same diagnostic tests used in those who are not infected with HIV: darkfield microscopy of a mucocutaneous lesion and standard serologic tests. Results with VDRL and RPR may be higher, lower, or delayed in HIV-infected versus HIV-uninfected patients with early-stage syphilis.33-37 No data indicate that treponemal tests perform differently among HIV-infected patients compared with HIV-uninfected patients,38 although uncommon, false-negative serologic tests for syphilis can occur in both HIV-uninfected and HIV-infected patients with documented T. pallidum infection.36,37 Therefore, if serologic tests do not confirm the diagnosis of suspected syphilis, other diagnostic procedures, such as repeat serology in 2 to 4 weeks, exclusion of prozone phenomenon, biopsy, or darkfield examination, should be pursued. By definition, persons with latent syphilis have serological evidence of syphilis in the absence of clinical manifestations. Early-latent syphilis is defined as evidence of infection <1 year; late-latent syphilis is evidence of infection for >1 year after acquisition of syphilis or latent infection of unknown duration. Diagnostic testing recommended for detection of late-stage syphilis (i.e., cardiovascular and gummatous syphilis) in HIV-infected patients is the same as in patients who are not infected with HIV.19

All persons with syphilis and signs or symptoms suggesting neurologic disease (e.g., cranial nerve dysfunction, meningitis, stroke, alteration in mental status, auditory or ophthalmic abnormalities) warrant evaluation for neurosyphilis and for ocular or otic syphilis if ophthalmic or auditory symptoms are present. CSF abnormalities (i.e., elevated protein and mononuclear pleocytosis) are common in early syphilis and in patients with HIV infection, even those with no neurologic symptoms. There is no evidence that the clinical and prognostic significance of such CSF abnormalities differs between HIV-infected and -uninfected patients with primary, secondary, or early-latent syphilis. 

CSF examination should be performed in patients who have neurologic, auditory, or ophthalmic signs (e.g., iritis, uveitis) or symptoms, active tertiary syphilis, or serologic treatment failure. Several studies have demonstrated that in HIV-infected patients with syphilis, clinical and CSF abnormalities consistent with neurosyphilis are associated with CD4 counts ≤350 cells/mm3 alone or in combination with RPR titers ≥1:32..25,26,39,40 Unless neurologic symptoms are present, however, CSF examination in this setting has not been associated with improved clinical outcomes. The risk of later developing clinical neurosyphilis and the benefits of a CSF examination in this circumstance are unknown.

Laboratory testing is useful in supporting the diagnosis of neurosyphilis, but no single test can be used to diagnose it. In patients who are not HIV infected, CSF examination supports diagnosis of neurosyphilis, which may indicate mild mononuclear pleocytosis (6–200 cells/mm3), normal or mildly elevated protein concentration, or a reactive (CSF-VDRL).19,25,26 CSF-VDRL is specific but not sensitive, and a reactive test establishes the diagnosis of neurosyphilis, but a non-reactive test does not exclude it. In comparison, CSF FTA-ABS is less specific than CSF-VDRL but highly sensitive. Calculated indices (T. pallidum hemaglutination assay index) are of limited value in establishing the diagnosis of neurosyphilis. Polymerase-chain-reaction-based diagnostic methods are not currently recommended as diagnostic tests for neurosyphilis. A reactive CSF-VDRL and a CSF white blood cell (WBC) count >10 cells/mm3 support the diagnosis of neurosyphilis; in the absence of other abnormalities, elevation in CSF protein concentrations should not be used as the sole diagnostic criterion. Therefore, the laboratory tests used to support the diagnosis of neurosyphilis depend on various combinations of reactive serologic tests, CSF cell count and protein, and a reactive CSF-VDRL with or without clinical manifestations.

Establishing the diagnosis of neurosyphilis can be more difficult in patients with HIV infection because HIV infection itself may be associated with mild mononuclear CSF pleocytosis (6–15 cells/mm3). Using a higher CSF WBC cutoff of >20 WBC/mm3 may improve the specificity of neurosyphilis diagnosis in HIV-infected patients.41 CSF FTA-ABS testing in HIV-uninfected persons suggests that the CSF FTA-ABS test is less specific for neurosyphilis than the CSF-VDRL but is highly sensitive.19,42 Thus, the use of this test may be considered in HIV-infected patients.

Preventing Exposure

The resurgence of syphilis in patients with HIV infection in the United States underscores the importance of primary prevention of syphilis in this population, which should begin with routine discussion of sexual behaviors. Health care providers should discuss client-centered risk reduction messages and provide specific actions that can reduce the risk of acquiring sexually transmitted diseases and of transmitting HIV infection.19,43-47 Routine serologic screening for syphilis is recommended at least annually for all HIV-infected patients who are sexually active, with more frequent screening (every 3–6 months) for those who have multiple partners, unprotected intercourse, sex in conjunction with illicit drug use, or use methamphetamines (or whose partners participate in such activities).19,48-50 The occurrence of syphilis in an HIV-infected individual is an indication of high-risk behavior and should prompt intensified counseling messages and strong consideration of referral for behavioral intervention. Patients undergoing screening or treatment for syphilis also should be evaluated for all common sexually transmitted diseases such as chlamydia and gonorrhea at anatomic sites of exposure.19,51

Preventing Disease

The same measures that apply to preventing exposure apply to preventing disease. Studies in the pre-HIV era demonstrated that approximately one-third of the sex partners of patients who have infectious syphilis will develop syphilis within 30 days of exposure, and empiric treatment of incubating syphilis will prevent the development of disease in those who are exposed.52-55 Those exposed sexually to a patient with syphilis in any stage should be evaluated clinically and serologically and treated presumptively with regimens outlined in current recommendations.19 Specifically, individuals who were exposed within the 90 days preceding diagnosis of primary, secondary, or early-latent syphilis in a sex partner may be infected even if they are seronegative. Therefore, they should be treated presumptively (AII). Individuals exposed >90 days before 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 (AIII).

Treating Disease

Management of syphilis in HIV-infected patients is similar to that in individuals who are HIV-uninfected.13,19,34 Most HIV-infected patients respond appropriately to standard treatment. Closer follow-up is recommended, however, because rates of serologic treatment failure may be higher in those who are HIV infected and they may be at increased risk of neurologic complications.15,56,57

Penicillin remains the treatment of choice for syphilis regardless of a patient’s HIV status. HIV-infected patients with early-stage (primary, secondary, or early-latent) syphilis should receive a single intramuscular (IM) injection of 2.4 million units of benzathine penicillin G (AII).19 The available data demonstrate that high-dose amoxicillin given with probenecid in addition to benzathine penicillin G in early syphilis is not associated with improved clinical outcomes.34 Patients with a penicillin allergy whose compliance or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin (AIII). The efficacy of alternative non-penicillin regimens in HIV-infected patients with early syphilis has not been evaluated sufficiently to warrant their use as first-line treatment. 

Regardless of HIV infection status, use of any alternative penicillin treatment regimen should be undertaken only with close clinical and serologic monitoring. Several retrospective studies support use of doxycycline, 100 mg twice daily, to treat early syphilis (BII); however, the majority of the patients were HIV uninfected.58,59 Limited clinical studies suggest that ceftriaxone, 1 g daily either IM or intravenously (IV) for 10 to 14 days, is effective for treating early syphilis (BII), but the optimal dose and duration of therapy have not been defined.60 A single 2-g oral dose of azithromycin is effective for treating early syphilis;61-63 however T. pallidum chromosomal mutations associated with azithromycin resistance and treatment failures have been reported and are more common in men who have sex with men (MSM).64-69 Azithromycin treatment has not been well studied in HIV-infected patients with early syphilis and it should be used with caution in instances when treatment with penicillin or doxycycline is not feasible (BII). Azithromycin should not be used in MSM or in pregnant women (AII).

In HIV-infected patients with late-latent syphilis and no signs or symptoms of neurosyphilis, treatment with 3 weekly IM injections of 2.4 million units benzathine penicillin G is recommended (AII). Alternative therapy with doxycycline, 100 mg by mouth twice a day for 28 days, has not been sufficiently evaluated in HIV-infected patients to warrant use as first-line treatment (BIII). Limited clinical studies and biologic and pharmacologic evidence suggest that ceftriaxone may be effective; however, the optimal dose and duration of therapy have not been determined.70,71 If the clinical situation requires use of an alternative to penicillin, treatment should be undertaken with close clinical and serologic monitoring.

HIV-infected patients with clinical evidence of late-stage (tertiary) syphilis (cardiovascular or gummatous disease) should have CSF examination to rule out neurosyphilis before therapy is initiated. Recommended treatment of late-stage syphilis is 3 weekly IM injections of 2.4 million units benzathine penicillin G (AII).19 However, the complexity of tertiary syphilis management is beyond the scope of these guidelines and health care providers are advised to consult an infectious disease specialist.

HIV-infected patients diagnosed with neurosyphilis or ocular or otic syphilis should receive IV aqueous crystalline penicillin G, 18 to 24 million units daily, administered 3 to 4 million units IV every 4 hours or by continuous infusion for 10 to 14 days (AII) or procaine penicillin, 2.4 million units IM once daily plus probenecid 500 mg orally 4 times a day for 10 to 14 days (BII).19,25,26 HIV-infected patients who are allergic to sulfa-containing medications should not be given probenecid because of potential allergic reaction (AIII).

Because neurosyphilis treatment regimens are of shorter duration than those used in late-latent syphilis, 2.4 million units benzathine penicillin IM once per week for up to 3 weeks after completion of neurosyphilis treatment can be considered to provide a comparable duration of therapy (CIII).19 Desensitization to penicillin is the preferred approach to treating neurosyphilis in patients who are allergic to penicillin. However, limited data indicate that ceftriaxone (2 g daily IV for 10–14 days) may be an acceptable alternative regimen (BII).71 Other alternative regimens for neurosyphilis have not been evaluated adequately. Syphilis treatment recommendations are also available in the 2010 Centers for Disease Control and Prevention STD Treatment Guidelines.19

Special Considerations with Regard to Starting ART

There are no special considerations regarding the initiation of antiretroviral therapy (ART) in patients with syphilis. Specifically, there is currently no evidence that treatment with ART needs to be delayed until treatment for syphilis has been completed. Immune reconstitution inflammatory syndrome (IRIS) in association with syphilis and treatment with ART in HIV-infected persons is uncommon.72

Monitoring and Adverse Events (Including IRIS)

Clinical and serologic responses (four-fold decrease from the titer at the time of treatment) to treatment of early-stage (primary, secondary, and early-latent) disease should be monitored at 3, 6, 9, 12, and 24 months after therapy. Serologic responses to treatment are similar in patients who are HIV infected and HIV uninfected; subtle variations can occur, however, including the temporal pattern of response.13,19,34,73 If clinical signs and symptoms persist or recur or there is a sustained four-fold increase in non-treponemal titers, treatment failure should be considered and managed per recommendations below.

After successful treatment for early syphilis (HIV-infected and -uninfected persons), 15% to 20% of patients may remain “serofast,” meaning that serum non-treponemal test titers remain reactive at a stable level, usually <1:8, for prolonged periods.19,34 This serofast state probably does not represent treatment failure. Serologic detection of potential re-infection should be based on at least a sustained four-fold increase in titer above the established serofast baseline and syphilis risk assessment.

Response to therapy for late-latent syphilis should be monitored using non-treponemal serologic tests at 6, 12, 18, and 24 months to ensure at least a four-fold decline in titer, if initially high (≥1:32), within 12 to 24 months of therapy. If clinical symptoms develop or a four-fold increase in non-treponemal titers is sustained, then treatment failure should be considered and managed per recommendations.19 The earliest CSF indicator of response to neurosyphilis treatment is a decline in CSF lymphocytosis. The CSF-VDRL may respond more slowly. If CSF pleocytosis was present initially, a CSF examination should be repeated at 6 months. Limited data suggest that changes in CSF parameters may occur more slowly in HIV-infected patients, especially those with advanced immunosuppression.14,25 If the cell count has not decreased after 6 months or if the CSF WBC is not normal after 2 years, re-treatment should be considered. 

Use of ART in HIV-infected patients with syphilis has been associated with a reduced risk of serologic failure of syphilis treatment,14 a lower risk of developing neurosyphilis,14 and normalization of CSF parameters associated with decline in serum RPR titers after treatment.74 

The Jarisch-Herxheimer reaction is an acute febrile reaction frequently accompanied by headache and myalgia that can occur within the first 24 hours after initiation of treatment for syphilis. Antipyretics can be used to manage symptoms but have not been proven to prevent this reaction. The Jarisch-Herxheimer reaction occurs most frequently in patients with early syphilis, high non-treponemal antibody titers, and prior penicillin treatment.75

Managing Treatment Failure

Re-treatment should be considered for patients with early-stage syphilis who
  1. Do not have at least a four-fold decrease in serum non-treponemal titers 6 to 12 months after treatment 
  2. Have a sustained four-fold increase in serum non-treponemal titers after an initial four-fold decrease following treatment, or 
  3. Have persistent or recurring clinical signs or symptoms of disease, whether as a result of treatment failure or of re-infection. 
HIV-infected persons in whom treatment fails should be managed in the same manner as those who are HIV negative. Because re-infection is difficult to document and treatment failure is difficult to rule out, CSF examination and re-treatment should be considered in those who meet the previously described criteria. If CSF examination does not confirm the diagnosis of neurosyphilis, benzathine penicillin G, 2.4 million units at 1-week intervals for 3 weeks, should be administered (BIII). Failure of non-treponemal tests to decline four-fold within 6 to 12 months after therapy for early syphilis may be indicative of treatment failure, but clinical trial data have demonstrated that regardless of HIV infection, >15% of persons with early syphilis treated with recommended therapy will not achieve the four-fold decline in non-treponemal titer used to define treatment response at 1 year.34 If titers do not respond appropriately after CSF examination and re-treatment, the value of repeated CSF examination or additional therapy is unclear, but it is generally not recommended. Person with HIV infection may be at increased risk of treatment failure, but the magnitude of these risks is not precisely defined and is likely low.19,24,57 Treatment with benzathine penicillin, 2.4 million units IM, and close clinical follow-up can be considered in patients with a four-fold increase in non-treponemal titers within the past year who are at high risk of syphilis re-infection (CIII).

Patients treated for late-latent syphilis should have a CSF examination and be retreated if they develop clinical signs or symptoms of syphilis, have a sustained four-fold increase in serum non-treponemal test titer, or experience an inadequate serologic response (less than four-fold decline in an initially high [≥1:32] non-treponemal test titer) within 12 to 24 months of therapy. If CSF examination is consistent with CNS involvement, re-treatment should follow the neurosyphilis recommendations. Patients with late-latent syphilis and a normal CSF examination should be treated with benzathine penicillin 2.4 million units IM weekly for 3 doses (BIII). As with early-stage syphilis, treatment with benzathine penicillin, 2.4 million units IM, and close clinical follow-up can be considered in patients with a four-fold increase in non-treponemal titers within the past year who are at high risk of re-infection (CIII). Re-treatment for neurosyphilis should be considered if the CSF WBC count has not decreased 6 months after completion of treatment. Limited data suggest that changes in CSF parameters may occur more slowly in HIV-infected patients, especially those with advanced immunosuppression.25 If the cell count has not decreased after 6 months or if the CSF WBC count is not normal after 2 years, re-treatment should be considered.19

Preventing Recurrence

No recommendations indicate the need for secondary prophylaxis or prolonged chronic maintenance antimicrobial therapy for syphilis in HIV-infected patients. Targeted mass treatment of high-risk populations has not been demonstrated to be effective and is not recommended.76 Azithromycin is not recommended as secondary prevention because of azithromycin treatment failures reported in HIV-infected patients and reports of chromosomal mutations associated with macrolide-resistant T. pallidum.64-66,68,69

Special Considerations During Pregnancy

Pregnant women should be screened for syphilis at the first prenatal visit. Syphilis screening should be performed again early in the third trimester and at delivery in areas where syphilis prevalence is high and in women at high risk of infection and those who were previously untested.19 Syphilis screening also should be offered at sites providing episodic care to pregnant women at high risk, including emergency departments, jails, and prisons. Antepartum screening with non-treponemal testing is typical but treponemal screening is being used in some settings. Pregnant women with reactive treponemal screening tests should have reflex confirmatory testing with non-treponemal tests (see Diagnosis section above). No infant should leave the hospital without documentation of maternal syphilis-serology status determined at least once during pregnancy.77 All women who deliver stillborn infants after 20 weeks of gestation also should be tested for syphilis.

Rates of transmission to the fetus and adverse pregnancy outcomes for untreated syphilis are highest with primary, secondary, and early-latent syphilis and decrease with increasing duration of infection. Pregnancy does not appear to alter the clinical course, manifestations, or diagnostic test results for syphilis infection in adults. Concurrent syphilis infection has been associated with increased risk of perinatal transmission of HIV to the infant.78-83

Treatment of syphilis during pregnancy should consist of the same regimen recommended for HIV-infected adults who are not pregnant. Penicillin is effective for preventing maternal transmission to the fetus and for treatment of fetal infection, but current evidence is insufficient to determine the optimal penicillin regimen.84 There is some evidence to suggest that additional therapy should be considered in HIV-uninfected pregnant women with early syphilis: a second dose of benzathine penicillin G, 2.4 million units IM administered 1 week after the initial dose in women who have primary, secondary, and early-latent syphilis.19,85,86 Because of concerns about the efficacy of standard therapy in pregnant women who are not HIV infected, a second injection in 1 week should be considered for HIV-infected pregnant women (BIII).

No alternatives to penicillin have been proven effective and safe for treatment of syphilis during pregnancy or for prevention of fetal infection. Pregnant women who have a history of penicillin allergy should undergo desensitization and treatment with penicillin (AIII).19 Erythromycin and azithromycin do not reliably cure maternal or fetal infection (AII); tetracyclines should not be used during pregnancy because of concerns about hepatotoxicity and staining of fetal bones and teeth (AII).81,87 Data are insufficient on use of ceftriaxone88 for treatment of maternal infection and prevention of congenital syphilis (BIII).

Treatment of syphilis during the second half of pregnancy may precipitate preterm labor or fetal distress if it is associated with a Jarisch-Herxheimer reaction.89 Pregnant women should be advised to seek obstetric attention after treatment if they notice contractions or a decrease in fetal movement. During the second half of pregnancy, syphilis management can be facilitated with sonographic fetal evaluation for congenital syphilis, but this evaluation should not delay therapy. Sonographic signs of fetal or placental syphilis indicate a greater risk of fetal treatment failure.90 Such cases should be managed in consultation with obstetric specialists. Evidence is insufficient to recommend specific regimens for these situations. After >20 weeks of gestation, fetal and contraction monitoring for 24 hours after initiation of treatment for early syphilis should be considered when sonographic findings indicate fetal infection.

Repeat serologic titers should be performed in the third trimester and at delivery for women treated for syphilis during pregnancy. Data are insufficient on the non-treponemal serologic response to syphilis after stage-appropriate therapy in HIV-infected pregnant women. Non-treponemal titers can be assessed monthly in women at high risk of re-infection. Clinical and non-treponemal antibody titers should be appropriate for the stage of disease, although most women will deliver before their serologic response can be definitively assessed. Maternal treatment is likely to be inadequate if delivery occurs within 30 days of therapy, if a woman has clinical signs of infection at delivery, or if the maternal antibody titer is four-fold higher than the pre-treatment titer.19

Recommendations for Treating Treponema pallidum Infections (Syphilis) Preventing Infection
Empiric treatment of incubating syphilis is recommended to prevent the development of disease in those who are sexually exposed.

Indication for Treatment:
  • An individual who was exposed sexually within 90 days preceding the diagnosis of primary, secondary, or early-latent syphilis in a sex partner (AII)
  • Individuals exposed >90 days before syphilis diagnosis in a sex partner, if serologic test results are not available immediately and the opportunity for follow-up is uncertain (AIII).
  • Same as for early stage syphilis listed below
General Considerations for Treating Syphilis:
  • The efficacy of non-penicillin alternatives has not been well evaluated in HIV-infected persons and should be undertaken only with close clinical and serologic monitoring.
  • The Jarisch-Herxheimer reaction is an acute febrile reaction accompanied by headache and myalgias that can occur within the first 24 hours after therapy for early syphilis.
Treatment Recommendations Depending on Stage of Disease:

Early Stage (Primary, Secondary, and Early-Latent Syphilis)
Preferred Therapy:
  • Benzathine penicillin G 2.4 million units IM for 1 dose (AII)
Alternative Therapy (For Penicillin-Allergic Patients):
  • Doxycycline 100 mg PO BID for 14 days (BII), or
  • Ceftriaxone 1 g IM or IV daily for 10-14 days (BII), or
  • Azithromycin 2 g PO for 1 dose (BII)
Note: Chromosomal mutations associated with azithromycin resistance and treatment failures have been reported. Azithromycin should be used with caution only when treatment with penicillin or doxycycline is not feasible. Azithromycin is not recommended for MSM or pregnant women (AII)
Note: Patients with penicillin allergy whose compliance or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin

Late-Latent Disease (>1 year or Of Unknown Duration, and No Sign of Neurosyphilis)
Preferred Therapy:
  • Benzathine penicillin G 2.4 million units IM weekly for 3 doses (AII)
Alternative Therapy (For Penicillin-Allergic Patients):
  • Doxycycline 100 mg PO BID for 28 days (BIII)
Note: Patients with penicillin allergy whose compliance or follow-up cannot be ensured should be desensitized and treated with benzathine penicillin

Late-Stage (Tertiary—Cardiovascular or Gummatous Disease)
  • Perform CSF examination to rule out neurosyphilis and obtain infectious diseases consultation to guide management
Preferred Therapy:
  • Benzathine penicillin G 2.4 million units IM weekly for 3 doses (AII)
Neurosyphilis, Otic, or Ocular Disease
Preferred Therapy:
  • Aqueous crystalline penicillin G, 18–24 million units per day, administered as 3–4 million units IV q4h or by continuous IV infusion for 10–14 days (AII) +/- benzathine penicillin G 2.4 million units IM weekly for 3 doses after completion of IV therapy (CIII)
Alternative Therapy:
  • Procaine penicillin G 2.4 million units IM daily plus probenecid 500 mg PO QID for 10–14 days (BII) +/- benzathine penicillin G 2.4 million units IM weekly for 3 doses after completion of above (CIII)
  • Patients who are allergic to sulfa-containing medications should not be given probenecid, thus the procaine penicillin regimen is not recommended for these patients (AIII).
For Penicillin-Allergic Patients:
  • Desensitization to penicillin is the preferred approach; if not feasible, ceftriaxone 2 g IM or IV daily for 10–14 days (BII)
Key to Acronyms: BID = twice a day; CSF = cerebrospinal fluid; IM = intramuscular; IV = intraveneously; MSM = men who have sex with men; PO = orally; QID = four times a day; q(n)h = every "n" hours


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