Penicillin or Ceftriaxone for Neurosyphilis in People With HIV: A Retrospective, Propensity Score–Matched Multicenter Study in Mexico

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Background: Neurosyphilis, ocular syphilis, and otosyphilis occur more frequently among people with HIV-1 and are associated with higher morbidity and treatment failure. Intravenous penicillin G remains the standard therapy but requires hospitalization or prolonged intravenous access, creating barriers that are amplified in resource-limited settings facing recurrent penicillin shortages. Ceftriaxone is a potential alternative; however, comparative data in people with HIV are limited. Methods: We conducted a multicenter retrospective cohort study of adults with HIV at 5 public hospitals and 2 outpatient HIV clinics in Mexico (2015-2024). Participants had confirmed neurosyphilis, ocular syphilis, or otosyphilis. Participants received intravenous penicillin G (18-24 million IU/day) or ceftriaxone (1-2 g/day) for 10-14 days. The primary outcome was early serological response (ESR), defined as a ≥4-fold nontreponemal titer decline or seroreversion at 6 months. We performed 1:1 propensity score matching (39 pairs, n = 78), followed by logistic regression in the matched cohort. The results were consistent across all prespecified sensitivity analyses. Conclusions: In this multicenter cohort of people with HIV diagnosed with neurosyphilis, ocular syphilis, or otosyphilis, ceftriaxone showed comparable ESR to intravenous penicillin G. These findings support ceftriaxone as a reasonable alternative when standard therapy is limited by penicillin shortages, limited inpatient capacity, or financial constraints.