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During the last decade, bacterial sexually transmitted infections (STIs) have surged in the U.S. While incidence has escalated most rapidly among men who have sex with men (MSM), it has also been on the rise among women. Three clinical trials enrolling MSM have shown that postexposure prophylaxis with doxycycline (DoxyPEP; 200 mg within 72 hours of condomless intercourse) reduces risk for syphilis, chlamydia, and gonorrhea. In a U.S. study involving MSM and transgender women (TGW), this approach reduced risk for syphilis by 87%, chlamydia by 88%, and gonorrhea by 55%. Following consultation with experts in public health and infectious diseases, CDC has published guidelines on this approach.