513. Cefiderocol Retains in vitro Activity Against Enterobacterales Non-Susceptible to β-lactam-β-lactamase Inhibitor Combinations
Authors: DeJonge Boudewijn L , Nguyen Sean T , Bryowsky Jason J , Maher Joshua , Mendes Rodrigo E , Longshaw Christopher M , Takemura Miki , Yamano Yoshinori 
Published: January 2025

Abstract

Background
Over the past ten years β-lactam-β-lactamase inhibitor combinations, such as ceftazidime-avibactam (CZA), meropenem-vaborbactam (MVB), imipenem-relebactam (I/R) have been introduced onto the market as options to treat infections caused by carbapenem-resistant Enterobacterales. With resistance emerging against these agents, we assessed the in vitro activity for cefiderocol (CFDC), a siderophore conjugated cephalosporin, against isolates that were collected between 2020-2022 in Europe and the USA as part of the SENTRY Antimicrobial Surveillance Program that were non-susceptible CZA, MVB, or I/R.Table 1.Activity for cefiderocol, ceftazidime-avibactam, meropenem-vaborbactam, and imipenem-relebactam against various non-susceptible phenotypic subsets of Enterobacterales isolates collected from European and US hospitals as part of the SENTRY surveillance program (2020-2022).

Methods
A total of 24,084 Enterobacterales were collected and minimum inhibitory concentrations (MIC) for CZA, MVB, I/R were determined according to CLSI guidelines using broth microdilution with cation-adjusted Mueller-Hinton broth (CAMHB), while for CFDC iron-depleted CAMHB was used. Susceptibility was assessed according to 2024 CLSI, FDA, and EUCAST breakpoints. Non-susceptibility to CZA, MVB, I/R was assessed using CLSI breakpoints.

Results
Few isolates collected were non-susceptible to CZA (0.6%), MVB (0.8%), or I/R (1.0%). 83.9%, 91.4% and 92.6% of CZA-NS, MVB-NS, and I/R-NS isolates tested susceptible for CFDC, according to CLSI breakpoints (Table 1). These percentages were lower when EUCAST breakpoints were applied; 58.4%, 68.8% and 72.9%, respectively, a result of a significant number of isolates with CFDC MIC values of 4 µg/mL. Regardless of the breakpoints used, susceptibility to CFDC was higher compared to any of the β-lactam-β-lactamase inhibitor combinations, which demonstrated a high degree of cross-resistance. This high degree of cross-resistance could be largely explained by the presence of metallo-β-lactamases in CZA-NS (126/137), MVB-NS (104/186) and I/R-NS (113/229) isolates.

Conclusion
CFDC remains active against Enterobacterales that are non-susceptible against β-lactam-β-lactamase inhibitor combinations. In contrast, cross resistance was observed for the β-lactam-β-lactamase inhibitor combinations. CFDC should be considered as a treatment option when Enterobacterales non-susceptible to β-lactam-β-lactamase inhibitor combinations are encountered.

Disclosures
Boudewijn L. DeJonge, PhD, Shionogi Inc.: Employee Sean T. Nguyen, PharmD, Shionogi Inc.: Employee Jason J. Bryowsky, PharmD, MS, Shionogi: Employee Rodrigo E. Mendes, PhD, JMI: RM is an employee of JMI. JMI was contracted by and received financial support from GSK to conduct gepotidac|Paratek Pharmaceuticals: Advisor/Consultant|Paratek Pharmaceuticals: Grant/Research Support Christopher M. Longshaw, PhD, Shionogi BV: Employee Miki Takemura, n/a, Shionogi & Co., Ltd.: Employee Yoshinori Yamano, PhD, Shionogi & Co., Ltd.: Employee