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Ceftazidime-Avibactam Resistance Associated with Increased bla KPC-3 Gene Copy Number Mediated by pKpQIL Plasmid Derivatives in Sequence Type 258 Klebsiella pneumoniae.
Antimicrob Agents Chemother. 2020 03 24; 64(4)AA

Abstract

This study reports on the characterization of two ceftazidime-avibactam (CZA)-resistant KPC-producing Klebsiella pneumoniae strains (KP-14159 and KP-8788) sequentially isolated from infections occurred in a patient never treated with CZA. Whole-genome sequencing characterization using a combined short- and long-read sequencing approach showed that both isolates belonged to the same ST258 strain, had altered outer membrane porins (a truncated OmpK35 and an Asp137Thr138 duplication in the L3 loop of OmpK36), and carried novel pKpQIL plasmid derivatives (pIT-14159 and pIT-8788, respectively) harboring two copies of the Tn4401a KPC-3-encoding transposon. Plasmid pIT-8788 was a cointegrate of pIT-14159 with a ColE replicon (that was also present in KP-14159) apparently evolved in vivo during infection. pIT-8788 was maintained at a higher copy number than pIT-14159 and, upon transfer to Escherichia coli DH10B, was able to increase the CZA MIC by 32-fold. The present findings provide novel insights about the mechanisms of acquired resistance to CZA, underscoring the role that the evolution of broadly disseminated pKpQIL plasmid derivatives may have in increasing the bla KPC gene copy number and KPC-3 expression in bacterial hosts. Although not self-transferable, similar elements, with multiple copies of Tn4401 and maintained at a high copy number, could mediate transferable CZA resistance upon mobilization.

Authors+Show Affiliations

Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.Laboratory of Clinical Pathology, Microbiology, and Virology, IRCCS-ISMETT, Palermo, Italy.Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy.Laboratory of Clinical Pathology, Microbiology, and Virology, IRCCS-ISMETT, Palermo, Italy. Department of Research, IRCCS-ISMETT, Palermo, Italy.Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy gianmaria.rossolini@unifi.it. Clinical Microbiology and Virology Unit, Florence Careggi University Hospital, Florence, Italy.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31964792

Citation

Coppi, Marco, et al. "Ceftazidime-Avibactam Resistance Associated With Increased Bla KPC-3 Gene Copy Number Mediated By pKpQIL Plasmid Derivatives in Sequence Type 258 Klebsiella Pneumoniae." Antimicrobial Agents and Chemotherapy, vol. 64, no. 4, 2020.
Coppi M, Di Pilato V, Monaco F, et al. Ceftazidime-Avibactam Resistance Associated with Increased bla KPC-3 Gene Copy Number Mediated by pKpQIL Plasmid Derivatives in Sequence Type 258 Klebsiella pneumoniae. Antimicrob Agents Chemother. 2020;64(4).
Coppi, M., Di Pilato, V., Monaco, F., Giani, T., Conaldi, P. G., & Rossolini, G. M. (2020). Ceftazidime-Avibactam Resistance Associated with Increased bla KPC-3 Gene Copy Number Mediated by pKpQIL Plasmid Derivatives in Sequence Type 258 Klebsiella pneumoniae. Antimicrobial Agents and Chemotherapy, 64(4). https://doi.org/10.1128/AAC.01816-19
Coppi M, et al. Ceftazidime-Avibactam Resistance Associated With Increased Bla KPC-3 Gene Copy Number Mediated By pKpQIL Plasmid Derivatives in Sequence Type 258 Klebsiella Pneumoniae. Antimicrob Agents Chemother. 2020 03 24;64(4) PubMed PMID: 31964792.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ceftazidime-Avibactam Resistance Associated with Increased bla KPC-3 Gene Copy Number Mediated by pKpQIL Plasmid Derivatives in Sequence Type 258 Klebsiella pneumoniae. AU - Coppi,Marco, AU - Di Pilato,Vincenzo, AU - Monaco,Francesco, AU - Giani,Tommaso, AU - Conaldi,Pier Giulio, AU - Rossolini,Gian Maria, Y1 - 2020/03/24/ PY - 2019/09/04/received PY - 2020/01/12/accepted PY - 2020/1/23/pubmed PY - 2021/1/12/medline PY - 2020/1/23/entrez KW - CAZ-AVI KW - KPC KW - Tn4401 KW - avibactam KW - carbapenem-resistant Enterobacterales KW - carbapenemase KW - double copy KW - porin alterations JF - Antimicrobial agents and chemotherapy JO - Antimicrob Agents Chemother VL - 64 IS - 4 N2 - This study reports on the characterization of two ceftazidime-avibactam (CZA)-resistant KPC-producing Klebsiella pneumoniae strains (KP-14159 and KP-8788) sequentially isolated from infections occurred in a patient never treated with CZA. Whole-genome sequencing characterization using a combined short- and long-read sequencing approach showed that both isolates belonged to the same ST258 strain, had altered outer membrane porins (a truncated OmpK35 and an Asp137Thr138 duplication in the L3 loop of OmpK36), and carried novel pKpQIL plasmid derivatives (pIT-14159 and pIT-8788, respectively) harboring two copies of the Tn4401a KPC-3-encoding transposon. Plasmid pIT-8788 was a cointegrate of pIT-14159 with a ColE replicon (that was also present in KP-14159) apparently evolved in vivo during infection. pIT-8788 was maintained at a higher copy number than pIT-14159 and, upon transfer to Escherichia coli DH10B, was able to increase the CZA MIC by 32-fold. The present findings provide novel insights about the mechanisms of acquired resistance to CZA, underscoring the role that the evolution of broadly disseminated pKpQIL plasmid derivatives may have in increasing the bla KPC gene copy number and KPC-3 expression in bacterial hosts. Although not self-transferable, similar elements, with multiple copies of Tn4401 and maintained at a high copy number, could mediate transferable CZA resistance upon mobilization. SN - 1098-6596 UR - https://www.unboundmedicine.com/medline/citation/31964792/Ceftazidime_Avibactam_Resistance_Associated_with_Increased_bla_KPC_3_Gene_Copy_Number_Mediated_by_pKpQIL_Plasmid_Derivatives_in_Sequence_Type_258_Klebsiella_pneumoniae_ L2 - http://aac.asm.org/cgi/pmidlookup?view=long&pmid=31964792 DB - PRIME DP - Unbound Medicine ER -