A New Chapter for Treating MBL-Producing Gram-Negative Infections

The treatment landscape for multidrug-resistant Gram-negative infections—particularly those caused by metallo-β-lactamase (MBL)–producing organisms—continues to evolve. While the European Medicines Agency has granted marketing authorization for MJH across a broad indication in adults with limited treatment options, clinical experience underscores the importance of pathogen-specific selection. Data from the GAME CHANGER trial demonstrated that cefiderocol, although non-inferior overall, showed reduced effectiveness against MBL producers, with New Delhi metallo-β-lactamase (NDM) emerging as a key vulnerability. Laboratory and clinical insights now suggest that cefiderocol can be inactivated by NDM enzymes, limiting its utility in this high-risk subgroup.

In contrast, aztreonam–avibactam offers a mechanistically distinct and increasingly compelling alternative. Metallo-β-lactamases do not hydrolyze aztreonam; however, aztreonam alone is often compromised by co-produced ESBLs or AmpC enzymes. Avibactam provides critical protection against these additional β-lactamases, restoring aztreonam’s activity in organisms harboring MBLs. As a result, aztreonam–avibactam has become a key part of the antimicrobial armamentarium for treating MBL-producing Enterobacterales.

Although randomized clinical trial data in bloodstream infections remain limited, clinicians have growing confidence in aztreonam–avibactam based on established pharmacokinetic and pharmacodynamic profiles of both components and long-standing clinical experience with avibactam-containing regimens. For serious infections such as NDM-producing Klebsiella bacteremia, this combination is increasingly viewed as a viable—and often preferred—option.

Compared with historical therapies like polymyxins, tigecycline, or aminoglycosides, which carry concerns around toxicity or inadequate bloodstream exposure, newer agents represent meaningful progress. Looking ahead, ongoing development of cefiderocol in combination with MBL-active β-lactamase inhibitors reflects this learning curve. For now, aztreonam–avibactam stands out as a front-line choice for bloodstream infections caused by MBL producers.