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. 2025 Jun 4;69(6):e0029625.
doi: 10.1128/aac.00296-25. Epub 2025 May 15.

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

Meredith A Hackel  1 , James A Karlowsky  1   2 , Daniel F Sahm  1 , Joshua M West  3 , Nicole E Scangarella-Oman  3
Affiliations

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

Meredith A Hackel et al. Antimicrob Agents Chemother. .

Abstract

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 in vitro 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), Enterococcus faecalis (500), and Staphylococcus saprophyticus (250) collected globally from 2012 to 2020. Gepotidacin MIC90s against the Enterobacterales species tested were 4 µg/mL for Escherichia coli (1,000) and Klebsiella oxytoca (250), 8 µg/mL for Citrobacter spp. (250) and Klebsiella aerogenes (250), 16 µg/mL for Proteus mirabilis (250) and Providencia rettgeri (250), and 32 µg/mL for Enterobacter cloacae (500) and Klebsiella pneumoniae (500). Against the gram-positive species, gepotidacin MIC90s were 0.12 µg/mL and 4 µg/mL for S. saprophyticus (250) and E. faecalis (500), respectively. Gepotidacin MIC90s for ciprofloxacin not susceptible isolates ranged from 4 µg/mL for E. coli (352) to 128 µg/mL for P. rettgeri (48). Gepotidacin MIC90s for presumptive extended spectrum beta-laactamase (ESBL)-positive E. coli (228) and K. pneumoniae (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.

Keywords: gepotidacin; triazaacenaphthylene; type II topoisomerase inhibitor; urinary tract infections.

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Conflict of interest statement

M.A.H. and D.F.S. are employees of IHMA and do not have any personal financial interests in the sponsor (GSK) of this manuscript. J.A.K. is a consultant to IHMA. J.M.W. and N.E.S.-O. are employees of the GSK group of companies.

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