Activity of ceftazidime-avibactam alone and in combination with polymyxin B against carbapenem-resistant Klebsiella pneumoniae in a tandem in vitro time-kill/in vivo Galleria mellonella survival model analysis

Abstract

Ceftazidime-avibactam is used clinically in combination with a polymyxin for the treatment of carbapenem-resistant Gram-negative infections; however, there are limited data to support this practice. The objective of this study was to evaluate the activity of ceftazidime-avibactam and polymyxin B alone and in combination against Klebsiella pneumoniae carbapenemase (KPC)-producing Klebsiella pneumoniae in a tandem in vitro time-kill/in vivo Galleria mellonella survival model assay. Three KPC-3-producing K.pneumoniae clinical isolates were used for all experiments. All isolates harbored mutations in ompk35 and one isolate in ompk36; two isolates were susceptible to both ceftazidime-avibactam and polymyxinB, and one was resistant to both. Ceftazidime-avibactam was bactericidal against 2 of 3 strains at ≥2x minimum inhibitory concentration (MIC) whereas polymyxin B was not bactericidal against any strain at any concentration. Combinations at 1/4x or 1/2x MIC were not bactericidal or synergistic against any of the 3 isolates. In survival experiments, ceftazidime-avibactam at 4x MIC significantly improved larval survival over the untreated control strain whereas polymyxin B at 4x MIC did not. Combining polymyxin B with ceftazidime-avibactam at 4x MIC did not improve survival compared to ceftazidime-avibactam alone. This work indicates there is no improvement in in vitro bactericidal activity or in vivo efficacy when polymyxin B is combined with ceftazidime-avibactam against KPC-producing K.pneumoniae. This combination should be avoided in lieu of ceftazidime-avibactam alone or other potentially more efficacious, less toxic combination regimens.