The treatment landscape for infections caused by metallo-β-lactamase (MBL)–producing Gram-negative bacteria has become clearer—but no less challenging—as more clinical data emerge. A key insight is that MBLs are not uniform; important subtypes such as NDM, IMP, and VIM differ in how they respond to available agents. Cefiderocol, for example, appears most compromised against NDM producers, while retaining potential activity against IMP- or VIM-producing organisms, particularly when guided by rapid diagnostics. In these cases, some clinicians favor its use in combination therapy to maximize efficacy.
For serious infections caused by NDM producers, aztreonam–avibactam is increasingly viewed as the treatment of choice. However, the relentless evolution of bacterial resistance continues to erode confidence in any single option. Emerging mechanisms—such as NDM-producing E. coli with PBP3 insertions—can compromise aztreonam–avibactam, cefiderocol, and other agents, reinforcing that no current therapy is foolproof.
In contrast, for KPC or OXA-48 producers, established agents like ceftazidime–avibactam remain preferred despite early signs of resistance pressure. Against this backdrop, the GAME CHANGER trial for cefiderocol, conducted under difficult conditions including the COVID-19 pandemic, has helped clarify therapeutic roles and highlighted the urgent need for continued innovation in treating MBL infections.