Abstract
Clinical management of patients with syphilis is controversial. This article summarizes recent research on syphilis treatment efficacy and outcomes and is based on a comprehensive systematic review of published literature, relevant abstracts, conference proceedings, technical reports, and guidelines. Penicillin remains the drug of choice for the treatment of syphilis. Although several studies have suggested that azithromycin may have clinical efficacy, macrolide resistance has been widely documented among strains of Treponema pallidum, and treatment failures have been reported. Ceftriaxone is effective for the treatment of syphilis when used in multiple-dose regimens. Lumbar puncture should be performed for human immunodeficiency virus—infected patients with syphilis of >1 year's duration and a serum nontreponemal test titer ⩾1 : 32, as well for other patients for whom the clinical suspicion of neurosyphilis is high. Newer laboratory tests for syphilis are undergoing extensive evaluation and may prove to be useful for future clinical care. American and European approaches to syphilis treatment are similar, but they vary across several parameters.
Background
Despite several advances in key areas, the management of patients with syphilis remains difficult and controversial. Several new lines of research have led to updated evidence-based recommendations for clinical decision making, particularly in the areas of diagnostic testing and the use of antibiotics for the treatment of syphilis. This is especially important in light of the increasing rates of syphilis in the United States, as well as the increasing recognition of concurrent syphilis and HIV infection among men who have sex with men. During 2000–2004, the number of reported cases of primary and secondary syphilis increased by 33%, from a historic nadir of 5979 cases to 7980 cases, driven primarily by an 80% increase in cases among males. Currently, the male-to-female rate ratio for primary and secondary syphilis (the rate of reported cases among males divided by the rate of reported cases among females) has increased from 1.5 to 5.9 over the same period [1]. The purpose of this review is to present new evidence that has appeared since the most recent update [2] in support of specific management recommendations for patients with syphilis or patients who have been exposed to infectious syphilis. New research may be primarily summarized in 4 separate but interrelated categories dealing with syphilis management and prevention: (1) the use of azithromycin to treat patients with syphilis or their sexual contacts, (2) the appropriate role of ceftriaxone in the treatment of patients with syphilis, (3) the use of lumbar puncture to evaluate patients for neurosyphilis, and (4) new laboratory tests for syphilis.
Methods
A comprehensive search of the literature via Medline was conducted to cover the period from July 2000 (the date through which the last comprehensive review of the literature was conducted by Augenbraun [2]) through December 2004. Medline subject search terms included “syphilis,” in all documents and all subheadings (“syphilis” or “exp syphilis, latent/” or “exp syphilis, cardiovascular/” or “exp syphilis, cutaneous/” or “exp syphilis/” or “exp syphilis serodiagnosis/”), as well as “Treponema pallidum,” in all documents and all subheadings (“Treponema pallidum” or “exp Treponema pallidum/”). The key words “syphilis” and “Treponema pallidum” were also searched in Medline. This strategy resulted in the retrieval of a total of 3207 documents. In addition, a systematic review was undertaken of published abstracts from important sexually transmitted disease (STD) meetings and conferences between 2001 and 2004, including the International Society for STD Research conferences in 2001 and 2003, the National STD Prevention Conferences in 2002 and 2004, and additional relevant abstracts from annual meetings of infectious diseases experts and HIV care conferences. A review was undertaken of all available workshop papers and unpublished “gray literature” (i.e., non—peer-reviewed or limited peer-reviewed documents) that addressed STD management and decision making. These sources included the 2004 International Union against Sexually Transmitted Infections/World Health Organization Syphilis Workshop conference proceedings, as well as various World Health Organization laboratory-evaluation technical reports and Web-based European treatment guidelines documents. Finally, relevant recent articles from the published literature were included in later drafts of the analysis, as they were identified through the peer-review process.
Studies were reviewed for salience and relevance to the clinical management of adults with syphilis. Studies were excluded if they did not directly address the issues of syphilis detection, treatment, and prevention in human populations. Available evidence was then prepared in tabular form to summarize the key study findings, the potential generalizability of the findings, and the implications for recommendations regarding the management of syphilis (table 1). Expert opinion from a variety of STD researchers and clinicians was sought to discuss and highlight these recommendations.
Review of syphilis studies: key study findings, the potential generalizability of the findings, and the implications for recommendations regarding the management of syphilis.
Results
Use of Azithromycin in the Treatment of Patients with Syphilis or Their Sexual Contacts
After the appearance of case reports of successful open-label treatment of patients with azithromycin [3, 4], several investigators reported equivalent outcomes of treatment with azithromycin and benzathine penicillin G (BPG) in randomized clinical trials. In a study of patients with early syphilis in the United States, researchers compared single-dose BPG (2.4 million U intramuscularly) with azithromycin (administered either as a single 2-g oral dose or as two 2-g oral doses 1 week apart) [5]. The serologic response rates were equivalent among patients in the 3 groups. Similar findings were reported among patients with serologically confirmed syphilis in Uganda [6] and patients with primary syphilis or high-titer latent syphilis in Tanzania [7], when BPG (2.4 million U intramuscularly) was compared with azithromycin (a single 1-g oral dose) and, in the case of the Ugandan study, with combination therapy involving BPG and azithromycin. Clinical outcomes and serologic responses were similar for patients in all groups and were irrespective of the concomitant HIV infection status of patients, suggesting that azithromycin may have clinical utility in the treatment of patients with syphilis. In the United States, an ongoing, randomized, controlled trial is comparing azithromycin with BPG for the treatment of early syphilis in HIV-negative patients (E.W. Hook III, personal communication). The study has enrolled >400 participants, and although investigators are blinded to the outcome data, an independent data safety monitoring board has found no reason to stop the study.
Other investigators have found azithromycin to be useful as empirical treatment for sexual contacts of patients with infectious syphilis in California [8] and as part of a targeted mass-treatment campaign among high-risk populations in Vancouver, Canada [9,10–11]. In resource-poor settings, azithromycin offers certain advantages over traditional intramuscular therapy with BPG, including an oral route of delivery, the capability of treatment in the field, and even “secondary carry” by target populations to other at-risk individuals who may not access medical services. Although such gastrointestinal adverse effects as nausea, bloating, and self-limited diarrhea have been reported in 10%–30% of patients receiving treatment with a single oral dose of azithromycin, these effects are relatively short lived, and the medication is generally well tolerated, even at the higher 2-g dosage. Furthermore, economic modeling studies have found azithromycin to be cost-effective at current public health pricing [12]. The fact that azithromycin is now available as a generic drug in the United States (and, therefore, is less expensive than in the past) would further serve to enhance its cost-effectiveness if it is used more widely to treat syphilis.
However, starting in late 2002, several clinical treatment failures were noted in San Francisco among men who have sex with men and who were treated with azithromycin for early syphilis or as sexual contacts of patients with active syphilis [13]. Molecular analysis of erythromycin-resistant T. pallidum isolates demonstrated a 23S ribosomal RNA mutation that conferred resistance to macrolide antibiotics and was associated with treatment failure [14,15–16]. An extremely high prevalence of the mutation (88%) was found in Dublin, Ireland, and moderately high prevalences were found in US cities (22% in San Francisco, 13% in Seattle, and 11% in Baltimore). The prevalence of the mutation in other parts of the United States is unknown, because molecular analysis is not routinely available. In San Francisco, a clinical trial comparing azithromycin with BPG for the treatment of sexual contacts of patients with infectious syphilis was terminated early by the study's data safety monitoring board, after 2 treatment failures were reported among 12 patients treated with azithromycin [17]. In this light, caution must be exercised when recommending azithromycin for the treatment of syphilis, because molecular resistance may be extensive. A recent editorial by Holmes [79] acknowledged that there is a lack of prospective data on the effect of the influence of the 23S ribosomal RNA mutation on treatment outcomes, and it places the use of azithromycin in perspective as a possible alterative for the treatment of early syphilis in persons with an allergy to penicillin. However, the lack of a sustained effect of azithromycin in the management of outbreaks, coupled with the rapid emergence of macrolide resistance and the absence of routine surveillance for resistance mutations among T. pallidum strains, makes the routine use of azithromycin problematic at best. Penicillin remains the drug of choice for the treatment of syphilis, and patients who are treated with azithromycin require close clinical and serologic follow-up and monitoring of treatment response.
Appropriate Role of Ceftriaxone in the Treatment of Patients with Syphilis
Although ceftriaxone has been used by some experts as an alternative to penicillin, clinical data have been lacking to guide recommendations regarding the dosage or duration of treatment. Researchers in the United Kingdom reported successful treatment of a patient with neurosyphilis by use of parenteral ceftriaxone (1 g daily for 14 days) [18]. Moreover, a prospective, randomized, controlled trial of ceftriaxone involving HIV-infected patients with high-titer latent syphilis demonstrated the clinical equivalence of parenteral ceftriaxone (1 g daily for 15 days) and standard therapy involving procaine penicillin plus probenecid [19]. In this trial, serologic outcomes were similar among patients treated with ceftriaxone and patients treated with penicillin, although sample sizes were small and relapse/nonresponse rates were relatively high in both groups. Most patients in the study were believed to have late latent syphilis, and the study was conducted before the widespread use of HAART for HIV infection. Although these reports provide some additional data to support the use of ceftriaxone in certain clinical scenarios, the usefulness of ceftriaxone remains to be validated in larger clinical trials. It is important to note that single-dose ceftriaxone has never been shown to be effective for the treatment of syphilis and is not recommended. Clinicians electing to use ceftriaxone for the treatment of syphilis should use multiple-dose regimens, given the relatively short half-life of this agent compared with that of BPG. Current treatment recommendations for early syphilis include ceftriaxone (1 g intramuscularly daily for 8–10 days) as an alternative treatment for patients with an allergy to penicillin.
Use of Lumbar Puncture in the Evaluation of Patients for Neurosyphilis
Significant new clinical data address the issue of which patients should undergo lumbar puncture for evaluation of possible neurosyphilis; however, interpretation of these data has been controversial. On one hand, although it has long been known that treponemal invasion of the CNS occurs quite frequently in early syphilis, most patients seem to respond to standard, nonneurosyphilis treatment regimens for early syphilis [80]. On the other hand, much of those data come from the pre-HIV era, and the natural history of treponemal invasion of the CNS in HIV-infected patients is not clear, particularly in patients with advanced immunosuppression. A recent multicenter, prospective study of 326 patients in several US cities who had syphilis and who underwent lumbar puncture for neurosyphilis evaluation found that a serum rapid plasma reagin (RPR) titer ⩾1 : 32 was highly predictive of the presence of neurosyphilis (defined as either a positive result of a Venereal Disease Research Laboratory [VDRL] test performed on a CSF specimen or a CSF WBC count >20 cells/µL), regardless of the stage of syphilis, the HIV-infection status, or previous receipt of nonneurosyphilis treatment [20]. Among HIV-positive patients, neurosyphilis was 6.0 times more likely to occur in patients with a serum RPR titer ⩾1 : 32 and 3.1 times more likely to occur in patients with a CD4 cell count ⩽350 cells/µL. A smaller retrospective study of syphilis in HIV-infected patients in Belgium and Spain also found an increased risk of neurosyphilis in persons with a serum RPR titer ⩾1 : 32, independent of the stage of syphilis [21]. A follow-up study of individuals treated for neurosyphilis showed that HIV-infected patients had slower resolution of serum RPR and CSF-VDRL titers after treatment [22]. On the basis of these data, some investigators have suggested that lumbar puncture should be considered for all patients with a serum nontreponemal test titer ⩾1 : 32, regardless of the stage of syphilis, particularly for persons with concomitant HIV infection.
However, approximately one-third of patients with high serum RPR titers in the prospective treatment trial had early syphilis (secondary and early latent infection) [20], and compelling data are lacking to suggest that CSF abnormalities in early syphilis reliably predict the need for more-aggressive treatment regimens. Stated another way, there is no evidence that asymptomatic neurosyphilis in this population does not respond to standard syphilis treatment regimens appropriately. However, many experts remain concerned about the possibility of negative outcomes associated with CNS invasion in HIV-infected patients with high nontreponemal test titers, particularly when immunosuppression is present. Lumbar puncture should therefore be performed for all HIV-infected patients who had syphilis of >1 year's duration (i.e., late syphilis) and a serum nontreponemal test titer ⩾1 : 32, and, if clinical suspicion is high, consideration should be given to performing lumbar puncture for other HIV-infected patients with high nontreponemal test titers.
Once the decision has been made to perform lumbar puncture, it is still often difficult to determine whether the patient actually has neurosyphilis. Although a positive CSF-VDRL test result is diagnostic, this test is relatively insensitive, and most clinicians rely on indirect markers of CNS inflammation, such as an elevated WBC count in the CSF. European investigators recently proposed the use of additional diagnostic criteria for neurosyphilis, including the T. pallidum hemagglutination assay (TPHA) index, the CSF TPHA titer, the CSF IgG index, and the T. pallidum particle agglutination index. In a retrospective case series study of 60 patients with neurosyphilis compared with 54 patients with previously treated syphilis, a TPHA index >70 and a CSF TPHA titer >1 : 320 were each 98.3% sensitive and 100% specific for neurosyphilis [23]. Similar results have been reported with the use of the CSF IgG index and the T. pallidum particle agglutination index for the diagnosis of neurosyphilis in Europe [75]. However, the studies were based on small numbers of patients, and these findings will require further validation in larger case series before recommendations for their routine use can be made.
New Laboratory Tests for Syphilis
In recent years, there has been an explosion of evaluation studies looking at new syphilis diagnostics. Many of these are laboratory validation studies or initial field trials of rapid treponemal tests, such as the immunochromatographic strip test, which can be used in resource-poor settings in developing countries [24,25,26,27,28,29,30,31,32,33,34,35,36–37]. Other studies have looked at new reference laboratory standards for syphilis, such as Western blot (WB) analysis or EIA [38,39,40,41,42,43,44,45,46,47,48,49,50,51,52–53], or the use of nucleic acid amplification, molecular strain typing, or other innovative technologies [54,55,56,57,58,59–60]. Although the rapid treponemal immunochromatographic strip tests appear to be promising for use in field conditions, no such test is currently approved by the Food and Drug Administration for use in the United States.
Historically, screening for syphilis has involved the use of nontreponemal tests, such as the RPR or VDRL test. Positive results of nontreponemal tests of specimens are then confirmed using a more specific treponemal test, such as the T. pallidum particle agglutination test or the TPHA, because a number of other conditions may cause a false-positive nontreponemal test result. However, nontreponemal tests can be cumbersome and time consuming when performed on large samples, because of the lack of automation for performance of these tests. In recent years, a number of commercial laboratories, blood banks, and some public health laboratories in the United States have begun to use automated treponemal EIAs for the screening of large samples. Such tests are particularly useful for the detection of syphilis in populations in which the prevalence of syphilis is low, and positive test results are then confirmed by nontreponemal testing and titer determination. In Europe, some investigators have even begun to call for the discontinuation of nontreponemal tests altogether, recommending the use of treponemal EIA tests for primary screening of samples, with positive EIA results confirmed using another treponemal test, such as the T. pallidum particle agglutination test or the TPHA [74].
However, samples for which results of treponemal EIAs are positive and results of nontreponemal tests are negative are potentially confusing to clinicians, because this scenario is ambiguous. Patients with such findings may have untreated, late, latent syphilis; old, treated syphilis; or partially treated syphilis resulting from the use of antibiotics for treatment of other infections. The test findings also may represent a biological false-positive treponemal test result. Particularly when used in populations with high rates of adequately treated previous cases of syphilis (such as STD clinic populations), treponemal screening tests may yield a large number of positive results that do not denote the presence of active infection.
Clinical data are lacking to guide the interpretation and management of patients with equivocal test results, and additional research in this area is required. Clinicians who evaluate patients with a positive treponemal EIA result should perform a nontreponemal serologic test, as well as a second treponemal test, to confirm results. If the results of either of these follow-up tests are positive, and if previous treatment of syphilis cannot be verified, patients should be treated for syphilis.
Clinical Management of Patients with Syphilis
Several real-world clinical management issues remain with regard to treatment of syphilis for which no new data are available to guide treatment decisions. In these circumstances, expert opinion remains the best source of advice for the management of patients. The areas of controversy are described below:
Definition of treatment failure.Treatment failure is considered to be an indication for CSF examination to rule out occult, sequestered CNS infection that has not been adequately treated. Smith et al. [19] defined treatment failure as a ⩾4-fold increase in the RPR titer, a titer persistently ⩾1 : 64, or clinical progression to disease, and they also defined the categories of relapse (i.e., a ⩾4-fold decrease in the RPR titer, followed by a return to the original titer or a higher titer) and nonresponse (i.e., ⩽2-fold change in the RPR titer throughout the study period [in this case, a median follow-up of 2 years]). Many experts suggest that the more general category of treatment failure, as understood by practicing clinicians, largely includes all of these circumstances, and the recommendation for CSF examination should apply to any patient whose condition fails to respond appropriately to syphilis treatment with an adequate, sustained ⩾4-fold decrease in nontreponemal test titers 6 months after treatment.
Management of asymptomatic patients who meet the criteria for CSF examination but decline lumbar puncture.Such individuals may or may not have occult CNS infection. All patients should be counseled that CSF evaluation will provide the best clinical information to guide management decisions. Nevertheless, some patients may decline this procedure even after receiving appropriate counseling. If close clinical and serologic follow-up can be assured, some experts would recommend a standard nonneurosyphilis treatment regimen, with clinical and serologic follow-up performed 3 and 6 months after treatment. Patients who do not demonstrate an appropriate serologic response (i.e., a ⩾4-fold decrease in the nontreponemal test titer or sustained seroreversion occurring within 6 months of treatment) should be strongly advised to have CSF evaluation performed at that time. However, if close clinical and serologic follow-up cannot be assured, then empirical use of a neurosyphilis treatment regimen may be appropriate at the outset. All patients should be counseled that CSF evaluation will provide the best clinical information to guide management decisions.
Evaluation and treatment of HIV-infected patients with syphilis.This is an important area of clinical management, particularly in the context of increasing rates of syphilis among HIV-infected men who have sex with men [81, 82]. Several recent studies seem to confirm what had been widely argued previously: concomitant HIV infection may have small effects on clinical presentations of syphilis, but serologic responses are generally comparable to those noted in HIV-uninfected patients. Rompalo et al. [61, 62] found that HIV-positive patients were more likely to present with multiple ulcers, deeper ulcers, or concomitant primary and secondary lesions, although these effects were small. In a study of antenatal clinic attendees with syphilis, Sturm et al. [63] found that RPR titers did not vary according to HIV-infection status, although TPHA titers were somewhat lower in patients with HIV infection. By and large, most experts agreed that clinical manifestations of and serologic responses to syphilis are similar in HIV-infected and -uninfected individuals, although subtle variations in clinical presentation may occur.
With regard to treatment of syphilis in HIV-infected patients, there are no new data to contradict previous recommendations that HIV-infected individuals should receive the same treatment regimens as persons without HIV infection. Browning et al. [64] found no difference in the responses to treatment of ocular syphilis between HIV-positive and HIV-negative patients. Similarly, Long et al. [65] found that HIV-infection status did not influence outcomes of syphilis treatment in a population-based study of patients with serologically confirmed syphilis. Although syphilis treatment failures among HIV-infected patients have been reported [66, 67], there is no evidence that these failures occur more frequently among such patients than among patients without HIV infection or that additional treatment above and beyond the standard therapy for HIV-negative patients would necessarily prevent such failures. Finally, recent studies suggest that acquisition of syphilis by HIV-infected individuals causes an increase in the serum HIV load and a decrease in the CD4 cell count, but that these parameters improve with standard syphilis treatment [67, 68].
Harmonization of US and international syphilis treatment guidelines.A number of other international organizations have moved to establish evidence-based guidelines for STD treatment. Since 2000, new guidelines and position papers have been published by the World Health Organization, by experts in the United Kingdom, and by the European branch of the International Union against Sexually Transmitted Infections [69,70,71,72,73,74,75,76,77–78]. In general, all the guidelines are based on the same foundation documents and evidence base; however, significant variations exist in certain areas, reflecting differing interpretations of the same data. For example, BPG is considered to be first-line therapy in the United States; however, in the United Kingdom, procaine PCN is preferred, primarily because UK experts remain concerned about the small numbers of case studies in which patients have experienced BPG treatment failure. However, US experts emphasize that procaine PCN regimens require daily intramuscular injections for 10 days, compared with a single injection of BPG. Other differences remain, including the European use of amoxicillin plus probenecid to treat neurosyphilis or the use of erythromycin to treat early syphilis. Some experts on both sides of the Atlantic have called for consensus workshops to try to harmonize these recommendations and develop common strategies for patient care.
Conclusion
Significant research advances in recent years have influenced the management of patients with syphilis. Despite the promising clinical outcomes data that have been noted with the use of azithromycin, molecular resistance to macrolide antibiotics appears to be widespread, and resistance testing of clinical isolates is not readily available in most practice sites. For this reason, routine use of azithromycin cannot be recommended. Ceftriaxone appears to be clinically efficacious in the treatment of syphilis, although it must be given daily and requires a parenteral route of administration. High serum nontreponemal test titers appear to correlate with a diagnosis of neurosyphilis, confirming the need to perform lumbar puncture for HIV-infected individuals with late syphilis and high serum titers. Controversy exists as to the need for lumbar puncture among HIV-infected patients with early syphilis and high nontreponemal test titers or among HIV-uninfected persons who are asymptomatic but have high nontreponemal test titers. Evolving diagnostic criteria for neurosyphilis require validation in larger clinical trials. Newer laboratory tests for syphilis are promising, but the transition from nontreponemal to automated treponemal screening tests will require close scrutiny by clinicians, to make sense of disparate test results.
Acknowledgments
I thank the following individuals for assistance in data retrieval for this study: George Schmid, Nathalie Broutet, Francis Ndowa, Timothy Farley, and Leslie Wright.
Supplement sponsorship.This article was published as part of a supplement entitled “Sexually Transmitted Diseases Treatment Guidelines,” sponsored by the Centers for Disease Control and Prevention.
Potential conflicts of interest.B.P.S.: no conflicts.
Comments