Aztreonam-avibactam at the frontline: A dual-agent approach to metallo-β-lactamase resistance

Metallo-β-lactamase (MBL)-producing Gram-negative bacteria pose a significant problem to antibiotic treatment due to their ability to inactivate most β-lactam antibiotics and resist inhibition by conventional β-lactamase inhibitors. While aztreonam-avibactam (ATM-AVI) has proven to be an effective treatment for these bacteria, previous reviews have been largely narrative, either from a microbiological perspective or a clinical perspective in isolation. This review seeks to provide a mechanism-based and translational synthesis of ATM-AVI by combining molecular antibiotic science, pharmacokinetic/pharmacodynamic (PK/PD) concepts, antimicrobial susceptibility testing, and clinical data. The mechanism of action of ATM-AVI is based on the natural stability of aztreonam to MBLs, resistance to co-produced serine β-lactamases by avibactam, and appropriate exposure strategies to ensure target attainment. There is consistent activity against MBL-producing Enterobacterales and Pseudomonas aeruginosa in surveillance and clinical trials, but emerging resistance due to PBP3 insertions, porin mutations, and efflux pump overexpression identifies important biological targets. The future clinical utility of ATM-AVI will depend on mechanism-based susceptibility testing, rapid diagnostic integration, and stewardship-driven use, particularly in high-prevalence settings. Beyond its current clinical utility, ATM-AVI provides insight into principles for the rational development and responsible use of next-generation antibiotics in the face of complex resistance.