Impaired inhibition by avibactam and resistance to the ceftazidime-avibactam combination due to the D179Y substitution in the {beta}-lactamase KPC-2 [PublishAheadOfPrint]

The ceftazidime-avibactam combination was recently shown to be at risk of emergence of resistance under treatment. To gain insight into the underlying mechanism, we have analyzed the catalytic properties of a 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 resistance. In contrast, the D¹⁷⁹Y substitution abolished hydrolysis of aztreonam and imipenem indicating these drugs might provide therapeutic alternatives.

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