Carbapenem-resistant organisms (CRO) cause life-threatening infections with few effective therapies. Cefiderocol is one of the few agents with activity against a broad range of CRO, but its utility is threatened by limitations in susceptibility testing approaches, emerging resistance, and sparse clinical effectiveness data. This proposal will investigate the epidemiology and mechanisms of cefiderocol resistance in the United States; identify host, treatment, and microbiologic risk factors that can be synthesized into a decision tree to predict an individual patient's likelihood of resistance emergence during therapy; and determine clinical outcomes and the emergence of resistance during therapy for patients receiving FDC versus novel l3-lactam/l3-lactamase inhibitors for the treatment of CRO infections.