1. A 4.5-Year Within-Patient Evolution of a Colistin-Resistant Klebsiella pneumoniae Carbapenemase–Producing K. pneumoniae Sequence Type 258
- Author
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Eric Farfour, Rémy A. Bonnin, Isabelle Rosinski-Chupin, Philippe Glaser, Agnès B Jousset, Laurent Dortet, Delphine Girlich, Hélène Frech, Thierry Naas, Gaelle Cuzon, Nicolas Cabanel, Centre National de Référence Associé de la Résistance aux Antibiotiques, AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre), Hôpital Bicêtre, Hôpital Bicêtre-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Sud - Paris 11 (UP11), Ecologie et Evolution de la Résistance aux Antibiotiques / Ecology and Evolution of Antibiotics Resistance (EERA), Institut Pasteur [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Sud Orsay-Centre National de la Recherche Scientifique (CNRS), Structure, Dynamique, Fonction Et Expression Des Beta-Lactamases À Large Spectre, Université Paris-Sud - Paris 11 - Faculté de médecine (UP11 UFR Médecine), Université Paris-Sud - Paris 11 (UP11)-Université Paris-Sud - Paris 11 (UP11)-Centre National de Référence de la Résistance aux Antibiotiques (CNR), Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon)-Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Université de Bordeaux (UB), CHI Poissy-Saint-Germain, Hôpital Foch [Suresnes], This work was supported by the Assistance Publique–Hôpitaux de Paris, Université Paris Sud (grant number EA 7361), LabEx Laboratoire d’Excellence en Recherche sur le Médicament et l’InnovationThérapeutique, supported by the French National Research Agency (grant number Agence Nationale de la Recherche [ANR]-10-LABX-33), by a project of ANR LabEx Integrative Biology of Emerging Infectious Diseases, and the Joint Program Initiative on Antimicrobial Resistance (grant number ANR-14-JAMR-0002)., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-14-JAMR-0002,DesInMBL,Structure-guided design of pan inhibitors of metallo-ß-lactamases(2014), Centre National de Référence Associé de la Résistance aux Antibiotiques [Hôpital Bicêtre AP-HP] (CNRARA/Service de Microbiologie), Université Paris-Sud - Paris 11 (UP11)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Bicêtre, and Université Paris-Sud - Paris 11 (UP11)-Institut Pasteur [Paris] (IP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Centre National de la Recherche Scientifique (CNRS)
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Male ,0301 basic medicine ,MESH: Fatal Outcome ,Klebsiella pneumoniae ,MESH: Klebsiella pneumoniae ,Respiratory chain ,MESH: beta-Lactamases ,Bacteremia ,Drug resistance ,phylogeny ,Fatal Outcome ,carrier ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,polycyclic compounds ,Medicine ,MESH: Bacteremia ,MESH: Bacterial Proteins ,MESH: Microbial Sensitivity Tests ,biology ,MESH: Polymorphism, Single Nucleotide ,within-host evolution ,Anti-Bacterial Agents ,3. Good health ,MESH: Klebsiella Infections ,Infectious Diseases ,NGS ,Carrier State ,MESH: Equipment Contamination ,MESH: Carrier State ,MESH: Whole Genome Sequencing ,medicine.drug ,Microbiology (medical) ,MESH: Mutation ,030106 microbiology ,Virulence ,Microbial Sensitivity Tests ,MESH: Biofilms ,Polymorphism, Single Nucleotide ,beta-Lactamases ,MESH: Endoscopy ,MESH: Fimbriae, Bacterial ,Microbiology ,Evolution, Molecular ,03 medical and health sciences ,Antibiotic resistance ,Bacterial Proteins ,MESH: Anti-Bacterial Agents ,Drug Resistance, Bacterial ,MESH: Drug Resistance, Bacterial ,Humans ,MESH: Humans ,Whole Genome Sequencing ,Colistin ,business.industry ,Endoscopy ,[SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology ,MESH: Colistin ,biochemical phenomena, metabolism, and nutrition ,bacterial infections and mycoses ,biology.organism_classification ,medicine.disease ,MESH: Male ,Klebsiella Infections ,KPC ,Carriage ,Biofilms ,Fimbriae, Bacterial ,Mutation ,Equipment Contamination ,business - Abstract
International audience; Background. Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae (KPC-Kp) has emerged globally over the last decade as a major nosocomial pathogen that threatens patient care. These highly resistant bacteria are mostly associated with a single Kp clonal group, CG258, but the reasons for its host and hospital adaptation remain largely unknown. Methods. We analyzed the in vivo evolution of a colistin-resistant KPC-Kp CG258 strain that contaminated a patient following an endoscopy and was responsible for a fatal bacteremia 4.5 years later. Whole-genome sequencing was performed on 17 KPC-Kp isolates from this patient; single-nucleotide polymorphisms were analyzed and their implication in antimicrobial resistance and bacterial host adaptation investigated. Results. The patient KPC-Kp strain diversified over 4.5 years at a rate of 7.5 substitutions per genome per year, resulting in broad phenotypic modifications. After 2 years of carriage, all isolates restored susceptibility to colistin. Higher expression of the fimbriae conferred the ability to produce more biofilm, and the isolate responsible for a bacteremia grew in human serum. The convergent mutations occurring in specific pathways, such as the respiratory chain and the cell envelope, revealed a complex long-term adaptation of KPC-Kp. Conclusions. Broad genomic and phenotypic diversification and the parallel selection of pathoadaptive mutations might contribute to long-term carriage and virulence of KPC-Kp CG258 strains and to the dissemination of this clone.
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- 2018