Antimicrobial Resistance and Clinical Safety of Doxycycline Post-Exposure Prophylaxis for Bacterial Sexually Transmitted Infections: A Systematic Review

Objectives: To evaluate antimicrobial resistance, microbiome/resistome changes and clinical safety during event-driven doxycycline post-exposure prophylaxis (doxy-PEP), distinguishing clinical outcomes from laboratory surrogates.Methods: PubMed, Europe PMC and ClinicalTrials.gov were searched on 11 October 2026. Primary human studies were eligible; companion publications were linked to study families. Outcome-specific appraisal used RoB 2, ROBINS-I or design-appropriate JBI tools, followed by GRADE. A single review workflow was used. Synthesis followed SWiM because analysis units, phenotypes, follow-up and exposure contrasts were incompatible with pooling. Results: After deduplication, 496 database records yielded 55 retained reports; three registry results brought the evidence map to 58 reports in 37 study families. Twenty-one reports from 11 families contributed target-outcome information. High-level gonococcal tetracycline-resistance signals arose in DOXYVAC and three observational settings, with very low certainty of causal effects. These culture-conditioned results do not estimate absolute resistant-infection incidence. One selected DoxyPEP substudy showed tetracycline-resistome enrichment. In IPERGAY, gastrointestinal adverse events occurred in 62/116 versus 47/116 participants (risk ratio 1.32, 95% CI 0.999–1.74; low certainty). King County reported greater resistant S. aureus and group A streptococcal carriage in exposed screening visits, with very low certainty. DOXYVAC documented one drug-related serious fixed drug eruption. Serious-event and laboratory data did not establish comparative safety equivalence. Conclusions: Doxy-PEP has documented intolerance and organism-specific resistance signals. The magnitude of any increase in absolute resistant-infection risk remains uncertain. Clinical interpretation and surveillance should preserve distinctions between patients, sampled organisms, molecular markers and exposure periods.