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      An Outbreak of Carbapenem-Resistant and Hypervirulent Klebsiella pneumoniae in an Intensive Care Unit of a Major Teaching Hospital in Wenzhou, China

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          Abstract

          Carbapenem-resistant, hypervirulent Klebsiella pneumoniae (CR-hvKP) has recently emerged as a significant threat to public health. In this study, 29 K. pneumoniae isolates were isolated from eight patients admitted to the intensive care unit (ICU) of a comprehensive teaching hospital located in China from March 2017 to January 2018. Clinical information of patients was the basis for the further analyses of the isolates including antimicrobial susceptibility tests, identification of antibiotic resistance and virulence gene determinants, multilocus sequence typing (MLST), XbaI-macrorestriction by pulsed-field gel electrophoresis (PFGE). Selected isolates representing distinct resistance profiles and virulence phenotypes were screened for hypervirulence in a Galleria mellonella larvae infection model. In the course of the outbreak, the overall mortality rate of patients was 100% ( n = 8) attributed to complications arising from CR-hvKP infections. All isolates except one (28/29, 96.6%) were resistant to multiple antimicrobial agents, and harbored diverse resistance determinants that included the globally prevalent carbapenemase bla KPC−2. Most isolates had hypervirulent genotypes being positive for 19 virulence-associated genes, including iutA (25/29, 86.2%), rmpA (27/29, 93.1%), ybtA (27/29, 93.1%), entB (29/29, 100%), fimH (29/29, 100%), and mrkD (29/29, 100%). MLST revealed ST11 for the majority of isolates (26/29, 89,7%). Infection assays demonstrated high mortality in the Galleria mellonella model with the highest LD 50 values for three isolates (<10 5 CFU/mL) demonstrating the degree of hypervirulence of these CR-hvKP isolates, and is discussed relative to previous outbreaks of CR-hvKP.

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          Hypervirulent (hypermucoviscous) Klebsiella pneumoniae

          Alyssa S. Shon, Rajinder Bajwa, Thomas Russo (2013)
          A new hypervirulent (hypermucoviscous) variant of Klebsiella pneumoniae has emerged. First described in the Asian Pacific Rim, it now increasingly recognized in Western countries. Defining clinical features are the ability to cause serious, life-threatening community-acquired infection in younger healthy hosts, including liver abscess, pneumonia, meningitis and endophthalmitis and the ability to metastatically spread, an unusual feature for enteric Gram-negative bacilli in the non-immunocompromised. Despite infecting a healthier population, significant morbidity and mortality occurs. Although epidemiologic features are still being defined, colonization, particularly intestinal colonization, appears to be a critical step leading to infection. However the route of entry remains unclear. The majority of cases described to date are in Asians, raising the issue of a genetic predisposition vs. geospecific strain acquisition. The traits that enhance its virulence when compared with “classical” K. pneumoniae are the ability to more efficiently acquire iron and perhaps an increase in capsule production, which confers the hypermucoviscous phenotype. An objective diagnostic test suitable for routine use in the clinical microbiology laboratory is needed. If/when these strains become increasingly resistant to antimicrobials, we will be faced with a frightening clinical scenario.
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            Carbapenemase-Producing Klebsiella pneumoniae, a Key Pathogen Set for Global Nosocomial Dominance.

            Johann D D Pitout, Patrice Nordmann, Laurent Poirel (2015)
            The management of infections due to Klebsiella pneumoniae has been complicated by the emergence of antimicrobial resistance, especially to carbapenems. Resistance to carbapenems in K. pneumoniae involves multiple mechanisms, including the production of carbapenemases (e.g., KPC, NDM, VIM, OXA-48-like), as well as alterations in outer membrane permeability mediated by the loss of porins and the upregulation of efflux systems. The latter two mechanisms are often combined with high levels of other types of β-lactamases (e.g., AmpC). K. pneumoniae sequence type 258 (ST258) emerged during the early to mid-2000s as an important human pathogen and has spread extensively throughout the world. ST258 comprises two distinct lineages, namely, clades I and II, and it seems that ST258 is a hybrid clone that was created by a large recombination event between ST11 and ST442. Incompatibility group F plasmids with blaKPC have contributed significantly to the success of ST258. The optimal treatment of infections due to carbapenemase-producing K. pneumoniae remains unknown. Some newer agents show promise for treating infections due to KPC producers; however, effective options for the treatment of NDM producers remain elusive.
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              A Novel Virulence Gene in Klebsiella pneumoniae Strains Causing Primary Liver Abscess and Septic Metastatic Complications

              Chi-Tai Fang, Yi-Ping Chuang, Chia-Tung Shun … (2004)
              Primary Klebsiella pneumoniae liver abscess complicated with metastatic meningitis or endophthalmitis is a globally emerging infectious disease. Its pathogenic mechanism remains unclear. The bacterial virulence factors were explored by comparing clinical isolates. Differences in mucoviscosity were observed between strains that caused primary liver abscess (invasive) and those that did not (noninvasive). Hypermucoviscosity correlated with a high serum resistance and was more prevalent in invasive strains (52/53 vs. 9/52; P < 0.0001). Transposon mutagenesis identified candidate virulence genes. A novel 1.2-kb locus, magA, which encoded a 43-kD outer membrane protein, was significantly more prevalent in invasive strains (52/53 vs. 14/52; P < 0.0001). The wild-type strain produced a mucoviscous exopolysaccharide web, actively proliferated in nonimmune human serum, resisted phagocytosis, and caused liver microabscess and meningitis in mice. However, magA − mutants lost the exopolysaccharide web and became extremely serum sensitive, phagocytosis susceptible, and avirulent to mice. Virulence was restored by complementation using a magA-containing plasmid. We conclude that magA fits molecular Koch's postulates as a virulence gene. Thus, this locus can be used as a marker for the rapid diagnosis and for tracing the source of this emerging infectious disease.
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                Author and article information

                Contributors
                Journal
                Journal ID (nlm-ta): Front Public Health
                Journal ID (iso-abbrev): Front Public Health
                Journal ID (publisher-id): Front. Public Health
                Title: Frontiers in Public Health
                Publisher: Frontiers Media S.A.
                ISSN (Electronic): 2296-2565
                Publication date (Electronic): 19 August 2019
                Publication date Collection: 2019
                Volume: 7
                Electronic Location Identifier: 229
                Affiliations
                [1] 1School of Laboratory Medicine and Life Science, Wenzhou Medical University , Wenzhou, China
                [2] 2Department of Clinical Laboratory, The First Affiliated Hospital of Wenzhou Medical University , Wenzhou, China
                [3] 3Infection and Immunity Program, Department of Microbiology, Biomedicine Discovery Institute, Monash University , Melbourne, VIC, Australia
                [4] 4School of Medicine, The Fourth Affiliated Hospital of Zhejiang University , Jinhua, China
                [5] 5Department of Microbiology and Immunology, The Peter Doherty Institute, The University of Melbourne , Melbourne, VIC, Australia
                Author notes

                Edited by: Kai Zhou, Zhejiang University, China

                Reviewed by: Pedro Xavier-Elsas, Federal University of Rio de Janeiro, Brazil; Yvonne Pfeifer, Robert Koch Institute, Germany; Richard Vernon Goering, Creighton University, United States

                *Correspondence: Trevor Lithgow trevor.lithgow@ 123456monash.edu

                This article was submitted to Infectious Diseases - Surveillance, Prevention and Treatment, a section of the journal Frontiers in Public Health

                Article
                DOI: 10.3389/fpubh.2019.00229
                PMC ID: 6736603
                PubMed ID: 31552210
                SO-VID: ba42ae37-cde3-4221-b7f0-731d529e7c21
                Copyright © Copyright © 2019 Zhao, Zhang, Torres, Liu, Rocker, Zhang, Wang, Chen, Bi, Lin, Strugnell, Zhang, Lithgow, Zhou and Cao.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                Date received : 28 March 2019
                Date accepted : 30 July 2019
                Page count
                Figures: 4, Tables: 1, Equations: 0, References: 69, Pages: 11, Words: 8254
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Funded by: National Health and Medical Research Council 10.13039/501100000925
                Categories
                Subject: Public Health
                Subject: Original Research

                Keywords: klebsiella pneumoniae,hypervirulent,carbapenem-resistance,st11,epidemiology
                Data availability:
                Keywords: klebsiella pneumoniae, hypervirulent, carbapenem-resistance, st11, epidemiology

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