A multicenter randomized non-inferiority trial enrolling 249 adults with early syphilis found that a single intramuscular injection of benzathine penicillin G (BPG) 2.4 million units was non-inferior to three weekly injections. Serologic response by six months was 76% with one dose versus 70% with three doses — a difference well within the pre-specified 10% non-inferiority margin. Crucially, the finding held regardless of HIV status: 76% of people living with HIV responded to one dose, comparable to the 71% who received three doses. No clinical treatment failures or relapses occurred in either group. These results directly challenge longstanding clinical practice of giving multiple BPG doses to HIV-positive patients and have major implications for antimicrobial stewardship and managing ongoing global BPG shortages.
