While doxycycline postexposure prophylaxis (doxyPEP) can prevent bacterial sexually transmitted infections (STIs), concern surrounds the volume of antibiotic use needed to realize this benefit. We estimated incidence rates of gonorrhea, chlamydia, and syphilis diagnoses and related antibiotic prescribing among US males and transgender individuals using Merative MarketScan® Research Databases during 2017-2019. Follow-up encompassed 38,543 person-years among recipients of HIV pre-exposure prophylaxis (PrEP), 29,228 person-years among people living with HIV (PLWH), and 19,918 person-years among people with prior-year STI diagnoses. Incidence rates of STI diagnoses among PLWH and PrEP recipients with ≥1 prior-year STI diagnosis totaled 33.3-35.5 per 100 person-years. Direct effects of doxyPEP could prevent 7.4-9.6 gonorrhea diagnoses, 7.3-8.1 chlamydia diagnoses, and 3.1-5.9 syphilis diagnoses per 100 person-years of use. However, expected increases in tetracycline consumption resulting from doxyPEP implementation totaled 271.9-312.9 additional 7-day doxycycline treatment courses per 100 person-years of use. These increases corresponded to 37.0-38.7, 36.5-37.0, and 46.1-100.2 additional 7-day doxycycline treatment courses for each prevented gonorrhea, chlamydia, and syphilis diagnosis, respectively. Increases in doxycycline use exceeded anticipated reductions in STI-related prescribing of cephalosporins, macrolides, and penicillins by 16-69-fold margins. Anticipated changes in antibiotic use as well as STI incidence should inform priority-setting for doxyPEP.