Efficacy and <i>in vitro</i> activity of gepotidacin against bacterial uropathogens, including subsets with molecularly characterized resistance mechanisms and genotypes/epidemiological clones, in females with uncomplicated urinary tract infections:

Gepotidacin, a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial, was noninferior to nitrofurantoin in two pivotal trials (EAGLE-2 and EAGLE-3) in females with uncomplicated urinary tract infections (uUTIs). Using pooled data, gepotidacin <i>in vitro</i> activity and clinical efficacy were evaluated for subsets of molecularly characterized isolates in the microbiological Intent-to-Treat population. The subsets of isolates were characterized based on phenotypic/MIC criteria; all microbiological failure isolates were also characterized. Of 1,159 <i>Escherichia coli</i> isolates<i>,</i> 30% harbored quinolone resistance-determining region (QRDR) mutations; most prevalent was <i>gyrA</i> S83L, D87N (27%). Extended-spectrum β-lactamases (ESBLs) were detected in 13% of <i>E. coli</i> isolates. For 114 <i>Klebsiella pneumoniae</i> isolates, 22% were plasmid-mediated quinolone resistance (PMQR) gene-positive, 11% had QRDR mutations, and 12% had ESBLs. Among 67 <i>Proteus mirabilis</i> isolates, 21% harbored QRDR mutations. Gepotidacin MIC₉₀ values ranged from 1 to 32 µg/mL against qualifying Enterobacterales uropathogens and genotypic subcategories, with no isolates considered resistant to gepotidacin. For all genotypic subcategories, gepotidacin MIC₉₀ values were similar (i.e., lower, equal to, or 1-dilution higher) compared with the overall species (4 µg/mL), with the exception of <i>E. coli</i> isolates with the PMQR <i>qnrS1</i> gene (16 µg/mL); all were gepotidacin-susceptible. For the majority of uropathogens, including those with genotypes likely to cause resistance to standard uUTI therapies, success rates for gepotidacin were similar across genotypic subcategories for each species. These data show gepotidacin's efficacy and <i>in vitro</i> activity against a wide range of uropathogen genotypes. Additionally, these pooled results provide a robust, contemporary data set and insight into current genotypic mechanisms of resistance.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04020341 and NCT04187144.