P Zhang1, Q Shi1, H Hu1, B Hong2, X Wu1, X Du1, M Akova3, Y Yu4. 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.
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 blaKPC 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 blaKPC-2 (D179Y). In 12 wild-type blaKPC-2 isolates, the relative copy number and expression of blaKPC-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, blaKPC-2 point mutation and high KPC expression played an important role in CAZ/AVI resistance.
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 blaKPC 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 blaKPC-2 (D179Y). In 12 wild-type blaKPC-2 isolates, the relative copy number and expression of blaKPC-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, blaKPC-2 point mutation and high KPC expression played an important role in CAZ/AVI resistance.
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