Efficacy and in vitro activity of gepotidacin against bacterial uropathogens, including subsets with molecularly characterized resistance mechanisms and genotypes/epidemiological clones, in females with uncomplicated urinary tract infections: results from two global, pivotal, phase 3 trials (EAGLE-2 and EAGLE-3)

Abstract

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 in vitro 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 Escherichia coli isolates, 30% harbored quinolone resistance-determining region (QRDR) mutations; most prevalent was gyrA S83L, D87N (27%). Extended-spectrum β-lactamases (ESBLs) were detected in 13% of E. coli isolates. For 114 Klebsiella pneumoniae isolates, 22% were plasmid-mediated quinolone resistance (PMQR) gene-positive, 11% had QRDR mutations, and 12% had ESBLs. Among 67 Proteus mirabilis 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 E. coli isolates with the PMQR qnrS1 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 in vitro 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.

Keywords: acute cystitis; antibacterial resistance; extended-spectrum β-lactamase; genotype; gepotidacin; molecular characterization; nitrofurantoin; uncomplicated urinary tract infection; uropathogen.

Fig 1

Therapeutic (A), clinical (B), and microbiological (C) success at TOC by selected baseline qualifying uropathogens and genotypic subcategories with n ≥ 10 participants for at least one treatment group for pooled EAGLE-2 and EAGLE-3 data (micro-ITT population). Footnotes: ^aOnly select baseline qualifying uropathogens (present at ≥10⁵ CFU/mL) and genotypic subcategories with n ≥ 10 isolates for the pooled trials in at least one treatment group are displayed. Uropathogens may have more than one genotype. Of note, epidemiological clone results for E. coli are not included as the subset of isolates for molecular characterization included all microbiological failure isolates; therefore, the efficacy data are biased toward failure. ^bFor clinical and therapeutic response, a participant was counted once under a uropathogen category if multiple qualifying uropathogens within that category were isolated at baseline for the participant. Participants for whom all uropathogens were not eradicated and all symptoms were not resolved were considered therapeutic failures for all uropathogens. For therapeutic and clinical success: n/N1 = (n) the number of participants within the category with a response of success/(N1) the total number of participants within the category, and is the denominator for corresponding percentages. ^cThe N in the header represents the total number of participants in the treatment arm. ^dFor microbiological response, a participant was counted more than once under a uropathogen category if multiple qualifying uropathogens within that category were isolated at baseline for the participant. For microbiological success: n/N1 = (n) the number of isolates that are a microbiological success/(N1) the total number of isolates in the category, and is the denominator for the corresponding percentages.