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High ceftazidime hydrolysis activity and porin OmpK35 deficiency contribute to the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae.
J Antimicrob Chemother. 2017 07 01; 72(7):1930-1936.JA

Abstract

Objectives

To investigate mechanisms for the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae (KPC-KP).

Methods

A total of 24 isolates, 8 each with ceftazidime/avibactam MICs of 4-8, 1-2 and ≤0.5 mg/L, were randomly selected from 214 clinical isolates of KPC-KP, and the β-lactamase hydrolysis activity and porin expression profiles were determined. Plasmid profile and relative expression and copy number of the bla KPC gene were also analysed.

Results

Ceftazidime/avibactam MIC 50 and MIC 90 were 2 and 4 mg/L, respectively, for the 214 KPC-KP isolates. The hydrolysis activities of nitrocefin and ceftazidime in both of the ceftazidime/avibactam MIC 4-8 and 1-2 mg/L groups were significantly higher than those of the MIC ≤0.5 mg/L group, while the hydrolysis activities were 4-4.6-fold higher in the MIC 4-8 mg/L group than in the other two groups when 4 mg/L avibactam was added. The relative expression and copy number of the bla KPC gene in the MIC 4-8 mg/L group were 4.2-4.8-fold higher than in the other two groups. Meanwhile, SDS-PAGE showed that all isolates in the two groups with MIC ≥1 mg/L lacked OmpK35, which had either an early frameshift with a premature stop codon (n = 15, ST11) or overexpression of the negative regulation genes, micF and ompR (n = 1, ST15), whereas OmpK35 and OmpK36 could both be observed in all isolates with MIC ≤0.5 mg/L.

Conclusions

Decreased ceftazidime/avibactam susceptibility in KPC-KP clinical isolates is caused by high ceftazidime hydrolysis activity and OmpK35 porin deficiency and the majority of isolates belong to ST11.

Authors+Show Affiliations

Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission of People's Republic of China, Shanghai, China.Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission of People's Republic of China, Shanghai, China.Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission of People's Republic of China, Shanghai, China.Department of Infectious Diseases, Shanghai Jiaotong University Affiliated Sixth Hospital, Shanghai, China.Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission of People's Republic of China, Shanghai, China.Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission of People's Republic of China, Shanghai, China.Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission of People's Republic of China, Shanghai, China.Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission of People's Republic of China, Shanghai, China.Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China. Key Laboratory of Clinical Pharmacology of Antibiotics, National Health and Family Planning Commission of People's Republic of China, Shanghai, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28333323

Citation

Shen, Zhen, et al. "High Ceftazidime Hydrolysis Activity and Porin OmpK35 Deficiency Contribute to the Decreased Susceptibility to Ceftazidime/avibactam in KPC-producing Klebsiella Pneumoniae." The Journal of Antimicrobial Chemotherapy, vol. 72, no. 7, 2017, pp. 1930-1936.
Shen Z, Ding B, Ye M, et al. High ceftazidime hydrolysis activity and porin OmpK35 deficiency contribute to the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae. J Antimicrob Chemother. 2017;72(7):1930-1936.
Shen, Z., Ding, B., Ye, M., Wang, P., Bi, Y., Wu, S., Xu, X., Guo, Q., & Wang, M. (2017). High ceftazidime hydrolysis activity and porin OmpK35 deficiency contribute to the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae. The Journal of Antimicrobial Chemotherapy, 72(7), 1930-1936. https://doi.org/10.1093/jac/dkx066
Shen Z, et al. High Ceftazidime Hydrolysis Activity and Porin OmpK35 Deficiency Contribute to the Decreased Susceptibility to Ceftazidime/avibactam in KPC-producing Klebsiella Pneumoniae. J Antimicrob Chemother. 2017 07 1;72(7):1930-1936. PubMed PMID: 28333323.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - High ceftazidime hydrolysis activity and porin OmpK35 deficiency contribute to the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae. AU - Shen,Zhen, AU - Ding,Baixing, AU - Ye,Meiping, AU - Wang,Peng, AU - Bi,Yingmin, AU - Wu,Shi, AU - Xu,Xiaogang, AU - Guo,Qinglan, AU - Wang,Minggui, PY - 2016/07/12/received PY - 2017/02/07/accepted PY - 2017/3/24/pubmed PY - 2018/4/28/medline PY - 2017/3/24/entrez SP - 1930 EP - 1936 JF - The Journal of antimicrobial chemotherapy JO - J Antimicrob Chemother VL - 72 IS - 7 N2 - Objectives: To investigate mechanisms for the decreased susceptibility to ceftazidime/avibactam in KPC-producing Klebsiella pneumoniae (KPC-KP). Methods: A total of 24 isolates, 8 each with ceftazidime/avibactam MICs of 4-8, 1-2 and ≤0.5 mg/L, were randomly selected from 214 clinical isolates of KPC-KP, and the β-lactamase hydrolysis activity and porin expression profiles were determined. Plasmid profile and relative expression and copy number of the bla KPC gene were also analysed. Results: Ceftazidime/avibactam MIC 50 and MIC 90 were 2 and 4 mg/L, respectively, for the 214 KPC-KP isolates. The hydrolysis activities of nitrocefin and ceftazidime in both of the ceftazidime/avibactam MIC 4-8 and 1-2 mg/L groups were significantly higher than those of the MIC ≤0.5 mg/L group, while the hydrolysis activities were 4-4.6-fold higher in the MIC 4-8 mg/L group than in the other two groups when 4 mg/L avibactam was added. The relative expression and copy number of the bla KPC gene in the MIC 4-8 mg/L group were 4.2-4.8-fold higher than in the other two groups. Meanwhile, SDS-PAGE showed that all isolates in the two groups with MIC ≥1 mg/L lacked OmpK35, which had either an early frameshift with a premature stop codon (n = 15, ST11) or overexpression of the negative regulation genes, micF and ompR (n = 1, ST15), whereas OmpK35 and OmpK36 could both be observed in all isolates with MIC ≤0.5 mg/L. Conclusions: Decreased ceftazidime/avibactam susceptibility in KPC-KP clinical isolates is caused by high ceftazidime hydrolysis activity and OmpK35 porin deficiency and the majority of isolates belong to ST11. SN - 1460-2091 UR - https://www.unboundmedicine.com/medline/citation/28333323/High_ceftazidime_hydrolysis_activity_and_porin_OmpK35_deficiency_contribute_to_the_decreased_susceptibility_to_ceftazidime/avibactam_in_KPC_producing_Klebsiella_pneumoniae_ DB - PRIME DP - Unbound Medicine ER -