Strategies for addressing MBL infections with targeted antibiotic combination therapy, and clinical insights from the REVISIT study

Combining a monobactam antibiotic like aztreonam with a β-lactamase inhibitor such as avibactam is a clever strategy designed to tackle complex bacterial resistance mechanisms. Aztreonam is uniquely stable against hydrolysis by metallo-β-lactamases (MBLs), enzymes that degrade many β-lactam antibiotics, but it is vulnerable to serine β-lactamases, which can inactivate it. Avibactam inhibits these serine β-lactamases, effectively protecting aztreonam and restoring its activity. This combination offers a powerful therapeutic option against multidrug-resistant Gram-negative pathogens, including Klebsiella pneumoniae and Pseudomonas aeruginosa, that produce both MBLs and serine β-lactamases. This dual-action approach expands treatment possibilities where previously few effective options existed.

The recent phase 3 clinical trial, REVISIT, evaluated this combination in infections caused by Gram-negative bacteria, including intra-abdominal infections and hospital-acquired pneumonia. Although the study enrolled around 340 patients, it primarily included infections with susceptible organisms rather than the resistant strains targeted by the drug’s design. The trial demonstrated that the aztreonam-avibactam combination was as effective and safe as comparator treatments, but it did not show a significant advantage in resistant infections due to the low number of such cases enrolled. This highlights the challenge in conducting clinical trials for drugs aimed at rare but highly resistant pathogens, where patient recruitment is difficult and clinical data remain limited.

Another smaller trial, the ASSEMBLE study, aimed to assess this combination specifically in patients with infections caused by MBL-producing bacteria but enrolled only 15 patients before early termination. Results showed modest cure rates, reflecting the difficulty in treating these infections. Although laboratory data are promising and the concept is innovative, more extensive clinical experience and postmarketing surveillance are needed to fully understand the drug’s role. These studies underscore the ongoing challenge in developing and testing therapies for multidrug-resistant organisms and the urgent need for continued research in this area.