Evaluating Single-Dose Versus Multi-Dose Benzathine Penicillin G for Syphilis Treatment
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Reviewed & Translated by Dat Tien Nguyen, B.A, ScM.
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Posted on September 22nd, 2025
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Although syphilis is a manageable infection, its incidence has been rising in recent years. Current guidelines in Western countries recommend treatment with long-acting penicillin, specifically benzathine penicillin G, yet there is no clear consensus on the optimal dosing regimen. In light of recent shortages of this medication, the U.S. National Institute of Allergy and Infectious Diseases sponsored a study to compare the effectiveness of one versus three doses of benzathine penicillin G for treating syphilis.
The clinical trial enrolled 249 participants with confirmed syphilis, diagnosed by reactive rapid plasma reagin and T. pallidum particle agglutination assays. Nineteen percent had primary syphilis, 47% had secondary infection, and 33% had early latent disease. HIV co-infection was present in 61% of participants, of whom 92% were receiving antiretroviral therapy. Participants were randomized to receive either a single intramuscular injection of 2.4 million units of benzathine penicillin G or three weekly doses of the same regimen.
At six-month follow-up, bacterial clearance was achieved in 76% of the single-dose group and 70% of the three-dose group, demonstrating that single-dose therapy was as effective as the multi-dose approach. This equivalence holds across different stages of syphilis and in patients with HIV co-infection. However, the study had limitations, including the predominance of male participants and the absence of pregnant women, which may restrict generalizability. The authors note that further research should also investigate alternative antibiotics, given the prevalence of penicillin allergy.
The clinical trial enrolled 249 participants with confirmed syphilis, diagnosed by reactive rapid plasma reagin and T. pallidum particle agglutination assays. Nineteen percent had primary syphilis, 47% had secondary infection, and 33% had early latent disease. HIV co-infection was present in 61% of participants, of whom 92% were receiving antiretroviral therapy. Participants were randomized to receive either a single intramuscular injection of 2.4 million units of benzathine penicillin G or three weekly doses of the same regimen.
At six-month follow-up, bacterial clearance was achieved in 76% of the single-dose group and 70% of the three-dose group, demonstrating that single-dose therapy was as effective as the multi-dose approach. This equivalence holds across different stages of syphilis and in patients with HIV co-infection. However, the study had limitations, including the predominance of male participants and the absence of pregnant women, which may restrict generalizability. The authors note that further research should also investigate alternative antibiotics, given the prevalence of penicillin allergy.