Interpreting Safety and Mortality Signals in Carbapenem-Resistant Infections

In the carbapenem-resistant subgroup of the Game Changer trial, mortality numerically favored standard therapy over cefiderocol, prompting careful examination of whether this represents a true safety signal or reflects patient and pathogen heterogeneity. Investigators concluded that cefiderocol did not deliver the transformative benefit initially hoped for in all carbapenem-resistant infections, but still retains an important, targeted role within the treatment armamentarium.

Critically, the observed mortality imbalance was largely driven by infections caused by metallo-β-lactamase (MBL)–producing organisms, particularly MBL-producing Enterobacterales. This finding suggests that pathogen-specific resistance mechanisms, rather than a class-wide drug effect, likely explain the signal. In contrast, outcomes with cefiderocol appeared more favorable in carbapenem-resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and certain non-fermenters, supporting continued consideration of cefiderocol in these settings. From a clinical standpoint, the data reinforce the value of rapid diagnostics to identify resistance mechanisms early and guide more precise patient selection.

All treatment-related serious adverse events were reported in the cefiderocol arm, raising questions about tolerability. However, investigators cautioned against overinterpretation. As an investigator-initiated trial using risk-based monitoring, adverse events—particularly those associated with polymyxins in the standard-of-care arm—may not have been captured with the same rigor as in registrational studies. Most cefiderocol-related serious adverse events were low severity, including rash and transient liver enzyme elevations.

Overall, clinicians should view these findings as a call for nuance rather than alarm. Cefiderocol appears safe and clinically useful when deployed thoughtfully, with careful attention to pathogen type, resistance mechanisms, and patient-specific risk–benefit considerations