Doxycycline After Sex to Prevent Syphilis, Chlamydia and Gonorrhea: CDC's 2024 Guidelines

There are no vaccines and few preventive medicines for the bacterial sexually transmitted infections (STIs) syphilis, chlamydia and gonorrhea. All three keep rising in the United States, and they fall hardest on gay, bisexual and other men who have sex with men (MSM) and on transgender women (TGW). In three large randomized trials, 200 mg of doxycycline taken within 72 hours after sex cut syphilis and chlamydia by more than 70% and gonorrhea by about 50%.

In 2024 CDC issued its first guidelines for this approach, doxycycline postexposure prophylaxis (doxy PEP): a prescription the patient keeps and takes themselves after sex, for as long as it is needed.

The recommendation

• Who. Providers should counsel MSM and TGW who have had syphilis, chlamydia or gonorrhea diagnosed in the past 12 months about the benefits and harms of doxy PEP and, through shared decision-making, offer a prescription. CDC rates this its strongest recommendation, backed by randomized trials.
• Dose. 200 mg of doxycycline, any formulation, taken as soon as possible — and no later than 72 hours — after oral, vaginal or anal sex. Never more than 200 mg in 24 hours.
• How much. Enough doses to cover the person's expected sexual activity until the next visit. Whether doxy PEP is still needed is reviewed every 3–6 months.
• Others. Doxy PEP could also be discussed with MSM and TGW who have had no bacterial STI in the past year but expect sex that is known to raise the chance of one. For cisgender women, cisgender heterosexual men, transgender men and other queer and nonbinary people assigned female at birth, the evidence is too thin for a recommendation; providers should use clinical judgement and shared decision-making.

As part of wider sexual health care

Doxy PEP belongs inside comprehensive care: risk-reduction counseling, STI screening and treatment, recommended vaccines, and links to HIV PrEP, HIV care and other services.

At the first visit

• Test for gonorrhea and chlamydia (nucleic acid amplification tests at every site of exposure) and for syphilis (blood test), and treat what is found. Screen for HIV following the HIV PrEP guidelines for people on PrEP; for HIV-negative people not on PrEP, consider HIV screening every 3–6 months.
• Discuss condoms, fewer partners, and HIV PEP, PrEP or treatment as needed.
• Explain the benefits and possible harms: sensitivity to sunlight, irritation and discomfort of the esophagus, nausea, vomiting and diarrhea, and the chance of antimicrobial resistance in other bacteria, changes in the microbiome and unknown long-term effects.
• To protect the esophagus, take doxycycline on a full stomach with a full glass of liquid and don't lie down for 1 hour afterwards.
• Take it exactly as prescribed and only for this purpose.
• Keep it at least 2 hours apart from dairy products, antacids and supplements containing calcium, iron, magnesium or sodium bicarbonate. Review all the person's medicines, over-the-counter ones included, for interactions; no clinically relevant interaction with gender-affirming hormones is likely.

Every 3–6 months

• Test for gonorrhea and chlamydia at the sites of exposure, and for syphilis; screen for HIV as above.
• Check for side effects, counsel on risk reduction, provide condoms, encourage HIV PrEP (and assess the need for HIV PEP), and confirm links to HIV care for people with HIV.
• Decide whether doxy PEP is still needed, and provide enough doses until the next visit.

Also consider hepatitis B and C screening, hepatitis B vaccination for those not immune, other vaccines as indicated (mpox, hepatitis A, HPV), and referral for primary care, mental health and substance use services.

The evidence

Doxycycline is a broad-spectrum tetracycline antibiotic, well absorbed and well tolerated, with a half-life of about 12 hours. It is already taken to prevent malaria and Lyme disease, is the recommended treatment for chlamydia, and is an alternative for syphilis. Resistance keeps it off the list of recommended treatments for gonorrhea, though many U.S. strains still respond to it.

• IPERGAY (France). 232 HIV-negative MSM and TGW on HIV PrEP took 200 mg after condomless sex — ideally within 24 hours, at most 72, up to three times a week — or nothing. Over 10 months, doxy PEP cut chlamydia by 70% and syphilis by 73%; gonorrhea did not differ.
• DoxyPEP (San Francisco and Seattle). 501 MSM and TGW — 174 with HIV and 327 on PrEP — who had had an STI in the past year. Doxy PEP sharply lowered the risk of gonorrhea (relative risk 0.45 on PrEP, 0.43 with HIV), chlamydia (0.12 and 0.26) and early syphilis (0.13 and 0.23; in the group with HIV the confidence interval, 0.04–1.29, includes no effect). Treating about 4.7 people on PrEP, or 5.3 with HIV, prevented one quarterly visit with a new STI. In the doxy PEP group, 86% took it always or often and 71% never missed a dose after condomless sex.
• DOXYVAC (France). MSM on PrEP with a recent STI took doxycycline within 24–72 hours of sex (332) or not (170). The trial was stopped early because doxy PEP worked: gonorrhea fell by about half (adjusted hazard ratio 0.49), chlamydia (0.11) and syphilis (0.21) far more.
• Kenya. The only trial among cisgender women (449 women, 2020–2022) found no significant reduction in bacterial STIs. Women reported taking their doses in 78% of weekly surveys, but hair tests found doxycycline in only 29% of the doxycycline group — so poor adherence may explain the result, though biological differences still need study.

Side effects

• In IPERGAY, gastrointestinal effects were more common with doxy PEP (53% against 41%).
• In DoxyPEP, no serious adverse event was attributed to doxycycline, and weight change did not differ. Five people in the doxy PEP group stopped it for intolerance or preference.
• In DOXYVAC, 3 people (0.9%) stopped: two for gastrointestinal effects, one for fear of them.
• A review of 67 studies of daily doxycycline for 8 weeks or more (mostly for acne, malaria and rosacea), and a meta-analysis of 18 placebo-controlled ones, found more gastrointestinal and skin effects than placebo but no difference in severe or neurological events. Serious side effects were rare.

Resistance: the open question

The worry is that doxy PEP breeds antibiotic resistance, in the STIs themselves and in other bacteria such as Staphylococcus aureus.

• In DoxyPEP, S. aureus in the nose fell in the doxy PEP group from 44% to 31% of people after 12 months, but among those who still carried it, tetracycline-resistant S. aureus rose from 5% to 13%. The standard-care group did not change. (The report calls the fall in carriage a 14% reduction; its own figures, 44% to 31%, do not give that.)
• Few gonorrhea samples could be tested: 24% were tetracycline-resistant at the start, against 30% of new infections in the doxy PEP group and 11% in the standard-care group.
• In DOXYVAC, every gonorrhea sample tested at the start (seven) was tetracycline-resistant. Among new infections, 67% were resistant and 33% highly resistant with doxy PEP, against 81% and 19% without.
• No clear resistance trend appeared in chlamydia, and rates of MRSA and ESBL-producing E. coli did not differ between groups.
• Studies of daily, lower-dose doxycycline for acne and malaria mostly found no resistance in skin bacteria or diarrheal pathogens, but one found more doxycycline-resistant S. aureus in people taking it for malaria. Nothing yet shows what long-term, intermittent use does to the microbiome.

The data so far favour doxy PEP, but resistance and microbiome changes must be watched as it is used.

Why aim it at people with a recent STI

The goal is to reach those who benefit most while using as little antibiotic as possible. In DoxyPEP, participants took about 43 extra doses a year to prevent an average of 1.3 STIs. STIs cluster: in one study of 2,981 MSM on HIV PrEP, 25% of them had 76% of the infections. In a model of MSM, TGW and nonbinary people assigned male at birth, prescribing doxy PEP for 12 months after an STI diagnosis was the most efficient strategy, averting 42% of STIs, with 2.2 people treated for a year for each STI averted.

How the guidelines were made

A work group of CDC physicians reviewed the trials published through June 2023 (and conference abstracts), graded the evidence, and weighed benefits, harms, acceptability, equity and feasibility. Reviews also examined the harms of long-term doxycycline. A two-day consultation with experts and community members (December 5–6, 2022), a bioethics consultation (April 14 and May 1, 2023), peer review, and 45 days of public comment from October 2, 2023, fed into the final text. By 2023–2024 other countries' positions ranged from advising against widespread use, because of resistance, to conditional use for MSM and TGW at risk of syphilis, to case-by-case use. CDC will update the guidelines as data accumulate.

Sources

• Laura H. Bachmann, Lindley A. Barbee, Philip Chan, Hilary Reno, Kimberly A. Workowski, Karen Hoover, Jonathan Mermin and Leandro Mena, "CDC Clinical Guidelines on the Use of Doxycycline Postexposure Prophylaxis for Bacterial Sexually Transmitted Infection Prevention, United States, 2024," MMWR Recommendations and Reports 73(2), 2024. https://www.cdc.gov/mmwr/volumes/73/rr/rr7302a1.htm
• Search strategies and evidence reviews: https://www.cdc.gov/std/treatment/guidelines-for-doxycycline.htm