Association between the consumption of antimicrobial agents in animal husbandry and the occurrence of resistant bacteria among food animals

Antimicrobial agents are used in food animals for therapy and prophylaxis of bacterial infections and in feed to promote growth. The use of antimicrobial agents for food animals may cause problems in the therapy of infections by selecting for resistance among bacteria pathogenic for animals or humans. The emergence of resistant bacteria and resistance genes following the use of antimicrobial agents is relatively well documented and it seems evident that all antimicrobial agents will select for resistance. However, current knowledge regarding the occurrence of antimicrobial resistance in food animals, the quantitative impact of the use of different antimicrobial agents on selection for resistance and the most appropriate treatment regimens to limit the development of resistance is incomplete. Surveillance programmes monitoring the occurrence and development of resistance and consumption of antimicrobial agents are urgently needed, as is research into the most appropriate ways to use antimicrobial agents in veterinary medicine to limit the emergence and spread of antimicrobial resistance.     

Epidemiology of resistance to antibiotics. Links between animals and humans

An inevitable side effect of the use of antibiotics is the emergence and dissemination of resistant bacteria. Most retrospective and prospective studies show that after the introduction of an antibiotic not only the level of resistance of pathogenic bacteria, but also of commensal bacteria increases. Commensal bacteria constitute a reservior of resistance genes for (potentially) pathogenic bacteria. Their level of resistance is considered to be a good indicator for selection pressure by antibiotic use and for resistance problems to be expected in pathogens. Resistant commensal bacteria of food animals might contaminate, like zoonotic bacteria, meat (products) and so reach the intestinal tract of humans. Monitoring the prevalence of resistance in indicator bacteria such as faecal Escherichia coli and enterococci in different populations, animals, patients and healthy humans, makes it feasible to compare the prevalence of resistance and to detect transfer of resistant bacteria or resistance genes from animals to humans and vice versa. Only in countries that use or used avoparcin (a glycopeptide antibiotic, like vancomycin) as antimicrobial growth promoter (AMGP), is vancomycin resistance common in intestinal enterococci, not only in exposed animals, but also in the human population outside hospitals. Resistance genes against antibiotics, that are or have only been used in animals, i.e. nourseothricin, apramycin etc. were found soon after their introduction, not only in animal bacteria but also in the commensal flora of humans, in zoonotic pathogens like salmonellae, but also in strictly human pathogens, like shigellae. This makes it clear that not only clonal spread of resistant strains occurs, but also transfer of resistance genes between human and animal bacteria. Moreover, since the EU ban of avoparcin, a significant decrease has been observed in several European countries in the prevalence of vancomycin resistant enterococci in meat (products), in faecal samples of food animals and healthy humans, which underlines the role of antimicrobial usage in food animals in the selection of bacterial resistance and the transport of these resistances via the food chain to humans. To safeguard public health, the selection and dissemination of resistant bacteria from animals should be controlled. This can only be achieved by reducing the amounts of antibiotics used in animals. Discontinuing the practice of routinely adding AMGP to animal feeds would reduce the amounts of antibiotics used for animals in the EU by a minimum of 30% and in some member states even by 50%.     

Antibiotic usage in animals: impact on bacterial resistance and public health.

Antibiotic use whether for therapy or prevention of bacterial diseases, or as performance enhancers will result in antibiotic resistant micro-organisms, not only among pathogens but also among bacteria of the endogenous microflora of animals. The extent to which antibiotic use in animals will contribute to the antibiotic resistance in humans is still under much debate. In addition to the veterinary use of antibiotics, the use of these agents as antimicrobial growth promoters (AGP) greatly influences the prevalence of resistance in animal bacteria and a poses risk factor for the emergence of antibiotic resistance in human pathogens. Antibiotic resistant bacteria such as Escherichia coli, Salmonella spp., Campylobacter spp. and enterococci from animals can colonise or infect the human population via contact (occupational exposure) or via the food chain. Moreover, resistance genes can be transferred from bacteria of animals to human pathogens in the intestinal flora of humans. In humans, the control of resistance is based on hygienic measures: prevention of cross contamination and a decrease in the usage of antibiotics. In food animals housed closely together, hygienic measures, such as prevention of oral-faecal contact, are not feasible. Therefore, diminishing the need for antibiotics is the only possible way of controlling resistance in large groups of animals. This can be achieved by improvement of animal husbandry systems, feed composition and eradication of or vaccination against infectious diseases. Moreover, abolishing the use of antibiotics as feed additives for growth promotion in animals bred as a food source for humans would decrease the use of antibiotics in animals on a worldwide scale by nearly 50%. This would not only diminish the public health risk of dissemination of resistant bacteria or resistant genes from animals to humans, but would also be of major importance in maintaining the efficacy of antibiotics in veterinary medicine.     

Clinical pharmacology of antimicrobial use in humans and animals

Veterinary public health is a frontier in the fight against human disease, charged to control and eradicate zoonotic diseases that are naturally transmitted between vertebrate animals and man. Currently there is a need for clinical pharmacologists and all health care givers to limit the development of bacterial resistance in humans to contain the increased health care expenditures related to morbidity and mortality associated with the use of antimicrobials. The development of resistance predates the use of antibiotics and will always be a problem to the successful treatment of patients. Ongoing discussion debates the extent to which antibiotic use in animals contributes to the development of antibiotic resistance in humans. The veterinary use ofantibiotics as antimicrobial growth promoters is thought to influence the prevalence of resistance in animal bacteria and to be a risk factor for the emergence of antibiotic resistance in human pathogens. Transfer of antibiotic resistant bacteria from animals to humans may occur via contact, including occupational exposure and via the food chain. Resistance genes may transferfrom bacteria of animals to human pathogens in the intestinal flora of humans. Prevention of the development of resistance in humans necessitates good animal husbandry and hygienic measures to prevent cross contamination and a decrease in the use of antibiotics. Appropriate use of antibiotics for food animals will preserve the long-term efficacy of existing antibiotics, support animal health and welfare, and limit the risk of transfer of antibiotic resistance to humans. Investigators must also develop new antimicrobial agents. Poole (J Pharmacy Pharmacol 2001;53:283) recommends targeting the three predominate mechanisms of development of resistance by antimicrobials (i.e., antibiotic inactivation, target site modification, and altered uptake via restricted entry and/or enhanced efflux) to specifically complement the development of novel agents with novel bacterial targets. Bacterial resistance and its selection may be evaluated by comparing the relationship to antibiotic pharmacokinetic (PK) values obtained from serum concentrations and organism MICs (minimum inhibitory concentrations; concentration-dependent killing) to reveal culture and sensitivity tests in patients. Pharmacodynamic (PD) models may be developed to identify factors associated with the probability that bacterial resistance will develop. Thomas et al (Antimicrobial Agents Chemotherapy 1998;42:521) used this combined approach of PK/PD and MICs to examine data retrospectively. The role of clinical pharmacology is to work with PK/PD models such as these to determine the best use of antibiotics in humans to minimize the development of resistance. The role of any regulatory body responsible for the protection of the public health and food safety for consumers is to assess risk and to then communicate and manage the risk. Scientific uncertainty must be interpreted to propose sound policy options. The conversion of sound science into an appropriate regulatory policy to protect the public health is most important.     

Quinolone resistance in the food chain

Antimicrobials are used in pet animals and in animal husbandry for prophylactic and therapeutic reasons and also as growth promoters, causing selective pressure on bacteria of animal origin. The impact of quinolones or quinolone-resistant bacteria on the management of human infections may be associated with three different scenarios. (i) Quinolone-resistant zoonotic bacterial pathogens are selected and food is contaminated during slaughter and/or preparation. (ii) Quinolone-resistant bacteria non-pathogenic to humans are selected in the animal. When the contaminated food is ingested, the bacteria may transfer resistance determinants to other bacteria in the human gut (commensal and potential pathogens). And (iii) quinolones remain in residues of food products, which may allow the selection of antibiotic-resistant bacteria after the food is consumed. In this review, we analyse the abovementioned aspects, emphasising the molecular basis of quinolone resistance in Escherichia coli, Salmonella spp. and Campylobacter spp.     

Transfert de la résistance à la vancomycine entre entérocoques d’origine animale et humaine

Enterococci are a dominant bacterial group in the intestinal flora of humans and animals. They have emerged as important nosocomial pathogens over the last two decades, at least in part because of their intrinsic and acquired resistance to many antimicrobial agents, including vancomycin. Two main reservoirs of vancomycin resistant enterococci were described: the hospital and the animal reservoirs. It should be noted that glycopeptide avoparcin has been used as a growth promoter in animal husbandry in Europe since 1970 and an association between the incidence of vancomycin resistance in humans and avoparcin usage in animals has been suggested. In recent years, transfer of resistance genes from animal bacteria to human bacteria causes great concern. By using the vancomycin resistant enterococci, we studied genetic transfers between bacteria in vitro and in vivo in the digestive tract of germ-free mice.The horizontal transfer of vanA gene from Enterococcus faecium strains of animal origin towards E. faecium of human origin within the digestive tract is possible and occurs at high frequencies. This transfer is also possible towards Enterococcus faecalis, the predominant enterococcal species of human digestive tract, at lower frequencies. Early transfer of the vanA operon suggests that even a brief transit of enterococci of animal origin would allow resident human bacteria to acquire glycopeptide resistance, as well as other resistance genes. This transfer occurs at a lower rate in the presence of complex flora.     

Discussion

Many studies and meeting reports have suggested that the use of some antibiotics in food animals can compromise the treatment of some infectious diseases in humans. Although the studies and reports are timely and important, it is difficult to assess the relative value of the conclusions in relationship to the overall situation concerning antibiotic resistant foodborne bacteria because the data used in the analyses are often of disparate origin. The studies have attempted to establish a cause and effect relationship between the use ('consumption') of antibiotics in food animals and treatment failures in human disease on the basis of [1] antibiotic usage data; [2] in vitro determinations of antibiotic susceptibility of animal and human isolates, [3] results obtained from controlled animal experiments or [4] epidemiological data. Each approach has sought to associate bacterial antibiotic resistance data with it's own immediate focus area of investigation. However, a true assessment of the degree of contribution to human antibiotic resistance problems from animal use can only be facilitated by comprehensively organizing these different approaches into a concerted, coordinated effort. Concurrently, the implementation of a multinational programme aimed at monitoring antibiotic usage in food animals and resistance in specific bacteria associated with those animals should be instituted. In parallel with this endeavour is the implementation of new prudent use guidelines for antibiotic use by veterinarians. Through the use of science-based approaches like these, the development and spread of antibiotic resistant bacteria associated with food animals could be minimized and contained.     

Assessment of factors contributing to changes in the incidence of antimicrobial drug resistance in Salmonella enterica serotypes Enteritidis and Typhimurium from humans in England and Wales in 2000, 2002 and 2004

An investigation into changes in the occurrence of antimicrobial resistance in Salmonella enterica serotypes Enteritidis and Typhimurium from human infection in England and Wales in 2000, 2002 and 2004 has shown that the incidence of strains of S. Enteritidis with resistance to nalidixic acid coupled with decreased susceptibility to ciprofloxacin has more than doubled between 2000 and 2004, whereas the overall levels of resistance in S. Typhimurium have fallen by ca. 25%. In relation to published data on veterinary sales of antimicrobials in the UK, the findings demonstrate that changes in the incidence of resistance do not correlate with changes in veterinary usage. For S. Enteritidis, important factors in the increased incidence of resistance were foreign travel and the consumption of imported foods contaminated with drug-resistant strains. For S. Typhimurium, the most important factor has been an overall decline in the occurrence of multiple drug-resistant S. Typhimurium definitive phage type 104. These studies have demonstrated that changes in the incidence of resistance in predominant salmonellas in humans in England and Wales from 2000 to 2004 are multifactorial. The findings also demonstrate that, in order to combat drug resistance in zoonotic salmonellas causing infections in humans, controls on the use of antibiotics in food animals analogous to those in operation in the UK should be implemented in countries that regularly import food into the UK.     

Antimicrobial resistance in foodborne pathogens--a cause for concern?

The widespread use of antibiotics in food animal production systems has resulted in the emergence of antibiotic resistant zoonotic bacteria that can be transmitted to humans through the food chain. Infection with antibiotic resistant bacteria negatively impacts on public health, due to an increased incidence of treatment failure and severity of disease. Development of resistant bacteria in food animals can result from chromosomal mutations but is more commonly associated with the horizontal transfer of resistance determinants borne on mobile genetic elements. Food may represent a dynamic environment for the continuing transfer of antibiotic resistance determinants between bacteria. Current food preservation systems that use a combination of environmental stresses to reduce growth of bacteria, may serve to escalate development and dissemination of antibiotic resistance among food related pathogens. The increasing reliance on biocides for pathogen control in food production and processing, heightens the risk of selection of biocide-resistant strains. Of particular concern is the potential for sublethal exposure to biocides to select for bacteria with enhanced multi-drug efflux pump activity capable of providing both resistance to biocides and cross-resistance to multiple antibiotics. Although present evidence suggests that biocide resistance is associated with a physiological cost, the possibility of the development of adaptive mutations conferring increased fitness cannot be ruled-out. Strategies aimed at inhibiting efflux pumps and eliminating plasmids could help to restore therapeutic efficacy to antibiotics and reduce the spread of antibiotic resistant foodborne pathogens through the food chain.     

Role of veterinary medicine in public health: antibiotic use in food animals and humans and the effect on evolution of antibacterial resistance

Veterinary public health is another frontier in the fight against human disease. The veterinary public health scope includes the control and eradication of zoonoses, diseases that are naturally transmitted between vertebrate animals and man. These diseases pose a continuous hazard to the health and welfare of the public. More than 100 diseases are categorized as zoonoses, including salmonellosis. It is important to understand how antibiotics are used in humans and in food animals and how these uses affect the evolution of antibacterial resistance. Appropriate use of antibiotics for food animals will preserve the long-term efficacy of existing antibiotics, support animal health and welfare, and limit the risk of transfer of antibiotic resistance to humans. An understanding of the epidemiology of antimicrobial resistance allows development of preventive strategies to limit existing resistance and to avoid emergence of new strains of resistant bacteria. Risk assessments are being used by the Center for Veterinary Medicine at the U.S. Food and Drug Administration as regulatory tools to assess potential risk to humans resulting from antibiotic use in food-producing animals and to then develop microbial safety policies to protect the public health. The veterinary public health scope, in addition to the control and eradication of zoonoses, also includes the development and supervision of food hygiene practices, laboratory and research activities, and education of the public. Thus, it may be seen that there are many ways in which veterinary medicine plays a very important role in public health.     

Antibiotic resistance of commensal Escherichia coli of food-producing animals from three Vojvodinian farms, Serbia

Commensal bacteria of food-producing animals are considered an important reservoir of antibiotic resistance. The aim of this study was to determine the current prevalence of resistance to 18 different antibiotics in animal commensal Escherichia coli isolated from food-producing animals from three different farms with specific modes of antimicrobial use. A very high prevalence of resistance was found to tetracycline, a moderate level to streptomycin, ampicillin, cefalothin and nalidixic acid and a low of resistance to the other tested antibiotics. Resistance to two or more antibiotics was observed among all swine E. coli, 63.2% of broiler isolates and 37.5% of cattle isolates. The results show that commensals of food-producing animals from Vojvodina region are important reservoirs of resistance to older-generation antibiotics.     

Veterinary drug usage and antimicrobial resistance in bacteria of animal origin

In the production of food animals, large amounts of antimicrobial agents are used for therapy and prophylaxis of bacterial infections and in feed to promote growth. There are large variations in the amounts of antimicrobial agents used to produce the same amount of meat among the different European countries, which leaves room for considerable reductions in some countries. The emergence of resistant bacteria and resistance genes due to the use of antimicrobial agents are well documented. In Denmark it has been possible to reduce the usage of antimicrobial agents for food animals significantly and in general decreases in resistance have followed. Guidelines for prudent use of antimicrobial agents may help to slow down the selection for resistance and should be based on knowledge regarding the normal susceptibility patterns of the causative agents and take into account the potential problems for human health. Current knowledge regarding the occurrence of antimicrobial resistance in food animals, the quantitative impact of the use of different antimicrobial agents on selection of resistance and the most appropriate treatment regimes to limit the development of resistance is incomplete. Programmes monitoring the occurrence and development of resistance and consumption of antimicrobial agents are strongly desirable, as is research into the most appropriate ways to use antimicrobial agents in veterinary medicine.     

应用噬菌体控制假单胞菌的研究进展

假单胞菌属细菌中的部分菌株是动植物和人类的致病菌，也是食品的腐败菌，会导致动植物和人类的高死亡率和严重的食品安全事故。噬菌体作为一种细菌性病毒，特异性高、自我增殖快且无副作用。这些特性使其成为了解决细菌性问题的新思路和新方法。本文就利用噬菌体防控假单胞菌属致病菌和腐败菌在食品、水产、植物、医疗等方面的研究和应用进行综述，以便为后期的深入研究提供一定的参考。     

Selective pressure by antibiotic use in livestock

Selective pressure exerted by the use of antibiotics as growth promoters in food animals appears to have created large reservoirs of transferable antibiotic resistance in these ecosystems. This first became evident for oxytetracycline and later for the streptothricin antibiotic nurseothricin, for which a transfer of relevant resistance determinants (sat genes) to bacterial pathogens of humans was demonstrated. With the emergence of glycopeptide resistance in Enterococcus faecium outside hospitals, a large reservoir of transferable resistance (vanA gene cluster) was identified in animal husbandry due to the use of avoparcin as feed additive. The spread of resistance, which reaches the human enterococcal flora via meat products, is probably due to the dissemination of the vanA gene cluster integrated into different conjugative plasmids among a variety of different strains. Streptogramin resistance associated with the resistance genes vatA and vatG has been found in E. faecium of animal and of clinical origin. Because virginiamycin has been used as growth promoter in animals but streptogramins have been used infrequently in human medicine, this again suggests an animal origin of resistance. Since the use of avoparcin ended, a decline in the rates of glycopeptide-resistant E. faecium (GREF) from animals and humans in the community has been recorded. This supports the ban of antibacterial growth promoters that might interfere with human chemotherapy that has been introduced in European Union countries.     

世界卫生组织、欧盟和中国抗生素耐药性监测现状

随着抗生素在人类和动物中的使用,抗生素耐药性已经成为一个危害健康的全球性问题。人类、动物和食品之间的活动,加强了耐药细菌及耐药基因的传播。本文综述了世界卫生组织、欧盟国家和我国近年来对来源于人医和兽医上的耐药细菌的监测现状。     

Agricultural Applications for Antimicrobials. A Danger to Human Health: An Official Position Statement of the Society of Infectious Diseases Pharmacists

The use of antibiotics in agriculture, particularly in food‐producing animals, is pervasive and represents the overwhelming majority of antibiotic use worldwide. The link between antibiotic use in animals and antibiotic resistance in humans is unequivocal. Transmission can occur by ingesting undercooked meats harboring resistant bacteria, by direct contact of animals by animal handlers, and by various other means. Antibiotics used in aquaculture and antifungals used in horticulture are also an evolving threat to human health. Regulations aimed at decreasing the amount of antibiotics used in food production to limit the development of antibiotic resistance have recently been implemented. However, further action is needed to minimize antibiotic use in agriculture. This article describes the extent of this current problem and serves as the official position of the Society of Infectious Diseases Pharmacists on this urgent threat to human health.     

Impact of antimicrobial resistance on regulatory policies in veterinary medicine: Status report

Increasing resistance to antimicrobial agents is of growing concern to public health officials worldwide. The concern includes infections acquired in hospitals, community infections acquired in outpatient care settings, and resistant foodborne disease associated with drug use in food-producing animals. In the United States, a significant source of antimicrobial-resistant foodborne infections in humans is the acquisition of resistant bacteria originating from animals. The US Food and Drug Administration's (FDA's) goal in resolving the public health impact arising from the use of antimicrobial drugs in food-producing animals is to ensure that significant human antimicrobial therapies are not compromised or lost while providing for the safe use of antimicrobials in food animals. The FDA's approach to the problem is multipronged and innovative. The strategy includes revision of the pre-approval safety assessment for new animal drug applications, use of risk assessment to determine the human health effect resulting from the use of antimicrobials in food animals, robust monitoring for changes in susceptibilities among foodborne pathogens to drugs that are important both in human and veterinary medicine, research, and risk management.     

A risk analysis framework for the long-term management of antibiotic resistance in food-producing animals

In recent years, there has been increasing concern that the use of antibiotics in food-producing animals, particularly their long-term use for growth promotion, contributes to the emergence of antibiotic-resistant bacteria in animals. These resistant bacteria may spread from animals to humans via the food chain. They may also transfer their antibiotic-resistance genes into human pathogenic bacteria, leading to failure of antibiotic treatment for some, possibly life-threatening, human conditions. To assist regulatory decision making, the actual risk to human health from antibiotic use in animals needs to be determined (risk assessment) and the requirements for risk minimisation (risk management and risk communication) determined. We propose a novel method of risk analysis involving risk assessment for three interrelated hazards: the antibiotic (chemical agent), the antibiotic-resistant bacterium (microbiological agent) and the antibiotic-resistance gene (genetic agent). Risk minimisation may then include control of antibiotic use and/or the reduction of the spread of bacterial infection and/or prevention of transfer of resistance determinants between bacterial populations.     

欧盟和北美抗生素耐药性监测调查现状比较

抗生素耐药性问题引起国际间的高度关注，许多发达国家已经陆续建立起耐药监测系统，如美国的NARMS，加拿大的CIPARS，欧盟的EARS-Net、丹麦的DANMAP等。本文主要介绍这些耐药性监测系统及其最新的研究成果，重点对比分析了目前欧盟和北美地区的耐药情况和采取的预防控制措施。同时亦将中国的CARSS系统列举在内作为比较。借鉴上述抗生素耐药性监测系统的先进经验和我国目前所面临的挑战，提出促进我国抗生素耐药性监测和研究的建议，主要包括提高完善耐药监测系统、采纳国际社会良好实践、规范抗生素管理和加快新抗菌药的研发等。     

Patterns of ethanol and water consumption as a function of restricted ethanol access and feeding condition

Sixteen male albino rats were divided into two groups of eight animals and maintained at either their free-feeding or at 80% of their free-feeding weight. For four animals, access to 8% ethanol was unrestricted, for the remaining four, access was restricted to eight 20-min access periods per day. Mean amounts of ethanol consumed per bout were greater during restricted access than during unrestricted access for food-deprived animals but not for free-feeding animals. Total daily ethanol consumption was greatest when animals were food deprived and access to ethanol unrestricted. Total fluid consumption and the within session distribution of water and ethanol responding were affected by feeding condition. For food-deprived animals, the amount of water consumed per session remained relatively constant. The increase in ethanol consumption over sessions resulted in an increase in total fluid consumption. For the free-feeding animals, increases in ethanol consumption resulted in decreases in water consumption so that total fluid consumption remained constant. In addition, food-deprived animals consumed all their daily water intake at the beginning of each session when food was present. Free-feeding animals consumed water throughout the session.