Background: Antibiotic resistance has become a public health problem to be solved worldwide and metallo-β-lactamase (MBL)-producing bacteria make this problem even more challenging.
Methods: The interactions of meropenem (MEM) in combination with avibactam (AVI) in growth inhibition on MBL-producing carbapenem-resistant Klebsiella pneumoniae (CRKP) strains were tested. In vitro interactions of MEM+AVI were tested using the microdilution checkerboard assay and time-kill curves. In vivo interactions of MEM+AVI were tested using the Galleria mellonella model.
Results: All strains were multi-drug resistant strains and six of them were proved to produce MBLs. We show that the combination of MEM+AVI generates profound synergistic effects on growth inhibition of all strains, which was better than that of MEM+vaborbactam or imipenem+relebactam. The time-kill curves further confirmed the potent synergistic antibacterial effects of MEM+AVI against MBL-producing CRKP strains. Galleria mellonella studies were consistent with in vitro analysis. Combining MEM with AVI improved survival rates and mean survival days were obviously prolonged compared to the drug alone and the untreated controls.
Conclusions: To our knowledge, this study is the first report of MEM+AVI collaborating against MBL-producing CRKP strains. Our findings showed that the combination of MEM+AVI has the potential for antibiotic drug development to combat MBL-producing pathogens.
Keywords: Galleria mellonella; Metallo-β-lactamase; avibactam; carbapenem resistant Klebsiella pneumoniae; meropenem; synergy.