More evidence has emerged that a CDC-endorsed STI prevention strategy that involves taking the antibiotic doxycycline after having unprotected sex may be contributing to antibiotic resistance in the United States.
The CDC last year recommended that clinicians consider prescribing doxycycline post-exposure prophylaxis — commonly called doxy-PEP — for transgender women and men who have sex with men if they have had a bacterial STI within the past year. The agency instructs providers to prescribe 200 mg of doxycycline that patients can take as soon as possible within 72 hours after sex.
The guidance was based on promising study findings that showed doxy-PEP can significantly reduce the risk for chlamydia and syphilis, and conflicting evidence that it may also have an impact on gonorrhea, which has more of a knack for developing resistance to antibiotics than the other two STIs.
Because of gonorrhea’s existing high level of resistance to tetracyclines, a class of broad-spectrum antibiotics that includes doxycycline, doxy-PEP studies were limited in their ability to assess the intervention’s impact on resistance. But two studies have now provided some evidence of a negative effect.
In the first, researchers in Seattle — where part of one major doxy-PEP study was conducted — saw a rapid increase in tetracycline resistance among gonococcal isolates collected in King County, Washington, from 2021 to 2024, with most isolates from MSM showing high levels of resistance, according to results reported earlier this year in Clinical Infectious Diseases.
And this week, researchers from the Harvard T.H. Chan School of Public Health and University of Georgia College of Veterinary Medicine reported a similar trend after assessing more than 14,000 gonorrhea genetic samples kept by the CDC. They found that the percentage of isolates carrying a gene called tetM, which confers a high level of resistance to tetracycline antibiotics, increased from less than 10% in 2020 to more than 30% in the first quarter of 2024.
Writing in The New England Journal of Medicine, the researchers ascribed the increase in resistance starting in 2020 to updated CDC guidance recommending doxycycline over azithromycin for chlamydia. Another increase starting in mid-2022 coincided with the announcement of results from a major doxy-PEP study at the International AIDS Conference, they said. That fall, San Francisco became the first city in the U.S. to recommend doxy-PEP, beating the CDC’s recommendation by almost 2 years. Seattle followed, publishing doxy-PEP guidelines the following June.
The researchers noted a third reason for an increase in doxycycline use in recent years: the shortage of benzathine penicillin to treat syphilis.
The results of the new research “suggest that widespread use of doxycycline for the treatment and prevention of sexually transmitted infections may be contributing to reshaping of the gonococcal population in the United States,” the authors wrote.
They noted in their paper that lineages carrying a gene that increases resistance to ceftriaxone, the last remaining antibiotic recommended by the CDC to treat gonorrhea, are also spreading globally.
The findings were published at an uncertain time for STIs. Last November, the CDC’s annual STI report showed an overall decline in cases of chlamydia, gonorrhea and syphilis for the second year in a row after years of steady increases, although cases still numbered in the millions and some experts wondered if the decrease was real or a mirage. And earlier this year, the Trump administration abruptly closed the CDC’s lynchpin STI laboratory — home to the country’s gonorrhea surveillance program — before reopening it in June, a game of public health ping-pong that has unsettled experts.
By Gerard Gallagher
References:
- CDC. Doxy PEP for bacterial STI prevention. https://www.cdc.gov/sti/hcp/doxy-pep/index.html. Updated Dec. 5, 2024. Accessed July 10, 2025.
- Helekal D, et al. N Engl J Med. 2025;doi:10.1056/NEJMc2504010.
- Public Health – Seattle & King County. https://cdn.kingcounty.gov/-/media/king-county/depts/dph/documents/health-safety/disease-illness/hiv-sti/doxypep-guidelines.pdf. Published January 2025. Accessed July 10, 2025.
- San Francisco Department of Public Health. Doxycycline post-exposure prophylaxis reduces incidence of sexually transmitted infections. https://www.sf.gov/sites/default/files/2024-04/Health-Update-Doxycycline-Post-Exposure-Prophylaxis-Reduces-Incidence-of-Sexually-Transmitted-Infections-SFDPH-FINAL-10.20.2022.cleaned.pdf. Published Oct. 20, 2022. Accessed July 10, 2025.
- Soge OO, et al. Clin Infect Dis. 2025;doi:10.1093/cid/ciaf089.
Perspective
Doxycycline use for the treatment and prevention of STIs has risen substantially in recent years. This increase has been driven by shifts in clinical guidelines, including the 2020 change recommending doxycycline as first-line chlamydia treatment, and by the rapid uptake of doxy-PEP in many parts of the United States, fueled by patient demand for effective, evidence-based STI prevention tools.
A recent report in The New England Journal of Medicine highlights a striking increase in tetracycline-resistant Neisseria gonorrhea in the U.S. between 2018 and 2024, underscoring the potential impact of expanded doxycycline use on antibiotic resistance in gonorrhea. Even more dramatic increases have been reported by a sexual health clinic in Seattle, where resistance was highest among patients who had taken more than three doses of doxy-PEP in the prior month.
Our experience at Kaiser Permanente Northern California mirrors these national trends in gonorrhea resistance. In our study of over 2,200 adults who were prescribed both HIV PrEP and doxy-PEP, we observed an 80% decline in chlamydia and syphilis rates following doxy-PEP initiation. In contrast, reductions in gonorrhea were more modest, with only a 12% decrease overall and no decline in pharyngeal gonorrhea. Our findings reflected a smaller reduction in gonorrhea incidence than observed in earlier randomized trials.
Although doxycycline is no longer used to treat gonorrhea, rising tetracycline resistance may serve as a sentinel for broader resistance. The emergence of ceftriaxone resistance, in particular, could lead to increased treatment failures. Nevertheless, these concerns must be weighed against the substantial benefits of doxy-PEP, including a dramatic reduction in rates of syphilis and chlamydia. Given the rising rates of congenital syphilis and the serious complications associated with this infection, doxy-PEP remains a vital STI prevention tool.
Ultimately, the increasing gonorrhea resistance highlights the need for continued investment in alternative prevention and treatment strategies, including novel antibiotics and vaccine development.
References:
Helekal D, et al. N Engl J Med. 2025;doi:10.1056/NEJMc2504010.
Soge OO, et al. Clin Infect Dis. 2025;doi:10.1093/cid/ciaf089.
Traeger MW, et al. JAMA Intern Med. 2025;doi:10.1001/jamainternmed.2024.7186.
Jonathan E Volk, MD, MPH
Infectious Diseases Specialist
Kaiser Permanente Northern California
Disclosures: Volk reports no relevant financial disclosures.
Source : Healio
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