Doxycycline: Still Demonstrating its Clinical Usefulness Including as a Novel Prophylactic Tool

The antibiotic, doxycycline, is a broad spectrum therapeutic within the tetracycline class and used in a variety of clinical applications.¹It was patented in 1957 and was established as a commercial product in 1967.¹ In addition, the World Health Organization has included it on its List of Essential Medicines. And as close as 2020, the antibiotic was the 79th most commonly prescribed medication in the United States, with more than 9 million prescriptions.¹

Although it is an older therapy, in 2 studies published this year for 2 different clinical applications, doxycycline demonstrated its utility as a prophylactic in preventing sexually transmitted infections (STIs) as well as reducing the risk of 1 health care-associated infection.

The incidence rates for STIs continues to challenge public health officials and clinicians. According to the Centers for Disease Control and Prevention (CDC), an estimated 2.5 million cases of syphilis, gonorrhea, and chlamydia occurred in 2021 up from 2.4 million cases in 2020. With these increased rates of STIs, investigators wanted to take a novel approach to preventing these bacterial infections.²

Earlier this year, a study published in the New England Journal of Medicine showed that doxycycline prevented the acquisition of STIs among men who have sex with men (MSM) and transgender women who took the medication within 72 hours of having condomless sex.²

This approach, termed doxy-PEP (post-exposure prophylaxis), resulted in a two-thirds reduction in the incidence of syphilis, gonorrhea, and chlamydia among the study participants, all of whom reported having an STI within the previous year.²

“Effective methods for preventing sexually transmitted infections are badly needed,” said Hugh Auchincloss, MD, National Institute of Allergy and Infectious Diseases (NIAID), acting director. “This is an encouraging finding that could help reduce the number of sexually transmitted infections in populations most at-risk.” The research was funded by NIAID, which is part of the National Institutes of Health.²

Investigators performed an open-label, randomized study using 2 cohorts and involving 501 participants. The first one had MSM and transgender women who were taking PrEP against HIV infection, with 327 participants known as the (PrEP cohort), and the other cohort had 173 participants living with HIV infection (persons living with HIV [PLWH) cohort) and who had gonorrhea, chlamydia, or syphilis in the past year.³

Participants were randomly assigned in a 2:1 ratio to take 200 mg of doxycycline within 72 hours after condomless sex (doxycycline postexposure prophylaxis) or receive standard care without doxycycline. STI testing was performed quarterly. The primary end point was the incidence of at least one STI per follow-up quarter.³

“In the PrEP cohort, an STI was diagnosed in 61 of 570 quarterly visits (10.7%) in the doxycycline group and 82 of 257 quarterly visits (31.9%) in the standard-care group, for an absolute difference of −21.2 percentage points and a relative risk of 0.34 (95% confidence interval [CI], 0.24 to 0.46; P<0.001),” the investigators wrote.³

One thing to note, the investigators did report they saw a slight increase in antibacterial resistance. Initially, the doxy-PEP regimen had a ancillary benefit for reducing Staphylococcus aureusby 50% after a year, but for those participants who still had Staphylococcus aureus colonization at month 12, a modestly higher proportion of those in the doxy-PEP group had doxycycline resistance (16% vs 8%). This is significant clinical discovery since this antibiotic may be used to treat methicillin-resistant Staphylococcus aureus skin and soft tissue infections.²

What You Need to Know

Doxycycline, an established antibiotic patented in 1957, has shown significant efficacy in preventing sexually transmitted infections (STIs) among men who have sex with men (MSM) and transgender women.

In the context of community-acquired pneumonia (CAP) treatment, doxycycline was found to be associated with a decreased risk of Clostridioides difficile infection (CDI) compared to azithromycin when used alongside ceftriaxone.

These findings underscore the importance of recognizing and utilizing the clinical utility of older antibiotics like doxycycline in specific contexts.

In a recent large study performed through the Veterans Affairs health care system, it was found doxycycline usage had a decreased risk of C diff infection (CDI) when treated for CAP.

The study was published in the American Journal of Infection Control and included 156,107 hospitalized patients treated for CAP. The primary outcome was the development of CDI within 30 days of initiation of doxycycline or azithromycin, as part of a standard pneumonia regimen.⁴

“A 17% decreased risk of CDI was identified with doxycycline compared to azithromycin when used with ceftriaxone for the treatment of pneumonia (P = .03). In patients who had a prior history of CDI, doxycycline decreased the incidence of CDI by 45% (odds ratio 0.55; P = .02),” the investigators wrote.⁴

In fact, the antibiotic was a singular, beneficial factor in preventing the health care-associated infection.

"Our analysis found that in patients with a prior history of C diff, doxycycline was the only factor associated with a reduction in the incidence of new C diff infections," senior author Kari A. Mergenhagen, PharmD, Veterans Affairs of Western New York Healthcare System, said in a statement. "These results suggest that in cases where Legionella pneumonia can be ruled out prior to treatment, patients at increased risk of C diff may benefit from the use of doxycycline as a first-line agent."

These aforementioned, therapeutic applications for reducing incidence of STIs and C diff, can serve as a reminder that older, established antibiotics can demonstrate their utility in the right clinical circumstances, and may provide clinical benefits including optimal patient outcomes and antimicrobial stewardship.

3. Luetkemeyer AF, Donnell D, Dombrowski JC, et al. Postexposure Doxycycline to Prevent Bacterial Sexually Transmitted Infections. N Engl J Med. 2023;388(14):1296-1306. doi:10.1056/NEJMoa2211934

4. O'Leary AL, Chan AK, Wattengel BA, Xu J, Mergenhagen KA. Impact of doxycycline on Clostridioides difficile infection in patients hospitalized with community-acquired pneumonia. Am J Infect Control. Published online November 2, 2023. doi:10.1016/j.ajic.2023.09.007