Resistance is a growing concern amid rising use of doxyPEP

As doxycycline post-exposure prophylaxis (doxyPEP) for prevention of sexually transmitted infections (STIs) enters widespread use, questions remain about its implementation in the real world. At a symposium yesterday at the 13th International AIDS Society Conference on HIV Science (IAS 2025), experts discussed outstanding challenges, including increasing antibiotic resistance.

DoxyPEP involves taking a 200mg dose of the antibiotic doxycycline within 72 hours after sex. As reported in 2022, a study of men who have sex with men and transgender women in San Francisco and Seattle showed that doxyPEP significantly reduced the risk of chlamydia, syphilis and gonorrhoea. However, doxyPEP was less effective against gonorrhoea in French trials, likely because the background level of drug resistance is higher. A study of young cisgender women in Kenya found that doxyPEP was not effective, largely due to inconsistent use.

At the IAS conference, Professor Annie Luetkemeyer of the University of California San Francisco, who co-led the San Francisco and Seattle trial, offered practical advice for addressing clinical challenges in doxyPEP delivery. Professor Elizabeth Bukusi of the Kenya Medical Research Institute, a principal investigator for the dPEP Kenya trial, discussed implementing doxyPEP for cisgender women. Professor Jean-Michel Molina of Hôpital St Louis in Paris, who has led multiple STI and HIV prevention trials, discussed how to move forward with doxyPEP in the face of antimicrobial resistance – which moderator Dr Troy Grennan of the British Columbia Centre for Disease Control called “the elephant in the room.”

Since these trial results were reported, several cities and countries have issued doxyPEP guidelines, Luetkemeyer noted. San Francisco, which released the first guidance in 2022, gives a broad recommendation that goes beyond the populations included in clinical trials. These guidelines include people who have condomless sex with at least one partner but have not had an STI in the past year, because “we don’t want to wait until the horse is out of barn,” she said. “If you try to restrict doxyPEP only to certain populations at the very highest risk, you’re going to avert less STIs.”

More recent guidance from Australia is more cautious. The British Association for Sexual Health and HIV (BASHH) issued the first UK doxyPEP guidelines last month, emphasising syphilis prevention. Belgium and the Netherlands, among others, do not recommend doxyPEP for STI prevention, although many Dutch men in a recent survey reported informal use.

The main reason for caution is that widespread use of doxycycline for PEP – or daily use for pre-exposure prophylaxis (doxyPrEP) – could promote antibiotic resistance. This is primarily a concern for gonorrhoea, which is often already resistant to tetracyclines (the drug class that includes doxycycline) and most other drugs once used to treat it. What’s more, Neisseria gonorrhoeae can potentially transfer tetracycline resistance genes to other species of bacteria. Tetracycline resistance is not a concern for chlamydia or syphilis.

An early analysis from the San Francisco and Seattle trial did not show a marked increase in antimicrobial resistance associated with doxyPEP use. Presenting the results in 2023, Luetkemeyer called the findings “reassuring,” but said that larger and longer studies were needed.

As doxyPEP use has risen, these concerns about resistance have been confirmed. The week before the conference, a report in The New England Journal of Medicine showed that extensively drug-resistant gonorrhoea is spreading.

Dr David Helekal of the Harvard T.H. Chan School of Public Health and colleagues analysed more than 14,000 N. gonorrhoeae genome sequences from 2018 to 2024, generated through the US Centers for Disease Control and Prevention surveillance system.

They found that the proportion of isolates carrying tetM, a gene conferring high-level resistance to tetracyclines, rose from less than 10% in 2020 to over 30% in the first quarter of 2024. Furthermore, the number of N. gonorrhoeae lineages carrying the gene rose from one to four. Concerningly, two of these lineages also carried mutations that reduce sensitivity to ceftriaxone, one of the only remaining effective drugs.

The increase coincided with a shift away from azithromycin toward doxycycline for chlamydia treatment and also growing use of doxyPEP. “These results 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 researchers wrote.

The prevalence of drug resistance varied by region in the US, being highest in the northwest – which includes Seattle, an early adopter of doxyPEP. A previous report from the city found that high-level tetracycline resistance among gay men with gonorrhoea rose from 2% in early 2021 to 65% by the end of 2024. Specifically, taking more than three doses of doxyPEP per month was associated with having both overall and high-level resistance. In addition, tetracycline-resistant Staphylococcus aureus and group A Streptococcus were more common among doxyPEP users compared with non-users.

Gonorrhoea resistance rates are even higher in other parts of the world. A recent systematic review and meta-analysis published in JAC-Antimicrobial Resistance, which included studies done before the advent of doxyPEP, found that the prevalence of tetracycline-resistant N gonorrhoeae ranged from 27% in North America to about 50% in Europe to more than 80% in sub-Saharan Africa and east Asia.

Molina recalled that in the DoxyVAC trial, gonorrhoea isolates with high-level tetracycline resistance were threefold more common among doxyPEP users compared with non-users. All strains remained susceptible to ceftriaxone, though reduced sensitivity to cefixime (another cephalosporin antibiotic) increased among doxyPEP users.

“Clearly, doxyPEP is well tolerated. It’s highly accessible and very cheap. But there are still long-term uncertainties which need to be addressed in the future. We need to continue to monitor antimicrobial resistance,” he said. “I think we can do better, but it is time to implement doxyPEP in people at risk. We need to be cautious. It’s not for everyone. I think it would be wise to limit the number of doses of doxyPEP per week…one to two dose per week seems to be reasonable.”

Bukusi stressed that young women in Africa are at very high risk for STIs and their complications, including pelvic inflammatory disease and infertility, largely driven by chlamydia. Her team is winding up a study of whether doxyPEP works for cisgender women if taken consistently, which did not happen in the dPEP trial in part due to disruptions at the start of the COVID pandemic. They are exploring directly observed therapy – an approach widely used for tuberculosis treatment – at a clinic, another safe place or via telemedicine.

As for whether we can currently recommend doxyPEP as an STI prevention tool for cisgender women, “We don’t have answers yet, and these answers seem to be very difficult to come by. However, when we delay guidelines, there are real consequences for women,” she said. “It is not just about clinicians being able to have the power to make decisions, it is about talking to these young women and finding out what works for them.”

The experts agreed that while doxyPEP is an effective intervention for preventing chlamydia and syphilis, it will be challenging to use antimicrobial approaches for gonorrhoea due to drug resistance.

“With gonorrhoea, clearly, antibiotic prophylaxis is not the way to go, and we need to find other interventions,” Molina said. “A vaccine would be great, and there are a number of ongoing trials to look at vaccines for gonorrhoea. So far, we’ve seen very disappointing results, but let’s hope that in future, we get better results.”