Sexually transmitted infections (STIs) represent a significant public health challenge, with increasing prevalence worldwide. Disproportionately affecting young individuals, gay and bisexual men who have sex with men (gbMSM), persons with HIV or on HIV prevention medications, and racial and ethnic minorities, effective prevention strategies are essential. Doxycycline post-exposure prophylaxis (Doxy-PEP) has been shown to reduce bacterial STIs; however, knowledge gaps remain, and there are concerns about engagement, effective use, and the potential antimicrobial resistance consequences. This study proposes a threefold approach to address these questions. (1) Establish a prospective cohort of 300 Doxy-PEP users (Doxy-PEP cohort) to examine baseline and longitudinal factors mapped to the information-motivation-behavioral skills theoretical framework and identify factors associated with Doxy-PEP care engagement and effective use. (2) Collect biological samples from the Doxy-PEP cohort and enroll 100 Doxy-PEP eligible non-users (Control cohort) to evaluate the impact of antimicrobial resistance in persons taking Doxy-PEP using laboratory methods including culture and resistance testing and metagenomics. (3) Collect biological samples from up to 600 sexual partners of the Doxy-PEP and control-cohorts to assess the potential for transmission of bacteria between sexual partners using comparative genomics. By addressing these aims, the study will provide valuable insights into the risks, benefits, implementation, and impact of Doxy-PEP, informing future strategies to optimize engagement and maximize STI incidence reduction while minimizing antimicrobial resistance risks.

Narrative: This study aims to examine the engagement, effective use, the potential for antimicrobial resistance, and potential transmission of bacteria among Doxy-PEP users. A prospective cohort of Doxy-PEP users will be enrolled to investigate factors, mapped to the information-motivation-behavioral skills theoretical model, to evaluate their impact on Doxy-PEP engagement and effective use. Biological samples from Doxy- PEP users, eligible non-users (a control cohort), and their sexual partners will be collected to assess trends in antimicrobial resistance of specific pathogens, the impact on the presence or absence of resistance genes, and the potential for transmission of pathogenic bacteria between sexual partners.