Cefiderocol Comparative Resistance and Clinical Predictors in CRE-BSI: Data from an OXA-48–Endemic Region with Rising OXA-48/NDM Coproducers

<b>Background/Objectives</b>: Bloodstream infections (BSIs) caused by carbapenem-resistant Enterobacterales (CREs) are a growing public health threat due to limited therapeutic options and high mortality. In Turkey, oxacillinase-48 (OXA-48) producers predominate, while OXA-48/New Delhi metallo-β-lactamase (NDM) co-producers are increasingly detected. Although ceftazidime-avibactam (CAZ-AVI) is effective against OXA-48, treating NDM-positive isolates remains challenging. Cefiderocol, a novel siderophore cephalosporin active against both serine- and metallo-β-lactamases, is not yet available in Turkey. Establishing baseline susceptibility rates and identifying clinical predictors of resistance are, therefore, crucial before its introduction. <b>Methods</b>: This retrospective study included adult patients with CRE-BSIs diagnosed at a tertiary university hospital in Istanbul between January and December 2023. Demographic, clinical, and microbiological data were collected from electronic medical records. Susceptibility to cefiderocol, CAZ-AVI, and colistin was determined according to the European Committee on Antimicrobial Susceptibility Testing (EUCAST) 2023 criteria. Risk factors for cefiderocol resistance were analyzed. <b>Results</b>: Among 202 isolates, cefiderocol showed the highest susceptibility (94%, <i>n</i> = 190), followed by CAZ-AVI (82%, <i>n</i> = 166) and colistin (70%, <i>n</i> = 141), with all pairwise differences being statistically significant (<i>p</i> < 0.001). Cefiderocol resistance (6%, <i>n</i> = 12) was significantly associated with hematologic malignancy, hematopoietic stem cell transplantation, prior CAZ-AVI or polymyxin exposure, prolonged hospitalization, and repeated admissions. <b>Conclusions</b>: Cefiderocol demonstrated potent in vitro activity against CRE-BSI isolates, with resistance confined to distinct high-risk clinical settings. This pre-implementation study provides baseline microbiological and epidemiological data from an OXA-48 endemic region with rising NDM prevalence, underscoring the importance of early surveillance and stewardship strategies before cefiderocol becomes clinically available.