Doxycyclineの曝露後予防（PEP）が腸内レジストームとマイクロバイオームに及ぼす閾値効果：変化点分析からのエビデンス

Doxycycline post-exposure prophylaxis (doxy-PEP) is recommended to prevent bacterial sexually transmitted infections (STIs) 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 analysed data from the US DoxyPEP trial, a randomized clinical trial that enrolled men who have sex with men (MSM) and transgender women who received either doxy-PEP (200 mg doxycycline after condomless sex) or standard of care (SOC). Change-point analysis was applied to six-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 six 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 six 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.