THE NOVEL siderophore cephalosporin cefiderocol has shown comparable clinical outcomes to standard antibiotic therapy in patients with health-care-associated and hospital-acquired Gram-negative bloodstream infections, according to results from the GAME CHANGER randomised clinical trial.
Cefiderocol Versus Standard Treatment
Bloodstream infections caused by carbapenem-resistant Gram-negative bacilli remain a major cause of morbidity and mortality in hospitals worldwide. The limited efficacy of existing treatments and the rise of multidrug resistance have prompted interest in cefiderocol, an antibiotic designed to penetrate bacterial defences by exploiting iron transport mechanisms.
The trial, conducted across 17 tertiary hospitals in Australia, Malaysia, Singapore, Taiwan, Thailand, and Türkiye, enrolled 513 adults with confirmed Gram-negative bacteraemia. Participants were randomised to receive either cefiderocol (2 g every 8 hours intravenously) or the clinician’s choice of standard-of-care antibiotic therapy.
Trial Finds Cefiderocol Safe and Effective
Among 504 participants included in the main analysis, 20 (8%) of 250 patients in the cefiderocol arm and 17 (7%) of 254 in the standard-care arm had died within 14 days of randomisation, indicating that cefiderocol was non-inferior to standard therapy.
In the subgroup with bloodstream infection due to carbapenem-resistant organisms (127 patients), mortality was 14% for cefiderocol and 10% for standard therapy.
Adverse events associated with cefiderocol were infrequent and generally mild. Five serious adverse events (delirium, stupor, rigors, abnormal liver chemistry, and rash) were considered possibly or probably related to the drug, and all resolved with minimal or no intervention.
These findings suggest that cefiderocol offers a clinically viable alternative for treating severe Gram-negative infections, including those with carbapenem resistance, where treatment options remain limited.
A Step Toward Tackling Antibiotic Resistance
The results provide reassurance regarding the efficacy and safety of cefiderocol for bloodstream infections in regions with high antimicrobial resistance prevalence. Although the antibiotic did not demonstrate superiority over standard regimens, it remains a key option for pathogens resistant to multiple antibiotic classes.
Investigators recommend further studies to determine the optimal use of cefiderocol, including in patient subgroups with high resistance burdens or treatment failure on conventional regimens. As antimicrobial resistance continues to challenge health systems globally, cefiderocol represents an important addition to the limited range of available therapeutic options.
Reference
Paterson DL et al. Cefiderocol versus standard therapy for hospital-acquired and health-care-associated Gram-negative bacterial bloodstream infection (the GAME CHANGER trial): an open-label, parallel-group, randomised trial. Lancet Infect Dis. 2025; DOI:10.1016/S1473-3099(25)00469-4.
