Introduction

Doxycycline post-exposure prophylaxis (doxy-PEP) is a new biomedical prevention strategy for sexually transmitted infections (STIs). It involves taking a single 200 mg dose of doxycycline within 72 hours after condomless sex to reduce the risk of acquiring bacterial STIs.

Unlike traditional prevention (condoms, regular screening, partner notification), doxy-PEP is a biomedical approach, comparable in concept to HIV PrEP but targeting bacterial infections. The main infections of interest are chlamydia, syphilis, and gonorrhoea—three of the most common STIs worldwide, with especially high prevalence in MSM (men who have sex with men) and transgender women.

Recent years have seen rising rates of syphilis and gonorrhoea in Australia and globally. Syphilis can cause serious long-term complications if untreated, and gonorrhoea is increasingly difficult to treat due to antibiotic resistance. Against this background, doxy-PEP offers a potentially powerful additional tool for prevention in high-risk groups.

Evidence from randomized controlled trials (RCTs) shows doxy-PEP substantially reduces chlamydia and syphilis incidence, with variable effects on gonorrhoea depending on local antibiotic resistance patterns. Doxycycline is widely available and generally well tolerated, making it feasible in practice.

However, there are important cautions:

• Tetracycline resistance in gonorrhoea is already common (up to 70–100% in some regions, including Australia).
• Repeated doxycycline use raises concerns about broader antimicrobial resistance and microbiome effects.

For this reason, guidelines such as those from the CDC (US) and ASHM (Australia) recommend a targeted approach: doxy-PEP may be offered to MSM and transgender women with recent STI history, but not yet for heterosexual populations, pending further evidence.

Key Randomized Evidence

1. IPERGAY Substudy (France, MSM on HIV PrEP, 2015–2017)

• Design: Open-label RCT.
• Results: ~70% reduction in chlamydia & syphilis, no effect on gonorrhoea (high baseline resistance).
• Ref: Molina J-M, Lancet Infect Dis 2018.

2. DoxyPEP Trial (US; MSM & TGW with HIV or on PrEP, 2020–2022)

• Design: RCT, multicentre (San Francisco & Seattle).
• Results: 65% reduction in overall bacterial STIs. Strong effect on chlamydia & syphilis; gonorrhoea effect modest.
• Ref: Luetkemeyer AF, NEJM 2023.

3. ANRS DOXYVAC Trial (France; MSM on HIV PrEP, 2021–2022)

• Design: RCT of doxy-PEP + meningococcal B vaccine.
• Results: Significant reductions in chlamydia & syphilis; gonorrhoea incidence reduced in this setting (likely due to lower resistance).
• Ref: Molina J-M, Lancet Infect Dis 2024.

Guidelines (2024–2025)

• CDC (US, 2024):
  • Recommend doxy-PEP for MSM and TGW with ≥1 bacterial STI in the past 12 months.
  • Regimen: 200 mg doxycycline within 72 h of condomless sex (max once daily).
  • Reassess every 3–6 months.
  • Not recommended for heterosexual populations.
• Australia (ASHM Consensus 2024):
  • Supports targeted use for MSM with recurrent STIs, with shared decision-making.
  • Emphasises surveillance of antimicrobial resistance (AMR).
  • Not recommended for heterosexual men/women pending further data.
• WHO:
  • No global recommendation yet.
  • Acknowledges strong trial evidence in MSM/TGW and highlights AMR concerns.

Resistance Considerations

• Gonorrhoea:
  • High tetracycline resistance limits benefit; in Australia, >70% of isolates show resistance.
  • In France, lower resistance explains why ANRS DOXYVAC showed protective effect.
• Other bacteria:
  • Possible selection of resistance in Staphylococcus aureus (including MRSA) and commensal gut flora.
  • Ongoing studies are assessing ecological and microbiome impacts.

Safety

• Generally well tolerated.
• Side effects: GI upset, photosensitivity, oesophagitis if not taken with water/upright.
• No major safety concerns identified in RCTs, but long-term ecological impacts remain uncertain.

Bottom Line

• Strong RCT evidence supports doxy-PEP in MSM & TGW, with clear reductions in chlamydia & syphilis, and variable effects on gonorrhoea.
• Best evidence-based use: MSM/TGW with ongoing high STI risk.
• Caution: Not recommended for heterosexual populations due to lack of evidence.
• Resistance monitoring is essential; especially for gonorrhoea in Australia.

References

1. Molina J-M et al. Post-exposure doxycycline to prevent STI in MSM on HIV PrEP (IPERGAY substudy). Lancet Infect Dis. 2018.
   https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(17)30725-9/fulltext
2. Luetkemeyer AF et al. Doxycycline PEP for STI prevention in MSM and TGW. N Engl J Med. 2023.
   https://www.nejm.org/doi/full/10.1056/NEJMoa2211934
3. Molina J-M et al. ANRS DOXYVAC Trial. Lancet Infect Dis. 2024.
   https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(24)00236-6/fulltext
4. CDC. CDC Clinical Guidelines on Doxy-PEP. MMWR Recomm Rep. 2024;73(2):1–8.
   https://www.cdc.gov/mmwr/volumes/73/rr/rr7302a1.htm
5. ASHM. Consensus Statement on Doxycycline PEP. 2024.
   https://ashm.org.au/resources/doxy-pep-consensus-statement/
6. WHO Western Pacific Region. Gonococcal Antimicrobial Surveillance Programme (GASP).
   https://www.who.int/westernpacific/activities/gonococcal-antimicrobial-surveillance-programme

Trembizki E et al. Tetracycline-resistant Neisseria gonorrhoeae global estimates.JAC-AMR. 2024.
https://academic.oup.com/jacamr/article/7/4/dlaf120/8194499