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Successive Emergence of Ceftazidime-Avibactam Resistance through Distinct Genomic Adaptations in blaKPC-2-Harboring Klebsiella pneumoniae Sequence Type 307 Isolates.

Abstract

Ceftazidime-avibactam (CAZ-AVI) is a promising novel treatment for infections caused by carbapenem-resistant Enterobacteriaceae (CRE). Despite improved treatment outcomes compared to those achieved with aminoglycoside- and colistin-based regimens, the rapid evolution of CAZ-AVI resistance during treatment has previously been reported in Klebsiella pneumoniae sequence type 258 (ST258) blaKPC-3-harboring isolates. Here, we report the stepwise evolution and isolation of two phenotypically distinct CAZ-AVI-resistant Klebsiella pneumoniae isolates from a patient with pancreatitis. All susceptible (n = 3) and resistant (n = 5) isolates were of the ST307 clonal background, a rapidly emerging clone. Taking advantage of short-read Illumina and long-read Oxford Nanopore sequencing and full-length assembly of the core chromosome and plasmids, we demonstrate that CAZ-AVI resistance first occurred through a 532G → T blaKPC-2 point mutation in blaKPC-2 (D179Y protein substitution) following only 12 days of CAZ-AVI exposure. While subsequent isolates exhibited substantially decreased meropenem (MEM) MICs (≤2 μg/ml), later cultures demonstrated a second CAZ-AVI resistance phenotype with a lower CAZ-AVI MIC (12 μg/ml) but also MEM resistance (MIC > 128 μg/ml). These CAZ-AVI- and MEM-resistant isolates showed evidence of multiple genomic adaptations, mainly through insertions and deletions. This included amplification and transposition of wild-type blaKPC-2 into a novel plasmid, an IS1 insertion upstream of ompK36, and disruption of the rfb gene locus in these isolates. Our findings illustrate the potential of CAZ-AVI resistance to emerge in non-K. pneumoniae ST258 clonal backgrounds and alternative blaKPC variants. These results raise concerns about the strong selective pressures incurred by novel carbapenemase inhibitors, such as avibactam, on isolates previously considered invulnerable to CAZ-AVI resistance. There is an urgent need to further characterize non-KPC-mediated modes of carbapenem resistance and the intrinsic bacterial factors that facilitate the rapid emergence of resistance during treatment.

Authors+Show Affiliations

Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA. Department of Medicine Microbiome & Pathogen Genomics Core, Columbia University Medical Center, New York, New York, USA.Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA. Department of Infectious Diseases, Austin Hospital, Heidelberg, Victoria, Australia.Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA. Department of Medicine Microbiome & Pathogen Genomics Core, Columbia University Medical Center, New York, New York, USA.Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA. Department of Medicine Microbiome & Pathogen Genomics Core, Columbia University Medical Center, New York, New York, USA.Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA.Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA.New York Presbyterian Hospital, New York, New York, USA.Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA.Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center, New York, New York, USA au2110@columbia.edu. Department of Medicine Microbiome & Pathogen Genomics Core, Columbia University Medical Center, New York, New York, USA.

Pub Type(s)

Case Reports
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

29263067

Citation

Giddins, Marla J., et al. "Successive Emergence of Ceftazidime-Avibactam Resistance Through Distinct Genomic Adaptations in blaKPC-2-Harboring Klebsiella Pneumoniae Sequence Type 307 Isolates." Antimicrobial Agents and Chemotherapy, vol. 62, no. 3, 2018.
Giddins MJ, Macesic N, Annavajhala MK, et al. Successive Emergence of Ceftazidime-Avibactam Resistance through Distinct Genomic Adaptations in blaKPC-2-Harboring Klebsiella pneumoniae Sequence Type 307 Isolates. Antimicrob Agents Chemother. 2018;62(3).
Giddins, M. J., Macesic, N., Annavajhala, M. K., Stump, S., Khan, S., McConville, T. H., ... Uhlemann, A. C. (2018). Successive Emergence of Ceftazidime-Avibactam Resistance through Distinct Genomic Adaptations in blaKPC-2-Harboring Klebsiella pneumoniae Sequence Type 307 Isolates. Antimicrobial Agents and Chemotherapy, 62(3), doi:10.1128/AAC.02101-17.
Giddins MJ, et al. Successive Emergence of Ceftazidime-Avibactam Resistance Through Distinct Genomic Adaptations in blaKPC-2-Harboring Klebsiella Pneumoniae Sequence Type 307 Isolates. Antimicrob Agents Chemother. 2018;62(3) PubMed PMID: 29263067.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Successive Emergence of Ceftazidime-Avibactam Resistance through Distinct Genomic Adaptations in blaKPC-2-Harboring Klebsiella pneumoniae Sequence Type 307 Isolates. AU - Giddins,Marla J, AU - Macesic,Nenad, AU - Annavajhala,Medini K, AU - Stump,Stephania, AU - Khan,Sabrina, AU - McConville,Thomas H, AU - Mehta,Monica, AU - Gomez-Simmonds,Angela, AU - Uhlemann,Anne-Catrin, Y1 - 2018/02/23/ PY - 2017/10/11/received PY - 2017/12/07/accepted PY - 2017/12/22/pubmed PY - 2019/5/15/medline PY - 2017/12/22/entrez KW - Klebsiella pneumoniae KW - antimicrobial resistance KW - bacterial genomics KW - carbapenem-resistant Enterobacteriaceae KW - ceftazidime-avibactam KW - long-read sequencing JF - Antimicrobial agents and chemotherapy JO - Antimicrob. Agents Chemother. VL - 62 IS - 3 N2 - Ceftazidime-avibactam (CAZ-AVI) is a promising novel treatment for infections caused by carbapenem-resistant Enterobacteriaceae (CRE). Despite improved treatment outcomes compared to those achieved with aminoglycoside- and colistin-based regimens, the rapid evolution of CAZ-AVI resistance during treatment has previously been reported in Klebsiella pneumoniae sequence type 258 (ST258) blaKPC-3-harboring isolates. Here, we report the stepwise evolution and isolation of two phenotypically distinct CAZ-AVI-resistant Klebsiella pneumoniae isolates from a patient with pancreatitis. All susceptible (n = 3) and resistant (n = 5) isolates were of the ST307 clonal background, a rapidly emerging clone. Taking advantage of short-read Illumina and long-read Oxford Nanopore sequencing and full-length assembly of the core chromosome and plasmids, we demonstrate that CAZ-AVI resistance first occurred through a 532G → T blaKPC-2 point mutation in blaKPC-2 (D179Y protein substitution) following only 12 days of CAZ-AVI exposure. While subsequent isolates exhibited substantially decreased meropenem (MEM) MICs (≤2 μg/ml), later cultures demonstrated a second CAZ-AVI resistance phenotype with a lower CAZ-AVI MIC (12 μg/ml) but also MEM resistance (MIC > 128 μg/ml). These CAZ-AVI- and MEM-resistant isolates showed evidence of multiple genomic adaptations, mainly through insertions and deletions. This included amplification and transposition of wild-type blaKPC-2 into a novel plasmid, an IS1 insertion upstream of ompK36, and disruption of the rfb gene locus in these isolates. Our findings illustrate the potential of CAZ-AVI resistance to emerge in non-K. pneumoniae ST258 clonal backgrounds and alternative blaKPC variants. These results raise concerns about the strong selective pressures incurred by novel carbapenemase inhibitors, such as avibactam, on isolates previously considered invulnerable to CAZ-AVI resistance. There is an urgent need to further characterize non-KPC-mediated modes of carbapenem resistance and the intrinsic bacterial factors that facilitate the rapid emergence of resistance during treatment. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/29263067/Successive_Emergence_of_Ceftazidime_Avibactam_Resistance_through_Distinct_Genomic_Adaptations_in_blaKPC_2_Harboring_Klebsiella_pneumoniae_Sequence_Type_307_Isolates_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=29263067 DB - PRIME DP - Unbound Medicine ER -