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.     

Analysis of antimicrobial sales data of the main distributor in Quebec from 2016 to 2019: An estimate of usage in dairy cattle,horses, and small animals

Because antimicrobial usage (AMU) data are crucial in understanding and dealing with the threat that antimicrobial resistance (AMR) poses to global health, data of the sale of antimicrobials from 2016 to 2019 of CDMV Inc. — a major distributor of veterinary products in Canada — were collected and analyzed for the province of Quebec. The primary objective was to describe the evolution of AMU sales data for dairy cattle, small animals, and horses; a secondary objective was to determine effects of a new provincial regulation on antimicrobials of very high importance (in Quebec) on sales for dairy cattle. Results are described in milligrams of antimicrobials per kilogram of animal biomass (mg/PCU) for dairy cattle, small animals, and horses; intramammary products were analyzed for number of treatments per 100 cow-years; and results for dairy cattle were compared in Canadian-defined course doses for cattle (DCDbovCA) per 100 cow-years to a recent study for this species in Quebec. Between 2016 and 2019, there were decreased sales of Category 1 antimicrobials for all species included in the study (Category 1-VI for small animals). This reduction was even more apparent for dairy cattle, for which a 76% decrease occurred from 2018 to 2019 (1.7 to 0.4 mg/PCU). This marked reduction was attributed to the new regulation implemented in February 2019. Since a farm- and clinic-level AMU monitoring system has not yet been implemented in Quebec, analysis of CDMV Inc. sales enabled observations of temporal trends in AMU for dairy cattle, horses, and small animals. These temporal trends based on CDMV Inc. sales will be useful for making comparisons and validating trends derived from farm- and clinic-level data generated by a monitoring system.     

Animal health pharmaceutical industry

The animal health pharmaceutical industry has proactively reported on the volumes of member company antimicrobial active ingredients sold in the U.S. At the individual company level, reporting of finished product distribution data to the FDA is a regulatory requirement, with applications to surveillance and pharmacovigilance. An accounting of product manufactured is done for purposes of good business practices, as well as marketing analyses. Additional applications of antimicrobial usage data might include use in risk assessments, such as for the FDA's Center for Veterinary Medicine Guidance for Industry #152 for the evaluation of the microbiological safety of antimicrobials intended for use in food animals. Compilation of national usage data will be a complex undertaking, hindered by issues such as confidentiality, auditing, field use practice variations, population dynamics (e.g. disease incidence, market conditions for poultry and livestock production), and generic usage. The amounts or volumes in pounds should be considered relative to the large number of animals under husbandry in the United States. Large volumes might seem impressive unless put into proper context. Until such time as a clearly defined application of national usage data is agreed, it is recommended that local usage programs will provide more useful information to perpetuate prudent antimicrobial use in animals.     

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.     

Factors associated with routine mass antimicrobial usage in fattening pig units in a high pig-density area

One hundred and seven fattening pig units randomly selected in Catalonia (Spain) were surveyed during 2001-2003, in order to determine the frequency of the prophylactic use of antimicrobials and mass treatments against respiratory and enteric disease outbreaks. Logistic regression and regression tree analysis were done to determine the factors associated with the on-farm mass antimicrobial usage. Fifty-eight per cent of the surveyed farms used mass antimicrobial prophylaxis; among them, 39% used two or more antimicrobials. The more frequently administered drugs were colistin, beta-lactams and tetracyclines. Fattening units from strict finishing farms were more likely to use antimicrobials than farrow-to-finish farms (Odds Ratio = 11.7) and farms with changing facilities were less likely to use these compounds (OR = 0.17). In the event of a respiratory disease outbreak, most farms applied mass treatment and 46% used two or more compounds, with tetracyclines, beta-lactams and sulphonamides being the most popular ones. Mass treatment with several compounds in case of respiratory problems was significantly related to the use of growth promoters on the farm (OR = 4.3). If an outbreak of an enteric disease occurred, most farms resorted also to a mass treatment and 48% used two or more drugs. The most frequent antimicrobial agent for the treatment of enteric disease was colistin. Fattening farms (OR = 6.9) and operations that perform routine antimicrobial prophylaxis (OR = 2.0) were more likely to use more than one antimicrobial agent for enteric diseases.     

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.     

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.     

2019年我国兽用抗菌药物使用情况分析研究

对2019年国内兽用抗菌药物销量数据进行了统计分析,按照兽用抗菌药销售量等同于使用量的评价指标,结果发现,国内兽药使用总量为37159.12吨;其中,使用量最大的是四环素类,占比36.56%;促生长用抗菌药的用量为14871.05吨,占比48.12%;每吨动物产品兽用抗菌药使用量为160 g。与2018年相比,兽用抗菌药物使用量略有上升,每吨动物产品使用的抗菌药物量也同比增加,这提示我国兽用抗菌药物使用管理不能放松,减抗政策需继续实施,久久为功。     

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.     

On-farm quantification of sustainability indicators: an application to egg production systems

1. On-farm quantification of sustainability indicators (SI) is an effective way to make sustainable development measurable. The egg production sector was used as a case study to illustrate this approach. 2. The objective was to select SI for economic, ecological and societal issues, and to analyse the performance on selected SI of different production systems. 3. For the case study, we compared 4 egg production systems, characterised by differences in the housing systems which are most common in the Netherlands: the battery-cage system, the deep-litter system with and without outdoor run, and the aviary system with outdoor run. 4. Based on a clear set of criteria, we selected SI for animal welfare, economics, environmental impact, ergonomics and product quality. 5. We showed that on-farm quantification of SI was an appropriate method to identify the strengths and weaknesses of different systems. 6. From this analysis it appears that the aviary system with outdoor run is a good alternative for the battery-cage system, with better scores for the aviary system on animal welfare and economics, but with worse scores on environmental impact.     

Metrics for quantifying antimicrobial use in beef feedlots

Accurate antimicrobial drug use data are needed to enlighten discussions regarding the impact of antimicrobial drug use in agriculture. The primary objective of this study was to investigate the perceived accuracy and clarity of different methods for reporting antimicrobial drug use information collected regarding beef feedlots. Producers, veterinarians, industry representatives, public health officials, and other knowledgeable beef industry leaders were invited to complete a web-based survey. A total of 156 participants in 33 US states, 4 Canadian provinces, and 8 other countries completed the survey. No single metric was considered universally optimal for all use circumstances or for all audiences. To effectively communicate antimicrobial drug use data, evaluation of the target audience is critical to presenting the information. Metrics that are most accurate need to be carefully and repeatedly explained to the audience.     

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.     

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.     

Antigen quantification as in vitro alternative for potency testing of inactivated viral poultry vaccines

Routine batch control of licensed inactivated viral vaccines for poultry usually includes a potency assay as a measure of vaccine efficacy. Potency assays often consist of vaccination-challenge experiments in the target species or in laboratory animals. Instead of measuring the protection of vaccinated animals against virulent pathogens, the serological response after vaccination can be quantified for some vaccines. In vitro antigen quantification assays would be attractive alternatives for the current potency assays because the time and costs involved could be greatly reduced and animal use could be avoided. Such in vitro assays will only be acceptable when the correlation between results and efficacy or potency has been demonstrated convincingly. The results of our studies on antigen quantification assays indicate that, in principle, quantification of viral antigens from inactivated oil-adjuvanted vaccines is feasible and reproducible using specially developed antigen capture ELISAs in combination with specific software for statistical analysis of the ELISA data. We have developed methods to quantify the haemagglutination-neuraminidase (HN) and fusion (F) proteins of Newcastle disease virus (NDV), the viral protein 3 (VP3) of the infectious bursal disease virus (IBDV), and the spike-1 (S1) protein of the infectious bronchitis virus (IBV). Vaccination experiments with inactivated ND vaccines indicate that the in vitro quantified HN- or F-proteins of NDV are reliable indicators of the serological response after vaccination.     

Clinical, bacteriological and therapeutic aspects of bovine mastitis caused by aerobic and anaerobic pathogens.

Twenty cows and three heifers with summer mastitis-like signs were included in the study. Forty aerobic and 38 anaerobic bacterial isolates representing 23 different species were isolated from udder secretions, the mean number of species being 3.4/sample. Pathogens most often were recovered in quantities exceeding 10(5) CFU/ml. Growth of pathogenic bacteria in the blood was found in only one case. Most cases occurred in housed animals and had often been preceded by teat injury. No anaerobic growth was found in milk samples of a control group consisting of 29 cows with ordinary acute mastitis. Values of indicators of inflammation in milk (NAGase and plasmin activity) were high, mean values being 914.1 and 1.3 units. The animals with aerobic/anaerobic mastitis were treated using various antimicrobial agents. All but three quarters were lost to milk production. Two animals with complete recovery were given a combination of penicillin G and tinidazole.     

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.