A dose of the oral antibiotic doxycycline taken after engaging in high-risk sexual activity has significantly lowered the rates of sexually transmitted infections (STIs) in areas where this method is implemented.
Although it’s proving effective, the approach known as doxy-PEP (doxycycline post-exposure prophylaxis) may carry risks, particularly with long-term use. Experts are concerned about how it might affect the community of gut bacteria, referred to as the microbiome, and the potential for the development of antibiotic-resistant bacteria.
Researchers at UC San Francisco have applied metagenomic sequencing to examine the effects of frequent doxycycline use over six months on the gut microbiome. Their findings provide both reassurance and noteworthy concerns.
While doxy-PEP did not significantly alter the overall makeup of bacterial communities in the digestive systems of participants, there were indications of increasing resistance to tetracycline, the antibiotic class related to doxycycline, which could reduce its effectiveness.
The study was published on October 3 in the journal Nature Medicine.
“Although doxy-PEP didn’t seem to drastically affect the gut microbiome overall, it did influence the resistance of gut bacteria to antibiotics, both in terms of the prevalence of tetracycline resistance genes and their level of expression,” stated Chaz Langelier, MD, PhD, an associate professor of medicine in the UCSF Division of Infectious Diseases and the paper’s senior author. “Thus, it’s not completely without risks.”
San Francisco’s Significant Role in STI Prevention
Doxy-PEP stands for doxycycline post-exposure prophylaxis, and it requires individuals to take two 100-milligram pills within 72 hours following unprotected sex.
Following initial promising results from clinical trials, San Francisco became the first city in the U.S. in October 2022 to suggest doxy-PEP for gay and bisexual men, as well as transgender women who have a record of unprotected encounters with multiple partners.
In March 2024, the San Francisco Department of Public Health announced that after about a year, this method led to a 50% reduction in the incidence of chlamydia and early syphilis. Subsequently, in June, the Centers for Disease Control and Prevention (CDC) released guidelines endorsing doxy-PEP for these groups, marking its first new STI prevention tool in several decades.
Nonetheless, widespread antibiotic use raises fears about increasing resistance and potential negative effects on gut health, particularly regarding the balance of bacteria and other microbes. Disruptions may result in symptoms such as diarrhea, nausea, fever, and abdominal pain, and up until now, limited research has been conducted on these side effects.
Collaborating with the Chan Zuckerberg Biohub and researchers from Washington and Georgia, UCSF scientists examined participants from a recent doxy-PEP clinical trial conducted in San Francisco and Seattle, led by Annie Luetkemeyer, MD, a professor of medicine in UCSF’s Division of Infectious Diseases.
The study involved 100 individuals who took doxy-PEP and 50 individuals who followed standard care and did not use doxy-PEP. Researchers analyzed rectal swabs obtained at the start and after six months to investigate the presence of DNA and RNA from gut bacteria and their resistance genes.
“While we observed no significant changes in the gut bacteria community among doxy-PEP users, we noted a gradual increase in tetracycline resistance genes over time in these individuals,” commented Victoria T. Chu, MD, MPH, an assistant professor of pediatrics in UCSF’s Division of Global Health and Infectious Diseases and the study’s first author. “It also seemed to be dose-dependent, indicating that higher usage of doxy-PEP corresponded with a more substantial increase.”
Further research is required to identify which gut bacteria are activating these tetracycline-resistant genes and whether this could lead to more infections resistant to doxycycline among users and the broader community.
“Currently, it appears that the benefits outweigh the drawbacks,” Langelier expressed. “Especially considering the significant rise in STIs, particularly syphilis, seen over the last decade.”
Authors: Other contributors from UCSF and Biohub include Abigail Glascock, PhD, Chase Cannon, MD, MPH, Stephanie E. Cohen, MD, MPH, Katrina L. Kalantar, PhD, Ryan Ward, MS, and Christina Love, BS.
Funding: This research received support from grants provided by the National Institutes of Health (NCT03980223), the National Heart, Lung, and Blood Institute (R01HL155418), and the National Institute of Allergy and Infectious Diseases (K23AI144036, R01AI143439, R01AI143431).
