Indirect and direct effects of doxycycline post-exposure prophylaxis: an observational study in a US healthcare system

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ABSTRACT Importance Doxycycline post-exposure prophylaxis (doxyPEP) is recommended to prevent bacterial sexually-transmitted infections (bSTIs) among certain men who have sex with men and transgender women. Impacts on bSTI transmission are unknown. Objective To quantify the impact of doxyPEP implementation on bSTI risk, distinguishing indirect and direct protection. Design Longitudinal cohort study, January 2022 to June 2025, with a nested test-negative design study among individuals potentially eligible to receive doxyPEP. Setting Kaiser Permanente Southern California healthcare system. Participants Individuals aged 16-59 years, including: “at-risk males” assigned male sex at birth, who were living with HIV or who recently received HIV pre- or post-exposure prophylaxis; other males; and females. The nested test-negative design study included at-risk males who received bSTI testing after doxyPEP implementation. Exposures Oral doxyPEP prescription dispense, defined as a ≥30-dose supply of 200mg doxycycline absent accompanying bSTI diagnoses. Main outcomes and measures Incident laboratory-confirmed gonorrhea, chlamydia, and syphilis. We quantified indirect effects as incidence rate ratios comparing observed to expected incidence of each bSTI, absent doxyPEP implementation, among doxyPEP non-recipients. We quantified direct effects among recipients via the adjusted odds ratio of recent doxyPEP dispenses among individuals testing positive or negative for each bSTI. Results Analyses included 30,185 at-risk males, among whom 2,713 (9.0%) received ≥1 doxyPEP fill; 1,212,854 other males; and 1,321,363 females. Among all at-risk males, overall doxycycline consumption increased 2.31-fold (95% confidence interval: 1.99-2.64; absolute increase by 18,953 [16,052-21,048] defined daily doses per 1,000 person-years) after doxyPEP implementation, without accompanying changes in consumption among other males or females. Resulting indirect protection was associated with 41.4% (95% confidence interval: 33.0-48.8%) and 29.0% (13.4-41.8%) lower-than-expected incidence of chlamydia and syphilis, respectively, among at-risk males who did not receive doxyPEP. We observed no indirect effect against gonorrhea among at-risk males, and no indirect effect against any bSTI among other males or females. Among 22,937 at-risk males in the nested test-negative design study, direct protection from doxyPEP was associated with 66.8% (47.6-78.7%) and 50.1% (2.1-74.2%) further reductions in chlamydia and syphilis risk, respectively, and no reduction in gonorrhea risk. Among doxyPEP recipients, one case of chlamydia and one case of syphilis was prevented for every 2,785 (1,553-5,491) and 20,001 (5,725-182,569) doses dispensed, respectively. Conclusions and relevance DoxyPEP implementation conferred indirect as well as direct protection against chlamydia and syphilis among at-risk males. However, substantial volumes of antibiotic use were needed to realize this benefit. Tailoring doxyPEP guidance to circumstances associated with the greatest bSTI risk may be warranted to minimize unnecessary antibiotic use.

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