As rates of sexually transmitted infections continue to skyrocket across the United States, a growing number of physicians are prescribing a commonly used antibiotic as a way to prevent chlamydia, gonorrhea and syphilis infections in gay and bisexual men and transgender women.
Doxycycline is a class of medications traditionally used to treat bacterial STIs after someone has been infected. Yet recent research suggests that one 200mg dose of the drug can be effective in preventing such infections among men who have sex with men if taken within 72 hours after unprotected sex.
This approach, called doxyPEP, has garnered so much attention that the US Centers for Disease Control and Prevention is expected to post draft guidance for public comment in the next several weeks on how health care workers may deploy the preventative treatment, such as how many pills should go into a prescription or which people could benefit most from the drug.
“The number of syphilis cases in the United States are at their highest level in over 50 years. The nation needs new tools to prevent STIs,” Dr. Jonathan Mermin, director of CDC’s National Center for HIV, Viral Hepatitis, STD, and TB Prevention, said in an email.
“CDC is working on formal clinical guidelines on the use of doxycycline as STI PEP and will be requesting public comment on the agency’s draft recommendations,” he wrote. “This step allows us to gather important input before finalizing guidance, and gives clinical providers, people affected by STIs, and partner organizations the opportunity to weigh in before our guidance is finalized.”
However, some local health departments already have their own recommendations for the use of doxyPEP to prevent STIs.
The San Francisco Department of Public Health released doxyPEP guidance in October. In April, the California Department of Public Health released similar guidance for health care providers recommending doxyPEP to men who have sex with men or transgender women who have had at least one bacterial STI in the past 12 months.
“We have high rates of sexually transmitted infections in San Francisco, and we consider this to be one of our urgent public health issues that we face as a city. And so, we felt like there was an imperative to move forward with providing a framework for the safe and equitable use of this innovative new tool for sexual health,” said Dr. Stephanie Cohen, director of the HIV/STI Prevention Section in the San Francisco Department of Public Health’s Disease Prevention and Control branch.
“We knew that it would take the CDC some time to develop and release consensus guidelines. But we also knew that we had people in our community and providers who were prescribing doxyPEP, so we didn’t feel that we could wait,” she said. “We’re now not the only health department who has released guidelines. A growing number of health departments throughout the country are putting out guidelines as they also see the need for this in their community.”
Cohen noted that Seattle and King County in Washington state have also released guidelines on the use of doxyPEP to prevent bacterial STIs in men and transgender people who have sex with men.
But not all of these local and state guidelines are aligned, she said, and there are some “subtle differences” emerging, especially when it comes to who is recommended to use doxyPEP. The hope is that any forthcoming CDC guidance can help settle those differences and clarify which people may be eligible.
“Right now, clinicians are learning from each other in real time how to provide doxycycline as STI PEP,” David C. Harvey, executive director of the National Coalition of STD Directors, said in an email. He added that any guidance from the CDC will help “fill gaps,” provide direction to clinics and offer a framework for using doxyPEP for STI prevention.
“An increasing number of doctors are providing their patients with doxycycline as STI PEP, including many of the nation’s most renowned STI clinics. Doxycycline is a safe, inexpensive, well-understood drug, and the evidence it works as PEP for men and transgender women is well-documented and consistent across research,” Harvey wrote. “Doctors recognize the urgency of the STI epidemic, which is why so many clinics are moving forward and so many bigger agencies are pressing CDC to provide them with the information they need to roll it out more broadly.”
‘It’s a way to prevent a full-blown infection’
DoxyPEP was found to be about 65% effective at reducing the incidence of gonorrhea, chlamydia and syphilis in a recent study.
About 500 men who have sex with men and transgender women were enrolled in the study from August 2020 through May 2022. The participants — who all had a history of STIs in the past year — were randomly assigned to receive either doxyPEP or their usual standard of care without doxyPEP. The study, published in April in the New England Journal of Medicine, was conducted at clinics in San Francisco and Seattle.
“This is not a new concept, the concept of post-exposure prophylaxis. We use it for a number of other infectious diseases like Lyme disease. If someone’s been bitten by a tick and there’s concern that they might have been exposed to Lyme disease, they can be given a single dose of doxycycline,” said Dr. Annie Luetkemeyer, professor of infectious diseases at Zuckerberg San Francisco General Hospital at UCSF and co-principal investigator of the study.
“It’s a way to prevent a full-blown infection,” she said. “We know that some populations of men who have sex with men are really disproportionately impacted by sexually transmitted infections.”
Among the study participants without HIV, a bacterial STI was diagnosed in about 10.7% of quarterly visits to clinics in the doxyPEP group, compared with 31.9% of visits in the standard care group.
Among the participants living with HIV, a bacterial STI was diagnosed in about 11.8% of quarterly visits to clinics in the doxyPEP group, compared with 30.5% of visits in the standard care group.
At the end of the study, the researchers found that every quarter — or about every three months — the combined incidence of gonorrhea, chlamydia and syphilis was lower by two-thirds among those who took doxyPEP within 72 hours after having sex without a condom than in those with standard care.
“There was a large reduction in chlamydia and syphilis. We weren’t sure if it was going to work against gonorrhea,” Luetkemeyer said. “But we saw about a 55% reduction in gonorrhea.”
However, the researchers also found a slight increase in the number of gonorrhea infections with doxycycline-class resistance in the doxyPEP group compared with the standard-care group in the study. This suggests that doxyPEP may offer less protection against existing gonorrhea strains that have developed resistance to doxycycline.
Still, the number of gonorrhea cases that were tested for resistance was low, and population-based evaluations of people taking doxyPEP will be needed to understand the potential impact of doxycycline use on gonorrhea antibiotic resistance.
Antimicrobial resistance happens when germs, such as bacteria and fungi, develop the ability to defeat the medications that have been engineered to destroy them. Bacteria can sometimes develop this ability when certain antibiotics are being overused.
There are some remaining questions about long-term effects on antimicrobial resistance in particular, said Dr. Connie Celum, professor of global health and medicine at the University of Washington and co-principal investigator of the doxyPEP study.
“The challenge is, we don’t have a great outpatient antibiotic resistance surveillance system. Most of what we know about antibiotic resistance system is from hospitalized patients,” she said. “Now, we’re talking about doing doxyPEP in outpatient settings. So we’re trying to think about how to nest in antibiotic resistance surveillance in selected implementation projects to give us more information on antimicrobial resistance.”
As doxycycline is an antibiotic, doxyPEP doesn’t prevent viral sexually transmitted infections such as mpox, herpes or HIV. There also hasn’t been much research on the medication as post-exposure prophylaxis in cisgender women.
In one study, more than 400 women in Kenya were separated into two groups: One group was given doxyPEP to take after having sex, and the other group wasn’t. The researchers — from Hennepin Healthcare Research Institute, the University of Washington and Kenya Medical Research Institute — found that there was not much of a difference in the incidence of bacterial STIs between the two groups.
“It was a disappointment to see that doxycycline PEP was not protective for cisgender women in the dPEP Kenya Study. We now have data to help understand these results a bit more,” Dr. Jenell Stewart, project director for the DoxyPEP Kenya study and infectious disease physician at Hennepin Healthcare and the University of Minnesota, said in an email.
That new data reveals that there were low rates of women in the study actually taking doxycycline, Stewart said, as well as a high prevalence of a gonorrhea strain that is known to be resistant to the medication. She added that it remains unclear why some of the study participants were not taking their doxyPEP pills, which probably skewed the study findings.
“Additional studies are needed among cisgender women, transgender men, and nonbinary people with vaginas to provide additional data on the potential of doxycycline PEP to be an effective preventive tool regardless of sex and gender,” Stewart wrote.
“Condoms work very well at preventing STIs, but it’s clear from rising rates of STIs around the world that condoms don’t fit into everyone’s sex life, so we need additional options for preventing infections and reducing the spread of STIs,” she said. “I don’t think everyone needs to use doxycycline PEP, but this is a potentially important tool, especially for people who are not in monogamous sexual relationships.
US sees surging STI rates
When used for STI prevention, doxyPEP is an off-label prescription, since the US Food and Drug Administration has not officially approved it for STI post-exposure prophylaxis and the CDC has yet to release its final guidance.
Along with STI clinics providing doxycycline as a post-exposure prophylaxis medication, people can order it online from some providers, such as the sexual health care company Wisp.
Even though most of the studies on doxyPEP have been in men, Wisp offers doxyPEP for everyone, including women, Dr. Suneer Chander, a provider at Wisp, said in an email, adding that that decision is due to the ongoing rise in STIs among both men and women in the United States.
“Considering the potential impact of this treatment and the low risk associated with a single dose of doxycycline, Wisp believes it’s important for all our patients, especially those with limited access to care, to have access to this preventative treatment,” Chander wrote.
“Some people may be worried about antibiotic resistance if they take doxyPEP without actually having been exposed to a bacterial STI. Currently, clinical trials have not proven that doxyPEP will increase antibiotic resistance,” Chander said in part. “Drug resistance when taking doxyPEP is currently being studied in people using this treatment for STI prevention. Still, given the increase in STI cases in the US over the past few years, this treatment is vital in preventing STI spread.”
Rates of sexually transmitted infections have been rising across the United States, with more than 2.5 million cases reported in 2021, a jump of 7% in one year, according to data released in April by the CDC.
Chlamydia accounted for more than half of those cases, with rates increasing about 4% in 2021. Cases of gonorrhea rose nearly 5%. Cases of syphilis surged 32% in one year, including an alarming rise in infections passed from pregnant mothers to babies developing in the womb. In 2021, congenital syphilis caused 220 stillbirths and infant deaths.
The CDC’s Mermin said that publishing guidance on doxyPEP is not the end of the agency’s efforts to reduce rates of STIs across the country.
“To decrease incidence of STIs and reduce health disparities, we will need to remove barriers to STI services and prioritize equitable access to this new prevention strategy so it can reach the people who need it most,” he wrote in his email.
“There are still many STI prevention and treatment gaps left to fill. Continued research and investment are needed to discover new interventions and fully implement testing, prevention, and treatment solutions for everyone impacted by STIs,” he said. “In STI prevention, we’ve been relying on tools that are decades, sometimes centuries old. This new intervention is not enough, but it brings hope that we can finally turn the STI epidemic around.”
