Cefiderocol was non-inferior, but not superior to standard of care empiric treatment of hospital-acquired and healthcare-associated Gram-negative bloodstream infection, in an open-label, multi-national trial1
The "GAME CHANGER" trial was conducted to ascertain whether cefiderocol, a novel siderophore cephalosporin antibiotic currently approved for complicated urinary tract infection and noscomial pneumonia, might serve as an alternative to broader spectrum agents commonly used as empiric treatment for noscomial bloodstream infections.
"Increasing rates of resistance to antibiotics commonly used for bloodstream infections are problematic and may lead to initial empiric therapy not having activity against the pathogen isolated," observed David Paterson, MBBS, PhD, The University of Queensland Centre for Clinical Research (UOCCR), Herston, Queensland, Australia, and colleagues.2
"Given the broad spectrum of activity against Gram-negative organisms, including those with resistant phenotypes, cefiderocol may be an ideal agent for use in the setting of bloodstream infections acquired in the hospital or healthcare setting," the investigators posited, "but to date, no clinical trial has examined this."
GAME CHANGER Trial Specifics
The investigators recruited 504 adult participants with noscomial positive blood cultures and Gram-negative bacilli on Gram stain, from 17 tertiary hospitals with more than 500 beds in Australia, Malaysia, Singapore, Taiwan, Thailand and Turkey. Infections were considered hospital-acquired if they occurred greater than 48 hours after admission.Infections were associated with healthcare if occurring within 48 hours of admission in patients with such conditions as an intravascular catheter/line as the source of infection, or had received hemodialysis or intravenous chemotherapy.
Participants were randomized 1:1 to receive either cefiderocol 2gm IV administered over 3 hours every 8 hours (with adjustments made for renal function) or a standard of care agent selected by patient's clinical team.These standard-of-care agents included carbapenems, piperacillin-tazobactam, and cefepime with or without an aminoglycoside. Nine patients (6 in cefiderocol group and 3 in standard-of-care) were excluded from analysis for withdrawing consent or their blood cultures did not grow an aerobic Gram-negative bacillus.
The primary outcome of the trial was all-cause mortality at 14 days after randomization.The margin for non-inferiority was 10%; and analysis for superiority was conducted when non-inferiority was shown, in both the main population and in those with at least one carbapenem-resistant organism causing bloodstream infection.
What You Need to Know
Cefiderocol was found to be noninferior to standard empiric therapy in treating hospital-acquired and healthcare-associated Gram-negative bloodstream infections, confirming non-inferiority but not superiority for 14-day mortality outcomes.
Efficacy was consistent even in carbapenem-resistant infections, though mortality remained slightly higher in the cefiderocol arm, underscoring the need for more targeted evidence in this subset of resistant pathogens.
Safety signals were limited but notable, with treatment-related adverse events (eg, delirium, rash, abnormal liver tests) occurring only in the cefiderocol group, all resolving except for one requiring intervention.
Paterson and colleagues reported that 20/250 (8%) of patients in the cefiderocol group and 17/254 (7%) receiving standard-of care had died at 14 days. The corresponding mortality at 14 days among those with a carbapenem-resistant organism was 9/64 (14%) in the cefiderocol group and 6/63 (10%) receiving standard-of-care.
The 5 treatment-emergent serious adverse events likely related to treatment were all in the cefiderocol group, including delirium, stupor, rigors, abnormal liver chemistry, and rash.All resolved without treatment, except for the rash which required hydrocortisone and anti-histamines.
"In both the main analysis population and the carbapenem–resistant subset, cefiderocol was not superior to standard of care," Paterson and colleagues concluded.
While cefiderocol appeared efficacious in these patients with health-care associated Gram-negative bloodstream infection who are at high risk of antibiotic resistance, the investigators acknowledge that "more evidence is required to define its efficacy when carbapenem-resistant organisms are the cause."
References
1. Paterson DL, Sulaiman H, Liu P-Y, et al. Cefiderocol versus standard therapy for hospital-acquired and healthcare-associated Gram negative bacterial bloodstream infection (the GAME CHANGER trial): an open-label parallel-group, randomised trial. Lancet Infect Dis. 2025. Published Online October 7. https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(25)00469-4/abstract.
2. Wright H, Harris NA, Chatfield MD, et al. Investigator-driven randomised controlled trial of cefiderocol versus standard therapy for healthcare-associated and hospital-acquired gram-negative bloodstream infection: Study protocol (the GAME CHANGER trial): study protocol for an open-label, randomised controlled trial. Trials. 2021; 22:889. https://doi.org/10.1186/s13063-021-05870-w.
