Optimizing cefiderocol use in clinical practice

PURPOSE OF REVIEW: 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. RECENT FINDINGS: 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. SUMMARY: With its unique structure and broad activity against resistant gram-negative pathogens, cefiderocol represents an important and evolving addition to the AMR therapeutic landscape.