Real-world Use of Cefiderocol in Neonatal and Pediatric Populations: A Multicenter Case Series and Systematic Review

Background: Cefiderocol is a novel siderophore-conjugated cephalosporin with activity against antimicrobial-resistant Gram-negative bacteria. Despite increasing off-label use in critically ill neonates and children, data on its safety and effectiveness remain limited. Methods: We performed a retrospective case series of neonatal and pediatric patients (≤18 years) who received off-label cefiderocol across 3 tertiary-care hospitals in Greece for suspected or documented infections due to multidrug-resistant Gram-negative bacteria. We also conducted a systematic review of pediatric cases published through June 2025. Results: Fifteen patients [median age 65 months (range 4–183)] received 21 cefiderocol courses. The systematic review identified 37 additional treatment courses (32 patients, 6 of them <3 months of age), primarily for bloodstream infections (86%), pneumonia (24.3%) and febrile neutropenia (18.9%). Most patients had received multiple antibiotics before and concomitantly with cefiderocol for extensively resistant Gram-negative bacteria. Clinical response occurred in 16/21 (76.2%) courses in the case series study and 22/28 (78.6%) courses in the systematic review. Microbiologic clearance was observed in 7/9 (78%) courses in the case series. Cefiderocol was well-tolerated without serious adverse events in all cases. Most isolates (14/18, 78%) were susceptible to cefiderocol according to current breakpoints, with a single instance of resistance emergence. Conclusions: This is the largest pediatric cohort to date combining real-world and published cefiderocol cases, suggesting that cefiderocol is a safe, well-tolerated and potentially effective option for severe, difficult-to-treat antimicrobial-resistant Gram-negative infections in neonates and children. These results support cautious off-label use in critically ill patients, while underscoring the urgent need for further pediatric trials.