A genomic analysis of US gonorrhea isolates shows a dramatic increase in tetracycline resistance.
In a letter published this week in the New England Journal of Medicine, researchers from the Harvard TH Chan School of Public Health and the University of Georgia reported that their analysis of more than 14,000 publicly available Neisseria gonorrhoeae genome sequences collected through the Centers for Disease Control and Prevention's N gonorrhoeae surveillance system from 2018 through 2024 show that the percentage of isolates carrying the tetM resistance gene rose from 10% in 2020 to more than 30% in 2024. The tetM gene confers high-level resistance to tetracycline antibiotics.
The analysis also found that the number of large tetM-carrying N gonorrhoeae lineages increased from one to four over the period. The researchers suggest that increased use of doxycycline for treatment of chlamydia infections and for doxycycline post-exposure prophylaxis (doxyPEP) may be playing a role.
Resistance increase tied to doxyPEP rollout
"The increase in tetM prevalence in 2020 coincided with the shift away from azithromycin and toward doxycycline for treatment of chlamydia, and the increase that started in the summer of 2022 coincided with the reporting of the results of the DoxyPEP trial," the researchers wrote, citing a conference abstract.
The highest prevalence of tetM-carrying N gonorrhoeae was in the Pacific Northwest. Seattle was also one of two cities (along with San Francisco) in which a large randomized clinical trial of doxyPEP was conducted. It was among the earliest adopters of doxyPEP for the prevention of sexually transmitted infections (STIs) for high-risk groups.
The increase in tetM prevalence in 2020 coincided with the shift away from azithromycin and toward doxycycline for treatment of chlamydia, and the increase that started in the summer of 2022 coincided with the reporting of the results of the DoxyPEP trial.
The doxyPEP trial, conducted from August 2020 to May 2022, found that taking a dose of doxycycline within 72 hours of unprotected sex significantly reduced incidence of chlamydia and syphilis by 88% and 87%, respectively, and gonorrhea by 55% in men who have sex with men (MSM) and transgender women. Public health departments in San Francisco and Seattle began recommending the strategy for these groups shortly after the trial results were announced in the summer of 2022.
The data from the doxyPEP trial and other clinical trials formed the evidence base for the CDC's recommendation of doxyPEP for gay, bisexual, and other MSM and transgender women in June 2024. Agency officials hailed it as the first new prevention tool against STIs in decades.
Concerns about highly drug-resistant gonorrhea strains
To date, several studies have shown doxyPEP to be highly effective in real-world settings against chlamydia and syphilis and moderately effective against gonorrhea. But the new study is the latest to add to concerns that doxyPEP use may be promoting tetracycline resistance in gonorrhea—a result that even proponents of the strategy have said needs to be monitored.
Although doxycycline is no longer used to treat gonorrhea, rising tetracycline resistance could reduce doxyPEP's already limited effectiveness at preventing gonorrhea infections. There's also concern about tetracycline resistance in "off-target" bacteria.
In a study published earlier this year, researchers with the University of Washington found that, among gonorrhea isolates collected at a sexual health clinic in Seattle, the prevalence of tetracycline resistance genes rose from 27% in 2017 to 70% by the middle of 2024. They also found that colonization with tetracycline-resistant Staphylococcus aureus and group A Streptococcus bacteria—which are often present in the body sites where N gonorrhoeae is found—was more common among doxyPEP users than non-users.
"Public health authorities should implement additional surveillance monitoring to assess the impact of doxy PEP implementation on bacterial colonization and AMR [antimicrobial resistance], including monitoring for clinically significant events related to doxy PEP induced changes in patients' microbiomes," the authors of that study concluded.
Concerns over potentially untreatable gonorrhea
Another concerning finding in the new study is that of the four major tetM-carrying N gonorrhoeae lineages identified, two carry mutations in another gene (penA) that confer high-level resistance to ceftriaxone, which is the currently recommended treatment and last remaining effective antibiotic for gonorrhea. The strains are also resistant to fluoroquinolone and macrolide antibiotics.
China and other countries in Asia have reported increases in incidence of these highly drug-resistant gonorrhea strains in recent years, raising concerns about the potential for untreatable gonorrhea.
"The strength of selection in the United States for tetM, as indicated by the increasing proportion of isolates that carry the gene and the expansion of major tetM-carrying lineages, suggests a favorable environment for these highly drug-resistant strains to spread within the country and highlights the need for continued surveillance," the researchers wrote.
Lead author Yonatan Grad, MD, PhD, says increasing use of doxycycline is contributing to that favorable environment.
"The rise in use of doxycycline, combined with the use of ceftriaxone for treatment, will increase selection for strains carrying tetM and mosaic penA 60 and 237 (which are also often resistant to other antibiotics)," Grad told CIDRAP News in an email.
To date, the United States, Germany, Australia, and the United Kingdom are the only countries to officially recommend use of doxyPEP for the prevention of STIs. But in a report published last week in Eurosurveillance, Dutch researchers noted that informal use of doxyPEP in the Netherlands has been rising, despite lack of formal guidance from the Dutch health officials. They warned that lack of monitoring and regulation could lead to overuse and misuse.
Editor's note: This story was update on July 12 with comments from Yonatan Grad, MD, PhD.
