Ask AI
Back Back
DoxyPEP
DoxyPEP: Grappling with a Double-Edged Sword

Released: November 25, 2025

Darrell H. S. Tan
Darrell H. S. Tan, MD, FRCPC, PhD
Activity Information

Activity

Progress
1
Course Completed
Continue
Key Takeaways
  • Data in early stages of investigation suggest that doxycycline concentrations following a single dose of DoxyPEP may be sufficient to protect from infections for several days afterwards, although further investigation is needed to assess protective efficacy.

Canada will soon release clinical guidelines on doxycycline postexposure prophylaxis (PEP) for the prevention of bacterial sexually transmitted infections (STIs), and several abstracts at European AIDS Clinical Society (EACS) 2025 presented findings relevant to this topic.

DoxyPEP Efficacy for Prevention of STIs
First, the open-label extension of the DoxyVac trial confirmed the highly efficacious nature of DoxyPEP among men who have sex with men. For the group from the standard of care arm of the original randomized trial (ie, no intervention) who switched to DoxyPEP, the incidence of first episodes of chlamydia, syphilis, and gonorrhea declined by 75%, 76%, and 55%, respectively. However, among the group with exposure to DoxyPEP, doxycycline resistance in N. gonorrhoeae was also higher, with tetM detection in 54.5% of positive NAAT samples, compared to in 27.9% among those without DoxyPEP exposure.

Overall, these data bolster my confidence in prescribing DoxyPEP both to my patients living with HIV and those on HIV pre-exposure prophylaxis who are at risk of bacterial STIs, but they also highlight the fundamental trade-off with DoxyPEP: Protection from STIs at the cost of its contribution to antimicrobial resistance. 

DoxyPEP for Reduction of Syphilis Infections
Bacterial STI rates continue to rise in Canada. Syphilis rates are particularly concerning: between 2018 and 2023 infectious syphilis nearly doubled, from 6371 to 12135 cases per year. So I think we should welcome any intervention that can meaningfully decrease this burden.

However, even this comes with caveats. We still lack data from randomized trials demonstrating that DoxyPEP works in cisgender women, the population in whom some of our highest syphilis rates persist, and in whom prevention is critical to avoid devastating congenital syphilis infections, which were diagnosed in a staggering 53 infants in 2023—more than 3 times more than in 2018. 

Contribution to Antimicrobial Resistance
Clearly, the downside of DoxyPEP is its contribution to antimicrobial resistance, but it is less clear how healthcare professionals should weigh the importance of this microbiologic outcome in comparison to the clinical benefits of STI prevention.

Regardless, strategies are needed to minimize antimicrobial resistance burden among DoxyPEP users. A strategy I sometimes use is to advise patients who anticipate sex more than once in a period of 2-3 days that they could potentially wait to take DoxyPEP until after the additional exposures occur, (as long as the dose is taken within 72 hours after the earliest episode, since this is the maximum timeframe that was studied in the key clinical trials).

DoxyPEP as STI PrEP
Although still in early stages of investigation, additional data at EACS suggest that we could exploit the pharmacokinetic/pharmacodynamic principles of this drug to further minimize antibiotic exposure.

A prospective study of 14 men who have sex with men evaluated doxycycline concentrations in blood, urine, and oropharyngeal and rectal secretions at various timepoints after a single dose of DoxyPEP. Investigators estimated that drug levels in urine should remain 4 times above the minimum inhibitory concentration of typical chlamydia, syphilis and low-level resistant gonorrhea strains for roughly 5-7 days, and that levels in rectal secretions would achieve these benchmarks for 32-42 hours. Unfortunately, levels were not quantifiable in oropharyngeal secretions.

To me, these data suggest that this drug could potentially behave as a sort of STI pre-exposure prophylaxis. That is, for a patient who anticipates multiple exposures, a single dose of doxyPEP taken to protect from STI exposures over the preceding 72 hours could potentially also offer “forward” protection—at least in the urine and rectal compartments—for sexual exposures in the upcoming day and a half or so. Clinical data are still needed in this important and evolving area, but I believe the potential is there.

Your Thoughts
What data do you think is still needed to determine whether the benefits of STI prevention with DoxyPEP outweigh the risk of antimicrobial resistance? Leave a comment to join the discussion!

Continue