Breaking the deadlock of metallo-β-lactamases: evidence and prospects for Aztreonam/Avibactam

Multidrug-resistant Gram-negative bacteria pose a significant threat to global public health, with resistance mediated by metallo-β-lactamases being particularly prominent. Aztreonam/avibactam (AZA), a novel β-lactam/β-lactamase inhibitor combination, had been approved in China and the European Union for treating complicated intra-abdominal infections and hospital-acquired pneumonia (including ventilator-associated pneumonia) in adults. The combination exhibits broad-spectrum antimicrobial activity against carbapenemase-producing Enterobacterales. It inhibits KPC and OXA-48, and importantly, aztreonam (ATM) is stable against metallo-β-lactamases. Current in vitro activity studies strongly support the use of AZA against MBL-producing Enterobacterales, while its activity against non-fermenting bacteria appears to vary depending on the species and isolate, requiring further clinical confirmation. As a prime example of "repurposing existing drugs," its pharmacokinetics and pharmacodynamics have been thoroughly studied, and phase III studies have provided supportive safety and efficacy data, but the clinical evidence specifically concerning microbiologically confirmed MBL-producing infections remains limited and exploratory because of very small subgroup sizes. It is important to note that the combination of ceftazidime/avibactam (CZA) with ATM differs significantly from AZA in pharmacokinetic properties. Therefore, CZA plus ATM (CZA + ATM) cannot be considered an equivalent substitute for AZA. Currently, the resistance rate for AZA is low, with most cases being isolated events. The primary mechanisms of resistance involve mutations in the PBP3 gene, mutations and overexpression of β-lactamases, reduced outer membrane permeability, and overexpression of efflux pumps. Available data suggest that AZA is an important treatment option for severe infections caused by multidrug-resistant Enterobacterales, including MBL-producing strains, although pharmacoeconomic conclusions remain context-dependent.