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Ceftazidime/avibactam Improves the Antibacterial Efficacy of Polymyxin B Against Polymyxin B Heteroresistant KPC-2-Producing Klebsiella pneumoniae and Hinders Emergence of Resistant Subpopulation in vitro.
Front Microbiol 2019; 10:2029FM

Abstract

Due to the increasing multidrug resistance and limited antibiotics, polymyxin B revived as the last resort for the treatment of carbapenemase-producing Klebsiella pneumoniae (CRKP). Unfortunately, the heteroresistance hampers polymyxin B monotherapy treatment via the amplification of resistant subpopulation. Reliable polymyxin B based combinations are demanded. Ceftazidime/avibactam has been regarded as a new salvage therapy against CRKP. The occurrence of heteroresistance was confirmed by population analysis profiling (PAP). Our study demonstrated that polymyxin B and ceftazidime/avibactam combinations improved the in vitro antimicrobial activity of polymyxin B and delayed or suppressed the regrowth of resistant subpopulation by time-kill studies. Ceftazidime/avibactam at around MIC values (0.5-1 × MIC) plus clinically achievable concentrations of polymyxin B (0.5-2 mg/L) resulted in sustained killing against polymyxin B-heteroresistant isolates. Active PmrAB and PhoPQ systems and a pmrA mutation (G53R) in resistant subpopulation might associate with heteroresistance, but further investigation was required. Our findings suggested that the heteroresistance represented barriers to polymyxin B efficacy, and the combination of polymyxin B with ceftazidime/avibactam could be potentially valuable for the treatment of heteroresistant CRKP. Further, in vivo studies need to be performed to evaluate the efficacy of this combination against heteroresistant strains.

Authors+Show Affiliations

Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.Department of Laboratory Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.Department of Laboratory Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.Department of Laboratory Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.Public Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, NJ, United States.Department of Laboratory Medicine, The Second Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China. Department of Laboratory Medicine, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China.Department of Laboratory Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31551966

Citation

Ma, Xingyan, et al. "Ceftazidime/avibactam Improves the Antibacterial Efficacy of Polymyxin B Against Polymyxin B Heteroresistant KPC-2-Producing Klebsiella Pneumoniae and Hinders Emergence of Resistant Subpopulation in Vitro." Frontiers in Microbiology, vol. 10, 2019, p. 2029.
Ma X, He Y, Yu X, et al. Ceftazidime/avibactam Improves the Antibacterial Efficacy of Polymyxin B Against Polymyxin B Heteroresistant KPC-2-Producing Klebsiella pneumoniae and Hinders Emergence of Resistant Subpopulation in vitro. Front Microbiol. 2019;10:2029.
Ma, X., He, Y., Yu, X., Cai, Y., Zeng, J., Cai, R., ... Huang, B. (2019). Ceftazidime/avibactam Improves the Antibacterial Efficacy of Polymyxin B Against Polymyxin B Heteroresistant KPC-2-Producing Klebsiella pneumoniae and Hinders Emergence of Resistant Subpopulation in vitro. Frontiers in Microbiology, 10, p. 2029. doi:10.3389/fmicb.2019.02029.
Ma X, et al. Ceftazidime/avibactam Improves the Antibacterial Efficacy of Polymyxin B Against Polymyxin B Heteroresistant KPC-2-Producing Klebsiella Pneumoniae and Hinders Emergence of Resistant Subpopulation in Vitro. Front Microbiol. 2019;10:2029. PubMed PMID: 31551966.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ceftazidime/avibactam Improves the Antibacterial Efficacy of Polymyxin B Against Polymyxin B Heteroresistant KPC-2-Producing Klebsiella pneumoniae and Hinders Emergence of Resistant Subpopulation in vitro. AU - Ma,Xingyan, AU - He,Yuting, AU - Yu,Xuegao, AU - Cai,Yimei, AU - Zeng,Jianming, AU - Cai,Renxin, AU - Lu,Yang, AU - Chen,Liang, AU - Chen,Cha, AU - Huang,Bin, Y1 - 2019/09/03/ PY - 2019/02/08/received PY - 2019/08/19/accepted PY - 2019/9/26/entrez PY - 2019/9/26/pubmed PY - 2019/9/26/medline KW - KPC-2-producing Klebsiella pneumoniae KW - bacterial killing activity KW - ceftazidime/avibactam KW - heteroresistance KW - polymyxin B SP - 2029 EP - 2029 JF - Frontiers in microbiology JO - Front Microbiol VL - 10 N2 - Due to the increasing multidrug resistance and limited antibiotics, polymyxin B revived as the last resort for the treatment of carbapenemase-producing Klebsiella pneumoniae (CRKP). Unfortunately, the heteroresistance hampers polymyxin B monotherapy treatment via the amplification of resistant subpopulation. Reliable polymyxin B based combinations are demanded. Ceftazidime/avibactam has been regarded as a new salvage therapy against CRKP. The occurrence of heteroresistance was confirmed by population analysis profiling (PAP). Our study demonstrated that polymyxin B and ceftazidime/avibactam combinations improved the in vitro antimicrobial activity of polymyxin B and delayed or suppressed the regrowth of resistant subpopulation by time-kill studies. Ceftazidime/avibactam at around MIC values (0.5-1 × MIC) plus clinically achievable concentrations of polymyxin B (0.5-2 mg/L) resulted in sustained killing against polymyxin B-heteroresistant isolates. Active PmrAB and PhoPQ systems and a pmrA mutation (G53R) in resistant subpopulation might associate with heteroresistance, but further investigation was required. Our findings suggested that the heteroresistance represented barriers to polymyxin B efficacy, and the combination of polymyxin B with ceftazidime/avibactam could be potentially valuable for the treatment of heteroresistant CRKP. Further, in vivo studies need to be performed to evaluate the efficacy of this combination against heteroresistant strains. SN - 1664-302X UR - https://www.unboundmedicine.com/medline/citation/31551966/Ceftazidime/avibactam_Improves_the_Antibacterial_Efficacy_of_Polymyxin_B_Against_Polymyxin_B_Heteroresistant_KPC-2-Producing_Klebsiella_pneumoniae_and_Hinders_Emergence_of_Resistant_Subpopulation_in_vitro L2 - https://doi.org/10.3389/fmicb.2019.02029 DB - PRIME DP - Unbound Medicine ER -