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One Dose versus Three Doses of Benzathine Penicillin G in Early Syphilis
2025
In this randomized, controlled trial, persons with early syphilis received a single treatment or three treatments with benzathine penicillin G at a dose of 2.4 million units. No benefit was seen with the additional doses.
Journal Article
Factors Associated with Serological Cure and the Serofast State of HIV-Negative Patients with Primary, Secondary, Latent, and Tertiary Syphilis
2013
Some syphilis patients remain in a serologically active state after the recommended therapy. We currently know too little about the characteristics of this serological response.
We conducted a cohort study using the clinical database from Zhongshan Hospital, Medical College of Xiamen. In total, 1,327 HIV-negative patients with primary, secondary, latent, and tertiary syphilis were enrolled. Bivariate and multivariate analyses were utilised to identify factors associated with a serological cure and serofast state in syphilis patients one year after therapy. Chi-square tests were used to determine the differences in the serological cure rate across different therapy time points.
One year after the recommended therapy, 870 patients achieved a serological cure, and 457 patients (34.4%) remained in the serofast state. The serological cure rate increased only within the first 6 months. The bivariate analysis indicated that male or younger patients had a higher likelihood of a serological cure than female or older patients. Having a baseline titre ≤ 1∶2 or ≥ 1∶64 was associated with an increased likelihood of a serological cure. The serological cure rate decreased for the different disease stages in the order of primary, secondary, latent, and tertiary syphilis. A distinction should be drawn between early and late syphilis. The multivariate analysis indicated that a serological cure was significantly associated with the disease phase, gender, age, and baseline rapid plasma reagin (RPR) titre.
The serofast state is common in clinical work. After one year of the recommended therapy, quite a few syphilis patients remained RPR positive. The primary endpoint of the study indicated that disease phase, gender, age and baseline RPR titre were crucial factors associated with a serological cure.
Journal Article
Secondary Syphilis
2020
A 62-year-old man presented with a rash on his hands, feet, trunk, and genitals. A rapid plasma reagin test was conducted, and a diagnosis of secondary syphilis was made.
Journal Article
Incidence and Risk Factors for the Prozone Phenomenon in Serologic Testing for Syphilis in a Large Cohort
2014
Background. The prozone phenomenon is known to be associated with high antibody titers; other associations, such as host factors, have not been elucidated. Methods. A retrospective analysis was conducted to evaluate the incidence of the prozone phenomenon of the syphilis rapid plasma reagin (RPR) test among 46 856 clinical samples, between June 2010 and June 2013. Logistic regression was used to analyze the risk factors of the prozone phenomenon. Results. Our results showed that the incidence of the prozone phenomenon was low (0.83%) and could occur during any clinical phase, particularly during primary and secondary syphilis. Pregnancy and neurosyphilis were associated with the prozone phenomenon; sex, age, and whether the patient had been treated were not. The results also revealed that the prozone phenomenon not only occurred in patients with a high titer but also could occur in patients with a moderate/low titer. In fact, almost 31% of the patients with the prozone phenomenon had titers ≤1:16. Conclusions. The prozone phenomenon in the RPR test was associated with the phase of syphilis, pregnancy, and neurosyphilis as well as a range of RPR titers between 1:8 and 1:512. This latter finding is in contrast to previous reports that the prozone phenomenon is associated with very high RPR titers.
Journal Article
Oral linezolid compared with benzathine penicillin G for treatment of early syphilis in adults (Trep-AB Study) in Spain: a prospective, open-label, non-inferiority, randomised controlled trial
2024
Management of syphilis, a sexually transmitted infection (STI) with increasing incidence, is challenged by drug shortages, scarcity of randomised trial data, an absence of non-penicillin alternatives for pregnant women with penicillin allergy (other than desensitisation), extended parenteral administration for neurosyphilis and congenital syphilis, and macrolide resistance. Linezolid was shown to be active against Treponema pallidum, the causative agent of syphilis, in vitro and in the rabbit model. We aimed to assess the efficacy of linezolid for treating early syphilis in adults compared with the standard of care benzathine penicillin G (BPG).
We did a multicentre, open-label, non-inferiority, randomised controlled trial to assess the efficacy of linezolid for treating early syphilis compared with BPG. We recruited participants with serological or molecular confirmation of syphilis (either primary, secondary, or early latent) at one STI unit in a public hospital and two STI community clinics in Catalonia (Spain). Participants were randomly allocated in a 1:1 ratio using a computer-generated block randomisation list with six participants per block, to receive either oral linezolid (600 mg once per day for 5 days) or intramuscular BPG (single dose of 2·4 million international units) and were assessed for signs and symptoms (once per week until week 6 and at week 12, week 24, and week 48) and reagin titres of non-treponemal antibodies (week 12, week 24, and week 48). The primary endpoint was treatment response, assessed using a composite endpoint that included clinical response, serological response, and absence of relapse. Clinical response was assessed at 2 weeks for primary syphilis and at 6 weeks for secondary syphilis following treatment initiation. Serological cure was defined as a four-fold decline in rapid plasma reagin titre or seroreversion at any of the 12-week, 24-week, or 48-week timepoints. The absence of relapse was defined as the presence of different molecular sequence types of T pallidum in recurrent syphilis. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference in rates of treatment response was higher than –10%. The primary analysis was done in the per-protocol population. The trial is registered at ClinicalTrials.gov (NCT05069974) and was stopped for futility after interim analysis.
Between Oct 20, 2021, and Sept 15, 2022, 62 patients were assessed for eligibility, and 59 were randomly assigned to linezolid (n=29) or BPG (n=30). In the per-protocol population, after 48 weeks' follow-up, 19 (70%) of 27 participants (95% CI 49·8 to 86·2) in the linezolid group had responded to treatment and 28 (100%) of 28 participants (87·7 to 100·0) in the BPG group (treatment difference –29·6, 95% CI –50·5 to –8·8), which did not meet the non-inferiority criterion. The number of drug-related adverse events (all mild or moderate) was similar in both treatment groups (five [17%] of 29, 95% CI 5·8 to 35·8 in the linezolid group vs five [17%] of 30, 5·6 to 34·7, in the BPG group). No serious adverse events were reported during follow-up.
The efficacy of linezolid at a daily dose of 600 mg for 5 days did not meet the non-inferiority criteria compared with BPG and, as a result, this treatment regimen should not be used to treat patients with early syphilis.
European Research Council and Fondo de Investigaciones Sanitarias.
Journal Article
Risk factors and diagnostic indicators for congenital syphilis: a Nationwide retrospective survey
2025
This nationwide retrospective study in Japan aimed to identify risk factors and diagnostic indicators for congenital syphilis (CS) and improve diagnostic accuracy. Data were collected from 230 pregnant women diagnosed with syphilis and their infants between 2015 and 2024. Of these, 49 infants were diagnosed with definite or highly probable CS, while 73 infants with excluded CS served as the control group. Multivariable logistic regression analysis revealed two significant risk factors for CS: maternal treatment not completed more than 4 weeks before delivery (odds ratio [OR]: 7.20; 95% confidence interval [CI]: 1.38–37.56; p = 0.02) and elevated total IgM levels in the infant (>20 mg/dL) (OR: 65.31; 95% CI: 4.53–941.39; p = 0.002). When using infant rapid plasma reagin (RPR) ≥1 as a diagnostic indicator, sensitivity was 93.8% (n = 48). In contrast, the infant-to-mother RPR ratio ≥1 showed a lower sensitivity of 34.3%, with fewer cases available for analysis (n = 35) due to limited maternal data. These findings indicate that delayed maternal treatment and high total IgM levels in the infant are significant risk factors, while the infant’s RPR titre serves as a useful diagnostic indicator for CS.
Journal Article
Evaluation of the BioPlex 2200 syphilis total screen (IgG/IgM) with reflex to an automated rapid plasma reagin test
by
Rourk, Angela R.
,
Litwin, Christine M.
in
Agglutination
,
Antibodies, Bacterial - blood
,
Antibodies, Bacterial - immunology
2019
Background We evaluated the recently FDA cleared BioPlex 2200 Syphilis Total Screen and automated rapid plasma reagin (RPR) assay for the detection of total (IgG/IgM) treponemal and non‐treponemal antibodies in the reverse syphilis algorithm. Methods Prospectively submitted samples (n = 885) were assayed by both the IgG/IgM BioPlex Syphilis Screen and the original IgG BioPlex Syphilis Screen. The IgG screen reactive samples were reflexed to traditional RPR, and IgG/IgM screen reactive samples were reflexed to the automated RPR. Nonreactive RPR samples were tested by the Treponemal Pallidum Particle Agglutination test (TP‐PA). Additional samples were collected (n = 404 total samples) to directly compare the automated and traditional RPR assays with each other. Results The sensitivity and specificity of the IgG/IgM screen with automated RPR was 95.6% (95% confidence interval [CI] 87.0‐99.1) and 99.6% (CI 99.2‐99.8) while the sensitivity and specificity of the BioPlex IgG screen with traditional RPR was 97.8% (CI 89.1‐99.9) and 99.3% (CI 98.8‐99.4). The sensitivity and specificity of the BioPlex RPR compared with traditional RPR was 95.8% (CI 93.9‐97.0) and 94.1% (CI 89.4‐91.1) and 95.3% (CI 92.6‐97.1). The mean of the titer differences between the BioPlex RPR and the traditional RPR was 1.0 ± 0.9 SD titers. Conclusion The addition of the detection of treponemal IgM antibodies to the IgG/IgM screen did not significantly affect the sensitivity and specificity compared to the original IgG screen. However, the addition of the comparable BioPlex RPR assay to the instrumentation significantly reduces the overall labor of syphilis screening and confirmation.
Journal Article
Rate of Decline in Nontreponemal Antibody Titers and Seroreversion After Treatment of Early Syphilis
by
Langley, Carol
,
Hook, Edward W.
,
Seña, Arlene C.
in
Adolescent
,
Adult
,
Anti-Bacterial Agents - therapeutic use
2017
BACKGROUNDSyphilis management is complex and demonstration of treatment response requires monitoring of nontreponemal antibody titers for a ≥ 4-fold decline and/or seroreversion to nonreactive titers.
METHODSWe evaluated data from a multicenter clinical trial of syphilis treatment conducted from 2000 to 2009 involving human immunodeficiency virus (HIV)–negative patients 18 years or older with early syphilis. To assess the rate of titer decline and seroreversion after effective therapy, rapid plasma reagin (RPR) titers were analyzed at 1, 3, 6, 9, and 12 months among patients with an appropriate treatment response. We plotted the rate of RPR titer decline after treatment, estimated the frequency of seroreversion, and conducted multivariate analyses to assess characteristics associated with seroreversion.
RESULTSAmong 369 (79.4%) of 465 HIV-negative patients with early syphilis who had an appropriate treatment response, 333 participants had complete RPR data over 12 months. Although the decline in RPR titers was ≥ 4-fold among 88.0% (293/333) of participants at 3 months and ≥ 8-fold among 77.8% at 6 months, only 9.6% achieved complete RPR seroreversion at 6 months and 17.1% at 12 months after therapy. Male sex (adjusted odds ratio, 4.3; 95% confidence interval, 1.8–10.5) and baseline RPR titers ≤ 1:32 (adjusted odds ratio, 14.5; 95% confidence interval, 6.8–31.2) were associated with higher odds of seroreversion compared with females and titers > 1:32, respectively.
CONCLUSIONSDespite a ≥ 4-fold RPR titer decline after treatment, the majority of HIV-negative patients with early syphilis failed to have seroreversion at 12 months. Nontreponemal antibody titers often persist despite an appropriate treatment response.
Journal Article
Modified TPPA combined with western blotting facilitates syphilis diagnosis in isolated reactive treponemal chemiluminescence immunoassay sera: a prospective cohort study
2025
Background
The challenge of dealing with isolated reactive treponemal chemiluminescence immunoassay (CIA) results in clinical practice has prompted the development of a more efficient algorithm for distinguishing true infection from false reactivity in isolated CIA sera.
Methods
A prospective cohort study was conducted at Wuhan Tongji Hospital, involving 119,002 individuals screened for syphilis using CIA from January 1, 2015, to January 6, 2017. Samples with reactive CIA results underwent simultaneous testing with the
T. pallidum
passive particle agglutination assay (TPPA) and the rapid plasma reagin test (RPR). Additionally, a subgroup of 189 individuals with differing TPPA statuses was selected for further analysis using Western blotting (WB) and a modified TPPA assay (titer, 1:20). To identify the optimal serological approach for distinguishing true from false reactivity in sera with isolated reactive CIAs (CIA
+
TPPA
−
RPR
−
), two distinct algorithms were developed and evaluated. The first algorithm involved reflexively testing CIA
+
TPPA
−
RPR
−
sera with the modified TPPA, followed by WB if nonreactive. The second algorithm began with WB, followed by the modified TPPA if nonreactive or indeterminate.
Results
WB demonstrated lower sensitivity compared to TPPA, but it identified six syphilis cases among the 89 CIA
+
TPPA
−
samples. Both WB and modified TPPA exhibited a specificity of 100%. The two supplementary confirmatory algorithms detected 12 additional syphilis cases, with the first algorithm being more cost-effective and labor-saving.
Conclusion
A combination of a modified TPPA (titer, 1:20) and WB can serve as a reliable algorithm for distinguishing true syphilis infection from false reactive signals in isolated reactive CIA sera.
Clinical trial number
Not applicable.
Journal Article
The Resurgence of Syphilis: A 20-Year Evaluation of Epidemiological Trends and Serological Test Performance Using Rapid Plasma Reagin and Indirect Hemagglutination Assays
2025
Background and Objectives: This retrospective single-center study aimed to evaluate the epidemiological, clinical, and laboratory characteristics of syphilis cases diagnosed at our hospital between 2005 and 2024, with a focus on the performance of serological tests used for diagnosis. The study also sought to characterize changing epidemiological trends of syphilis over this 20-year period. Materials and Methods: Data from 671 patients with confirmed syphilis diagnoses were retrospectively analyzed. Demographic information, transmission routes, co-infection status, and serological test results—including Rapid Plasma Reagin (RPR) and Indirect Hemagglutination Assay (IHA)—were evaluated. Statistical analyses were performed using chi-square and Fisher-based tests, with Bonferroni correction applied for multiple comparisons Results: Of the 671 cases, 74.6% were male and 25.4% female, with the highest incidence in the 22–41 age group. The number of diagnosed cases increased approximately 6-fold after 2016 compared to the preceding years. Unprotected sexual contact was the most common transmission route. HIV co-infection was present in 32.6% of cases, predominantly in males. Significant differences in RPR and IHA titers were observed across clinical stages of syphilis, with notably higher titers in late latent and neurosyphilis cases. Conclusions: The 6-fold increase in syphilis diagnoses since 2016, alongside a high rate of HIV co-infection, underscores the need for targeted prevention and screening programs for high-risk populations. Serological testing remains essential for diagnosis and disease monitoring.
Journal Article