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In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase-producing Klebsiella pneumoniae.

Abstract

Background

In recent years, the incidence of carbapenem-resistant Enterobacteriaceae (CRE) infections has increased rapidly. Since the CRE strain is usually resistant to most of antimicrobial agents, patients with this infection are often accompanied by a high mortality. Therefore, it instigates a severe challenge the clinical management of infection. In this study, we study the in vitro and in vivo bactericidal activity of ceftazidime-avibactam administrated either alone or in combination with aztreonam against KPC or NDM carbapenemase-producing Klebsiella pneumoniae, and explore a new clinical therapeutic regimen for infections induced by their resistant strains.

Methods

The microdilution broth method was performed to analyze the minimal inhibitory concentration (MIC). The time-kill curve assay of ceftazidime-avibactam at various concentrations was conducted in 16 strains of KPC-2 and 1 strain of OXA-232 carbapenemase-producing Klebsiella pneumoniae. The in vitro synergistic bactericidal effect of ceftazidime-avibactam combined with aztreonam was determined by checkerboard assay on 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase-producing Klebsiella pneumoniae. According to calculating grade, the drugs with synergistic bactericidal effect were selected as an inhibitory concentration index. The in vitro bactericidal tests of ceftazidime-avibactam combined with aztreonam were implemented on 12 strains among them. Effect of ceftazidime-avibactam antibiotic against KPC carbapenemase-producing K. pneumoniae strain Y8 Infection was performed in the mouse model.

Results

The time-kill assays revealed that ceftazidime-avibactam at various concentrations of 2MIC, 4MIC and 8MIC showed significant bactericidal efficiency to the resistant bacteria strains. However, in 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase- producing Klebsiella pneumoniae, only 7 strains appeared the susceptibility to ceftazidime-avibactam treatment, MIC50 and MIC90 were 64 mg/L and 256 mg/L, respectively. Antimicrobial susceptibility testing of ceftazidime-avibactam combined with aztreonam disclosed the synergism of two drugs in 90% (27/30) strains, an additive efficiency in 3.3% (1/30) strains, and irrelevant effects in 6.6% (2/30) strains. No antagonism was found. The subsequent bactericidal tests also confirmed the results mentioned above. Therapeutic efficacy of Ceftazidime-Avibactam against K. pneumoniae strain Y8 infection in mouse indicated 70% of infection group mice died within 4 days, and all mice in this group died within 13 days. Bacterial load testing results showed that there was no significant difference in the amount of bacteria in the blood between the infected group and the treatment group. However, the spleen and liver of treatment group mice showed lower CFU counts, as compare with infected group, indicating that ceftazidime-avibactam has a significant effect on the bacteria and led to a certain therapeutic efficacy.

Conclusion

This study indicated ceftazidime-avibactam therapy occupied significant bactericidal effects against KPC-2 and OXA-232 carbapenemase-producing Klebsiella pneumoniae. While combined with aztreonam, the stronger synergistic bactericidal effects against NDM carbapenemase-producing Klebsiella pneumoniae were achieved.

Authors+Show Affiliations

1Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Rd, Shanghai, 200040 China. 2Department of Clinical Laboratory, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, 528 Zhangheng Rd, Shanghai, 201203 China.1Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Rd, Shanghai, 200040 China. 4Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.3Department of Medical Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China.3Department of Medical Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China.1Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Rd, Shanghai, 200040 China. 4Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.1Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Rd, Shanghai, 200040 China. 4Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.1Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Rd, Shanghai, 200040 China. 4Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.3Department of Medical Microbiology and Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025 China.1Institute of Antibiotics, Huashan Hospital, Fudan University, 12 M. Wulumuqi Rd, Shanghai, 200040 China. 4Key Laboratory of Clinical Pharmacology of Antibiotics, Ministry of Health, Shanghai, China.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30479755

Citation

Zhang, Wenxia, et al. "In Vitro and in Vivo Bactericidal Activity of Ceftazidime-avibactam Against Carbapenemase-producing Klebsiella Pneumoniae." Antimicrobial Resistance and Infection Control, vol. 7, 2018, p. 142.
Zhang W, Guo Y, Li J, et al. In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase-producing Klebsiella pneumoniae. Antimicrob Resist Infect Control. 2018;7:142.
Zhang, W., Guo, Y., Li, J., Zhang, Y., Yang, Y., Dong, D., Zhu, D., He, P., & Hu, F. (2018). In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase-producing Klebsiella pneumoniae. Antimicrobial Resistance and Infection Control, 7, 142. https://doi.org/10.1186/s13756-018-0435-9
Zhang W, et al. In Vitro and in Vivo Bactericidal Activity of Ceftazidime-avibactam Against Carbapenemase-producing Klebsiella Pneumoniae. Antimicrob Resist Infect Control. 2018;7:142. PubMed PMID: 30479755.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - In vitro and in vivo bactericidal activity of ceftazidime-avibactam against Carbapenemase-producing Klebsiella pneumoniae. AU - Zhang,Wenxia, AU - Guo,Yan, AU - Li,Jiayin, AU - Zhang,Yiyuan, AU - Yang,Yang, AU - Dong,Dong, AU - Zhu,Demei, AU - He,Ping, AU - Hu,Fupin, Y1 - 2018/11/21/ PY - 2018/09/23/received PY - 2018/11/08/accepted PY - 2018/11/28/entrez PY - 2018/11/28/pubmed PY - 2019/10/1/medline KW - Aztreonam KW - Carbapenemase KW - Ceftazidime-avibactam KW - Klebsiella pneumoniae KW - Time-kill curve assay SP - 142 EP - 142 JF - Antimicrobial resistance and infection control JO - Antimicrob Resist Infect Control VL - 7 N2 - Background: In recent years, the incidence of carbapenem-resistant Enterobacteriaceae (CRE) infections has increased rapidly. Since the CRE strain is usually resistant to most of antimicrobial agents, patients with this infection are often accompanied by a high mortality. Therefore, it instigates a severe challenge the clinical management of infection. In this study, we study the in vitro and in vivo bactericidal activity of ceftazidime-avibactam administrated either alone or in combination with aztreonam against KPC or NDM carbapenemase-producing Klebsiella pneumoniae, and explore a new clinical therapeutic regimen for infections induced by their resistant strains. Methods: The microdilution broth method was performed to analyze the minimal inhibitory concentration (MIC). The time-kill curve assay of ceftazidime-avibactam at various concentrations was conducted in 16 strains of KPC-2 and 1 strain of OXA-232 carbapenemase-producing Klebsiella pneumoniae. The in vitro synergistic bactericidal effect of ceftazidime-avibactam combined with aztreonam was determined by checkerboard assay on 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase-producing Klebsiella pneumoniae. According to calculating grade, the drugs with synergistic bactericidal effect were selected as an inhibitory concentration index. The in vitro bactericidal tests of ceftazidime-avibactam combined with aztreonam were implemented on 12 strains among them. Effect of ceftazidime-avibactam antibiotic against KPC carbapenemase-producing K. pneumoniae strain Y8 Infection was performed in the mouse model. Results: The time-kill assays revealed that ceftazidime-avibactam at various concentrations of 2MIC, 4MIC and 8MIC showed significant bactericidal efficiency to the resistant bacteria strains. However, in 28 strains of NDM and 2 strains of NDM coupled with KPC carbapenemase- producing Klebsiella pneumoniae, only 7 strains appeared the susceptibility to ceftazidime-avibactam treatment, MIC50 and MIC90 were 64 mg/L and 256 mg/L, respectively. Antimicrobial susceptibility testing of ceftazidime-avibactam combined with aztreonam disclosed the synergism of two drugs in 90% (27/30) strains, an additive efficiency in 3.3% (1/30) strains, and irrelevant effects in 6.6% (2/30) strains. No antagonism was found. The subsequent bactericidal tests also confirmed the results mentioned above. Therapeutic efficacy of Ceftazidime-Avibactam against K. pneumoniae strain Y8 infection in mouse indicated 70% of infection group mice died within 4 days, and all mice in this group died within 13 days. Bacterial load testing results showed that there was no significant difference in the amount of bacteria in the blood between the infected group and the treatment group. However, the spleen and liver of treatment group mice showed lower CFU counts, as compare with infected group, indicating that ceftazidime-avibactam has a significant effect on the bacteria and led to a certain therapeutic efficacy. Conclusion: This study indicated ceftazidime-avibactam therapy occupied significant bactericidal effects against KPC-2 and OXA-232 carbapenemase-producing Klebsiella pneumoniae. While combined with aztreonam, the stronger synergistic bactericidal effects against NDM carbapenemase-producing Klebsiella pneumoniae were achieved. SN - 2047-2994 UR - https://www.unboundmedicine.com/medline/citation/30479755/In_vitro_and_in_vivo_bactericidal_activity_of_ceftazidime_avibactam_against_Carbapenemase_producing_Klebsiella_pneumoniae_ L2 - https://aricjournal.biomedcentral.com/articles/10.1186/s13756-018-0435-9 DB - PRIME DP - Unbound Medicine ER -