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Antimicrobial drug-resistant Neisseria gonorrhoeae (GC) infections in men using doxycycline postexposure prophylaxis. A substudy of the ANRS 174 DOXYVAC trial Bacterial STI prevention by doxycycline postexposure prophylaxis (DoxyPEP) in men who have sex with men (MSM) has raised concerns about antimicrobial drug resistance (AMR). We studied the impact of DoxyPEP on Neisseria gonorrhoeae (GC) AMR in the ANRS 174 DOXYVAC trial.MethodsMSM on HIV PrEP randomized to DoxyPEP (n= 362) or no-PEP (n=183) arms were tested for GC at baseline and every three months thereafter, by culture and NAAT. MICs were determined with Etest (Biomerieux) and interpreted according to EUCAST guidelines. We performed whole-genome sequencing and/or PCR sequencing on GC isolates and NAAT-positive samples, using Fisherâ€™s exact tests for comparisons.ResultsFrom January 2021 to February 2023, MICs were determined for 78 GC isolates, and 233 NAAT only GC-positive samples were analysed to identify the molecular determinants of resistance. All GC isolates were resistant to tetracycline with a significant increase in rate of high-level tetracycline resistance mediated by the tetM gene in the DoxyPEP arm than in the no-PEP arm (35.5 vs. 12.5%, respectively p=0.043). The MICs of ceftriaxone, fluoroquinolones and azithromycin were similarly distributed in the DoxyPEP and no-PEP arms. All GC isolates were susceptible to ceftriaxone and cefixime, but isolates with decreased susceptibility to cefixime linked to the mosaic penA34.007 allele were more frequent in the DoxyPEP arm than the no-PEP arm (32.3% vs 10.0%, respectively p=0.033).ConclusionsDoxyPEP use was associated with a significant increase in high-level tetracycline resistance and decreased susceptibility to cefixime in GC. AMR should therefore be closely monitored when using this strategy. https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf591/8317541?rss=1