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      Rapid phenotypic evolution in multidrug-resistant Klebsiella pneumoniae hospital outbreak strains

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          Carbapenem-resistant Klebsiella pneumoniae (CRKP) increasingly cause high-mortality outbreaks in hospital settings globally. Following a patient fatality at a hospital in Beijing due to a bla KPC-2-positive CRKP infection, close monitoring was put in place over the course of 14 months to characterize all bla KPC-2-positive CRKP in circulation in the hospital. Whole genome sequences were generated for 100 isolates from bla KPC-2-positive isolates from infected patients, carriers and the hospital environment. Phylogenetic analyses identified a closely related cluster of 82 sequence type 11 (ST11) isolates circulating in the hospital for at least a year prior to admission of the index patient. The majority of inferred transmissions for these isolates involved patients in intensive care units. Whilst the 82 ST11 isolates collected during the surveillance effort all had closely related chromosomes, we observed extensive diversity in their antimicrobial resistance (AMR) phenotypes. We were able to reconstruct the major genomic changes underpinning this variation in AMR profiles, including multiple gains and losses of entire plasmids and recombination events between plasmids, including transposition of bla KPC-2. We also identified specific cases where variation in plasmid copy number correlated with the level of phenotypic resistance to drugs, suggesting that the number of resistance elements carried by a strain may play a role in determining the level of AMR. Our findings highlight the epidemiological value of whole genome sequencing for investigating multi-drug-resistant hospital infections and illustrate that standard typing schemes cannot capture the extraordinarily fast genome evolution of CRKP isolates.

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          Most cited references 42

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          ISfinder: the reference centre for bacterial insertion sequences

          ISfinder () is a dedicated database for bacterial insertion sequences (ISs). It has superseded the Stanford reference center. One of its functions is to assign IS names and to provide a focal point for a coherent nomenclature. It is also the repository for ISs. Each new IS is indexed together with information such as its DNA sequence and open reading frames or potential coding sequences, the sequence of the ends of the element and target sites, its origin and distribution together with a bibliography where available. Another objective is to continuously monitor ISs to provide updated comprehensive groupings or families and to provide some insight into their phylogenies. The site also contains extensive background information on ISs and transposons in general. Online tools are gradually being added. At present an online Blast facility against the entire bank is available. But additional features will include alignment capability, PsiBLAST and HMM profiles. ISfinder also includes a section on bacterial genomes and is involved in annotating the IS content of these genomes. Finally, this database is currently recommended by several microbiology journals for registration of new IS elements before their publication.
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            The real threat of Klebsiella pneumoniae carbapenemase-producing bacteria.

            From early this decade, Enterobacteriaceae that produce Klebsiella pneumoniae carbapenemases (KPC) were reported in the USA and subsequently worldwide. These KPC-producing bacteria are predominantly involved in nosocomial and systemic infections; although they are mostly Enterobacteriaceae, they can also be, rarely, Pseudomonas aeruginosa isolates. KPC beta lactamases (KPC-1 to KPC-7) confer decreased susceptibility or resistance to virtually all beta lactams. Carbapenems (imipenem, meropenem, and ertapenem) may thus become inefficient for treating enterobacterial infections with KPC-producing bacteria, which are, in addition, resistant to many other non-beta-lactam molecules, leaving few available therapeutic options. Detection of KPC-producing bacteria may be difficult based on routine antibiotic susceptibility testing. It is therefore crucial to implement efficient infection control measures to limit the spread of these pathogens.
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              ClonalFrameML: Efficient Inference of Recombination in Whole Bacterial Genomes

              Recombination is an important evolutionary force in bacteria, but it remains challenging to reconstruct the imports that occurred in the ancestry of a genomic sample. Here we present ClonalFrameML, which uses maximum likelihood inference to simultaneously detect recombination in bacterial genomes and account for it in phylogenetic reconstruction. ClonalFrameML can analyse hundreds of genomes in a matter of hours, and we demonstrate its usefulness on simulated and real datasets. We find evidence for recombination hotspots associated with mobile elements in Clostridium difficile ST6 and a previously undescribed 310kb chromosomal replacement in Staphylococcus aureus ST582. ClonalFrameML is freely available at

                Author and article information

                Microb Genom
                Microb Genom
                Microbial Genomics
                Microbiology Society
                April 2019
                2 April 2019
                2 April 2019
                : 5
                : 4
                [ 1]UCL Genetics Institute, University College London , Gower Street, London WC1E 6BT, UK
                [ 2]Department of Clinical Laboratory, Peking University People's Hospital , Beijing, 100044, PR China
                [ 3]Nuffield Department of Medicine, John Radcliffe Hospital , Oxford OX3 7BN, UK
                [ 4]Infectious Diseases and Environmental Health, Norwegian Institute of Public Health , Lovisenberggata 8, 0456, Oslo, Norway
                [ 5]Medical Research Council Centre for Medical Mycology at the University of Aberdeen, Aberdeen Fungal Group, Institute of Medical Sciences , Foresterhill, Aberdeen AB25 2ZD, UK
                [ 6]School of Life Sciences and the Department of Statistics, University of Warwick , Coventry CV4 7AL, UK
                Author notes
                *Correspondence: Lucy van Dorp, lucy.dorp.12@
                Francois Balloux, f.balloux@

                These authors contributed equally to this work


                These authors also contributed equally to this work.

                © 2019 The Authors

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                Funded by: Newton Fund (GB)
                Award ID: MR/P007597/1
                Funded by: National Natural Science Foundation of China-Yunnan Joint Fund
                Award ID: 81661138006
                Research Article
                Microbial Evolution and Epidemiology: Mechanisms of Evolution
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