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Extended Spectrum Β-Lactamase (ESBL) Producing Escherichia Coli in Pigs and Pork Meat in the European Union

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Extended Spectrum Β-Lactamase (ESBL) Producing Escherichia Coli in Pigs and Pork Meat in the European Union antibiotics Review Extended Spectrum β-Lactamase (ESBL) Producing Escherichia coli in Pigs and Pork Meat in the European Union Ieva Bergšpica 1,2,*, Georgia Kaprou 1 , Elena A. Alexa 1 , Miguel Prieto 1,3 and Avelino Alvarez-Ordóñez 1,3,* 1 Department of Food Hygiene and Technology, Universidad de León, 24007 León, Spain; [email protected] (G.K.); [email protected] (E.A.A.); [email protected] (M.P.) 2 Institute of Food Safety, Animal Health and Environment BIOR, LV-1076 Riga, Latvia 3 Institute of Food Science and Technology, Universidad de León, 24007 León, Spain * Correspondence: [email protected] (I.B.); [email protected] (A.A.-O.) Received: 10 September 2020; Accepted: 3 October 2020; Published: 7 October 2020 Abstract: The aim of this article is to review the fast and worldwide distribution of ESBL enzymes and to describe the role of the pork production chain as a reservoir and transmission route of ESBL-producing Escherichia coli and ESBLs in the European Union (EU). The use of β-lactam antibiotics in swine production and the prevalence of ESBL producing E. coli in fattening pigs and pork meat across Europe is analyzed. Overall, an increasing trend in the prevalence of presumptive ESBL producing E. coli in fattening pigs in the EU has been observed in the last decade, although with major differences among countries, linked to different approaches in the use of antimicrobials in pork production within the EU. Moreover, the various dissemination pathways of these bacteria along the pork production chain are described, along with factors at farm and slaughterhouse level influencing the risk of introducing or spreading ESBL producing bacteria throughout the food chain. Keywords: ESBL; E. coli; prevalence; pigs; pork meat; EU 1. Introduction Antimicrobial resistance (AMR) is a global concern in public health, threatening to complicate the treatment of infections worldwide. Emergence and spread of AMR has been attributed to the misuse or overuse of antibiotics in human and veterinary medicine. Antimicrobial resistance occurs as microorganisms modify their genetic information when they are exposed to antimicrobial drugs [1]. The use of antibiotics dates back to the beginning of the 20th century, when Paul Ehrlich discovered a chemical called arsphenamine which was effective against Treponema pallidum, the bacterium causing syphilis [2]. Twenty years later, in 1928, Alexander Fleming isolated penicillin, a β-lactam antibiotic from the fungus Penicillium notatum and, since then, the strike of the antibiotic’s era began. β-lactams, such as penicillins, carbapenems, monobactams, and cephalosporins account for 60% (by weight) of all antibiotics used worldwide, and in human medicine are one of the most widely prescribed antibiotic classes [3,4]. Intensive use and misuse of β-lactam antibiotics both in human and in veterinary medicine has led to the spread of extended spectrum β-lactamase (ESBL) producing resistant bacteria. The World Health Organization (WHO) has indicated that third generation resistant Enterobacteriaceae, including ESBL-producing Enterobacteriaceae, are among the world’s most serious and critical threats of the 21st century [5]. β-lactams interfere with the synthesis of the bacterial cell wall, which results in the inhibition of bacterial growth, by binding to penicillin-binding-proteins (PBPs) that are enzymes involved in Antibiotics 2020, 9, 678; doi:10.3390/antibiotics9100678 www.mdpi.com/journal/antibiotics Antibiotics 2020, 9, x 2 of 24 generation resistant Enterobacteriaceae, including ESBL-producing Enterobacteriaceae, are among the world’s most serious and critical threats of the 21st century [5]. β-lactams interfere with the synthesis of the bacterial cell wall, which results in the inhibition of Antibiotics 2020, 9, 678 2 of 23 bacterial growth, by binding to penicillin-binding-proteins (PBPs) that are enzymes involved in the synthesis of peptidoglycan. β-lactam antibiotics are used to treat infections caused by both Gramthe synthesis-positive ofand peptidoglycan. Gram-negativeβ bacteria.-lactam They antibiotics all share are as used a common to treat structure infections a four caused-membered by both lactamGram-positive ring, known and Gram-negativeas the β-lactambacteria. ring (Figure They 1) all. This share is asa cyclic a common amide structure with a heteroatomic a four-membered ring structurelactam ring, that known consists as of the threeβ-lactam carbon ring atoms (Figure and1 one). This nitrogen is a cyclic atom amide [6]. β- withlactam a heteroatomic antibiotics act ring on thestructure formation that consists of the ofbacterial three carbon cell atomswall andby interfering one nitrogen with atom the [6]. βPBPs-lactam at antibioticsthe final actstage on theof peptidoglycanformation of the synthesis bacterial [6]. cell wall by interfering with the PBPs at the final stage of peptidoglycan synthesisThe intensive [6]. use of β-lactam antibiotics for the past 70 years has led to the evolution of β-lactamThe intensiveresistance use in ofbacteria.β-lactam Resistance antibiotics against for the β past-lactam 70 years antibiotics has led in to bacteria the evolution can be of βensured-lactam throughresistance three in bacteria.different Resistancemechanisms. against The firstβ-lactam mechanism antibiotics includes in bacteria the mutation can be in ensured genes encoding through forthree PBPs, diff erentthe creation mechanisms. of mosaic The firstPBPs mechanism or obtaining includes alternative the mutation PBPs [6]. in genesThe second encoding mechanism for PBPs, consiststhe creation of changes of mosaic in PBPsthe permeability or obtaining of alternative the cell wall PBPs that [6]. could The second be due mechanism to alterations consists in the of expressionchanges in of the porins permeability or active of efflux the cell pumps wall that [6]. couldHowever, be due the to most alterations frequent in themechanism expression is the of porins third oneor active—the einactivationfflux pumps of [ 6the]. However, antibiotic theby the most expression frequent mechanismof β-lactamases is the [6]. third one—the inactivation of theThe antibiotic first β-lactamases by the expression were discovered of β-lactamases in 1940 [6 ].by Edward Penley Abraham [7]. β-lactamases are enzymesThe first producedβ-lactamases by bacteria were discovered that inactivate in 1940 the by β Edward-lactam Penleyring by Abraham breaking [the7]. β amide-lactamases bond areof theenzymes β-lactam produced ring byand bacteria adding that a inactivatewater molecule the β-lactam to the ring ring by- breakingopened molecule. the amide bondNarrow of the spectrumβ-lactam βring-lactamases and adding are aalso water called molecule penicillinases to the ring-opened or cephalosporinases, molecule. Narrow depending spectrum on theβ-lactamases target. Moreover, are also somecalled penicillinasesGram-negative or cephalosporinases,bacteria, especially depending members on theof target.the Enterobacteriaceae Moreover, some Gram-negativefamily, and Grambacteria,-positive especially bacteria, members e.g., Staphylococcus of the Enterobacteriaceae aureus, can alsofamily, produce and an Gram-positive array of extended bacteria, spectrum e.g., βStaphylococcus-lactamases (ESBLs), aureus, canenzymes also produce that hydroly an arrayze many of extended different spectrum β-lactamsβ-lactamases and can cause (ESBLs), resistance enzymes to oxyithatmino hydrolyze-cephalosporins many di fferent(cefotaxime,β-lactams ceftazidime, and can cause ceftriaxone, resistance cefuroxime, to oxyimino-cephalosporins cefepime) and monobactams(cefotaxime, ceftazidime,(aztreonam), ceftriaxone,but not to cefuroxime, cephamycins cefepime) (cefoxitin, and cefotetan) monobactams or carbapenems (aztreonam), (imipenem,but not to cephamycins meropenem, (cefoxitin,ertapenem, cefotetan) doripenem) or carbapenems [8–10]. ESBLs (imipenem, are inhibited meropenem, by ESBL ertapenem,inhibitors, suchdoripenem) as clavulanate, [8–10]. ESBLssulbactam are inhibitedand tazobactam by ESBL (older inhibitors, β-lactamase such as clavulanate,inhibitors) and sulbactam avibactam, and relebactamtazobactam and (older vaborbactamβ-lactamase (latest inhibitors) Food andand avibactam, Drug Administration relebactam and(FDA) vaborbactam-approved (latestinhibitors), Food whichand Drug are therefore Administration frequently (FDA)-approved included with inhibitors), β-lactam whichantibiotics aretherefore in the formulation frequently of included therapeutic with drugsβ-lactam [11]. antibiotics in the formulation of therapeutic drugs [11]. FigureFigure 1. 1. StructureStructure of of ββ--lactamlactam antibiotics, antibiotics, adapted adapted from from [12]. [12]. β AsAs β--lactamaseslactamases shareshare some some sequence sequence homology homology with with PBPs, PBPs, it is consideredit is considered that they that have they evolved have β evolvedfrom them from [10 them,13]. [1-lactamase0,13]. β-lactamase encoding encoding genes (bla genes) can ( bebla) located can be in located chromosomes in chromosomes or plasmids. or β plasmids.The first plasmid-mediated The first plasmid-mediated-lactamase β (TEM-1)-lactamase in Gram-negatives(TEM-1) in Gram was-negatives described was in 1965,described from anin 1965,isolate from from an a patientisolate from named a Temonierapatient named in Greece, Temoniera therefore in Greece, named therefore TEM [14]. named Since then, TEM hundreds [14]. Since of β then,different hundreds-lactamases of different have beenβ-lactamases discovered, have and been the
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