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Selection and dissemination of antimicrobial resistance in Agri-food production

Selection and dissemination of antimicrobial resistance in Agri-food production Public unrest about the use of antimicrobial agents in farming practice is the leading cause of increasing and the emergences of Multi-drug Resistant Bacteria that have placed pressure on the agri-food industry to act. The usage of antimicrobials in food and agriculture have direct or indirect effects on the development of Antimicrobial resistance (AMR) by bacteria associated with animals and plants which may enter the food chain through consumption of meat, fish, vegetables or some other food sources. In addition to antimicrobials, recent reports have shown that AMR is associated with tolerance to heavy metals existing naturally or used in agri-food production. Besides, biocides including disinfectants, antiseptics and preservatives which are widely used in farms and slaughter houses may also contribute in the development of AMR. Though the direct transmission of AMR from food-animals and related environment to human is still vague and debatable, the risk should not be neglected. Therefore, combined global efforts are necessary for the proper use of antimicrobials, heavy metals and biocides in agri-food production to control the development of AMR. These collective measures will preserve the effectiveness of existing antimicrobials for future generations. Keywords: Antimicrobial resistance, Co-selection, Heavy metal, Biocide, Dissemination, Antimicrobial resistance gene Introduction used in animal husbandry [2]. It was estimated, that glo- Antimicrobials, including antibiotics and related semi bally each kilogram of meat harvested from cattle, chick- synthetic or synthetic drugs exhibit high antimicrobial ens and pigs would lead to the consumption of 45 mg, potency and selective toxicity to allow their use as anti- 148 mg, and 172 mg of antimicrobials respectively, which infective agents [1]. Over the years, antimicrobials have is expected to increase by 67% from 2010 to 2030 [3]. also been used in animal husbandry and aquaculture for Anti-microbial resistance is a recognized public health growth promotion, feed efficiency improvement, prophy- concern since its emergence limits the therapeutic op- laxis as well as in the treatment of infectious diseases. tions available to both clinicians and veterinarians. The From the animal welfare perspective, the use of antimi- first economic report on the impact of AMR proposed crobials improves the general health of farm animals and that if nothing was done, AMR-related deaths would in- the hygiene of farming environments [1]. The agricul- crease from 700,000 to 10 million annually by 2050. It tural food industry benefits from the use of antimicro- would cost trillions of USD in healthcare industry [4]. bials for food-animal production and crop protection. In The improper use of antimicrobials for purposes other United States, nearly 80% of antibiotics produced are than treatment of infections has resulted in the selection for AMR in food production environments. Bacteria de- velop de novo resistance due to exposure to sub- * Correspondence: chengguyue@mail.hzau.edu.cn inhibitory levels of antibiotics in their surroundings or Guyue Cheng and Jianan Ning contributed equally to this work. MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and directly acquire resistance mechanisms from other bac- Poultry Products, Huazhong Agricultural University, Wuhan 430070, China teria via, Horizontal Gene Transfer (HGT) [5]. Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 2 of 13 Although widespread AMR has been mostly attributed [29]. The gut microbiome of a pre-Columbian Andean to the selective pressure generated by overuse and mis- mummy (dating of 980–1170 AD) was recently found to use of antimicrobials, concerns have been raised based harbor β-lactam, Fosfomycin, Chloramphenicol, Amino- on recent growing evidences regarding co-selection for glycoside, Macrolide, Sulfa, Quinolones, Tetracycline, AMR among bacteria exposed to non-antibiotic com- and Vancomycin resistance genes [30]. In a screen of pounds used in agri-food industry, such as biocides used sample of the culture-able microbiome of Lechuguilla as disinfectants, antiseptics and preservatives, heavy Cave isolated for over 4 million years, the surface mi- metals existing in nature and used in agricultural pro- crobes were highly resistant to antimicrobials and some duction [6]. The use of antimicrobials, heavy metals and strains were resistant to 14 different commercially avail- biocides in food and agriculture has direct as well as in- able antimicrobials including daptomycin and macrolide direct effects on the development of AMR in bacteria [31]. The results of these studies gave direct experimen- which can enter the food chain. Increasing unrest among tal evidence that AMR is ancient, and provided a public about antimicrobials usage in farming practices glimpse into the evolutionary history of a natural envir- and the emergence of Multi-drug Resistant Bacteria has onmental phenomenon. placed pressure on the agricultural food industry to act. A major area under scrutiny is the livestock food chain, Selection of AMR in mutant selection window and sub- from farms through slaughter houses and processing inhibitory concentrations plants food to packaging and retail facilities [7]. This re- The concentration of an antimicrobial, either in the Mu- view will summarize the major factors in the selection tant Selection Window (MSW) or below the minimum in- and dissemination of food borne AMR along the food hibitory concentration (MIC) of a wild-type population chain. (also called sub-inhibitory concentration or sub-MIC con- centration) is important for the selection of AMR [32]. Selection of AMR by using antimicrobials MSW is a concentration range between the lowest con- Mechanisms of AMR and pre-existence of antimicrobial centration that exerts selective pressure, often approxi- resistance genes (ARGs) mated by the minimal concentration that inhibits colony Antimicrobial resistance includes two levels of resist- formation by 99% (MIC99) and the MIC of the least drug- ance, the cellular level resistance and blocking of anti- resistant mutant subpopulation, a value called the mutant microbial target and reduce entry of antimicrobials into prevention concentration (MPC) [33]. Drug-resistant mu- or active efflux of antimicrobials out of the bacterial cell tant subpopulations present prior to the initiation of anti- [2]. Reduced susceptibility of an organism to an anti- microbial treatment are enriched and amplified when microbial may be innate (due to features of the mi- antimicrobial concentrations fall within the MSW. crobe’s cell envelope, energy metabolism or the presence Antimicrobials at sub-inhibitory concentrations (concen- of an alternative metabolic pathway). It is also acquired trations below MIC) are found in many natural environ- via single or multi-step mutation that affects the target ments like soil and water. Sub inhibitory concentrations are site and the effective concentration of the antimicrobial also generated as a result of antimicrobial therapy in within the cell, or by the acquisition of genetic element humans and livestock (suboptimal dosing therapy, poor encoding a feature such as an inactivating enzyme or an pharmacokinetics, usage of low-quality drugs, and a poor alternative to the target molecule i.e. HGT of resistance patient compliance) as well as administered as a feed addi- determinants. Table 1 show the representative mobile tives to promote growth of animals [5]. In sub-MIC concen- ARGs which are transferable between different bacterial trations, the susceptible strains continue growing at a strains and species. The community level resistance (bio- reduced growth rate, and the lowest antimicrobial concen- films and persisters) is also an issue causing antimicro- tration needed to choose for the resistant mutant over the bial therapy difficulties [26]. wild type is called The Minimal Selective Concentration Antimicrobial resistance however, did not originate as (MSC), from which to MIC the selection for the resistant a product of agricultural antimicrobial use. Antibiotic re- mutantsoccurs[34]. Beside the pre-existed resistant mu- sistance is an ancient bacterial trait, existing in soil bac- tants, de novo bacterial resistance may be promoted through teria (the soil resistome) and carried on plasmids such as sub-therapeutic antimicrobial concentrations by inducing serine β-lactamases, millions of years before the dawn of non-specific mutagenesis resulting from stimulating the pro- agriculture [27]. Recent work has uncovered resistance duction of Reactive Oxygen Species [35]. in ancient permafrost, isolated caves, and in human specimens preserved for hundreds of years [28]. It had Selection of ARGs in food production system been shown that gene-encoding resistance to β-lactam, Antimicrobial feeding in food animals has been as a se- Tetracycline, and Glycopeptide antibiotics was present lective force in the evolution of their intestinal bacteria, in metagenome samples of 30,000-year-old permafrost particularly by increasing the prevalence and diversity of Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 3 of 13 Table 1 Mobile antimicrobial resistance genes Antibiotic Class Mechanisms of Gene Gene Species Reference resistance location β-lactams Drug degradation: Class A: Plasmid Multiples species of Enterobacteriaceae, [8–10] β-lactamases Serine Penicillinases: TEM, Acinetobacter and Pseudomonas SHV, CTX-M; Carbapenemases: KPC, IMI-2, GES Class B (Metallo-β-Lactamases): Stenotrophomonas maltophilia and NDM-1, IMP, VIM, NDM-9 Enterobacteriaceae (NDM-1), Klebsiella variicola (NDM-9) Class C (Cephalosporinases): Enterobacteriaceae and Pseudomonas AmpC Class D (oxacillinases): Acinetobacter, Enterobacteriaceae, OXA-23, OXA-48, OXA-181, Aeromonas, Citrobacter freundii OXA-143, OXA-372 Class A: GES-1,VEB-1 Integron K. pneumonia, P. aeruginosa and A. baumannii Class B: NDM-1, IMP, VIM, Stenotrophomonas maltophilia, Enterobacteriaceae and A. baumannii (NDM-1) Aminoglycosides Drug modification Nucleotidyltransferases: Plasmid Staphylococcus epidermidis, S. [11, 12] ANT(6)-Ia, ANT(9)-Ib, Transposon aureus, E. faecium, Streptococcus ANT(4′)-Ia C, ANT(4′)-IIa Plasmid, suis, P. aeruginosa, A. baumannii, ANT(6)-Ib, ANT(4′)-IIb, transposon, P. aeruginosa, Vibrio cholera, ANT(9)-Ia, ANT(2″)-Ia, integrin Salmonella spp. S. enterica, E. coli, ANT(3″)-Ia Integron Aeromonas media, Pasteurella aadA31 multocida, Yersinia enterocolitica, C. glutamicum, B. subtilis Pasteurella multocida and Histophilus somni Phosphotransferases: Plasmid E. coli, S. enterica, P. aeruginosa, K. APH(4)-Ia, APH(6)-Id, Transposon pneumoniae, Salmonella spp., APH(3′)-Ib, −IIIa C, −Via, Plasmid, Pseudomonas spp., V. cholerae, −VIb, −VIIa, APH(2″)-Ia, −IIIa C transposon Edwardsiella tarda, Pasteurella APH(6)-Ic, multocida, Aeromonas bestiarum, APH(3′)-Ia, −IIa C A. baumannii, S.marcescens, APH(3′)-Ic, APH(2″)-Ie, Corynebacteriumspp., Photobacterium APH(3″)-Ib spp., Citrobacter spp. S. aureus, Enterococcus spp. E. casseliflavus Acetyltransferases: Integron P. aeruginosa, P. fluorescens, S. AAC(3)-Ia C, −Ib, −Ic, −Id, Plasmid enterica, E. coli, E. cloacae, Salmonella −Ie, −Ib, AAC(6′)-Ib” Plasmid, typhimurium, Proteus mirabilis, E. AAC(3)-IIa, −IIb, −IIc, −IVa, VIa transposon, faecalis, E. faecium, Streptomyces AAC(6′)-Ia, −Ib C, −Ib’, −Ie, −If, integron albulus, C. freundii, A. baumannii, −Ih, −Ip, −Iq, −Im, −Il, −Isa, S. marcescens, Actinobacillus −Iad, −Iae, −Iaf, −Iai, −Ib, − 31, pleuropneumoniae, S. typhimurium, − 32, − 33, −I30, −IIa, −IIb, Citrobacter freundii −IIc, −Ib-cr, −Ie-APH(2″)-Ia, − 30/AAC(6′)-Ib’, ANT (3″)-Ii-AAC(6′)-IId Target modification: armA, rmtB, rmtC, rmtH Plasmid K. pneumonia, E. coli, S. enterica, [13] 16S rRNA P. stuartii, methyltransferase E. aerogenes, armA, rmtA, rmtB, rmtC, npmA, Transposon/ C. freundii, P. aerugonosa, rmtD, rmtE, rmtD2 integron S. marcescens, P. mirabilis, E. coli, Quinolones Drug modification Acetyltransferase: aac(6′)-Ib-cr Plasmid Multiple species of Enterobacteriaceae [14] Target protection qnrA, qnrB, qnrS, qnrC, qnrD, Plasmid Multiple species of Enterobacteriaceae, qnrVC also Acinetobacter, Aeromonas, Pseudomonas, and Vibrio spp. Efflux pumps oqxAB, qepA Plasmid Multiples species of Enterobacteriaceae Macrolides Efflux pumps mefB Plasmid E. coli [15, 16] Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 4 of 13 Table 1 Mobile antimicrobial resistance genes (Continued) Antibiotic Class Mechanisms of Gene Gene Species Reference resistance location mefC marine bacteria including Vibrio and Photobacterium mefI Transposon S. pneumoniae mefA, mefE Integron Streptococcus, Staphylococci /transposon msr(A) Plasmid Staphylococci Drug modification Phosphotransferase: Plasmid S. aureus, E. coli, Serratia marscescens, mphC, mphA, mphE K. pneumonia, A. baumannii, E. coli, Citrobacter freundii Esterase: ereA, ereB Plasmid E. coli Target modification: erm Plasmid/ Multiple species 23S rRNA methylase transposon/ integron Ribosomal protection: msr(A) Plasmid staphylococci, enterococci, streptococci ABC-F proteins Tetracyclines Drug modification tetX, Bacteroides, Aeromonas, Pseudomonas, [17] tet34 Serratia, Vibrio tet37 Ribosomal protection tetM, tetS, tetT, tetB(P), tetQ, Transposon Acinetobacter, Afipia, Enterobacter, tetW, tet32, tet36, otrA Erysipelothrix, Escherichia, Klebsiella, Lactobacillus, Lactococcus, Microbacterium, tetO, poxtA Plasmid/ Mitsuokella, Mycobacterium, Neisseria, transponson Prevotella, Porphyromonas, Ralstonia, Photobacterium, Pseudomonas, Selenomonas, Streptomyces, Vibrio, Megasphaera, Neisseria, Lactococcus, Lactobacillus, Veillonella, Actinomyces, Arcanobacterium, Bacillus, Butyrivibrio, Clostridium, Megasphaera, Roseburia, Staphylococcus, Bacteroides Efflux pump tetA, tetB tetC, tetD, tetE, tetG Plasmid/ Acinetobacter, Haemophilus, Veillonella, tetH, tetJ, tetK, tetL tetA(P), tetV Transposon Acinetobacter, Brevundimonsa, Neisseria, tetY, tetZ, tet30, tet31, tet33, Photobacterium, Pseudomonas, Aeromonas, tet35, tet38, tet39 Chlamydia, Alteromonas, Escherichia tcr3 Providencia, Actinobacillus, Moraxella, otrB, otrC Pasteurella, Lactobacillus, Norcardia, Streptomyces, Morganella, Norcardia, Salmonella, Veillonella, Corynebacterium, Stenotrophomonas, Vibrio, Staphylococcu Unknown tetU Staphylococci Lincosamides Drug modification: lnuA Plasmid Staphylococci [18–20] nucleotidyltransferases lnuB Plasmid/ Staphylococci, streptococci, Erysipelothrix lnuC integron rhusiopathiae lnuE Transposon S. agalactiae, Haemophilus parasuis lnuF, linG Transposon Streptococcus suis, S. aureus linA E. coli, Salmonella enterica N2 lnuG Bacteroides Enterococcus faecalis Target modification: cfr Plasmid Staphylococci, Bacillus spp., Enterococcus spp., 23S rRNA methylase Macrococcus caseolyticus, Jeotgalicoccus pinnipedialis, E. coli erm Plasmid/ Multiple species transposon/ integron Ribosomal protection: vga Plasmid/ Staphylococci, enterococci, streptococci ABC-F proteins lsa transposon Efflux pump lsa(B) Plasmid Staphylococci lsa(E) Integron Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 5 of 13 Table 1 Mobile antimicrobial resistance genes (Continued) Antibiotic Class Mechanisms of Gene Gene Species Reference resistance location vga(A), vga(E) Transposon/ Staphylococci, streptococci, plasmid enterococci vga(C) Plasmid sal(A) Integron Staphylococci Phenicols Drug modification: catA Plasmid/ Multiple species of Gram-positive Acetyltransferase catB transposon and Gram-negative bacteria Integron/ Multiple species of Gram-negative transposon bacteria Target modification: cfr Plasmid Staphylococci, Bacillus spp., [21] 23S rRNA methylase Enterococcus spp., Macrococcus caseolyticus, Jeotgalicoccus pinnipedialis, E. coli Efflux pump optrA Plasmid Enterococci [19, 22] cmr, cmx Plasmid/ Corynebacterium spp., transposon Rhodococcus spp. floR Plasmid/ E. coli, K. pneumoniae, integron Pasteurella multocida, Pasteurella trehalosi, A. pleuropneumoniae, Stenothrophomonas maltophilia, P. multocida fexA Transposon Staphylococci fexB Plasmid Enterococci oqxAB Plasmid Multiple species of Enterobacteriaceae Streptogramin Drug modification Streptogramin A Plasmid Staphylococci [19] acetyltransferase: Enterococci vat(A), vat(B), vat(C) vat(D), vat(E), vat(H) Streptogramin B lactone Plasmid Staphylococci hydrolase: vgb(A), vgb(B) Target modification: streptogramin A: cfr Plasmid Staphylococci, Bacillus spp., 23S rRNA methylase Enterococcus spp., Macrococcus caseolyticus, Jeotgalicoccus pinnipedialis, E. coli streptogramin B: erm Plasmid/ Multiple species transposon/ intergron Ribosomal protection: streptogramin B: msr(A) Plasmid Staphylococci, enterococci, ABC-F proteins streptococci Efflux pump streptogramin A: Plasmid/ Staphylococci, enterococci, vga, lsa(A), sal(A) transposon/ streptococci intergron streptogramin B: Plasmid/ msr(A), msr(C) integron Polymyxin LPS modification Phosphoethanolamine Plasmid E. coli, K. pneumonia, Salmonella, [23, 24] transferase: mcr-1, −2, −3, −4, Shigella sonnei, Enterobacter, −5, −6, −7, and − 8 Cronobacter sakazakii, Kluyvera ascorbata Vancomycin Target modification vanA–G Plasmid/ Staphylococci, enterococci, [25] transposon/ streptococci, Oerskovia turbata, integron Arcanobacterium haemolyticum ARGs [27]. However, the association between antimicro- Danish pig farms demonstrated that the effect of anti- bial use and selection of resistance determinants is not microbial exposure on the levels of seven ARGs (ermB, as direct as often presumed. A recent study done in ermF, sulI, sulII, tetM, tetO, and tetW) was complex and Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 6 of 13 unique for each individual gene. Several antimicrobial Multidrug-resistant CTX-M-(15, 9, 2) and KPC-2- classes had both negative and positive correlations with producing Enterobacter hormaechei and E. asburiae are the ARGs, indicating that antimicrobial exposure is not found to possess a set of acquired Silver (Ag) resistance the only important determinant of the ARG levels [36]. genes [50]. Other heavy metals including Nickel (Ni), Cad- In American swine production system, Ceftiofur is often mium (Cd), and Chromium (Cr) are also reported to co- administered to piglets at birth with males receiving a select certain AMR [42, 51–53]. A recent study showed that second dose at castration, and this operation may pro- genes potentially conferring metal-resistance, including vide the selection pressure required for the dissemin- arsA (Arsenic compounds), cadD (Cd), copB (Cu) and czrC ation of Carbapenemase-producing Enterobacteriaceae (Zn/Cd) were frequently present in livestock associated [37]. In Campylobacter jejuni isolates from beef cattle in MRSA [54]. A Chinese study even found only a weak posi- confined feeding operations in Southern Alberta Canada, tive correlation between ARGs and their corresponding an- selection for resistance to fluoroquinolones was subtype timicrobials, while significant positive correlations were dependent, whereas selection for resistance to tetracy- found between some ARGs (sulA and sulIII)and typical cline’s was not [38]. It was shown that the development heavy metals such as Hg, Cu, and Zn [49]. of ciprofloxacin resistance was quite different among dif- The molecular mechanisms for the ability of bacteria ferent serovar strains, due to the different mutation fre- to develop heavy metal resistance are similar to those quency and ciprofloxacin accumulation level [39]. for AMR since heavy metals have known antimicrobial effects [55]. Co-selection is achieved in two ways: (1) Co-selection of AMR by using non-antimicrobial Co-resistance, whereby selection for one gene fosters compounds the maintenance of another resistance gene and (2) Widespread AMR is mostly attributed to the selective Cross-resistance, whereby one resistance gene can offer pressure by overuse and misuse of antimicrobials. How- protection from multiple toxic chemicals [56]. Co- ever, concerns have been raised based on growing evi- resistance/Co-transfer for a heavy metal and an anti- dences regarding co-selection of AMR among bacteria microbial is often caused by the co-resident metal and exposed to biocides which are used as disinfectants, anti- antimicrobial- resistance genes, which can be physically septics, preservatives and various cationic heavy metals localized to plasmids or chromosomes that also contain included in animal diets as nutritional supplements, oneormoreARGs[57, 58]. For example, MRSA from growth promoters and therapeutic agents for livestock livestock have been described harboring plasmids carry- [6]. These metals can also be spread on pastures to sup- ing resistance genes for Cu and Cd (copA, cadDX and port crop growth and protection. mco) and for multiple antimicrobials including Macro- lides, Lincosamides, Streptogramin B, Tetracyclines, Co-selection of AMR by heavy metals Aminoglycosides and Trimethoprim (erm(T), tet(L), Heavy metals occur everywhere in the environment, and aadD and dfrK)[59]. The link between Zn usage in ani- on occasion at high concentrations in certain settings mal feeds and the occurrence of MRSA is explained by when they are used in agriculture production for various the physical presence of the Zn resistance gene, czrC, purposes. Heavy metals can continue to exist in the en- on the methicillin resistance-encoding SCCmec element vironment and remain stable for prolonged periods. [60, 61]. Another example of co-resistance involved a While most veterinary antimicrobial compounds can be number of resistance genes such as aadA2 (streptomy- R R metabolized and cleared from the food-producing ani- cin ), qacED1 (spectinomycin )and sul1 (sulfonami- mals within weeks or months. The bioavailability of de ) located to Tn5045 where chromate resistance commonly feed-used minerals (mostly inorganic) is usu- genes chrBACF are found [62]. A Portuguese study ally quite low in animals, and the unabsorbed heavy found in monophasic S. Typhimurium variants of hu- metals are excreted as fecal material in higher concen- manand pigorigin thatARGs inthis multi-drug- trations than in feeds [40]. resistant Pathovar were co-located with sil operon The correlation between heavy metal tolerance and AMR which encoded an efflux for Cu and Ag on the chromo- had already been observed several decades ago. Copper some or a non-transferable plasmid [63]. A conjugation (Cu) has been reported to be related to resistance against assay demonstrated co-transfer of tcrB and erm(B) Ampicillin, Sulphanilamide [41], Erythromycin [42], Enro- genes between E. faecium and E. faecalis strains [64]. floxacin [43], Vancomycin [44], and Glycopeptide [45]. Genomic analysis of E. faecalis from Cu-supplemented Methicillin-resistant Staphylococcus aureus (MRSA) is often Danish pigs revealed the presence of chromosomal Cu- associated with Zinc (Zn) [45–48]and Cu [45]. There are insusceptibility genes, including the tcrYAZB operon positive correlations between Mercury(Hg)tolerantgene and Tetracycline (tetM) and Vancomycin (vanA)resist- merA and transposon Tn21 [42]. sulA and sulIII were ance genes were present in one of the “Cu-insuscep- strongly correlated with levels of Cu, Zn and Hg [49]. tible” isolates [65]. The genetic linkage of Cu, Zn and Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 7 of 13 ARGs in bacteria has been comprehensively summa- Co-selection of AMR by biocides rized in a recent review written by Keith Poole [57]. Biocides can be used as antiseptics on body surfaces, as Like antimicrobials, metals are stressors that activate a disinfectants on equipment and surfaces in many envi- variety of adaptive/protective responses in bacteria, and ronments including farms and hospitals, as decontami- this can make co-regulation of metal and antimicrobial nants on carcass surfaces following slaughter, and as resistance resulting in cross-resistance [66]. In Gram- preservatives in pharmaceuticals, cosmetics and food negative bacteria, The Membrane Stress Responsive [81]. A possible cross-resistance between biocides and Two Component System CpxRA which is linked to re- antimicrobials is still controversial. Some studies have sistance against variety of cell envelope-targeting drugs reported that there is no cross-resistance between bio- [67] is also Cu-responsive and contributes to Cu toler- cides and antimicrobials. For example, no cross- ance [68]. In the presence of Zn, TCS CscRS in Pseudo- resistance between Chlorhexidine and five antimicrobials monas aeruginosa influences the transcription of czcCBA was found in 130 Salmonella spp. from two Turkey operon encoding an RND-type efflux pump which con- farms [82]. Among 101 genetically distinct isolates of fers resistance to Zn, Cd and cobalt (Co), meanwhile the Burkholderia cepacia, no correlation was found between CscRS system also reduces the expression of porin OprD the susceptibility to Chlorhexidine and 10 different anti- through which imipenem enters the bacteria [69]. In Lis- microbials [83]. On Enterococcus faecium, low doses of teria monocytogenes, a Multidrug efflux pump MdrL Peracetic Acid, usually used as disinfectant in wastewater confers resistance against a range of antimicrobials, and treatments, promoted a bacterial adaptation but without the same transport system also works for heavy metals affecting the abundance of the AGRs [84]. such as Zn, Co and Cr [70]. Similarly, the Envelope On the other hand, several surveys have been per- Stress Response Sigma Factor RpoE activated by Poly- formed on the co-selection of AMR by biocides in bac- myxin B and linked to Polymyxin B resistance in a num- terial isolates from food-animals and aquacultures. It has ber of Gram-negative bacteria [71] is also activated by been indicated that the overall exposure to Chlorhexi- Zn in E. coli and contributes to Zn and Cu tolerance dine Digluconate increases the risk for resistance to a [72]. Cu has also been shown to increase expression of variety of antimicrobials [85]. When 310 Gram-positive the Oxidative Stress-responsive Regulatory Gene soxS isolates from milking cow teats were subjected to Iodine that is linked to expression of the AcrAB efflux pump or Chlorhexidine antisepsis, a significant association and multidrug resistance in E. coli [73]. among Streptococci between reduced susceptibility to Biofilms, in which bacteria are embedded in extra cellular Chlorhexidine and to Ampicillin, Tetracycline and three polymeric substances, are more resistant to heavy metals Aminoglycoside antibiotics [86]. In 87 isolates from sea- than their planktonic counterparts [74]. In turn, the biofilm foods, moderate positive correlations were detected for matrix may drive the frequency of mutation in the bacterial the biocides Cetrimide, Hexadecylpyridinium chloride genomes, which is favorable for co-selection for AMR [75]. and Triclosan with the antibiotic Cefotaxime, and also Many reports have described in several Gram-negative bac- for Triclosan with Chloramphenicol and Trimethoprim/ teria that Cu induces a Viable but Nonculturable (VNC) Solfamethoxazole and with the phenolic compound Thy- state, which is a stress-induced antimicrobial-resistant dor- mol [87]. It was reported in E. coli O157 and various mant state [76]. A Zn-linked VNC state has also been seen Salmonella serovars reductions in susceptibility to a in Xylella Fastidiosa, and it appears to hasten the onset of panel of antimicrobials following stepwise training of the VNC state in this organism [77]. Moreover, the exposure Triclosan, Chlorhexidine and Benzalkonium chloride of E. coli to Cu has been shown to increase the recovery of [88]. Exposure of veterinary field E. coli isolates to three small colony variants, and the slow-growing variants are typ- quaternary ammonium compounds yielded elevations of ically antimicrobial-resistant for a variety of bacteria [78]. MIC that were above the clinical breakpoints for Pheni- Heavy metals can also facilitate the HGT. A recent study col, Tetracycline, Fluoroquinolone, β-lactams and Tri- suggested that sub-inhibitory concentrations of heavy metals methoprim [89]. Salmonella Enteritidis surviving a short accelerate the horizontal transfer of plasmid-mediated ARGs exposure to in-use concentrations of Chlorine exhibited in water environment by promoting conjugative transfer of up to eight-fold increases in MIC values for Tetracyc- genes between E. coli strains [79]. Another study showed line, Nalidixic Acid and Chloramphenicol [90], similar to that via Cu shock at 10 and 100 mg/L loading on bacteria those observed with stepwise training procedures. from a drinking water bio-filter, bacterial resistance to Ri- There are more surveys and investigations that have fampin, Erythromycin, Kanamycin, and a few others was sig- involved hospitals or other healthcare environments nificantly increased. Furthermore, the relative abundance of about the co-selection of AMR by biocides [6]. When most ARGs, particularly the mobile genetic elements (MGE) the aerobic microbial communities were exposed to Ben- intI and transposons, were markedly enriched by at least zalkonium Chloride, the community-wide MIC values one-fold [80]. for Benzalkonium Chloride, Ciprofloxacin, Tetracycline Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 8 of 13 and Penicillin G were all increased [91]. Recent data waste. Land application of animal manure is a common showed that exposure of vancomycin-resistant E. fae- agricultural practice potentially leading to dispersal and cium to Chlorhexidine for only 15 min up-regulates the propagation of ARGs in environmental settings. Many vanA-type Vancomycin resistance gene (vanHAX) and studies have proved that MGEs and ARGs are closely as- genes associated with reduced Daptomycin susceptibility sociated in their persistence in the composts under anti- (liaXYZ)[92]. microbial selection [107]. Different manure sources may It has been demonstrated a role of efflux for the co- influence the fate of resistome in agro-ecosystems as selection of AMR in some biocide training studies [93], shown recently in a study demonstrating that application and reduced susceptibility to biocides may follow from of swine and poultry manures might enrich more soil the development of AMR vice versa [94–96]. Under ARGs than cattle manure, and the relative abundance of Benzalkonium Chloride exposure, the expression of two ARGs had significantly positive correlations with inte- non-specific efflux pumps genes (lde and mdrL)in Lis- grase and transposase genes [108]. A study compared teria monocytogenes isolated from pork meat processing 864 metagenomes from humans, animals and external plants was evaluated [97]. The expression of lde was environments and found that water, sediments and soil dose-dependent in the case of the post cleaning and dis- generally carried low relative abundance and few var- infection procedure strain, while the expression of mdrL ieties of known ARGs, furthermore the wastewater/ was inhibited under low biocidal stress (10 ppm) and en- sludge was on par with the human gut, indicating that hanced in the presence of high stress (100 ppm). In a the environments with the largest relative abundance study of biofilm formation potential and efflux pump ac- and/or diversity of ARGs were those subjected to indus- tivity, E. coli isolates from dairy equipment that had re- trial antibiotic pollution [109]. duced susceptibility to Benzalkonium Chloride and In food animals, ARBs are usually developed in ani- Ciprofloxacin proved to have superior biofilm capacity, mals’ bodies (especially in the gastrointestinal tract) after in parallel with increased efflux activity [98]. Improved using antibiotics. Differently, AMR in fruits, vegetables biofilm capability plus efflux has also been seen in and other foods of plant origin is often due to the con- Triclosan-adapted E. coli [99]. Genetic co-occurrences tamination with ARBs and ARGs along the food chain, suggest that plasmids provide limited opportunities for from primary production to consumption [110]. Import- biocides and metals to promote horizontal transfer of ant sources of microbial contamination in the pre- AMR through co-selection, whereas quite large possibil- harvest environment include soil, organic fertilizers and ities exist for indirect selection via chromosomal bio- irrigation water. cide/metal resistance genes [100]. Transduction is a significant mechanism of horizontal There are a lot of theoretical and experimental evi- gene transfer in natural environments, which has trad- dences that certain biocides may co-select for AMR, itionally been underestimated as compared to transform- mainly by close link of biocide resistance determinants ation. A study found that soil phages were the most to AMR determinants. However, there is lack of empir- versatile in terms of ARG carriage, and the phages from ical data to indicate that the use of biocides drives this organized farms showed varied ARGs as compared to co-selection of AMR in the food chain [101, 102]. the unorganized sector [111]. Another study screened pig feces from three commercial farms for 32 clinically Transfer and dissemination of AMR in food chain relevant ARG types and found that bacteriophage DNA The environmental resistome comprises both the natural contained 35.5% of the target ARG types and sul1, bla- AMR pool and contaminant AMR pool resulting from and ermB were found in 100% of the phage DNA TEM human activities [103]. The transfer of ARG from nat- samples [112]. Using the ratio index of the abundance of ural reservoirs to other bacteria may be a rare and ran- ARGs in bacteriophages and bacteria as an estimator of dom event, contaminant ARBs and ARGs may be able to bacteriophage ability to transmit ARGs, it was found − 1 spread rapidly and widely ((e.g. New Delhi metallo-beta- that the ratio for qnrA was the greatest (about 10 ) and lactamase, blaNDM-1 [104]; extended-spectrum beta- differed from the most abundant bacteriophage ARG lactamase blaCTXM-15 [105]; MRSA [106]). ermB, and fexA not floR had the lowest ratio value − 6 (about 10 ). Transmission of AMR from food animals to the environments Microbiomes encounter low-doses or sub-therapeutic Transmission of AMR from the environments to humans levels of antimicrobial agents from all mechanistic clas- The antimicrobial resistome is harbored by; (i) ses in food animal production. This modern practice ex- Antimicrobial-resistant bacteria called carriers that can erts broad effects on the gut microbiome of food spread ARG in the environment, but cannot colonize or animals, which is subsequently transferred to animal infect the human or animal body. Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 9 of 13 (ii) Antimicrobial-resistant bacteria called vectors that For heavy metals, associations have been identified be- can colonize and sometimes invade the human or animal tween reduced Zn or Cu susceptibility and AMR among body [103]. Even though carriers are not able to colonize pig Salmonella isolates, which are foodborne pathogens and infect humans, their spread and proliferation in the [6]. Co-transmission of the Cu efflux-associated tcrB and environment would increase the abundance and diversity erythromycin resistance erm(B) genes has been proved of ARG in vectors. Hence, it may increase the risks of between a marine sediment-derived livestock species En- transmission of ARB to humans. It should be noted that terococcus hirae and E. faecalis in conjugation experi- most vectors are not pathogens, because even if vectors ments. The experiments highlighted the scope for AMR can colonize the human body, they may lack crucial selection by the marine environment through heavy virulence genes and therefore unable to cause disease in metals and its possible involvement in antibiotic- a healthy host [103]. resistant enterococcal infections [117]. Moreover, there In searching a literature on the evidence for human is reasonable evidence of a co-resistance phenomenon exposure to extended-spectrum β-lactamase (ESBL) pro- involving Cu, Macrolides and perhaps Vancomycin ducing Enterobacteriaceae, MRSA, and Vancomycin- among Enterococci of pigs, whereas the relevance of this resistant Enterococcus spp. in the environment, a review to disease-causing strains in humans remains undeter- paper published in 2015 found that ARBs were detected mined [6]. in the contamination sources (66/66) such as wastewater and manure, and no direct evidence was found for trans- Conclusions and perspectives mission to humans through the environment [113]. Al- The contribution of AMR originally selected for in the though several studies performed on molecular typing of agricultural sector to resistance in human pathogens is human and environmental isolates, only one obtained not known exactly, but is unlikely to be negligible. Since this level of evidence, but the direction of transmission dosing regimens are less controlled in agriculture than could not be determined (environment transmitting in human health care, veterinary and environmental mi- AMR bacteria to humans or vice versa) [114]. crobes are often exposed to sub-inhibitory concentration of antimicrobials, which is considered as a risk factor for de novo resistance, transfer of ARGs, and selection for Transmission of AMR from animals to humans through already existing resistance [118]. Based on the present food chain or close contacts knowledge, short treatments with the highest dose that Many pathogens of animals are zoonotic, and therefore does not cause unacceptable side-effects may be optimal any development of resistance in pathogens associated for achieving therapeutic goals while minimizing devel- with food animals may spread to humans through food opment of resistance. Novel approaches such as combin- chain. Human infections by antibiotic-resistant patho- ation or alternating therapy are promising, but need to gens such as Campylobacter spp., Salmonella spp., E. be explored further before they can be implemented in coli and S. aureus are increasing [2]. daily practice. The impact of animal reservoirs on human health re- Co-selection of genes that confer resistance to antimi- mains debatable and unclear; nonetheless, there are crobials, biocides, heavy metals and other chemical haz- some examples of direct links that have been identified. ards is a potentially ecologically and clinically important In ESBL/AmpC and Carbapenemase-producing Entero- phenomenon. Non-antibiotic compounds used in agri- bacteriaceae occurring in animals, ESBL/AmpC- or food production, such as antibacterial biocides and Carbapenemase-encoding genes are most often located heavy metals, may also contribute to the promotion of on MGEs favoring their dissemination [115]. In most Af- AMR through co-selection. This may occur when resist- rican surveys, among ESBLs, certain blaCTX-M-15-har- ance genes to both antimicrobials and metals/biocides bouring clones (ST131/B2 or ST405/D) are mainly are co-located together in the same cell (co-resistance), identified in humans. But these have also been reported or a single resistance mechanism (an efflux pump) con- in livestock species from Tanzania, Nigeria or Tunisia; fers resistance to both antimicrobials and biocides/ international trade of poultry meat seems to have con- metals (cross-resistance), leading to co-selection of bac- tributed to the spread of other ESBL variants, such as terial strains, or mobile genetic elements (MGEs) that CTX-M-14, and clones [116]. Even though exposure to they carry [119]. animals is regarded as a risk factor, evidence for a direct The agri-food industry is coming under pressure to re- transfer of ESBL/AmpC-producing bacteria from ani- duce its usage of antimicrobial compounds. A recent mals to humans through close contacts is limited. The study analyzing AMR and antibiotic consumption world- extent to which food contributes to potential transmis- wide versus many potential contributing factors found sion of ESBL/AmpC producers to humans is also not that antibiotic consumption was not significantly associ- well established. ated with antimicrobial resistance index. This suggest Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 10 of 13 that reduction of antibiotic consumption will not be suf- Received: 31 May 2019 Accepted: 9 October 2019 ficient to control AMR because the spread of resistant strains and resistance genes seems to be the dominant References contributing factor [120]. Moreover, even when no anti- 1. Hao H, Cheng G, Iqbal Z, Ai X, Hussain HI, Huang L, et al. Benefits and risks microbial compounds are used, certain heavy metals or of antimicrobial use in food-producing animals. 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Selection and dissemination of antimicrobial resistance in Agri-food production

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Biomedicine; Medical Microbiology; Drug Resistance; Infectious Diseases
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Abstract

Public unrest about the use of antimicrobial agents in farming practice is the leading cause of increasing and the emergences of Multi-drug Resistant Bacteria that have placed pressure on the agri-food industry to act. The usage of antimicrobials in food and agriculture have direct or indirect effects on the development of Antimicrobial resistance (AMR) by bacteria associated with animals and plants which may enter the food chain through consumption of meat, fish, vegetables or some other food sources. In addition to antimicrobials, recent reports have shown that AMR is associated with tolerance to heavy metals existing naturally or used in agri-food production. Besides, biocides including disinfectants, antiseptics and preservatives which are widely used in farms and slaughter houses may also contribute in the development of AMR. Though the direct transmission of AMR from food-animals and related environment to human is still vague and debatable, the risk should not be neglected. Therefore, combined global efforts are necessary for the proper use of antimicrobials, heavy metals and biocides in agri-food production to control the development of AMR. These collective measures will preserve the effectiveness of existing antimicrobials for future generations. Keywords: Antimicrobial resistance, Co-selection, Heavy metal, Biocide, Dissemination, Antimicrobial resistance gene Introduction used in animal husbandry [2]. It was estimated, that glo- Antimicrobials, including antibiotics and related semi bally each kilogram of meat harvested from cattle, chick- synthetic or synthetic drugs exhibit high antimicrobial ens and pigs would lead to the consumption of 45 mg, potency and selective toxicity to allow their use as anti- 148 mg, and 172 mg of antimicrobials respectively, which infective agents [1]. Over the years, antimicrobials have is expected to increase by 67% from 2010 to 2030 [3]. also been used in animal husbandry and aquaculture for Anti-microbial resistance is a recognized public health growth promotion, feed efficiency improvement, prophy- concern since its emergence limits the therapeutic op- laxis as well as in the treatment of infectious diseases. tions available to both clinicians and veterinarians. The From the animal welfare perspective, the use of antimi- first economic report on the impact of AMR proposed crobials improves the general health of farm animals and that if nothing was done, AMR-related deaths would in- the hygiene of farming environments [1]. The agricul- crease from 700,000 to 10 million annually by 2050. It tural food industry benefits from the use of antimicro- would cost trillions of USD in healthcare industry [4]. bials for food-animal production and crop protection. In The improper use of antimicrobials for purposes other United States, nearly 80% of antibiotics produced are than treatment of infections has resulted in the selection for AMR in food production environments. Bacteria de- velop de novo resistance due to exposure to sub- * Correspondence: chengguyue@mail.hzau.edu.cn inhibitory levels of antibiotics in their surroundings or Guyue Cheng and Jianan Ning contributed equally to this work. MOA Laboratory for Risk Assessment of Quality and Safety of Livestock and directly acquire resistance mechanisms from other bac- Poultry Products, Huazhong Agricultural University, Wuhan 430070, China teria via, Horizontal Gene Transfer (HGT) [5]. Full list of author information is available at the end of the article © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 2 of 13 Although widespread AMR has been mostly attributed [29]. The gut microbiome of a pre-Columbian Andean to the selective pressure generated by overuse and mis- mummy (dating of 980–1170 AD) was recently found to use of antimicrobials, concerns have been raised based harbor β-lactam, Fosfomycin, Chloramphenicol, Amino- on recent growing evidences regarding co-selection for glycoside, Macrolide, Sulfa, Quinolones, Tetracycline, AMR among bacteria exposed to non-antibiotic com- and Vancomycin resistance genes [30]. In a screen of pounds used in agri-food industry, such as biocides used sample of the culture-able microbiome of Lechuguilla as disinfectants, antiseptics and preservatives, heavy Cave isolated for over 4 million years, the surface mi- metals existing in nature and used in agricultural pro- crobes were highly resistant to antimicrobials and some duction [6]. The use of antimicrobials, heavy metals and strains were resistant to 14 different commercially avail- biocides in food and agriculture has direct as well as in- able antimicrobials including daptomycin and macrolide direct effects on the development of AMR in bacteria [31]. The results of these studies gave direct experimen- which can enter the food chain. Increasing unrest among tal evidence that AMR is ancient, and provided a public about antimicrobials usage in farming practices glimpse into the evolutionary history of a natural envir- and the emergence of Multi-drug Resistant Bacteria has onmental phenomenon. placed pressure on the agricultural food industry to act. A major area under scrutiny is the livestock food chain, Selection of AMR in mutant selection window and sub- from farms through slaughter houses and processing inhibitory concentrations plants food to packaging and retail facilities [7]. This re- The concentration of an antimicrobial, either in the Mu- view will summarize the major factors in the selection tant Selection Window (MSW) or below the minimum in- and dissemination of food borne AMR along the food hibitory concentration (MIC) of a wild-type population chain. (also called sub-inhibitory concentration or sub-MIC con- centration) is important for the selection of AMR [32]. Selection of AMR by using antimicrobials MSW is a concentration range between the lowest con- Mechanisms of AMR and pre-existence of antimicrobial centration that exerts selective pressure, often approxi- resistance genes (ARGs) mated by the minimal concentration that inhibits colony Antimicrobial resistance includes two levels of resist- formation by 99% (MIC99) and the MIC of the least drug- ance, the cellular level resistance and blocking of anti- resistant mutant subpopulation, a value called the mutant microbial target and reduce entry of antimicrobials into prevention concentration (MPC) [33]. Drug-resistant mu- or active efflux of antimicrobials out of the bacterial cell tant subpopulations present prior to the initiation of anti- [2]. Reduced susceptibility of an organism to an anti- microbial treatment are enriched and amplified when microbial may be innate (due to features of the mi- antimicrobial concentrations fall within the MSW. crobe’s cell envelope, energy metabolism or the presence Antimicrobials at sub-inhibitory concentrations (concen- of an alternative metabolic pathway). It is also acquired trations below MIC) are found in many natural environ- via single or multi-step mutation that affects the target ments like soil and water. Sub inhibitory concentrations are site and the effective concentration of the antimicrobial also generated as a result of antimicrobial therapy in within the cell, or by the acquisition of genetic element humans and livestock (suboptimal dosing therapy, poor encoding a feature such as an inactivating enzyme or an pharmacokinetics, usage of low-quality drugs, and a poor alternative to the target molecule i.e. HGT of resistance patient compliance) as well as administered as a feed addi- determinants. Table 1 show the representative mobile tives to promote growth of animals [5]. In sub-MIC concen- ARGs which are transferable between different bacterial trations, the susceptible strains continue growing at a strains and species. The community level resistance (bio- reduced growth rate, and the lowest antimicrobial concen- films and persisters) is also an issue causing antimicro- tration needed to choose for the resistant mutant over the bial therapy difficulties [26]. wild type is called The Minimal Selective Concentration Antimicrobial resistance however, did not originate as (MSC), from which to MIC the selection for the resistant a product of agricultural antimicrobial use. Antibiotic re- mutantsoccurs[34]. Beside the pre-existed resistant mu- sistance is an ancient bacterial trait, existing in soil bac- tants, de novo bacterial resistance may be promoted through teria (the soil resistome) and carried on plasmids such as sub-therapeutic antimicrobial concentrations by inducing serine β-lactamases, millions of years before the dawn of non-specific mutagenesis resulting from stimulating the pro- agriculture [27]. Recent work has uncovered resistance duction of Reactive Oxygen Species [35]. in ancient permafrost, isolated caves, and in human specimens preserved for hundreds of years [28]. It had Selection of ARGs in food production system been shown that gene-encoding resistance to β-lactam, Antimicrobial feeding in food animals has been as a se- Tetracycline, and Glycopeptide antibiotics was present lective force in the evolution of their intestinal bacteria, in metagenome samples of 30,000-year-old permafrost particularly by increasing the prevalence and diversity of Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 3 of 13 Table 1 Mobile antimicrobial resistance genes Antibiotic Class Mechanisms of Gene Gene Species Reference resistance location β-lactams Drug degradation: Class A: Plasmid Multiples species of Enterobacteriaceae, [8–10] β-lactamases Serine Penicillinases: TEM, Acinetobacter and Pseudomonas SHV, CTX-M; Carbapenemases: KPC, IMI-2, GES Class B (Metallo-β-Lactamases): Stenotrophomonas maltophilia and NDM-1, IMP, VIM, NDM-9 Enterobacteriaceae (NDM-1), Klebsiella variicola (NDM-9) Class C (Cephalosporinases): Enterobacteriaceae and Pseudomonas AmpC Class D (oxacillinases): Acinetobacter, Enterobacteriaceae, OXA-23, OXA-48, OXA-181, Aeromonas, Citrobacter freundii OXA-143, OXA-372 Class A: GES-1,VEB-1 Integron K. pneumonia, P. aeruginosa and A. baumannii Class B: NDM-1, IMP, VIM, Stenotrophomonas maltophilia, Enterobacteriaceae and A. baumannii (NDM-1) Aminoglycosides Drug modification Nucleotidyltransferases: Plasmid Staphylococcus epidermidis, S. [11, 12] ANT(6)-Ia, ANT(9)-Ib, Transposon aureus, E. faecium, Streptococcus ANT(4′)-Ia C, ANT(4′)-IIa Plasmid, suis, P. aeruginosa, A. baumannii, ANT(6)-Ib, ANT(4′)-IIb, transposon, P. aeruginosa, Vibrio cholera, ANT(9)-Ia, ANT(2″)-Ia, integrin Salmonella spp. S. enterica, E. coli, ANT(3″)-Ia Integron Aeromonas media, Pasteurella aadA31 multocida, Yersinia enterocolitica, C. glutamicum, B. subtilis Pasteurella multocida and Histophilus somni Phosphotransferases: Plasmid E. coli, S. enterica, P. aeruginosa, K. APH(4)-Ia, APH(6)-Id, Transposon pneumoniae, Salmonella spp., APH(3′)-Ib, −IIIa C, −Via, Plasmid, Pseudomonas spp., V. cholerae, −VIb, −VIIa, APH(2″)-Ia, −IIIa C transposon Edwardsiella tarda, Pasteurella APH(6)-Ic, multocida, Aeromonas bestiarum, APH(3′)-Ia, −IIa C A. baumannii, S.marcescens, APH(3′)-Ic, APH(2″)-Ie, Corynebacteriumspp., Photobacterium APH(3″)-Ib spp., Citrobacter spp. S. aureus, Enterococcus spp. E. casseliflavus Acetyltransferases: Integron P. aeruginosa, P. fluorescens, S. AAC(3)-Ia C, −Ib, −Ic, −Id, Plasmid enterica, E. coli, E. cloacae, Salmonella −Ie, −Ib, AAC(6′)-Ib” Plasmid, typhimurium, Proteus mirabilis, E. AAC(3)-IIa, −IIb, −IIc, −IVa, VIa transposon, faecalis, E. faecium, Streptomyces AAC(6′)-Ia, −Ib C, −Ib’, −Ie, −If, integron albulus, C. freundii, A. baumannii, −Ih, −Ip, −Iq, −Im, −Il, −Isa, S. marcescens, Actinobacillus −Iad, −Iae, −Iaf, −Iai, −Ib, − 31, pleuropneumoniae, S. typhimurium, − 32, − 33, −I30, −IIa, −IIb, Citrobacter freundii −IIc, −Ib-cr, −Ie-APH(2″)-Ia, − 30/AAC(6′)-Ib’, ANT (3″)-Ii-AAC(6′)-IId Target modification: armA, rmtB, rmtC, rmtH Plasmid K. pneumonia, E. coli, S. enterica, [13] 16S rRNA P. stuartii, methyltransferase E. aerogenes, armA, rmtA, rmtB, rmtC, npmA, Transposon/ C. freundii, P. aerugonosa, rmtD, rmtE, rmtD2 integron S. marcescens, P. mirabilis, E. coli, Quinolones Drug modification Acetyltransferase: aac(6′)-Ib-cr Plasmid Multiple species of Enterobacteriaceae [14] Target protection qnrA, qnrB, qnrS, qnrC, qnrD, Plasmid Multiple species of Enterobacteriaceae, qnrVC also Acinetobacter, Aeromonas, Pseudomonas, and Vibrio spp. Efflux pumps oqxAB, qepA Plasmid Multiples species of Enterobacteriaceae Macrolides Efflux pumps mefB Plasmid E. coli [15, 16] Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 4 of 13 Table 1 Mobile antimicrobial resistance genes (Continued) Antibiotic Class Mechanisms of Gene Gene Species Reference resistance location mefC marine bacteria including Vibrio and Photobacterium mefI Transposon S. pneumoniae mefA, mefE Integron Streptococcus, Staphylococci /transposon msr(A) Plasmid Staphylococci Drug modification Phosphotransferase: Plasmid S. aureus, E. coli, Serratia marscescens, mphC, mphA, mphE K. pneumonia, A. baumannii, E. coli, Citrobacter freundii Esterase: ereA, ereB Plasmid E. coli Target modification: erm Plasmid/ Multiple species 23S rRNA methylase transposon/ integron Ribosomal protection: msr(A) Plasmid staphylococci, enterococci, streptococci ABC-F proteins Tetracyclines Drug modification tetX, Bacteroides, Aeromonas, Pseudomonas, [17] tet34 Serratia, Vibrio tet37 Ribosomal protection tetM, tetS, tetT, tetB(P), tetQ, Transposon Acinetobacter, Afipia, Enterobacter, tetW, tet32, tet36, otrA Erysipelothrix, Escherichia, Klebsiella, Lactobacillus, Lactococcus, Microbacterium, tetO, poxtA Plasmid/ Mitsuokella, Mycobacterium, Neisseria, transponson Prevotella, Porphyromonas, Ralstonia, Photobacterium, Pseudomonas, Selenomonas, Streptomyces, Vibrio, Megasphaera, Neisseria, Lactococcus, Lactobacillus, Veillonella, Actinomyces, Arcanobacterium, Bacillus, Butyrivibrio, Clostridium, Megasphaera, Roseburia, Staphylococcus, Bacteroides Efflux pump tetA, tetB tetC, tetD, tetE, tetG Plasmid/ Acinetobacter, Haemophilus, Veillonella, tetH, tetJ, tetK, tetL tetA(P), tetV Transposon Acinetobacter, Brevundimonsa, Neisseria, tetY, tetZ, tet30, tet31, tet33, Photobacterium, Pseudomonas, Aeromonas, tet35, tet38, tet39 Chlamydia, Alteromonas, Escherichia tcr3 Providencia, Actinobacillus, Moraxella, otrB, otrC Pasteurella, Lactobacillus, Norcardia, Streptomyces, Morganella, Norcardia, Salmonella, Veillonella, Corynebacterium, Stenotrophomonas, Vibrio, Staphylococcu Unknown tetU Staphylococci Lincosamides Drug modification: lnuA Plasmid Staphylococci [18–20] nucleotidyltransferases lnuB Plasmid/ Staphylococci, streptococci, Erysipelothrix lnuC integron rhusiopathiae lnuE Transposon S. agalactiae, Haemophilus parasuis lnuF, linG Transposon Streptococcus suis, S. aureus linA E. coli, Salmonella enterica N2 lnuG Bacteroides Enterococcus faecalis Target modification: cfr Plasmid Staphylococci, Bacillus spp., Enterococcus spp., 23S rRNA methylase Macrococcus caseolyticus, Jeotgalicoccus pinnipedialis, E. coli erm Plasmid/ Multiple species transposon/ integron Ribosomal protection: vga Plasmid/ Staphylococci, enterococci, streptococci ABC-F proteins lsa transposon Efflux pump lsa(B) Plasmid Staphylococci lsa(E) Integron Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 5 of 13 Table 1 Mobile antimicrobial resistance genes (Continued) Antibiotic Class Mechanisms of Gene Gene Species Reference resistance location vga(A), vga(E) Transposon/ Staphylococci, streptococci, plasmid enterococci vga(C) Plasmid sal(A) Integron Staphylococci Phenicols Drug modification: catA Plasmid/ Multiple species of Gram-positive Acetyltransferase catB transposon and Gram-negative bacteria Integron/ Multiple species of Gram-negative transposon bacteria Target modification: cfr Plasmid Staphylococci, Bacillus spp., [21] 23S rRNA methylase Enterococcus spp., Macrococcus caseolyticus, Jeotgalicoccus pinnipedialis, E. coli Efflux pump optrA Plasmid Enterococci [19, 22] cmr, cmx Plasmid/ Corynebacterium spp., transposon Rhodococcus spp. floR Plasmid/ E. coli, K. pneumoniae, integron Pasteurella multocida, Pasteurella trehalosi, A. pleuropneumoniae, Stenothrophomonas maltophilia, P. multocida fexA Transposon Staphylococci fexB Plasmid Enterococci oqxAB Plasmid Multiple species of Enterobacteriaceae Streptogramin Drug modification Streptogramin A Plasmid Staphylococci [19] acetyltransferase: Enterococci vat(A), vat(B), vat(C) vat(D), vat(E), vat(H) Streptogramin B lactone Plasmid Staphylococci hydrolase: vgb(A), vgb(B) Target modification: streptogramin A: cfr Plasmid Staphylococci, Bacillus spp., 23S rRNA methylase Enterococcus spp., Macrococcus caseolyticus, Jeotgalicoccus pinnipedialis, E. coli streptogramin B: erm Plasmid/ Multiple species transposon/ intergron Ribosomal protection: streptogramin B: msr(A) Plasmid Staphylococci, enterococci, ABC-F proteins streptococci Efflux pump streptogramin A: Plasmid/ Staphylococci, enterococci, vga, lsa(A), sal(A) transposon/ streptococci intergron streptogramin B: Plasmid/ msr(A), msr(C) integron Polymyxin LPS modification Phosphoethanolamine Plasmid E. coli, K. pneumonia, Salmonella, [23, 24] transferase: mcr-1, −2, −3, −4, Shigella sonnei, Enterobacter, −5, −6, −7, and − 8 Cronobacter sakazakii, Kluyvera ascorbata Vancomycin Target modification vanA–G Plasmid/ Staphylococci, enterococci, [25] transposon/ streptococci, Oerskovia turbata, integron Arcanobacterium haemolyticum ARGs [27]. However, the association between antimicro- Danish pig farms demonstrated that the effect of anti- bial use and selection of resistance determinants is not microbial exposure on the levels of seven ARGs (ermB, as direct as often presumed. A recent study done in ermF, sulI, sulII, tetM, tetO, and tetW) was complex and Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 6 of 13 unique for each individual gene. Several antimicrobial Multidrug-resistant CTX-M-(15, 9, 2) and KPC-2- classes had both negative and positive correlations with producing Enterobacter hormaechei and E. asburiae are the ARGs, indicating that antimicrobial exposure is not found to possess a set of acquired Silver (Ag) resistance the only important determinant of the ARG levels [36]. genes [50]. Other heavy metals including Nickel (Ni), Cad- In American swine production system, Ceftiofur is often mium (Cd), and Chromium (Cr) are also reported to co- administered to piglets at birth with males receiving a select certain AMR [42, 51–53]. A recent study showed that second dose at castration, and this operation may pro- genes potentially conferring metal-resistance, including vide the selection pressure required for the dissemin- arsA (Arsenic compounds), cadD (Cd), copB (Cu) and czrC ation of Carbapenemase-producing Enterobacteriaceae (Zn/Cd) were frequently present in livestock associated [37]. In Campylobacter jejuni isolates from beef cattle in MRSA [54]. A Chinese study even found only a weak posi- confined feeding operations in Southern Alberta Canada, tive correlation between ARGs and their corresponding an- selection for resistance to fluoroquinolones was subtype timicrobials, while significant positive correlations were dependent, whereas selection for resistance to tetracy- found between some ARGs (sulA and sulIII)and typical cline’s was not [38]. It was shown that the development heavy metals such as Hg, Cu, and Zn [49]. of ciprofloxacin resistance was quite different among dif- The molecular mechanisms for the ability of bacteria ferent serovar strains, due to the different mutation fre- to develop heavy metal resistance are similar to those quency and ciprofloxacin accumulation level [39]. for AMR since heavy metals have known antimicrobial effects [55]. Co-selection is achieved in two ways: (1) Co-selection of AMR by using non-antimicrobial Co-resistance, whereby selection for one gene fosters compounds the maintenance of another resistance gene and (2) Widespread AMR is mostly attributed to the selective Cross-resistance, whereby one resistance gene can offer pressure by overuse and misuse of antimicrobials. How- protection from multiple toxic chemicals [56]. Co- ever, concerns have been raised based on growing evi- resistance/Co-transfer for a heavy metal and an anti- dences regarding co-selection of AMR among bacteria microbial is often caused by the co-resident metal and exposed to biocides which are used as disinfectants, anti- antimicrobial- resistance genes, which can be physically septics, preservatives and various cationic heavy metals localized to plasmids or chromosomes that also contain included in animal diets as nutritional supplements, oneormoreARGs[57, 58]. For example, MRSA from growth promoters and therapeutic agents for livestock livestock have been described harboring plasmids carry- [6]. These metals can also be spread on pastures to sup- ing resistance genes for Cu and Cd (copA, cadDX and port crop growth and protection. mco) and for multiple antimicrobials including Macro- lides, Lincosamides, Streptogramin B, Tetracyclines, Co-selection of AMR by heavy metals Aminoglycosides and Trimethoprim (erm(T), tet(L), Heavy metals occur everywhere in the environment, and aadD and dfrK)[59]. The link between Zn usage in ani- on occasion at high concentrations in certain settings mal feeds and the occurrence of MRSA is explained by when they are used in agriculture production for various the physical presence of the Zn resistance gene, czrC, purposes. Heavy metals can continue to exist in the en- on the methicillin resistance-encoding SCCmec element vironment and remain stable for prolonged periods. [60, 61]. Another example of co-resistance involved a While most veterinary antimicrobial compounds can be number of resistance genes such as aadA2 (streptomy- R R metabolized and cleared from the food-producing ani- cin ), qacED1 (spectinomycin )and sul1 (sulfonami- mals within weeks or months. The bioavailability of de ) located to Tn5045 where chromate resistance commonly feed-used minerals (mostly inorganic) is usu- genes chrBACF are found [62]. A Portuguese study ally quite low in animals, and the unabsorbed heavy found in monophasic S. Typhimurium variants of hu- metals are excreted as fecal material in higher concen- manand pigorigin thatARGs inthis multi-drug- trations than in feeds [40]. resistant Pathovar were co-located with sil operon The correlation between heavy metal tolerance and AMR which encoded an efflux for Cu and Ag on the chromo- had already been observed several decades ago. Copper some or a non-transferable plasmid [63]. A conjugation (Cu) has been reported to be related to resistance against assay demonstrated co-transfer of tcrB and erm(B) Ampicillin, Sulphanilamide [41], Erythromycin [42], Enro- genes between E. faecium and E. faecalis strains [64]. floxacin [43], Vancomycin [44], and Glycopeptide [45]. Genomic analysis of E. faecalis from Cu-supplemented Methicillin-resistant Staphylococcus aureus (MRSA) is often Danish pigs revealed the presence of chromosomal Cu- associated with Zinc (Zn) [45–48]and Cu [45]. There are insusceptibility genes, including the tcrYAZB operon positive correlations between Mercury(Hg)tolerantgene and Tetracycline (tetM) and Vancomycin (vanA)resist- merA and transposon Tn21 [42]. sulA and sulIII were ance genes were present in one of the “Cu-insuscep- strongly correlated with levels of Cu, Zn and Hg [49]. tible” isolates [65]. The genetic linkage of Cu, Zn and Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 7 of 13 ARGs in bacteria has been comprehensively summa- Co-selection of AMR by biocides rized in a recent review written by Keith Poole [57]. Biocides can be used as antiseptics on body surfaces, as Like antimicrobials, metals are stressors that activate a disinfectants on equipment and surfaces in many envi- variety of adaptive/protective responses in bacteria, and ronments including farms and hospitals, as decontami- this can make co-regulation of metal and antimicrobial nants on carcass surfaces following slaughter, and as resistance resulting in cross-resistance [66]. In Gram- preservatives in pharmaceuticals, cosmetics and food negative bacteria, The Membrane Stress Responsive [81]. A possible cross-resistance between biocides and Two Component System CpxRA which is linked to re- antimicrobials is still controversial. Some studies have sistance against variety of cell envelope-targeting drugs reported that there is no cross-resistance between bio- [67] is also Cu-responsive and contributes to Cu toler- cides and antimicrobials. For example, no cross- ance [68]. In the presence of Zn, TCS CscRS in Pseudo- resistance between Chlorhexidine and five antimicrobials monas aeruginosa influences the transcription of czcCBA was found in 130 Salmonella spp. from two Turkey operon encoding an RND-type efflux pump which con- farms [82]. Among 101 genetically distinct isolates of fers resistance to Zn, Cd and cobalt (Co), meanwhile the Burkholderia cepacia, no correlation was found between CscRS system also reduces the expression of porin OprD the susceptibility to Chlorhexidine and 10 different anti- through which imipenem enters the bacteria [69]. In Lis- microbials [83]. On Enterococcus faecium, low doses of teria monocytogenes, a Multidrug efflux pump MdrL Peracetic Acid, usually used as disinfectant in wastewater confers resistance against a range of antimicrobials, and treatments, promoted a bacterial adaptation but without the same transport system also works for heavy metals affecting the abundance of the AGRs [84]. such as Zn, Co and Cr [70]. Similarly, the Envelope On the other hand, several surveys have been per- Stress Response Sigma Factor RpoE activated by Poly- formed on the co-selection of AMR by biocides in bac- myxin B and linked to Polymyxin B resistance in a num- terial isolates from food-animals and aquacultures. It has ber of Gram-negative bacteria [71] is also activated by been indicated that the overall exposure to Chlorhexi- Zn in E. coli and contributes to Zn and Cu tolerance dine Digluconate increases the risk for resistance to a [72]. Cu has also been shown to increase expression of variety of antimicrobials [85]. When 310 Gram-positive the Oxidative Stress-responsive Regulatory Gene soxS isolates from milking cow teats were subjected to Iodine that is linked to expression of the AcrAB efflux pump or Chlorhexidine antisepsis, a significant association and multidrug resistance in E. coli [73]. among Streptococci between reduced susceptibility to Biofilms, in which bacteria are embedded in extra cellular Chlorhexidine and to Ampicillin, Tetracycline and three polymeric substances, are more resistant to heavy metals Aminoglycoside antibiotics [86]. In 87 isolates from sea- than their planktonic counterparts [74]. In turn, the biofilm foods, moderate positive correlations were detected for matrix may drive the frequency of mutation in the bacterial the biocides Cetrimide, Hexadecylpyridinium chloride genomes, which is favorable for co-selection for AMR [75]. and Triclosan with the antibiotic Cefotaxime, and also Many reports have described in several Gram-negative bac- for Triclosan with Chloramphenicol and Trimethoprim/ teria that Cu induces a Viable but Nonculturable (VNC) Solfamethoxazole and with the phenolic compound Thy- state, which is a stress-induced antimicrobial-resistant dor- mol [87]. It was reported in E. coli O157 and various mant state [76]. A Zn-linked VNC state has also been seen Salmonella serovars reductions in susceptibility to a in Xylella Fastidiosa, and it appears to hasten the onset of panel of antimicrobials following stepwise training of the VNC state in this organism [77]. Moreover, the exposure Triclosan, Chlorhexidine and Benzalkonium chloride of E. coli to Cu has been shown to increase the recovery of [88]. Exposure of veterinary field E. coli isolates to three small colony variants, and the slow-growing variants are typ- quaternary ammonium compounds yielded elevations of ically antimicrobial-resistant for a variety of bacteria [78]. MIC that were above the clinical breakpoints for Pheni- Heavy metals can also facilitate the HGT. A recent study col, Tetracycline, Fluoroquinolone, β-lactams and Tri- suggested that sub-inhibitory concentrations of heavy metals methoprim [89]. Salmonella Enteritidis surviving a short accelerate the horizontal transfer of plasmid-mediated ARGs exposure to in-use concentrations of Chlorine exhibited in water environment by promoting conjugative transfer of up to eight-fold increases in MIC values for Tetracyc- genes between E. coli strains [79]. Another study showed line, Nalidixic Acid and Chloramphenicol [90], similar to that via Cu shock at 10 and 100 mg/L loading on bacteria those observed with stepwise training procedures. from a drinking water bio-filter, bacterial resistance to Ri- There are more surveys and investigations that have fampin, Erythromycin, Kanamycin, and a few others was sig- involved hospitals or other healthcare environments nificantly increased. Furthermore, the relative abundance of about the co-selection of AMR by biocides [6]. When most ARGs, particularly the mobile genetic elements (MGE) the aerobic microbial communities were exposed to Ben- intI and transposons, were markedly enriched by at least zalkonium Chloride, the community-wide MIC values one-fold [80]. for Benzalkonium Chloride, Ciprofloxacin, Tetracycline Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 8 of 13 and Penicillin G were all increased [91]. Recent data waste. Land application of animal manure is a common showed that exposure of vancomycin-resistant E. fae- agricultural practice potentially leading to dispersal and cium to Chlorhexidine for only 15 min up-regulates the propagation of ARGs in environmental settings. Many vanA-type Vancomycin resistance gene (vanHAX) and studies have proved that MGEs and ARGs are closely as- genes associated with reduced Daptomycin susceptibility sociated in their persistence in the composts under anti- (liaXYZ)[92]. microbial selection [107]. Different manure sources may It has been demonstrated a role of efflux for the co- influence the fate of resistome in agro-ecosystems as selection of AMR in some biocide training studies [93], shown recently in a study demonstrating that application and reduced susceptibility to biocides may follow from of swine and poultry manures might enrich more soil the development of AMR vice versa [94–96]. Under ARGs than cattle manure, and the relative abundance of Benzalkonium Chloride exposure, the expression of two ARGs had significantly positive correlations with inte- non-specific efflux pumps genes (lde and mdrL)in Lis- grase and transposase genes [108]. A study compared teria monocytogenes isolated from pork meat processing 864 metagenomes from humans, animals and external plants was evaluated [97]. The expression of lde was environments and found that water, sediments and soil dose-dependent in the case of the post cleaning and dis- generally carried low relative abundance and few var- infection procedure strain, while the expression of mdrL ieties of known ARGs, furthermore the wastewater/ was inhibited under low biocidal stress (10 ppm) and en- sludge was on par with the human gut, indicating that hanced in the presence of high stress (100 ppm). In a the environments with the largest relative abundance study of biofilm formation potential and efflux pump ac- and/or diversity of ARGs were those subjected to indus- tivity, E. coli isolates from dairy equipment that had re- trial antibiotic pollution [109]. duced susceptibility to Benzalkonium Chloride and In food animals, ARBs are usually developed in ani- Ciprofloxacin proved to have superior biofilm capacity, mals’ bodies (especially in the gastrointestinal tract) after in parallel with increased efflux activity [98]. Improved using antibiotics. Differently, AMR in fruits, vegetables biofilm capability plus efflux has also been seen in and other foods of plant origin is often due to the con- Triclosan-adapted E. coli [99]. Genetic co-occurrences tamination with ARBs and ARGs along the food chain, suggest that plasmids provide limited opportunities for from primary production to consumption [110]. Import- biocides and metals to promote horizontal transfer of ant sources of microbial contamination in the pre- AMR through co-selection, whereas quite large possibil- harvest environment include soil, organic fertilizers and ities exist for indirect selection via chromosomal bio- irrigation water. cide/metal resistance genes [100]. Transduction is a significant mechanism of horizontal There are a lot of theoretical and experimental evi- gene transfer in natural environments, which has trad- dences that certain biocides may co-select for AMR, itionally been underestimated as compared to transform- mainly by close link of biocide resistance determinants ation. A study found that soil phages were the most to AMR determinants. However, there is lack of empir- versatile in terms of ARG carriage, and the phages from ical data to indicate that the use of biocides drives this organized farms showed varied ARGs as compared to co-selection of AMR in the food chain [101, 102]. the unorganized sector [111]. Another study screened pig feces from three commercial farms for 32 clinically Transfer and dissemination of AMR in food chain relevant ARG types and found that bacteriophage DNA The environmental resistome comprises both the natural contained 35.5% of the target ARG types and sul1, bla- AMR pool and contaminant AMR pool resulting from and ermB were found in 100% of the phage DNA TEM human activities [103]. The transfer of ARG from nat- samples [112]. Using the ratio index of the abundance of ural reservoirs to other bacteria may be a rare and ran- ARGs in bacteriophages and bacteria as an estimator of dom event, contaminant ARBs and ARGs may be able to bacteriophage ability to transmit ARGs, it was found − 1 spread rapidly and widely ((e.g. New Delhi metallo-beta- that the ratio for qnrA was the greatest (about 10 ) and lactamase, blaNDM-1 [104]; extended-spectrum beta- differed from the most abundant bacteriophage ARG lactamase blaCTXM-15 [105]; MRSA [106]). ermB, and fexA not floR had the lowest ratio value − 6 (about 10 ). Transmission of AMR from food animals to the environments Microbiomes encounter low-doses or sub-therapeutic Transmission of AMR from the environments to humans levels of antimicrobial agents from all mechanistic clas- The antimicrobial resistome is harbored by; (i) ses in food animal production. This modern practice ex- Antimicrobial-resistant bacteria called carriers that can erts broad effects on the gut microbiome of food spread ARG in the environment, but cannot colonize or animals, which is subsequently transferred to animal infect the human or animal body. Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 9 of 13 (ii) Antimicrobial-resistant bacteria called vectors that For heavy metals, associations have been identified be- can colonize and sometimes invade the human or animal tween reduced Zn or Cu susceptibility and AMR among body [103]. Even though carriers are not able to colonize pig Salmonella isolates, which are foodborne pathogens and infect humans, their spread and proliferation in the [6]. Co-transmission of the Cu efflux-associated tcrB and environment would increase the abundance and diversity erythromycin resistance erm(B) genes has been proved of ARG in vectors. Hence, it may increase the risks of between a marine sediment-derived livestock species En- transmission of ARB to humans. It should be noted that terococcus hirae and E. faecalis in conjugation experi- most vectors are not pathogens, because even if vectors ments. The experiments highlighted the scope for AMR can colonize the human body, they may lack crucial selection by the marine environment through heavy virulence genes and therefore unable to cause disease in metals and its possible involvement in antibiotic- a healthy host [103]. resistant enterococcal infections [117]. Moreover, there In searching a literature on the evidence for human is reasonable evidence of a co-resistance phenomenon exposure to extended-spectrum β-lactamase (ESBL) pro- involving Cu, Macrolides and perhaps Vancomycin ducing Enterobacteriaceae, MRSA, and Vancomycin- among Enterococci of pigs, whereas the relevance of this resistant Enterococcus spp. in the environment, a review to disease-causing strains in humans remains undeter- paper published in 2015 found that ARBs were detected mined [6]. in the contamination sources (66/66) such as wastewater and manure, and no direct evidence was found for trans- Conclusions and perspectives mission to humans through the environment [113]. Al- The contribution of AMR originally selected for in the though several studies performed on molecular typing of agricultural sector to resistance in human pathogens is human and environmental isolates, only one obtained not known exactly, but is unlikely to be negligible. Since this level of evidence, but the direction of transmission dosing regimens are less controlled in agriculture than could not be determined (environment transmitting in human health care, veterinary and environmental mi- AMR bacteria to humans or vice versa) [114]. crobes are often exposed to sub-inhibitory concentration of antimicrobials, which is considered as a risk factor for de novo resistance, transfer of ARGs, and selection for Transmission of AMR from animals to humans through already existing resistance [118]. Based on the present food chain or close contacts knowledge, short treatments with the highest dose that Many pathogens of animals are zoonotic, and therefore does not cause unacceptable side-effects may be optimal any development of resistance in pathogens associated for achieving therapeutic goals while minimizing devel- with food animals may spread to humans through food opment of resistance. Novel approaches such as combin- chain. Human infections by antibiotic-resistant patho- ation or alternating therapy are promising, but need to gens such as Campylobacter spp., Salmonella spp., E. be explored further before they can be implemented in coli and S. aureus are increasing [2]. daily practice. The impact of animal reservoirs on human health re- Co-selection of genes that confer resistance to antimi- mains debatable and unclear; nonetheless, there are crobials, biocides, heavy metals and other chemical haz- some examples of direct links that have been identified. ards is a potentially ecologically and clinically important In ESBL/AmpC and Carbapenemase-producing Entero- phenomenon. Non-antibiotic compounds used in agri- bacteriaceae occurring in animals, ESBL/AmpC- or food production, such as antibacterial biocides and Carbapenemase-encoding genes are most often located heavy metals, may also contribute to the promotion of on MGEs favoring their dissemination [115]. In most Af- AMR through co-selection. This may occur when resist- rican surveys, among ESBLs, certain blaCTX-M-15-har- ance genes to both antimicrobials and metals/biocides bouring clones (ST131/B2 or ST405/D) are mainly are co-located together in the same cell (co-resistance), identified in humans. But these have also been reported or a single resistance mechanism (an efflux pump) con- in livestock species from Tanzania, Nigeria or Tunisia; fers resistance to both antimicrobials and biocides/ international trade of poultry meat seems to have con- metals (cross-resistance), leading to co-selection of bac- tributed to the spread of other ESBL variants, such as terial strains, or mobile genetic elements (MGEs) that CTX-M-14, and clones [116]. Even though exposure to they carry [119]. animals is regarded as a risk factor, evidence for a direct The agri-food industry is coming under pressure to re- transfer of ESBL/AmpC-producing bacteria from ani- duce its usage of antimicrobial compounds. A recent mals to humans through close contacts is limited. The study analyzing AMR and antibiotic consumption world- extent to which food contributes to potential transmis- wide versus many potential contributing factors found sion of ESBL/AmpC producers to humans is also not that antibiotic consumption was not significantly associ- well established. ated with antimicrobial resistance index. This suggest Cheng et al. Antimicrobial Resistance and Infection Control (2019) 8:158 Page 10 of 13 that reduction of antibiotic consumption will not be suf- Received: 31 May 2019 Accepted: 9 October 2019 ficient to control AMR because the spread of resistant strains and resistance genes seems to be the dominant References contributing factor [120]. Moreover, even when no anti- 1. Hao H, Cheng G, Iqbal Z, Ai X, Hussain HI, Huang L, et al. Benefits and risks microbial compounds are used, certain heavy metals or of antimicrobial use in food-producing animals. 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