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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. 2020 Jan; 55(1):105852.IJ

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 polymyxin B, 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.

Authors+Show Affiliations

College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA.Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; XDR Pathogen Laboratory, University of Pittsburgh, Pittsburgh, PA, USA.College of Pharmacy, University of Illinois at Chicago, Chicago, IL, USA. Electronic address: wenzler@uic.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31770627

Citation

Borjan, Jovan, et al. "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." International Journal of Antimicrobial Agents, vol. 55, no. 1, 2020, p. 105852.
Borjan J, Meyer KA, Shields RK, et al. 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. 2020;55(1):105852.
Borjan, J., Meyer, K. A., Shields, R. K., & Wenzler, E. (2020). 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. International Journal of Antimicrobial Agents, 55(1), 105852. https://doi.org/10.1016/j.ijantimicag.2019.11.009
Borjan J, et al. 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. 2020;55(1):105852. PubMed PMID: 31770627.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Borjan,Jovan, AU - Meyer,Kevin A, AU - Shields,Ryan K, AU - Wenzler,Eric, Y1 - 2019/11/23/ PY - 2019/07/11/received PY - 2019/10/15/revised PY - 2019/11/13/accepted PY - 2019/11/27/pubmed PY - 2020/10/8/medline PY - 2019/11/27/entrez KW - CRE KW - Ceftazidime-avibactam KW - Combination KW - Galleria mellonella KW - KPC KW - Klebsiella pneumoniae KW - Polymyxin B KW - Synergy SP - 105852 EP - 105852 JF - International journal of antimicrobial agents JO - Int J Antimicrob Agents VL - 55 IS - 1 N2 - 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 polymyxin B, 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. SN - 1872-7913 UR - https://www.unboundmedicine.com/medline/citation/31770627/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_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0924-8579(19)30323-1 DB - PRIME DP - Unbound Medicine ER -