In Vitro Activity of Cefiderocol Against Multidrug-Resistant Gram-Negative Clinical Isolates

Abstract

Background: New antimicrobials are being developed as a response to the global threat of multidrug-resistant and panresistant bacterial pathogens. Cefiderocol (FDC; Shionogi & Co) is a novel parenteral siderophore cephalosporin with activity against gram-negative rods. Here, we report on the in vitro activity of FDC against multidrug-resistant gram-negative isolates collected by the CDC, including isolates available through the CDC and FDA Antibiotic Resistance Isolate Bank (AR Isolate Bank). Methods: The challenge set of gram-negative isolates (n = 339), most of which were obtained from the AR isolate bank (n = 258), comprised 188 Enterobacteriaceae (ENT), 72 Pseudomonas aeruginosa (PSA), and 79 Acinetobacter baumannii (ACB). Minimum inhibitory concentrations (MICs) for FDC in iron-depleted cation-adjusted Mueller-Hinton broth were determined using frozen reference broth microdilution panels (IHMA, Schaumburg, IL) according to CLSI guidelines. Isolates displaying nonsusceptibility to FDC (MIC >4 µg/mL) underwent additional testing with β-lactamase inhibitors (FDC with 4 µg/mL avibactam, FDC with 100 µg/ml dipicolinic acid (DPA), and FDC with both 100 µg/mL dipicolinic acid (DPA) and 4 µg/mL avibactam). Results: Cefiderocol MICs ranged from ≤0.03 to >64 µg/mL, and 313 (92.3%) isolates displayed susceptibility to FDC (MIC ≤4 μg/mL). The proportions of susceptible ENT, PSA, and ACB were 93.1%, 94.4%, and 88.6%, respectively. Among isolates harboring Ambler class A, class B, or class D carbapenemases, the proportions of susceptible isolates were 96.5%, 79.5%, and 94.0%, respectively. Overall, 26 (7.7%) isolates were categorized as FDC nonsusceptible (MIC ≥ 8 µg/mL); 65% of these were NDM producers. We selected 23 isolates for testing with β-lactamase inhibitors. The combination FDC-avibactam reduced the MIC to susceptible for all isolates harboring an Ambler class A or D carbapenemase, except for 1 OXA-71–producing ACB and 1 KPC-producing Citrobacter farmeri. The combination FDC-DPA reduced the MIC to susceptible for 9 of 13 (69.2%) NDM-producing and 4 of 4 (100%) OXA-23–producing ACB. By combining FDC with both DPA and avibactam, the MIC was reduced to susceptible (91%) for all but 1 KPC-producing and 1 NDM-producing Enterobacteriaceae isolate. Conclusions: Cefiderocol (FDC) demonstrated potent activity against a diverse collection of multidrug-resistant, gram-negative isolates, including producers of Ambler class A, B, and D carbapenemases. Among the 26 FDC nonsusceptible isolates, 65% were NDM positive. Our data indicate that FDC combined with β-lactamase inhibitors may restore susceptibility in FDC nonsusceptible isolates. Additional studies are needed to understand the underlying mechanism(s) of FDC resistance and to further explore the use of β-lactamase inhibitors in combination with FDC. Funding: None Disclosures: None