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.     

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.     

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.     

OIE抗菌药耐药性国际标准

兽用抗菌药耐药性已经成为一个全球普遍关注的公共健康问题,各国际组织都积极采取相应的措施控制耐药性的产生和蔓延。介绍了国际组织世界动物卫生组织OIE制定的五个国际标准,包括协调抗菌药耐药性监督和检测程序指南、畜牧业抗菌药消耗量监测指南、兽用抗菌药慎用指南、抗菌药敏感性检测的实验室方法指南、动物源抗菌药耐药性对公共健康潜在影响的风险分析方法指南,以期为我国政策制定者和决策者参照国际标准制定出符合我国国情的耐药性相关指南。     

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.     

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.     

Developing new regulatory approaches to antimicrobial safety

Resistance to antimicrobial agents is of concern to public health officials worldwide. In industrialized countries, a significant source of antimicrobial-resistant food-borne infections in humans is the acquisition of resistant bacteria originating from animals. The US Food and Drug Administration (FDA) is committed to resolving the public health impact arising from the use of antimicrobial drugs in food-producing animals. The FDAs goal is to ensure that significant human antimicrobial therapies are not compromised or lost while providing for the safe use of antimicrobials in food animals. Recently the FDA published a guidance document titled 'Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to their Microbiological Effects on Bacteria of Human Health Concern' (US Food and Drug Administration, Center for Veterinary Medicine, 2003). This document outlines a pathway drug sponsors can use to address concerns about antimicrobial resistance prior to approval of their drug. The process uses a qualitative risk assessment approach to assess the potential of the intended use of a product to develop resistance in bacteria that may harm humans. The level of risk determines the level of risk management that is required for the drug to be used. The Food and Drug Administration (FDA) always has the option of not approving a drug if the risk of a public health consequence is too high.     

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.     

Towards the establishment and standardization of a veterinary antimicrobial resistance surveillance and monitoring programme in South Africa

The objective of this study was to establish a repeatable, standardized laboratory procedure for monitoring the development of antimicrobial resistance in bacteria isolated from animals and food of animal origin in South Africa, with reagents prepared in-house. The emergence of resistance and the spread of resistant bacteria can be limited by implementing a veterinary antimicrobial drug policy, in which inter alia systematic monitoring and prudent use play essential roles. The bacteria included in this study represented three different categories, namely zoonotic bacteria (Salmonella), indicator bacteria (Escherichia coli, Enterococcus faecalis and Enterococcus faecium) and veterinary pathogens (Mannheimia haemolytica). Thirty isolates of each species were collected with the aim of standardizing the laboratory methodology for a future national veterinary surveillance and monitoring programme. Susceptibility to ten selected antimicrobial drugs was determined by means of minimum inhibitory concentrations (MICs) using the microdilution method. The method according to the National Committee for Clinical Laboratory Standards was used as the standard. Multi-well plates containing varying dilutions of antimicrobial drugs and prepared in-house for MIC determinations, yielded repeatable results. Storage of plates for 2 months at -70 degrees C did not influence results meaningfully. Within this limited sample of bacteria, MIC results did not indicate meaningful resistance against any of the ten selected antimicrobial drugs. The findings of the study will be used to establish a national veterinary antimicrobial resistance surveillance and monitoring programme in South Africa. To allow for international comparison of data, harmonisation of the surveillance and monitoring programme in accordance with global trends is encouraged. Ideally it should be combined with a programme monitoring the quantities of antimicrobial drugs used. The aim is to contribute to slowing down the emergence of resistance and the problems associated with this phenomenon by means of the rational use of antimicrobial drugs.     

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.     

基因盒-整合子系统介导的细菌多重耐药性

细菌多重耐药性的传播和扩散变得越来越严重，给临床治疗带来诸多困难，使得抗菌药物在兽医临床上的应用引起很大的争议。细菌可通过多种方式逃避抗菌药物的治疗，最主要的是从外源获得耐药基因，基因盒-整合子系统是近年来的研究热点，细菌通过整合子系统捕获外来的耐药基因，并在位于整合子上游的启动子的作用下得到表达，使细菌具有耐药及多重耐药性。本文主要对基因盒-整合子系统的耐药机制进行探讨。     

动物应用抗菌药的风险及防制对策

食品动物因大量应用抗菌药物产生耐药菌株，对动物和人类健康及生态环境造成危害，为此欧盟对多种促生长抗菌药颁布了禁令，导致了动物治疗用抗菌药的急剧增加及畜牧业经济效益的降低。本文就此展开讨论，强调必须开发新型抗菌药物，合理应用抗菌药，加强抗菌药药效学及药动学研究，健全食源性病原菌耐药性监测系统等。     

Evidence of an association between use of anti-microbial agents in food animals and anti-microbial resistance among bacteria isolated from humans and the human health consequences of such resistance

Several lines of evidence indicate that the use of anti-microbial agents in food animals is associated with anti-microbial resistance among bacteria isolated from humans. The use of anti-microbial agents in food animals is most clearly associated with anti-microbial resistance among Salmonella and Campylobacter isolated from humans, but also appears likely among enterococci, Escherichia coli and other bacteria. Evidence is also accumulating that the anti-microbial resistance among bacteria isolated from humans could be the result of using anti-microbial agents in food animals and is leading to human health consequences. These human health consequences include: (i) infections that would not have otherwise occurred and (ii) increased frequency of treatment failures and increased severity of infection. Increased severity of infection includes longer duration of illness, increased frequency of bloodstream infections, increased hospitalization and increased mortality. Continued work and research efforts will provide more evidence to explain the connection between the use of anti-microbial agents in food animals and anti-microbial-resistant infections in humans. One particular focus, which would solidify this connection, is to understand the factors that dictate spread of resistance determinants, especially resistant genes. With continued efforts on the part of the medical, veterinary and public health community, such research may contribute to more precise guidelines on the use of anti-microbials in food animals.     

Cross-sectional study of antimicrobial-resistant bacteria in horses. Part 2: Risk factors for faecal carriage of antimicrobial-resistant Escherichia coli in horses

Reasons for performing study: The increasing prevalence of antimicrobial resistant bacteria such as antimicrobial‐resistant and extended spectrum β‐lactamase (ESBL)‐producing Escherichia coli represents a significant problem for human and veterinary medicine. Despite this, the risk factors for faecal carriage of such bacteria by horses in the UK, particularly those in the wider community, have not been well described. Objectives: To characterise the risk factors for faecal carriage of antimicrobial‐resistant E. coli amongst horses in the mainland UK. Methods: A cross‐sectional study of horses recruited by 65 randomly selected equine veterinary practices was conducted, with a faecal sample collected and self‐administered questionnaire completed by the horse owner. Faecal samples were cultured for antimicrobial‐resistant E. coli, with isolates confirmed as E. coli having their antimicrobial resistance profile determined. Multilevel, multivariable logistic regression models were used to investigate risk factors for the carriage of antimicrobial‐resistant E. coli in the sample population. Results: Faecal samples and completed questionnaires were obtained for 627 horses located on 475 premises. Recent hospitalisation, contact with specific types of nonequid animals, the type of premises, the surrounding land use, the reason for veterinary treatment received in the last 6 months and antimicrobial treatment in the previous 10 days were identified as risk factors for many of the antimicrobial‐resistance outcomes considered. Being stabled on the same yard as a recently hospitalised horse was identified as a risk factor for increased risk of carriage of ESBL‐producing E. coli. Conclusions and potential relevance: Increasing antimicrobial resistance may have significant health implications for the horse population of Great Britain. This form of epidemiological investigation highlights potential risk factors that may be controlled to limit the extent of the problem.     

Nosocomial infections.

Nosocomial infections and antimicrobial resistance are topics that have been intensely studied in human medicine because of their significant impact on human health. In recent years, concerns have been raised that the use of antibiotics in veterinary medicine, animal husbandry, and agriculture may be contributing to the development of resistance in common bacterial species affecting human beings. Although there is inadequate proof at this time that the resistance is transmitted from animals to people, if antibiotics continue to be used indiscriminately in veterinary medicine, veterinarians may find themselves facing regulations restricting the use of some antibiotics. Nosocomial infections have been reported in veterinary medicine and are likely to increase in prevalence with the increase in intensive care practices in many hospitals. Prolonged hospitalization and the use of invasive devices and procedures increase the risk of nosocomial disease. As in human medicine, organisms isolated in the nosocomial infections reported in veterinary patients have an increasingly broad spectrum of antimicrobial resistance. Despite these findings, the use of empiric and prophylactic antibiotic therapy is still widespread in veterinary medicine. Nosocomial infections and antimicrobial resistance may have a serious impact on the future of [table: see text] veterinary medicine, because the cost and ability to treat our patients may be affected by the loss of access to or effectiveness of antimicrobial drugs. Despite the millions of dollars spent on research to reduce the incidence of nosocomial infections in human patients, the strategies that have consistently proven successful are simple and inexpensive to implement. The most important factor in preventing nosocomial infections is improving the hygiene practices of health care providers. Hand-washing or the use of disposable gloves can dramatically reduce the transmission of bacteria between patients. Aseptic technique should be used in the placement and management of all invasive devices. All staff members should be educated on the risks and symptoms associated with nosocomial infections so that cases can be detected early and treated appropriately. We in the veterinary profession have the opportunity to learn from the experiences of the human medical profession and can take steps to prevent the escalation of nosocomial infections and their impact on our profession.     

欧盟兽用抗菌药耐药性管理概述

介绍负责管理欧盟兽用抗菌药耐药性的欧洲药品局下设的兽用药品委员会、健康与消费者保护司和食品安全局等相关管理机构以及成立耐药性管理工作组、进行耐药性风险分析、制定相关文件和实施耐药性监测等的管理措施,为我国兽药耐药性相关政策的制定和措施的实行提供参考.     

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.     

美国兽用抗菌药耐药性管理

全面介绍了美国兽用抗菌药耐药性的管理机构和管理措施,希望为我国兽药耐药性相关政策的制定和措施的实行提供一定的依据和参考。     

Fluoroquinolones in animal health

The fluoroquinolones are a series of synthetic antibacterial agents that are undergoing extensive investigation for both human and veterinary use in the treatment of a variety of bacterial infections. These agents work through the inhibition of DNA gyrase, interfering with the supercoiling of bacterial chromosomal material. As a result, these agents are rapidly bactericidal primarily against gram-negative bacteria, mycoplasma, and some grampositive bacteria, with most having little to no activity against group D streptococci and obligate anaerobic bacteria. Resistance develops slowly and is almost always chromosomal and not plasmid-mediated. However, development of resistance to the fluoroquinolones and transfer of that resistance among animal and human pathogens have become a hotly debated issue among microbiologists. The fluoroquinolones are a current antimicrobial class whose use in veterinary medicine is being scrutinized. From a pharmacokinetic perspective, these agents are variably but well absorbed from the gastrointestinal tract and almost completely absorbed from parenteral injection sites, and they are well distributed to various tissues in the body. The fluoroquinolones are metabolized and renally excreted, with many of them having approximately equal excretion by the hepatic and the renal excretory systems. The primary toxicity observed at therapeutic doses involves the gastrointestinal system and phototoxicity, although at higher doses central nervous system toxicity and ocular cataracts are observed. Administration to immature animals may result in erosive arthropathies at weight-bearing joints, and administration of high doses to pregnant animals results in maternotoxicity and occasionally embryonic death. The fluoroquinolones are approved for indications such as urinary tract infections and soft tissue infections in dogs and cats and colibacillosis in poultry. Approval for bovine respiratory disease in the United States is being sought. Other indications for which the fluoroquinolones have been used in animal health include deep-seated infections, prostatitis, and other bacterial infections resistant to standard antimicrobial therapy.