P-1059. <i>In vitro</i> Activity of Gepotidacin against <i>Klebsiella pneumoniae</i>, Including Molecularly Characterized ESBL and Carbapenemase positive Subsets Causing Urinary Tract Infections in the United States (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 infection [uUTI] uropathogens and Neisseria gonorrhoeae) of two different type II topoisomerase enzymes. GEP recently completed two phase 3 trials for the treatment of uUTI. This study reports the activity of GEP and other oral antibacterials against K. pneumoniae, including molecularly characterized ESBL and carbapenemase producing isolates collected from UTI patients in the US. Methods A total of 2,001 K. pneumoniae were collected from 73 sites. CLSI methods were used for both susceptibility testing and MIC interpretation. Isolates with aztreonam, ceftazidime, ceftriaxone or meropenem MIC of ≥2 mg/L were subjected to genome sequencing, and screening of plasmid-mediated AmpC (pAmpC), ESBL, and carbapenemase genes. Results A total of 11.0% (220/2,001) K. pneumoniae were screened for β-lactamase genes (Table). Majority of these isolates carried blaCTX-M alone (78.2%; 172/220), and a small number carried combinations of blaCTX-M and ESBL variants of blaSHV (2.7%; 6/220), blaSHV alone (2.7%; 6/220), or pAmpC alone (2.3%; 5/220). Among screened isolates, 9.1% (20/220) carried carbapenemases. GEP had MIC50 and MIC90 of 4 mg/L and 8 mg/L, respectively, against isolates that did not meet the MIC criteria for screening of β-lactamases. Other oral agents showed susceptibilities of 92.8–99.5% against this group, except for nitrofurantoin (35.7%). GEP had an MIC90 of 32 mg/L against screened strains carrying ESBL and pAMPC, and an MIC90 of 16 mg/L against carbapenemase positive isolates. Other oral agents had limited activity (&amp;lt; 42%) against strains carrying ESBL and/or pAMPC. Conclusion GEP showed activity against UTI-causing K. pneumoniae in US medical centers, including against isolates carrying ESBL, pAmpC and/or carbapenemases. These data support further clinical development of GEP as a potential treatment option for uUTI caused by K. pneumoniae including when other oral treatment options have limited activity 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)