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.

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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.

Int J Antimicrob Agents. 2019 Nov 23;:

Authors: Borjan J, Meyer KA, Shields RK, Wenzler E

Abstract
Ceftazidime-avibactam is used clinically in combination with a polymyxin for the treatment of carbapenem-resistant Gram negative infections, despite the lack of 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 KPC-producing Klebsiella pneumoniae in a tandem in vitro time-kill/in vivo G. 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 polymyxin B, while one was resistant to both. Ceftazidime-avibactam was bactericidal against 2 of 3 strains at ≥2x MIC while 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 suggests a lack of improved 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.

PMID: 31770627 [PubMed - as supplied by publisher]