Update: Does the literature support the use of doxycycline for post-exposure prophylaxis against sexually transmitted infections?

Background
The incidence of bacterial sexually transmitted infections (STIs), specifically gonorrhea, chlamydia, and syphilis, has increased both nationally and globally.1,2 There are no vaccines and limited chemoprophylaxis options for the prevention of these bacterial STIs.2 Therefore, new strategies are necessitated to address the STI epidemic, particularly for populations that are disproportionately affected such as gay, bisexual, and other men who have sex with men (MSM) and transgender women (TGW).

Doxycycline, a moderate-spectrum, second-generation tetracycline, is used first-line agent for treatment of chlamydia and as an alternative regimen for treatment of syphilis.3 The drug is also known for its use as pre-exposure prophylaxis (PrEP) or postexposure prophylaxis (PEP) in preventing diseases like malaria and Lyme disease.2,3 Doxycycline has only recently been considered for PEP in preventing STIs; PEP is a form of chemoprophylaxis and involves taking medication(s) after a potential exposure to prevent an infection.2

A frequently asked question (FAQ) was published in July 2023 summarizing data for the use of doxycycline as PEP (commonly referred to as “doxy-PEP”) for STI prevention (available here). At the time the 2023 FAQ was published, emerging data supported the effectiveness of doxy-PEP; however, medical societies had not yet adopted doxy-PEP as standard care. Since the publication of this FAQ, the Centers for Disease Control and Prevention (CDC) has published a guideline for the use of doxy-PEP for bacterial STI prevention.2 This update will focus on recommendations from this guideline, as well as newer primary literature that addresses the question.

CDC guideline recommendations
The 2024 CDC guideline on doxy-PEP supports its use as a novel, patient-managed biomedical strategy for STI prevention in certain populations, based on shared decision-making.2 The CDC strongly recommends that healthcare providers counsel all gay, bisexual, and other MSM and TGW with a history of ≥1 bacterial STI (syphilis, chlamydia, or gonorrhea) during the past 12 months about the benefits and harms of doxy-PEP. Although not directly assessed in the research studies, the CDC also recommends that doxy-PEP could be discussed with MSM and TGW who did not have a bacterial STI in the previous year but will be participating in sexual activities that are known to increase the likelihood of exposure to STIs. There are limited clinical data to support doxy-PEP in cisgender women, cisgender heterosexual men, transgender men, and other queer and nonbinary persons assigned female at birth; therefore, providers should use their clinical judgement and shared decision-making to determine use of doxy-PEP in these populations.

If offering doxy-PEP, providers should write a prescription for patient self-administration of 200 mg of doxycycline (any formulation) within 72 hours of oral, vaginal, or anal sex.2 The dosage should not exceed 200 mg every 24 hours. Prescribers should provide enough doses until the next follow-up visit based on the patient’s anticipated sexual activity, and offer the following counseling points regarding doxycycline therapy:

  • Take doxy-PEP with ≥8 ounces of water and food to minimize gastrointestinal side effects (e.g., nausea, upset stomach, esophageal irritation).
  • Avoid lying down for 1 hour after taking doxycycline to prevent esophagitis.
  • Separate the doxycycline dose by ≥2 hours from dairy products, antacids, or supplements containing iron, calcium, or magnesium.
  • Use sunscreen or wear protective clothing to shield from the sun during doxycycline therapy.

Furthermore, doxy-PEP should be integrated into a comprehensive sexual health strategy, which includes risk reduction counseling, STI screening and treatment, recommended vaccination, and referrals to HIV PrEP, HIV care, or other relevant services.2 Individuals prescribed doxy-PEP should be tested for bacterial STIs at the sites of exposure initially and every 3 to 6 months thereafter. Ongoing need for doxy-PEP also should be assessed every 3 to 6 months. Additionally, HIV screening should be performed for HIV-negative MSM and TGW in accordance with current practice guidelines.

Literature review
The CDC guideline describes 4 studies that assessed the efficacy of doxy-PEP in reducing bacterial STIs.4-7 Three of these studies are summarized in detail in the 2023 FAQ (available here).4-6 The fourth study, published after the 2023 FAQ, was a randomized, open-label trial comparing doxy-PEP (doxycycline hyclate 200 mg administered within 72 hours after condomless sex) with standard care among Kenyan women 18 to 30 years of age (N=449) who were receiving HIV PrEP.7 This is the only trial conducted among cisgender women.2 The primary end point was any incident infection with Chlamydia trachomatis (chlamydia), Neisseria gonorrhoeae (gonorrhea), or Treponema pallidum (syphilis).7 Hair samples were collected quarterly for objective assessment of doxycycline use, and patients were followed quarterly over 12 months. The study found no significant reduction in any bacterial STI (the primary endpoint); relative risk (RR), 0.88; 95% confidence interval (CI), 0.60 to 1.29. Similarly, there was no significant reduction in chlamydia (RR, 0.73; 95% CI, 0.47 to 1.13) or gonorrhea (RR, 1.64; 95% CI, 0.78 to 3.47). Syphilis efficacy could not be evaluated because there were only 2 syphilis infections during the study.2 In 78% of weekly surveys, women assigned to doxy-PEP reported taking the medication on at least as many days as they had sex.2,8 However, hair analyses revealed that doxycycline was found in only 29% of patients in the doxycycline group, indicating that nonadherence may have contributed to the lack of efficacy.2 Other potential reasons for lack of efficacy, like biological differences, also require further study.

Potential concerns
The CDC guideline reviewed available data on the safety of doxy-PEP and determined that potential harms appear minimal in the short term.2 However, current data are insufficient to evaluate the long-term effects of doxy-PEP use on antimicrobial resistance in bacterial STIs and other common bacteria (e.g., Staphylococcus aureus). Moreover, there is a lack of research on the long-term effects of doxy-PEP on the microbiome, including beneficial bacteria in the intestines and skin. Studies are ongoing to assess doxy PEP and PrEP, including the risk of developing antimicrobial resistance. To reduce the risk of antimicrobial resistance while maximizing benefits, the CDC guideline recommendations target specific groups for whom doxy-PEP has been shown to be effective for STI prevention. The guideline states that recommendations will be updated as additional information becomes available.

Conclusion
Doxy-PEP is the first new STI prevention tool in decades.2 Given the rising national rates of syphilis, chlamydia, and gonorrhea, the available evidence suggests that this approach should be considered for MSM and TGW who are significantly at risk of acquiring bacterial STIs. However, data are insufficient to assess the benefits and risks of doxy-PEP in other populations, such as cisgender women. Questions also remain regarding the long-term safety of doxy-PEP, including the potential development of antimicrobial resistance and impacts on the microbiome. The CDC, in collaboration with federal partners and research organizations, is utilizing existing data systems to track the adoption of doxy-PEP, study its effect on bacterial STI rates, assess national prescribing trends for doxycycline, and identify any potential emergence of antimicrobial resistance.9 As additional data on doxy-PEP use in other populations and from any other research in the field emerge, the CDC guideline will be updated.

References

  1. New report flags major increase in sexually transmitted infections, amidst challenges in HIV and hepatitis. World Health Organization. May 21, 2024. Accessed September 3, 2024.
  2. 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
  3. Grant JS, Stafylis C, Celum C, et al. Doxycycline prophylaxis for bacterial sexually transmitted infections. Clin Infect Dis. 2020;70(6):1247-1253. doi:10.1093/cid/ciz866
  4. Molina JM, Charreau I, Chidiac C, et al. 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. Leutkemeyer A, Donnell D, Dombrowski JC, et al. Postexposure doxycycline to prevent bacterial sexually transmitted infections. N Engl J Med. 2023;388(14):1296-1306. doi:10.1056/NEJMoa2211934
  6. Molina JM, Bercot B, Assoumou L, et al. ANRS 174 DOXYVAC: an open-label randomized trial to prevent STIs in MSM on PrEP. Oral Abstract Session-03 presented at: 29th Conference on Retroviruses and Opportunistic Infections; February 19-22, 2023; Seattle, WA. Abstract number 119. Accessed September 23, 2024. Available at: https://www.natap.org/2023/CROI/croi_03.htm.
  7. Stewart J, Oware K, Donnell D, et al. Doxycycline prophylaxis to prevent sexually transmitted infections in women. N Engl J Med. 2023;389(25):2331-2340. doi:10.1056/NEJMoa2304007
  8. Stewart JOK, Donnell D, Violette L, et al. Self-reported adherence to event-driven doxycycline postexposure prophylaxis for sexually transmitted infection prevention among cisgender women. STI and HIV World Congress; Chicago, IL: 2023 July 24, 2023. Accessed September 23, 2024. Available at: https://www.croiconference.org/abstract/doxycycline-postexposure-prophylaxis-for-prevention-of-stis-among-cisgender-women/.
  9. Doxy PEP for bacterial STI prevention. Centers for Disease Control and Prevention. August 14, 2024. Accessed September 23, 2024. https://www.cdc.gov/sti/hcp/doxy-pep/index.html

Prepared by:
Honey Joseph, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

October 2024

The information presented is current as of September 23, 2024. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.