Antimicrobial resistance, equine practitioners and human health: A true One Health issue or political interference?

Abstract

Political attention to antimicrobial resistance (AMR) has never been greater. Governments worldwide are concerned that AMR threatens to undo modern medical achievements with the spectre of a post antibiotic era in which commonplace infections, once eminently treatable, become nontreatable causes of serious morbidity and mortality 1. With suggestions that AMR and multi-drug resistant organisms are as important as climate change and could cast the world back into the dark ages of medicine, ranking alongside terrorism as matters of national risk 2, 3, the political landscape on this subject has been clearly set. Concerns about AMR and its health impact are, of course, not new and began at almost the same time as the introduction of antimicrobials. In 1945, just after the introduction of penicillin as a therapeutic agent in humans and animals, Fleming warned in his Nobel Prize acceptance speech that misuse of antimicrobials could result in bacterial resistance. This prediction rapidly became true with the discovery of each new class of antimicrobial quickly followed by the appearance of resistance to it. By the 1960s there was widespread realisation, and acceptance in the scientific community and lay press, that antimicrobial use (and misuse) resulted in rapid selection for resistance against all classes of antimicrobials. What is new, and has changed the political and regulatory landscape for AMR completely, is the realisation that science is not able to out-pace the microbes. There have been no completely new classes of antimicrobials discovered and brought to market since the 1980s, perhaps not surprising given the relatively small range of bacterial targets and the rapid rate of antimicrobial discovery during the ‘golden age’ from the mid 1940s onwards 4. Although there are some rays of hope, for example the recently reported new compound ‘teixobactin’ 5, the pipeline for new antimicrobials is practically dry. In other words, the solutions to AMR must come from within the medical, veterinary and animal industry sectors by addressing the underlying causes of, and changing the therapeutic approaches to, infectious disease. The political and scientific view that antimicrobials can no longer be regarded as the panacea or ‘magic bullet’ capable of eradicating infectious disease is widely accepted, and it is now clear that the human and animal health care sectors need to respond accordingly. A major challenge for the politicians is that there are still significant gaps in the surveillance data required to fully understand the drivers of AMR in both humans and animals 6, 7 and, critically, to measure the effects of interventional measures to reduce AMR. It is therefore not surprising that scientific opinion continues to be divided on practically every key question about AMR except that it is now a serious global problem causing significant economic loss with welfare, morbidity and mortality impacts in humans and animals. Antimicrobial resistance is a natural phenomenon: bacteria produce antimicrobial substances as part of their repertoire to compete in the struggle for colonisation, space and nutrients. Resistance therefore existed long before the introduction of antimicrobial drugs: the effect of using antimicrobials has been to accelerate AMR through classical selective pressure. That this has happened in both veterinary and human populations of bacteria is not disputed; the evidence for interconnection of AMR in these two populations is, however, inconclusive and is the subject of continuing political and scientific debate with contradictory evidence produced by both sides 8-10. It does appear that antimicrobial use in animals increases AMR in animal bacteria and that treating people with antimicrobials increases AMR in human bacteria. However, current scientific evidence does not allow definitive assessment of whether reducing antimicrobial use in animals has reduced AMR in medical pathogens. The extent to which AMR in populations of animal bacteria threatens public health therefore remains uncertain. The evidence for resistance in animal bacteria acting as genetic reservoirs of resistance for transfer to bacteria of public health importance is also inconclusive. Even for zoonotic bacteria such as Salmonella typhimurium DT104, the links between animal and human bacterial populations have become less clear with the application of sophisticated molecular typing bacterial methods and population genetics adding new complexity to the AMR debate 11. However, the lack of conclusive evidence notwithstanding, the prevailing political and regulatory opinion continues to be that antimicrobial use, and associated AMR, in animals is a driver of AMR in medical pathogens and that controlling veterinary prescription of antimicrobials will help safeguard public health. The ongoing political and public health scrutiny of veterinary use of antimicrobials is not surprising and the assumption that veterinary antimicrobial use contributes to, or is perhaps even directly the cause of, AMR in human medicine is understandable. The fact that the classes of antimicrobials used in veterinary and human medicine are the same 12; that food-borne and other zoonotic infections provide an opportunity for transfer of resistant bacteria from animals to humans; that populations of pathogenic and nonpathogenic animal bacteria may act as genetic reservoirs of resistance for important medical pathogens, with close contact between people and companion animals, in addition to food products, providing opportunity for genetic exchange; and, perhaps most importantly from a political perspective, that in many countries around the world the total quantity (gross weight) of antimicrobials used in veterinary medicine is greater than in human medicine 13, 14, has put antimicrobial use in animals at the centre of the public health AMR debate. When combined with the use of antimicrobials for disease prevention at herd or flock level and, in around half of the world's countries, for growth promotion, it is little wonder that antimicrobial use in animals has resulted in sustained political concern over the contribution that veterinarians and the animal sector in general may be making to the growing crisis of antimicrobial resistance in humans, with frequent calls for restriction or even banning of veterinary use of antimicrobials. Despite numerous political recommendations that coordinated, overarching surveillance of AMR is implemented at national and international level 15, 16 there are still relatively few examples of harmonised and integrated surveillance in humans and animals that allow comparison of data. Examples include The National Antimicrobial Resistance Monitoring System (NARMS) in the USA, Canadian Integrated Program for Antimicrobial Resistance Surveillance (CIPARS) in Canada, Japanese Veterinary Antimicrobial Resistance Monitoring System (JVARM) in Japan and several European schemes including Danish Integrated Antimicrobial Resistance Monitoring and Research Programme (DANMAP) (Denmark), NORM-VET (Norway), Swedish Veterinary Antimicrobial Resistance Monitoring (SVARM) (Sweden) and NethMap/Monitoring of Antimicrobial Resistance and Antibiotic usage in Animals in the Netherlands (MARAN) (the Netherlands). At EU level, the European Food Safety Authority (EFSA) and the European Centre for Disease Prevention and Control (ECDC) monitor AMR in the food chain and food-borne zoonotic pathogens, but not in companion animals. In the absence of sufficient scientific evidence about AMR, in particular the key question of the impact of veterinary antimicrobial use on public health, politicians around the world have faced difficult decisions. In the absence of scientific certainty politicians have adopted the ‘precautionary principle’, allowing preventive action to be taken when there is a possibility of harm but where the scientific evidence is not sufficiently complete to allow full assessment. The result in Europe is a continuing European political focus on banning or restricting veterinary antimicrobial use, especially in the agricultural sector, and reducing the total quantities of antimicrobials used in animals. In the political and regulatory environment in the USA, the precautionary principle has been applied somewhat differently with less political appetite for banning or restricting antimicrobials 9. The first active political engagement with antimicrobial resistance occurred in 1968 in response to growing concerns over multidrug resistant Salmonella in humans and animals, with the establishment of an independent advisory committee by the UK Government chaired by Professor Michael Swann. The Swann Report 17, published in 1969, recommended restriction of the use of antimicrobials as growth promoters, which took 45 years to fully implement in Europe, and establishment of overarching monitoring of AMR in humans and animals, which has still not been implemented globally. Almost 50 years on, this report continues to set the political stage in relation to veterinary antimicrobial use and possible impacts on human health. We would do well not to lose sight of the lessons learned in the decades following its publication, specifically that sensible recommendations based on competent assessment of the available, even if incomplete, scientific evidence should not be sidelined pending collection of conclusive evidence; instead the two should progress in parallel with continuous monitoring and refinement as evidence is gathered. The global political thrust in relation to AMR in the human and animal health sectors continues to be that overuse of antimicrobials is the cause of the problem and that reducing their use is the solution. In Europe, most political effort since 1969 has been directed at the food animal sector through reducing the use of antimicrobials as growth promoters and, more recently, reducing total antimicrobial use. It was not until 2006 that a EU-wide ban on antimicrobial growth promoters was eventually implemented, completing a political process that had started four decades previously with the banning of tetracycline, penicillin and streptomycin for growth promotion in 1974, followed by complete bans of antimicrobial growth promoters in Sweden and Denmark in 1988 and 1994. Denmark also implemented restrictions on veterinary dispensing of antimicrobials; decoupling veterinary prescription of antimicrobials from supply remains on the European political agenda and, if implemented, would have significant impact on veterinary practice business models in many countries. Monitoring, and reducing, antimicrobial use has become a key global political driver. The European Medicines Agency monitors the sales of antimicrobial agents for food producing animals and horses across Europe 18 providing benchmarks against which political targets for reduction are set. In some countries governmental targets for reduction in the sales of veterinary antimicrobials have been agreed with stakeholders. For example, the Netherlands decreased sales of antimicrobials by 49% between 2010 and 2012 with further reduction targets agreed; antimicrobial sales in Scandinavia have been progressively reduced through a series of government–stakeholder agreed targets 18. Nevertheless, the estimated consumption of antimicrobials (corrected for estimated biomass) in animals continues to be greater than in humans across Europe as a whole 6. It is becoming increasingly clear, however, that the concept of overuse as the key driver of AMR may be overly simplistic 19. Antimicrobial resistance is a complex public and animal health issue and there is recognition that integrated strategies across all sectors, backed by political will, stakeholder buy-in and sufficient economic support, are required to control it 1. Although overprescribing of antimicrobials is undoubtedly an important factor, reducing their use in human medicine has not consistently resulted in reduction of resistance for key pathogen–antimicrobial combinations with examples of resistance remaining apparently stable or even increasing despite reduced antimicrobial use. The question of whether phasing out antimicrobials as growth promoters across Europe and the restrictions placed on therapeutic use of antimicrobials in Scandinavia, with associated reductions in quantities used, has resulted in a positive impact on human health continues to be the subject of scientific and political disagreement. Responsible, or ‘prudent’, use of antimicrobials has emerged as a parallel precautionary approach to the control of AMR. Initially, the political focus was on restricting veterinary use of antimicrobials used to treat multidrug resistant human pathogens presenting significant risk to public health. Since 2005 the World Health Organization has published lists of ‘critically important antimicrobials for human medicine’, ranked according their importance with the goal that their use should be restricted in all sectors to preserve their effectiveness 20. This approach has been extended by the World Organisation for Animal Health (OIE) with the publication of a list of antimicrobials of veterinary importance which contains recommendations for restricting the use in food animals of antimicrobials that are critically important for both human and animal health 21. This list includes fluoroquinolones and third- and fourth-generation cephalosporins and forms a rational basis for responsible guidelines worldwide. There are several examples of stakeholder groups at national and international level that have responded to the AMR challenge and shown leadership in producing responsible use guidelines. In the late 1990s the UK veterinary and farming sectors established the RUMA (responsible use of medicines in agriculture) alliance and in 2005 EPRUMA (European platform for responsible use of medicines in animals) was established. Stakeholder groups have now produced a variety of responsible use guidelines for antimicrobials in veterinary practice. Examples include general guidance to veterinary practitioners from the British Veterinary Association (BVA) and the Federation of Veterinarians in Europe (FVE), guidelines on antimicrobial use in companion animal practice from the Federation of European Companion Animal Veterinary Associations (FECAVA), the British Small Animal Veterinary Association (BSAVA), the American Veterinary Medical Association (AVMA) and in equine practice from the British Equine Veterinary Association (BEVA). Widespread adoption of responsible use guidelines in equine practice is an important goal, coupled with accurate recording of use (as, for example, already happens in Scandinavia), that will go some way to addressing political concerns about the prescription of critically important antimicrobials and cascade prescribing by veterinarians, including equine practitioners 22, 23. It is understandable, given the importance of food-borne zoonotic bacteria, that the political lens has thus far been focused mainly on the food animal sector. It is only recently that antimicrobial use in companion animals and horses has received political attention 7, 24 probably because comparatively small quantities (<10% of total quantities sold each year) of antimicrobials are used in these species 18 and because of a public health focus on food-borne pathogens. There are now recommendations that systematic international surveillance of AMR is established for companion animals and horses and a recognition that the close relationship between people and companion animals may provide new opportunities for transfer of resistance to human pathogens 7, 24. Antimicrobial resistance is now a highly important One Health issue with political impact squarely on companion animal and equine veterinary medicine; it is no longer a subject confined to the food animal sector. Antimicrobial resistance is, of course, also important for companion animal and equine health with multidrug resistant pathogens such as meticillin-resistant Staphylococcus aureus (MRSA) causing clinical disease in horses and with evidence of transfer of MRSA between humans and horses 25 and of carriage in horses 26. As would be expected, therapeutic treatment of horses with antimicrobials temporarily increases the prevalence of resistant sentinel Escherichia coli, including multidrug resistance and production of extended spectrum β-lactamases 27, acting as a reminder of the impact of ‘routine’ veterinary therapy on microbial populations. The message is clear that it is time to apply common sense and sound scientific principles to address AMR in equine practice. As a minimum, further surveillance in horses is required, along with universal adoption of responsible use guidelines 28. Irrespective of the scientific uncertainties, AMR is a true One Health issue that is relevant to the equine industry. Whatever the political dimensions of this debate it is essential that the equine veterinary profession and equine industry continue to engage actively with the AMR agenda, promote public and political confidence by demonstrating leadership through responsible use of antimicrobials and monitoring of AMR, and participate in evidence-based practice.