N Engl J Med

Single-dose penicillin matches three-dose regimen for early syphilis

September 5, 2025

Study details: In a multicenter, randomized, phase 4 trial sponsored by NIH (NCT03637660), 249 adults with early syphilis (primary, secondary, or early latent) were assigned to receive either a single IM dose of benzathine penicillin G (BPG) 2.4 million units or three weekly doses of the same. Participants were predominantly male (97%), and 64% were living with HIV. The primary endpoint was serologic response at 6 months, defined as a ≥4-fold decline in RPR titer or seroreversion.

Results: At 6 months, serologic response rates were 76% (single dose) and 70% (three doses), with a difference of -6 percentage points (90% confidence interval [CI], -15 to 3), meeting noninferiority criteria. No clinical relapses or treatment failures occurred in either group. Serologic response rates were similar in HIV-infected and uninfected subgroups. Injection-site pain/tenderness was common in both arms.

Clinical impact: These findings support simplifying early syphilis treatment to a single-dose BPG regimen, which may improve adherence, reduce burden on patients and providers, and help conserve limited antibiotic supplies, especially critical amid rising syphilis rates and ongoing drug shortages.

Source:

Hook EW 3rd, et al. (2025, September 4). N Engl J Med. One Dose versus Three Doses of Benzathine Penicillin G in Early Syphilis. https://pubmed.ncbi.nlm.nih.gov/40902161/