High in vitro activity of the novel antimicrobial gepotidacin against Neisseria gonorrhoeae isolates in eight WHO Enhanced Gonococcal Antimicrobial Surveillance Programme countries in three WHO regions, 2021-24.

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.