Coloured scanning electron micrograph (SEM) of Gonorrhoea bacteria.

Gonorrhoea bacteria (pictured) have developed resistance to some antibiotics. Credit: SPL

A health department in the United States has become one of the first to recommend that people who are at high risk of getting a sexually transmitted infection (STI) take a preventive dose of antibiotics after unprotected sex. Clinical trials have shown the strategy can reduce infections such as chlamydia, syphilis and gonorrhoea. But some researchers worry it will contribute to antibiotic resistance.

Last month, the San Francisco Department of Public Health recommended that people at high risk of infection take a dose of the antibiotic doxycycline after unprotected sex to prevent bacterial STIs.

Rates of bacterial STIs have been climbing steadily over the past decade, particularly in men who have sex with other men (MSM). “We don't have any tool to reduce the rate of [bacterial] STIs, except asking people to use condoms,” including for oral sex, says infectious-diseases physician Jean-Michel Molina at the University of Paris.

Molina led the first trial1 of doxycycline post-exposure prophylaxis ― a preventive-treatment strategy known as doxyPEP ― which reported results in 2018. In that trial, 22% of those using doxyPEP, and 44% who were not, were infected with an STI over nine months. Antibiotic use led to a 70% reduction in chlamydia infections and a 73% reduction in syphilis infections in participants. Gonorrhoea infections weren’t substantially reduced.

DoxyPEP is similar to the hugely successful strategy of taking antivirals before unprotected sex to prevent infection from HIV ― known as HIV-PrEP. Taking HIV-PrEP reduces the risk of getting HIV from sex by about 99%.

Trial success

San Francisco adopted the policy after interim results from another trial ― called DoxyPEP ― were presented at the International AIDS Conference in Montreal in late July. That trial, involving MSM and transgender women either living with HIV or taking HIV-PrEP, was stopped early because taking doxycycline after unprotected sex was so effective at reducing STIs. Everyone enrolled in the trial, led by infectious-diseases physician Annie Luetkemeyer at the University of California, San Francisco, was then offered doxyPEP. Chlamydia and syphilis infections were more than 70% lower, and gonorrhoea infections were 55% lower in each three-month period in those who took doxyPEP. In people who didn’t take doxyPrep, around 30% were infected with one or more STI each quarter.

Syphilis in men can cause serious health problems, such as blindness and nerve damage if left untreated. Chlamydia and gonorrhoea infections in men are rarely serious, but in women, they can lead to infertility. And syphilis can pass to unborn children and cause miscarriage, still birth, or brain and organ damage in babies born with the disease.

But researchers are divided about whether the evidence of effectiveness in MSM alone is enough to make the decision to officially roll-out doxyPEP. Manik Kohli, a sexual-health physician and researcher at University College London, says more data from multiple trials are required to show whether doxyPEP drives antibiotic resistance.

Other jurisdictions are taking a more cautious approach than the San Francisco Department of Public Health, who did not respond to Nature’s request for comment. The UK Health Security Agency and the British Association for Sexual Health and HIV state they do not endorse the doxyPEP strategy for prevention of syphilis or chlamydia, in part because of a lack of data on antimicrobial resistance.

Facing resistance

When exposed to antibiotics, bacteria that harbour resistance and survive can spread. Chris Kenyon, a microbiologist at the Institute of Tropical Medicine in Antwerp, Belgium, says that using doxycycline to prevent infections drastically increases a person’s exposure to the antibiotic, which could drive resistance. In the DoxyPEP trial, some participants took more than 20 doses of doxycycline each month, an amount that Kenyon describes as “astronomical”.

Doxycycline is a “critically important” antibiotic for treating other conditions, including skin infections caused by Staphylococcus aureus and bacterial pneumonia, says Kenyon. DoxyPEP could lead to the emergence of antibiotic resistance in the bacteria that cause these infections and limit treatment options, he says.

He says that health-care workers should take a precautionary approach when prescribing antibiotics as a preventive treatment, particularly among MSM. They are a key population for the emergence of antibiotic resistance if antibiotic use is high, because people tend to have multiple sex partners and networks that increase the chance of resistant bacteria spreading. Sex workers are another group in which antimicrobial resistance has emerged in the past.

Resistance to tetracycline-class antibiotics, which includes doxycycline, is already common for gonorrhoea. In the United States, around 25% of gonorrhoea cases are caused by tetracycline-resistant bacteria. Elsewhere, rates of resistance are higher, with studies reporting rates closer to 60% or 70% in Europe1,3.

Molina expects that the effectiveness of doxyPEP against gonorrhoea will depend on the rates of resistance in the local community and will probably decline over time as resistance levels rise.

But Luetkemeyer says that early results from a second French trial, called DOXYVAC, show doxycycline reduces gonorrhoea infections ― in spite of high resistance levels. The results suggest that the drug still prevents an infection from taking hold, even if it is ineffective at treating an established infection. “It often takes a lot less of a drug to prevent a disease than it does to cure a disease,” she says.

Other infections

Doxycycline resistance has not emerged in chlamydia or syphilis. Working out whether doxyPEP leads to resistance in these infections could take years, says Molina.

Luetkemeyer and her colleagues have collected swab and stool samples to see if people using doxycycline as a preventive tool alters the community of microorganisms that live in the gut or increases antibiotic resistance. Those results will be presented at a conference in February 2023. Luetkemeyer also notes that there are other sources of doxycycline in the community that could contribute to resistance.

One hope is that doxyPEP use in MSM could lower rates of bacteria STIs in the broader community ― including in women, who bear the greatest effects of chlamydia and gonorrhoea infections ― just as HIV-PrEP has done for HIV in high-income countries.

But Kenyon is sceptical that doxyPEP will lower STI rates, which can remain stubbornly high even after large-scale interventions. In the late 1990s, a mass treatment campaign with the antibiotic azithromycin to eliminate an outbreak of syphilis in Vancouver lowered rates initially, but they soon rebounded2.

Off-label use

Since Molina and his colleagues published results of the first doxyPEP study in 2018, people have been using doxycycline off-label as a preventive tool, he says. Kenyon fears that doxyPEP could expose people to the antibiotic for years or even decades.

For people already using doxyPEP, public-health recommendations are unlikely to convince them to stop, says Kohli. Following Luetkemeyer’s presentation at the International AIDS Conference in July, the US Centers for Disease Control and Prevention published information to guide the use of doxyPEP. The agency will publish subsequent guidance when the final data is published and reviewed, a spokesperson told Nature.

Guidelines about use are important for informing people about the safety of a strategy they might already be using, and making preventive treatment available to people who might not be in a position to advocate for doxyPEP on their own, says sexual-health physician Jenell Stewart at Hennepin Healthcare in Minneapolis, Minnesota. Stewart is leading a trial of doxycycline prophylaxis in Kenya for women taking HIV-PrEP4.

Despite the unknowns, Stewart says that the benefits outweigh the risks. “People should have access to this tool, if it makes sense for them and their lifestyle,” she says.