Optimizing cefiderocol use in clinical practice

Cefiderocol is the first clinically available antibiotic to exploit bacterial iron transport systems to enter gram-negative pathogens. As its availability expands, questions remain regarding: its role relative to other agents for infections caused by NDM-producing Enterobacterales, difficult-to-treat resistant (DTR) Pseudomonas aeruginosa , carbapenem-resistant Acinetobacter baumannii complex (CRAB), Stenotrophomonas maltophilia , and rarer nonfermenters; performance and interpretation of antimicrobial susceptibility testing; dosing in special populations; and emergence of resistance. This review addresses these uncertainties, emphasizing practical guidance for clinicians.

Emerging preclinical and clinical data have better defined cefiderocol's role in antimicrobial resistant (AMR) infections, supporting its preferential use for NDM-producing Enterobacterales and S. maltophilia , while reserving it for DTR P. aeruginosa and CRAB when preferred alternatives are unavailable or unsuitable. Susceptibility testing remains complex: breakpoints differ across standards organizations, broth microdilution requires specialized iron-depleted media, and disk diffusion is practical but may overcall resistance. Cefiderocol resistance is typically driven by a convergence of mechanisms, including impaired siderophore uptake, increased β-lactamase production or modification, reduced permeability, or PBP3 alterations.

With its unique structure and broad activity against resistant gram-negative pathogens, cefiderocol represents an important and evolving addition to the AMR therapeutic landscape.