DOI: 10.1093/ofid/ofae142 ISSN: 2328-8957

Syphilis Treatment: Systematic Review and Meta-Analysis Investigating Non-Penicillin Therapeutic Strategies

Gustavo Yano Callado, Maria Celidonio Gutfreund, Isabele Pardo, Mariana Kim Hsieh, Vivian Lin, Mindy Marie Sampson, Guillermo Rodriguez Nava, Tássia Aporta Marins, Rodrigo Octávio Deliberato, Marinês Dalla Valle Martino, Marisa Holubar, Jorge L Salinas, Alexandre R Marra
  • Infectious Diseases
  • Oncology



Penicillin's long-standing role as the gold standard in syphilis treatment has led to global reliance. However, this dependence presents challenges, prompting the need for alternative strategies. We performed a systematic literature review and meta-analysis to evaluate the efficacy of these alternative treatments against non-neurological syphilis.


We searched MEDLINE, CINAHL, Embase, Cochrane, Scopus, and Web of Science from database inception to August 28th, 2023, and included studies that compared penicillin or amoxicillin monotherapy to other treatments for the management of non-neurological syphilis. Our primary outcome was serological cure rates. Random-effect models were used to obtain pooled mean differences, and heterogeneity was assessed using the I2 test.


Of 6,478 screened studies, 27 met the inclusion criteria, summing 6,710 patients. The studies were considerably homogeneous, and stratified analyses considering each alternative treatment separately revealed that penicillin monotherapy did not outperform ceftriaxone (pooled OR, 1.66; 95% CI, 0.97–2.84; I2 = 0%), azithromycin (pooled OR, 0.92; 95% CI, 0.73–1.18; I2 = 0%), or doxycycline (pooled OR, 0.82; 95% CI, 0.61–1.10; I2 = 1%) monotherapies regarding serological conversion.


Alternative treatment strategies have equivalent serological cure rates to penicillin, potentially reducing global dependence on this antibiotic.

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