Impaired Inhibition by Avibactam and Resistance to the Ceftazidime-Avibactam Combination Due to the D179Y Substitution in the KPC-2 β-Lactamase

Abstract

The ceftazidime-avibactam antibiotic combination was recently shown to be at risk for the emergence of resistance under treatment. To gain insight into the underlying mechanism, we have analyzed the catalytic properties of a Klebsiella pneumoniae carbapenemase type 2 (KPC-2) β-lactamase harboring the D¹⁷⁹Y substitution. We show that impaired inhibition by avibactam combined with significant residual activity for ceftazidime hydrolysis accounts for the resistance. In contrast, the D¹⁷⁹Y substitution abolished the hydrolysis of aztreonam and imipenem, indicating that these drugs might provide therapeutic alternatives.

Keywords: KPC-2; avibactam; carbapenemase; ceftazidime; β-lactamase inhibitor.