Management of Adult Syphilis

1. Khalil G. Ghanem1 and 2. Kimberly A. Workowski2,3 + Author Affiliations 1. 2. Johns Hopkins University School of Medicine, Baltimore, Maryland National Center for HIV/AIDS, Viral Hepatitis, STD and TB Prevention, Centers for Disease Control and Prevention 3. 3Emory University, Atlanta, Georgia
2 1

1. Correspondence: Khalil G. Ghanem, MD, PhD, Division of Infectious Diseases, JHUBMC, 4940 Eastern Ave, B3N, Baltimore, MD 21224 (kghanem@jhmi.edu).

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Abstract
There are several important unanswered key questions in the management of adult syphilis. A systematic literature review was conducted and tables of evidence were constructed to answer these important questions. A single dose of 2.4 million units of benzathine penicillin G remains the drug of choice for managing early syphilis. Enhanced antibiotic therapy has not been shown to improve treatment outcomes, regardless of human immunodeficiency virus (HIV) status. Although additional data on the efficacy of azithromycin in treating early syphilis have emerged, reported increases in the prevalence of a mutation associated with azithromycin resistance precludes a recommendation for its routine use. Cerebrospinal fluid (CSF) examination should be performed in all persons with serologic evidence of syphilis infection and neurologic symptoms. In those persons with early syphilis who do not achieve a 4-fold serologic decline in their rapid plasma reagin (RPR) titers 612 months after adequate therapy and those with late latent infection who do not achieve a similar decline within 1224 months, CSF examination should be considered. Among HIV-infected persons, CSF examination among all those with asymptomatic late latent syphilis is not recommended owing to lack of evidence that demonstrates clinical benefit. HIV-infected persons with syphilis of any stages whose RPR titers are 1:32 and/or whose CD4 cell counts are <350 cells/mm3 may be at increased risk for asymptomatic neurosyphilis. If CSF pleocytosis is evident at initial CSF examination, these examinations should be repeated every 6 months until the cell count is normal. Several important questions regarding the management of syphilis remain unanswered and should be a priority for future research. In the United States, rates of syphilis have continued to increase since 2000 [1]. The majority of cases occur in men who have sex with men, many of whom are also infected with human immunodeficiency virus (HIV). Recently, increases in the number of syphilis cases diagnosed in women and congenital syphilis cases have also been reported [1]. Important questions about the management of syphilis remain unanswered. A recent survey of infectious diseases practitioners who care for patients infected with syphilis demonstrated

a heterogeneous approach to clinical management [2] and an accompanying editorial highlighted some of the limitations and shortcomings of existing guidelines [3]. Most of these limitations regarding syphilis management are the result of a paucity of clinical trials. Despite >60 years of penicillin use, there is still uncertainty among practitioners about optimal dosing of penicillin for treatment of syphilis in HIV- infected and HIV-uninfected persons. The use of alternate agents for therapy is limited by a paucity of efficacy data for some (eg, doxycycline) and concerns about emerging resistance for others (eg, azithromycin). The optimal management in persons whose serologic titers do not respond appropriately to therapy is unclear because the long-term implications of serofast titers have not been well defined in the antibiotic era. The need for a cerebrospinal fluid (CSF) examination in these persons who remain serofast is also unclear, as is the role of lumbar punctures (LPs) in those without neurologic symptoms, especially those who are HIV infected. To further complicate matters, firm diagnostic criteria for neurosyphilis are lacking. Finally, new syphilis serologic testing algorithms have been adopted by some laboratories that use treponemal-specific tests as the initial screening tests for syphilis; however, questions have arisen about the interpretation of test results in clinical settings. As such, the Centers for Disease Control and Prevention (CDC) Adult Syphilis Treatment Guidelines Committee systematically assessed the literature to review the evidence and to answer some key questions in syphilis management.

METHODS
Figure 1 summarizes our approach. We sent a survey to experts in the field of syphilis to help define relevant key questions in syphilis management. A literature review was then conducted based on these key questions. We searched MEDLINE, SCOPUS, ISI, POPLINE, Excerpta Medica, and Cochrane Central Register of Controlled Trials databases from 22 December 2004 (the date of the last systematic review) to 15 September 2008, with a limited follow-up search (MEDLINE only) to 5 January 2009. We used the search terms Treponema pallidum or treponemal infections/therapy. Reference lists of the retrieved articles were also manually searched for other potentially relevant papers. We also reviewed conference abstracts (International Society for Sexually Transmitted Diseases Research, CDC STD Prevention Conferences, Infectious Diseases Society of America, Interscience Conference on Antimicrobial Agents and Chemotherapy, Conference on Retroviruses and Opportunistic Infections). We assessed both English and non-English language articles. Only articles with primary data were included. All abstracts were read, and if an abstract found to be relevant to any of the key questions identified, the full article was reviewed. We constructed tables of evidence for each key question. The data collected were presented at the CDC Treatment Guidelines Meeting held in Atlanta on 2829 April 2009 to a group of syphilis experts. Preliminary answers to the key questions were drafted based on the tables of evidence or expert opinion where there was no supporting evidence.

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Figure 1. Process used to identify the key questions and revise the guidelines. Abbreviations: CDC, Centers for Disease Control and Prevention; STD, sexually transmitted disease. Eight key questions were identified and agreed on by a panel of 10 external experts. The literature search yielded 267 references, including 15 conference abstracts. Of those, 52 references were relevant (including 7 conference abstracts) to the key questions and were included in the tables of evidence (Table 1). Below is a list of the 8 key questions, a summary of the data from the tables of evidence for each question, and an overview of the discussion surrounding each question. View this table:

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Table 1. Tables of Evidence Summarizing Relevant Data for the 8 Key Questions Previous SectionNext Section

RESULTS AND DISCUSSION

1. What Is the Appropriate Role for Azithromycin in the Treatment of Early Syphilis?
The use of azithromycin for the treatment of syphilis offers certain advantages over conventional intramuscular therapy with benzathine penicillin G (BPG): oral route of delivery, ability to treat in the field, and the possibility of partner-delivered therapy. Since

2004, data from 2 randomized controlled trials and a meta-analysis have supported previous findings [52] demonstrating excellent efficacy of azithromycin in treating early syphilis [4 6]. However, increasing detection of a 23S ribosomal RNA (rRNA) mutation associated with resistance to macrolides has been reported worldwide [8, 1113, 53]. Although there are no data to delineate what in proportion of persons with the mutation therapy actually fails, the association of this mutation with clinical failures in small studies [5456] is concerning. The current debate is whether to include azithromycin at all as an alternate single-dose therapy for the treatment of early stage syphilis, given the concern for resistance and possible treatment failures. Efficacy data for single-dose azithromycin from randomized controlled trials were unequivocally strong and were much more robust than the data supporting the use of the alternate recommended agents [4, 6]. Azithromycin has been used outside the United States, including in some areas with more limited access to antibiotics, and macrolide resistance appears uncommon in some of those locations [57]. However, there are concerns that the 23S rRNA mutation associated with azithromycin resistance has been documented in multiple geographic locations in the United States, and azithromycin will therefore not be a recommended regimen for the treatment of early syphilis. In addition, recent reports have also documented the 23S rRNA mutation associated with azithromycin resistance in men who have sex with men [58]; similarly, azithromycin does not reliably eradicate maternal infection and should not be administered to pregnant women [14]. Azithromycin may have a role as an alternative regimen in instances of penicillin allergy when doxycycline administration is not feasible; however, close clinical follow-up is strongly recommended in this setting. Azithromycin is not a recommended regimen for the treatment of early syphilis. However, it may be an alternative regimen for early syphilis, with close clinical follow-up, in the setting of penicillin allergy or when doxycycline use is not feasible.

2. What Are the Alternative Options for the Treatment of Syphilis When Penicillin Therapy Is Not Feasible?
Two retrospective studies evaluated the use of doxycycline for the treatment of early syphilis [16, 17]. In the first study, 34 persons with early syphilis were treated with 100 mg of oral doxycycline twice a day for 2 weeks [17]. After a median of 9 months of follow-up, 100% had achieved a 4-fold decline in nontreponemal titers. In the second study, a similar regimen used in 25 persons with early syphilis reported 100% serologic response after 24 months of follow-up [16]; neither study evaluated doxycycline for the treatment of late latent syphilis, and few HIV-infected persons were included. There were no new data for ceftriaxone use in syphilis that might change existing recommendations. Doxycycline (100 mg orally twice daily for 14 days) remains the preferred alternate therapy in nonpregnant adults with early syphilis when BPG cannot be used, but close clinical followup is advised. In nonpregnant persons with late latent syphilis or syphilis of unknown duration, limited clinical data suggest that doxycycline (100 mg orally twice daily for 28 days) may be considered in those whose compliance with treatment (and follow-up) can be assured. Ceftriaxone is an approved alternate agent for use in neurosyphilis, and limited clinical data suggest utility in the treatment of early syphilis [59]. The data for using these alternate agents in HIV-infected persons are limited; if such treatment is administered, careful serologic follow-up at 3, 6, 9, 12, and 24 months after therapy is essential.

3. Does Enhanced Therapy for Early Syphilis With Additional Doses of BPG Provide Improved Clinical or Serologic Outcomes?
The 2006 CDC STD Treatment Guidelines recommend the use of 2.4 million units (MU) of BPG for the treatment of all persons with early syphilis. A common clinical question is whether enhanced therapy for early syphilis is more efficacious than the 2.4-MU dose currently recommended. Moreover, a recent survey of infectious diseases practitioners found that the majority would deviate from the guidelines and use three 2.4-MU doses of BPG to treat HIV-infected persons with early syphilis [2]. The drive to use additional doses of BPG may be, in part, based on the belief that additional doses of BPG are more effective in treating possible underlying central nervous system involvement. In the 1960s and 1970s, three 2.4-MU doses of BPG was an alternate regimen in the treatment of neurosyphilis. Despite an acceptable clinical response [60], it was discovered that this alternate regimen did not achieve reliable treponemicidal levels in the CSF [61], and it was no longer recommended for treating neurosyphilis. All the data supporting the use of a single 2.4-MU dose of BPG to treat syphilis preceded 2004. In the first report of the use of BPG for the treatment of early syphilis, Smith et al compared results for BPG (2.5 MU) and penicillin monoesterate (4.8 MU) (n = 855) They reported excellent serologic responses in both groups and no clinical failures. In the 30-year review of the use of penicillin for the treatment of syphilis, Idsoe et al presented no comparison data between 2.4 MU of BPG and higher doses for the treatment of early syphilis [63]. However, they referenced a study by de Graciansky from 1960 with findings suggesting that responses to 2.4 MU were excellent for seronegative primary syphilis but inferior for seropositive primary and secondary syphilis. In that study, 147 French patients with early syphilis were followed up for up to 7 years after therapy with 1 of 3 different regimens of penicillin, ranging from 2.4 to 3.0 MU [64]. After 7 years, seroreversal of nontreponemal titers had been achieved in 84% of patients, 10% were lost to follow-up, and the remainder had evidence of low-titer positivity without clinical signs or symptoms. There was no comparison with other penicillin doses. The treatment failures referred to by Idsoe et al were lack of nontreponemal titer seroreversion (ie, reversion of nontreponemal serologic titers from positive to negative); the clinical significance of this serologic finding in the antibiotic era is unclear. Schroeter et al reevaluated the comparative efficacy of different antibiotic schedules for the treatment of early syphilis in 586 persons [65]. There was no statistically significant difference between 2.4 MU and higher doses with respect to treatment failures. Finally, a randomized controlled trial comparing 2.4 MU of BPG with enhanced therapy using additional amoxicillin plus probenecid did not reveal improved clinical or serologic outcomes [66] in either HIV-infected or HIV-uninfected persons. The review of existing evidence clearly supports the recommendation of 2.4 MU of BPG for treating early syphilis. Although data for HIV-infected persons were more limited, there were no data to suggest that enhanced therapy in this population improved clinical outcomes. The primary recommended treatment for early syphilis remains a single 2.4-MU intramuscular dose of BPG in both HIV-infected and HIV-uninfected persons.

4. What Is the Appropriate Approach to Management in Persons Who Do Not Demonstrate an Adequate Serologic Decline After Stage-Appropriate Therapy?

The Wassermann test was a nontreponemal serologic test for syphilis that predated the VDRL and rapid plasma reagin (RPR) tests. Persons with Wassermann titers that did not decline in response to therapy and those whose titers declined but did not revert completely back to negative were referred to as Wassermann fast. In the prepenicillin era, Wassermann fastness in early syphilis was a poor prognostic indicator, because 30% of such persons ultimately developed neurologic complications [67]. However, Wassermann fastness was not associated with poor outcomes in latent syphilis. In the antibiotic era, there are no systematic studies of the long-term clinical impact of lack of 4-fold serologic (RPR or VDRL) decline (henceforth referred to as lack of decline) or adequate serologic decline but lack of complete serologic reversion from positive to negative (henceforth referred to as a serofast titer). In a recent study, among 13 HIV-infected persons with serologic evidence of syphilis who were treated with adequate, stageappropriate antibiotic regimens but whose serologic titers had not adequately declined a median of 287 days after therapy, 4 (31%) were found to have CSF abnormalities consistent with asymptomatic neurosyphilis [20]. The optimal approach in persons who do not achieve an adequate serologic decline in titers remains unclear due to lack of data to guide clinical management. Given the potential for underlying CSF involvement in some of these persons, LP is warranted. The current recommendations suggest that lack of 4-fold decline in serologic titers within 612 months after therapy in early syphilis (primary, secondary, or early latent), or 1224 months for late latent syphilis might reflect treatment failure (reinfection is a possibility in such cases but is often difficult to ascertain). Serologic titers may decline more slowly in HIV-infected persons [38] and 15%20% of patients remain serofast 12 months after stage-appropriate therapy irrespective of HIV infection [66]. The clinical significance of this is unknown, but clinicians may elect to follow up asymptomatic HIV-infected persons for a full 12 months for early syphilis or 24 months for late latent syphilis before labeling them treatment failures. It is unknown whether persons whose titers respond appropriately to standard therapy by declining 4-fold but remain positive (serofast) would benefit from LP and/or additional therapy; moreover, the clinical significance of high-titer serofastness (eg, 1:32) versus low-titer serofastness (eg, 1:2) is also unknown. CSF examination to exclude neurosyphilis is indicated for all persons with early syphilis who do not achieve a 4-fold or greater serologic decline in their RPR titers 612 months after adequate therapy and those with late latent infection who do not achieve a similar decline within 1224 months. If the CSF examination findings are normal, BPG (2.4 MU given intramuscularly) should be administered once weekly for 3 consecutive weeks. There are no data at this time to recommend additional therapy for persons whose titers remain serofast. Moreover, the clinical implications of a low versus a higher serofast titer are unknown.

5. Who Should Have a Cerebrospinal Fluid Examination to Evaluate for Neurosyphilis?

This question continues to be the source of significant controversy, especially in HIVcoinfected persons. A retrospective study of 112 HIV-infected persons with serologic evidence of syphilis who underwent LP found that both serum RPR titer and presence of neurologic symptoms increased the probability of detecting neurosyphilis cases [25]. A receiver operating characteristic curve analysis demonstrated that an RPR 1:32 had 100%

sensitivity and 40% specificity for both symptomatic and asymptomatic neurosyphilis cases. Another retrospective study of 202 HIV-infected persons with serologic evidence of syphilis and no neurologic symptoms compared performance characteristics of different stratification criteria for LP to detect asymptomatic neurosyphilis. In 46 patients who underwent LP before therapy, 10 cases (22%) of asymptomatic neurosyphilis were detected [20]. This study also found that HIV-infected persons with a CD4 cell count 350 cells//mm3 and/or a RPR titer 1:32 were more likely to have asymptomatic neurosyphilis than HIV-infected persons with late latent syphilis. Routine CSF examination in all HIV-infected persons with syphilis has been suggested by some specialists, but given the lack of modern data to support improved clinical outcomes with routine LP for those persons without neurologic symptoms, this approach has not been widely endorsed. Among HIV-infected persons, CSF examination among all those with asymptomatic late latent syphilis is not recommended owing to lack of evidence that demonstrates clinical benefit. Several reports have suggested that among HIV-infected persons with syphilis, the presence of RPR titers 1:32 and/or CD4 cell counts 350 cells//mm3 increases the likelihood of identifying patients with neurologic involvement due to syphilis [20, 25, 68]. The data were reviewed, and several limitations were noted: 2 of the 3 studies included persons who had neurologic symptoms and would therefore warrant CSF examination [25, 68], and the study that only included asymptomatic persons was retrospective [20]. Moreover, none of the 3 studies addressed long-term benefits of performing a CSF examination among asymptomatic patients. Finally, another layer of complexity was the lack of a standard laboratory definition for neurosyphilis. A persistent problem relates to the lack of a standard laboratory definition for neurosyphilis. The diagnosis of neurosyphilis should be based on both clinical and laboratory criteria as no single group of laboratory tests can adequately predict the presence of neurosyphilis with optimal sensitivity and specificity. Second, it is well established that CSF abnormalities (ie, mononuclear pleocytosis and increased protein) can occur in HIV-infected persons who do not have syphilis. Although attempts have been made to improve the specificity of defining neurosyphilis among HIV-infected persons [6870], the data are still limited, and CSF abnormalities should be interpreted in conjunction with clinical and serologic findings. Finally, although data from the prepenicillin era suggested that detecting and treating asymptomatic CSF abnormalities reduced the risk of late neurologic complications [71, 72], there are no such data from the penicillin era. Regardless of HIV status, CSF examination should be performed in all persons with serologic evidence of syphilis infection and neurologic symptoms, including isolated ophthalmic syphilis. Moreover, CSF examination to exclude neurosyphilis is indicated for those who do not achieve an adequate serologic decline in their RPR titers after therapy (see key question 4). A CSF examination among all HIV-infected persons with late latent syphilis is not recommended because to lack of evidence demonstrating clinical benefit. Several studies have demonstrated CSF abnormalities consistent with neurosyphilis in HIV-infected persons with syphilis and RPR titers 1:32 and/or CD4 cell counts 350 cells/mm3; however, unless neurologic symptoms are present, there is no evidence that CSF examination in this setting is associated with improved clinical outcomes.

6. What Is the Role of Follow-up CSF Examination After the Treatment of Neurosyphilis?

In a recent study, 110 persons with neurosyphilis were prospectively followed up (86 HIVinfected and 68 HIV-uninfected persons with early syphilis) with serial LP and serum RPR titers at 4, 7, and 13 months after therapy [26]. Normalization of serum RPR predicted normalization of CSF white blood cell counts, CSF VDRL, and clinical symptoms in >90% of patients at 13 months. Normalization of serum RPR was less successful at predicting normalization of CSF protein and less likely to predict CSF normalization in HIV-positive persons not receiving antiretroviral therapy (ART). Overall, 37% of 98 patients did not experience normalization of at least a CSF or clinical abnormality when serum RPR titer had normalized (in the majority, it was the CSF protein concentration that failed to normalize). The implications of a persistently elevated CSF protein concentration are unclear, and longterm clinical follow-up was not available. Of note, among HIV-infected persons without serologic evidence of syphilis, ART use has also been shown to decrease the odds of CSF pleocytosis [69]. Given the limited data, if CSF pleocytosis is present at initial CSF examination, 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 concentration after therapy; however, changes in these 2 parameters occur more slowly than do cell counts, and persistent abnormalities might be less important. If the cell count has not decreased after 6 months or if the CSF is not normal after 2 years, retreatment should be considered.

7. Other Than More Frequent Follow-up, Are There Any Additional Interventions for HIV-Infected Persons With Syphilis?
Although most clinical manifestations of syphilis have not been shown to differ significantly by HIV status, early meningeal neurosyphilis (previously referred to as neurorecurrence) was noted to be a frequent neurologic presentation of syphilis among HIV-infected persons [31, 73]. Several studies evaluated serologic response to syphilis therapy in HIV-infected persons [3444]; they were limited by small sample size or retrospective study design. The 2 largest studies [37, 38] both included HIV-negative control groups and suggested an increased risk of serologic failure in the HIV-positive group. In addition, 1 study found that 64% of HIV-infected persons never returned for serologic follow-up after therapy [38]. A recent study using procaine penicillin plus probenecid for 17 days in 105 HIV-infected persons with early syphilis [34]) demonstrated a 99% serologic success rate at 6 months after therapy. Immune preservation/reconstitution using ART in dually infected patients was associated with reduced risk of serologic failure [30], lower risk of developing neurosyphilis [31], and enhanced clinical response to therapy [26]. In a prospective study, 112 patients (86 HIV positive) with neurosyphilis were treated and had follow-up CSF examinations at 3, 6 and 12 months. HIV-positive patients receiving ART were 4 times more likely to have normalized CSF white blood cell count and protein concentrations than HIV-positive patients not receiving ART, and 13 times more likely to have resolved symptoms [26]. In a retrospective study of 231 episodes of syphilis conducted within an HIV-positive clinical cohort, there was a 60% reduction in serologic failures associated with ART (82% reduction when ART led to increases in CD4 cell counts) [30]. In the same cohort, use of any ART by persons diagnosed with syphilis reduced the odds of neurosyphilis diagnosis by 65% [31].

Compared with HIV-negative persons, HIV-positive persons who have early syphilis might be at increased risk for early neurologic complications and might have slightly higher rates of treatment failure with currently recommended regimens. However, no treatment regimens for uncomplicated syphilis have been demonstrated to be more effective in preventing neurosyphilis in HIV-infected persons than the syphilis regimens recommended for HIVnegative persons. Careful serologic follow-up at 3, 6, 9, 12, and 24 months after therapy is essential. Any neurologic symptoms, even after stage-appropriate syphilis therapy, warrant CSF examination. The use of ART according to current US Department of Health and Human Services guidelines [74] may decrease the risk of neurologic complications, decrease the risk of serologic failure after syphilis therapy, and enhance clinical responses in HIVinfected persons with neurosyphilis.

8. What Is the Most Appropriate Approach to Dealing With a Positive Treponemal Test and a Negative Nontreponemal Test?
A number of laboratories in the United States are using an algorithm that involves a treponemal test as the initial screening test for syphilis, followed by a reflex nontreponemal test when the treponemal test is positive. In a recent survey of 4 laboratories in New York City [47], 6% (6548) of 116 822 specimens had a positive treponemal test; of those, 56% (3664) had a negative nontreponemal test; 83% (2512) of the positive treponemal enzyme immunoassays (EIAs) were found to be positive using another treponemal test (ie, confirmed positive). Several possibilities could account for a positive treponemal test but a negative nontreponemal test: (1) a false-positive treponemal test, (2) early primary syphilis, (3) adequately treated past syphilis, (4) untreated late latent syphilis, and (5) the prozone phenomenon. A study from New York comparing treponemal screening (Captia IgG EIA) with nontreponemal screening (followed by treponemal confirmation with Fluorescent Treponemal Antibody (FTA) or Treponema pallidum particle agglutination assay [TPPA]) found that among 129 HIV-negative persons, 6 of 12 persons with a reactive EIA had a nonreactive RPR and among 113 HIV-positive persons, 18 of 39 with a reactive EIA had a nonreactive RPR [50]. Risk factors for discordance between treponemal and nontreponemal tests included HIV infection and older age. A modeling study from Canada evaluated the cost effectiveness of 2 testing strategies: RPR followed by TPPA or FTA testing protocol versus EIA followed by RPR titration protocol [49]. When compared with RPR/FTA, EIA/RPR strategy was cost-effective in both prenatal and nonprenatal populations. The EIA strategy generated a few more correct diagnoses, and fewer heath service costs. However, in a retrospective study of persons with late latent syphilis who had both serologic test results and CSF test results available, the authors found that all cases of neurosyphilis were detected in those with a positive serum VDRL test [51]. Upcoming guidelines regarding syphilis diagnostic testing are anticipated from the CDC later this year. Any initial reactive treponemal test warrants immediate nontreponemal (ie, RPR or VDRL) reflex testing. The nontreponemal titers should be used to monitor response to therapy. When results are reactive to the treponemal test but nonreactive to the nontreponemal test, a second, different treponemal test should be performed (preferably a TPPA). If the second treponemal test is also positive, persons with a history of treatment will require no further management unless history or results of a physical examination suggest a recent infection. Persons without a history of syphilis treatment should be assessed clinically. If active signs or symptoms of syphilis are absent, they should be treated for syphilis of unknown duration (three 2.4-MU doses of BPG weekly). If the second treponemal test result is negative, syphilis is unlikely. If

the person is at risk for syphilis, repeating the nontreponemal test several weeks later may be considered. Previous SectionNext Section

RESEARCH PRIORITIES
There are still many fundamental unanswered questions in the management of syphilis. Subjects of priority for research include (1) the optimal approach to managing positive treponemal antibody tests and negative nontreponemal tests when not all treponemal-specific tests perform identically; (2) the clinical significance of the azithromycin 23S rRNA A to G mutation in T. pallidum; (3) the optimal management in persons whose nontreponemal test titers do not decline appropriately after penicillin therapy; (4) the long-term clinical significance of the serofast nontreponemal titer; (5) the clinical implications of detecting asymptomatic neurosyphilis in the penicillin and HIV eras; and (6) the cost-effectiveness, logistics, and complication rate of CSF examinations in the evaluation of neurosyphilis. Previous SectionNext Section

Notes
Previous SectionNext Section

Acknowledgments.
We would like to thank the following for their help and/or advice: Christina Marra, Sheila Lukehart, Hunter Handsfield, Ned Hook, Bradley Stoner, David Martin, Michael Augenbraun, Jeffrey Klausner, Anne Rompalo, Emily Erbelding, and Jonathan Zenilman. Previous SectionNext Section

Supplement sponsorship.
This article was published as part of a supplement entitled Sexually Transmitted Disease Treatment Guidelines sponsored by the Centers for Disease Control and Prevention. Previous SectionNext Section

Potential conflicts of interest.

All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

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References
1. 1. Centers for Disease Control and Prevention. Sexually transmitted diseases surveillance, 2008. Atlanta, GA: US Department of Health and Human Services; 2009. 2. 2. 1. 2. 3. 4. 5. 6. Dowell D, Polgreen PM, Beekmann SE, Workowski KA, Berman SM, Peterman TA

. Dilemmas in the management of syphilis: a survey of infectious diseases experts. Clin Infect Dis 2009;49:1526-9. Abstract/FREE Full Text 3. 3. 1. Gross PA . When guidelines don't guide the physician. Clin Infect Dis 2009;49:1530-1. FREE Full Text 4. 4. 1. 2. 3. 4. Hook EW 3rd., Behets F, Van Damme K, et al

. A phase III equivalence trial of azithromycin versus benzathine penicillin for treatment of early syphilis. J Infect Dis 2010;201:1729-35. Abstract/FREE Full Text 5. 5. 1. Bai ZG,

2. Yang KH, 3. Liu YL, 4. et al . Azithromycin vs. benzathine penicillin G for early syphilis: a meta-analysis of randomized clinical trials. Int J STD AIDS 2008;19:217-21. Abstract/FREE Full Text 6. 6. 1. 2. 3. 4. Riedner G, Rusizoka M, Todd J, et al

. Single-dose azithromycin versus penicillin G benzathine for the treatment of early syphilis. N Engl J Med 2005;353:1236-44. CrossRefMedlineWeb of Science 7. 7. 1. 2. 3. 4. Kiddugavu MG, Kiwanuka N, Wawer MJ, et al

. Effectiveness of syphilis treatment using azithromycin and/or benzathine penicillin in Rakai, Uganda. Sex Transm Dis 2005;32:1-6. CrossRefMedlineWeb of Science 8. 8. 1. 2. 3. 4. 5. Toutous-Trellu L, Gayet-Ageron A, Ninet B, Piguet V, Schrenzel J

. In: 48th Annual Intersciences Conference on Antimicrobial Agents and Chemotherapy and Infectious Diseases Society of America 46th Annual Meeting; 25 28 October 2008. Washington, DC: ICAAC/IDSA; 2008. Frequent resistance of Treponema pallidum to azithromycin in Geneva. Search Google Scholar 9. 9. 1. 2. 3. 4. Katz KA, Ahrens K, Engelman J, Godornes C,

5. Lukehart S, 6. Klausner J . In: 2008 National STD Prevention Conference; 10-13 March 2008. Chicago, IL: Centers for Disease Control and Prevention; 2008. Increasing rate of azithromycin resistance in Treponema pallidum infections: San Francisco, 20052006. Search Google Scholar 10. 10. 1. 2. 3. 4. Pandori MW, Gordones C, Castro L, et al

. Detection of azithromycin resistance in Treponema pallidum by real-time PCR. Antimicrob Agents Chemother 2007;51:3425-30. Abstract/FREE Full Text 11. 11. 1. 2. 3. 4. Marra CM, Colina AP, Godornes C, et al

. Antibiotic selection may contribute to increases in macrolide-resistant Treponema pallidum. J Infect Dis 2006;194:1771-3. Abstract/FREE Full Text 12. 12. 1. 2. 3. 4. 5. 6. Mitchell SJ, Engelman J, Kent CK, Lukehart SA, Godornes C, Klausner JD

. Azithromycin-resistant syphilis infection: San Francisco, California, 20002004. Clin Infect Dis 2006;42:337-45. Abstract/FREE Full Text 13. 13. 1. Morshed MG, 2. Jones HD . Treponema pallidum macrolide resistance in BC. CMAJ 2006;174:349.

FREE Full Text 14. 14. 1. 2. 3. 4. 5. Zhou P, Qian Y, Xu J, Gu Z, Liao K

. Occurrence of congenital syphilis after maternal treatment with azithromycin during pregnancy. Sex Transm Dis 2007;34:472-4. CrossRefMedline 15. 15. 1. 2. 3. 4. Spooner K, Barthel RV, Robertson J, et al

. Azithromcyin might not protect against Treponema pallidum infection or reactivation in HIV type 1-infected patients. Clin Infect Dis 2005;41:419-20. CrossRefMedline 16. 16. 1. Wong T, 2. Singh AE, 3. De P . Primary syphilis: serological treatment response to doxycycline/tetracycline versus benzathine penicillin. Am J Med 2008;121:903-8. CrossRefMedline 17. 17. 1. 2. 3. 4. Ghanem KG, Erbelding EJ, Cheng WW, Rompalo AM

. Doxycycline compared with benzathine penicillin for the treatment of early syphilis. Clin Infect Dis 2006;42:e45-9. Abstract/FREE Full Text 18. 18. 1. Zhou P, 2. Gu Z, 3. Xu J,

4. Wang X, 5. Liao K . A study evaluating ceftriaxone as a treatment agent for primary and secondary syphilis in pregnancy. Sex Transm Dis 2005;32:495-8. CrossRefMedline 19. 19. 1. 2. 3. 4. 5. Gutierrez-Galhardo MC, do Valle GF, Sa FC, Schubach Ade O, do Valle AC

. Clinical characteristics and evolution of syphilis in 24 HIV+ individuals in Rio de Janeiro, Brazil. Rev Inst Med Trop Sao Paulo 2005;47:153-7. Medline 20. 20. 1. 2. 3. 4. 5. 6. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA

. Lumbar puncture in HIV-infected patients with syphilis and no neurologic symptoms. Clin Infect Dis 2009;48:816-21. Abstract/FREE Full Text 21. 21. 1. 2. 3. 4. 5. Wang L-, Zuo Y-, Liu Y-, Liu X-, Zheng H-

. Incidence of seroresistance of syphilis and its relevant factors. Acta Acad Med Sin 2008;30:338-41. Search Google Scholar 22. 22. 1. 2. 3. 4. Carpenter T, Malik F, Lazzaro D, Lazzaro E,

5. Augenbraun M . In: 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy and Infectious Diseases Society of America 46th Annual Meeting. ICAAC/IDSA,. 2008. Clinical ophthalmologic findings and syphilis serology poorly predict neurosyphilis [abstract L-652]. Search Google Scholar 23. 23. 1. 2. 3. 4. 5. 6. Thng C, Poluri R, Komolafe A, Ratcliffe L, Javier V, Higgins S

. In: British Association of Sexual Health and HIV and the American Sexually Transmitted Diseases Association Third Joint Conference. BASHH/ASTDA,. 2008. Use of lumbar puncture in the management of patients with early syphilis [abstract B22]. Search Google Scholar 24. 24. 1. 2. 3. 4. 5. 6. Taylor MM, Aynalem G, Olea LM, He P, Smith LV, Kerndt PR

. A consequence of the syphilis epidemic among men who have sex with men (MSM): neurosyphilis in Los Angeles, 20012004. Sex Transm Dis 2008;35:430-4. CrossRefMedlineWeb of Science 25. 25. 1. 2. 3. 4. Libois A, De Wit S, Poll B, et al

. HIV and syphilis: when to perform a lumbar puncture. Sex Transm Dis 2007;34:141-4. CrossRefMedlineWeb of Science 26. 26. 1. Marra CM,

2. 3. 4. 5.

Maxwell CL, Tantalo LC, Sahi SK, Lukehart SA

. Normalization of serum rapid plasma reagin titer predicts normalization of cerebrospinal fluid and clinical abnormalities after treatment of neurosyphilis. Clin Infect Dis 2008;47:893-9. Abstract/FREE Full Text 27. 27. 1. 2. 3. 4. McClelland RS, Lavreys L, Katingima C, et al

. Contribution of HIV-1 infection to acquisition of sexually transmitted disease: a 10year prospective study. J Infect Dis 2005;191:333-8. Abstract/FREE Full Text 28. 28. 1. 2. 3. 4. 5. Branger J, van der Meer JT, van Ketel RJ, Jurriaans S, Prins JM

. High incidence of asymptomatic syphilis in HIV-infected MSM justifies routine screening. Sex Transm Dis 2009;36:84-5. CrossRefMedlineWeb of Science 29. 29. 1. 2. 3. 4. Cohen CE, Winston A, Asboe D, et al

. Increasing detection of asymptomatic syphilis in HIV patients. Sex Transm Infect 2005;81:217-9. Abstract/FREE Full Text 30. 30. 1. 2. 3. 4. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ,

5. Zenilman JM, 6. Gebo KA . Antiretroviral therapy is associated with reduced serologic failure rates for syphilis among HIV-infected patients. Clin Infect Dis 2008;47:258-65. Abstract/FREE Full Text 31. 31. 1. 2. 3. 4. 5. 6. Ghanem KG, Moore RD, Rompalo AM, Erbelding EJ, Zenilman JM, Gebo KA

. Neurosyphilis in a clinical cohort of HIV-1-infected patients. AIDS 2008;22:114551. CrossRefMedlineWeb of Science 32. 32. 1. 2. 3. 4. Cicconi P, Cozzi-Lepri A, Orlando G, et al

. Recent acquired STD and the use of HAART in the Italian Cohort of Naive for Antiretrovirals (I.co.N.A): analysis of the incidence of newly acquired hepatitis B infection and syphilis. Infection 2008;36:46-53. CrossRefMedlineWeb of Science 33. 33. 1. 2. 3. 4. Park WB, Jang HC, Kim SH, et al

. Effect of highly active antiretroviral therapy on incidence of early syphilis in HIVinfected patients. Sex Transm Dis 2008;35:304-6. CrossRefMedlineWeb of Science 34. 34. 1. Warwick Z, 2. Dean G, 3. Fisher M

. Should syphilis be treated differently in HIV-positive and HIV-negative individuals? Treatment outcomes at a university hospital, Brighton, UK. Int J STD AIDS 2009;20:229-30. Abstract/FREE Full Text 35. 35. 1. 2. 3. 4. Poliseli R, Vidal JE, De Oliveira ACP, Hernandez AV

. Neurosyphilis in HIV-infected patients: clinical manifestations, serum venereal disease research laboratory titers, and associated factors to symptomatic neurosyphilis. Sex Transm Dis 2008;35:425-9. CrossRefMedline 36. 36. 1. 2. 3. 4. 5. 6. Mishra S, Walmsley SL, Loutfy MR, Kaul R, Logue KJ, Gold WL

. Otosyphilis in HIV-coinfected individuals: a case series from Toronto, Canada. AIDS Patient Care STDS 2008;22:213-9. CrossRefMedlineWeb of Science 37. 37. 1. Manavi K, 2. McMillan A . The outcome of treatment of early latent syphilis and syphilis with undetermined duration in HIV-infected and HIV-uninfected patients. Int J STD AIDS 2007;18:8148. Abstract/FREE Full Text 38. 38. 1. 2. 3. 4. Ghanem KG, Erbelding EJ, Wiener ZS, Rompalo AM

. Serological response to syphilis treatment in HIV-positive and HIV-negative patients attending sexually transmitted diseases clinics. Sex Transm Infect 2007;83:97-101.

Abstract/FREE Full Text 39. 39. 1. 2. 3. 4. Balba GP, Kumar PN, James AN, et al

. Ocular syphilis in HIV-positive patients receiving highly active antiretroviral therapy. Am J Med 2006;119:448.e21-5. CrossRefMedline 40. 40. 1. 2. 3. 4. Kofoed K, Gerstoft J, Mathiesen LR, Benfield T

. Syphilis and human immunodeficiency virus (HIV)-1 coinfection: influence on CD4 T-cell count, HIV-1 viral load, and treatment response. Sex Transm Dis 2006;33:1438. CrossRefMedlineWeb of Science 41. 41. 1. 2. 3. 4. Long CM, Klausner JD, Leon S, et al

. Syphilis treatment and HIV infection in a population-based study of persons at high risk for sexually transmitted disease/HIV infection in Lima, Peru. Sex Transm Dis 2006;33:151-5. CrossRefMedlineWeb of Science 42. 42. 1. 2. 3. 4. Walter T, Lebouche B, Miailhes P, et al

. Symptomatic relapse of neurologic syphilis after benzathine penicillin G therapy for primary or secondary syphilis in HIV-infected patients. Clin Infect Dis 2006;43:78790. Abstract/FREE Full Text 43. 43.

1. 2. 3. 4.

Abraham B, Marih L, Thevenet S, et al

. Outbreak of syphilis among HIV-infected patients: descriptive data from a Parisian hospital. Sex Transm Dis 2005;32:718-9. CrossRefMedline 44. 44. 1. 2. 3. 4. Palacios R, Jimenez-Onate F, Aguilar M, et al

. Impact of syphilis infection on HIV viral load and CD4 cell counts in HIV-infected patients. J Acquir Immune Defic Syndr 2007;44:356-9. CrossRefMedlineWeb of Science 45. 45. 1. 2. 3. 4. Mwapasa V, Rogerson SJ, Kwiek JJ, et al

. Maternal syphilis infection is associated with increased risk of mother-to-child transmission of HIV in Malawi. AIDS 2006;20:1869-77. MedlineWeb of Science 46. 46. 1. 2. 3. 4. Sadiq ST, McSorley J, Copas AJ, et al

. The effects of early syphilis on CD4 counts and HIV-1 RNA viral loads in blood and semen. Sex Transm Infect 2005;81:380-5. Abstract/FREE Full Text 47. 47. Centers for Disease Control and Prevention (CDC). Syphilis testing algorithms using treponemal tests for initial screeningfour laboratories, New York City, 20052006. MMWR Morb Mortal Wkly Rep 2008;57:872-5. Medline

48. 48. 1. Singh AE, 2. Wong T, 3. De P . Characteristics of primary and late latent syphilis cases which were initially nonreactive with the rapid plasma reagin as the screening test. Int J STD AIDS 2008;19:464-8. Abstract/FREE Full Text 49. 49. 1. 2. 3. 4. 5. Chuck A, Ohinmaa A, Tilley P, Singh A, Jacobs P

. Cost effectiveness of enzyme immunoassay and immunoblot testing for the diagnosis of syphilis. Int J STD AIDS 2008;19:393-9. Abstract/FREE Full Text 50. 50. 1. Augenbraun M, 2. Abu-Lawi K, 3. Phillips S . In: 17th International Society for STD research; 29 July to 1 August 2007;. Seattle, WA: International Society for Sexually Transmitted Diseases Research.; 2007. Discordant ELISA and RPR tests for syphilis in HIV infected and uninfected individuals. Search Google Scholar 51. 51. 1. Woehrl S, 2. Geusau A . Neurosyphilis is unlikely in patients with late latent syphilis and a negative blood VDRL test. Acta Derm Venereol 2006;86:335-9. CrossRefMedlineWeb of Science 52. 52. 1. 2. 3. 4. 5.

Hook EW 3rd., Martin DH, Stephens J, Smith BS, Smith K

. A randomized, comparative pilot study of azithromycin versus benzathine penicillin G for treatment of early syphilis. Sex Transm Dis 2002;29:486-90. MedlineWeb of Science 53. 53. 1. Katz KA, 2. Klausner JD . Azithromycin resistance in Treponema pallidum. Curr Opin Infect Dis 2008;21:8391. CrossRefMedlineWeb of Science 54. 54. 1. 2. 3. 4.

Martin IE, Tsang RS, Sutherland K, et al

. Molecular characterization of syphilis in patients in Canada: azithromycin resistance and detection of Treponema pallidum DNA in whole-blood samples versus ulcerative swabs. J Clin Microbiol 2009;47:1668-73. Abstract/FREE Full Text 55. 55. 1. 2. 3. 4. Martin IE, Gu W, Yang Y, Tsang RS

. Macrolide resistance and molecular types of Treponema pallidum causing primary syphilis in Shanghai, China. Clin Infect Dis 2009;49:515-21. Abstract/FREE Full Text 56. 56. 1. 2. 3. 4.

Lukehart SA, Godornes C, Molini BJ, et al

. Macrolide resistance in Treponema pallidum in the united states and Ireland. N Engl J Med 2004;351:154-8. CrossRefMedlineWeb of Science 57. 57. 1. Van Damme K,

2. Behets F, 3. Ravelomanana N, 4. et al . Evaluation of azithromycin resistance in Treponema pallidum specimens from Madagascar. Sex Transm Dis 2009;36:775-6. CrossRefMedlineWeb of Science 58. 58. 1. 2. 3. 4.

Su J, Hook E, Kenney K, et al

. In: 18th International Society for STD research; 28 June to 1 July 2009. London, United Kingdom; 2009. Prevalence of the 23S rRNA point mutation in Treponema pallidum in the United States and associated factors, 20062008. Search Google Scholar 59. 59. 1. Hook EW 3rd., 2. Roddy RE, 3. Handsfield HH . Ceftriaxone therapy for incubating and early syphilis. J Infect Dis 1988;158:881-4. FREE Full Text 60. 60. 1. Cuddy PG . Benzathine penicillin G in the treatment of neurosyphilis. Drug Intell Clin Pharm 1982;16:205-10. Abstract 61. 61. 1. 2. 3. 4. 5. 6.

Mohr JA, Griffiths W, Jackson R, Saadah H, Bird P, Riddle J

. Neurosyphilis and penicillin levels in cerebrospinal fluid. JAMA 1976;236:2208-9. Abstract/FREE Full Text

62. 62. 1. 2. 3. 4. Smith CA, Kamp M, Olansky S, Price EV

. Benzathine penicillin G in the treatment of syphilis. Bull World Health Organ 1956;15:1087-96. Medline 63. 63. 1. Idsoe O, 2. Guthe T, 3. Willcox RR . Penicillin in the treatment of syphilis: the experience of three decades. Bull World Health Organ 1972;47:1-68. MedlineWeb of Science 64. 64. 1. de Gracianski P, 2. Grupper C . Results of the treatment of primosecondary syphilis with a single injection of longacting depot penicillin: apropos of 147 cases. Sem Hop 1960;36:1441-50. Medline 65. 65. 1. 2. 3. 4.

Schroeter AL, Lucas JB, Price EV, Falcone VH

. Treatment for early syphilis and reactivity of serologic tests. JAMA 1972;221:471-6. Abstract/FREE Full Text 66. 66. 1. 2. 3. 4.

Rolfs RT, Joesoef MR, Hendershot EF, et al

. A randomized trial of enhanced therapy for early syphilis in patients with and without human immunodeficiency virus infection. the syphilis and HIV study group. N Engl J Med 1997;337:307-14.

CrossRefMedlineWeb of Science 67. 67. 1. Moore JE, 2. Padget P . The problem of seroresistant syphilis (so-called Wassermann fastness). J Am Med Assoc 1938;110:96-100. Abstract/FREE Full Text 68. 68. 1. 2. 3. 4.

Marra CM, Maxwell CL, Smith SL, et al

. Cerebrospinal fluid abnormalities in patients with syphilis: association with clinical and laboratory features. J Infect Dis 2004;189:369-76. Abstract/FREE Full Text 69. 69. 1. 2. 3. 4. 5.

Marra CM, Maxwell CL, Collier AC, Robertson KR, Imrie A

. Interpreting cerebrospinal fluid pleocytosis in HIV in the era of potent antiretroviral therapy. BMC Infect Dis 2007;7:37. CrossRefMedline 70. 70. 1. 2. 3. 4.

Marra CM, Longstreth WT Jr., Maxwell CL, Lukehart SA

. Resolution of serum and cerebrospinal fluid abnormalities after treatment of neurosyphilis. influence of concomitant human immunodeficiency virus infection. Sex Transm Dis 1996;23:184-9. MedlineWeb of Science 71. 71. 1. Moore JE

. Studies in asymptomatic neurosyphilis. II. The classification, treatment, and prognosis of early asymptomatic neurosyphilis. Bull Johns Hopkins Hosp 1922;33:231-46. Web of Science 72. 72. 1. Moore JE, 2. Hopkins HH . Asymptomatic neurosyphilis. VI. The prognosis of early and late asymptomatic neurosyphilis. J Am Med Assoc 1930;95:1637-41. Abstract/FREE Full Text 73. 73. Centers for Disease Control and Prevention (CDC). Symptomatic early neurosyphilis among HIV-positive men who have sex with menfour cities, United States, January 2002June 2004. MMWR Morb Mortal Wkly Rep 2007;56:625-8. Medline 74. 74. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Service, 2011; 1166. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.