Efficacy and in vitro activity of gepotidacin against bacterial uropathogens, including drug-resistant phenotypes, in females with uncomplicated urinary tract infections: results from two global, pivotal, phase 3 trials (EAGLE-2 and EAGLE-3)

Abstract

Two recent Phase 3 trials demonstrated the efficacy of gepotidacin compared with nitrofurantoin to treat uncomplicated urinary tract infections (uUTIs) in females. Pretreatment urine specimens were obtained from all participants. Based on pooled trial data (treatment groups combined), central laboratory culture results identified 1,421 (45%) participants with ≥1 baseline qualifying (≥10⁵ CFU/mL) uropathogen (i.e., pooled microbiological Intent-to-Treat population). Escherichia coli, Klebsiella pneumoniae, and Proteus mirabilis were the most common qualifying uropathogens. Among 1,159 E. coli isolates, 28%, 28%, 15%, and 28% were fluoroquinolone resistant (FQ-R), trimethoprim-sulfamethoxazole resistant (SXT-R), extended-spectrum β-lactamase positive (ESBL+), and multidrug resistant (MDR), respectively. For 114 K. pneumoniae isolates, 25%, 23%, 16%, and 16% were nitrofurantoin resistant, SXT-R, FQ-R, and ESBL+, respectively. Of 67 P. mirabilis isolates, 25%, 21%, and 31% were SXT-R, FQ-R, and MDR, respectively. Gepotidacin MIC₉₀ values against all qualifying uropathogens and drug-resistant phenotypes ranged from 0.25 to 32 µg/mL, with no isolates of Enterobacterales, Staphylococcus saprophyticus, or Enterococcus faecalis considered resistant to gepotidacin. For all uropathogen drug-resistant phenotypes, gepotidacin MIC₉₀ values were similar (i.e., lower, equal to, or 1-dilution higher) compared with the MIC₉₀ of the overall species. Gepotidacin's efficacy, based on therapeutic, clinical, and microbiological success rates, was generally consistent across phenotypic subgroups of E. coli, K. pneumoniae, and P. mirabilis. This pooled analysis represents a robust, contemporary, clinically relevant, and unbiased (i.e., baseline urine specimens obtained from all enrolled participants regardless of uUTI history) collection of data from community-acquired uUTIs in females.CLINICAL TRIALSThis study is registered with ClinicalTrials.gov as NCT04020341 and NCT04187144.

Keywords: acute cystitis; antibacterial resistance; extended-spectrum β-lactamase; gepotidacin; multidrug resistant; nitrofurantoin; phenotype; uncomplicated urinary tract infection; uropathogen.

Fig 1

Therapeutic (A), clinical (B), and microbiological (C) success at TOC by selected baseline qualifying uropathogens and drug-resistant phenotypes with n ≥ 10 participants for at least one treatment group for pooled EAGLE-2 and EAGLE-3 data (micro-ITT population). ^aAll drug-resistant phenotypes were per the CSLI or EUCAST guidelines as described in the footnotes. Phenotypes were determined per CLSI M100 2022 guidelines (19) with the exception of cefadroxil and nitroxoline, which were determined by EUCAST 2022 guidelines (21). Isolates with intermediate susceptibility interpretations were not included in the corresponding drug-resistant phenotypic categories. Only baseline qualifying uropathogen (present at ≥10⁵ CFU/mL) phenotypes with n ≥ 10 isolates for the pooled trials in at least one treatment group are displayed. Of note, additional phenotypes are presented in Table 2 due to the different threshold of ≥10 participants in the combined treatment groups. ^bFor therapeutic and clinical 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 for pooled data. ^dBreakpoints for therapy of uUTIs; tested according to CLSI guidelines in a 2:1 ratio. ^eTested by the disk diffusion method. Breakpoints and interpretations per EUCAST guidelines for uUTIs only. ^fBreakpoints for when used as a surrogate test for oral cephalosporins for treatment of uUTIs due to E. coli. ^gFQ-R resistance to ciprofloxacin and/or levofloxacin using CLSI breakpoints. ^hTested by the disk diffusion method. Interpretations were per CLSI guidelines for testing and reporting of E. coli urinary tract isolates only. ⁱTested by the disk diffusion method. Breakpoints and interpretations per EUCAST guidelines for uUTIs only due to E. coli. ^jESBL+ indicates extended spectrum β-lactamase production per CLSI M100 Table 3A. ^kMDR was defined as resistance to ≥3 relevant antibacterial classes. ^lFor 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.