<i>In vitro</i> activity of gepotidacin against urinary tract infection isolates of Enterobacterales, <i>Enterococcus faecalis</i> , and <i>Staphylococcus saprophyticus</i>

Gepotidacin is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication through a distinct binding site and unique mechanism of action, providing well-balanced inhibition of two different type II topoisomerase enzymes for most uropathogens. Phase III clinical trials, NCT04020341 (EAGLE-2) and NCT04187144 (EAGLE-3), showed gepotidacin to be non-inferior and superior, respectively, to nitrofurantoin for the treatment of patients with uncomplicated urinary tract infections (uUTIs). To better define gepotidacin <i>in vitro</i> activity against pathogens that commonly cause UTIs, CLSI broth microdilution MICs were determined for gepotidacin and seven comparator agents, and agar dilution MICs were determined for fosfomycin, against 4,000 predominantly UTI isolates of Enterobacterales (3,250), <i>Enterococcus faecalis</i> (500), and <i>Staphylococcus saprophyticus</i> (250) collected globally from 2012 to 2020. Gepotidacin MIC₉₀s against the Enterobacterales species tested were 4 µg/mL for <i>Escherichia coli</i> (1,000) and <i>Klebsiella oxytoca</i> (250), 8 µg/mL for <i>Citrobacter</i> spp. (250) and <i>Klebsiella aerogenes</i> (250), 16 µg/mL for <i>Proteus mirabilis</i> (250) and <i>Providencia rettgeri</i> (250), and 32 µg/mL for <i>Enterobacter cloacae</i> (500) and <i>Klebsiella pneumoniae</i> (500). Against the gram-positive species, gepotidacin MIC₉₀s were 0.12 µg/mL and 4 µg/mL for <i>S. saprophyticus</i> (250) and <i>E. faecalis</i> (500), respectively. Gepotidacin MIC₉₀s for ciprofloxacin not susceptible isolates ranged from 4 µg/mL for <i>E. coli</i> (352) to 128 µg/mL for <i>P. rettgeri</i> (48). Gepotidacin MIC₉₀s for presumptive extended spectrum beta-laactamase (ESBL)-positive <i>E. coli</i> (228) and <i>K. pneumoniae</i> (145) were 8 µg/mL and 32 µg/mL, respectively. Gepotidacin was bactericidal (minimum bactericidal concentration [MBC]/MIC ratio ≤4) against 94% (47/50) of isolates tested.