P-1061. <i>In vitro</i> Activity of Gepotidacin against <i>Klebsiella pneumoniae</i>, Including Molecularly Characterized Fluoroquinolone not Susceptible Subsets Causing Urinary Tract Infections in the United States (2019-2022)

Abstract Background Gepotidacin (GEP) is a novel, bactericidal, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication by a unique mechanism of action, distinct binding site and provides well-balanced inhibition (for most uUTI uropathogens) of two different type II topoisomerase enzymes. This study reports the activity of GEP and other oral antibiotics against K. pneumoniae, including molecularly characterized fluoroquinolone (FQ) not susceptible (NS) isolates collected from urinary tract infection (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 (S) testing and MIC interpretation. Isolates with MIC≥0.5 mg/L for ciprofloxacin (NS) and/or ≥1 mg/L for levofloxacin (NS) were screened for FQ-resistance (R) mechanisms (plasmid-mediated quinolone resistance [PMQR]), QRDR mutations, and expression of acrAB and oqxAB by qRT-PCR. Results GEP inhibited 94.9% of all these isolates at ≤16 mg/L (MIC50/90 = 4/16mg/L). GEP MIC50/90 against FQ-S isolates was 4/8 mg/L, and other agents showed activity against ≥90% of isolates, except nitrofurantoin (37.4%S). 14.5% (291/2,001) of isolates were screened for FQ-R mechanisms. GEP MIC50/90 against FQ-NS strains was 16/32 mg/L, whereas other agents had S of 5.8–48.5%. GEP had generally similar activity (MIC50/90, 16-32/32-64 mg/L) against isolates with wildtype QRDR and with or without PMQR genes. Most of the isolates (95.2%) without PMQR genes overexpressed oqxAB and/or acrAB, against which amoxicillin-clavulanate and cefazolin (90.3–95.2%S) were active. GEP had consistent MIC90 of 16 mg/L against isolates with distinct QRDR mutations and absence of PMQR genes, whereas other agents had S of ≤68%. Conclusion GEP showed activity against FQ-S and FQ-NS K. pneumoniae UTI isolates from the US, in particular against FQ-NS isolates carrying QRDR mutations, where standard oral antibiotics showed limited activity. GEP MICs were not substantially affected by QRDR mutations. Highest MICs were seen against FQ-NS isolates with wildtype QRDR and PMQR genes and/or overexpression of efflux-pump genes. These data support the development of GEP for the treatment of uUTI caused by K. pneumoniae. 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)