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      Multispecies and Clonal Dissemination of OXA-48 Carbapenemase in Enterobacteriaceae From Companion Animals in Germany, 2009—2016

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          The increasing spread of carbapenemase-producing Enterobacteriaceae (CPE) poses a serious threat to public health. Recent studies suggested animals as a putative source of such bacteria. We investigated 19,025 Escherichia coli, 1607 Klebsiella spp. and 570 Enterobacter spp. isolated from livestock, companion animal, horse, and pet samples between 2009 and 2016 in our routine diagnostic laboratory for reduced susceptibility to carbapenems (CP) by using meropenem-containing media. Actively screened CP non-susceptible strains as well as 367 archived ESBL/AmpC-β-lactamase-producing Enterobacteriaceae were then tested for the presence of CP genes by PCRs. Among 21,569 isolates, OXA-48 could be identified as the sole carbapenemase type in 137 (0.64%) strains. The bla OXA-48 gene was located on an ∼60-kb IncL plasmid and sequence analysis revealed high similarity to reference plasmid pOXA-48a, which has been involved in the global spread of the bla OXA-48 gene in humans for many years. Klebsiella pneumoniae was the predominant OXA-48 producer ( n = 86; 6.6% of all K. pneumoniae isolates), followed by E. cloacae ( n = 28; 5.0%), Klebsiella oxytoca ( n = 1; 0.3%), and E. coli ( n = 22, 0.1%). OXA-48 was not found in livestock, but in dogs (120/3182; 3.8%), cats (13/792; 1.6%), guinea pig (1/43; 2.3%), rat (1/23; 4.3%), mouse (1/180; 0.6%), and one rabbit (1/144; 0.7%). Genotyping identified few major clones among the different enterobacteria species, including sequence types ST11 and ST15 for K. pneumoniae, ST1196 for E. coli, and ST506 and ST78 for E. cloacae, most of which were previously involved in the dissemination of multidrug-resistant strains in humans. The majority of OXA-48 isolates ( n = 112) originated from a university veterinary clinic (UVC), while animals from further 16 veterinary institutions were positive. Clonal analyses suggested nosocomial events related to different species and STs in two veterinary clinics and horizontal transfer of the pOXA-48-like plasmid between bacterial species and animals. A systematic monitoring is urgently needed to assess the dissemination of CPE not only in livestock but also in companion animals and veterinary clinics.

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          Most cited references 52

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          Carbapenemase-Producing Klebsiella pneumoniae, a Key Pathogen Set for Global Nosocomial Dominance.

          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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            Extraintestinal Pathogenic Escherichia coli: A Combination of Virulence with Antibiotic Resistance

            Escherichia coli represents an incredible versatile and diverse enterobacterial species and can be subdivided into the following; (i) intestinal non-pathogenic, commensal isolates. (ii) Intestinal pathogenic isolates and (iii) extraintestinal pathogenic E. coli or ExPEC isolates. The presence to several putative virulence genes has been positively linked with the pathogenicity of ExPEC. E. coli remains one of the most frequent causes of nosocomial and community-acquired bacterial infections including urinary tract infections, enteric infections, and systemic infections in humans. ExPEC has emerged in 2000s as an important player in the resistance to antibiotics including the cephalosporins and fluoroquinolones. Most importantly among ExPEC is the increasing recognition of isolates producing “newer β-lactamases” that consists of plasmid-mediated AmpC β-lactamases (e.g., CMY), extended-spectrum β-lactamases (e.g., CTX-M), and carbapenemases (e.g., NDM). This review will highlight aspects of virulence associated with ExPEC, provide a brief overview of plasmid-mediated resistance to β-lactams including the characteristics of the successful international sequence types such as ST38, ST131, ST405, and ST648 among ExPEC.
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              Genetic features of the widespread plasmid coding for the carbapenemase OXA-48.

              Complete sequencing of plasmid pOXA-48a carrying the bla(OXA-48) gene from a Klebsiella pneumoniae isolate was performed. Its backbone corresponded to that of an IncL/M-type plasmid, in which the bla(OXA-48) gene had been integrated through the acquisition of the Tn1999 composite transposon without any other antibiotic resistance gene. Molecular epidemiology using a collection of international OXA-48 producers revealed the wide diffusion of pOXA-48a or closely related plasmids.

                Author and article information

                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                14 June 2018
                : 9
                1Institute of Hygiene and Infectious Diseases of Animals, Justus Liebig University Giessen , Giessen, Germany
                2Institute of Microbiology, University of Veterinary Medicine Hannover, Foundation , Hanover, Germany
                3Vet Med Labor GmbH, Division of IDEXX Laboratories , Ludwigsburg, Germany
                4Microbial Genomics (NG1), Robert Koch Institute , Berlin, Germany
                Author notes

                Edited by: Miklos Fuzi, Semmelweis University, Hungary

                Reviewed by: Eelco Franz, Centre for Infectious Disease Control (RIVM), Netherlands; Jian Sun, South China Agricultural University, China

                *Correspondence: Christa Ewers, christa.ewers@

                Shared first authorship

                This article was submitted to Antimicrobials, Resistance and Chemotherapy, a section of the journal Frontiers in Microbiology

                Copyright © 2018 Pulss, Stolle, Stamm, Leidner, Heydel, Semmler, Prenger-Berninghoff and Ewers.

                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 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.

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                Figures: 3, Tables: 2, Equations: 0, References: 59, Pages: 12, Words: 0
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