Agnès B Jousset1,2,3,4, Rémy A Bonnin2,3,4, Isabelle Rosinski-Chupin4,5, Delphine Girlich3,4, Gaëlle Cuzon1,2,3,4, Nicolas Cabanel4,5, Hélène Frech6, Eric Farfour7, Laurent Dortet1,2,3,4, Philippe Glaser4,5, Thierry Naas1,2,3,4. 1. Department of Bacteriology-Parasitology-Hygiene, Hôpital de Bicêtre, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris. 2. Associated French National Reference Center for Antibiotic Resistance, Paris. 3. Faculty of Medicine, Paris-Sud University, Le Kremlin-Bicêtre, Paris. 4. Joint Research Unit Evolution and Ecology of Resistance to Antibiotics, Institut Pasteur, AP-HP, University Paris Sud, Paris. 5. Centre de la Recherche Scientifique, Unité mixte de recherche, Paris. 6. Department of Biology, Hôpital de Poissy-Saint-Germain-en-Laye, Poissy. 7. Department of Microbiology, Hôpital Foch, Suresnes, France.
Abstract
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.
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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