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Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections.


ABSTRACT: Ceftazidime-avibactam is a novel ?-lactam/?-lactamase inhibitor with activity against carbapenem-resistant Enterobacteriaceae (CRE) that produce Klebsiella pneumoniae carbapenemase (KPC). We report the first cases of ceftazidime-avibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant K. pneumoniae emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Whole-genome sequencing (WGS) of longitudinal ceftazidime-avibactam-susceptible and -resistant K. pneumoniae isolates was used to identify potential resistance mechanisms. WGS identified mutations in plasmid-borne blaKPC-3, which were not present in baseline isolates. blaKPC-3 mutations emerged independently in isolates of a novel sequence type 258 sublineage and resulted in variant KPC-3 enzymes. The mutations were validated as resistance determinants by measuring MICs of ceftazidime-avibactam and other agents following targeted gene disruption in K. pneumoniae, plasmid transfer, and blaKPC cloning into competent Escherichia coli In rank order, the impact of KPC-3 variants on ceftazidime-avibactam MICs was as follows: D179Y/T243M double substitution > D179Y > V240G. Remarkably, mutations reduced meropenem MICs ?4-fold from baseline, restoring susceptibility in K. pneumoniae from two patients. Cefepime and ceftriaxone MICs were also reduced ?4-fold against D179Y/T243M and D179Y variant isolates, but susceptibility was not restored. Reverse transcription-PCR revealed that expression of blaKPC-3 encoding D179Y/T243M and D179Y variants was diminished compared to blaKPC-3 expression in baseline isolates. In conclusion, the development of resistance-conferring blaKPC-3 mutations in K. pneumoniae within 10 to 19 days of ceftazidime-avibactam exposure is troubling, but clinical impact may be ameliorated if carbapenem susceptibility is restored in certain isolates.

SUBMITTER: Shields RK 

PROVIDER: S-EPMC5328542 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne <i>bla</i><sub>KPC-3</sub> Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections.

Shields Ryan K RK   Chen Liang L   Cheng Shaoji S   Chavda Kalyan D KD   Press Ellen G EG   Snyder Avin A   Pandey Ruchi R   Doi Yohei Y   Kreiswirth Barry N BN   Nguyen M Hong MH   Clancy Cornelius J CJ  

Antimicrobial agents and chemotherapy 20170223 3


Ceftazidime-avibactam is a novel β-lactam/β-lactamase inhibitor with activity against carbapenem-resistant <i>Enterobacteriaceae</i> (CRE) that produce <i>Klebsiella pneumoniae</i> carbapenemase (KPC). We report the first cases of ceftazidime-avibactam resistance to develop during treatment of CRE infections and identify resistance mechanisms. Ceftazidime-avibactam-resistant <i>K. pneumoniae</i> emerged in three patients after ceftazidime-avibactam treatment for 10 to 19 days. Whole-genome seque  ...[more]

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