Effective Alternative Treatment Regimens for People with Infectious Syphilis: A Systematic Review and Network Meta-Analysis

Background: Given increasing rates of syphilis and shortages of the first-line agent benzathine penicillin, alternative treatment options are needed. This systematic review examined the existing evidence for alternative treatment regimens for infectious syphilis. Methods: We searched MEDLINE and EMBASE from January 15, 2021, to January 15, 2025, including eligible studies from two previously published systematic reviews. A systematic review with network meta-analysis (NMA) of randomized controlled trials (RCTs) and a meta-analysis (MA) of observational studies was conducted when appropriate. RCTs, cohort studies, case-control studies, and cross-sectional studies published in English that included adult and adolescent participants with infectious syphilis comparing two or more treatment regimens for syphilis were eligible. Risk of bias was assessed using the Cochrane RoB2 tool and Newcastle-Ottawa Scale, and a GRADE assessment was performed. Results: Fourteen RCTs and 20 observational studies were identified. All studies defined cure based on serologic plus/minus clinical response. Thirteen RCTs were eligible for the NMA, representing 1,623 participants and 10 treatments. Benzathine penicillin, followed by ceftriaxone, and then doxycycline was reported to be superior to benzathine penicillin alone. However, considering the low quality of the evidence and practicalities of this regimen, this should be interpreted with caution. All other comparisons did not show statistically significant differences in cure rates. However, the pooled point estimates were in favour of doxycycline compared to the standard of care in the NMA (OR of 6.88, lower CrI 0.14). The level of evidence was low for RCTs and very low for observational studies. Conclusions: Despite low-quality evidence, doxycycline is the best-supported alternative to benzathine penicillin for syphilis treatment.