Rapid loss of doxycycline effectiveness against gonorrhea after implementation of post-exposure prophylaxis in southern California: an observational study

ABSTRACT Background Post-exposure prophylaxis with doxycycline (doxyPEP) within 72 hours after sex is recommended to prevent chlamydia, gonorrhea, and syphilis among United States men who have sex with men (MSM) and transgender women (TGW). However, concerns surround potential expansion of Neisseria gonorrhoeae lineages harboring antimicrobial resistance (AMR) in settings that implement doxyPEP. Methods We assessed the effectiveness of doxyPEP against chlamydia, gonorrhea, and syphilis among individuals receiving care from the Kaiser Permanente Southern California integrated healthcare system between 1 January, 2023 and 30 June, 2025. Primary analyses estimated treatment effectiveness by comparing history of doxyPEP prescription fills ≤90 days before positive or negative tests for infection with Chlamydia trachomatis, N. gonorrhoeae , and Treponema pallidum . We evaluated changes in treatment effectiveness against gonorrhea over time and in association with the proportion of local N. gonorrhoeae isolates harboring tetM , a plasmid-borne gene conferring high-level tetracycline resistance. Results Among 26,582 individuals meeting eligibility criteria, 2,262 (8·5%) received ≥1 doxyPEP fill during the study period. DoxyPEP fills occurred ≤90 days before 39 of 4,659 (0·8%) positive and 3,288 of 130,138 (2·5%) negative C. trachomatis tests; 212 of 6,539 (3·2%) positive and 3,112 of 128,238 (2·4%) negative N. gonorrhoeae tests; and 11 of 2,169 (0·5%) positive and 794 of 26,913 (3·0%) negative T. pallidum tests. Throughout the study period, treatment effectiveness of doxyPEP against chlamydia, gonorrhea, and syphilis was 66·5% (53·6–75·9%), –1·8% (–18·5 to 12·5%), and 60·7% (28·3–78·5%), respectively. Treatment effectiveness against gonorrhea declined from 42·3% (2·7–65·8%) before statewide doxyPEP implementation to –15·0% (–51·1 to 11·4%) from January–June, 2025, in association with rapid expansion of tetM prevalence among circulating N. gonorrhoeae lineages. Treatment effectiveness during periods with tetM detected among 20-29·9% of N. gonorrhoeae isolates was 47·2% (4·1–70·3%), declining to −8·5% (−33·2 to 11·2%) during periods with tetM detected among ≥50% of isolates. Conclusions We report rapid loss of doxyPEP effectiveness against gonorrhea within the first year after doxyPEP implementation among MSM and TGW in southern California, associated with expansion of high-level tetracycline resistance in N. gonorrhoeae . This outcome, alongside persisting effectiveness against chlamydia and syphilis, may inform risk-benefit considerations for doxyPEP implementation strategies. Funding US Centers for Disease Control and Prevention