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Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections.
Antimicrob Agents Chemother. 2017 03; 61(3)AA

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.

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Authors+Show Affiliations

Shields RK
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Chen L
Public Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
Cheng S
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Chavda KD
Public Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
Press EG
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Snyder A
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Pandey R
Public Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
Doi Y
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Kreiswirth BN
Public Health Research Institute Tuberculosis Center, New Jersey Medical School, Rutgers University, Newark, New Jersey, USA.
Nguyen MH
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA mhn5@pitt.edu. XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA.
Clancy CJ
Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA. XDR Pathogen Laboratory, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania, USA.

MeSH

AgedAmino Acid SubstitutionAnti-Bacterial AgentsAzabicyclo CompoundsBacterial ProteinsCefepimeCeftazidimeCeftriaxoneCephalosporinsCloning, MolecularDrug CombinationsEscherichia coliFemaleGene ExpressionGenome, BacterialHigh-Throughput Nucleotide SequencingHumansKlebsiella InfectionsKlebsiella pneumoniaeMaleMeropenemMicrobial Sensitivity TestsMiddle AgedMutationPlasmidsRecombinant ProteinsThienamycinsbeta-Lactam Resistancebeta-Lactamases

Pub Type(s)

Case Reports
Journal Article

Language

eng

PubMed ID

28031201

Citation

Shields, Ryan K., et al. "Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations During Treatment of Carbapenem-Resistant Klebsiella Pneumoniae Infections." Antimicrobial Agents and Chemotherapy, vol. 61, no. 3, 2017.
Shields RK, Chen L, Cheng S, et al. Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections. Antimicrob Agents Chemother. 2017;61(3).
Shields, R. K., Chen, L., Cheng, S., Chavda, K. D., Press, E. G., Snyder, A., Pandey, R., Doi, Y., Kreiswirth, B. N., Nguyen, M. H., & Clancy, C. J. (2017). Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections. Antimicrobial Agents and Chemotherapy, 61(3). https://doi.org/10.1128/AAC.02097-16
Shields RK, et al. Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations During Treatment of Carbapenem-Resistant Klebsiella Pneumoniae Infections. Antimicrob Agents Chemother. 2017;61(3) PubMed PMID: 28031201.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Emergence of Ceftazidime-Avibactam Resistance Due to Plasmid-Borne blaKPC-3 Mutations during Treatment of Carbapenem-Resistant Klebsiella pneumoniae Infections. AU - Shields,Ryan K, AU - Chen,Liang, AU - Cheng,Shaoji, AU - Chavda,Kalyan D, AU - Press,Ellen G, AU - Snyder,Avin, AU - Pandey,Ruchi, AU - Doi,Yohei, AU - Kreiswirth,Barry N, AU - Nguyen,M Hong, AU - Clancy,Cornelius J, Y1 - 2017/02/23/ PY - 2016/09/28/received PY - 2016/11/18/accepted PY - 2016/12/30/pubmed PY - 2017/9/28/medline PY - 2016/12/30/entrez KW - Klebsiella pneumoniae KW - Klebsiella pneumoniae carbapenemase KW - carbapenem-resistant Enterobacteriaceae KW - ceftazidime-avibactam KW - resistance KW - sequence type 258 JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 61 IS - 3 N2 - 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. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/28031201/Emergence_of_Ceftazidime_Avibactam_Resistance_Due_to_Plasmid_Borne_blaKPC_3_Mutations_during_Treatment_of_Carbapenem_Resistant_Klebsiella_pneumoniae_Infections_ DB - PRIME DP - Unbound Medicine ER -