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Mechanisms of Resistance

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

Ryan K. Shields, Liang Chen, Shaoji Cheng, Kalyan D. Chavda, Ellen G. Press, Avin Snyder, Ruchi Pandey, Yohei Doi, Barry N. Kreiswirth, M. Hong Nguyen, Cornelius J. Clancy
Ryan K. Shields
aDepartment of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
bXDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Liang Chen
cPublic Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Shaoji Cheng
aDepartment of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Kalyan D. Chavda
cPublic Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Ellen G. Press
aDepartment of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Avin Snyder
aDepartment of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Ruchi Pandey
cPublic Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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Yohei Doi
aDepartment of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
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Barry N. Kreiswirth
cPublic Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA
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M. Hong Nguyen
aDepartment of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
bXDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
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Cornelius J. Clancy
aDepartment of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA
bXDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
dVA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA
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DOI: 10.1128/AAC.02097-16
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ABSTRACT

Ceftazidime-avibactam is a novel β-lactam/β-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.

FOOTNOTES

    • Received 28 September 2016.
    • Returned for modification 16 November 2016.
    • Accepted 18 November 2016.
    • Accepted manuscript posted online 28 December 2016.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.02097-16 .

  • Copyright © 2017 American Society for Microbiology.

All Rights Reserved .

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Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections
Ryan K. Shields, Liang Chen, Shaoji Cheng, Kalyan D. Chavda, Ellen G. Press, Avin Snyder, Ruchi Pandey, Yohei Doi, Barry N. Kreiswirth, M. Hong Nguyen, Cornelius J. Clancy
Antimicrobial Agents and Chemotherapy Feb 2017, 61 (3) e02097-16; DOI: 10.1128/AAC.02097-16

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Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections
Ryan K. Shields, Liang Chen, Shaoji Cheng, Kalyan D. Chavda, Ellen G. Press, Avin Snyder, Ruchi Pandey, Yohei Doi, Barry N. Kreiswirth, M. Hong Nguyen, Cornelius J. Clancy
Antimicrobial Agents and Chemotherapy Feb 2017, 61 (3) e02097-16; DOI: 10.1128/AAC.02097-16
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KEYWORDS

Anti-Bacterial Agents
Azabicyclo Compounds
Bacterial Proteins
ceftazidime
Genome, Bacterial
Klebsiella Infections
Klebsiella pneumoniae
beta-lactam resistance
beta-lactamases
ceftazidime-avibactam
resistance
carbapenem-resistant Enterobacteriaceae
Klebsiella pneumoniae
Klebsiella pneumoniae carbapenemase
sequence type 258

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