Emergence of ceftazidime/avibactam resistance in carbapenem-resistant Klebsiella pneumoniae in China

P Zhang; Q Shi; H Hu; B Hong; X Wu; X Du; M Akova; Y Yu

doi:10.1016/j.cmi.2019.08.020

Emergence of ceftazidime/avibactam resistance in carbapenem-resistant Klebsiella pneumoniae in China

Clin Microbiol Infect. 2020 Jan;26(1):124.e1-124.e4. doi: 10.1016/j.cmi.2019.08.020. Epub 2019 Sep 5.

Authors

P Zhang¹, Q Shi¹, H Hu¹, B Hong², X Wu¹, X Du¹, M Akova³, Y Yu⁴

Affiliations

¹ Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China.
² Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Department of Infectious Diseases, Haining People's Hospital, Zhejiang, China.
³ Department of Infectious Disease, Hacettepe University School of Medicine, Ankara, 06100, Turkey.
⁴ Department of Infectious Diseases, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China; Key Laboratory of Microbial Technology and Bioinformatics of Zhejiang Province, Hangzhou, China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Centre for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China. Electronic address: yvys119@zju.edu.cn.

PMID: 31494252
DOI: 10.1016/j.cmi.2019.08.020

Abstract

Objectives: The aim was to investigate the activity of ceftazidime/avibactam (CAZ/AVI) against carbapenem-resistant Klebsiella pneumoniae (CRKP) and identify the resistance mechanisms before CAZ/AVI coming to Chinese market.

Methods: Clinical CRKP isolates were continuously collected from 36 tertiary hospitals in China from 1 March 2017 to 31 July 2017. CAZ/AVI MICs were determined by agar dilution method. CAZ/AVI resistant isolates were submitted to whole genome sequencing. The copy number and relative expression of bla_KPC were determined by quantitative PCR.

Results: A total of 872 CRKP isolates were collected, and MIC₅₀ and MIC₉₀ of CAZ/AVI were 4 and 8 mg/L. The resistant rate of CAZ/AVI was 3.7% (32/872). Among the resistant isolates, 53.1% (17/32) were metallo-β-lactamase-producing K. pneumoniae (MBL-KP), 40.6% (13/32) were Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-KP) and 6.3% (2/32) produced both MBL and KPC. One of the KPC-KP with high level CAZ/AVI resistance (>128 mg/L) harboured mutated bla_KPC-2 (D179Y). In 12 wild-type bla_KPC-2 isolates, the relative copy number and expression of bla_KPC-2 gene were 2.5-fold and 2.7-fold higher than that in the CAZ/AVI MIC ≤0.5 mg/L group (p < 0.05), and when added avibactam at a fixed concentration of 8 mg/L, 91.7% (11/12) isolates could restore susceptibility.

Conclusions: Resistance against CAZ/AVI in CRKP emerged before clinical use of CAZ/AVI in China, although most of the CRKP isolates maintained the susceptibility. MBL production, bla_KPC-2 point mutation and high KPC expression played an important role in CAZ/AVI resistance.

Keywords: Carbapenem-resistant Klebsiella pneumoniae; Ceftazidime/avibactam; Metallo-β-lactamase; bla(KPC); Ω-loop.

MeSH terms

Anti-Bacterial Agents / pharmacology*
Azabicyclo Compounds / pharmacology*
Bacterial Proteins / genetics
Carbapenems / pharmacology*
Ceftazidime / pharmacology*
China
Drug Combinations
Drug Resistance, Multiple, Bacterial / genetics*
Humans
Klebsiella Infections / microbiology
Klebsiella pneumoniae / drug effects*
Klebsiella pneumoniae / enzymology
Klebsiella pneumoniae / genetics*
Microbial Sensitivity Tests
Point Mutation
Tertiary Care Centers / statistics & numerical data
Whole Genome Sequencing
beta-Lactamases / genetics

Substances

Anti-Bacterial Agents
Azabicyclo Compounds
Bacterial Proteins
Carbapenems
Drug Combinations
avibactam, ceftazidime drug combination
Ceftazidime
beta-Lactamases
carbapenemase-2, Klebsiella pneumoniae