A promising line of attack against sexually transmitted infections puts a cheap and widely available medication to a new use.

The treatment – a form of post-exposure prophylaxis, or PEP – is a dose of the antibiotic doxycycline taken in the hours immediately after sex which works to extinguish an STI before it leads to symptoms or spreads to others.

A growing body of research shows using doxycycline in this way can substantially lower the risk of contracting three of the most common bacterial STIs — chlamydia, gonorrhea and syphilis.

Called doxy-PEP, the preventative treatment has instilled enough confidence that the Centers for Disease Control and Prevention plans to roll out guidance later this summer to give doctors and public health departments a roadmap for how to offer it.

While doxy-PEP will not be recommended for everyone, including most women, and the implications for antibiotic resistance need to be closely monitored, experts say its potential to curb the rising rates of STIs cannot be ignored.

"Our efforts to control STIs for the last 50 years have not succeeded," says Dr. Edward Hook, a professor of medicine and epidemiology at the University Alabama, Birmingham. "It's time to do something different."

Early results show promise

At this point, most of the research has focused on how well doxy-PEP works when offered to gay and bisexual men, and transgender women — groups that have disproportionately high rates of STIs.

"You really see a signal that there are consistent reductions across the board," says Dr. Annie Luetkemeyer, a professor of medicine and infectious diseases at the University of California, San Francisco who led a recent clinical trial on doxy-PEP, based in Seattle and San Francisco. "We saw that this was safe. We saw that it was well tolerated. We saw that it reduced sexually transmitted infections," she says.

Luetkemeyer's study, published earlier this year in the New England Journal of Medicine, found a 65% overall reduction in new STIs among those who took doxycycline within 24 to 72 hours after condomless sex.

Specifically, doxy-PEP cut new cases of chlamydia by about 80% and gonorrhea by more than 50%. It also reduced cases of syphilis, but there were fewer cases to report in their trial, she says. It proved so effective that the trial was stopped early so the control group, which wasn't using the antibiotic, could also start receiving it.

"Our study does not inform everybody," says Luetkemeyer, noting that participants either had an HIV diagnosis or were taking the HIV prevention drug, PrEP, and had at least one STI in the past year. "It informs a group of people who already had an elevated risk of sexually transmitted infections."

The research builds on promising results from Europe.

For example, researchers in France previously found doxy-PEP led to about a 70% reduction in the incidence of chlamydia and syphilis among men who have sex with men, compared to those who didn't receive the medication. And data presented earlier this year from another trial in France showed a 65% overall drop in new infections, including gonorrhea.

"The evidence is very strong," says Dr. Leandro Mena, director of the CDC's Division of STD Prevention. "More tools are needed in the nation's fight against bacterial STIs," which is why CDC is moving quickly on doxy-PEP, he says.

In fact, other recent research finds that if doxycycline is prescribed for 12 months at a time to patients with a STI diagnosis, that could reduce future infections by more than 40%.

"That's quite a big reduction," says Michael Traeger, a research fellow at Harvard Medical School who conducted the analysis.

While the federal guidelines are expected to focus on offering doxy-PEP to men who have sex with men and transgender women — the groups who were included in the U.S. and European clinical trials — Luetkemeyer says it's possible that could change in time: "There is a very reasonable argument that you could offer this to men who're at higher risk of sexually transmitted infections, regardless of their sexual orientation."

But the evidence diverges when it comes to doxy-PEP's effectiveness for most women.

A recent trial that included more than 400 Kenyan women, who were at high risk of STIs, concluded that doxy-PEP led to no reductions in STIs.

"It's a huge disappointment," says Dr. Jenell Stewart, an infectious disease physician at Hennepin Healthcare who led the trial. "It's incredibly disappointing that we don't have a solution to offer them right now."

The findings are likely due to some combination of "differences in anatomy, differences in antimicrobial resistant strains in different parts of the world, and adherence" to the medication, says Stewart, who emphasizes that there need to be more studies before drawing any firm conclusions that doxy-PEP doesn't work in most women.

Antibiotic resistance a concern — but early signs are reassuring

Broadening access to doxy-PEP would raise concerns about its potential contribution to antibiotic resistance, a global crisis that threatens to undermine some of our only treatments for certain bacterial and fungal infections.

"This is a really important novel biomedical intervention," says Dr. Manik Kohli, an academic clinical fellow at University College London. "For an effective rollout, there needs to be clear data and a clear plan in place for how you monitor for new antibiotic resistance."

While there are still questions about what could happen if doxy-PEP gains popularity, researchers have tried to look for signs of increased antimicrobial resistance among those taking the treatment.

For example, Staphylococcus aureus — a bacteria that's usually found on the nose and skin — can harbor resistance to doxycycline, and the U.S. trial found an 8% increase in resistance levels among those who took doxy-PEP.

"What that trajectory would look like over time is hard to know, but it's going to be really important to understand that," says Luetkemeyer.

She points out doxycycline isn't actually used to treat most staph infections, although one exception is MRSA, a nasty type of staph that can lead to lethal infections. MRSA can also hang out in people's noses without causing serious infections in most cases. Luetkemeyer says not many people had doxycycline-resistant MRSA in their nose at the beginning of her study, and there didn't appear to be an increase in resistance among those who took the medication.

Gonorrhea is another area of concern because of its propensity to develop resistance. About a quarter of gonorrhea cases in the U.S. are already resistant to the class of antibiotics that doxycycline is a part of, and, in some parts of the world, it's much higher.

This well-documented resistance is why doxycycline isn't recommended for treating gonorrhea and other antibiotics are used instead, says Hook at the University of Alabama, Birmingham. Doxy-PEP trials do show it's less effective at preventing gonorrhea compared to chlamydia, but the fact that it made a meaningful dent in gonorrhea at all should be seen as a "bonus," rather than cause for concern, he says.

"It's reasonable to assume that resistance rates for gonorrhea in particular will increase [with wider adoption of doxy-PEP]," Hook says. "I don't think it should stand in the way of people seriously considering using this as a public health intervention."

Even if widespread use of doxy-PEP runs the risk of increasing antibiotic resistance, Luetkemeyer stresses that using doxy-PEP isn't ultimately "a choice between antibiotics and no antibiotics." That's because many of those who didn't receive doxycycline in her study ended up contracting STIs and needing antibiotics eventually for treatment.

Coming soon to a doctor near you?

The growing evidence and the anticipated federal recommendations are expected to help move doxy-PEP more into the mainstream of STI prevention and LGBTQ+ health care.

But it won't necessarily be new to everyone.

Already, some have adopted doxy-PEP to ward off bacterial STIs.

"It's been working," says Keith Byrd, a gay man who lives in Fort Lauderdale and was prescribed doxycycline by his primary care doctor.

Byrd first heard about the idea of doxy-PEP from a friend who's in public health and decided to give it a try after reading more about the research. It's not something he does regularly, but he has taken doxycycline a number of times in the past year after having new sexual partners.

"I have certainly talked with a lot of my friends about it, but I don't think it's very mainstream in the gay community at this point," he says.

Encouraged by the evidence, San Francisco's health department released its own recommendations on doxy-PEP and began offering it to patients at its STI clinic in the fall.

"Interest has been very high," says Dr. Oliver Bacon, who's a senior supervising physician at San Francisco City Clinic, which is run by the local health department.

Bacon says the motivation to move quickly on doxy-PEP — faster than even the CDC — was, in part, because some patients were already "unofficially" using antibiotics in one way or another to prevent STIs

"They were taking doxy randomly. It was sort of like 'doxy anarchy' out there," says Bacon. "We don't want that to happen. That's not good for anybody. It doesn't treat the problem and it certainly doesn't help issues of antibiotic resistance."

In the U.K., Dr. Kohli says he's also found some patients have resorted to using an "assortment of antibiotics," depending on what they have lying around at home."

"They're not always using doxycycline and that's obviously important to address because actually there's no data around using different antibiotics," he says. "We have no idea if they would work."

The CDC's Mena says the agency recognizes that many health departments and clinicians are waiting for their guidance — what will help "establish standards of care" — before moving forward.

At the San Francisco clinic, Dr. Bacon says they try to have honest conversations with patients about what's known and isn't known about doxy-PEP, but generally the people who would benefit seem eager to protect themselves and their partners.

"Sometimes people think, 'oh, STDs, what's the big deal? It's not HIV. Who cares?'" says Bacon. "People do care. They don't want to get gonorrhea, chlamydia or syphilis. They don't want the symptoms themselves. They don't want to infect their sexual partners. There can be quite a lot of stigma associated with having an infection."