In vitro interaction of ceftazidime–avibactam in combination with different antimicrobials against KPC-producing Klebsiella pneumoniae clinical isolates

Abstract

Objectives: Combination therapy has been recommended when using ceftazidime–avibactam (CAZ–AVI) for the treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp), but the optimal combination is unknown. Six common antimicrobial agents (ertapenem, imipenem, meropenem, gentamicin, tigecycline, and ciprofloxacin) were evaluated for synergy with the recently approved cephalosporin–β-lactamase inhibitor combination CAZ–AVI in this study. Methods: Different antimicrobial combinations were tested against 13 KPC-Kp, including CAZ–AVI-susceptible (n = 11) and resistant (n = 2) clinical isolates. In vitro interactions of CAZ–AVI with different antimicrobials were tested using the gradient synergy test. Changes in the minimum inhibitory concentration (MIC) value were interpreted using the fractional inhibitory concentration (FIC) index and susceptible breakpoint index (SBPI). Results: The combination of CAZ–AVI with gentamicin or ciprofloxacin displayed no synergism against any of the KPC-Kp isolates, whereas synergistic activity was observed with imipenem and meropenem against all KPC-Kp isolates. Notably, CAZ–AVI reduced MICs for meropenem and imipenem below the resistance breakpoints against all strains. The SBPI analysis showed that CAZ–AVI in combination with imipenem achieved higher SBPI values than other CAZ–AVI-based combinations. Conclusions: These data suggest that combinations of CAZ–AVI with imipenem may be considered a useful therapeutic option for the treatment of KPC-Kp infections. Keywords: KPC-producing Klebsiella pneumoniae, Ceftazidime–avibactam, Synergy, Carbapenem, Imipenem