Abstract
OBJECTIVES: The spread of ceftriaxone-resistant Neisseria gonorrhoeae is threatening the last option for gonorrhoea treatment, ceftriaxone. Gepotidacin, the first-in-class triazaacenaphthylene bacterial topoisomerase type IIA inhibitor, recently showed non-inferiority compared to ceftriaxone-azithromycin for treatment of uncomplicated urogenital gonorrhoea in a Phase 3 randomized controlled trial. We evaluated the in vitro susceptibility to gepotidacin in clinical gonococcal isolates (n = 2912), including 125 (4.3%) ceftriaxone-resistant isolates, collected 2021-24 in eight WHO Enhanced Gonococcal Antimicrobial Surveillance Programme (EGASP) countries in three WHO regions. METHODS: Isolates from Cambodia (n = 474), Indonesia (n = 107), Malawi (n = 111), the Philippines (n = 817), South Africa (n = 578), Thailand (n = 249), Uganda (n = 342) and Vietnam (n = 234) were examined. MICs of gepotidacin were determined using agar dilution. Gepotidacin target genes (gyrA and parC) were examined with Illumina sequencing. RESULTS: Gepotidacin showed high in vitro activity, with MICs ranging from <0.016 to 4 mg/L. The modal MIC was 0.5 mg/L, MIC₅₀ 0.5 mg/L and MIC₉₀ 1 mg/L. Minor variations in the MIC distributions across countries were observed. ParC D86N, which in suboptimal gepotidacin concentrations predisposes for resistance development, was found in 35.5% of isolates. CONCLUSIONS: We show that the in vitro susceptibility to gepotidacin in N. gonorrhoeae isolates, including 4.3% ceftriaxone-resistant isolates, collected 2021-24 in eight WHO EGASP countries, including five Asian countries, is high. Our findings support gepotidacin's continued clinical development, registration and introduction as a novel oral treatment for gonorrhoea. However, as with all new novel antimicrobials, cautious and optimal introduction, and surveillance of phenotypic and genomic susceptibility to gepotidacin internationally, pre- and post-licencing, should accompany any clinical implementation.