Threshold effects of doxycycline postexposure prophylaxis (PEP) on the gut resistome and microbiome: Evidence from change-point analyses

Highlights
• ∼65-dose threshold was identified where ARG levels rose significantly.
• Microbiome breakpoints centered near ∼43 doses, with few genera showing stable shifts.
• Results offer actionable dose thresholds to inform doxy-PEP policy and surveillance.

Abstract

Background
Doxycycline postexposure prophylaxis (doxy-PEP) is recommended to prevent bacterial sexually transmitted infections in high-risk populations in some countries, but its potential to promote antimicrobial resistance (AMR) remains a concern. We aimed to determine the cumulative doxycycline intake threshold at which significant shifts occur in antimicrobial resistance genes (ARGs) and gut microbial community composition.

Methods
We analyzed data from the US doxy-PEP trial, a randomized clinical trial that enrolled men who have sex with men and transgender women who received either doxy-PEP (200 mg doxycycline after condomless sex) or standard of care. Change-point analysis was applied to 6-month cumulative doxycycline exposure to identify dosing thresholds associated with shifts in the gut resistome and microbiome.

Results
Segmented change-point analysis identified a resistome threshold of 64.68 (95% CI: [64.06, 65.3]) doxycycline doses over 6 months, above which significant increases in ARG abundance were observed. For the microbiome, segmented breakpoints were estimated for 133 genera: the median breakpoint was 43.22 doses (IQR 38.42-49.21). Using prespecified significance criteria, 4/133 (3%) genera exhibited significant abundance shifts, which included Acutalibacter, Anaerotignum, Petrimonas, and Sphingobacterium.

Conclusion
Doxy-PEP is associated with a dose-dependent enrichment of gut ARGs, with a threshold effect at ∼65 doses over 6 months and taxon-specific abundance shifts in the gut microbiome centered around 43 doses. These dose thresholds provide actionable data to optimize safe doxy-PEP implementation and highlight the need for monitoring strategies that mitigate AMR and microbiome disruption risks.