Antimicrobial resistance in Neisseria gonorrhoeae among men who have sex with men: a 10-year analysis with implications for doxycycline post-exposure prophylaxis

ABSTRACT The implementation of HIV pre-exposure prophylaxis and doxycycline post-exposure prophylaxis may influence antimicrobial resistance in Neisseria gonorrhoeae among men who have sex with men (MSM). We examined trends in antimicrobial resistance among MSM, stratified by HIV and PrEP status, and assessed tetracycline resistance in relation to doxyPEP use. We included all MSM with an N. gonorrhoeae isolate at Melbourne Sexual Health Centre (MSHC) between 2015 and 2024. Resistance was defined using 2025 EUCAST breakpoints and epidemiological cutoff values. Trends were assessed using the Cochran-Armitage test, and tetracycline resistance was compared between doxyPEP users and non-users using the chi-square test. A total of 11,334 isolates from 6,611 MSM were included. Ceftriaxone resistance remained rare (3/11,334; 0.03%). The proportion of isolates with acquired azithromycin resistance mechanisms increased from 0.9% (8/940) in 2015 to 6.4% (102/1,584) in 2024 ( P trend < 0.001), above the 5% level at which the WHO recommends that an antimicrobial no longer be used for empirical treatment. Ciprofloxacin resistance increased substantially, from 18.5% (170/920) to 55.2% (875/1,584) ( P trend < 0.001), with significant trends in all three groups. Tetracycline resistance, assessable from 2019 onward, was consistently high (around 80%), with no significant trend. Among 1,020 isolates with known doxyPEP status, tetracycline resistance was significantly higher in doxyPEP users than in non-users (89.2% [107/120] vs 77.2% [695/900], P = 0.003). High-level tetracycline resistance (MIC > 8 mg/L) was also more common among doxyPEP users (54.2% vs 29.7%, P < 0.001). Ceftriaxone remains effective for empirical gonorrhea treatment among MSM in Melbourne. Rising the proportion of azithromycin non-wild-type raises concerns about its ongoing utility in dual therapy. Higher tetracycline resistance among doxyPEP users, particularly high-level tetracycline resistance, underscores the need to monitor for multidrug-resistant strains as doxyPEP use expands. IMPORTANCE Antimicrobial-resistant Neisseria gonorrhoeae is an urgent global health threat, and the expanding use of doxyPEP among MSM has raised concerns regarding its selective pressure on resistance. Linking a decade of individual-level clinical data to over 11,000 isolates from a major Australian sexual health clinic, we show that the proportion of azithromycin non-wild-type has risen to 6.4%, surpassing the 5% threshold at which the WHO recommends discontinuing an agent for empirical therapy. This finding raises concerns about the ongoing utility of dual ceftriaxone-azithromycin treatment. Furthermore, tetracycline resistance was significantly higher among doxyPEP users, with a disproportionate increase in high-level resistance (MIC >8 mg/L) that was associated with ciprofloxacin co-resistance. These findings provide timely real-world evidence to inform gonorrhea treatment guidelines and antimicrobial surveillance as doxyPEP implementation expands globally.