Doxycycline Postexposure Prophylaxis Reshapes STI Prevention

SIDP Reviewers:

This article was reviewed by Society of Infectious Diseases Pharmacists committee members Clara Ni, PharmD, BCIDP; and Monica Cozad, PharmD, MS, BCIDP.

Introduction

Bacterial sexually transmitted infections (STIs), including Neisseria gonorrhoeae, Chlamydia trachomatis, and Treponema pallidum, continue to rise in incidence in the United States and globally. Men who have sex with men (MSM) and transgender women experience a disproportionate burden of disease,¹ with complications including ocular syphilis and increasing rates of congenital infection. In the absence of effective vaccines and with limited preventive options, novel biomedical strategies to reduce bacterial STI transmission are urgently needed.

Doxycycline postexposure prophylaxis (doxy-PEP) has emerged as an effective prevention strategy. This approach involves patient-initiated administration of doxycycline 200 mg as soon as possible or up to 72 hours following condomless sexual exposure.^1,2 The biologic rationale is supported by doxycycline’s high oral bioavailability, prolonged elimination half-life, low cost, minimal clinically significant drug-drug interactions, and well-established safety profile.

Clinical Trial Evidence

The efficacy of doxy-PEP was established in the DoxyPEP randomized controlled trial (NCT03980223) published in 2023. This open-label phase 4 study enrolled 501 MSM and transgender women receiving HIV preexposure prophylaxis (PrEP) or living with HIV, all with a documented bacterial STI within the 12 months preceding trial commencement. Participants were randomly assigned 2:1 to receive doxy-PEP (200 mg within 72 hours of condomless sexual exposure) or standard care (no doxy-PEP).²

The trial was terminated early following interim analyses demonstrating substantial efficacy. Across both cohorts, doxy-PEP reduced overall bacterial STI incidence by approximately two-thirds. Reductions were greatest for chlamydia and syphilis, with relative risk reductions of approximately 75% to 90%, while more modest but still statistically significant reductions were observed for gonorrhea (approximately 50%-60%).² The number needed to treat to prevent 1 quarterly STI was fewer than 6. An open-label extension confirmed sustained benefit among participants who initiated doxy-PEP after crossover.³

Supporting International Evidence

Earlier randomized data from the French ANRS IPERGAY substudy (NCT01473472) demonstrated an approximate 50% reduction in overall STI incidence among MSM using event-driven HIV PrEP, driven primarily by reductions in chlamydia and syphilis, with no significant effect on gonorrhea. This finding is likely attributable to higher baseline N gonorrhoeae tetracycline resistance and lower cumulative doxycycline exposure, evidenced by detectable serum doxycycline concentrations in only approximately 30% of patients.⁴

More recent evidence from the ANRS 174 DOXYVAC trial (NCT04597424) demonstrated robust reductions in chlamydia and syphilis but limited efficacy against gonorrhea.⁵ Higher rates of high-level tetracycline resistance were observed among breakthrough gonococcal isolates in the doxy-PEP arm, highlighting the influence of regional resistance patterns on clinical effectiveness.^5,6

Evidence in Cisgender Women

A randomized trial (NCT04050540) evaluating doxy-PEP among cisgender women in Kenya did not demonstrate efficacy.⁷ Objective adherence measures via analysis of hair samples indicated minimal doxycycline exposure, which the authors wrote suggest suboptimal adherence rather than biological inefficacy. Pharmacokinetic modeling supports the plausibility of doxy-PEP for vaginal exposures, and its use may be considered on an individualized basis for select patients at elevated risk.⁸

Guideline Recommendations

In 2024, the CDC issued clinical guidelines recommending that MSM and transgender women with a bacterial STI diagnosis within the prior 12 months be counseled regarding doxy-PEP and offered a prescription following shared decision-making. The recommended regimen is doxycycline 200 mg administered within 72 hours after condomless oral, vaginal, or anal sexual exposure, not exceeding 1 dose per 24 hours.^1,2,9

The CDC emphasizes that doxy-PEP should be implemented within comprehensive sexual health care, including routine STI screening every 3 to 6 months, vaccination, risk-reduction counseling, and linkage to HIV PrEP or HIV care.¹ International professional societies have issued concordant recommendations.^9-11

Real-World Effectiveness and Safety

Observational data from integrated health systems demonstrate substantial reductions in chlamydia and syphilis positivity following doxy-PEP implementation among HIV PrEP users, suggesting potential population-level benefits. Gonorrhea rates have remained persistently elevated, consistent with resistance-related limitations observed in clinical trials.¹²

Doxy-PEP has been well tolerated in both clinical trials and real-world settings. Adverse events are uncommon and predominantly mild, with gastrointestinal symptoms and photosensitivity reported most frequently.¹³

Antimicrobial Resistance Considerations

Antimicrobial resistance remains a key consideration in doxy-PEP implementation. Variable effectiveness against gonorrhea reflects regional differences in tetracycline resistance. Clinical trials have demonstrated increased proportions of tetracycline-resistant N gonorrhoeae among doxy-PEP recipients, particularly in European cohorts.^3-7,12,13 To date, resistance has not been observed in C trachomatis or T pallidum.

Among commensal organisms such as Staphylococcus aureus, doxy-PEP use may increase the proportion of resistant isolates among carriers; however, overall colonization rates appear reduced, resulting in no net increase in resistant carriage.¹⁴

Conclusion

Doxycycline postexposure prophylaxis represents a major advancement in bacterial STI prevention among MSM and transgender women with recent STI history. The intervention provides substantial protection against chlamydia and syphilis and modest, resistance-limited protection against gonorrhea. Endorsement by the CDC and international professional societies supports its incorporation into comprehensive sexual health care. Ongoing resistance surveillance and further research in additional populations remain essential to optimize the long-term public health impact of doxy-PEP.^1,2

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(2):1-8. doi:10.15585/mmwr.rr7302a1

2. Luetkemeyer AF, Donnell D, Dombrowski JC, et al; DoxyPEP Study Team. Postexposure doxycycline to prevent bacterial sexually transmitted infections. N Engl J Med. 2023;388(14):1296-1306. doi:10.1056/NEJMoa2211934

3. Luetkemeyer AF, Donnell D, Cohen SE, et al. Doxycycline to prevent bacterial sexually transmitted infections in the USA: final results from the DoxyPEP multicentre, open-label, randomised controlled trial and open-label extension. Lancet Infect Dis. 2025;25(8):873-883. doi:10.1016/S1473-3099(25)00085-4

4. Molina JM, Charreau I, Chidiac C, et al; ANRS IPERGAY Study Group. Post-exposure prophylaxis with doxycycline to prevent sexually transmitted infections in men who have sex with men: an open-label randomised substudy of the ANRS IPERGAY trial. Lancet Infect Dis. 2018;18(3):308-317. doi:10.1016/S1473-3099(17)30725-9

5. Molina JM, Bercot B, Assoumou L, et al; ANRS 174 DOXYVAC Study Group. Doxycycline prophylaxis and meningococcal group B vaccine to prevent bacterial sexually transmitted infections in France (ANRS 174 DOXYVAC): a multicentre, open-label, randomised trial with a 2 × 2 factorial design. Lancet Infect Dis. 2024;24(10):1093-1104. doi:10.1016/S1473-3099(24)00236-6

6. Bercot B, Assoumou L, Caméléna F, et al. Antimicrobial drug-resistant Neisseria gonorrhoeae (GC) infections in men using doxycycline postexposure prophylaxis: a substudy of the ANRS 174 DOXYVAC trial. Clin Infect Dis. Published online November 10, 2025. doi:10.1093/cid/ciaf591

7. Stewart J, Oware K, Donnell D, et al; dPEP Kenya Study Team. Doxycycline prophylaxis to prevent sexually transmitted infections in women. N Engl J Med. 2023;389(25):2331-2340. doi:10.1056/NEJMoa2304007

8. Haaland RE, Fountain J, Edwards TE, et al. Pharmacokinetics of single dose doxycycline in the rectum, vagina, and urethra: implications for prevention of bacterial sexually transmitted infections. EBioMedicine. 2024;101:105037. doi:10.1016/j.ebiom.2024.105037

9. Gandhi RT, Landovitz RJ, Sax PE, et al. Antiretroviral drugs for treatment and prevention of HIV in adults: 2024 recommendations of the International Antiviral Society-USA Panel. JAMA. 2025;333(7):609-628. doi:10.1001/jama.2024.24543

10. Saunders J, Deering J, Dewsnap C, et al. British Association for Sexual Health and HIV (BASHH) UK national guideline for the use of doxycycline post-exposure prophylaxis (DoxyPEP) for the prevention of syphilis, 2025. Int J STD AIDS. 2025;36(10):756-764. doi:10.1177/09564624251352053

11. Cornelisse VJ, Riley B, Medland NA. Australian consensus statement on doxycycline post-exposure prophylaxis (doxy-PEP) for the prevention of syphilis, chlamydia and gonorrhoea among gay, bisexual and other men who have sex with men. Med J Aust. 2024;220(7):381-386. doi:10.5694/mja2.52258

12. 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(3):273-281. doi:10.1001/jamainternmed.2024.7186

13. Horberg M, Thompson M, Agwu A, et al. Primary care guidance for providers of care for persons with human immunodeficiency virus: 2024 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. Published online October 12, 2024. doi:10.1093/cid/ciae479

14. Soge OO, Thibault CS, Cannon CA, et al. Potential impact of doxycycline post-exposure prophylaxis on tetracycline resistance in Neisseria gonorrhoeae and colonization with tetracycline-resistant Staphylococcus aureus and group A Streptococcus. Clin Infect Dis. 2025;80(6):1188-1196. doi:10.1093/cid/ciaf089