J. vet. Pharmacol. Therap. doi: 10.1111/jvp.12226


The management of risk arising from the use of antimicrobial agents in veterinary medicine in EU/EEA countries – a review € K. T ORNEKE* J. TORREN-EDO

K. GRAVE † & D. K. J. MACKAY † *L€akemedelsverket, Uppsala, Sweden; † European Medicines Agency, London, UK

T€ orneke, K., Torren-Edo, J., Grave, K., Mackay, D. The management of risk arising from the use of antimicrobial agents in veterinary medicine in EU/ EEA countries – a review. J. vet. Pharmacol. Therap. doi: 10.1111/jvp.12226. 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. (Paper received 4 March 2014; accepted for publication 1 March 2015) Jordi Torren-Edo, European Medicines Agency, 30 Churchill Place, Canary Wharf, London E14 5EU, UK. E-mail: [email protected] The views expressed in this article are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.

INTRODUCTION Antimicrobial resistance has been acknowledged as a potential consequence of the use of antimicrobial agents since the first days of the discovery of these compounds. In the time since Fleming’s identification and isolation of penicillin in September 1928, we have learnt about these drugs and the threats against their effectiveness. Likewise concern is also now being increasingly focussed on the use of antimicrobial agents in veterinary medicine for the treatment of food-producing species, particularly as resistance levels in foodborne zoonotic bacteria are increasing (European Food Safety Authority/European Centre for Disease Prevention and Control, EFSA/ECDC, 2011, © 2015 John Wiley & Sons Ltd

2012). In the light of these figures, it is timely to reflect on the measures in place within the European Union/European Economic Area (EU/EAA) that are intended to reduce or contain the risks arising from the use of antimicrobial agents in veterinary medicines. This study reviews current risk management strategies that are applied within the EU/EAA to minimize this risk as a contribution to the current debate as to whether or not additional measures are required. It is now apparent that the supply of new antimicrobial agents will be insufficient to replace those for which increased resistance levels have compromised their effectiveness. Therefore, the problem of AMR will remain for the foreseeable future. In addition, the number and spread of resistance genes 1

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is constantly increasing, implying an increased number of Multidrug-resistant (MDR) strains against which few currently available antimicrobial agents are effective. As a consequence of this, human medicine has been forced to use compounds such as colistin that are effective against MDR organisms but that have previously been little used due to their adverse effects (Falagas & Kasiakou, 2005). The use of antimicrobial agents in human and animals is intrinsically linked as currently there are no classes of antimicrobial agents that are authorized exclusively for use in veterinary medicine and that are not also used in human for treatment of bacterial infections (with the exception of ionophores for which there is a minor use in human medicine). Antimicrobial resistance should be seen in a ‘one health’ perspective (Sundberg & Schofield, 2009; OIE, 2013), in which human and animal health are addressed together, as zoonotic bacteria and commensals carrying transmissible genetic elements can be transferred between animals and humans both directly and indirectly via food and the surrounding environment. Currently, scarce data are available to estimate the extent to which animals and food contribute to the overall burden of antimicrobial resistance to public health. The contribution from resistant zoonotic bacteria, for example Salmonella, Campylobacter and livestock-associated Meticillin-resistant Staphylococcus aureus (MRSA) (ECDC, EFSA & EMA, 2009), is relatively easy to track as this represents a direct clonal spread which will likely follow similar patterns independent of the type of resistance involved. One example of such a scenario is presented in the paper by Dutil and co-workers (Dutil et al., 2010) who discussed ceftiofur resistance in Salmonella in Canada. However, the contribution that such clonal spread represents in terms of the overall burden on human health from resistant bacteria originating from animals remains unknown. Furthermore, the contribution made by genetic elements responsible for resistance that are transferred via food is more difficult to map as the link between the transfer of resistance between animals and humans is then complicated by the rate and likelihood of transfer of genes between bacteria of animal and human origin. Tracing bacteria alone would then not be sufficient. Mapping of resistance genes and mobile genetic elements is also needed as was used in the Netherlands, for example, where Overdevest and co-workers reported a high level of similarity between cephalosporin-resistant E. coli in retail chicken and humans in the same country in retail chicken and humans living in the same area (Overdevest et al., 2011, 2012), in one of the studies a high prevalence of ESBL genes was found in chicken meat. However, also in such cases where similarity in gene patterns is shown, causality needs to be further assessed. Transfer of resistance is not limited to food-producing species and, in the cases of companion animals, dogs and cats colonized with resistant zoonotic bacteria such as MRSA and E. coli may transfer their resistance to humans due to the tight human–animal bond (Guardabassi et al., 2004; Lloyd et al., 2007; van Duijkeren et al., 2011a,b). Likewise, horses may also be hosts for resistant bacteria of human concern (van Duijkeren et al., 2010). Transmission of resistant

bacteria from humans to animals has also been described (Wieler et al., 2011), this possible route of transmission should also be taken into account when analysing the complexity of the epidemiology of AMR. The European Parliament and European Commission have identified the risk of transmission of resistance from animals to humans as a key issue (European Commission, 2011). As a consequence, work to minimize public health risks related to AMR associated with animals and food has been intensified during recent years. In addition, there is an increased need to consider the animal health aspects of AMR as in the absence of new antimicrobial agents on the veterinary market, increased resistance levels in animal pathogens has the potential to compromise animal welfare and production. To date, lack of effective antimicrobial agents has not been reported as a major problem in veterinary medicine, at least not for foodproducing animals. However, there are reports of MDR bacteria such as Meticillin-resistance Staphylococcus Pseudointermedius (MRSP) in dogs (van Duijkeren et al., 2011a,b) for which antimicrobial agents currently authorized for veterinary use are ineffective. It is also possible that the problem of antimicrobial resistance in veterinary medicines might be larger than assumed as there are scarce data on resistance in target animal pathogens in the EU. Today, reporting of resistance in target animal pathogens is to a large extent limited to scientific publications and these are occasional. However, there are data indicating considerable differences between EU/EEA countries and some of the figures raise concern, particularly from Southern Europe (Hendriksen et al., 2008). Notwithstanding the fact that most cases of multidrug-resistant infections in humans are unrelated to veterinary medicine, there is a need to further consider the human-animal link. The ‘animal contribution factor’ to the overall resistance situation in human is likely to vary between EU countries and cannot currently accurately be estimated. However, even in the absence of a quantitative risk assessment, the data available to date are sufficiently concerning to require that the issue is given urgent attention. There is a need to have strategies to control the risk from AMR and programmes in place for implementation and monitoring of compliance. Such strategies should be balanced and consider both animal and human health aspects in a ‘one health’ perspective.

RISK FACTORS FOR EMERGENCE AND SPREAD OF AMR FROM ANIMALS TO HUMANS There are numerous risk factors involved in the ‘animal contribution’ to the overall risk to public health from AMR. To date, foodborne risks have been the main focus and, as most people are exposed to food of animal origin, these are deemed to be the most important risks to address. Intensive animal production systems appear to have a significant role as an amplifier of resistance, independent of its origin. This amplification is likely to be linked to the use of antimicrobial agents either of the same class as the one for which resistance is a concern or © 2015 John Wiley & Sons Ltd

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other classes with which the bacteria in question express co- or cross-resistance. Due to the phenomenon of co- and cross-resistance, this potential amplification may be problematic even in the case of antimicrobial agents that have never been authorized in food-producing animals such as carbapenems (Fischer et al., 2012). Besides use of antimicrobial agents, a variety of farm management factors such as insufficient biosecurity have been identified (Dewulf et al., 2007; Persoons et al., 2011) as being especially linked to the spread of resistance. To minimize spread, factors related to biosecurity and trade are important and, in addition, control of zoonotic diseases such as salmonellosis is a key factor. Thus, the idiom ‘prevention is better than cure’ expresses very well the gold standard for combating AMR. One example that deserves to be mentioned is the measures to reduce the dependency on antimicrobial agents in aquaculture in Norway by use of vaccines. Between 1992 and 1996, the therapeutic use in fish farming declined by 96% in spite of an increased level of production, mainly due to the introduction of effective vaccines against furunculosis (Markestad & Grave, 1997) and since then the consumption has continued to be very low (Norm-Vet 2011, 2012). In addition to preharvest factors (e.g. factors determining the occurrence of resistant bacteria in and on the animals at slaughter), the risk to humans will depend on whether or not these bacteria survive and amplify during slaughter and at retail. It could be assumed that any factor which is important for the overall microbiological risk assessment will also be of relevance for the risks from AMR as the pattern of survival and spread of bacteria during slaughter and retail is likely independent of whether or not they carry resistance genes. For this reason, hygiene at different steps during food production and handling is important to limit the spread of AMR.

DIVERSITY IN FARM MANAGEMENT AMR risk mitigation strategies in the EU are complicated by the fact that neither the market nor the legislation at national level is fully harmonized. One of the slogans of the EU is ‘united in diversity’. The EU consists of 28 member states with differences in history and culture. From reindeers in the north to buffalos in the south, the EU covers a variety of different kinds of animal production including intensive rearing systems, free range and small traditional family farms. Although regional differences can be identified such as having a higher number of smaller units in eastern Europe, generally there is a mix between intensive and extensive rearing systems throughout the EU. Broiler farming is an exception as it is built upon a pyramidal hierarchy with only a small number of parental stock at the top of the pyramid (European Commission, 2012). Swine production is also quite specialized with 75% of fattening pigs reared by just 1.5% of the largest production units (Marquer, 2010a,b). Animal transport between countries is a common practice, especially for pigs (Marquer, 2010a,b), which can accelerate transmission of disease and resistance across considerable geographical distances in a short space of time. The situation is © 2015 John Wiley & Sons Ltd

complicated as, although there is free movement of goods and animals within the EU, many important preharvest risk factors (e.g. farm conditions before animals are sent to slaughter) for spread of resistant bacteria are governed by national law and may therefore differ considerably between countries. In contrast, the regulation of marketing authorizations for veterinary medicinal products is harmonized in the EU/EEA by Regulation (EC) No 726/2004 (OJ L 136, 30.4.2004) and Directive 2001/82/EC (OJ L 331, 28.11.2001), as amended. There are two main routes to authorization, centralized and national. Although it is currently not obligatory, most new antimicrobial agents are centrally approved by the European Medicines Agency leading to the same approved conditions of use all over EU/EEA. In contrast, most of the older antimicrobial agents have been authorized through national procedures, with varying degrees of harmonization with respect to the authorized conditions of use. As a result, for noncentrally authorized antimicrobial agents, the terms of the authorization frequently differ between countries leading to product literature that includes different dosing strategies and even different species in which the product is approved. SURVEILLANCE OF CONSUMPTION AND RESISTANCE IN EU/EEA COUNTRIES European Surveillance of Veterinary Antimicrobial Consumption (ESVAC) Sales of antimicrobial agents are collected from EU member states/EEA countries by the European Surveillance of Veterinary Antimicrobial Consumption project which is run by the European Medicines Agency. Harmonized data are collated based on national sales figures collected at package level and published annually. The ESVAC applies an estimated animal biomass to normalize the sales data with respect to the animal population that can be subjected to treatment with antimicrobial agents. From the 2012 report, a significant difference in the sales, expressed as mg active ingredient sold per estimated animal biomass, is observed between the most- and least-selling countries (EMA/ESVAC, 2014) (European Medicines Agency). In addition, there are considerable differences observed also regarding the classes of antimicrobial agents used within the countries. For instance, consumption of tetracyclines is widespread in some countries, whereas penicillins dominates the market in others. This is in part likely to be due to differences in the composition of the animal population (e.g. more pigs than cattle, a high proportion of veal calves within the cattle population) in the various countries. There may also be considerable variation in terms of dosage used for the various antimicrobial agents, length of treatment period or formulation; this may also in part explain some of the differences between the countries. However, these factors can only partly explain the differences in the sales observed between the countries and suggest there may be room for reconsideration of some uses of antimicrobial agents in veterinary medicine in those countries with high relative consumption.

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Surveillance for resistance The EFSA is responsible for the surveillance of antimicrobial resistance in animals and foodstuff derived therefrom across the EU. EFSA also publishes baseline survey reports on the prevalence of antimicrobial resistance in the EU in specific animal populations, for instance MRSA in pigs, and provides guidance to national authorities on how to carry out their monitoring and reporting activities. Based on data provided by the EU member states, EFSA also produces, in cooperation with the ECDC, an annual European Union Summary Report on AMR illustrating the evolving situation in Europe. Data from 2010 cover resistance in zoonotic Salmonella and Campylobacter from humans, food and animals, and in the indicator organisms Escherichia coli and enterococci from animals and foods. Some data on MRSA in animals and foods are also included (EFSA/ECDC, 2012). Using the terminology, methodology and standards described in the relevant reports, antimicrobial resistant organisms are commonly detected in animals and food therefrom with considerable variability in prevalence between member states. In Salmonella and indicator E. coli isolates from fowl, pigs and cattle, and the meat thereof, resistance to tetracyclines, ampicillin and sulphonamides is the most commonly detected, whereas the prevalence of resistance to third-generation cephalosporins is still low. In addition, certain Salmonella isolates from turkeys, fowl and broiler meat are found to be nonwild type with regard to ciprofloxacin resistance (the fluoroquinolone antibiotic applied as indicator) in moderate-to-high levels. Campylobacter isolates from fowl, broiler meat, pigs and cattle are to large extent reported as nonwild type with regard to ciprofloxacin, nalidixic acid and tetracycline resistance, whereas the levels of nonwild type phenotypes were much lower for erythromycin and gentamicin resistance. Among the indicator enterococci isolates from animals and food, nonwild type bacteria with regard to tetracyclines and erythromycin resistance has been commonly detected. In addition to these foodborne bacteria, MRSA (predominantly ST398) has been detected in some animal species (EFSA/ECDC, 2012). No complete co-analysis has yet been presented where data on consumption of antimicrobial agents in animals is compared with resistance levels in different EU member states; however, an integrated analysis of the ECDC, EFSA and EMA has been published on the consumption of antimicrobial agents and occurrence of antimicrobial resistance in bacteria from humans and food-producing animals (ECDC, EFSA & EMA, 2015). To draw any conclusion about causality between consumption of antimicrobial agents in animals and the occurrence of resistance in animals, and foodstuffs derived therefrom, as well as in humans, further more detailed studies are required.

RISK MITIGATION STRATEGIES APPLIED IN THE EU Due to the perceived increase of risk from AMR and the lack of new antimicrobial agents, several bodies have expressed a need

to reinforce and expand the strategy to minimize AMR and to do so in a structured way across the EU. The Committee for Medicinal Products for Veterinary Use (CVMP) at the European Medicines Agency adopted in December 2010 their strategy on antimicrobial agents for 2011–2015, this being the third fiveyear CVMP strategy covering this area (EMA/CVMP, 2011). In this document, the need was expressed for an holistic approach involving an overall strategy for the use of antimicrobial agents in veterinary medicine in the EU. In 2011 and 2012, the European Parliament published three resolutions on AMR covering both human and veterinary medicine (European Parliament, 2011; European Parliament, 2012a,b). The two first resolutions were followed by an ‘Action Plan Against the Rising Threats from Antimicrobial Resistance’ from the European Commission in November 2011 (European Commission, 2011). These resolutions also point out the need for a holistic approach where one of the aims is to reduce the overall need for, and use of, antimicrobial agents in food-producing animals by promoting responsible use principles and by increasing biosecurity and disease control. The action plan of the European Commission includes considerations on whether or not there is a need to specifically restrict in the veterinary sector the use of certain antimicrobial agents that are newly developed or are classified as the most critically important for humans by the World Health Organisation (WHO, 2011). The holistic approach adopted in the European Commission’s Action Plan, covering the whole of the EU and all sectors of veterinary medicine (e.g. domestic animals, companion animals, horses etc.), is important, as AMR does not restrict itself to certain areas or certain sectors within veterinary medicine. This overarching EU strategy involves coordinating many activities to combat antimicrobial resistance in the animal sector in the EU where there are numerous actions ongoing. These include those that are both governmental and stakeholder initiated, national and local, and those that are recent and those that have been in place for decades. Below some examples are presented. Prescription status and nontherapeutic use The need to manage risks related to AMR has been acknowledged for many years within veterinary medicine. As early as 1968, the Swann report presented for the first time a comprehensive discussion on the risks to public and animal health due to AMR arising from the use of antimicrobial agents in veterinary medicine in Britain (Swann, 1969). In this report, both therapeutic and zoo-technical use of antimicrobial agents in animals are discussed with clear recommendations on how to minimize risks for resistance. The report concludes that ‘there are grave potential disadvantages for animal and humans health in adding in this way [as growth promoters] to the pool of organisms which are resistant to the antimicrobial agents of most value for the treatment of disease’ and suggests to classify antimicrobial agents into ‘feed antibiotics’ and ‘therapeutic antibiotics’ where the former could be used as feed additives only if they would ‘not © 2015 John Wiley & Sons Ltd

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impair the efficacy of a prescribed therapeutic antibiotic through the development of resistant strains or organisms’. In addition, the Swann report recommended that ‘therapeutic antibiotics’ should be available only ‘if prescribed by a member of the veterinarian profession who has the animals under his care’. This latter recommendation was implemented in the United Kingdom and has since been more widely adopted such that today all systemically used antimicrobial agents in EU member states and EEA countries are available only on prescription (EMA/ESVAC, 2013). As the international body responsible for food safety, Codex Alimentarius states that responsible use of antimicrobial agents does not include use in food-producing species for the purpose of growth promotion in case of compounds that belong to, or are able to cause cross-resistance to, classes of antimicrobial agents used (or submitted for approval) in humans in the absence of a risk analysis (Codex Alimentarius, 2009). Risks related to zootechnical use of antimicrobial agents have been discussed since the 1960s, and some European countries decided unilaterally to ban marketing authorization for some, or all, antimicrobial growth promoters (other than coccidiostatics of the ionophores class authorized as feed additives). Sweden was the first European country to discontinue all use of antimicrobial growth promoters in 1986. Other countries followed but it was not until January 1997 that the first antimicrobial agent (avoparcin) had its authorization withdrawn at EU level. This decision was followed by withdrawal of the authorization of other antimicrobial growth promoters, and since 1 January 2006, the authorizations of all antimicrobial agents for use as growth promoters have been withdrawn in the EU. The EU market has complied with this policy, but its’ impact remains somewhat controversial. It is argued that the use of antimicrobial agents as growth promoters has been replaced by an increase in their consumption for therapeutic purposes (Casewell et al., 2003). This assertion was, however, rejected by Grave et al. (2006) who analysed Scandinavian data and concluded that the discontinuation of antimicrobial growth promoters has considerably decreased the overall annual consumption of antimicrobial agents in animals in Denmark, Norway and Sweden. Danish data show an association between stopping the use of antimicrobial growth promoters and a reduction in the levels of antimicrobial resistance in food for some compound/bacteria/food combinations but not for others (Aarestrup, 2005; Aarestrup et al., 2010). Principles for responsible use of antimicrobial agents The single risk mitigation measure deemed most important by many bodies to decrease the risk of antimicrobial resistance from the use of antimicrobial agents in animals is to promote their responsible use (also termed ‘prudent use’). The World Organisation for Animal Health (OIE) defines responsible use in general in their Terrestrial and Aquatic codes (World Organisation for Animal Health (OIE), 2012);. These general recommendations are supplemented at EU level in terms of the more © 2015 John Wiley & Sons Ltd

detailed recommendations published by bodies such as the Federation of Veterinarians in Europe (FVE, 2012a,b), the multistakeholder European Platform for Responsible Use of medicines in Animals project (EPRUMA, 2013) and other, national, organizations such as the British Small Animal Veterinary Association (BSAVA, 2013). In addition, there are treatment guidelines available in many other member states of the EU. Denmark is the country in the EU that has developed the most detailed system for monitoring the responsible use of antimicrobial agents by veterinarians. Danish authorities provide the prescribers with information both with regard to choice of antimicrobial agent, dose and length of treatment (Danish Veterinary & Food Administration, 2013a,b). The European Commission is in the process of developing guidelines for the prudent use of antimicrobials in veterinary medicine, taking into account the experience gained in member states. In order to promote responsible use and assess to what extent it could be a valuable risk mitigation measure, it is crucial to know what is the actual practice of veterinary surgeons in terms of use and prescription of antimicrobial agents. For this reason, the Heads of Medicines Agencies in the EU (Heads of Medicines Agencies, 2013), in collaboration with the FVE, has recently conducted a survey of veterinarians across the EU to learn more about their prescription habits and a report of the results of the survey has been published (De Briyne et al., 2013). When discussing responsible use of antimicrobial agents, much of the focus has been on the choice of antimicrobial relative to the condition being treated, particularly with respect to the need to reduce or avoid certain molecules and classes. Of antimicrobial classes listed as critically important by WHO (WHO, 2011), fluoroquinolones, higher generation cephalosporins, penicillins, colistin, macrolides and aminoglycosides are approved for use in animals in EU/EEA. Supported by its Scientific Advisory Group on Antimicrobial Agents, the CVMP at EMA have presented risk profiles for the three classes of antimicrobial agents listed as highest priority for risk analysis by WHO (fluoroquinolones (EMEA/CVMP/SAGAM, 2007), 3rdand 4th-generation cephalosporins (EMEA/CVMP/SAGAM, 2009b) and macrolides (EMA/CVMP/SAGAM, 2011). Based on these risk profiles, the CVMP has recommended that fluoroquinolones and 3rd- and 4th-generation cephalosporins should only be used in cases which have responded poorly or are expected to respond poorly to other antimicrobial agents. Use of macrolides as first line treatment remains acceptable but in the case of macrolides administered orally, efforts should be taken to avoid underdosing and unnecessary long treatment periods. These recommendations are in compliance with most treatment guidelines and recommendations as presented by other national bodies in EU member states. Treatment guidelines for companion animals are available in some EU member states/EEA countries, for instance in the United Kingdom (BSAVA, 2013). To date, the main focus has been on minimizing the risk for resistance in target animal pathogens, but there is an increasing awareness of the zoonotic potential for AMR also from companion animals.

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MDR infections, such as those caused by MRSP, are getting more and more common (van Duijkeren et al., 2011a,b) and, as a consequence, veterinarians have started to prescribe substances that are used as last resort medicines to treat MDR infections in humans. Although no such compounds are approved as authorized veterinary medicines in EU member states/EEA countries, veterinarians are permitted to use antimicrobial agents authorized for human use, as off-label use is allowed in EU member states/EEA countries in exceptional cases where there are no approved veterinary medicinal products available to treat the condition in question. The CVMP of the EMA has published recommendations on antimicrobial use in the case of MRSP and suggests that treatment of MRSP with products containing substances listed by WHO as one of few alternatives to treat MRSA in human should be evidence based and restricted to very specific, carefully selected cases where the disease is life-threatening and alternative treatments (including nonantimicrobial treatments) have failed. The CVMP further recommends that MRSA carriers, animals in contact with people with confirmed MRSA infection of people at high risk for MRSA infections, should not be treated with such antimicrobial agents (EMEA/CVMP/SAGAM, 2009a). Means and targets to reduce consumption The issue of whether or not reducing the use of antimicrobials agents in veterinary medicine should be a target in itself is a controversial issue. Some consider that every effort should be taken to reduce consumption to the minimum possible, whilst others consider that reduced consumption may merely be an indirect outcome arising from measures to promote responsible use. Many authorities consider there is scope to reduce the consumption of antimicrobial agents, that reducing use will reduce the exposure of microbial agents to antimicrobials agents and that this is beneficial in itself in terms of reducing overall selection pressure. On this basis, measures to reduce the overall consumption of veterinary antimicrobial agents are applied in several EU/EEA countries to reduce their use to a level assumed to be more appropriate than would occur without additional control. The measures applied to achieve a reduction range from the setting of voluntary targets to the compulsory separation of the prescription from the actual sale of veterinary antimicrobial agents. The intention is that this will reduce any financial incentive that veterinary surgeons may have to prescribe antimicrobial agents (so-called decoupling). Due to the wide difference in attitude to the sales of veterinary medicines by veterinarians in different member states of the EU, decoupling is currently a controversial issue at EU level. For examples, in Scandinavian countries, legislation on decoupling of prescription from sales has been in place for many years. In 1994, Denmark restricted the profit that veterinarians could generate from sales/delivery of prescription only medicines to the farmers. Following the introduction of this measure, a 40% reduction was observed in the consumption of antimicrobial agents for therapeutic use in 1 year (Grave et al.,

2006). It should be noted that Finland, Norway and Sweden, together with Iceland, have all decoupled sales and prescription and now have the lowest sales figures for veterinary antimicrobial agents in EU/EEA per estimated animal biomass (EMA/ESVAC, 2013). In the Netherlands, the possibility of introducing a decoupling system was discussed in the so-called Berenschot report in 2010 (Beemer et al., 2010). In contrast to the Nordic countries, this report concluded that the decoupling of prescription and sales would be difficult to achieve in the Netherlands due to the lack of independent sales channels to replace sales by veterinarians and due to the structure of veterinary practice within the country. There was also uncertainty as to whether or not decoupling alone would achieve the desired reduction in sales. Instead a system requiring there to be a one-to-one relationship between farmers and veterinarians was proposed and has been put in place to restrict the ability of consumers of antimicrobial agents to ‘shop around’ for their supplies. At the same time, the Netherlands set a target for a reduction of the overall sales by 50% within 4 years with 2009 as the reference year. This target has already been met in 2012 (MARAN, 2012) through the combination of measures applied. In Denmark, further activities have been initiated to reduce consumption of antimicrobial agents in pig production in particular. A sophisticated system has been developed where the consumption on each farm is monitored in relation to a standard consumption pattern set for each type of production (sows, neonates/weaners and fattening pigs). Consumption above the standard pattern for the production type results in the generation of a ‘yellow card’ which triggers investigation into the reasons for raised consumption by the relevant authority. Ultimately, the possibility exists of penalties being applied in the case of persistent high usage without an appropriate explanation (Danish Veterinary & Food Administration, 2013a,b). French authorities have recently produced a plan to reduce antibiotic consumption in veterinary medicine by 25% in 5 years focussing particularly on reducing the consumption of critically important antimicrobial agents and, in particular, fluoroquinolones, and third- and fourth-generation cephalosporins (French Directorate-General for Food, 2013). These examples show the range of measures that can be applied to reduce the consumption of veterinary antimicrobial agents. The success of setting arbitrary targets for reducing consumption in countries that do not currently apply controls, other than the requirement that all antimicrobial agents are subject to veterinary prescription, appears to show that there is scope for further control. In order to be effective, detailed analysis is required of the form that these additional control measures should take in order to match the needs and nature of the animal production system, the veterinary profession and the distribution systems for veterinary medicines. It is unlikely that a ‘one size fits all’ approach to control would be appropriate to cope with the wide diversity that exists within the EU. © 2015 John Wiley & Sons Ltd

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Restriction of use of certain antimicrobial agents Finland is the only EU Member State where there are legally binding restrictions against use of some listed antimicrobial agents which are classified as ‘last resort medicines’ for humans (Act No 847/2008, see http://www.finlex.fi/sv/laki/ alkup/2008/20080847), and this is the only active ban against certain listed substances/uses currently applied in EU. This is in contrast to some other countries such as the United States of America where the use of fluoroquinolones in poultry in water was finally withdrawn from the market in 2005 (FDA, 2005). Nevertheless, there are other legally binding systems in place in some countries, for example Denmark and Sweden, where certain antimicrobial classes, for example fluoroquinolones, may only be used in exceptional circumstances and with permission from competent authorities.

ALTERNATIVES TO USE ANTIMICROBIAL AGENTS Many risk mitigation strategies focus on the possibility to reduce the consumption of (all or certain) antimicrobial agents without compromising animal health and welfare.. The ways in which this could be achieved are discussed in general terms in the European Commission action plan against the rising threats from antimicrobial resistance (European Commission, 2011) where increased biosecurity and disease control is mentioned as an important part of the strategy. To achieve the goal of increased animal health with less need for antimicrobial agents, much research has been focussed in recent years into the development of alternatives to such medicines. These alternatives take a wide variety of forms, representing a range of different approaches. In principle, alternatives may be based on immunological, biological or pharmaceutical means of controlling infections in the host. In terms of immunological approaches, the rise in AMR, and in the threat of AMR, has made the development of vaccines against bacterial diseases more attractive to pharmaceutical companies and their use more attractive to food consumers. The main limitations on the use of vaccines as alternative to antimicrobial agents are that they must be used prophylactically and that they provide protection only against one or a small number of specific infectious diseases at a time. There has been a tendency in recent years to market multivalent vaccines that protect against a number of different organisms associated with a particular disease syndrome, such as bovine respiratory disease or clostridial diseases of young animals. An alternative immunological approach is to stimulate nonspecific rather than specific immunity. This has the advantage that enhancing innate immunity increases protection against a range of pathogens. This can be achieved either with active ingredients that stimulate innate immunity in a nonspecific way or through the use of actives with specific, and known, biological activity. Nonspecific immune enhancers such as saponin and dextrans have been used for many years as adjuvants in a wide variety of vaccines. In recent years, nonspecific © 2015 John Wiley & Sons Ltd

immune stimulants are being developed as stand-alone products that are administered either to increase levels of general immunity in animals identified as at risk of syndromes such as respiratory or enteric disease or to boost the response to vaccination (Baca-Estrada et al., 2000; Zaharoff et al., 2007). One of the most interesting current biological approaches to controlling infections is through manipulation of the host microbiome (i.e. the natural microbial population of the host). Products affecting the microbiome are not new and have been marketed for many years in the form of bacterial populations used as probiotics and ‘competitive exclusion’ products, that is those where pathogenic bacteria are excluded from the host by competition with innocuous bacteria, usually introduced in the form of an additive to food (Patterson & Burkholder, 2003; Huyghebaert et al., 2011). Rapid progress is now being made in terms of understanding the mechanisms that underlie the homeostasis of the microbiome and how it can be manipulated. Gut transfer experiments, the use of genetically defined host recipients and the ability to apply massive parallel DNA sequencing are all starting to suggest ways in which the microbiome of domestic animals, particular pigs and chicken, might be manipulated to increase their resistance to disease and thereby reduce the need for antibiotics (Qu et al., 2008; Yang et al., 2009). The use of bacteriophages remains an area of some interest in circumstances where the target pathogen is clearly identified and known to be susceptible to the phage concerned. Although some phage products are marketed with more widespread indications, evidence for sustained efficacy in the field remains lacking (Callaway et al., 2008; Volozhantsev et al., 2011). In terms of alternative pharmaceutical products that can be used in place of antimicrobial agents, these are mostly directed to replacing antimicrobial agents with ‘natural’ ingredients such as phytonutrients (Patterson & Burkholder, 2003) or heavy metal compounds (Katouli et al., 1999) to affect gut physiology and function; however, heavy metals may act as coselectors for antibiotic resistance (Baker-Austin et al., 2006; Seiler & Berendonk, 2012).

SUMMARY Due to the fact that selection pressure for resistant strains is an unavoidable consequence of the use of antimicrobial agents, efforts have been taken in EU to limit the use of such medicines. In the veterinary field, the main focus has been on minimizing the risks arising from foodborne bacteria expressing resistance of public health concern. Risk management activities are in place both nationally and at EU level and include measures to reduce the need for antimicrobial medicines by promoting responsible use, biosecurity and disease control and, in addition, efforts are taken to develop alternative treatment options. Antimicrobial agents are only used for therapeutic purposes, that is not for growth promotion, and their use is subject to veterinary prescription. To further reduce the overall use of antimicrobial agents, targets for reduced consumption have been set at

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national level in some EU member states/EEA countries, and in some countries systems for ‘decoupling’ of prescription from sales have also been introduced. Currently, some classes of antimicrobial agents (fluoroquinolones and 3rd- and 4th-generation cephalosporins) are recommended for use only in cases that would respond poorly to other antimicrobial classes.

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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 agen...
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