ACVIM Consensus Statement on Therapeutic Antimicrobial Use in Animals and Antimicrobial Resistance

The epidemic of antimicrobial resistant infections continues to challenge, compromising animal care, complicating food animal production and posing zoonotic disease risks. While the overall role of therapeutic antimicrobial use in animals in the development AMR in animal and human pathogens is poorly defined, veterinarians must consider the impacts of antimicrobial use in animal and take steps to optimize antimicrobial use, so as to maximize the health benefits to animals while minimizing the likelihood of antimicrobial resistance and other adverse effects. This consensus statement aims to provide guidance on the therapeutic use of antimicrobials in animals, balancing the need for effective therapy with minimizing development of antimicrobial resistance in bacteria from animals and humans.     

Public health and policy

Antimicrobial agent usage data are essential for focusing efforts to reduce misuse and overuse of antimicrobial agents in food producing animals because these practices may select for resistance in bacteria of animals. Transfer of resistant bacteria from animals to humans can lead to human infection caused by resistant pathogens. Resistant infections can lead to treatment failures, resulting in prolonged or more severe illness. Multiple World Health Organization (WHO) reports have concluded that both antimicrobial resistance and antimicrobial usage should be monitored on the national level. The system for collecting antimicrobial usage data should be clear and transparent to facilitate trend analysis and comparison within and among countries. Therapeutic, prophylactic and growth promotion use should be recorded, along with route of administration and animal species and/or production class treated. The usage data should be compared to resistance data, and the comparison should be made available in a timely manner. In the United States, surveillance of antimicrobial resistance in foodborne bacteria is performed by the National Antimicrobial Resistance Monitoring System (NARMS) for enteric bacteria, however, the United States still lacks a mechanism for collecting antimicrobial usage data. Combined with antimicrobial resistance information from NARMS, antimicrobial usage data will help to direct education efforts and policy decisions, minimizing the risk that people will develop antimicrobial resistant infections as a result of eating food of animal origin. Ultimately mitigation strategies guided by usage data will be more effective in maintaining antimicrobial drugs for appropriate veterinary use and in protecting human health.     

Extended-spectrum beta-lactamases-producing gram-negative bacteria in companion animals: action is clearly warranted!

Extended-spectrum beta-lactamases (ESBL)-producing Gram-negative bacteria pose a serious threat to Public Health in human medicine as well as increasingly in the veterinary context worldwide. Several studies reported the transmission of zoonotic multidrug resistant bacteria between food-producing animals and humans, whilst the contribution of companion animals to this scenario is rather unknown. Within the last decades a change in the social role of companion animals has taken place, resulting in a very close contact between owners and their pets. As a consequence, humans may obtain antimicrobial resistant bacteria or the corresponding resistance genes not only from food-producing animals but also via close contact to their pets.This may give rise to bacterial infections with limited therapeutic options and an increased risk of treatment failure. As beta-lactams constitute one of the most important groups of antimicrobial agents in veterinary medicine, retaliatory actions in small animal and equine practices are urgently needed. This review addresses the increasing burden of extended-spectrum beta-lactam resistance among Enterobacteriaceae isolated from companion animals. It should emphasize the urgent need for the implementation of antibiotic stewardship as well as surveillance and monitoring programs of multi resistant bacteria in particular in view of new putative infection cycles between humans and their pets.     

Monitoring of antimicrobial resistance among food animals: principles and limitations

Large amounts of antimicrobial agents are in the production of food animals used for therapy and prophylactics of bacterial infections and in feed to promote growth. The use of antimicrobial agents causes problems in the therapy of infections through the selection for resistance among bacteria pathogenic for animals or humans. 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 regimes to limit the development of resistance is incomplete. Programmes monitoring the occurrence and development of resistance are essential to determine the most important areas for intervention and to monitor the effects of interventions. When designing a monitoring programme it is important to decide on the purpose of the programme. Thus, there are major differences between programmes designed to detect changes in a national population, individual herds or groups of animals. In addition, programmes have to be designed differently according to whether the aim is to determine changes in resistance for all antimicrobial agents or only the antimicrobial agents considered most important in relation to treatment of humans. In 1995 a continuous surveillance for antimicrobial resistance among bacteria isolated from food animals was established in Denmark. Three categories of bacteria, indicator bacteria, zoonotic bacteria and animal pathogens are continuously isolated from broilers, cattle and pigs and tested for susceptibility to antimicrobial agents used for therapy and growth promotion by disc diffusion or minimal inhibitory concentration determinations. This programme will only detect changes on a national level. However, isolating the bacteria and testing for several antimicrobial agents will enable us to determine the effect of linkage of resistance. Since 1995 major differences in the consumption pattern of different antimicrobial agents have occurred in Denmark. The Danish monitoring programme has enabled us to determine the effect of these changes on the occurrence of resistance. The Danish monitoring is, however, not suited to determine changes on a herd level or to detect emergence of new types of resistance only occurring at a low level.     

Nosocomial infections and antimicrobial resistance in critical care medicine

Objective: To review the human and companion animal veterinary literature on nosocomial infections and antimicrobial drug resistance as they pertain to the critically ill patient. Data sources: Data from human and veterinary sources were reviewed using PubMed and CAB. Human data synthesis: There is a large amount of published data on nosocomially‐acquired bloodstream infections, pneumonia, urinary tract infections and surgical site infections, and strategies to minimize the frequency of these infections, in human medicine. Nosocomial infections caused by multi‐drug‐resistant (MDR) pathogens are a leading cause of increased patient morbidity and mortality, medical treatment costs, and prolonged hospital stay. Epidemiology and risk factor analyses have shown that the major risk factor for the development of antimicrobial resistance in critically ill human patients is heavy antibiotic usage. Veterinary data synthesis: There is a paucity of information on the development of antimicrobial drug resistance and nosocomially‐acquired infections in critically ill small animal veterinary patients. Mechanisms of antimicrobial drug resistance are universal, although the selection effects created by antibiotic usage may be less significant in veterinary patients. Future studies on the development of antimicrobial drug resistance in critically ill animals may benefit from research that has been conducted in humans. Conclusions: Antimicrobial use in critically ill patients selects for antimicrobial drug resistance and MDR nosocomial pathogens. The choice of antimicrobials should be prudent and based on regular surveillance studies and accurate microbiological diagnostics. Antimicrobial drug resistance is becoming an increasing problem in veterinary medicine, particularly in the critical care setting, and institution‐specific strategies should be developed to prevent the emergence of MDR infections. The collation of data from tertiary‐care veterinary hospitals may identify trends in antimicrobial drug resistance patterns in nosocomial pathogens and aid in formulating guidelines for antimicrobial use.     

The management of risk arising from the use of antimicrobial agents in veterinary medicine in EU/EEA countries – a review

Antimicrobials are essential medicines for the treatment of many microbial infections in humans and animals. Only a small number of antimicrobial agents with new mechanisms of action have been authorized in recent years for use in either humans or animals. Antimicrobial resistance (AMR) arising from the use of antimicrobial agents in veterinary medicine is a concern for public health due to the detection of increasing levels of resistance in foodborne zoonotic bacteria, particularly gram‐negative bacteria, and due to the detection of determinants of resistance such as Extended‐spectrum beta‐lactamases (ESBL) in bacteria from animals and in foodstuffs of animal origin. The importance and the extent of the emergence and spread of AMR from animals to humans has yet to be quantified. Likewise, the relative contribution that the use of antimicrobial agents in animals makes to the overall risk to human from AMR is currently a subject of debate that can only be resolved through further research. Nevertheless, risk managers have agreed that the impact on public health of the use of antimicrobials in animals should be minimized as far as possible and a variety of measures have been introduced by different authorities in the EU to achieve this objective. This article reviews a range of measures that have been implemented within European countries to reduce the occurrence and the risk of transmission of AMR to humans following the use of antimicrobial agents in animals and briefly describes some of the alternatives to the use of antimicrobial agents that are being developed.     

Antimicrobial use in food and companion animals

The vast literature on antimicrobial drug use in animals has expanded considerably recently as the antimicrobial resistance (AMR) crisis in human medicine leads to questions about all usage of antimicrobial drugs, including long-term usage in intensively managed food animals for growth promotion and disease prevention. Attention is also increasingly focusing on antimicrobial use and on bacterial resistance in companion animals, which are in intimate contact with the human population. They may share resistant bacteria with their owners, amplify resistant bacteria acquired from their owners, and act as a reservoir for human infection. Considerable effort is being made to describe the basis of AMR in bacterial pathogens of animals. Documentation of many aspects of use of antimicrobials in animals is, however, generally less developed and only a few countries can describe quantities of drugs used in animals to kg levels annually. In recent years, many national veterinary associations have produced 'prudent use guidelines' to try to improve antimicrobial drug use and decrease resistance, but the impact of guidelines is unknown. Within the evolving global movement for 'antimicrobial stewardship', there is considerable scope to improve many aspects of antimicrobial use in animals, including infection control and reduction of use, with a view to reducing resistance and its spread, and to preserving antimicrobial drugs for the future.     

Multidrug-resistant extraintestinal pathogenic Escherichia coli of sequence type ST131 in animals and foods

Multidrug-resistant Escherichia coli sequence type 131 (ST131) has recently emerged as a globally distributed cause of extraintestinal infections in humans. Diverse factors have been investigated as explanations for ST131's rapid and successful dissemination, including transmission through animal contact and consumption of food, as suggested by the detection of ST131 in a number of nonhuman species. For example, ST131 has recently been identified as a cause of clinical infection in companion animals and poultry, and both host groups have been confirmed as faecal carriers of ST131. Moreover, a high degree of similarity has been shown among certain ST131 isolates from humans, companion animals, and poultry based on resistance characteristics and genomic background and human and companion animal ST131 isolates tend to exhibit similar virulence genotypes. However, most ST131 isolates from poultry appear to possess specific virulence genes that are typically absent from human and companion animal isolates, including genes associated with avian pathogenic E. coli. Since the number of reported animal and food-associated ST131 isolates is quite small, the role of nonhuman host species in the emergence, dissemination, and transmission of ST131 to humans remains unclear. Nevertheless, given the profound public health importance of the emergent ST131 clonal group, even the limited available evidence indicates a pressing need for further careful study of this significant question.     

Antimicrobial resistance.

Development of antimicrobial resistance is an inevitable consequence of exposure of microorganisms to antimicrobial agents. Although emergence of resistance cannot be prevented, it can be retarded by minimizing use of antimicrobial agents and avoiding selection of relatively resistant pathogenic and nonpathogenic strains caused by exposure to tissue concentrations that confer a competitive advantage. Most attention in veterinary medicine has focused on the emergence of resistance in food-borne pathogens, with relatively little attention being devoted to small companion animals, despite the frequent use of antimicrobial agents in these animals, evidence that resistance is emerging, and potential for transfer of resistance between companion animals and people. To retard further emergence of resistance in small companion animals, it is imperative that surveillance programs be instituted to monitor development of resistance.     

Stakeholder position paper: economist's perspectives on antibiotic use in animals

Economics seeks to understand and explain the allocation of resources within society and to suggest appropriate policy to achieve goals such as optimal efficiency. Relating antimicrobial use and antibiotic resistance is a complex task and requires very clear and careful analyses of many relationships. To address these relationships, antibiotic use data must be linked with other basic data. Ideally, a complex relational database needs to be developed. These must include data on: antimicrobial usage, farm-level animal productivity, basic disease, basic farm management, consumer response, and antimicrobial resistance at multiple levels (farm, during process, on a variety of both animal, vegetable and grain-derived food products, from humans, from other animal species, and from the environment) among other data. Such a complex relational database can help with the attribution and risk assessment process. Also these linked data are needed in order to develop the economic production models and other economic models, as well as control for confounding so that there is both adequate and appropriate statistical control. Antimicrobial usage data may become economically important for reasons unrelated to animal productivity and animal health. With expanding global trade of animals and animal products, there have been changes in restrictions and regulations associated with the movement of products. Future trade opportunities may be linked to antimicrobial usage. The European Union banned the use of antimicrobials for growth-promoting purposes based on perceived risk and on public opinion. Monitoring antimicrobial use, disease occurrence, and resistance patterns following changes in usage that are a result of either policy changes or response to new information will help in the understanding of the complex relationships in microbial and disease ecology. There is a lot of evidence substantiating the productivity and profitability gains to producers from the use of antimicrobials. There is also evidence for the potential gains to consumers, both from an economic perspective as well as from a health perspective. Economists can help identify the implications of these relationships both at a micro- and macro-economic level; both relative to producer and to consumer welfare. We are at a pivotal time in history with sufficient analytical expertise and tools to address this complex issue from a scientific perspective. Linking various agencies so there can be coordination of data collection and data sharing is needed to successfully address this topic.     

Spread of resistant bacteria and resistance genes from animals to humans--the public health consequences

The paper reviews the lines of evidence which link the use of antimicrobial drugs for food animals with the emergence of antimicrobial drug resistance in bacteria pathogenic to humans, with a particular focus on the public health aspects. Deductions from the epidemiology of food-borne infections, ecological studies, outbreak investigations, typing studies and direct epidemiological observations show that resistant bacteria are transferred from food animals to man. In addition to transfer in the food chain, exchange of mobile genetic elements among commensal and pathogenic bacteria contributes to the emergence of drug resistance. There is growing evidence that this has measurable consequences for human public health. One consequence is increased transmission supported by unrelated use of anti-microbials in humans. Other consequences are related to reduced efficacy of early empirical treatment, limitations in the choices for treatment after confirmed microbiological diagnosis, and finally a possible coselection of virulence traits. Recent epidemiological studies have measured these consequences in terms of excess mortality associated with resistance, increased duration of illness, and increased risk of invasive illness or hospitalization following infections with resistant Salmonella.     

Antimicrobial drug use in veterinary medicine

Recognizing the importance of antimicrobial resistance and the need for veterinarians to aid in efforts for maintaining the usefulness of antimicrobial drugs in animals and humans, the Board of Regents of the American College of Veterinary Internal Medicine charged a special committee with responsibility for drafting this position statement regarding antimicrobial drug use in veterinary medicine. The Committee believes that veterinarians are obligated to balance the well-being of animals under their care with the protection of other animals and public health. Therefore, if an animal's medical condition can be reasonably expected to improve as a result of treatment with antimicrobial drugs, and the animal is under a veterinarian's care with an appropriate veterinarian-client-patient relationship, veterinarians have an obligation to offer antimicrobial treatment as a therapeutic option. Veterinarians also have an obligation to actively promote disease prevention efforts, to treat as conservatively as possible, and to explain the potential consequences associated with antimicrobial treatment to animal owners and managers, including the possibility of promoting selection of resistant bacteria. However, the consequences of losing usefulness of an antimicrobial drug that is used as a last resort in humans or animals with resistant bacterial infections might be unacceptable from a public or population health perspective. Veterinarians could therefore face the difficult choice of treating animals with a drug that is less likely to be successful, possibly resulting in prolonged or exacerbated morbidity, to protect the good of society. The Committee recommends that voluntary actions be taken by the veterinary profession to promote conservative use of antimicrobial drugs to minimize the potential adverse effects on animal or human health. The veterinary profession must work to educate all veterinarians about issues related to conservative antimicrobial drug use and antimicrobial resistance so that each individual is better able to balance ethical obligations regarding the perceived benefit to their patients versus the perceived risk to public health. Specific means by which the veterinary profession can promote stewardship of this valuable resource are presented and discussed in this document.     

Development of an antibiotic resistance monitoring system in Hungary

Because of the rapid development and spread of antimicrobial resistance it is important that a system be established to monitor antimicrobial resistance in pathogenic zoonotic and commensal bacteria of animal origin. Susceptibility testing of bacteria from carcasses and different samples of animal origin has been carried out in veterinary institutes for a long time but by an inconsistent methodology. The disc diffusion method proposed by the National Committee for Clinical Laboratory Standards (NCCLS) was introduced in all institutes in 1997. In order to obtain a coherent view of the antimicrobial resistance of bacteria a computer system was consulted, consisting of a central computer to store all data and some local computers attached to it through the network. At these local measuring stations computers are connected to a video camera, which displays the picture of Petri dishes on the monitor, and inhibition zone diameters of bacteria can be drawn with the mouse by the inspector. The software measures the diameters, evaluates whether or not the bacteria are sensitive, and stores the data. The evaluation is based upon the data of the NCCLS. The central computer can be connected to as many local computers with measuring stations as we wish, so it is suitable for an integrated system for monitoring trends in antimicrobial resistance of bacteria from animals, food and humans, facilitating comparison of the occurrence of resistance for each circumstance in the chain. It depends on the examiners which antibiotics they want to examine. Thirty-two different antibiotic panels were compiled, taking into consideration the active ingredients of medicinal products permitted for veterinary use in Hungary, natural resistance and cross-resistance, the mechanism of resistance and the animal species, i.e. which drugs were recommended for treatment in the given animal species, and the recommendations of the OIE Expert Group on Antimicrobial Resistance. The members of the panels can be changed any time, even during the measuring process. In addition to the inhibition zone diameters of bacteria the database also includes information about bacterial and animal species, the age of animals and the sample or organ where the bacteria are from. Since January 2001 the antibiotic susceptibility of E. coli, Salmonella, Campylobacter and Enterococcus strains isolated from the colons of slaughter cows, pigs and broiler chickens has also been examined. Each of the 19 counties of Hungary submits to the laboratory three tied colon samples from a herd of the above-mentioned animals every month.     

Antimicrobial resistance in staphylococci from animals with particular reference to bovine Staphylococcus aureus, porcine Staphylococcus hyicus, and canine Staphylococcus intermedius.

Besides their role as commensals on the skin and mucosal surfaces, staphylococci may be involved in a wide variety of diseases in animals. Staphylococcal infections in animals are mainly treated with antimicrobial agents and as a consequence, staphylococci from animal sources have developed and/or acquired resistance to the respective antimicrobial agents. Resistance statistics obtained from national monitoring programmes on staphylococci from cattle and pigs, but also from surveillance studies on staphylococci involved in diseases in dogs are reported and reviewed with regard to their comparability. This review mainly focusses on the genetic basis of antimicrobial resistance in staphylococci of animal origin. Particular attention is paid to resistance to those antimicrobial agents which are most frequently used in veterinary medicine, but also to antimicrobial agents, such as chloramphenicol and mupirocin, which are used in specific cases for the control of staphylococcal infections in pets and companion animals. In addition, plasmids and transposons associated with the respective resistance properties and their ways of spreading between members of the same or different staphylococcal species, but also between staphylococci and other gram-positive bacteria, are described.     

beta-Lactam resistance and beta-lactamases in bacteria of animal origin

beta-Lactams are among the most clinically important antimicrobials in both human and veterinary medicine. Bacterial resistance to beta-lactams has been increasingly observed in bacteria, including those of animal origin. The mechanisms of beta-lactam resistance include inaccessibility of the drugs to their target, target alterations and/or inactivation of the drugs by beta-lactamases. The latter contributes predominantly to beta-lactam resistance in Gram-negative bacteria. A variety of beta-lactamases have been identified in bacteria derived from food-producing and companion animals and may further serve as a reservoir for beta-lactamase-producing bacteria in humans. While this review mainly describes beta-lactamases from animal-derived Escherichia coli and Salmonella spp., beta-lactamases from animal-derived Campylobacter spp., Enterococcus spp., Staphylococcus spp. and other pathogens are also discussed. Of particular concern are the increasingly-isolated plasmid-encoded AmpC-type CMY and extended-spectrum CTX-M beta-lactamases, which mediate acquired resistance to extended-spectrum beta-lactams. The genes encoding these enzymes often coexist with other antimicrobial resistance determinants and can also be associated with transposons/integrons, increasing the potential enrichment of multidrug resistant bacteria by multiple antimicrobial agents as well as dissemination of the resistance determinants among bacterial species. Characterization of beta-lactam-resistant animal-derived bacteria warrants further investigation of the type and distribution of beta-lactamases in bacteria of animal origin and their potential impact on human medicine.     

欧盟禁用饲料药物添加剂的历史和法规

欧盟考虑到抗生素耐药性的发展和抗生素耐药基因可能从动物到人微生物的转移,决定从2006年1月1日起禁止抗生素作为生长促进剂,甚至还建议禁止在动物饲料中全面使用所有的抗菌剂。收集和整理欧盟饲料药物添加剂的禁用清单和法规,介绍欧盟禁用饲料药物添加剂的历史及其对动物健康的影响,以期为中国饲料药物添加剂的使用和管理提供借鉴和参考。     

Antimicrobial resistance in bacteria from Swiss veal calves at slaughter

Bacteria with antimicrobial resistance can be transferred from animals to humans and may compromise antimicrobial treatment in case of infection. To determine the antimicrobial resistance situation in bacteria from Swiss veal calves, faecal samples from 500 randomly selected calves originating from 129 farms were collected at four big slaughterhouses. Samples were cultured for Escherichia coli, Enterococcus sp. and Campylobacter sp. and isolated strains were tested for antimicrobial susceptibility to selected antimicrobial agents by the minimal inhibitory concentration technique using the broth microdilution method. From 100 farms, data on farm management, animal husbandry and antimicrobial treatments of the calves were collected by questionnaire. Risk factors associated with antimicrobial resistance were identified by logistic regression. In total, 467 E. coli, 413 Enterococcus sp. and 202 Campylobacter sp. were isolated. Of those, 68.7%, 98.7% and 67.8%, respectively, were resistant to at least one of the tested antimicrobial agents. Resistance was mainly observed to antimicrobials frequently used in farm animals. Prevalence of resistance to antimicrobials important for human treatment was generally low. However, a rather high number of quinupristin/dalfopristin-resistant Enterococcus faecium and ciprofloxacin-resistant Campylobacter sp. were detected. External calf purchase, large finishing groups, feeding of milk by-products and administration of antimicrobials through feed upon arrival of the animals on the farm significantly increased the risk of antimicrobial resistance at farm level. Participation in a quality assurance programme and injection of a macrolide upon arrival of the animals on the farm had a protective effect. The present study showed that veal calves may serve as a reservoir for resistant bacteria. To ensure food safety, veal calves should be included in the national monitoring programme for antimicrobial resistance in farm animals. By improving farm management and calf husbandry the prevalence of resistance may be reduced.     

饲用抗生素细菌耐药性的研究进展

饲用抗生素的不当使用,尤其是抗生素促长剂的滥用,导致动物体内细菌耐药性的产生并不断增强。耐药性细菌及其耐药基因会在动物、环境、人体之间水平传播,从而对人类健康造成了严重威胁。为此一些发达国家纷纷采取措施限制饲用抗生素的使用。研究表明,抗生素促长剂停用后,畜禽体内及动物性食品中耐药菌显著减少,相应地人体内耐药菌携带率亦随之显著下降。     

Antimicrobial resistance in bacteria from food-producing animals. risk management tools and strategies

The application of antimicrobial agents has proved to be the main risk factor for development, selection and spread of antimicrobial resistance. This link applies to the use of antimicrobial agents in human and in veterinary medicine. Furthermore, antimicrobial-resistant bacteria and resistant genes can be transmitted from animals to humans either by direct contact or via the food chain. In this context, risk management has to be discussed regarding prevention and control of the already existing antimicrobial resistance. One of the primary risk management measures in order to control the development and spread of antimicrobial resistances is by regulating the use of antimicrobial agents and subjecting their use to guidelines. Thereby, the occurrence of antimicrobial resistant bacteria in the human and veterinary habitat can be controlled to a certain degree. There is little information about past attempts to prevent the development of resistances or to control them, and even less is known about the effectiveness or the cost intensiveness of such efforts. Most of the strategies focus on preventing and controlling antimicrobial resistance by means of the reduction or limitation of the use of antimicrobial agents in food-producing animals.