Antimicrobial activity of aztreonam-avibactam against KPC variant-producing Klebsiella pneumoniae with ceftazidime-avibactam resistance.

Abstract

BACKGROUND: Klebsiella pneumoniae carbapenemase (KPC) mutations are a major mechanism of ceftazidime-avibactam resistance. We aimed to investigate the antimicrobial activity of aztreonam-avibactam against KPC variant-producing K. pneumoniae. METHODS: Antimicrobial susceptibility of 36 KPC variant-producing K. pneumoniae strains was determined by broth microdilution method. The bactericidal kinetic characteristics were analysed by time-kill assays. The interaction between aztreonam and avibactam was analysed by the checkerboard assay and inhibitory Emax model with a baseline effect parameter. blaKPC cloning, molecular docking and enzymatic kinetic analysis was performed to analyse the interactions between KPC variants and substrates. In vivo antibacterial activity was investigated using the Galleria mellonella infection model and the neutropenic mouse intraperitoneal infection model. RESULTS: Aztreonam-avibactam exhibited an MIC50 of 1 mg/L and an MIC90 of 2 mg/L against KPC variant-producing strains, with a rapid bactericidal effect; however, one KPC-14-producing strain showed resistance (8 mg/L). The inhibitory Emax model effectively fitted the observed values from checkerboard assay: aztreonam MICs decreased rapidly as avibactam concentration increased, and gradually reached a plateau. Despite a reduced susceptibility to avibactam inhibition, these KPC variants exhibit impaired aztreonam hydrolysis, with aztreonam MICs decreasing by 2- to 1024-fold relative to KPC-2. In vivo, aztreonam-avibactam significantly increased the survival rate of G. mellonella and reduced the bacterial load in the organs of mice infected with KPC variant-producing K. pneumoniae strain. CONCLUSIONS: Aztreonam-avibactam represents an effective therapeutic option for KPC variant-producing K. pneumoniae.