Antimicrobial use and antimicrobial resistance in horses

‘It is time to close the book on infectious diseases, and declare the war against pestilence won 1’. ‘The end of antibiotics, question mark? Well, now I would say you can change the title to The end of antibiotics, period 2.’ The first statement, incorrectly attributed to United States Surgeon General Dr William H. Stewart 1 and the second, recently uttered by Dr Arjun Srinivasan, Associate Director of the US Centers for Disease Control and Prevention 2, highlight the extremes of our confidence and concerns regarding infectious diseases and antimicrobial resistance. In less than a century, we have gone from the preantibiotic era, where bacterial infections were often fatal, through a phase of profound optimism based on the development of life-saving antimicrobials, to today's concern that this society-altering therapeutic approach may be entering its final phase. Like most controversies, the truth probably lies in between. Antimicrobials will continue to be critical and generally effective treatments for bacterial infections, but their usefulness will be countered by the ability of bacteria to resist their effects. In veterinary medicine, an additional challenge is encountered as there are pressures to restrict access to certain drug classes because of concerns about resistance in man. Antimicrobial resistance is a concern in a wide range of equine pathogens, including Salmonella, Escherichia coli and other Enterobacteriaceae, staphylococci, Klebsiella, Pseudomonas, and a wide range of other opportunistic pathogens. Identification of some high profile pathogens in horses, especially potentially zoonotic bacteria such as extended spectrum β-lactamase (ESBL)-producing Enterobacteriaceae 3-5, methicillin-resistant Staphylococcus aureus (MRSA) 6-8, and multidrug resistant Salmonella 9-11, has focused attention on antimicrobial resistance in horses. Beyond just identifying these pathogens in horses, studies implicated antimicrobial use in the emergence and dissemination of ESBL Enterobacteriaceae and MRSA 4, 5, 7, 8, and it is clear that use of antimicrobials can play a direct role in selection for resistance pathogens. This is not surprising, but focuses attention on antimicrobial use practices in horses and the potential animal and public health impacts. While pathogens such as ESBL-producing Enterobacteriaceae and MRSA attract much attention, are clearly important and appear to have become endemic in horses in many regions, they are likely to represent a small fraction of clinically relevant resistant bacteria. Despite not having a specific name such as ‘MRSA’ or ‘ESBL’, any infection caused by a bacterial pathogen that is refractory to antimicrobial treatment because of resistance is of concern. Understanding of the scope of resistance in the general horse population is relatively limited. Targeted research studies 12 and summaries of data from diagnostic laboratories are available from many regions 13-15, and although interesting data, one must remember that any study based on referral hospitals or culture data from diagnostic laboratories is likely to be biased. Referral hospitals tend to see a skewed study population of animals with more serious illnesses and more antimicrobial exposure, both in the hospital and prior to admission. Laboratory data only represent horses from which samples were submitted for culture, something that is biased towards horses that have more advanced disease or that have failed initial empirical treatment. The net result is a likely over-estimation of antimicrobial resistance, as horses with infections caused by susceptible bacteria that responded to empirical therapy are not captured. This is not meant to suggest that resistance noted in those types of studies is not of concern. Rather, it is meant to highlight yet another data gap that hampers assessment of the state of antimicrobial use and resistance in horses. Prospective unbiased surveillance activities are needed to better understand these issues, but these are expensive, time consuming, and tend to receive little interest from regulatory agencies focused on people or food animals. Evaluation of antimicrobial use in horses is challenging. It is difficult, if not impossible, to determine the volume of antimicrobials used in horses in most countries. Lack of this basic information hampers assessment of antimicrobial use practices and antimicrobial stewardship programmes. Moving beyond ‘how much’ antimicrobial use occurs in horses, an answer to the question ‘how are antimicrobials used in horses’ is similarly limited. Numerous studies have evaluated antimicrobial prescription practices in human medicine, often reporting excessive use and prescription in situations where bacterial infection is unlikely (e.g. viral upper respiratory tract infection) 16-18. Corresponding data are very limited in horses, restricted to a small number of studies focused on specific regions or conditions. These provide some initial insight and raise concerns. For example, a questionnaire administered to a cohort of British equine clinicians identified common use of inappropriate dosing regimens and widespread lack of antimicrobial use guidelines 19. As part of that study, responses to different scenarios were evaluated and there was a high tendency to recommend antimicrobials for horses with signs consistent with recurrent airway obstruction, a nonseptic process 19. This is consistent with a Canadian study where 69% of horses diagnosed with nonseptic inflammatory airway disease had been treated with antimicrobials prior to diagnosis, with many horses having received multiple courses of different drugs 20. Description of antimicrobial use for colic surgery has also been reported 21, 22, with one study identifying poor compliance with standard perioperative prophylaxis recommendations 22. These few studies certainly raise concerns but do not provide much direct insight into overall antimicrobial use practices in horses, particularly in ambulatory practice, where the bulk of antimicrobial use presumably occurs. Observational studies have been reported in small animals through the use of retrospective evaluation of medical records or prospective logbook-based study 23, 24. These have identified concerns about excessive and unnecessary use of antimicrobials and inappropriate use of broad spectrum drugs and antimicrobial prescription in situations where bacterial infection is unlikely, consistent with concerns in others species. Detailed studies such as these are needed in equine medicine to obtain a better grasp on antimicrobial use practices in horses, to understand better how antimicrobials are used, to identify concerns and to determine ways to optimise antimicrobial use practices. If, as is likely, deficiencies in antimicrobial use are present in equine medicine, an important question to ask is ‘why’? Is it because of inadequate clinician knowledge of infectious diseases and antimicrobial use? Is it lack of recognition by equine veterinarians of the need for antimicrobial stewardship? Is it from the desire to ‘do something’ in response to a sick horse, even if infection is probably not present? Is it because of pressure (true or perceived) from horse owners? Pressures from owners to use antimicrobials or use reserved antimicrobials can be particularly intense with expensive competition horses, despite the fact that horse worth has never been identified as a risk factor for antimicrobial resistance or treatment failure. Therefore, corresponding measures need to be directed at horse owners and caretakers to reduce the pressure to unnecessarily prescribe antimicrobials, to reduce the use of antimicrobials as a way to compensate for poor management and biosafety practices and, in some regions, to reduce self-directed antimicrobial administration that is made possible by over-the-counter availability of antimicrobials. Increased understanding by owners of the potential adverse consequences of antimicrobial use (e.g. colitis, antimicrobial resistance) is also required. Antimicrobials are critical drugs in equine medicine. As concerns about resistance in human pathogens and perceptions of overuse of antimicrobials in animals increase, there is likely to be increased pressure to restrict veterinary use of antimicrobials. Maintaining the balance between animal and human health is also challenged by political agendas, nonevidence-based decision making and reluctance to engage in productive discussion. Approaches to antimicrobial use in horses vary greatly between countries, ranging from completely uncontrolled to highly restrictive. Recent decisions to ban the use of certain drug classes in animals in some countries (e.g. Sweden, The Netherlands) should raise concern among equine clinicians. The question ‘does rare and controlled use of critically important antimicrobials in horses constitute any true public health risk compared to their widespread use in other animals?' remains unanswered. Proposals to ban dispensing of antimicrobials by veterinarians continue to arise, something that could have a profound impact on the practice of veterinary medicine in countries where veterinarians dispense medication. Although these are typically strongly opposed by veterinary organisations on the basis of a lack of evidence of a problem, those same organisations have done little to transparently consider and discuss the reasonable concerns about conflicts of interest when prescription and sale are linked. These issues, combined with the direct impacts of antimicrobial resistance on equine cases, should be a stimulus for equine clinicians and the broader equine industry to take these concerns seriously. Banning antimicrobial use in horses is impractical (and unethical from a welfare standpoint), but some current practices may be equally unjustifiable. The concept of antimicrobial stewardship must come to the fore, not just among academics, public health personnel and specialists, but also among primary care equine clinicians and equine caretakers. This requires education, research, communication and a willingness to change. ‘Cultural’ inertia, whereby there is resistance to change because ‘that's the way we've always done things’ is a major challenge in the equine industry. ‘Accepted’ incidences of disease and treatment may not necessarily be optimal or ‘acceptable’, and a willingness to challenge dogma and make changes is required for the advancement of horse care and equine medicine. Various measures to optimise antimicrobial use need to be considered. Although specific clinical treatment guidelines are now widespread in man and being introduced in small animals 25-27, these are limited in horses. Broad guidelines, such as the American College of Veterinary Internal Medicine consensus statements on antimicrobial use 28, 29 raise many important issues for clinicians to consider, but offer less specific guidance about how to treat individual cases. Development of recommendations that can be used to guide (but not dictate) clinicians in common clinical situations is needed to supplement these position statements 30. Although not designed to be standard of care and not covering all possible situations, clinical practice guidelines can help guide clinicians to more effective antimicrobial use and stimulate more thought. However, although improved understanding of antimicrobial use is important and adherence to guidance is desirable, there are major deficiencies in available guidance. Is there much objective evidence behind most of our antimicrobial approaches? It is concerning that many (if not most) antimicrobial use decisions in equine medicine are based on limited evidence but abundant anecdotes. When one delves into the literature to assess common use practices and recommendations, there is strikingly little information about optimal drugs, doses and durations for most conditions. Even antimicrobial label recommendations can run contrary to pharmacokinetic data and principles, with some commonly used drugs having outdated or questionable dosing regimens 28, 30. This does not necessarily mean that current practices are unacceptable. Rather, it means we do not know whether they are optimal from both clinical efficacy and antimicrobial resistance standpoints, as the desired outcome of any antimicrobial treatment should be to cure the case and minimise the risk of resistance. It is likely that antimicrobials are often misused and overused, and sometimes underused, but defining these requires investigation that is all too rare. Times are changing, and veterinary medicine must change in concert. As scrutiny of antimicrobial use practices increases and some countries take steps to limit access to certain antimicrobials in animals, veterinarians must find the balance between optimising patient care and minimising the potential impact on human health. Human medical and public health groups often point their fingers at veterinary medicine for overuse and misuse of antimicrobials. In return, some veterinary groups highlight well-documented misuse in man. However, in doing so, both groups miss the point that everyone who uses antimicrobials, from physician to veterinarian to animal owner, has a role to play, and as equine veterinarians, we can only realistically have an impact on antimicrobial use in horses. Rather than pointing fingers, we have to realise that virtually all groups that use antimicrobials sometimes (or often) use them improperly, and that we all must change. A head-in-the-sand approach to antimicrobial resistance has been proved ineffective, and the same type of approach to concerns about antimicrobial use in horses will be similarly useless. If efforts are not undertaken by us, an opening is created for other groups to make change for us, and it is unlikely that measures directed from outside the equine industry would be focused on optimal equine health care. Fortunately, internal efforts are increasing, as is awareness of the issues by some equine clinicians. Measures such as voluntary auditing of antimicrobial use practices (http://www.beva.org.uk/useful-info/Vets/Guidance/AMR/monitor) and the British Equine Veterinary Association's PROTECT ME toolkit (http://www.beva.org.uk/useful-info/Vets/Guidance/AMR) begin to offer practical measures that can engage general practitioners. Efforts to support these programmes and develop complementary programmes are needed to continue to build momentum in antimicrobial stewardship. Antimicrobial stewardship is a term that is increasingly recognised, but translation of principles into action can be difficult. As clinicians, our focus is rightly on the best outcome for our patients and their owners. However, the ‘best outcome’ may not be as clear as we once thought. Resolution of disease through a particular treatment regimen may be perceived as the best clinical outcome at that instance, but if it is accompanied by the emergence of antimicrobial resistance that could more broadly affect horses or people, it may not be the ideal result. Balancing ivory tower concepts, regulatory pressures and the realities of clinical equine medicine is a challenge, but one that needs to be met proactively. It is unlikely that we will completely conquer antimicrobial resistance, at least in the near future, and it is equally unlikely that the end of the antibiotic era is truly upon us. Antimicrobial stewardship must be embraced to maintain efficacy and access to antimicrobials. This requires a multifaceted approach, but particular emphasis should be given to the last two components of PROTECT ME: monitoring and education. A better understanding of antimicrobial use and antimicrobial resistance in horses is a critical foundation to any discussions of antimicrobial stewardship and optimal patient care, and efforts to obtain this information need to be improved. Parallel education efforts, directed not only at the prescribers (equine veterinarians) but at horse owners and regulatory personnel, must be initiated or continued to improve understanding, foster communication, enhance evidence-based decision-making and ultimately achieve the desired effects on equine and human health.

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