Comparison of efficacy of treatments for early syphilis: A systematic review and network meta-analysis of randomized controlled trials and observational studies

PLoS One. 2017 Jun 28;12(6):e0180001. doi: 10.1371/journal.pone.0180001. eCollection 2017.


Background: Parenteral penicillin is the first-line regimen for treating syphilis, but unsuitable for some patients due to penicillin allergy and lacking health resources. Unfortunately, the efficacy of penicillin alternatives remains poorly understood. This study aimed to assess the efficacy of ceftriaxone and doxycycline/tetracycline in treating early syphilis relative to that of penicillin, and thereby to determine which antibiotic is a better replacement for penicillin.

Method: By searching literature from PubMed, Cochrane Central Register of Controlled Trials, Embase, the Web of Science, and and systematically screening relevant studies, eligible randomized controlled trials (RCTs) and observational studies on treatments with penicillin, doxycycline/tetracycline, and ceftriaxone for early syphilis were identified and combined in this systematic review. Estimated risk ratios (RRs) and 95% confidence intervals (CIs) were utilized to compare their serological response and treatment failure rates. At 12-month follow up, serological response rates were compared by a direct meta-analysis and network meta-analysis (NMA), while treatment failure rates were compared with a direct meta-analysis.

Result: Three RCTs and seven cohort studies were included in this research. The results of NMA demonstrated that no significant differences existed in serological response rate at 12-month follow-up between any two of the three treatments (doxycycline/tetracycline vs. penicillin RR = 1.01, 95%CI 0.89-1.14; ceftriaxone vs. penicillin RR = 1.00, 95%CI 0.89-1.13; ceftriaxone vs. doxycycline/tetracycline RR = 0.99, 95%CI 0.96-1.03), which was consistent with the outcomes of the direct meta-analysis. In addition, the direct meta-analysis indicated that, at 12-month follow-up, penicillin and ceftriaxone treatment groups had similar treatment failure rates (RR = 0.92, 95%CI 0.12-6.93), while treatment failure rate was significantly lower among penicillin recipients than among doxycycline/tetracycline recipients (RR = 0.58, 95%CI 0.38-0.89).

Conclusion: Ceftriaxone is as effective as penicillin in treating early syphilis with regard to serological response and treatment failure rate. Compared with doxycycline/tetracycline, ceftriaxone appears to be a better choice as the substitution of penicillin.

Publication types

  • Comparative Study
  • Meta-Analysis
  • Review
  • Systematic Review

MeSH terms

  • Anti-Bacterial Agents / therapeutic use*
  • Ceftriaxone / administration & dosage
  • Ceftriaxone / therapeutic use
  • Drug Therapy, Combination
  • Humans
  • Observational Studies as Topic
  • Penicillins / therapeutic use
  • Randomized Controlled Trials as Topic
  • Syphilis / drug therapy*
  • Tetracycline / administration & dosage
  • Tetracycline / therapeutic use
  • Treatment Outcome


  • Anti-Bacterial Agents
  • Penicillins
  • Ceftriaxone
  • Tetracycline

Grants and funding

This work was supported by Scientific and technological innovation projects of medicine and health of Chinese Academy of Medical Sciences (2016-I2M-3-021). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.