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      Nested Russian Doll-Like Genetic Mobility Drives Rapid Dissemination of the Carbapenem Resistance Gene bla KPC

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          Abstract

          The recent widespread emergence of carbapenem resistance in Enterobacteriaceae is a major public health concern, as carbapenems are a therapy of last resort against this family of common bacterial pathogens. Resistance genes can mobilize via various mechanisms, including conjugation and transposition; however, the importance of this mobility in short-term evolution, such as within nosocomial outbreaks, is unknown. Using a combination of short- and long-read whole-genome sequencing of 281 bla KPC-positive Enterobacteriaceae isolates from a single hospital over 5 years, we demonstrate rapid dissemination of this carbapenem resistance gene to multiple species, strains, and plasmids. Mobility of bla KPC occurs at multiple nested genetic levels, with transmission of bla KPC strains between individuals, frequent transfer of bla KPC plasmids between strains/species, and frequent transposition of bla KPC transposon Tn 4401 between plasmids. We also identify a common insertion site for Tn 4401 within various Tn 2-like elements, suggesting that homologous recombination between Tn 2-like elements has enhanced the spread of Tn 4401 between different plasmid vectors. Furthermore, while short-read sequencing has known limitations for plasmid assembly, various studies have attempted to overcome this by the use of reference-based methods. We also demonstrate that, as a consequence of the genetic mobility observed in this study, plasmid structures can be extremely dynamic, and therefore these reference-based methods, as well as traditional partial typing methods, can produce very misleading conclusions. Overall, our findings demonstrate that nonclonal resistance gene dissemination can be extremely rapid, presenting significant challenges for public health surveillance and achieving effective control of antibiotic resistance.

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          Plasmids and the spread of resistance.

          Plasmids represent one of the most difficult challenge for counteracting the dissemination of antimicrobial resistance. They contribute to the spread of relevant resistance determinants, promoting horizontal gene transfer among unrelated bacteria. Undistinguishable plasmids were identified in unrelated bacterial strains isolated at huge geographically distant area, with no apparent epidemiological links. These plasmids belong to families that are largely prevalent in naturally occurring bacteria, usually carry multiple physically linked genetic determinants, conferring resistance to different classes of antibiotics simultaneously. Plasmids also harbour virulence factors and addiction systems, promoting their stability and maintenance in the bacterial host, in different environmental conditions. The characteristics of the most successful plasmids that were at the origin of the spread of carbapenemase, expanded-spectrum β-lactamase, and plasmid-mediated quinolone resistance genes are discussed in this review. Copyright © 2013 Elsevier GmbH. All rights reserved.
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            Outcomes of carbapenem-resistant Klebsiella pneumoniae infection and the impact of antimicrobial and adjunctive therapies.

            Carbapenem-resistant Klebsiella pneumoniae is an emerging healthcare-associated pathogen. To describe the epidemiology of and clinical outcomes associated with carbapenem-resistant K. pneumoniae infection and to identify risk factors associated with mortality among patients with this type of infection. Mount Sinai Hospital, a 1,171-bed tertiary care teaching hospital in New York City. Two matched case-control studies. In the first matched case-control study, case patients with carbapenem-resistant K. pneumoniae infection were compared with control patients with carbapenem-susceptible K. pneumoniae infection. In the second case-control study, patients who survived carbapenem-resistant K. pneumoniae infection were compared with those who did not survive, to identify risk factors associated with mortality among patients with carbapenem-resistant K. pneumoniae infection. There were 99 case patients and 99 control patients identified. Carbapenem-resistant K. pneumoniae infection was independently associated with recent organ or stem-cell transplantation (P=.008), receipt of mechanical ventilation (P=.04), longer length of stay before infection (P=.01), and exposure to cephalosporins (P=.02) and carbapenems (P<.001). Case patients were more likely than control patients to die during hospitalization (48% vs 20%; P<.001) and to die from infection (38% vs 12%; P<.001). Removal of the focus of infection (ie, debridement) was independently associated with patient survival (P=.002). The timely administration of antibiotics with in vitro activity against carbapenem-resistant K. pneumoniae was not associated with patient survival. Carbapenem-resistant K. pneumoniae infection is associated with numerous healthcare-related risk factors and with high mortality. The mortality rate associated with carbapenem-resistant K. pneumoniae infection and the limited antimicrobial options for treatment of carbapenem-resistant K. pneumoniae infection highlight the need for improved detection of carbapenem-resistant K. pneumoniae infection, identification of effective preventive measures, and development of novel agents with reliable clinical efficacy against carbapenem-resistant K. pneumoniae.
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              Carbapenemase-producing Klebsiella pneumoniae: molecular and genetic decoding.

              Klebsiella pneumoniae carbapenemases (KPCs) were first identified in 1996 in the USA. Since then, regional outbreaks of KPC-producing K. pneumoniae (KPC-Kp) have occurred in the USA, and have spread internationally. Dissemination of blaKPC involves both horizontal transfer of blaKPC genes and plasmids, and clonal spread. Of epidemiological significance, the international spread of KPC-producing K. pneumoniae is primarily associated with a single multilocus sequence type (ST), ST258, and its related variants. However, the molecular factors contributing to the success of ST258 largely remain unclear. In this review, we discuss the recent progresses in understanding KPC-producing K. pneumoniae that are contributing to our knowledge of plasmid and genome composition and structure among the KPC epidemic clone, and we identify possible factors that influence its epidemiological success. Copyright © 2014 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Antimicrob Agents Chemother
                Antimicrob. Agents Chemother
                aac
                aac
                AAC
                Antimicrobial Agents and Chemotherapy
                American Society for Microbiology (1752 N St., N.W., Washington, DC )
                0066-4804
                1098-6596
                11 April 2016
                23 May 2016
                June 2016
                23 May 2016
                : 60
                : 6
                : 3767-3778
                Affiliations
                [a ]Modernizing Medical Microbiology Consortium, Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Oxford University, Oxford, United Kingdom
                [b ]Icahn Institute and Department of Genetics and Genomic Sciences, Icahn School of Medicine, Mount Sinai, New York, New York, USA
                [c ]Food and Drug Administration, Laurel, Maryland, USA
                [d ]Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia, USA
                [e ]Office of Hospital Epidemiology, University of Virginia Health System, Charlottesville, Virginia, USA
                [f ]Public Health England, Microbiology Services, London, United Kingdom
                [g ]Clinical Microbiology, Department of Pathology, University of Virginia Health System, Charlottesville, Virginia, USA
                Author notes
                Address correspondence to Anna E. Sheppard, anna.sheppard@ 123456ndm.ox.ac.uk , or Amy J. Mathers, ajm5b@ 123456virginia.edu .
                [*]

                Present address: Adam Giess, Department of Informatics, University of Bergen, Bergen, Norway; Anthony J. Yeh, Pathogen Molecular Genetics Section, Laboratory of Human Bacterial Pathogenesis, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.

                Citation Sheppard AE, Stoesser N, Wilson DJ, Sebra R, Kasarskis A, Anson LW, Giess A, Pankhurst LJ, Vaughan A, Grim CJ, Cox HL, Yeh AJ, the Modernising Medical Microbiology Informatics Group, Sifri CD, Walker AS, Peto TE, Crook DW, Mathers AJ. 2016. Nested Russian doll-like genetic mobility drives rapid dissemination of the carbapenem resistance gene bla KPC. Antimicrob Agents Chemother 60:3767–3778. doi: 10.1128/AAC.00464-16.

                Author information
                http://orcid.org/0000-0002-4508-7969
                Article
                00464-16
                10.1128/AAC.00464-16
                4879409
                27067320
                ff9ff0a9-25e5-4e7b-aff9-734584fe8a8a
                Copyright © 2016 Sheppard et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

                History
                : 29 February 2016
                : 23 March 2016
                : 3 April 2016
                Page count
                Figures: 5, Tables: 2, Equations: 0, References: 55, Pages: 12, Words: 9008
                Funding
                This publication presents independent research commissioned by the Health Innovation Challenge Fund (grants HICF-T5-358 and WT098615/Z/12/Z), a parallel funding partnership of the Department of Health and Wellcome Trust, the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and the University of Oxford, and the NIHR Oxford Health Protection Research Unit on Healthcare Associated Infection and Antimicrobial Resistance (HPRU-2012-10041). The views expressed in this publication are those of the authors and not necessarily those of the funders. D.W.C. and T.E.P. are NIHR senior investigators. N.S. was supported by a Wellcome Trust University of Oxford research fellowship during this work. D.J.W. is a Sir Henry Dale Fellow jointly funded by the Wellcome Trust and the Royal Society (grant 101237/Z/13/Z).
                Categories
                Epidemiology and Surveillance

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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