In vitro activity of gepotidacin against a challenging panel of multidrug-resistant Neisseria gonorrhoeae isolates

Objectives Gepotidacin is a novel triazaacenaphthylene topoisomerase inhibitor that has demonstrated non-inferiority to 500 mg of intramuscular ceftriaxone plus 1 g of oral azithromycin for the treatment of uncomplicated urogenital gonorrhoea. We evaluated gepotidacin in vitro activity against a panel of ceftriaxone-resistant Neisseria gonorrhoeae isolates that were referred to the UK Health Security Agency between 2015 and 2023. Methods Gepotidacin and comparator antimicrobials were tested against 23 ceftriaxone-resistant (MIC ≥0.25 mg/L) N. gonorrhoeae isolates by agar dilution. Genomic sequences were examined for known resistance determinants and sequence types. Results Gepotidacin inhibited the majority (96%) of isolates at ≤2 mg/L, with MIC range, MIC₅₀ and MIC₉₀ values of 0.25–4, 0.5 and 2 mg/L, respectively. All 23 isolates had amino-acid modifications associated with ciprofloxacin resistance, including the rare GyrA A92P alteration in 10 isolates, none of which are believed to effect gepotidacin binding. All isolates had mutations causing the overexpression of the MtrCDE efflux pump and 10 isolates had mutations causing the overexpression of the NorM efflux pump. Nine different MLSTs were subdivided into 16 and 14 NG-MAST and NG-STAR types, respectively. MLST ST8123 was the most prevalent MLST and the gepotidacin MIC range against this sequence type was similar to the overall distribution. Conclusion Overall, gepotidacin was active in vitro against this challenging panel of ceftriaxone-resistant gonococcal clinical isolates. Gepotidacin activity does not seem to be affected in this ceftriaxone-resistant set of strains. A structural analysis suggests that the rare GyrA A92P alteration identified in this study does not affect gepotidacin binding.