Abstract
One of the major breakthroughs in the history of medicine is undoubtedly the discovery of antibiotics. Their use in animal husbandry and veterinary medicine has resulted in healthier and more productive farm animals, ensuring the welfare and health of both animals and humans. Unfortunately, from the first use of penicillin, the resistance countdown started to tick. Nowadays, the infections caused by antibiotic-resistant bacteria are increasing, and resistance to antibiotics is probably the major public health problem. Antibiotic use in farm animals has been criticized for contributing to the emergence of resistance. The use and misuse of antibiotics in farm animal settings as growth promoters or as nonspecific means of infection prevention and treatment has boosted antibiotic consumption and resistance among bacteria in the animal habitat. This reservoir of resistance can be transmitted directly or indirectly to humans through food consumption and direct or indirect contact. Resistant bacteria can cause serious health effects directly or via the transmission of the antibiotic resistance traits to pathogens, causing illnesses that are difficult to treat and that therefore have higher morbidity and mortality rates. In addition, the selection and proliferation of antibiotic-resistant strains can be disseminated to the environment via animal waste, enhancing the resistance reservoir that exists in the environmental microbiome. In this review, an effort is made to highlight the various factors that contribute to the emergence of antibiotic resistance in farm animals and to provide some insights into possible solutions to this major health issue.
Introduction
Antimicrobials have been used in human and veterinary medicine for more than 60 years. Almost simultaneously, the use of antimicrobials has been applied in agriculture to prevent, control, and treat infections and to improve growth and feed efficiency.Citation1,Citation2 The importance of the positive effects of the use of antibiotics in agriculture is summarized in a World Health Organization reference, in which it is stated that “antimicrobials are vital medicines for the treatment of bacterial infections in both humans and animals. Antimicrobials have also proved to be important for sustainable livestock production and for the control of animal infections that could be passed on to humans.”Citation3 Still, the overuse or misuse of antimicrobials has been blamed for the selection of resistant isolates, giving birth to the term antimicrobial resistance.Citation4 According to the World Health Organization, the following definition has been given: “Antimicrobial resistance … is resistance of a microorganism to an antimicrobial drug that was originally effective for treatment of infections caused by it.”Citation5 Still, the link between use and overuse of antibiotics and resistance is not easy to follow, as antimicrobial resistance is a very complex and nonvictimless phenomenon affecting both human and animal health.Citation6
The rise of antimicrobial resistance after the first use of antibiotics should have been expected.Citation2 Bacteria are quite adaptive organisms that have survived multiple environmental stresses during their existence on the planet. Still, the emergence of antibiotic-resistant bacteria occurred quite shortly after their first use. In 1948, Staphylococcus aureus strains isolated from patients in British hospitals were found to be resistant to penicillin,Citation7 and in the same year, soon after the drug’s first use, resistance to streptomycin was observed in Mycobacterium tuberculosis isolates.Citation8 In the 1950s, antimicrobial resistance was confirmed in other pathogenic bacteria, such as Escherichia coli, Shigella spp., and Salmonella enterica,Citation9–Citation11 whereas in the 1960s, antibiotic-resistant bacteria such as extended spectrum β-lactamases (ESBLs) producing Enterobacteriaceae, vancomycin-resistant Enterococcus spp. (VRE), methicillin-resistant S. aureus (MRSA), and multi-drug-resistant Acinetobacter baumannii were encountered.Citation11–Citation13 Concerning outbreaks resulting from resistant bacteria from animals, data are limited, mainly because of the difficulty in discriminating the origin of these bacteria. Therefore, outbreak data traced back to animal can be safely attributed when the vehicle of transmission is food of animal origin.
Antimicrobial use in agriculture, animal husbandry, and aquaculture
Antimicrobials have been used in animals for treatment of diseases, for prevention and control of diseases, and also as growth promoters.Citation13 Therapeutic use of antimicrobials in animal husbandry should be accompanied ideally by an antimicrobial susceptibility test. According to the determination of the results, the drug’s attributions (pharmacodynamics, pharmacokinetics, toxicity, and tissue distribution), the age, the immune status of the animal, the cost of the drug, and the approval of the species, the appropriate drug is chosen.Citation14 However, in the case of infectious diseases, usually the whole flock is treated to prevent the dissemination of illness in the flock, despite the exhibition of clinical symptoms in a few animals. This is known as metaphylaxis, in which usually high doses of antibiotics are given for a short period. Still, the red line between use of antibiotics for treatment or prevention is not clear.Citation15,Citation16 In contrast, the use of antimicrobials for prevention (also known as prophylaxis) refers to the administration of antimicrobials in the feed or the drinking water in low doses for a longer period of time, usually for several weeks. During this period, the animals are not showing clinical signs, but the risk for infection exists.Citation16
The benefits of use of antimicrobials as antimicrobial growth promoters were first reported by Stokstad and Jukes,Citation17 when they noticed that small subtherapeutic doses of penicillin and tetracycline could enhance weight gain. Antimicrobial growth promoters are no longer permitted in the European Union, but they are still used in North America and other countries.Citation16 Subtherapeutic levels of antibiotics promote growth, but still the mechanism of this action remains unclear. Among the hypotheses tested are the stimulation of intestinal synthesis of vitamins, the reduction of total bacteria in the intestinal tract and the subsequent reduction in nutrient competition between microorganisms and host, the inhibition of harmful bacteria, the reduced immune stimulation, and the modification of rumen microbial metabolism.Citation18,Citation19 These subtherapeutic doses are not sufficient to destroy the target bacteria, allowing the more resistant of them to survive.Citation16 A few years ago, the US Food and Drug Administration issued draft guidance to animal farmers, veterinarians, and drug makers, which represents a step toward stopping antibiotic use for growth promotion.Citation20 In the European Union, antimicrobial growth promoters were withdrawn in 2006, although ionophores continue to be administered in feed.Citation21
The use of veterinary antimicrobial agents in food-producing animals in countries of European Union and the United States of America is presented in and , as reported by the European Medicines Agency,Citation22–Citation25 and the US Food and Drug Administration.Citation26–Citation29 According to these data, the consumption of antibiotics for animal use has been augmented by ~4% in the European Union, whereas in the United States, it follows an ascending trend, despite the call for limiting antimicrobial use in livestock.
In cattle, antimicrobials such as amoxicillin, penicillin, erythromycin, quinolones, gentamicin, novobiocin, tylosin, tilmicosin, and tetracycline are extensively used. In meat-producing animals, antibiotics are mainly used for the treatment and prevention of bovine pneumonia, diarrhea, and shipping fever, which are the most common problems.Citation29 For the treatment of pneumonia, oxytetracyclines and spectinomycin are the first-choice antibiotics, with florfenicol and macrolides (particularly tilmicosin) considered as the second choice, with second-, third-, and fourth-generation cephalosporins being the last choice.Citation30 Still, antibiotics are administered at least once via feed for various reasons, such as liver abscesses, increased growth, and respiratory diseases.Citation31 The use of narrow-spectrum antimicrobials is favored in cases of clinical mastitis, with first-choice antimicrobials being the β-lactam antimicrobials used when treating mastitis resulting from streptococci, or penicillin when treating mastitis caused by staphylococci.Citation30,Citation32 In certain cases, the use of antibiotics intramammary in the nonlactating period is given to the whole herd to prevent infectious mastitis.Citation32
In pigs, the current trends in husbandry require animal segregation in groups according to age, where pigs are of similar size and weight, and therefore the antimicrobials can be administered in groups of pigs via the oral route by addition in the feed or water.Citation33,Citation34 Individual therapy of pigs by injection of antimicrobials is mainly considered in pigs reared for reproduction. Use of antimicrobials for prevention is a common practice in pig farms, especially in stressful periods that predispose for infectious diseases. Such periods are the time between birth and first lactation, where the cut of the umbilical cord and tail and the trimming of the canines takes place; the ablactation period, where the environment and diet change and the castration of males and vaccinations take place; and finally the fattening period, where overcrowding, inadequate aeration, and low or high temperatures can form a quite stressful environment.Citation35 Prophylactic use of antimicrobials is considered to be higher in the ablactation period, whereas at the end of fattening pigs, they do not receive antimicrobials so as to avoid residues detection after slaughter. For the prevention and treatment of enzootic pneumonia, large quantities of various antibiotics are used, with the most common being ceftiofur, tetracyclines, tiamulin, lincomycin, and enrofloxacin.Citation29,Citation34 In addition, in bacterial enteritis, especially when the etiological agent is E. coli or Clostridium perfringens, antibiotic treatment with penicillins, tetracyclines (chlortetracycline, oxytetracycline), quinolones (enrofloxacin), or aminoglycosides (gentamicin, neomycin) is required. Finally, in swine dysentery (Brahyspira hyodysenteriae) and ileitis (Lawsonia intracellularis), lincomycin, tiamulin, macrolides, or tetracyclines are mainly used.Citation36
In poultry, antibiotics used for therapeutic reasons are usually administered through water, in contrast to growth-promoting use, where antibiotics are added in feed.Citation37 The most commonly used antibiotics are penicillins (amoxicillin), quinolones (enrofloxacin), tetracyclines (doxycycline, oxytetracycline), macrolides (erythromycin, tylosin), aminoglycosides, the sulfonamide/trimethoprim combination, polymyxins (colistin), and other antimicrobials (tiamulin).Citation13 In the United States, the abovementioned antibiotics are used, with the exception of fluoroquinolones.Citation34
The antimicrobials commonly used in sheep and goats are amoxicillin, ampicillin, ceftiofur, the combination of amoxicillin/clavulanic acid, enrofloxacin, erythromycin, lincomycin, oxytetracycline, sulfonamides, penicillin G, trimethoprim and sulfonamide combination, tylosin, and tilmicosin (with the exception of goats, where subcutaneous injection of tilmicosin has been linked to death).Citation38 Ampicillin, erythromycin, lincomycin, the trimethoprim and sulfonamide combination, and certain sulfonamides (eg, sulfathiazole) can significantly alter the microbial flora of the rumen when administered per os, and in certain cases, they can lead to death.Citation38 Therefore, in the mature small ruminants, it is preferable to administer antimicrobials in other ways than the oral route (feed or water), with the exception of certain sulfonamides and tetracyclines, which can be absorbed efficiently by the rumen.
Concerns about the extensive use of nontherapeutic agents have arisen after the duplication of the antimicrobial use in aquaculture in the decade 1994–2004.Citation39,Citation40 In aquaculture animals, several classes of antibiotics have been used. Among them are antibiotics such as sulfonamides, penicillins, quinolones, tetracyclines, and phenicols, which are listed as critically or highly important antimicrobials for human medicine.Citation41,Citation42 The last three antimicrobial classes are widely used in salmon farming. Quinolones, tetracyclines, and phenicols are selective for a variety of antimicrobial resistance genes that occur in transposons, plasmids, and integrons that, when mobile, can induce their dissemination.Citation42–Citation44
Antimicrobial resistance in various bacteria of animal origin
Campylobacter spp
Thermotolerant Campylobacter spp. are one of the leading causes of foodborne disease worldwide. Although the disease is self-limiting with low mortality, the economic and public health consequences are quite severe, especially in industrialized countries.Citation45 Campylobacter spp. isolates are reported to be resistant toward quinolones, macrolides and lincosamides, chloramphenicol, aminoglycosides, tetracycline, ampicillin and other β-lactams, cotrimoxazole, and tylosin.Citation45–Citation48 Concerning macrolide resistance, the occurrence of erythromycin resistance is higher in Campylobacter coli than Campylobacter jejuni (0%–29% and 0%–20%, respectively). In contrast to macrolides, resistance to quinolones has emerged during the last 20 years, coinciding with the use of fluoroquinolones (mainly enrofloxacin) in veterinary medicine.Citation48 In the Netherlands, an increase was observed in fluoroquinolone-resistant Campylobacter spp. of poultry origin a few years after the use of fluoroquinolones in the country.Citation49 Regarding tetracyclines, they have been proposed as an alternative to Campylobacter spp. infection.Citation50 Still, the susceptibility of Campylobacter spp. to tetracyclines shows major geographical differences and generally follows increasing trends, as shown in Campylobacter spp. human isolates over the course of the last 20 years in CanadaCitation51,Citation52 and from 1989 to 1999 in Mexico.Citation48,Citation53 Concerning aminoglycosides, resistance has been low in most countries, with resistance to gentamicin reported in less than 2% of the isolates.Citation54,Citation55 Still, in the latest surveillance reports, up to 13.6% of the strains tested were resistant to gentamicin (as reported by Spain for 2012),Citation56 and therefore sensitivity testing is advised. In addition, the resistance to gentamicin of Campylobacter spp. from meat from broilers in the European Union ranged from 0% to 6.3%.Citation56 Similarly, in the United States, resistance of C. coli to gentamicin between 2007 and 2011 increased from almost zero to 12.2% for human isolates, 1% to 18% for chicken meat isolates, and 1% to 6% for chicken at slaughter isolates, whereas for C. jejuni, resistance remained low.Citation57
Salmonella spp
Salmonella is one of the most important foodborne pathogens. The National Antimicrobial Resistance Monitoring System (a collaboration among the US Food and Drug Administration, the Centers for Disease Control and Prevention, and the US Department of Agriculture) and the European Food Safety Authority, along with the European Centre for Disease Prevention and Control in Europe, are monitoring Salmonella susceptibility in isolates from farm animals, food stuff, and humans. In the case of Salmonellae, the link between antibacterial use and antibiotic-resistant strains at the farm level and the occurrence in humans is well established.Citation58,Citation59 Still, the role of crops where wastewater or manure is used for fertilization of the fields remains to be elucidated.
Salmonella has exhibited multidrug resistance to various agents, including tetracyclines, sulfonamides, streptomycin, kanamycin, chloramphenicol, and some of the β-lactam antibiotics (penicillins and cephalosporins).Citation60–Citation62 It should be noted that the percentage of isolates resistant to these antibiotics has decreased or remained stable since 1996. In contrast, drugs such as amoxicillin/clavulanic acid, ceftriaxone, ceftiofur, and nalidixic acid follow an increasing trend.Citation63 From 1998 to 2005, the percentage of amoxicillin/clavulanic acid- and ceftiofur-resistant isolates has increased from less than 2% to more than 15%, whereas ceftriaxone resistance increased from no resistance to ~1%. This increase in resistance in extended-spectrum cephalosporins is of utmost importance because ceftriaxone is used in severe salmonellosis in children.Citation64 Resistance to more than one antibiotic has been noted as early as the 1960s.Citation65 Nowadays, the most common multidrug resistance phenotype is the one conferring resistance to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracyclines.Citation63 It is also noteworthy that Salmonella spp. exhibit a remarkable ability to spread worldwide. One such example is the global dissemination of the MDR Salmonella Typhimurium DT104.Citation66–Citation68
Staphylococcus spp
S. aureus is one of the most common human and animal pathogens. Bovine strains produce mostly beta-hemolysin, whereas human isolates have the ability to produce alpha-hemolysin.Citation69 S. aureus was one of the first strains characterized as resistant to antimicrobials, with resistance to penicillins observed as early as 1948.Citation70 Nowadays, resistance of human isolates to penicillin is recorded as up to 90%.Citation71 Penicillin was first used in animal production in the late 1940s, mainly for the eradication or treatment of Streptococcus agalactiae in bovine mastitis. Its widespread use led to the selection of penicillin-resistant strains of S. aureus. Resistant pathogens have been noted in dairy milk, where according to Frey et al,Citation72 47% of coagulase-negative staphylococci showed resistance to oxacillin. Even though MRSA has been a major cause of hospital-acquired infections for more than 3 decades, MRSA clonal complex 398 (MRSA CC398), a new variant, has emerged in livestock.Citation73 Nasal carriage of livestock-associated MRSA CC398 among farmers and other persons in contact with animals has been widely reported.Citation74 Although MRSA CC398 is quite common among pigs, it does not seem to have pronounced host specificity, as it has been also isolated from cattle, dogs, horses, and chickens.Citation73
Enterococcus spp
Enterococci are commensal bacteria colonizing the intestinal tract of mammals and birds; they are considered indicators of enteric contamination of food and can survive in unfavorable environmental conditions such as high or low temperature, pH, and saline waters.Citation75–Citation77 During the most recent 2 decades, enterococci have emerged as an important cause of nosocomial and community-acquired infections, which are difficult to treat because they exhibit resistance to antibiotics.Citation78,Citation79 In addition, a rapid increase of VRE, isolated from livestock and related food products, has been observed, probably as a result of the widespread use or misuse of glycopeptide antimicrobials such as avoparcin in food-producing animals in countries other than the United States.Citation80,Citation81 Vancomycin and teicoplanin are used for the treatment of human infections in case of resistance or allergic reactions to β-lactams; however, the therapeutic action of vancomycin has been limited because of the emergence of VRE.Citation82,Citation83 Enterococci of foodborne origin are not identified as a direct cause of resistant enterococci in humans, but they could pose a risk in transfer of resistance determinants to human-adapted strains of the same genus or other genera, as shown for vancomycin resistance in S. aureus and tetracycline and erythromycin resistance in Listeria monocytogenes.Citation77,Citation80
ESBL-producing Gram negative bacteria
ESBLs are enzymes of Gram-negative bacteria conferring resistance against β-lactam antibiotics, such as third- or fourth-generation cephalosporins and monobactams. ESBL-producing Gram-negative bacteria have been reported in Europe and worldwide.Citation41,Citation84–Citation86 Most ESBL-producing bacteria are multidrug-resistant, and the majority of them are only susceptible to carbapenems.Citation21 Infections caused by these multidrug-resistant bacteria are associated with high morbidity, high mortality, high health care costs, and limited therapeutical options.Citation41
Resistance genes of the ESBL type are mostly plasmid-associated, and therefore can spread among bacteria.Citation87 Recently, there has been an ongoing concern about the dissemination of ESBL-producing strains in healthy food animals, with many reports referring to strains from Europe, Asia, and the United States.Citation70,Citation88 The increasing incidence of infection with ESBL-producing E. coli has been observed in food animals such as cattle, broiler chickens, and pigs.Citation41,Citation87 This observation suggests that animals, food, and environment are potent sources of ESBL-producing bacteria.Citation41 According to Reich et al,Citation87 ESBL-producing enterobacteria were isolated from 88.6% of carcasses and 72.5% of ceca at slaughter. Overdevest et alCitation89 found a high prevalence of ESBL-coding genes in retail chicken meat (79.8%), with genetic analysis showing that the predominant ESBL-coding genes in chicken meat and human rectal swab specimens were identical. Other data show clearly that antibiotic administration to chickens leads to more ESBL-producing bacteria in chicken meat.Citation90
Modes of spread to humans from farm animals and food
The possible transport routes between animals and humans are numerous. Still, the most probable ways of interaction are summarized in transmission through the food chain;Citation91 through direct or indirect contact with people working in close contact with animals, such as farmers and animal health workers;Citation92 and through manure contaminated environments and aquaculture.Citation93,Citation94 In particular, the role of the environment is extremely important, as it can serve as the reservoir of antibiotic-resistance genes.Citation95,Citation96
Although the immediate risk from antibiotic-resistant foodborne pathogens is easier to comprehend, perhaps the most perilous situation is the transfer of antimicrobial resistance characteristics through the genetic pool contained in bacteria, bacteriophages, or DNA fragments. According to Rossi et al,Citation97 horizontal gene transfer, the mechanism by which most bacteria could transfer antibiotic resistance genes, may occur in all matrices. Still, it is more probable in food categories containing high numbers of microbial cells (fermented, minimally processed, or raw foods).Citation97 The cohabitation of these factors with pathogenic bacteria in various environments, and especially in the human gut, could result in the appearance of resistant strains. This has been shown in vitro by Toomey et al,Citation98 who have demonstrated the transfer of erythromycin resistance genes from lactic acid bacteria to L. monocytogenes. In addition, Doucet-Populaire et alCitation99 report the transfer of tetracycline and erythromycin resistance genes from Enterococcus faecalis to L. monocytogenes strains in vitro and in the gastrointestinal tract of mice. Ampicillin resistance has been transferred from Salmonella typhimurium to E. coli in milk and ground beef.Citation100 Rizzotti et alCitation101 have succeeded in transferring tetracycline resistance genes from E. faecalis to Listeria innocua in meat.
In addition, the transfer of resistance is well documented in bacteria of the same species in the human digestive tract. In E. coli, genes encoding ESBLs could be harbored in mobile genetic elements and could therefore be transmitted to other E. coli strains, as demonstrated in vitro.Citation102 In addition, Leverstein-van Hall et alCitation103 provide indirect evidence of transfer of resistance to β-lactamic antibiotics through the food chain. They report that 54% of the E. coli of human origin carried ESBL genes that were genetically identical to those of poultry origin. Therefore, bacteria that contain antimicrobial resistance genes can be an indirect public health hazard, regardless of their pathogenicity, as the available genetic pool of resistance is increased.
Health risks to humans
The higher burden on human health of antibiotic-resistant foodborne pathogens versus antibiotic-sensitive ones has been well documented. Concerning Salmonella spp. and Campylobacter spp., the rise of antimicrobial resistance has resulted in an increased number of hospitalizations and increased morbidity and mortality. Doyle and Erickson,Citation104 in a review of emerging pathogens from meat, report selected outbreaks in which increased severity was exhibited, coinciding with the etiological agents being antibiotic-resistant bacteria.
In general, the increased severity of infection resulting from antibiotic-resistant bacteria could be summarized as follows:
Delay or failure of treatment. The administration of antibiotics in patients, especially in severe cases, is often given empirically before the results of the antibiogram. Therefore, antibiotic therapy fails. In some cases, the deterioration of the patient in the relapsed time is fatal.
Limited choice of antimicrobials. The available antimicrobials are limited because of the emergence of antibiotic-resistant pathogens. In addition, the increased use of the effective antimicrobials increases the possibility of the appearance of new resistant strains.
Selection of suppressed resistant pathogenic strains when antibiotic therapy is administered for treatment of other bacterial diseases.
CoexistenceCitation105,Citation106 and possibly increased regulationCitation107 of pathogenicity genes with resistance genes as a result of selection. The result is the emergence of highly pathogenic strains that are resistant to antibiotics. As an example, in S. typhimurium, DT104 multiple antibiotic resistance is expressed by a gene cluster (SGI1), in which genes encoding virulence proteins are contained.Citation104
The human health risks associated with consumption of raw or unpasteurized milk and milk products are well established and have been previously reviewed by Oliver et al.Citation108 In general, the precise quantification of the total effect of antibiotic resistance in terms of morbidity and mortality is quite difficult, as it is a problem added to the initial infection.Citation109 Still, the severity of the infection in terms of the total duration and seriousness is expected to be more profound. It has been documented that the augmenting appearance of antibiotic-resistant bacteria has led to an increase in foodborne illnesses.Citation110 More specifically, the augmenting percentages of antibiotic-resistant Salmonella spp. and Campylobacter spp. have been linked to increase in hospitalizations, risk for invasive infections, and mortality.Citation111 According to European Centre for Disease Prevention and Control/European Medicines Agency,Citation112 the burden of antibiotic-resistant bacteria that caused bloodstream infections in the European Union, Iceland, and Norway in 2007 was estimated to add 386,100 cases, 25,100 deaths, and 2,536,000 hospitalization days. Although the number of cases caused by Gram-positive antibiotic-resistant bacteria (namely, methicillin-resistant staphylococci and vancomycin-resistant enterococci) was comparable to that of Gram-negative bacteria, almost two-thirds of deaths were attributed to Gram negative antibiotic resistant bacteria.Citation112
Alternatives to nontherapeutic agents in agriculture and aquaculture
In an effort to estimate the increased health care economic burden of antibiotic-resistant bacteria, the National Academy of Sciences estimated that the annual cost ranged between $4 and $5 billion. Still, the loss of work days and productivity was not included.Citation113 In 2009, the annual cost was estimated at between $16.6 and $26 billion by the Cook County Hospital and the Alliance for Prudent Use of Antibiotics, exhibiting the increased consequences of resistance to antimicrobials.Citation114 Therefore, an urgent need to provide alternatives to antibiotics has been determined.
For proposing alternatives to antimicrobials, the initial scope of antibiotic usage, namely, therapy, should be considered. Prevention in the form of an immunization program by vaccination could limit the amount of antibiotics needed. In contrast, the cost of vaccination is usually high, and the cross-protection against some pathogens is limited.Citation115 Another way of preventing disease occurrence is the improvement of the gut bacterial flora by the use of probiotics, prebiotics, and synbiotics, as revised by Callaway et alCitation116 and Gaggia et alCitation117 The health of the gut microbial microecosystem contributes largely to the immune system functionality and nutrient use and provides less space for pathogen colonization.Citation115,Citation118 In poultry, a significant decrease in Salmonella colonization has been shown after administration of commensal anaerobic bacteria. The low number of the newly discovered Butyricicoccus pullicaecorum isolated from broiler cecum has been positively correlated with inflammatory bowel disease, with the disease reversed after oral administration of the bacterium.Citation119 In addition, selected yeasts with appropriate properties or certain genetically modified strains could be used as probiotics.Citation120 Although the improvement of the gut health seems promising, there is a need to access the effectiveness and the underlying mechanisms.Citation119,Citation121,Citation122
The use of phages is quite intriguing, as they are characterized by specificity and selective neutralization of the pathogen of interest during the lytic phase of their life cycle. Furthermore, the use of phages is compatible with the use of other antimicrobials, as there is no influence between these treatments. Although promising, the use of phages has been limited to treatment of topical infections in humans,Citation123 neutralization of foodborne pathogens in animals,Citation124 and control of plant pathogens.Citation125 Although they are considered more specific than antibiotics, they exhibit variable specificity, mainly influenced by the phage titer. Therefore, the effects of the phages on the microbiota, although expected to be lesser than those of the antibiotics, should be considered.Citation115,Citation126
Research on antimicrobial peptides is increasing, and the acquired knowledge is showing the way for future pharmaceutical applications. Antimicrobial peptides can be an alternative to traditional antibiotics, although some of these have been shown to have toxic effects on mammalian cells. One category of antimicrobial peptides lacking toxicity is the bacteriocins, which are ribosomally synthesized peptides.Citation127 Certain bacteriocins have already been used as food preservatives. Nisin A, a bacteriocin produced by lactic acid bacteria, is currently used officially in more than 50 countries, with the US Food and Drug Administration proposing a daily uptake of up to 2.9 mg per person per day.Citation115,Citation128 In general, they can be incorporated in a food product as an additive in the form of a purified compound, as a generally recognized as safe fermentate, or by adding the producer microbe as a starter culture.Citation128 Still, bacteriocins in food production systems have been reported to reduce Listeria by only 1 or 2 logCitation10.Citation129 Therefore, bacteriocins could be sufficient for pathogen destruction only if they form part of a hurdles system in which several low-efficiency antimicrobial treatments are used to produce a safe food product.Citation128 In addition, the optimization of bacteriocin production, possibly through genetic engineering of the producing bacterium, could increase its efficacy.Citation130 Although the application of bacteriocins involves mainly food products, they have been proposed for the control of zoonoses.Citation131,Citation132 Still, preceding their application, the bacteriocins should be examined for their in vivo stability, the appropriate delivery route, and possible toxicity issues.Citation133
Another possible alternative to antimicrobials is the use of predatory bacteria. Bdellovibrio and associated organisms show potential in combating pathogenic bacteria in various niches, as they possess a full arsenal of DNases and proteases.Citation115,Citation134,Citation135 Bdellovibrio and associated organisms show a nonspecific predation against Gram-negative bacteria.Citation134 One of the main advantages of these predatory bacteria is that they can prey quite effectively even on bacterial biofilms.Citation115,Citation135 Bdellovibrio bacteriovorus and Micavibrio aeruginosavorus have been shown to prey on multidrug-resistant pathogens such as A. baumannii, E. coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Pseudomonas putida, without being able to discriminate between antibiotic-resistant and antibiotic-susceptible strains.Citation134 Another interesting factor of their biology is that they could serve both as antibiotic and probiotic organisms. The administration of B. bacteriovorus lowered the cecal carriage of S. enterica.Citation136 In addition, they have been effectively used in treating ocular diseases such as the one caused by Shigella flexneri in rabbits and Moraxella bovis in cows.Citation137 In contrast, there are some limitations concerning their possible application. Their predation on bacteria is not exhaustive, as a small number of bacteria remain. Although regarded as aerobic, or at least microaerophilic,Citation138 they can destroy the natural flora of the body cavities.Citation134 In addition, the predation in environments in which Gram-positive bacteria exist could lower the efficacy of predation.Citation139 Therefore, it is evident that more research is needed toward the interaction among predatory bacteria, the host, and the commensal microbiota.Citation115
Measures to prevent emergence and transmission of antimicrobial-resistant bacteria
The global situation concerning antibiotic resistance worldwide is at least alarming. In the present time, the recognition of the importance of antibiotic resistance is almost catholic. Therefore, certain measures have been implied by the states so as to mitigate this problem. In 2001, the World Health Organization has set the basis for the establishment of measures toward controlling antibiotic resistance.Citation140 In summary, control measures should reduce the emergence and spread of antibiotic-resistant bacteria, improve use of antimicrobials, establish effective surveillance systems, enforce legislation, and encourage the development of new drugs and vaccines. More or less, these basic principles have been followed by both the European Union and the United States of America. The European Union, through the joint report by the European Centre for Disease Prevention and Control and the European Medicines Agency, has also expressed the urge for international cooperation so as to entrench antibiotic resistance. The White House has recently issued a national strategy plan for combating antibiotic resistance in which the goals issued have also added the necessity of international collaboration.Citation141 Most interestingly, defined expected outcomes have been calculated in this national strategy plan. In both the European Union and the United States, the multidisciplinary collaboration is reported to be crucial, as summarized in the One Health initiative.
In 2011, more than 70 experts representing 33 countries have gathered in the Third World Healthcare Associated Infections Forum (WHAIF) which was dedicated to antibiotic resistance awareness and action.Citation142 At the end of this forum, they have agreed on forming twelve actions by priority, which were also categorized according to the stakeholders that were addressed (). The stakeholders involved were the national and international health authorities and policy makers, the medical and veterinary communities, the general public, and industry. These messages are reported in . The results of the Third WHAIF have been received after 10 years from the World Health Organization and provide a revision of the World Health Organization principles. On the Fourth WHAIF, the priority actions agreed on during the Third WHAIF were reported as urgent after critical reconciliation of the findings reported by the participating experts.Citation70
Conclusion
Antibiotic-resistant bacteria of animal origin are considered an important contributor to the overall phenomenon of resistance to antibiotics. Although the magnitude of their importance is still under debate, there are certain indications that show a direct link between resistance and antibiotic use in farm animals. However, this is not the issue: everyone who has used antibiotics has a share in the emergence of resistance, and because the situation is quite alarming, every effort should be made for the reversal of it. Judicious use of antibiotics in animals is a requirement to delay the emergence of bacteria resistant to the still-working antibiotics. The invention of novel drugs or the use of alternatives to antibiotics should also be encouraged. Still, the increased awareness of the scientific community and the stakeholders in general is both alarming and promising at the same time. The planning of future strategies has already taken place, and in general, it has been agreed on. Therefore, a combined international action is needed toward the solution of this problem.
Disclosure
The authors report no conflicts of interest in this work.
References
- AnguloFJBakerNLOlsenSJAndersonABarrettTJAntimicrobial use in agriculture: controlling the transfer of antimicrobial resistance to humansSemin Pediatr Infect Dis2004152788515185190
- SilbergeldEKGrahamJPriceLBIndustrial food animal production, antimicrobial resistance, and human healthAnnu Rev Public Health200829115116918348709
- World Health AssociationThe Medical Impact of the Use of Antimicrobials in Food Animals World Health Organization1997 Available from: http://whqlibdoc.who.int/hq/1997/WHO_EMC_ZOO_97.4.pdfAccessed December 15, 2014
- DaviesJDaviesDOrigins and evolution of antibiotic resistanceMicrobiol Mol Biol Rev201074341743320805405
- World Health OrganizationAntimicrobial Resistance. Fact Sheet 194World Health Organization 2014 Available from: http://www.who.int/mediacentre/factsheets/fs194/en/Accessed December 15, 2014
- US Food and Drug AdminstrationGuidance for Industry #209: The Judicious Use of Medically Important Antimicrobial Drugs in Food-Producing AnimalsUS Food and Drug Administration2012 Available from: http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM216936.pdfAccessed December 15, 2014
- BarberMRozwadowska-DowzenkoMInfection by penicillin-resistant staphylococciLancet19482653064164418890505
- CroftonJMitchisonDAStreptomycin resistance in pulmonary tuberculosisBMJ1948245881009101518100441
- WatanabeTInfective heredity of multiple drug resistance in bacteriaBacteriol Rev1963278711513999115
- OlarteJAntibiotic resistance in MexicoAPUA Newslett198313
- CantasLShahSQACavacoLMA brief multi-disciplinary review on antimicrobial resistance in medicine and its linkage to the global environmental microbiotaFront Microbiol201349623675371
- LevySBMarshallBAntibacterial resistance worldwide: causes, challenges and responsesNat Med200410(12)(Suppl)S122S12915577930
- MarshallBMLevySBFood animals and antimicrobials: impacts on human healthClin Microbiol Rev201124471873321976606
- WattsJLindemanCAntimicrobial susceptibility testing of bacteria of veterinary originAarestrupFMAntimicrobial Resistance in Bacteria of Animal OriginWashington DCASM Press 20062935
- US Food and Drug Administration Center for Veterinary MedicineJudicious Use of Antimicrobials for Beef Cattle VeterinariansUS Food and Drug Administration Center for Veterinary Medicine Available from: http://www.fda.gov/downloads/AnimalVeterinary/SafetyHealth/AntimicrobialResistance/JudiciousUseofAntimicrobials/UCM095568.pdfAccessed December 10, 2014
- Compassion in World FarmingAntibiotics in Farm Animal Production. Public Health and Animal WelfareCompassion in World Farming2011 Available from: http://www.fao.org/fileadmin/user_upload/animalwelfare/antibiotics_in_animal_farming.pdfAccessed December 15, 2014
- StokstadELRJukesTHFurther observations on the “animal protein factor.”Proc Soc Exp Biol Med1950733523528
- GiguèreSAntimicrobial drug action and interactionGiguèreSPrescottJFDowlingPMAntimicrobial Therapy in Veterinary Medicine5th edAmes (IA)Blackwell Publishing2013110
- AlexanderTWYankeLJToppEEffect of subtherapeutic administration of antibiotics on the prevalence of antibiotic-resistant Escherichia coli bacteria in feedlot cattleAppl Environ Microbiol200874144405441618502931
- US Food Drug AssociationJudicious Use BrochuresUS Food and Drug Association Available from: http://www.fda.gov/AnimalVeterinary/SafetyHealth/AntimicrobialResistance/JudiciousUseofAntimicrobials/ucm378095.htmAccessed December 15, 2014
- HunterPADawsonSFrenchGLAntimicrobial-resistant pathogens in animals and man: prescribing, practices and policiesJ Antimicrob Chemother201065Suppl 1i3i1720045808
- European Medicines AgencyTrends in the Sales of Veterinary Antimicrobial Agents in Nine European Countries (2005–2009)European Medicines Agency2011 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2011/09/WC500112309.pdfAccessed December 15, 2014
- European Medicines AgencySales of Veterinary Antimicrobial Agents in 25 EU/EEA Countries in 2011European Medicines Agency2013 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2013/10/WC500152311.pdfAccessed December 15, 2014
- European Medicines AgencySales of Veterinary Antimicrobial Agents in 26 EU/EEA Countries in 2012European Medicines Agency2014 Available from: http://www.ema.europa.eu/docs/en_GB/document_library/Report/2014/10/WC500175671.pdfAccessed December 15, 2014
- FDA Center for Veterinary Medicine2009 Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing AnimalsUS Food and Drug Administration2014 Available from: http://www.fda.gov/downloads/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/UCM231851.pdf Accessed December 15, 2014
- FDA Center for Veterinary Medicine2010 Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing AnimalsUS Food and Drug Administration2014 Available from: http://www.fda.gov/downloads/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/UCM277657.pdfAccessed December 15, 2014
- FDA Center for Veterinary Medicine2011 Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing AnimalsUS Food and Drug Administration 2014 Available from: http://www.fda.gov/downloads/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/UCM338170.pdfAccessed December 15, 2014
- FDA Center for Veterinary Medicine2012 Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing AnimalsUS Food and Drug Administration 2014 Available from: http://www.fda.gov/downloads/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/UCM416983.pdfAccessed December 15, 2014
- McEwenSAFedorka-CrayPJAntimicrobial use and resistance in animalsClin Infect Dis200234(s3)(Suppl 3)S93S10611988879
- ConstablePPyoralaSSmithGWGuidelines for antimicrobial use in cattleGuardabassiLJensenLBKruseHGuide to Antimicrobial Use in AnimalsAmes (IA)Blackwell Publishing Ltd20081222
- US departmentof AgriculturePart III: Health Management and Biosecurity in US Feedlots, 1999US Department of Agriculture 2000 Available from: http://www.aphis.usda.gov/animal_health/nahms/feedlot/downloads/feedlot99/Feedlot99_dr_PartIII.pdfAccessed December 15, 2014
- WagnerSErskineRAntimicrobial drug use in mastitisGiguèreSPrescottJFDowlingPMAntimicrobial Therapy in Veterinary Medicine5th ed Ames (IA)Blackwell Publishing2013519528
- US Departmentof AgricultureCattle and Calves Nonpredator Death Loss in the United States, 2010US Department of Agriculture2011 Available from:http://www.aphis.usda.gov/animal_health/nahms/general/downloads/cattle_calves_nonpred_2010.pdf Accessed December 15 2014
- BurchDGSAntimicrobial drug use in swineGiguèreSPrescottJFDowlingPMAntimicrobial Therapy in Veterinary Medicine5th edAmes (IA)Blackwell Publishing2013553568
- DeweyCECoxBDStrawBEUse of antimicrobials in swine feeds in the United StatesSwine Health Prod1999711925
- DunlopRHMcEwenSAMeekAHFriendshipRAClarkeRCBlackWDAntimicrobial drug use and related management practices among Ontario swine producersCan Vet J1998392879610051955
- HofacreCLFrickeJAInglisTAntimicrobial drug use in poultryGiguèreSPrescottJFDowlingPMAntimicrobial Therapy in Veterinary Medicine5th edAmes (IA)Blackwell Publishing2013569587
- ClarkCRAntimicrobial drug use in sheep and goatsGiguèreSPrescottJFDowlingPMAntimicrobial Therapy in Veterinary Medicine5th edAmes (IA)Blackwell Publishing2013529539
- CabelloFCHeavy use of prophylactic antibiotics in aquaculture: a growing problem for human and animal health and for the environmentEnviron Microbiol2006871137114416817922
- HeuerOEKruseHGraveKCollignonPKarunasagarIAnguloFJHuman health consequences of use of antimicrobial agents in aquacultureClin Infect Dis20094981248125319772389
- World Health OrganizationTackling Antibiotic Resistance from a Food Safety Perspective in EuropeCopenhagenWorld Health Organization2011 Available from: http://www.euro.who.int/__data/assets/pdf_file/0005/136454/e94889.pdfAccessed December 15, 2014
- MirandaCDTelloAKeenPLMechanisms of antimicrobial resistance in finfish aquaculture environmentsFront Microbiol2013423323723986749
- SchwarzSKehrenbergCDoubletBCloeckaertAMolecular basis of bacterial resistance to chloramphenicol and florfenicolFEMS Microbiol Rev200428551954215539072
- RobertsMCUpdate on acquired tetracycline resistance genesFEMS Microbiol Lett2005245219520315837373
- KolumanADikiciAAntimicrobial resistance of emerging foodborne pathogens: status quo and global trendsCrit Rev Microbiol2013391576922639875
- PadungtonPKaneeneJBCampylobacter spp in human, chickens, pigs and their antimicrobial resistanceJ Vet Med Sci200365216117012655109
- AlfredsonDAKorolikVAntibiotic resistance and resistance mechanisms in Campylobacter jejuni and Campylobacter coliFEMS Microbiol Lett2007277212313218031331
- EngbergJKeelanMGerner-SmidtPTaylorDAntimicrobial resistance in CampylobacterAaerstrupFMAntimicrobial Resistance in Bacteria of Animal OriginWashingtonASM Press; 2006269291
- EndtzHPRuijsGJvan KlingerenBJansenWHvan der ReydenTMoutonRPQuinolone resistance in campylobacter isolated from man and poultry following the introduction of fluoroquinolones in veterinary medicineJ Antimicrob Chemother19912721992082055811
- BlaserMJCampylobacter jejuni and related speciesBennettJEDolinRPrinciples and Practice of Infectious DiseasesNew YorkChurchill Livingstone Inc200022762285
- GibreelATraczDMNonakaLNgoTMConnellSRTaylorDEIncidence of antibiotic resistance in Campylobacter jejuni isolated in Alberta, Canada, from 1999 to 2002, with special reference to tet(O)-mediated tetracycline resistanceAntimicrob Agents Chemother20044893442345015328109
- GaudreauCGilbertHAntimicrobial resistance of Campylobacter jejuni subsp jejuni strains isolated from humans in 1998 to 2001 in Montréal, CanadaAntimicrob Agents Chemother20034762027202912760892
- Tuz-DzibFGuerreroMLCervantesLEPickeringLKRuiz-PalaciosGMIncreased incidence of quinolone resistance among clinical isolates of Campylobacter jejuni in MexicoAbstracts of the 10th International Workshop on Campylobacter, Helicobacter and Related OrganismsSeptember 12–16 1999Baltimore, MD USA
- GuptaANelsonJMBarrettTJNARMS Working GroupAntimicrobial resistance among Campylobacter strains, United States, 1997–2001Emerg Infect Dis20041061102110915207064
- LuberPWagnerJHahnHBarteltEAntimicrobial resistance in Campylobacter jejuni and Campylobacter coli strains isolated in 1991 and 2001–2002 from poultry and humans in Berlin, GermanyAntimicrob Agents Chemother200347123825383014638490
- EFSA (European Food Safety Authority) and ECDC (European Centre for Disease Prevention and Control)The European Union Summary Report on antimicrobial resistance in zoonotic and indicator bacteria from humans, animals and food in 2012EFSA Journal20141233590
- Centers for Disease Control and Prevention US Department of Agriculture, US Food and Drug AdministrationNational Antimicrobial Resistance Monitoring System 2011 Executive Report Available from: http://www.fda.gov/downloads/AnimalVeterinary/SafetyHealth/AntimicrobialResistance/NationalAntimicrobialResistanceMonitoringSystem/UCM407962.pdfAccessed December 15, 2014
- HolmbergSDWellsJGCohenMLAnimal-to-man transmission of antimicrobial-resistant Salmonella: investigations of US outbreaks, 1971–1983Science198422546648338356382605
- SpikaJSWatermanSHHooGWSChloramphenicol-resistant Salmonella newport traced through hamburger to dairy farms. A major persisting source of human salmonellosis in CaliforniaN Engl J Med1987316105655703807951
- OlsenSJYingMDavisMFMultidrug-resistant Salmonella Typhimurium infection from milk contaminated after pasteurizationEmerg Infect Dis200410593293515200835
- GebreyesWAAltierCMolecular characterization of multidrug-resistant Salmonella enterica subsp. enterica serovar Typhimurium isolates from swineJ Clin Microbiol20024082813282212149335
- AlcaineSDWarnickLDWiedmannMAntimicrobial resistance in nontyphoidal SalmonellaJ Food Prot200770378079017388077
- FoleySLLynneAMFood animal-associated Salmonella challenges: pathogenicity and antimicrobial resistanceJ Anim Sci200886(14)(Suppl)E173E18717878285
- RabschWTschäpeHBäumlerAJNon-typhoidal salmonellosis: emerging problemsMicrobes Infect20013323724711358718
- HansonNDMolandESHossainANevilleSAGosbellIBThomsonKSUnusual Salmonella enterica serotype Typhimurium isolate producing CMY-7, SHV-9 and OXA-30 β-lactamasesJ Antimicrob Chemother20024961011101412039894
- BaggesenDLSandvangDAarestrupFMCharacterization of Salmonella enterica serovar typhimurium DT104 isolated from Denmark and comparison with isolates from Europe and the United StatesJ Clin Microbiol20003841581158610747147
- DavisMAHancockDDBesserTEMultiresistant clones of Salmonella enterica: the importance of disseminationJ Lab Clin Med2002140313514112271270
- McDermottPAntimicrobial resistance in nontyphoidal SalmonellaeAaerstrupFMAntimicrobial Resistance in Bacteria of Animal OriginWashingtonASM Press2006293314
- AarestrupFMSchwarzSAntimicrobial Resistance in Staphylococci and Streptococci of animal originAarestrupFMAntimicrobial Resistance in Bacteria of Animal OriginWashington DCASM Press 2006187212
- HuttnerAHarbarthSCarletJAntimicrobial resistance: a global view from the 2013 World Healthcare-Associated Infections ForumAntimicrob Resist Infect Control201323124237856
- GousiaPEconomouVSakkasHLeveidiotouSPapadopoulouCAntimicrobial resistance of major foodborne pathogens from major meat productsFoodborne Pathog Dis201181273821039131
- FreyYRodriguezJPThomannASchwendenerSPerretenVGenetic characterization of antimicrobial resistance in coagulase-negative staphylococci from bovine mastitis milkJ Dairy Sci20139642247225723415536
- CunyCFriedrichAKozytskaSEmergence of methicillin-resistant Staphylococcus aureus (MRSA) in different animal speciesInt J Med Microbiol20103002–310911720005777
- OppligerAMoreillonPCharrièreNGiddeyMMorissetDSakwinskaOAntimicrobial resistance of Staphylococcus aureus strains acquired by pig farmers from pigsAppl Environ Microbiol201278228010801422961904
- MurrayBEThe life and times of the EnterococcusClin Microbiol Rev19903146652404568
- HummelAHolzapfelWHFranzCMAPCharacterisation and transfer of antibiotic resistance genes from enterococci isolated from foodSyst Appl Microbiol20073011716563685
- WernerGCoqueTMFranzCMAntibiotic resistant enterococcitales of a drug resistance gene traffickerInt J Med Microbiol20133036–736037923602510
- TacconelliECataldoMAVancomycin-resistant enterococci (VRE): transmission and controlInt J Antimicrob Agents20083129910618164908
- StaleyCDunnyGMSadowskyMJChapter Four – Environmental and animal-associated enterococciSariaslaniSGaddGMAdvances in Applied Microbiology87San DiegoAcademic Press2014147186
- HayesJREnglishLLCarterPJPrevalence and antimicrobial resistance of enterococcus species isolated from retail meatsAppl Environ Microbiol200369127153716014660361
- GousiaPEconomouVBozidisPPapadopoulouCVancomycin resistance phenotypes, vancomycin resistance genes, and resistance to antibiotics of enterococci isolated from food of animal originFoodborne Pathog Dis Epub 162015
- MayhallCGPrevention and control of vancomycin resistance in gram-positive coccal microorganisms: fire prevention and fire fightingInfect Control Hosp Epidemiol19961763533558805064
- HaradaTKawaharaRKankiMTaguchiMKumedaYIsolation and characterization of vanA genotype vancomycin-resistant Enterococcus cecorum from retail poultry in JapanInt J Food Microbiol2012153337237722192623
- OteoJPérez-VázquezMCamposJExtended-spectrum [beta]-lactamase producing Escherichia coli: changing epidemiology and clinical impactCurr Opin Infect Dis201023432032620614578
- SimnerPJZhanelGGPitoutJCanadian Antimicrobial Resistance Alliance (CARA)Prevalence and characterization of extended-spectrum β-lactamase- and AmpC β-lactamase-producing Escherichia coli: results of the CANWARD 2007–2009 studyDiagn Microbiol Infect Dis201169332633421353961
- PathakAMarothiYKekreVMahadikKMacadenRLundborgCSHigh prevalence of extended-spectrum β-lactamase-producing pathogens: results of a surveillance study in two hospitals in Ujjain, IndiaInfect Drug Resist20125657322570555
- ReichFAtanassovaVKleinGExtended-spectrum β-lactamase- and AmpC-producing enterobacteria in healthy broiler chickens, GermanyEmerg Infect Dis20131981253125923876576
- ColpanAJohnstonBPorterSVICTORY (Veterans Influence of Clonal Types on Resistance: Year 2011) InvestigatorsEscherichia coli sequence type 131 (ST131) subclone H30 as an emergent multidrug-resistant pathogen among US veteransClin Infect Dis20135791256126523926176
- OverdevestIWillemsenIRijnsburgerMExtended-spectrum β-lactamase genes of Escherichia coli in chicken meat and humans, The NetherlandsEmerg Infect Dis20111771216122221762575
- KluytmansJAKOverdevestITWillemsenIExtended-spectrum β-lactamase-producing Escherichia coli from retail chicken meat and humans: comparison of strains, plasmids, resistance genes, and virulence factorsClin Infect Dis201356447848723243181
- SoonthornchaikulNGarelickHAntimicrobial resistance of Campylobacter species isolated from edible bivalve molluscs purchased from Bangkok markets, ThailandFoodborne Pathog Dis20096894795119622033
- LevySBFitzGeraldGBMaconeABChanges in intestinal flora of farm personnel after introduction of a tetracycline-supplemented feed on a farmN Engl J Med197629511583588950974
- PetersenAAndersenJSKaewmakTSomsiriTDalsgaardAImpact of integrated fish farming on antimicrobial resistance in a pond environmentAppl Environ Microbiol200268126036604212450826
- ShahSQAColquhounDJNikuliHLSørumHPrevalence of antibiotic resistance genes in the bacterial flora of integrated fish farming environments of Pakistan and TanzaniaEnviron Sci Technol201246168672867922823142
- RiesenfeldCSSchlossPDHandelsmanJMetagenomics: genomic analysis of microbial communitiesAnnu Rev Genet200438152555215568985
- D’CostaVMMcGrannKMHughesDWWrightGDSampling the antibiotic resistomeScience2006311575937437716424339
- RossiFRizzottiLFelisGETorrianiSHorizontal gene transfer among microorganisms in food: current knowledge and future perspectivesFood Microbiol20144223224324929742
- ToomeyNMonaghanAFanningSBoltonDJAssessment of antimicrobial resistance transfer between lactic acid bacteria and potential foodborne pathogens using in vitro methods and mating in a food matrixFoodborne Pathog Dis20096892593319799525
- Doucet-PopulaireFTrieu-CuotPDosbaaIAndremontACourvalinPInducible transfer of conjugative transposon Tn1545 from Enterococcus faecalis to Listeria monocytogenes in the digestive tracts of gnotobiotic miceAntimicrob Agents Chemother19913511851871849709
- WalshCDuffyGNallyPO’MahonyRMcDowellDAFanningSTransfer of ampicillin resistance from Salmonella Typhimurium DT104 to Escherichia coli K12 in foodLett Appl Microbiol200846221021518028324
- RizzottiLLa GioiaFDellaglioFTorrianiSMolecular diversity and transferability of the tetracycline resistance gene tet(M), carried on Tn916-1545 family transposons, in enterococci from a total food chainAntonie van Leeuwenhoek2009961435219333776
- SmetARasschaertGMartelAIn situ ESBL conjugation from avian to human Escherichia coli during cefotaxime administrationJ Appl Microbiol2011110254154921143712
- Leverstein-vanHall MACMDierikxStuart JCohenNational ESBL surveillance group. Dutch patients, retail chicken meat and poultry share the same ESBL genes, plasmids and strainsClin Microbiol Infect201117687388021463397
- DoyleMPEricksonMCEmerging microbiological food safety issues related to meatMeat Sci20067419811222062720
- FluitACTowards more virulent and antibiotic-resistant Salmonella?FEMS Immunol Med Microbiol200543111115607630
- GuerraBJunkerEMikoAHelmuthRMendozaMCCharacterization and localization of drug resistance determinants in multidrug-resistant, integron-carrying Salmonella enterica serotype Typhimurium strainsMicrob Drug Resist2004102839115256022
- GooderhamWJHancockREWRegulation of virulence and antibiotic resistance by two-component regulatory systems in Pseudomonas aeruginosaFEMS Microbiol Rev200933227929419243444
- OliverSPMurindaSEJayaraoBMImpact of antibiotic use in adult dairy cows on antimicrobial resistance of veterinary and human pathogens: a comprehensive reviewFoodborne Pathog Dis20118333735521133795
- CapitaRAlonso-CallejaCAntibiotic-resistant bacteria: a challenge for the food industryCrit Rev Food Sci Nutr2013531114823035919
- AnguloFJNunneryJABairHDAntimicrobial resistance in zoonotic enteric pathogensRev Sci Tech200423248549615702715
- VerraesCVan BoxstaelSVan MeervenneEAntimicrobial resistance in the food chain: a reviewInt J Environ Res Public Health20131072643266923812024
- European Centre for Disease Prevention and Control, European Medicines AgencyThe Bacterial Challenge: Time to React. A Call to Narrow the Gap Between Multidrug-Resistant Bacteria in the EU and the Development of New Antibacterial AgentsEuropean Centre for Disease Prevention and Control 2009 Available from: http://www.ecdc.europa.eu/en/publications/Publications/0909_TER_The_Bacterial_Challenge_Time_to_React.pdfAccessed December 15, 2014
- JassimSALimogesRGNatural solution to antibiotic resistance: bacteriophages ‘The Living Drugs’World J Microbiol Biotechnol20143082153217024781265
- US CongressHR 965 (112th)Preservation of Antibiotics for Medical Treatment Act of2011 Available from: https://www.govtrack.us/congress/bills/112/hr965Accessed December 15, 2014
- AllenHKTrachselJLooftTCaseyTAFinding alternatives to antibioticsAnn N Y Acad Sci2014132319110024953233
- CallawayTREdringtonTSAndersonRCProbiotics, prebiotics and competitive exclusion for prophylaxis against bacterial diseaseAnim Health Res Rev20089221722519102792
- GaggìaFMattarelliPBiavatiBProbiotics and prebiotics in animal feeding for safe food productionInt J Food Microbiol2010141Suppl 1S15S2820382438
- ZoetendalEGChengBKoikeSMackieRIMolecular microbial ecology of the gastrointestinal tract: from phylogeny to functionCurr Issues Intest Microbiol200452314715460065
- SealBSLillehojHSDonovanDMGayCGAlternatives to antibiotics: a symposium on the challenges and solutions for animal productionAnim Health Res Rev2013141788723702321
- BiliourisKBabsonDSchmidt-DannertCKaznessisYNStochastic simulations of a synthetic bacteria-yeast ecosystemBMC Syst Biol2012615822672814
- KennyMSmidtHMengheriEMillerBProbiotics – do they have a role in the pig industry?Animal20115346247022445413
- HuyghebaertGDucatelleRVan ImmerseelFAn update on alternatives to antimicrobial growth promoters for broilersVet J2011187218218820382054
- ChanBKAbedonSTLoc-CarrilloCPhage cocktails and the future of phage therapyFuture Microbiol20138676978323701332
- GoodridgeLDBishaBPhage-based biocontrol strategies to reduce foodborne pathogens in foodsBacteriophage20111313013722164346
- BaloghBJonesJBIriarteFBMomolMTPhage therapy for plant disease controlCurr Pharm Biotechnol2010111485720214607
- KoskellaBMeadenSUnderstanding bacteriophage specificity in natural microbial communitiesViruses20135380682323478639
- PapagianniMAnastasiadouSPediocins: the bacteriocins of Pediococci. Sources, production, properties and applicationsMicrob Cell Fact200981319133115
- SnyderABWoroboRWChemical and genetic characterization of bacteriocins: antimicrobial peptides for food safetyJ Sci Food Agric2014941284423818338
- LouYYousefAEAdaptation to sublethal environmental stresses protects Listeria monocytogenes against lethal preservation factorsAppl Environ Microbiol1997634125212559097420
- GálvezAAbriouelHLópezRLBen OmarNBacteriocin-based strategies for food biopreservationInt J Food Microbiol20071201–2517017614151
- SternNJEruslanovBVPokhilenkoVDBacteriocins reduce Campylobacter jejuni colonization while bacteria producing bacteriocins are ineffectiveMicrob Ecol Health Dis20082027479
- SternNJSvetochEAEruslanovBVPaenibacillus polymyxa purified bacteriocin to control Campylobacter jejuni in chickensJ Food Prot20056871450145316013385
- HammamiRFernandezBLacroixCFlissIAnti-infective properties of bacteriocins: an updateCell Mol Life Sci201370162947296723109101
- KadouriDEToKShanksRMDoiYPredatory bacteria: a potential ally against multidrug-resistant Gram-negative pathogensPLoS ONE201385e6339723650563
- LambertCSockettRENucleases in Bdellovibrio bacteriovorus contribute towards efficient self-biofilm formation and eradication of preformed prey biofilmsFEMS Microbiol Lett2013340210911623297829
- AtterburyRJHobleyLTillREffects of orally administered Bdellovibrio bacteriovorus on the well-being and Salmonella colonization of young chicksAppl Environ Microbiol201177165794580321705523
- DwidarMMonnappaAKMitchellRJThe dual probiotic and antibiotic nature of Bdellovibrio bacteriovorusBMB Rep2012452717822360883
- SchoeffieldAJWilliamsHNTurngBFacklerWAJrA comparison of the survival of intraperiplasmic and attack phase Bdellovibrios with reduced oxygenMicrob Ecol199632135468661540
- HobleyLKingJRSockettREBdellovibrio predation in the presence of decoys: three-way bacterial interactions revealed by mathematical and experimental analysesAppl Environ Microbiol200672106757676517021228
- World Health OrganizationWHO Global Strategy for Containment of Antimicrobial ResistanceWorld Health Organization2001 Available at: http://www.who.int/drugresistance/WHO_Global_Strategy_English.pdfAccessed December 15, 2014
- The President’s Council of Advisors on Science and TechnologyReport to the President on combating Antibiotic Resistance Available at: http://www.whitehouse.gov/sites/default/files/microsites/ostp/PCAST/pcast_carb_report_sept2014.pdfAccessed December 15, 2014
- JarlierVCarletJMcGowanJParticipants of the 3rd World Healthcare-Associated Infections ForumPriority actions to fight antibiotic resistance: results of an international meetingAntimicrob Resist Infect Control2012111722958318