Medicine may be about to achieve a long-sought goal: a “morning-after pill” to prevent sexually transmitted infections. It could sharply reduce soaring rates of illness and huge health care costs.

The effectiveness of this pill—and it literally is a pill, a 200-milligram tablet of the antibiotic doxycycline—has been studied for a decade, and people have taken it covertly for years. But study results published in The New England Journal of Medicine look likely to tip the pill into clinical practice. In the study, conducted in San Francisco and Seattle, participants who took a single dose within 72 hours of having sex without a condom were only a third as likely to contract chlamydia, gonorrhea, or syphilis as those who didn’t take the pills.

As with everything in medicine, there are footnotes to the findings, and risks to balance the benefits. The study was conducted only among gay and bisexual men, along with transgender women and nonbinary people assigned male at birth. Within those groups, it was limited to people who had been diagnosed with a sexually transmitted infection (STI) in the past year. The study didn’t include cisgender women; in past studies, the preventive antibiotic has not worked as well for them. And the study noted, but didn’t explore in depth, the possibility that routinely administering an antibiotic could provoke resistance either among the bacteria that cause STIs or others carried in participants’ bodies.

All that said, the results have created real excitement among physicians and people who would be eligible to take what’s being called doxyPEP (for doxycycline post-exposure prophylaxis)—even though health authorities, such as the US Centers for Disease Control and Prevention, haven’t yet made formal recommendations for its use. 

“I think this is a real game-changer,” says Paul Adamson, an infectious disease physician and assistant clinical professor of medicine at the University of California, Los Angeles. “We have a huge amount of bacterial STIs in the US. Gay and bisexual men who have sex with men are disproportionately burdened by them. And we have not had a lot of tools that we can use to help.”

To understand why doxyPEP could be so significant, it’s important to consider what’s been happening with STIs. Briefly: They’re skyrocketing. Since 2017, according to the CDC, the most important of these diseases have reached historic highs: Gonorrhea has increased by 28 percent, and syphilis by 74 percent. And while chlamydia diagnoses haven’t quite returned to their pre-Covid levels, the agency worries that might be due to pandemic disruptions to care, rather than to an actual decrease in transmission. All of those infections have profound long-term consequences if they are not diagnosed and treated, including making people more vulnerable to HIV infection. Collectively, they cost the US health care system more than $1 billion per year.

Meanwhile, congenital syphilis—passed from mother to infant at birth, a sign that the pregnant person never received adequate prenatal care—caused 220 stillbirths and infant deaths in 2021, the last year for which there are national figures. Gonorrhea is gaining resistance to the last antibiotics currently available to treat it.

In medicine, prevention is almost always preferable to treatment: Vaccines and other prophylactic measures are less expensive, and can be planned in advance. So it has been a research goal to find uncomplicated prevention for STIs—something that, like the morning-after pill for pregnancy, can be taken a short time after sex and doesn’t rely on the user making decisions in the moment. 

The first test of doxyPEP, a small US trial that took place in 2011 and 2012, was published in 2015, and showed that HIV-positive men who took the post-exposure dose cut their rate of STIs by three-fourths. Fairly soon after that, social networks of men who have sex with men picked up on the findings, and began sharing knowledge about using preventive doxycycline off-label. A large 2017 French study of men using pre-exposure prophylaxis for HIV, known as PrEP, included within it a study of STI rates among men taking post-exposure doxycycline; it showed that doxyPEP could cut rates of syphilis and chlamydia infection by almost 70 percent. And last summer and this spring, the two largest international HIV conferences included presentations that confirmed the doses were successful in most circumstances.

Several of those presentations were drawn from the San Francisco and Seattle study just published in NEJM. Its results were so dramatic that the authors stopped the trial earlier than planned, in May 2022: They revealed that, among 501 men who were either living with HIV or taking HIV PrEP, consuming that single dose of doxycycline within 72 hours of sex without a condom reduced the combined incidence of the three major STIs by roughly two-thirds. 

“Our goal was to understand this in a real-world setting, in a heterogeneous population of people taking HIV PrEP but also living with HIV—which biologically aren’t different populations, but may be different in terms of sexual behaviors, sexual networks,” says Anne Luetkemeyer, one of the study’s principal investigators and a professor of medicine at the University of California, San Francisco. Combined with the French research, she adds, “we now have two studies that really showed very remarkably similar efficacy in this population.”

Those two sets of results may be enough to let doxyPEP enter mainstream medicine. In some places, it already has. Last October, San Francisco’s public health department became the first local department to support doxyPEP use in its jurisdiction. And after the NEJM paper, individual physicians tweeted they would begin prescribing doxyPEP because the results looked so solid—something they can do off-label because the Food and Drug Administration already approved the drug decades ago to treat a range of infections

When a new way of controlling a disease seems likely to enter the US mainstream, the CDC is expected to weigh in. So far, the agency hasn’t published official guidelines regarding the use of doxyPEP. Following the release of preliminary data at conferences, the CDC published “considerations for individuals and healthcare providers,” a strategy for sharing what’s known so far, as well as an acknowledgment that doxyPEP already is being used off-label. A CDC spokesperson told WIRED by email that formal draft guidance for physicians could come “by the end of the summer.” 

When that guidance does arrive, it isn’t expected to recommend doxyPEP for everyone. “We should consider offering this to people who have an elevated risk” of STIs, Luetkemeyer says. “And that group is men who have sex with men, on PrEP, or living with HIV, who’ve had a history of STIs. I think that’s a reasonable group.” 

And eligible people may not want to take it. Like almost all antibiotics, doxycycline has side effects: sun sensitivity, diarrhea, serious nausea. And it hasn’t worked equally well for everyone. In the trial done in French men, the antibiotic did not suppress gonorrhea infections, even though it had a dramatic effect on reducing syphilis and chlamydia. In the one trial done so far among cis women, launched in Kenya in 2021, doxycycline prophylaxis (known in this case as dPEP) had no effect on suppressing STIs.  

That was disappointing; women who are at high risk of STIs need prevention as much as men do. Equally, it was mystifying for the researchers, who now are poring through their data to see what might have made a difference: whether the 449 participants had difficulty taking the drug at the right time, for instance, or whether doxycycline behaves differently in female organs than in men’s. “We had more than 200 women show up to hear the results, and they were so shocked and disappointed,” says Jenell Stewart, the study director and a physician-scientist and assistant professor at Hennepin Healthcare in Minneapolis. “We are very focused on understanding these results before we say this doesn’t work for women.”

One thing that might have played a role in Kenya and France—and is raising red flags for doxyPEP use in the US—is antibiotic resistance. Stewart says 100 percent of the gonorrhea isolates tested so far from women who became infected while on dPEP showed high levels of resistance to tetracycline, the drug family that doxycycline belongs to; at the time of the French study, the background rate of resistance in gonorrhea there was 56 percent. In the US, where doxycycline isn’t the first-line treatment for gonorrhea, the rate of resistance is only 20 percent. That may provide a clue to why doxyPEP worked better in the US trial than in any other. But it also immediately raises the concern that if doxyPEP goes into wide use, it might make resistance worse.

The US study could not provide an answer: Though some men in the trial did contract gonorrhea while taking doxyPEP, not enough testing was done to confirm whether their strains were resistant to the medication and thus not knocked out by the single dose. Tests did suggest the drug might be affecting other bacteria in participants’ bodies, but the results were contradictory.  Those taking doxyPEP ended up harboring 40 percent less staph bacteria—something that all of us carry—than those not taking the drug; but the staph they were still carrying showed “modestly higher” resistance. Whether killing some bacteria was more beneficial than making others potentially hazardous, the trial didn’t last long enough to say.

So the calculation inherent in doxyPEP may not be risk versus benefit, as much as it is risk versus risk: preventing an infection while provoking resistance through small doses, or contracting an infection that requires larger doses over a longer period of time. “We’re not comparing doxyPEP to no antibiotics,” says Adamson, who researches drug-resistant gonorrhea and has prescribed doxyPEP for some patients. “We’re comparing doxyPEP to potentially significant amounts of ceftriaxone, or penicillin, or doxycycline perhaps, if somebody’s getting infections a lot.”

It’s a question that research will have to answer—because, no matter how the CDC weighs in, doxyPEP use is moving ahead. Joseph Osmundson, a microbiologist and author in New York City—where STI rates are rising just as they are nationally—recently sought a prescription from his regular physician. As a queer sexual-health activist, he says, it only made sense, not only to prevent infections and antibiotic side effects for himself, but also to keep from increasing infection rates in an already overburdened city.

“When people want an intervention to have a healthier sex life, you cannot not give it to them,” he says. “Withholding the intervention will not prevent people from having the kind of sex that they enjoy. The question is: Are they going to be provided with as many interventions as possible to have that type of sex with less risk of infectious disease?”