Doxycycline PEP showed rapid loss of effectiveness against gonorrhoea within the first year after implementation in southern California, associated with expansion of high-level tetracycline resistance in N gonorrhoeae, while sustained effectiveness against chlamydia and syphilis was maintained more than 2 years after implementation.
Overall doxycycline PEP effectiveness against chlamydia was 66.5% throughout the study period.
Overall doxycycline PEP effectiveness against gonorrhoea was negligible at -1.8% throughout the study period.
Overall doxycycline PEP effectiveness against syphilis was 60.7% throughout the study period.
Doxycycline PEP effectiveness against gonorrhoea decreased significantly over time, from 42.3% before statewide implementation to -15.0% by January–June 2025.
Doxycycline PEP effectiveness against gonorrhoea declined in association with increasing prevalence of tetM, a plasmid-borne gene conferring high-level tetracycline resistance, in circulating N. gonorrhoeae lineages.
The study cohort comprised 33,118 eligible individuals, of whom 26,582 had one or more sexually transmitted infection tests and were included in primary analyses.
Risk-benefit considerations for doxycycline PEP implementation strategies should assume limited or transient benefits associated with gonorrhoea prevention and address potential consequences of AMR expansion in N. gonorrhoeae.
This research examined whether doxycycline taken after sexual exposure (called doxycycline PEP, or post-exposure prophylaxis) continued to protect against sexually transmitted infections (STIs) over time, particularly as the bacteria causing gonorrhoea evolved resistance to the drug. The study followed over 26,000 gay and bisexual men and transgender women in southern California who were either living with HIV or taking HIV prevention medication, tracking STI tests from 2023 to mid-2025. The researchers found that doxycycline PEP remained effective at preventing chlamydia (about 67% protective) and syphilis (about 61% protective) throughout the entire study period of more than two years. However, protection against gonorrhoea rapidly collapsed — dropping from roughly 42% before widespread doxycycline PEP use became common to essentially zero (and possibly slightly negative) by early 2025. The loss of protection against gonorrhoea was closely linked to the spread of a resistance gene called tetM in local gonorrhoea bacteria. When tetM was present in fewer than 30% of gonorrhoea samples, doxycycline PEP still offered meaningful protection (about 47%). But when tetM was found in 50% or more of samples, protection disappeared entirely. This suggests that widespread use of doxycycline as prevention created selective pressure that rapidly drove the spread of resistant gonorrhoea strains through the population within roughly one year of broad implementation. This research suggests that public health recommendations about doxycycline PEP should account for the likelihood that gonorrhoea protection will be short-lived as resistant strains spread. While the drug continues to offer real benefits against chlamydia and syphilis, policymakers and clinicians should monitor local gonorrhoea resistance patterns and factor in the potential for accelerating antibiotic resistance when weighing the risks and benefits of doxycycline PEP programs. The findings highlight the need for ongoing surveillance of antimicrobial resistance as a critical component of any STI prevention strategy involving antibiotics.
M. Yechezkel, D. Helekal, Banshri Kapadia, V. Hong, M. Pomichowski, Iris A. Reyes, et al.. (2026). Durability of doxycycline effectiveness against gonorrhoea after implementation of post-exposure prophylaxis in southern California, USA: a retrospective, test-negative, observational study.. Lancet. Infectious Diseases (Print). https://doi.org/10.1016/s1473-3099(26)00123-4