Therapeutic options for the treatment of infections owing to multidrug-resistant Gram-negative pathogens are often limited. Cefiderocol is a novel siderophore cephalosporin with activity against Gram-negative pathogens, including many multidrug-resistant strains. The activity of cefiderocol was examined against Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii that included (1) a recent surveillance collection of clinical isolates, (2) a collection of carbapenem-resistant isolates from a previous surveillance study, and (3) a collection of well-characterized isolates. Susceptibility testing for cefiderocol was performed with iron-depleted cation-adjusted Mueller-Hinton broth. Cefiderocol minimum inhibitory concentrations (MICs) were correlated with resistance mechanisms in the well-characterized isolates. For the Enterobacterales, including a collection of KPC-possessing Klebsiella pneumoniae, cefiderocol MICs were all ≤4 mg/L. Cefiderocol MICs were two- to fourfold higher in cephalosporin-resistant isolates. For K. pneumoniae, MICs did not correlate with expression of genes encoding porins or efflux systems. For P. aeruginosa, >99% of isolates were inhibited by ≤4 mg/L, including the collection of carbapenem-resistant isolates. For P. aeruginosa, cefiderocol activity was not affected by expression of ampC, oprD, or several efflux systems. All the surveillance isolates of A. baumannii, and 88% of the collection of carbapenem-resistant isolates, had cefiderocol MICs ≤4 mg/L. MICs were twofold higher in A. baummannii isolates with proven extended-spectrum beta-lactamases, and cefiderocol activity did not correlate with expression of efflux systems. Cefiderocol demonstrated potent activity against important nosocomial pathogens. Continued development of this agent as a therapeutic option against multidrug-resistant bacteria should be encouraged.

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