Post-trial data highlight doxyPEP resistance concerns

A new analysis of data from a clinical trial investigating the efficacy of doxycycline post-exposure prophylaxis (doxyPEP) raises more questions about its use for gonorrhea infections.

The trial, conducted in France in 2021 and 2022, was one of several randomized controlled trials and real-world studies that have found that use of doxyPEP, which involves taking a dose of doxycycline after unprotected sex, is highly effective at preventing syphilis and chlamydia in high-risk groups, such as in men who have sex with men (MSM) and transgender women. Compared with MSM who received placebo, doxyPEP users saw an 83% reduction in the combined incidence of chlamydia and syphilis.

But the trial investigators also found the strategy was less effective in reducing gonorrhea infections and observed an increase in tetracycline resistance in Neisseria gonorrhea samples from participants assigned to the doxyPEP arm.

In the study, published today in Clinical Infectious Diseases, the same researchers took a closer look at gonorrhea samples collected during the trial and found that high-level tetracycline resistance was nearly three times as frequent in doxyPEP users as in trial participants in the placebo group. More concerning, they also found reduced susceptibility to cefixime in doxyPEP users compared with those who received placebo.

Optimism and concern

With sexually transmitted infection (STI) rates continuing to rise around the world, public health officials have been cautiously optimistic that doxyPEP could be an effective STI reduction strategy. There have also been concerns, however, that the strategy could increase antibiotic consumption and promote antibiotic resistance, especially if it becomes more widely used. All of the known trials to date have found that doxyPEP is associated with increased tetracycline resistance in N gonorrhoeae.

Although doxycycline hasn’t been used to treat gonorrhea since 1985, the researchers note that there are concerns that the tetM gene (Tet-HLR) could be associated with cross resistance to other antibiotics that are currently used for gonorrhea.

“GC [gonococcal] AMR [antimicrobial resistance] is of concern worldwide, particularly resistance to third-generation cephalosporins and fluoroquinolones, and is considered a priority issue by the WHO [World Health Organization] and the US Centers for Disease Control and Prevention,” the study authors wrote.

In the ANRS 174 DOXYVAC trial, 545 participants were randomized into the doxyPEP (362) and no-doxyPEP (183) arms and tested for GC infection at baseline and every 3 months over 14 months. For the new study, the researcher examined antibiotic susceptibility data on 78 GC isolates collected during the trial and conducted whole-genome sequencing on 233 nucleic acid amplification test (NAAT)-positive samples to identify the molecular determinants of resistance.

The combined analysis showed that all GC isolates were resistant to tetracycline, with a significant increase in the rate of high-level tetracycline resistance mediated by Tet-HLR in the doxyPEP arm compared with the no-doxyPEP arm (35.5% vs 12.5%). 

Resistance levels to other antibiotics were similar in both arms of the trial. But while all of the GC isolates analyzed were still susceptible to ceftriaxone and cefixime (the recommended first-line and alternative treatments for gonorrhea), the researchers did find that isolates with decreased susceptibility to cefixime linked to a novel genetic mutation (the penA34.007 allele) were more frequent in the doxyPEP arm than the no-doxyPEP arm (32.2% vs 10.0%).

“Ongoing monitoring of this penA34.007 allele will be essential to identify the possible acquisition of additional resistance-associated mutations,” the authors wrote. 

Developing a gonorrhea vaccine essential

The authors note that the results have led French health officials to adopt a more cautious approach to doxyPEP, recommending it only for MSM and transgender women who are at high risk of STIs. Guidelines in the United States are similar. 

They add that the results suggest doxyPEP is not an appropriate solution for preventing gonorrhea infections, and that the development of a vaccine for gonorrhea is essential.