Exploring the evidence for use of cefiderocol as part of combination therapies: a systematic review of in vitro, in vivo, and clinical studies

BACKGROUND: Cefiderocol is a siderophore cephalosporin with potent activity against carbapenem-resistant Gram-negative bacteria (CR-GNB). While monotherapy is recommended for susceptible Enterobacterales and Pseudomonas aeruginosa, the role of cefiderocol-based combination therapy remains uncertain. We conducted a systematic review of preclinical and clinical evidence supporting cefiderocol combination regimens. METHODS: MEDLINE, ESCMID global and IDWeek sources (January 2015-January 2025) were systematically searched for in vitro, in vivo and clinical studies evaluating cefiderocol-based combinations. Randomised trials, observational studies and preclinical synergy studies were included. An exploratory random-effects meta-analysis compared cefiderocol monotherapy with combination therapy for mortality, clinical cure and microbiological eradication. RESULTS: Sixty-seven studies were included (34 in vitro, 5 in vivo and 31 clinical). Preclinical data showed enhanced cefiderocol activity when combined with β-lactamase inhibitors, tetracyclines and selected β-lactams, with in vivo models supporting improved bacterial killing and survival for selected combinations. Clinical studies were heterogeneous and frequently confounded. Combination therapy showed no consistent advantage over monotherapy for clinical cure or microbiological eradication, while mortality estimates were highly variable. CONCLUSIONS: Cefiderocol combinations show biologically plausible synergy in preclinical models, but current clinical evidence is limited and largely observational, failing to identify combinations that reliably improve patient-centred outcomes.