Although post-exposure prophylaxis (PEP) with doxycycline was recommended by the CDC in 20241 to prevent chlamydia, gonorrhea, and syphilis in high-risk individuals,subsequent assessments2,3 have found it less effective for gonorrhea, and a new study4 associates the protocol with rapid development of tetracycline class antibiotic-resistant Neisseria gonorrhea.
"If our findings of transient doxycycline PEP effectiveness against gonorrhea resemble observations in other settings, guidelines indicating doxycycline PEP for prevention of gonorrhea might merit revision," suggest study lead author Matan Yechezkel, PhD, Division of Epidemiology, School of Public Health, University of California Berkeley, Berkeley, CA, and colleagues.
The investigators conducted a retrospective, test-negative observational study with an at risk cohort of more than 26,000 males living with HIV or receiving HIV pre-exposure prophylaxis.The participants had received care in a Southern California health-care system in the period of July 2021 through June 2025.
The primary analysis, using the test-negative design, was determining the protective effectiveness of doxycycline PEP, from the positive or negative tests for the bacterial STDs reported 90 days or less after receipt of the PEP.In addition, the investigators correlated PEP prescriptions with the proportion of the N gonorrhea isolates with the tetM plasmid-borne gene that confers tetracycline resistance.
"In the USA, the proportion of N gonorrhea isolates carrying tetM increased from less than 10% in 2020, to more than 30% by the first quarter of 2024, suggesting that doxycyline PEP implementation might have contributed to antimicrobial resistance selection in N gonorrhea," they indicated.
Throughout the study period, Yechezkel and colleagues reported, preventive effectiveness of doxycycline PEP against chlamydia was 66.5% (95% CI, 53.6 to 75.9) and 60.7% (28.3 to 78.5) against syphilis; while substantially less against gonorrhea (-1.8% [-18.5 to 12.5]).The effectiveness of the PEP protocol against chlamydia and syphilis was found to be sustained during a follow-up of more than 2 years.
They investigators noted that the effectiveness against gonorrhea had decreased from 42.3% (2.7 to 65.8) before the doxycycline PEP implementation to -15.0% (-51.1 to 11.4) between January and June, 2025.In relation to the presence of the tetM gene, the effectiveness of doxycyline PEP was 47.2% during periods when tetM was detected in 20 to 29.9% of N gonorrhea isolates, and decreased to -8.5% (-33.2 to 11.2) during a period when tetM occurred in 50% or more of isolates.
What You Need to Know
The study found protective effectiveness of 66.5% against chlamydia and 60.7% against syphilis, while effectiveness against gonorrhea was not sustained and declined over time.
Investigators observed a sharp increase in Neisseria gonorrhoeae isolates carrying the tetM plasmid-borne tetracycline resistance gene, from less than 10% in 2020 to more than 30% by early 2024.
Gonorrhea prevention effectiveness fell from 42.3% before doxycycline PEP implementation to -15.0% by June 2025, with effectiveness dropping further in periods when tetM was detected in a greater proportion of gonorrhea isolates, suggesting resistance may be eroding the benefit of the intervention.
"These reductions in effectiveness aligned closely with accelerated increases in prevalence of the tetM gene in circulating N gonorrhea after doxycyline PEP implementation," Yechezkel and colleagues emphasized.
The investigators cite models that estimate that a 10% adoption of doxycyline PEP in an indicated population within a locality would result in a loss of doxycyline effectiveness against gonorrhea within 12.1 years; and within 1.6 years with 90% adoption.
In the current study, the PEP protocol was received by 8.4% of the cohort. Despite this modest uptake, they estimated that doxycyline PEP effectiveness against gonorrhea reached 0% between March and June, 2024.Although the retrospective study does not establish causality, they associate that reduction to the rapid response of N gonorrhea to doxycyline PEP-associated selective pressure.
"Rapid emergence of resistant lineages might inform risk-benefit considerations for doxycyline PEP implementation and underscores the need for ongoing antimicrobial resistance surveillance to guide these strategies," Yechezkel and colleagues advise.
References
1. Bachmann LH, Barbee LA, Chan P, et al. CDC clinical guidelines on the use of doxycycline postexposure prophylaxis for bacterial sexually transmitted infection prevention, United States, 2024. MMWR Recomm Rep. 2024; 73:1-8.
2. Traeger MW, Leyden WA, Volk JE, et al. Doxycycline postexposure prophylaxis and bacterial sexually transmitted infections among individuals using HIV preexposure prophylaxis. JAMA Intern Med. 2025; 185:273-281.
3. Scott HM, Roman J, Spinelli M, et al. Sexually transmitted infections after implementation of doxycycline postexposure prophylaxis. Sex Transm Infect. 2025; published online Dec 3, 2025. https://doi.org/10.1136/sextrans-2025-056674.
4. Yechezkel M, Helekal D, Kapadia B, et al. Durability of doxycycline effectiveness against gonorrhoea after implementation of post-exposure prophylaxis in southern California, USA: a retrospective, test-negative, observational study. Lancet Infect Dis. 2026, published online May 7, 2026. https://doi.org/10.1016/S1473-3099(26)00123-4.
