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Resistance to Ceftazidime-Avibactam Is Due to Transposition of KPC in a Porin-Deficient Strain of Klebsiella pneumoniae with Increased Efflux Activity.
Antimicrob Agents Chemother. 2017 10; 61(10)AA

Abstract

Ceftazidime-avibactam is an antibiotic with activity against serine beta-lactamases, including Klebsiella pneumoniae carbapenemase (KPC). Recently, reports have emerged of KPC-producing isolates resistant to this antibiotic, including a report of a wild-type KPC-3 producing sequence type 258 Klebsiella pneumoniae that was resistant to ceftazidime-avibactam. We describe a detailed analysis of this isolate, in the context of two other closely related KPC-3 producing isolates, recovered from the same patient. Both isolates encoded a nonfunctional OmpK35, whereas we demonstrate that a novel T333N mutation in OmpK36, present in the ceftazidime-avibactam resistant isolate, reduced the activity of this porin and impacted ceftazidime-avibactam susceptibility. In addition, we demonstrate that the increased expression of blaKPC-3 and blaSHV-12 observed in the ceftazidime-avibactam-resistant isolate was due to transposition of the Tn4401 transposon harboring blaKPC-3 into a second plasmid, pIncX3, which also harbored blaSHV-12, ultimately resulting in a higher copy number of blaKPC-3 in the resistant isolate. pIncX3 plasmid from the ceftazidime-avibactam resistant isolate, conjugated into a OmpK35/36-deficient K. pneumoniae background that harbored a mutation to the ramR regulator of the acrAB efflux operon recreated the ceftazidime-avibactam-resistant MIC of 32 μg/ml, confirming that this constellation of mutations is responsible for the resistance phenotype.

Authors+Show Affiliations

The Medicines Company, San Diego, California, USA.Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA.The Medicines Company, San Diego, California, USA.The Medicines Company, San Diego, California, USA.The Medicines Company, San Diego, California, USA.Department of Pathology, University of New Mexico, Albuquerque, New Mexico, USA.Icahn School of Medicine at Mount Sinai, New York, New York, USA.Icahn School of Medicine at Mount Sinai, New York, New York, USA.JAX Genomic Medicine, Farmington, Connecticut, USA.JAX Genomic Medicine, Farmington, Connecticut, USA.JAX Genomic Medicine, Farmington, Connecticut, USA.JAX Genomic Medicine, Farmington, Connecticut, USA.The Medicines Company, San Diego, California, USA.Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, California, USA rhumphries@mednet.ucla.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28739787

Citation

Nelson, Kirk, et al. "Resistance to Ceftazidime-Avibactam Is Due to Transposition of KPC in a Porin-Deficient Strain of Klebsiella Pneumoniae With Increased Efflux Activity." Antimicrobial Agents and Chemotherapy, vol. 61, no. 10, 2017.
Nelson K, Hemarajata P, Sun D, et al. Resistance to Ceftazidime-Avibactam Is Due to Transposition of KPC in a Porin-Deficient Strain of Klebsiella pneumoniae with Increased Efflux Activity. Antimicrob Agents Chemother. 2017;61(10).
Nelson, K., Hemarajata, P., Sun, D., Rubio-Aparicio, D., Tsivkovski, R., Yang, S., Sebra, R., Kasarskis, A., Nguyen, H., Hanson, B. M., Leopold, S., Weinstock, G., Lomovskaya, O., & Humphries, R. M. (2017). Resistance to Ceftazidime-Avibactam Is Due to Transposition of KPC in a Porin-Deficient Strain of Klebsiella pneumoniae with Increased Efflux Activity. Antimicrobial Agents and Chemotherapy, 61(10). https://doi.org/10.1128/AAC.00989-17
Nelson K, et al. Resistance to Ceftazidime-Avibactam Is Due to Transposition of KPC in a Porin-Deficient Strain of Klebsiella Pneumoniae With Increased Efflux Activity. Antimicrob Agents Chemother. 2017;61(10) PubMed PMID: 28739787.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Resistance to Ceftazidime-Avibactam Is Due to Transposition of KPC in a Porin-Deficient Strain of Klebsiella pneumoniae with Increased Efflux Activity. AU - Nelson,Kirk, AU - Hemarajata,Peera, AU - Sun,Dongxu, AU - Rubio-Aparicio,Debora, AU - Tsivkovski,Ruslan, AU - Yang,Shangxin, AU - Sebra,Robert, AU - Kasarskis,Andrew, AU - Nguyen,Hoan, AU - Hanson,Blake M, AU - Leopold,Shana, AU - Weinstock,George, AU - Lomovskaya,Olga, AU - Humphries,Romney M, Y1 - 2017/09/22/ PY - 2017/05/12/received PY - 2017/07/06/accepted PY - 2017/7/26/pubmed PY - 2018/5/31/medline PY - 2017/7/26/entrez KW - KPC KW - Klebsiella pneumoniae KW - ceftazidime-avibactam KW - porin mutation KW - resistance JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 61 IS - 10 N2 - Ceftazidime-avibactam is an antibiotic with activity against serine beta-lactamases, including Klebsiella pneumoniae carbapenemase (KPC). Recently, reports have emerged of KPC-producing isolates resistant to this antibiotic, including a report of a wild-type KPC-3 producing sequence type 258 Klebsiella pneumoniae that was resistant to ceftazidime-avibactam. We describe a detailed analysis of this isolate, in the context of two other closely related KPC-3 producing isolates, recovered from the same patient. Both isolates encoded a nonfunctional OmpK35, whereas we demonstrate that a novel T333N mutation in OmpK36, present in the ceftazidime-avibactam resistant isolate, reduced the activity of this porin and impacted ceftazidime-avibactam susceptibility. In addition, we demonstrate that the increased expression of blaKPC-3 and blaSHV-12 observed in the ceftazidime-avibactam-resistant isolate was due to transposition of the Tn4401 transposon harboring blaKPC-3 into a second plasmid, pIncX3, which also harbored blaSHV-12, ultimately resulting in a higher copy number of blaKPC-3 in the resistant isolate. pIncX3 plasmid from the ceftazidime-avibactam resistant isolate, conjugated into a OmpK35/36-deficient K. pneumoniae background that harbored a mutation to the ramR regulator of the acrAB efflux operon recreated the ceftazidime-avibactam-resistant MIC of 32 μg/ml, confirming that this constellation of mutations is responsible for the resistance phenotype. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/28739787/Resistance_to_Ceftazidime_Avibactam_Is_Due_to_Transposition_of_KPC_in_a_Porin_Deficient_Strain_of_Klebsiella_pneumoniae_with_Increased_Efflux_Activity_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=28739787 DB - PRIME DP - Unbound Medicine ER -