In vitro and in vivo activity of single and dual antimicrobial agents against KPC-producing Klebsiella pneumoniae

Objectives: Options for treatment of infections due to KPC-producing Klebsiella pneumoniae are limited and combination therapy is often recommended. In this report, the in vitro and in vivo activity of potential therapeutic agents and combinations was assessed against four KPC-producing K. pneumoniae isolates. Methods: Using clinically relevant concentrations, time-kill experiments and the Galleria mellonella model of infection were used to examine the activity of polymyxin B, ceftazidime/avibactam, meropenem, rifampicin and amikacin alone and in combination. Results: Two K. pneumoniae isolates were resistant to polymyxin B and had ceftazidime/avibactam MICs of 8/4 mg/L. When ceftazidime/avibactam was combined with either amikacin or meropenem, synergy was observed in vitro, and these combinations were associated with improved survival in the in vivo model. Improved survival was also observed using higher doses of ceftazidime/avibactam. The other two K. pneumoniae isolates were susceptible to polymyxin B and had lower (1/4 mg/L) MICs of ceftazidime/avibactam. For these two isolates, bactericidal activity was observed in vitro at ceftazidime/avibactam concentrations four times the MIC. At one-quarter of the MIC, synergy was observed when ceftazidime/avibactam was combined with meropenem. In the in vivo model with the two susceptible isolates, improved survival rates were observed following therapy with ceftazidime/avibactam monotherapy. For all four isolates, polymyxin B with or without rifampicin or meropenem performed poorly in the in vivo model. Conclusions: Pending clinical studies, combining ceftazidime/avibactam with another agent (e.g. a carbapenem) should be considered when treating serious infections due to these pathogens, particularly for isolates with ceftazidime/avibactam MICs near the susceptibility breakpoint.