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

Objectives: Combination therapy has been recommended when using ceftazidimeâavibactam (CAZâAVI) 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 cephalosporinâβ-lactamase inhibitor combination CAZâAVI in this study. Methods: Different antimicrobial combinations were tested against 13 KPC-Kp, including CAZâAVI-susceptible (n = 11) and resistant (n = 2) clinical isolates. In vitro interactions of CAZâAVI 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 CAZâAVI 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, CAZâAVI reduced MICs for meropenem and imipenem below the resistance breakpoints against all strains. The SBPI analysis showed that CAZâAVI in combination with imipenem achieved higher SBPI values than other CAZâAVI-based combinations. Conclusions: These data suggest that combinations of CAZâAVI with imipenem may be considered a useful therapeutic option for the treatment of KPC-Kp infections. Keywords: KPC-producing Klebsiella pneumoniae, Ceftazidimeâavibactam, Synergy, Carbapenem, Imipenem