P-1060. <i>In vitro</i> Activity of Gepotidacin Tested Against Molecularly Characterized <i>Escherichia coli</i> Isolates Responsible for Urinary Tract Infections in the US (2019-2022)

Abstract Background Gepotidacin (GEP) is a novel, bactericidal, first-in-class triazaacenaphthylene antibacterial that inhibits bacterial DNA replication by a unique mechanism of action, distinct binding site and provides well-balanced inhibition (for most uncomplicated urinary tract infections [uUTI] uropathogens and Neisseria gonorrhoeae) of two different type II topoisomerase enzymes GEP completed two phase 3 trials for treatment of uUTI This study reports the activity of GEP and other oral antibacterials against E. coli (EC), including molecularly characterized isolates carrying ESBL and carbapenemase genes collected from UTI patients in the US. Methods 3,995 EC collected from 52 US sites as part of the gepotidacin uropathogen global surveillance study were included (2019-2022). CLSI methods were used for susceptibility (S) testing and MIC interpretations. Isolates with aztreonam, ceftazidime, ceftriaxone or meropenem MIC of ≥2 mg/L were subjected to genome sequencing, and screening of β-lactamase genes and epidemiology typing (MLST, O:H, and fimH). Results A total of 86.2% (3,444/3,995) of EC did not meet the MIC criteria for molecular characterization (Table) and had GEP MIC50 and MIC90 values of 2 mg/L and 4 mg/L, respectively. Cefazolin (97.0%S), fosfomycin (FOS) (99.7%S), and nitrofurantoin (NIT) (98.7%S) had activity among oral comparator agents tested against this group. A total of 13.8% (551/3,995) of EC were screened for β-lactamase genes, and this group had GEP MIC50 and MIC90 values of 2 mg/L and 4 mg/L respectively. Other oral agents had limited activity, except for FOS (98.0%S) and NIT (92.7%S). In general, GEP retained activity with MIC50 and MIC90 values of 2 mg/L and 4 mg/L, respectively, against isolates carrying ESBL, AmpC and carbapenemase genes, and against clonal complex (CC) 131 and the resistant subset O25b:H4. Conclusion GEP showed generally consistent activity against UTI-causing EC in the US, including against isolates carrying ESBL, AmpC and/or carbapenemase genes. In addition, GEP had activity against the CC131 high-risk EC clone. These data support further clinical development of GEP as a potential treatment option for uUTI caused by EC including when other oral treatment options are limited due to drug resistance. Disclosures Rodrigo E. Mendes, PhD, GSK: Grant/Research Support Renuka Kapoor, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company) Didem Torumkuney, PhD, GSK: Employee|GSK: Stocks/Bonds (Public Company)