P-1360. Activity of Cefiderocol against Carbapenem Non-susceptible Enterobacterales, Including Molecularly Characterized Multidrug-resistant Clinical Isolates, Causing Infections in United States Hospitals (2020–2023)

Abstract Background Cefiderocol (FDC) is a siderophore cephalosporin that hijacks the iron transport system of Gram-negative bacteria to facilitate cell entry. FDC remains stable to hydrolysis in the presence of serine β-lactamases (BL) (e.g. ESBLs, KPC, and OXA-type carbapenemases) and metallo-BL (MBL). FDC and comparator activities were analyzed against carbapenem-nonsusceptible (nonS) Enterobacterales (ENT), including molecularly characterized isolates, collected as part of the SENTRY Antimicrobial Surveillance Program for the US. Methods 15,147 ENT were collected from 35 sites in 2020–2023. Susceptibility (S) testing was performed by broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB) for comparators and iron-depleted CAMHB for FDC. CLSI criteria (same as the FDA) were used for FDC; whereas CLSI were applied for comparators, except for colistin (EUCAST). ENT with MIC ≥2 mg/L (nonS by CLSI) for imipenem or meropenem (MER) were screened for BL genes. Results 1.4% (207/15,147) isolates were carbapenems-nonS, and among these 57.5% (119/207) carried carbapenemases. Class A blaKPC (72.3%; 86/119) prevailed, followed by class B MBL genes (17.6%; 21/119) and class D blaOXA-48 variants (5.9%; 7/119). FDC (96.6–98.3%S) had MIC50 of 0.5 mg/L and MIC90 of 4 mg/L against carbapenem-nonS and carbapenemase-carrying isolates; other agents had S of 6.7–86.5% (Table). FDC (100%S) and β-lactam-β-lactamase inhibitor (BL/BLI) combinations (96.6–100%S) were active against ENT carrying class A carbapenemases, whereas only FDC (MIC50/90, 2/4 mg/L; 95.2%S) had activity against those carrying class B genes. FDC and ceftazidime-avibactam (CAZ-AVI) were active (100%S for both) against ENT carrying class D genes. FDC (MIC50/90, 0.25/4 mg/L; 92.1%S), MER-vaborbactam (MIC50/90, 0.25/4 mg/L; 92.1%S) and CAZ-AVI (MIC50/90, 0.5/8 mg/L; 94.7%S) were most active against carbapenem-nonS, but carbapenemase-negative ENT. Conclusion FDC activity against carbapenem-nonS ENT collected in the US. FDC activity was consistent across different genotypes, including against isolates carrying carbapenemase genes, where approved BL/BLI combinations showed limited activity. These data demonstrate FDC as an important option for the treatment of infections caused by carbapenem-nonS ENT. Disclosures Rodrigo E. Mendes, PhD, GSK: Grant/Research Support