A new triple antimicrobial combination strategy to combat beta-lactamase producing bacterial isolates

This study investigates the potential of a triple combination of meropenem, a novel metallo-beta-lactamase (MBL) inhibitor, InC58, and avibactam, a serine-beta-lactamase (SBL) inhibitor for a broad-spectrum activity versus beta-lactamase producing bacteria. A diverse panel comprising MBL- and SBL-producing strains was adopted for susceptibility testing of the triple combination using agar dilution method. Frequency of resistance (FoR) against meropenem plus InC58 was tested. Mutants were sequenced for the analysis of resistant mechanism, and tested for cross resistance, bacterial fitness and stability of resistance phenotype. Spontaneous resistant mutant against drug combination were also included, along with their corresponding sensitive mutants acquired after passaging without antibiotic pressure. Comparing with dual combinations, the triple combination of meropenem with InC58 and avibactam showed a much wider spectrum of activity against different carbapenemase-producing bacteria, revealing a new strategy to combat beta-lactamase mediated antimicrobial resistance.