A Review of Doxycycline Post-Exposure Prophylaxis and Its Implications for Antimicrobial Resistance and the Human...

Sexually transmitted infections (STIs) remain a major global health burden, with rising incidence of Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum. Doxycycline post-exposure prophylaxis (DoxyPEP), consisting of a single 200 mg dose within 72 h after condomless sex, has emerged as a promising intervention. Randomized controlled trials demonstrate consistent efficacy in reducing chlamydia and syphilis, while protection against gonorrhea is variable, being strongly influenced by baseline tetracycline resistance and anatomical site. Surveillance data from San Francisco and King County confirm that high-frequency use can drive rapid increases in gonococcal tetracycline resistance. Although no cephalosporin resistance has yet been linked to DoxyPEP, genomic correlations raise concern for co-selection of multidrug-resistant strains, particularly FC428-like clones with mosaic penA alleles. C. trachomatis remains uniformly susceptible, with resistance limited to theoretical horizontal transfer from C. suis. T. pallidum shows no evidence of resistance, supported by genomic constraints and experimental studies. Mycoplasma genitalium demonstrates low intrinsic susceptibility to doxycycline, but no acquired tetracycline resistance has been confirmed. Beyond target pathogens, DoxyPEP alters the functional resistome of the human microbiome, amplifying tetracycline resistance gene expression in gut, skin, and oropharyngeal flora, and selecting for resistant Staphylococcus aureus and commensal Neisseria. These ecological shifts underscore the importance of molecular surveillance to monitor resistance spillover. Overall, DoxyPEP provides substantial benefit in controlling chlamydia and syphilis and conditional utility against gonorrhea in low-resistance settings. Its deployment should be coupled with antimicrobial stewardship, local resistance data, and strengthened genomic surveillance to balance individual protection with population-level risks.