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

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