Doxycycline PEP Loses Effect Against Gonorrhea: Southern California Real-World Evidence

The US currently recommends doxycycline within 72 hours after sex (doxycycline PEP) for men who have sex with men and transgender women to prevent chlamydia, gonorrhea, and syphilis; this study examines how that recommendation performs in the real world. ; The study population comprised over 26,000 people in HIV care or on PrEP in Southern California, followed up to two years after rollout: chlamydia infections fell 66.5% and syphilis fell 60.7%. ; Gonorrhea was the exception: pre-rollout protection was about 40% (very small sample), dropped to 28% within months after rollout and was already 'too uncertain to draw conclusions'; by 2024 and early 2025 no clear protection was detectable. ; Modeling via two pathways—by time and by resistance—estimated that protection fell to zero 11–14 months after rollout, i.e., between March and June 2024; over the same period, the share of gonorrhea samples in regional surveillance carrying the TETM resistance gene rose from 22% to 59%, with the rate of increase accelerating more than 6-fold after rollout. ; The authors are explicit: this is correlation, not proof of causation—the resistance data come from regional surveillance, not participants' own infections, and the study cannot prove that PEP directly caused the rise in resistance. ; Concluding recommendation: doxycycline PEP should no longer be used for gonorrhea prevention; protection against chlamydia and syphilis persisted throughout the study period, and risk-benefit assessments should assume gonorrhea prevention benefits are limited or short-lived, while attending to the consequences of expanded antibiotic exposure in gonorrhea.

• The US currently recommends doxycycline within 72 hours after sex (doxycycline PEP) for men who have sex with men and transgender women to prevent chlamydia, gonorrhea, and syphilis; this study examines how that recommendation performs in the real world.
• The study population comprised over 26,000 people in HIV care or on PrEP in Southern California, followed up to two years after rollout: chlamydia infections fell 66.5% and syphilis fell 60.7%.
• Gonorrhea was the exception: pre-rollout protection was about 40% (very small sample), dropped to 28% within months after rollout and was already 'too uncertain to draw conclusions'; by 2024 and early 2025 no clear protection was detectable.
• Modeling via two pathways—by time and by resistance—estimated that protection fell to zero 11–14 months after rollout, i.e., between March and June 2024; over the same period, the share of gonorrhea samples in regional surveillance carrying the TETM resistance gene rose from 22% to 59%, with the rate of increase accelerating more than 6-fold after rollout.
• The authors are explicit: this is correlation, not proof of causation—the resistance data come from regional surveillance, not participants' own infections, and the study cannot prove that PEP directly caused the rise in resistance.
• Concluding recommendation: doxycycline PEP should no longer be used for gonorrhea prevention; protection against chlamydia and syphilis persisted throughout the study period, and risk-benefit assessments should assume gonorrhea prevention benefits are limited or short-lived, while attending to the consequences of expanded antibiotic exposure in gonorrhea.
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