Game Changer Trial: What Noninferiority Means for Cefiderocol in High-Risk Gram-Negative Bacteremia

The Game Changer trial demonstrated that cefiderocol was noninferior, but not superior, to best available therapy for 14-day all-cause mortality in patients with Gram-negative bloodstream infections, including those caused by carbapenem-resistant organisms. For clinicians, this finding provides reassurance that cefiderocol is an effective and safe treatment option in bacteremia, even in a critically ill, high-risk population, but it also tempers expectations that the drug will outperform existing therapies across the board.

Importantly, the trial enrolled patients early—within 48 hours of a positive blood culture Gram stain—before full susceptibility data were available, closely mirroring real-world empiric decision-making. Most enrolled infections were carbapenem susceptible, making superiority over carbapenems unlikely and explaining the overall neutral result. The more clinically informative insights emerged from subgroup analyses of carbapenem-resistant pathogens.

While cefiderocol did not demonstrate superiority in carbapenem-resistant Enterobacterales overall—and appeared less favorable in metallo-β-lactamase (MBL)–producing organisms—it showed reasonable and sometimes numerically improved outcomes compared with standard of care in carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Stenotrophomonas maltophilia. Notably, mortality was not worse for Acinetobacter, addressing a key concern raised by earlier studies.

In real-world practice, clinicians should interpret noninferiority as confirmation that cefiderocol belongs in the treatment armamentarium for Gram-negative bacteremia, particularly when options are limited. Its use may be best targeted toward non-MBL-producing carbapenem-resistant pathogens and considered as part of combination therapy—aligned with contemporary IDSA guidance—rather than as a universal replacement for established first-line agents.