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.     

Stakeholder position paper: companion animal veterinarian

The total quantity of use in companion animals is generally believed to be relatively small in comparison with antimicrobial use in food animals. Use in companion animals is principally for treatment, whereas the greater proportion of use in food animals is for prophylaxis, metaphylaxis and growth promotion. Therefore, it is important to collect data on end use in companion animals so that overall estimates of use in companion animals can be generated and separated from estimates for food animals. However, data from antimicrobial use in companion animals are extremely limited and no serious attempts to collect such data have ever been made in the United States. The lack of usage data in is concomitant with the dearth of information on antimicrobial resistance in companion animals. Companion animals have been involved in the transmission to humans of, or become infected with, foodborne zoonotic bacteria such as Salmonella and Campylobacter. Companion animals are an integral part of the ecology of antimicrobial resistance through their contact with food animals and exposure to antimicrobials for disease treatment and through contact with humans and the environment. In the practice of companion animal medicine, antimicrobial use data are important for understanding the potential impact on companion animal heath posed by antimicrobial resistance transferred from food animals, humans and the environment, and the threat to humans and other companion animals posed by antimicrobial use in companion animals. Basic information on the patterns and quantities of antimicrobial use in combination with resistance surveillance data, could help companion animal veterinarians understand the potential for development, or evidence of, an antimicrobial resistance problem in their practices, the role of companion animals in the overall epidemiology of antimicrobial resistance, and for comparison with local, regional, or national data. The combination of data from either a sentinel site system of clinics or a use survey with national data from the pharmaceutical industry should provide sufficient data to credibly estimate the total volume and patterns of antimicrobial use in companion animal medicine. The time and effort for use monitoring or to complete a survey would likely become burdensome. Practice management software now utilized at most companion animal clinics could be used to generate antimicrobial use data as well as patient population data as surrogate for the true population at risk for patient encounters in a companion animal practice.     

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.     

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.     

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.     

Stakeholder position paper: epidemiological perspectives on antibiotic use in animals

Epidemiologists studying antimicrobial resistance are often interested in analyzing the association between antimicrobial resistance and antimicrobial use in animals, and on the impact of antimicrobial use in animals on the occurrence of resistance in bacteria affecting human populations. Given the various potential antimicrobial use data sources, it seems likely there will be some variability in the utility of the data for interpreting trends in antimicrobial resistance and investigating the relationship between antimicrobial use in animals and antimicrobial resistance in bacteria affecting human health. From an epidemiologic perspective, the major issues related to incorporation of antimicrobial use data into antimicrobial resistance monitoring programs are the further development of epidemiologic methods for collecting, quantifying, analyzing and interpreting use data; an open and realistic consideration of the limitations of the data; developing an understanding of scaling, temporal and spatial heterogeneity issues; and the interpretative problems of ecologic and atomistic fallacy. Given the many potential biases in antimicrobial use data, attempts to relate levels of antimicrobial use to levels of antimicrobial resistance should be done with caution until the data are better understood and the aforementioned issues have been addressed.     

Public health advocate

With antimicrobial resistance mounting, an important public health goal is to preserve therapeutic effectiveness of remaining antimicrobials. To that end, fewer antimicrobials should be used in human medicine and in agriculture. Public health initiatives to reduce antimicrobial overuse could benefit from concurrent collection of agricultural usage data; they could aid scientific understanding of the resistance problem and confirm the efficacy of interventions. Data collection in this context should be a priority. However, usage data are nonessential to achieving the public health goal. U.S. regulation of agricultural antimicrobials today is very reliant on risk assessment. While more data can be useful for use in risk assessment, microbial risk assessment itself may not be well suited to the purpose of reducing antimicrobial overuse. Among other recognized shortcomings, current microbial risk assessment models typically fail to account for the essential ecological nature of antimicrobial resistance. This makes it inadequate for fully characterizing the human health or ecological risks of animal antimicrobials. European success at phasing out unnecessary antimicrobial usage in agriculture, on the other hand, has derived from decisions based on public health concerns and political will, and not on the collection of usage data or on the successful completion of a risk assessment.     

Impact of antimicrobial drug usage measures on the identification of heavy users, patterns of usage of the different antimicrobial classes and time-trends evolution

Several measurement units are available to quantify antimicrobial usage in veterinary medicine, to obtain diverse measures such as the weight of active substance used, the live weight (LW) treated, the fraction of animals exposed, the number of treatments recorded or the cost represented. These measures can be applied to study practices variability between farms, to characterize patterns of usage of the different antimicrobial classes or to follow evolution of antimicrobial usage with time. An investigation was carried out to specifically explore the influence of measurement units on the conclusions obtained from such studies. Antimicrobial exposure was explored in a sample of turkey and chicken broiler flocks, using six different units [kg of active compound, treatments, days of administration, kg of LW treated, animal daily dose to treat 1 kg of LW (ADD_kg) and euros] to compare flocks usage variability and patterns of use of the different antimicrobial classes. Time-trends evolutions of macrolides usage in turkey broilers, characterized by percentage of flocks exposed and LW treated, were also compared. In all analyses, the measure gave different results without equivalences, highlighting the necessity for care in choosing the measurement unit and caution in interpreting the figures obtained.     

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 human health implication of the use of antimicrobial agents in animal feeds

Antimicrobials given in subtherapeutic levels in feed are credited with having contributed to lower cost of meat, milk and eggs. The practice often is associated with the acquisition of resistant enteric flora by the involved animals, and this may in turn contribute to the human reservoir of antimicrobial resistant coliforms and salmonellae. Associated farm workers may transiently acquire resistant flora and on rare occasions develop salmonellosis. Although irrefutable evidence of growth promotant properties of antibiotics in animal feed was provided 30 to 40 years ago, additional studies on mechanisms of the effect are presently needed. It may be possible to identify factors effective in promoting growth without deleterious effects on flora. A national surveillance programme of antimicrobial utilisation (both subtherapeutic and therapeutic) among food producing animals should be established. Molecular epidemiologic research efforts will need to be undertaken to establish whether genetic information of animal origin importantly contributes to the human environmental pool of antimicrobial resistance. In the meantime, it does not appear that the use of drugs as feed additives, while allowing their unrestricted use for therapy in both animals and persons, would favorably influence the problems of antimicrobial resistance of salmonellosis in human populations.     

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.     

The human health implication of the use of antimicrobial agents in animal feeds

Summary

Antimicrobials given in subtherapeutic levels in feed are credited with having contributed to lower cost of meat, milk and eggs. The practice often is associated with the acquisition of resistant enteric flora by the involved animals, and this may in turn contribute to the human reservoir of antimicrobial resistant coliforms and salmonellae. Associated farm workers may transiently acquire resistant flora and on rare occasions develop salmonellosis. Although irrefutable evidence of growth promotant properties of antibiotics in animal feed was provided 30 to 40 years ago, additional studies on mechanisms of the effect are presently needed. It may be possible to identify factors effective in promoting growth without deleterious effects on flora. A national surveillance programme of antimicrobial utilisation (both subtherapeutic and therapeutic) among food producing animals should be established. Molecular epidemiologic research efforts will need to be undertaken to establish whether genetic information of animal origin importantly contributes to the human environmental pool of antimicrobial resistance. In the meantime, it does not appear that the use of drugs as feed additives, while allowing their unrestricted use for therapy in both animals and persons, wouldfavorably influence the problems of antimicrobial resistance of salmonellosis in human populations.     

Monitoring of antibiotic consumption in livestock: a German feasibility study

Every application of antibacterial drugs in veterinary medicine may encourage selection for resistant bacteria. In Germany no valid data are available which would be suitable for a species specific estimation of drug consumption especially regarding food producing animals. Therefore, a representative monitoring of consumption of antibacterial drugs in food producing animals should be implemented. As a first step, a feasibility project was conducted to identify the technical preconditions and develop a concept for a regular monitoring system within Germany as a country with a non-central federal state system. The data were collected via the forms obligatory by German law concerning the treatment of animals and the delivery of animal drugs to the animal owners by the veterinarian. 24 veterinary practices and 65 farmers were visited, and all applications of antibiotics to farm animals during the course of one year (September 1, 2006 to August 31, 2007) were entered into a central database. A total of 95,584 records were collected and analysed statistically. Consumption of antibiotics was calculated in kg, but also the number of applications was analysed. The consumption of tetracyclines in kg reached 54.3% of all antimicrobial substances applied to pigs, but only 25.7% of all doses applied to pigs were tetracyclines. For the farms' data, the number of daily doses per animal year (DD(ay)) was estimated based on the number of daily doses recorded and on the number of animals kept in the farm. Correct and detailed data regarding the structures of the farms as well as of veterinary practices are necessary to estimate the consumption of antibiotics reliably. The proposed system is able to function as a monitoring system for antibiotic use in Germany, when the monitoring data are linked to the agricultural data (farm sizes) accounting for differences between German regional agricultural and animal husbandry structures. Furthermore, the results of the antibiotic use analyses may serve as basis to assess the results of the sales data of the pharmaceutical industry. Results are comparable to the outcome of respective systems in other European countries, e.g. the Netherlands and Denmark, and therefore it will contribute to a better understanding and development of strategies for the control of antimicrobial resistances on the European level.     

Stakeholder position paper: the need for antimicrobial use data for risk assessment

Risk assessment seeks to estimate the probability and impact of human health effects due to antimicrobial resistance arising from antimicrobial use in animals. Potential ecological pathways for the flow of antimicrobial resistant bacteria and resistance determinants through the food supply and environment are diverse and complicated and this has been a logistical barrier to direct epidemiological measure of risk. Consequently, a number of indirect approaches to assessment have been developed. This paper provides some examples of risk assessments that have been conducted with and without antimicrobial use data, and identifies possible benefits and applications of quantitative antimicrobial use data for risk assessment.     

Overview of issues pertaining to the manufacture, distribution, and use of antimicrobials in animals and other information relevant to animal antimicrobial use data collection in the United States

This paper provides condensed literature review and contextual information concerning antimicrobial use in animals and antimicrobial use data collection techniques. Information is summarized into the following topics: (I) antimicrobial use for animal growth promotion; (II) regulatory framework for approval of veterinary antimicrobials and feed additives in the United States; (III) animal health product manufacturing and distribution networks; (IV) existing estimates of animal antimicrobial use in the United States; (V) additional sources for animal use data in the United States; (VI) recommendations from international expert groups; (VII) animal antimicrobial use surveillance systems in other nations and (VIII) human use data collection systems in the United States.     

Veterinary antimicrobial-usage statistics based on standardized measures of dosage

In human medicine, the defined daily dose is used as a technical measure of drug usage, which is independent of the variations in the potency of the active compound and the formulation of the pharmaceutical product—therefore providing a measure of the relative importance of different drugs. A national system of animal defined daily doses (ADD) for each age-group and species has been defined in VetStat (the Danish national system monitoring veterinary therapeutic drug use). The usage is further standardized according to the number of animals in the target population, acquired from production data on the national level or on herd size by species and age in the Danish central husbandry register (CHR). Statistics based on standardized measures of VetStat data can be used for comparison of drug usage between different herds, veterinary practices, or geographic regions (allowing subdivision by animal species and animal production class, route of administration, disease categories, season and geographic location). Individual statistics are available as interactive reports to the control authorities, farmers and veterinary practitioners by a secure access to the database. The ADD also is used in pharmaco-epidemiogical research and to assist in the interpretation of resistance-surveillance data.     

Use of register data to assess the association between use of antimicrobials and outbreak of Postweaning Multisystemic Wasting Syndrome (PMWS) in Danish pig herds

In 2001, the first case of Postweaning Multisystemic Wasting Syndrome (PMWS) was reported in the Danish pig population. During subsequent years, the number of affected farms increased exponentially. The aim of this study was to determine how this increase influenced the use of antimicrobials between 2002 and 2004. We used national register data of herd characteristics, antimicrobial usage and disease occurrence. The analysis included data on antimicrobial usage in 3371 pig herds with weaners and 7434 pig herds with finishers, which accounted for 56 and 82% of the national amount of antimicrobials prescribed to weaners (prescribed by 347 practitioners) and finishers (prescribed by 522 practitioners), respectively.The estimation of the effect of PMWS was done by comparing the amount of antimicrobials (measured as Animal Defined Daily Doses (ADDkg) used per pig-day at risk each month in each herd) used in herds before and after an outbreak of PMWS, and by comparing the amount of antimicrobials used in herds experiencing PMWS with the amount of antimicrobials used in herds not experiencing PMWS. The effects were estimated in a three-level (veterinarian/herd/study-month) linear mixed regression model with an autoregressive correlation of order 1 (AR1).We found that after a herd had experienced an outbreak of PMWS, the antimicrobial usage in weaners was increased for a year. During the first 3 months post outbreak the usage increased by 22%, followed by an increase of 7% during the next 4th to 12th month when compared to the pre-outbreak usage. There was a significant variation between herds in this effect. Additionally, in herds experiencing an outbreak of PMWS, the usage of antimicrobials before the outbreak was 37 and 19% higher in herds with weaners and finishers, respectively, compared to herds not experiencing PMWS.Generalisation of the results to the entire Danish pig population indicated that the increase of PMWS infected herds from almost zero to about 20% during a 4-year period resulted in a national increase of 4–5% in antimicrobials usage in weaners. The effect of PMWS on usage of antimicrobials in finishers was unclear.     

Prevalence and characteristics of quinolone resistance in Escherichia coli in veal calves

Quinolone resistance is studied and reported increasingly in isolates from humans, food-producing animals and companion animals. Resistance can be caused by chromosomal mutations in topoisomerase genes, plasmid-mediated resistance genes, and active transport through efflux pumps. Cross sectional data on quinolone resistance mechanisms in non-pathogenic bacteria from healthy veal calves is limited. The purpose of this study was to determine the prevalence and characteristics of quinolone resistance mechanisms in Escherichia coli isolates from veal calves, after more than 20 years of quinolone usage in veal calves. MIC values were determined for all isolates collected as part of a national surveillance program on antimicrobial resistance in commensal bacteria in food-producing animals in The Netherlands. From the strains collected from veal calves in 2007 (n=175) all isolates with ciprofloxacin MIC ≥ 0.125 mg/L (n=25) were selected for this study, and screened for the presence of known quinolone resistance determinants. In this selection only chromosomal mutations in the topoisomerase type II and IV genes were detected. The number of mutations found per isolate correlated with an increasing ciprofloxacin MIC. No plasmid-mediated quinolone resistance genes were found. The contribution of efflux pumps varied from no contribution to a 16-fold increase in susceptibility. No correlation was found with the presence of resistance genes of other antimicrobial classes, even though all quinolone non-wild type isolates were resistant to 3 or more classes of antibiotics other than quinolones. Over twenty years of quinolone usage in veal calves in The Netherlands did not result in a widespread occurrence of plasmid-mediated quinolone resistance, limiting the transmission of quinolone resistance to clonal distribution.