Cefiderocol in clinical practice: from randomised trials to real-world evidence in the management of multidrug-resistant Gram-negative bacterial infections

Objectives: Multidrug-resistant Gram-negative bacteria (MDR-GNB) represent a major global health threat, with limited therapeutic options and high morbidity and mortality. Cefiderocol, a novel siderophore ce phalosporin, has emerged as a potential treatment for MDR-GNB infections. This narrative review aims to critically appraise evidence from randomised controlled trials (RCTs) and real-world studies to clarify the clinical effectiveness, safety, and optimal place-in-therapy of cefiderocol in the management of MDR-GNB infections. Methods: A narrative review of phase 2 and 3 RCTs and available real-world observational studies was performed. Evidence was synthesised focusing on mechanism of action, pharmacokinetic/pharmacody namic properties, resistance mechanisms, and clinical outcomes across different infection sites, pathogens, and treatment strategies. Results: RCTs demonstrated non-inferiority of cefiderocol compared with standard-of-care therapies in complicated urinary tract infections, nosocomial pneumonia, and bloodstream infections sustained by GNB. However, heterogeneous outcomes and mortality imbalances were observed in specific subgroups, parti cularly in Acinetobacter baumannii and metallo-β-lactamase (MBL)-producing pathogens. Real-world stu dies support cefiderocol use in critically ill patients, ventilator-associated pneumonia, and bloodstream infections, with more consistent benefits observed for Pseudomonas aeruginosa and carbapenem-resistant Enterobacterales. Outcomes in carbapenem-resistant A. baumannii infections remain variable. Early in itiation of therapy appears associated with improved outcomes, while no clear superiority of combination therapy over monotherapy has been established. Conclusions: Cefiderocol represents a valuable option for the treatment of MDR-GNB infections. Its optimal use requires careful patient and pathogen selection, early administration, and integration within anti microbial stewardship strategies. Further pathogen- and infection-specific trials are needed to better define its role, particularly in carbapenem-resistant A. baumannii and MBL-producing infections.