Clin Infect Dis. 2007 Stoner S130 46

SUPPLEMENT ARTICLE
Current Controversies in the Management of Adult Syphilis

Bradley P. Stoner
Department of Anthropology and Division of Infectious Diseases, Washington University in St. Louis, St. Louis, Missouri
Clinical management of patients with syphilis is controversial. This article summarizes recent research on syphilis treatment efcacy 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 efcacy, 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 immunodeciency virusinfected patients with syphilis of 11 years 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 difcult 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 20002004, 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 specic 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 sub
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Reprints or correspondence: Dr. Bradley P. Stoner, Dept. of Anthropology and Div. of Infectious Diseases, Washington University in St. Louis, One Brookings Dr., Campus Box 1114, St. Louis, MO 63130 (bstoner@wustl.edu). Clinical Infectious Diseases 2007; 44:S13046 2007 by the Infectious Diseases Society of America. All rights reserved. 1058-4838/2007/4407S3-0007$15.00 DOI: 10.1086/511426
S130 CID 2007:44 (Suppl 3) Stoner
headings (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., nonpeer-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 identied 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 ndings, the potential generalizability of the ndings, 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. 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 ndings were reported among patients with serologically conrmed 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 HIVnegative patients (E.W. Hook III, personal communication). The study has enrolled 1400 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 masstreatment campaign among high-risk populations in Vancouver, Canada [911]. 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 eld, 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 [1416]. 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 studys 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
Adult Syphilis CID 2007:44 (Suppl 3) S131
Table 1. Review of syphilis studies: key study ndings, the potential generalizability of the ndings, and the implications for recommendations regarding the management of syphilis.
Subject of study, name of rst author [reference] Study design Exposure/intervention Outcome measure(s) Reported ndings
Type of report
Study population/location or test(s)/aspect evaluated
Design analysis quality/biases
Azm treatment Open-label, noncomparative treatment study Patients with early syphilis; Croatia Azm (1-g initial po dose, followed by 500 mg daily for 8 days) Serologic resolution 6 months after treatment 6 months after treatment, a negative VDRL result was noted for 6 of 6 patients with primary syphilis and for 4 of 8 patients with secondary/early latent syphilis; minor GI adverse effects occurred in 2 patients 32-fold decrease in the RPR titer at 1-year follow-up Small sample size (14 evaluable patients)
Gruber [3]
Journal article
Campos-Outcalt [4]
Journal article
Case report
Homeless woman with syphilis Azm (1 g po daily for 12 doses) of unknown duration and a Pen allergy; United States
Serologic response to treatment
Treatment was apparently successful; patient had a psychiatric disorder and denied taking any other antibiotics, but she was an unreliable historian 74 patients enrolled, including 3 patients who were HIV+; 81% were followed for 3 months; response rates were as follows: for BPG, 86%; for single-dose Azm, 94%; and for 2 doses of Azm (1 week apart), 83% 952 persons were treated (18% received BPG; 17%, Azm; and 65%, combination treatment); patients with an initial titer 1:4 had higher cure rates with Azm or with BPG and Azm, compared with BPG alone Study included patients who were HIV infected, but no detailed results were given for these patients; 1 patient given BPG and 1 patient given 2 doses of Azm had treatment failure; 6 patients had a clinical response without a serologic response HIV-infection status did not affect cure rates; there was no difference in treatment outcomes for persons with a low initial titer
Hook [5]
Journal article
Randomized clinical trial
STD clinic patients with early syphilis; United States
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Population-based study Patients with serologically conrmed syphilis; Uganda Randomized clinical trial Patients with primary or hightiter latent syphilis (RPR titer, 1:8); Tanzania Retrospective chart review At-risk individuals with incubating syphilisnot otherwise dened; United States Targeted mass treatment At-risk groups; Canada Single-dose Azm (1.8 g po)
Single-dose BPG (2.4 million U) Resolution of clinical signs and symptoms; RPR serorevervs. single-dose Azm (2 g) vs. sion or a 4-fold decrease 2 doses of Azm (2 g 1 week in titer apart)
Kiddugavu [6]
Journal article
Single-dose BPG (2.4 million U) TRUST seroreversion or a 4fold decrease in the titer vs. single-dose Azm (1 g) vs. BPG and Azm (combination treatment)
Reidner [7]
Journal article
328 patients treated (25 with Single-dose BPG (2.4 million U) Decrease in the RPR titer 2 primary syphilis and 303 vs. single-dose Azm (2 g) dilutions within 9 months or with high-titer latent syphiepithelialization of primary ullis); cure rates were 97.7% cers within 12 weeks after for Azm vs. 95.0% for Pen treatment Single-dose BPG (2.4 million U) Persistent seronegative nontreponemal test result 3090 vs. single-dose Azm (1 g) vs. days after treatment Dox (100 mg b.i.d. for 14 days) Maximum number of at-risk persons who were treated or received prophylaxis 96 of 98 Azm-treated persons remained seronegative, compared with 15 of 16 Pentreated and 5 of 5 Doxtreated persons Attempt to distribute 17000 doses to at-risk groups
HIV-infection status did not affect cure rates; patients with primary lesions or high-titer latent syphilis had an earlier response Azm and BPG are equally effective in the treatment of incubating syphilis; results were independent of HIV-infection status Primary delivery and secondary carry to hard-to-reach individuals were used
Klausner [8]
Abstract
Rekart [9]
Journal article
Rekart [10]
Journal article
Targeted mass treatment
At-risk groups; Canada
Single-dose Azm (1.8 g po)
Reported rates of infectious syphilis; a change in antimicrobial resistance
4384 persons treated; syphilis rates decreased signicantly for 6 months but increased thereafter, returning to preintervention levels; no impact on Azm resistance at the community level
Absence of sustained effect; mass treatment feasible but should not be done routinely
Rekart [11]
Abstract
Targeted mass treatment
At-risk groups; Canada
Single-dose Azm (1.8 g po)
Participation in and support for intervention; characteristics of participants
Support for intervention among Difcult for sex trade workers to eliminate risk behaviors target groups but not among health care workers; 1 year after treatment, participants had positive changes in KAB but did not have fewer bacterial STDs Azm cost saving (at average wholesale price) is $17.32 when the efcacy rate is 90%; Azm results in fewer syphilis cases among exposed partners when the efcacy rate is 87%; Azm cost saving (at public health price) is $11.50 when the efcacy rate is 75% 8 treatment failures from Sep 2002 to July 2003; all patients were MSM, and 5 were HIV+ An ArG transition mutation in both 23S rRNA genes confers macrolide resistance Cost-effectiveness/modeling analysis
Blandford [12]
Journal article
Cost-effectiveness analysis
Sex partners of persons with infectious syphilis; United States
Azm provided to syphilis contacts
Averted cases of infectious syphilis and decreased associated costs
Azm resistance Epidemiological report Patients with early syphilis or sex partners of persons with syphilis in 20022003; San Francisco Em-resistant T. pallidum clinical isolate Patients with primary or secondary syphilis; United States and Ireland Gene sequencing and restriction digest analysis; in vivo resistance studies 23S rRNA gene analysis by PCR Treatment with Azm Clinical treatment failure Caution urged in using Azm for syphilis treatment
CDC [13]
Journal article
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Genetic analysis Molecular analysis Randomized clinical trial Sex contacts of persons with infectious syphilis; United States Case report 61-year-old HIV man who had symptomatic neurosyphilis; United Kingdom Ctri (1 g for 14 days [iv for 3 days and im for 11 days]) Prospective, randomized, controlled trial HIV+ patients with latent syphilis and an RPR titer 1:4; United States Procaine Pen (2.4 million U im each day) and Pro (500 mg po q.i.d. for 15 days) vs. Ctri (1 g im each day for 15 days)
Stamm [14]
Journal article
Comparison with Em-susceptible strains Identication of 23S rRNA mutation; conrmation of in vivo Azm resistance
Molecular basis for clinically observed macrolide treatment failures Prevalence of mutation, by city: 88% in Dublin, 22% in San Francisco, 13% in Seattle, and 11% in Baltimore; among historical samples (19121987), prevalence was 6% Treatment failure occurred in 2 of 12 patients receiving Azm vs. 0 of 13 patients receiving Pen (P p .18); study terminated early by DSMB In San Francisco, higher mutation rates were noted in 2003 than in 19992002; recommendation: avoid Azm in geographic areas where macrolide resistance is relatively high Small sample size, but Azm appeared to be inferior to Pen in the presence of high community levels of Azm resistance (56%)
Lukehart [15, 16]
Abstract/journal article
Klausner [17]
Letter
Single-dose BPG (2.4 million U) Efcacy of treatment of incuvs. single-dose Azm (1 g) bating syphilis (not further specied)
Ctri treatment CSF and serologic response 3 years after treatment, serum RPR titer decreased from 1: 128 to 1:16; CSF RPR titer and protein and glucose levels normalized Serologic response, nonresponse, relapse, or failure after treatment 24 evaluable patients (10 received Pen and 14, Ctri); response rate, by treatment, was 70% with Pen vs. 71% with Ctri; relapse rate, 20% with Pen vs. 7% with Ctri; failure rate: 0% with Pen vs. 14% with Ctri Evidence of cerebrovascular and parenchymal involvement; clinically, the patient had some improvement in memory, speech, and mobility No signicant difference in treatment outcomes with Pen vs. Ctri; relatively high nonresponse/relapse rates in both groups; no difference between patients with and without neurosyphilis
Shann [18]
Journal article
Smith [19]
Journal article
CSF evaluation for neurosyphilis Prospective, multicenter case series Patients with syphilis who met CDC criteria for LP; United States Clinical and laboratory correlates of neurosyphilis Neurosyphilis noted in 20.1% of 326 patients; a serum RPR titer 1:32 increased the odds of neurosyphilis in HIV patients (OR, 10.85) and HIV+ patients (OR, 5.98); a CD4 cell count 350 cells/ mL increased the odds for neurosyphilis in HIV+ patients (OR, 3.10) Neurosyphilis was dened as a CSF WBC count 120 cells/ mL or a reactive CSF-VDRL test result Follow-up analysis restricted to HIV+ patients with a reactive CSF-VDRL test result: OR, 6.0 (95% CI, 2.514.8); syphilis stage and nonneurosyphilis treatment not correlated with neurosyphilis diagnosis; 33% of patients had early syphilis, which could contribute to a high rate of positive CSF VDRL test results; scant prognostic data on the risk of symptomatic neurosyphilis developing from asymptomatic neurosyphilis Did not report the level of immune suppression (i.e., CD4 cell count); sample characteristics not provided Neurosyphilis noted in 23.2% of 112 patients; in asymptomatic patients (n p 15), the risk of neurosyphilis increased if the serum RPR titer was 1:32; no association with syphilis stage
Marra [20]
Journal article
Libois [21] Neurosyphilis dened as a CSF WBC count 20 cells/mL, a reactive CSF-VDRL test result, or a positive TPHA result
Abstract
Retrospective chart review
HIV+ patients with syphilis who Clinical and laboratory correlates of neurosyphilis underwent LP; Belgium and Spain
Marra [22]
Journal article
Prospective multicenter case series
Patients with neurosyphilis; United States
Treatment of neurosyphilis with Pen or Ctri
Normalization of laboratory parameters after treatment
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Retrospective case series HIV patients with or without neurosyphilis; Austria Laboratory predictors of a neurosyphilis diagnosis Sens. and spec. of serum and CSF indices Laboratory evaluation Laboratory evaluation Determine Syphilis TP (Abbott Laboratories) Compared with VDRL/FTA-ABS test results Sens. and spec. Agreement between test systems ICS tests performed using 17kDa and 47-kDa T. pallidum recombinant antigens; Peru Comparison with results obtained with RPR/MHA-TP Sens. and spec. Syphilis Fast latex agglutination Comparison with TPPA test test (Diesse, Diagnostica Senese) Laboratory evaluation
59 patients evaluated (78% were HIV+); HIV+ patients had decreased odds of CSFVDRL test results normalizing (HR, 0.4), and HIV+ patients with a CD4 cell count 200 cells/mL were least a likely to have normalization 60 patients with neurosyphilis, compared with 54 patients with previously treated syphilis were evaluated; for TPHA index 170, sens. was 98.3% and spec. was 100%; for CSF-TPHA titer 11 :320, sens. was 98.3% and spec. was 100%; for CSFVDRL test, sens. was 91.7% and spec. was 100%
Lack of a CSF response in HIV+ patients: after receiving adequate therapy, patients either had treatment failure or were slow to experience normalization after adequate therapy CSF protein level not helpful (elevated in 43 of 54 control subjects); small sample size
Luger [23]
Journal article
Laboratory tests for syphilis
Validation studies/ eld trials Sens., 94%98%; spec., 97%100% Agreement, 98.8% Reliable in high-risk populations; small sample sizes Rapid test (8 min); easy to read (could be used as point-of-care test) 47-kDa test of serum specimens had a sens. of 100% and a spec. of 87%; 17-kDa test of whole-blood specimens had a sens. of 94% and a spec. of 87% Demonstrated potential utility of an ICS test used with ngerstick specimens
Conde-Glez [24]
Abstract
Fears [25]
Journal article
Galvan [26]
Abstract
Garcia [27]
Abstract
Laboratory evaluation
Determine Syphilis TP (Abbott Laboratories), PATH-Omega strip test (Program for Appropriate Technology in Health), RPR test
Comparison with reference laboratory RPR test/TPHA results
Agreement with reference laboratory results
Of 19 true positives, Determine detected 19 (sens., 100%), Omega detected 18 (sens., 94.7%), and eld RPR detected 13 (sens., 68.4%); 18 (6%) of 302 eld RPR test results varied from reference laboratory results Sens., 95%; spec., 99.8% Among STD clinic patients, sens. of 92.4% and spec. of 98%; among antenatal patients, sens. of 89.5% and spec. of 100% For RST, sens. was 75.0% and spec. was 95.2%
Rapid tests in low-prevalence populations may improve case detection
Garcia-Bermejo [28] Laboratory evaluation Syphilis Fast test (Diesse, Diagnostica Senese) Compared with TPPA test results Sens. and spec.
Abstract
Syphilis Fast test (Diesse, Diagnostica Senese)
Compared with RPR test and IgM-IgG EIA
Sens. and spec.
Rapid, inexpensive, and could be useful screening test Lower test sens. (64%) among patients with primary syphilis
Lewis [29]
Abstract
West [30]
Journal article
RST immunochromatographic rapid test (Quorum Diagnostics), and a eld-performed RPR test; Gambia ICS test Compared with results obtained by RPR/FTA-ABS test Concordance with laboratory test results
Compared with results obtained by laboratory RPR test/TPHA
Sens. and spec.
RST easier to use in the eld than RPR test; low prevalence of syphilis (3%) hampered performance 100% agreement between ICS and FTA-ABS tests Pilot study; small sample sizes; ICS test requires no specialized equipment and takes 8 min to perform Sens., 93.6%; spec., 92.5% Results obtained in 15 min; no special equipment required, but there is some subjectivity in reading results Sens. range, 85%98%; spec. range, 93%98% Espline, Determine, and Bioline had the highest sens. (range, 95%98%); Visitect and Syphicheck had the highest spec. (98%); 4 tests c selected for eld evaluation
Zarakolu [31]
Journal article
Sato [32]
Journal article
Determine Syphilis TP immunochromatographic rapid test (Abbott Laboratories) 6 rapid treponemal tests Comparison with TPHA or TPPA test
b
Compared with serum specimens with serologically conrmed syphilis (VDRL, FTAABS, TPHA, and other tests) Sens. and spec.
Sens. and spec.
WHO [33]
Technical report
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Laboratory evaluation Determine Syphilis TP (Abbott Comparison with TPPA test Laboratories), Trep-Strip IV (Phoenix Bio-Tech), and One Step (Testmedica Diagnostics) performed on STD clinic patients; United States Clinical evaluation of laboratory tests 3 treponemal ICS tests performed for STD clinic patients; United States Comparison with TPPA results Cost-effectiveness analysis Women attending antenatal clinics On-site ICS test vs. on-site RPR test vs. off-site RPR test/TPHA
Siedner [34]
Journal article
Sens., percentage of indeterminate test results
Sens. and indeterminate results, respectively: for Determine (whole blood), 88% and 0.8%; for Determine (ngerstick), 100% and 2.9%; for Trep-Strip IV (whole blood), 69% and 30.5%; and One Step (whole blood), 72% and 6.5% Sens. and spec. in wholeblood, serum, and plasma specimens Sens. range: 35%83% for whole blood, 50%93% for serum, and 41%93% for plasma; spec. range, 92%99.5% Number of CS cases averted; incremental cost per averted case If maternal syphilis prevalence was 6.3%, an on-site ICS test would avert 82% of CS cases, with an incremental cost averted of $104/case; an off-site RPR test/TPHA would avert 55% of cases, incremental cost averted by $82/case; on-site RPR test less effective
Each test costs !$5; no equipment needed; results available in 15 min; some subjectivity in reading results; small sample sizes (70130 patients)
Zackery [35]
Abstract
Some rapid tests may be useful in US clinic settings; none are FDA approved
Blandford [36]
Unpublished data
On-site ICS test was cost-effective with a high prevalence of maternal syphilis
Bronzan [37]
Unpublished data
Clinical evaluation of a laboratory test
Treponemal ICS test and an on-site RPR test for antenatal clinic patients; South Africa
Comparison with standard offsite reference laboratory RPR test/TPHA
Percentage of women with syphilis who received correct diagnosis and treatment
1250 women screened; ICS test use led to identication and treatment of 89.4% of women with syphilis; an onsite RPR test led to 63.9% of women with syphilis red ceiving treatment; off-site RPR test/TPHA use led to treatment of 60.8% of women with syphilis (low return rates) 85% of patients obtained end point titer of 0.51 dilution more than that of natural antigen Determine results: 3 of 219 were false positive and 0 were false negative; Serodia TP/TPPA test results, 2 of 219 were false positive and 1 was false negative SIFA test and WB analysis both had a sens. of 99% and a spec. of 100%
On-site ICS test led to the highest number of women identied and treated; offsite strategy was less effective because patients need to return for treatment
Reference standards Laboratory evaluation Synthetic VDRL antigen Comparison with natural VDRL antigen Reactivity of serum specimens Synthetic VDRL antigen would increase standardization and stability Reduced spec. of Determine test when performed on whole-blood specimens
Castro [38]
Journal article
Lien [39]
Journal article
Determine Syphilis TP test (Abbott Laboratories) vs. Serodia TP test (Fujirebio) vs. Serodia TPPA test (Fujirebio) T. pallidum SIFA Comparison with WB analysis and FTA-ABS, MHA-TP and , TPI assays Comparison with MHA-TP (treponemal) and RPR (nontreponemal) tests Sens. and spec.
Comparison with serum specimens from patients with syphilis (positive RPR/VDRL test results), with EIA/FTAABS discordant resolution
Agreement with RPR/VDRL screening test results
Marangoni [40]
Journal article
SIFA test may be useful as a conrmatory test TPPA or Captia Syphilis-G test is appropriate substitute for MHA-TP test; Reagin II test could substitute for RPR test Agreement: between MHA-TP and TPPA tests, 97.4%; between MHA-TP and SyphilisG tests, 97.7%; and between RPR and Reagin II tests, 89.2%
Pope [41]
Journal article
Agreement between test systems
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Laboratory evaluation Bio-Rad syphilis IgG EIA (BioRad Laboratories) Comparison with the Captia Syphilis-G test, with discrepant resolution Comparison with TPPA and FTA-ABS tests Laboratory evaluation Laboratory evaluation T. pallidum WB analysis FTA-IgM and SPHA-IgM quanti- Detection of antibody in serum tative treponemal tests for patients with primary/secondary syphilis in Romania Recombinant WB for 5 T. pallidum recombinant antigens recomWell Treponema EIA (Mikrogen) WB analysis Comparison with whole-cell lysate WB analysis and an MHA-TP test Comparison with syphilis screening ELISA and MHATP test Compared with serum specimens conrmed by the VDRL, TPPA, and FTA-ABS tests and the anti-IgM EIA INNO-LIA Syphilis treponemal line immunoassay (Innogenetics) BioSCREEN antiT. pallidum recombinant-antigen EIA (Heber Biotec S.A.) Comparison with serologic conrmation by use of VDRL test, TPHA, and IgG FTAABS tests Comparison with TPHA Laboratory evaluation Laboratory evaluation Laboratory evaluation Laboratory evaluation Laboratory evaluation
Serodia TPPA (Fujirebio America), Captia Syphilis-G (treponemal; Trinity Biotech), and SpiroTek Reagin II (nontreponemal; Organon Teknika) tests
Tholcken [42]
Journal article
Agreement between test systems
Sens., 92.7% when used as a screening test; sens., 97.8% when used as a conrmatory test Sens. and spec. Antibody levels after syphilis treatment Sens., 100%; spec., 100% All patients had negative results 6 months after treatment Concordances, sens., and spec. Sens. and spec. Sens., 98.8%; spec., 97.1%
Compared favorably with Captia Syphilis-G test
Backhouse [43]
Journal article
Useful additional or alternative conrmatory test Small sample size; unclear clinical utility
Popescu [44]
Abstract
Sambri [45]
Journal article
Recombinant WB has potential as a syphilis conrmatory test Sens., 98.9%; spec., 98.3% Good performance across multiple test samples Sens. and spec. Sens., 95.5%; spec., 91.2% Did not perform as well as TPPA test for conrming syphilis serostatus Sens. and spec. Sens. 100%, spec. 99.3% Useful conrmatory test
Sambri [46]
Journal article
Young [47]
Abstract
Hagedorn [48]
Journal article
Rodriguez [49]
Journal article
Concordance, sens., and spec.
Agreement, 95.1%; sens., 93.3%; and spec., 95.5%
Easy-to-use, automated test to conrm nontreponemal test results
Aktas [50]
Abstract
Serodia TPPA (Fujirebio), Murex Syphilis ICE (Murex Biotech), and Enzywell TP tests (Diesse) T. pallidum IgG-IgM EIA for patients with STDs in Portugal Compared with MHA-TP and FTA-ABS test results Sens. and spec. Compared with MHA-TP test, sens. is 100% and spec. is 93%; compared with FTAABS test, sens. is 99.4% and spec. is 100% 3 proteins had high sens. and spec.: Tp0453 (sens., 100%; spec., 100%), Tp92 (sens., 98%; spec., 97%), and Gpd (sens., 91%; spec., 93%) 7 of 18 infants with a positive WB result had CS; 7 of 82 infants with a negative WB result had CS; ELISA and high RPR titer were less sensitive RPR test sens., 69.3%; FTAABS test sens., 87%; tests less sensitive with the presence of multiple infections 200120,000 copies/mL of blood; 22,0005.7 million copies/mL of ulcer uid 36 subtypes identied; strain clusters were noted in several cities Detection of T. pallidum Agreement with serologic results Sens. and spec. polA amplied in 37% of specimens PCR detected 4 syphilis cases among 70 seronegative men For primary syphilis: sens., 94.7%; spec., 98.6%; for secondary syphilis: sens., 80%; spec., 98.6% Determination of subtypes Subtype prevalence and clustering Clustering of subtype 14d noted in 19901991; different subtypes identied in 2002
Comparison with RPR test/ TPHA
Agreement with TPHA results
Agreement of TPHA with TPPA test was 97.6%; with ICE, 100%; and with Enzywell, 100%
All 3 tests performed adequately
Castro [51]
Journal article
High sens. and spec. of the test in all stages of syphilis; may be useful as a screening test 3 proteins also recognized serum specimens from patients with primary syphilis who had negative VDRL test results; Tp0453 shows particular promise T. pallidum IgM WB analysis identied mothers at higher risk of delivery of infants with CS
Van Voorhis [52]
Journal article
EIA using 6 recombinant T. pallidum antigens
Compared with serum specimens from patients with sye philis and other diseases
Sens. and spec.
Rawstron [53]
Journal article
Clinical evaluation of laboratory tests
TP IgM WB analysis and TP IgM ELISA for mother-infant pairs with reactive RPR and FTA-ABS test results; New York
Comparison with a maternal RPR titer 1:16
Diagnosis of CS in neonate
Molecular technologies Laboratory evaluation RPR and FTA-ABS tests for patients with GUD; South Africa Semiquantitative PCR performed on blood and ulcer specimens Molecular typing of T. pallidum strains for patients with GUD; South Africa PCR analysis of whole-blood specimens PCR analysis of whole-blood specimens T. pallidum PCR for anogenital and oral ulcers in GUM clinic patients; United Kingdom Molecular subtyping of T. pallidum strains in STD clinic patients; United States Amplication of T. pallidum polA gene Syphilis serologic test results (RPR test/TPHA) Compared with clinical and laboratory diagnosis of syphilis Determination of subtypes Amplication of T. pallidum polA gene Comparison with PCR Sens., spec., and impact of HIV infection Test performance appears to be similar in HIV+ and HIV patients Proof-of-principle study; may have future applications Useful for tracking networks, but no immediately apparent clinical relevance Subtype prevalence and clustering Spirochetemia detected at all stages of syphilis Proof-of-concept study, but limited applications at present; small sample size Only 29 patients with syphilis tested; no discussion of cost
Ballard [54]
Abstract
Liu [55]
Abstract
Detection and quantitation of T. pallidum
S137
Laboratory evaluation Laboratory evaluation Laboratory evaluation Laboratory evaluation Laboratory analysis Prospective, multicenter, randomized, controlled trial HIV+ and HIV patients with early syphilis; United States Treatment for early syphilis Prospective case series HIV+ and HIV patients seeking care for STDs; United States Diagnosis of GUD
Pillay [56]
Abstract
Sutton [57]
Abstract
Nagy [58]
Abstract
Palmer [59]
Journal article
Solis [60]
Abstract
May prove to be helpful in epidemiologic analyses
Syphilis in patients with HIV infection Clinical manifestations of early syphilis HIV+ patients with primary syphilis were more likely to have multiple ulcers; HIV+ patients with secondary syphilis were more likely to have co-occurring ulcers Clinical manifestations of syphilis ulcers HIV+ men more likely to have multiple ulcers, also deeper and larger ulcers; GUD more likely to be due to syphilis in HIV+ men HIV infection believed to have a small effect on clinical manifestations of primary and secondary syphilis; pre-HAART era data (19911994) Pre-HAART era data (19901992)
Rompalo [61]
Journal article
Rompalo [62]
Journal article
Sturm [63]
Abstract
Retrospective epidemiologic analysis
STD and antenatal clinic attendees; South Africa
Diagnosis of syphilis, with or without HIV infection
Inuence of HIV on quantitative syphilis serologic titers
4646 patients tested; no difference in RPR titers between patients who were HIV+ and those who were HIV patients; TPHA titers lower in HIV+ patients 14 patients evaluated (5 were HIV+ and 9 were HIV ); no differences in response to neurosyphilis treatment regimen Small sample size
No effect on reagin levels in patients who were HIV+
Browning [64]
Journal article
Retrospective case series
HIV+ and HIV patients with posterior segment ocular syphilis; United States iv penicillin G treatment for neurosyphilis Visual and laboratory correlates
Long [65]
Journal article
Prospective, population-based treatment trial
HIV+ and HIV persons with serologically conrmed syphilis; Peru Syphilis treatment with BPG or Dox 4-fold decrease in the RPR titer from the pretreatment level or seroreversion within 12 months of treatment
96 syphilis cases among 1261 Equivalent cure rates among HIV+ and HIV patients with persons screened; cure rates were 90.9% (10 of 11 syphilis, regardless of treatpatients) for HIV+ patients ment regimen and 93.8% (61 of 65 pa+ tients) for HIV patients (P p NS); persons with syphilis are more likely to have HIV infection than persons without syphilis (15.6% vs. 3.7%); cure rates somewhat lower if the initial RPR titer is 1:8 3 HIV+ patients developed neurosyphilis; neurosyphilis developed 17 months after initial treatment 41 patients evaluated; CD4 cell counts decreased and HIV RNA loads increased in patients with newly acquired syphilis; CD4 cell count and HIV RNA load returned to presyphilis levels or improved after treatment for syphilis Small sample size; neurosyphilis developed despite multiple doses of im BPG for early syphilis Immune function was adversely affected in HIV+ patients with syphilis; syphilis treatment restored baseline immune function
Walter [66]
Journal article
Case report
HIV+ persons with primary or secondary syphilis; France
Treatment with im BPG weekly Development of symptomatic for 2 or 3 weeks neurosyphilis
Kofoed [67] Diagnosis of syphilis (primary, secondary, and latent)
Journal article
Prospective case series
HIV+ persons receiving medical care; Denmark
S138
Retrospective case series HIV+ men; United States Acquisition of primary or secondary syphilis Guidelines Patients with syphilis and their sex partners; Europe Clinical management of infection and exposure to syphilis
Change in HIV RNA load and CD4 cell count before and after syphilis treatment
Buchacz [68]
Journal article
Impact on plasma HIV load and CD4 cell count before and after syphilis treatment
52 patients evaluated; syphilis associated with increased HIV loads (+0.22 RNA log10 copies/mL) and decreased CD4 cell counts ( 62 cells/ mL); syphilis treatment led to a decreased HIV load ( 0.10 RNA log10 copies/mL) and increased CD4 cell count (+33 cells/mL)
Syphilis associated with increased HIV loads and decreased CD4 cell counts; immune function improved after treatment
European/international treatment guidelines Cure or prevention of active infection Recommend LP for all HIV+ patients; additional CSF parameters: TPPA test, FTAABS test, IgG index, IgM index, and TPHA index; rstline and alternative f treatment Signicant variation with US guidelines
Goh [69]
Journal article
Clinical Effectiveness Group [70]
Technical report
Guidelines
Patients with early syphilis and their sex partners; United Kingdom
Clinical management of early syphilis infection and exposure
Cure or prevention of active infection
Procaine Pen preferred over BPG; Azm (500 each day for 10 days) okay for alternate treatment; Amox and Pro okay if parenteral treatment refused Procaine Pen daily for 17 days preferred over BPG; alternative treatment: Dox (200 b.i.d. for 28 days) or Amox and Pro; Dox okay for neurosyphilis Alternative treatment included procaine Pen; neurosyphilis treatment included Dox and Tet
Signicant variation with US guidelines
Clinical Effectiveness Group [71]
Technical report
Guidelines
Patients with late syphilis and their sex partners; United Kingdom
Clinical management of late syphilis infection
Cure of late syphilis infection
Signicant variation with US guidelines
WHO [72]
Technical report
Guidelines
Patients with syphilis and their sex partners
Clinical management of syphilis infection and exposure
Minor variation with US guidelines
Parkes [73]
Journal article
Review
Evidence in support of European and UK syphilis treatment guidelines
Clinical management of syphilis infection and exposure
Signicant variation with US First-line treatment in the guidelines (especially in UK United Kingdom is procaine practice) Pen (750 mg im each day for 10 days); in the United Kingdom, BPG (2 doses 1 week apart) may be given as alternate treatment; for neurosyphilis, treatment with Amox and Pro is okay in the United Kingdom; Dox is okay in Europe and the United Kingdom Use treponemal EIA as primary screening test, and conrm results with TPPA test or TPHA; RPR or VDRL test not recommended for g screening; FTA-ABS test not recommended as conrmatory test (low specicity); IgG immunoblot assay can be used for conrmation Recommendations suggest new approaches to screening and conrmation
Young [74]
Conference proceedings
Position paper
Serologic screening
Laboratory tests used for syphilis screening in Europe
Effective detection of syphilis infection
S139
Position paper Laboratory diagnosis of neurosyphilis Laboratory tests used to diagnose neurosyphilis in Europe Position paper Syphilis treatment Approaches to clinical management of syphilis in Europe
Schmidt [75]
Effective diagnosis of neurosyphilis
LL syphilis in HIV+ patients: suggest LP for those with a serum RPR titer 1:32 or a CD4 cell count !350 cells/ mL; CSF criteria for neurosyphilis are a positive CSF treponemal test result and 110 mononuclear cells plus one of the following: a CSF IgG index 0.70, a positive CSF VDRL test result, or a TPPA index Vienna 2000 170 Effective treatment of syphilis infection BPG: 1 dose sufciently effective for early syphilis, and 3 weekly doses sufciently effective for LL syphilis; recommend CSF examination h for HIV+ patients with LL; if Dox is used for LL, suggest higher doses and longer duration
TPPA index Vienna 2000 is CSF TPPA titer divided by albumin quotient (ratio of CSF to serum albumin level); TPPA index Vienna 2000 170 suggests that neurosyphilis highly probable; also, CSF TPPA titer 11:320 is indicative of neurosyphilis by itself
Parkes [76]
Review/summary/interpretation of recent, as well as historical, data
French [77]
Position paper
Serologic follow-up
Follow-up after treatment for syphilis in Europe
Effective follow-up of treated syphilis
Early syphilis: 15% of patients do not have a 4-fold titer i decrease in 6 months; for patients with late syphilis, if initial titer is 1:32, any titer decrease is an adequate response; if initial titer is !1: 32, absence of increase is okay
Lack of data re: appropriate serologic denition of treatment failure
Janier [78]
Position paper
Syphilis and HIV infection
Clinical and laboratory variation in HIV+ patients
Effective management of HIV+ patients with syphilis
Allows for more risky stratNo difference in the evolution egy of treating LL syphilis of nontreponemal test titers; with BPG (im for 3 days) (no standard treatment regimens LP) and following titers over are appropriate; for LL syphi+ time lis in HIV patients, wise to perform CSF examination, treat for neurosyphilis if positive, but convincing prospective data are lacking
NOTE. Amox, amoxicillin; Azm, azithromycin; b.i.d., twice daily; BPG, benzathine penicillin G; CDC, Centers for Disease Control and Prevention; CS, congenital syphilis; Ctri, ceftriaxone; Dox, doxycycline; DSMB, data safety monitoring board; Em, erythromycin; FDA, Food and Drug Administration; FTA, uorescent treponemal antibody; FTA-ABS, uorescent treponemal antibody absorption test; GI, gastrointestinal; GUD, genital ulcer disease; GUM, genitourinary medicine; HIV+, HIV positive; HIV , HIV negative; HR, hazard ratio; ICS, immunochromatographic strip; im, intramuscular; iv, intravenous; KAB, knowledge, attitudes, and behavior; LL, late latent; LP lumbar puncture; MHA-TP microhemagglutination assay for Treponema pallidum antibodies; MSM, men who have sex with men; NS, not signicant; Pen, penicillin; po, orally; q.i.d., four times daily; Pro, probenicid; , , RPR, rapid plasma reagin; rRNA, ribosomal RNA; RST, Rapid Syphilis Test; sens., sensitivity; SIFA, surface immunouorescence assay; spec., specicity; SPHA, solid-phase hemadsorption assay; STD, sexually transmitted disease; T. pallidum, Treponema pallidum; Tet, tetracycline; TPHA, T. pallidum hemagglutination assay; TPI, T. pallidum immobilization test; TPPA, T. pallidum particle agglutination; TRUST, toluidine red unheated serum test; VDRL, Venereal Disease Research Laboratory; WB, Western blot; WHO, World Health Organization.
A higher CSF WBC count at baseline correlated with more-rapid normalization; CSF protein levels were slow to normalize. Determine Syphilis TP (Abbott Laboratories), Syphilis Fast (Diesse, Diagnostica Senese), Espline TP (Fujirebio), Syphicheck-WB (Qualpro Diagnostics), SD Bioline Syphilis 3.0 (Standard Diagnostics), and Visitect Syphilis (Omega Diagnostics). c Determine (Abbott Laboratories), Syphicheck (Qualpro Diagnostics), Bioline (Standard Diagnostics), and Visitect (Omega Diagnostics). d Sens. less than that of the ICS test. e Conrmed by VDRL/MHA-TP tests. f First-line treatment included procaine Pen, benzyl Pen; alternative treatment included Em; and neurosyphilis treatment included Dox. g Use TPHA or TPPA test instead. h However, question the risk of symptomatic neurosyphilis developing, even if asymptomatic neurosyphilis is present. i Although clinical treatment failure is rare.
be extensive. A recent editorial by Holmes [79] acknowledged that there is a lack of prospective data on the effect of the inuence 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 810 days) as an alternative treatment for patients with an allergy to penicillin.
Use of Lumbar Puncture in the Evaluation of Patients for Neurosyphilis
Signicant 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 (dened as either a positive result of a Venereal Disease Research Laboratory [VDRL] test performed on a CSF specimen or a CSF WBC count 120 cells/mL), 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/mL. 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 HIVinfected 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 11 years 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 difcult 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 inammation, 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 170 and a CSF TPHA titer 11:320 were each 98.3% sensitive and 100% specic 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 ndings 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 eld trials of rapid treponemal tests, such as the immunochromatographic strip test, which can be used in resource-poor settings in developing countries [2437]. Other studies have looked at new reference laboratory standards for syphilis, such as Western blot (WB) analysis or EIA [3853], or the use of nucleic acid amplication, molecular strain typing, or other innovative technologies [54 60]. Although the rapid treponemal immunochromatographic strip tests appear to be promising for use in eld 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 conrmed using a more specic 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 conrmed 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 conrmed 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 ndings 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 ndings 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 conrm results. If the results of either of these follow-up tests are positive, and if previous treatment of syphilis cannot be veried, 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: Denition 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] dened treatment failure as a 4-fold increase in the RPR titer, a titer persistently 1:64, or clinical progression to disease, and they also dened 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 conrm 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 inuence outcomes of syphilis treatment in a population-based study of patients with serologically conrmed 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 [6978]. In general, all the guidelines are based on the same foundation documents and evidence base; however, signicant variations exist in certain areas, reecting differing interpretations of the same data. For example, BPG is considered to be rst-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 Signicant research advances in recent years have inuenced 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 efcacious 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, conrming the need to perform lumbar puncture for HIVinfected 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. Evolv-
ing 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
16.
17. 18. 19.
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 conicts of interest. B.P.S.: no conicts.
20.
21.
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SUPPLEMENT ARTICLE

Current Controversies in the Management of Adult Syphilis

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S130 CID 2007:44 (Suppl 3) Stoner

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Study population/location or test(s)/aspect evaluated

Design analysis quality/biases

Serologic response to treatment

Randomized clinical trial

STD clinic patients with early syphilis; United States

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Targeted mass treatment

At-risk groups; Canada

Single-dose Azm (1.8 g po)

Reported rates of infectious syphilis; a change in antimicrobial resistance

Targeted mass treatment

At-risk groups; Canada

Single-dose Azm (1.8 g po)

Participation in and support for intervention; characteristics of participants

Sex partners of persons with infectious syphilis; United States

Azm provided to syphilis contacts

Averted cases of infectious syphilis and decreased associated costs

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Lukehart [15, 16]

Retrospective chart review

Prospective multicenter case series

Patients with neurosyphilis; United States

Treatment of neurosyphilis with Pen or Ctri

Normalization of laboratory parameters after treatment

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Laboratory tests for syphilis

Comparison with reference laboratory RPR test/TPHA results

Agreement with reference laboratory results

Rapid tests in low-prevalence populations may improve case detection

Syphilis Fast test (Diesse, Diagnostica Senese)

Compared with RPR test and IgM-IgG EIA

Sens. and spec.

Compared with results obtained by laboratory RPR test/TPHA

Sens. and spec.

Sens. and spec.

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Sens., percentage of indeterminate test results

Clinical evaluation of a laboratory test

Comparison with standard offsite reference laboratory RPR test/TPHA

Agreement with RPR/VDRL screening test results

Agreement between test systems

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Agreement between test systems

Compared favorably with Captia Syphilis-G test

Concordance, sens., and spec.

Agreement, 95.1%; sens., 93.3%; and spec., 95.5%

Easy-to-use, automated test to conrm nontreponemal test results

Comparison with RPR test/ TPHA

Agreement with TPHA results

All 3 tests performed adequately

Van Voorhis [52]

EIA using 6 recombinant T. pallidum antigens

Sens. and spec.

Clinical evaluation of laboratory tests

Comparison with a maternal RPR titer 1:16

Detection and quantitation of T. pallidum

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May prove to be helpful in epidemiologic analyses