Threshold effects of doxycycline postexposure prophylaxis (PEP) on the gut resistome and microbiome: Evidence from...

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.

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.

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.

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.