Cefiderocol activity against multidrug-resistant isolates from the PERSEUS study: relationship between cefiderocol minimum inhibitory concentration and clinical outcomes

Abstract

Objective: The PERSEUS study was a retrospective analysis of cefiderocol use under the compassionate use and early access programmes in Spain for the treatment of MDR Gram-negative infections. We present the microbiological evaluation of 57 isolates collected from this study, along with their correlation to clinical outcomes. Methods: Cefiderocol susceptibility testing was performed using standard broth microdilution (BMD) in iron-depleted media, commercial BMD panels (UMIC®, ComASP®), gradient MIC strips, and disk diffusion. Results were interpreted according to EUCAST 2024 criteria. WGS was used to characterize β-lactamase genes and mutations in genes implicated in cefiderocol resistance. Patients’ clinical charts were reviewed. Results: Most isolates were identified as Pseudomonas aeruginosa (72%). Cefiderocol demonstrated an overall susceptibility rate of 86%, outperforming most comparators except colistin. Commercial BMD devices demonstrated high concordance with the reference method, supporting their potential value for routine use. Molecular analysis revealed a high prevalence of class B metallo-β-lactamases, as well as mutations in iron transport genes, among resistant isolates. Notably, clinical cure was achieved even in patients infected with cefiderocol-resistant isolates treated with cefiderocol monotherapy, suggesting that some putative resistance mechanisms affect the MIC, without necessarily leading to clinical failure. Conclusions: Positive clinical outcomes in patients infected by cefiderocol-resistant isolates by EUCAST breakpoints highlight the need for standardized susceptibility testing, as well as deeper genotype-phenotype correlation studies. Cefiderocol remains a promising option for treating MDR Gram-negative infections, especially those caused by P. aeruginosa. Its adoption in clinical practice should be supported by validated testing methods and ongoing surveillance.