Meta-Analysis of Effectiveness of Oral Antibiotics Versus Benzathine Penicillin G for Syphilis

Benzathine penicillin G (BPG) remains the standard treatment for syphilis, but oral alternatives are increasingly used when penicillin is unavailable or unsuitable. This study compared the effectiveness of oral antibiotics with intramuscular BPG in patients with confirmed syphilis. A systematic review and meta-analysis of randomized controlled trials and observational studies was conducted. Searches were performed in PubMed, ScienceDirect, Cochrane Library, and ProQuest through May 2025 according to PRISMA and MOOSE. Eligible studies compared oral antibiotic monotherapy, including doxycycline, azithromycin, or tetracycline, with BPG. One otherwise eligible study evaluating ceftriaxone, a parenteral non-penicillin regimen, was retained for secondary contextual comparison and excluded from the primary analysis. Outcomes included serological response, defined as a ≥4-fold decline in nontreponemal titers, clinical response at 3 and 6 months, and relapse. Risk of bias was assessed using RoB 2 and Newcastle-Ottawa Scale. Sixteen studies involving 2,231 patients were included. Pooled analysis showed no significant difference between oral antibiotics and BPG for serological response (RR 0.90, 95% CI 0.78 to 1.04), 3-month response (RR 0.94, 95% CI 0.82 to 1.08), or 6-month response (RR 1.00, 95% CI 0.82 to 1.23). Azithromycin showed a relapse rate comparable to BPG, whereas separately reviewed ceftriaxone study reported a higher relapse risk (RR 2.66, 95% CI 1.68 to 4.21). Oral antibiotics, particularly doxycycline and azithromycin, may be reasonable alternatives for early syphilis when BPG is unavailable or unsuitable. These findings should be interpreted cautiously because heterogeneity, possible publication bias, and variation in study design, population, and treatment regimen were present.