Antimicrobial stewardship: Time for change

Authors


In this issue, Barr and colleagues [1] highlight that all antimicrobials commonly used in horses have the potential to trigger antimicrobial diarrhoea while Hughes et al. have concluded that veterinarians prescribing antimicrobials for horses commonly use inappropriate doses and rarely utilise guidelines for antimicrobials designed to minimise resistance [2]. Antimicrobials are an essential part of modern equine practice; imagining clinical practice without them seems far fetched, yet antimicrobial resistance is an escalating problem for all healthcare professionals [3]. While we are not yet faced with the daily challenge of multidrug resistance with common equine pathogens, the evidence for an increasing threat of antimicrobial resistance in the horse is clear [4-11]. No other issue can be more accurately portrayed by the ‘One Health’ initiative; it is an issue that has been caused by healthcare providers of all species and needs to be tackled by healthcare providers of all species. The British Veterinary Association (BVA) have recently claimed that overuse in human healthcare is the ‘biggest problem’ [12] and while evidence of poor prescribing practices in human healthcare is common [13-17] the evidence for blame is, at best, incomplete. While there is no evidence-based strategy that will reduce existing resistance, the incontrovertible evidence is that antimicrobial use leads to antimicrobial resistance and that effective antimicrobial stewardship results in reduced antimicrobial use [18-22].

Antimicrobial stewardship does not mean stopping the use of antimicrobials; it involves the development of strategies to ensure that they are used effectively. The American College of Veterinary Internal Medicine (ACVIM) developed a consensus statement for the use of antimicrobials in animals [23] in response to the World Health Organization (WHO) global strategy [24-26]. These documents provide an evidenced-based approach to tackle the ongoing threats of antimicrobial resistance and call for the development of standard guidelines for the treatment of common clinical conditions. Such guidelines are now commonplace in human healthcare and have been shown to reduce the use of antimicrobials, especially those drugs of particular concern [27]. The Small Animal Medicine Society (SAMSoc) and the British Small Animal Veterinary Association (BSAVA) provided the first veterinary framework to enable practitioners to develop such policies in their own practice under the acronym of PROTECT [28]. Last year, the British Equine Veterinary Association (BEVA) released a more detailed toolkit (http://www.beva.org.uk/useful-info/Vets/Guidance/AMR) to facilitate the development of local practice-based policies on antimicrobial use [29], these can be found as Supporting Information files to this editorial (Supporting Information Items 1–7).

The project, titled ‘Protect ME’, is not simply an anthropomorphic plea from the antimicrobials; it is an acronym that represents 9 steps that can be used to develop policies on antimicrobial use in the horse in order to reduce inappropriate use. Its core principles mimic those set out by BSAVA and ACVIM, to identify common clinical conditions and identify guidelines for empirical treatment of these conditions. The British Equine Veterinary Association believes that policies should be created at a local level, following simple key concepts and not be regional or national edicts developed by those within ivory towers. This is important since empirical antimicrobial choice should reflect a number of factors, including knowledge of local resistance patterns, an understanding of local disease epidemiology and types of animals being treated. A further advantage of the development of local policies is that it enables the establishment of ‘best practice’. As such, the empirical choices contained in the documents are not the ‘correct’ choices and indeed were not formulated by endless debate and consensus that would have led to compromise, they are dynamic documents that can be amended and hopefully shared with BEVA to help develop improved guidelines for the future.

The Protect ME documents also highlight the importance of those drugs that have been classified as Critically Important Antimicrobials (CIAs) by the WHO. These drugs are listed as ‘protected’, in that they should not be used without appropriate bacterial sensitivity testing, or ‘avoided’ where their role in equine practice is questionable. Other modifications from the BSAVA PROTECT poster include addition of the watchwords ‘monitor’ and ‘educate’. Monitoring is essential both to audit compliance, but also to modify protocols when they are ineffective. They propose monitoring of local culture and sensitivity results as well as a requirement to record the use of ‘protected’ antimicrobials (CIAs) such that their use can be reviewed and if necessary further actions can be taken to induce change in prescribing practices. Education of the importance of antimicrobial resistance is essential, to this end a detailed bibliography including links to studies and reviews from Equine Veterinary Journal (EVJ) and Equine Veterinary Education are included to help formulate practice-based policies. Education also needs to focus on consumers, and BEVA are working on further documents to help clients understand the importance of antimicrobial resistance. The importance of education through BEVA's journals is vital, and there is a potential, albeit small, risk that research studies into novel antimicrobials could promote their misguided use in conditions where existing products would be equally effective. To this end, EVJ has extended it authors' guidelines to include a statement on antimicrobial stewardship http://onlinelibrary.wiley.com/journal/10.1001/(ISSN)2042-3306/homepage/ForAuthors.html [30]; it is the first journal, worldwide, to adopt such a policy. The editors in no way wish to stifle innovation and research will continue to be published regarding novel antimicrobial use in the horse. Indeed, these are essential if we are to overcome the challenges of antimicrobial resistance. However, where drugs are defined as critically important for human health (CIAs) by the WHO, the authors will be required to draw the readers' attention to their importance. It is hoped that other journals will adopt similar policies and that antimicrobial stewardship will be promoted by all future research.

The antimicrobial stewardship guidelines relate to the drugs classified as critically important for human health. These currently include the 3rd and 4th generation cephalosporins, the fluoroquinolones and the macrolides [31]. These are all drugs commonly used in veterinary practice and, in some cases, the evidence for their use is compelling. For example, ACVIM have reviewed and graded the evidence for the treatment of Rhodococcus equi in the foal. They concluded that azithromycin with rifampin is the most appropriate combination therapy for this condition [32]. This provides a valuable evidence-based resource to support the ongoing use of this product in the horse and provides evidence to support its classification as ‘essential for the treatment of equidae’ [33]. As such, azithromycin is proposed as an appropriate empirical treatment for Rhodococcus equi in the horse, despite being classified as a CIA. In a study published in this issue, workers investigated a novel method for the sustained release of antimicrobials into the joint of horses with synovial sepsis using a dextran gel [34]. The technique is novel, leaves no tissue residues and provides effective antimicrobial concentrations for a prolonged period. The use of local antimicrobials is to be encouraged, since it does not expose commensal bacteria, such as those in the gastrointestinal tract, to the selection pressures of resistance that could be induced by the systemic use of such drugs. They also reduce potential side effects that can be induced by antimicrobial use in the horse that is highlighted by a further study in this issue [1]. Indeed, clindamycin and vancomycin used in this gel are not usually considered in our arsenal of drugs in the horse, due to the high risks of antimicrobial-induced diarrhoea. However the critical importance of vancomycin to treat life-threatening Enterococcus faecalis infections in man resulted in its proposed classification as ‘AVOIDED’ in the ‘Protect ME’ documents. While its use may be indicated in exceptional circumstances [35], it must be used with care, to ensure that we do not risk human life. As such it must only be considered when no other drug or drug combination is effective based on in vitro sensitivity testing. In future, such studies published in EVJ, will require a statement highlighting the importance of such drugs in human health.

Although antimicrobial resistance could ultimately lead to a situation where these drugs were no longer effective, a more imminent threat to the availability of drugs comes from proposed legislation. The WHO has long called for the withdrawal of CIAs from veterinary use and legislation is current being considered by the European Parliament to prevent the use of the 3rd and 4th generation cephalosporins in animals [36]. At the same time, ‘decoupling’ is being proposed, separating the right to prescribe from the right to sell antimicrobials. Again, this is in line with WHO calls to end any financial incentive that promotes antimicrobial use [25]. The BVA and the Federation of Veterinarians of Europe (FVE) are undertaking active lobbying against these proposals on behalf of the profession. However their arguments are not evidence-based, despite calling for science-based approaches. They claim this legislation is ‘kneejerk’ and that veterinarians are responsible ‘gate-keepers’ of antimicrobials [37, 38]. They ignore the fact that WHO have been calling for such action for over a decade, along with the development of standard-treatment guidelines. However, advice issued by both FVE and BVA has stopped short of recommending such policies [39, 40], despite their success in human healthcare in affecting change. There is evidence of lack of responsible use among both small animal [41] and equine professions. A Canadian study of 55 racehorses with a diagnosis of nonseptic lower airway disease, showed that 69% of cases received antimicrobials for an average of 9.9 days, with over 10% receiving the 3rd generation cephalosporins [42]. Data in this issue shows similar practices in the UK with 53% of respondents indicating that they would administer antimicrobials for a clinical scenario that clearly mimicked a diagnosis of recurrent airway obstruction (RAO), although only the small minority of these (2%) used 3rd or 4th generation cephalosporins or fluoroquinolones [2]. While RAO may reduce effectiveness of respiratory defence mechanisms, resulting in secondary bacterial infection, the ‘first-line’ use of antimicrobials in this scenario cannot be condoned or described as responsible. Similar challenges are faced in human healthcare with the widespread use of antimicrobials for the treatment of respiratory viruses [43-47] and asthma [48]. However, the profession acknowledges this and measures are being taken to address such practices through a variety of approaches. The veterinary profession needs to stop blaming human healthcare, it needs to identify areas of best practice and adopt them. The same study in this issue indicated that only 1% of responding practices currently had such antimicrobial guidelines [2].

Of additional concern in the antimicrobial use study is the source of evidence respondents used to identify appropriate and especially dosing advice. It is clear that sub-therapeutic dosing provides an excellent environment for further development of antimicrobial resistance. Evidence of under dosing is not unique to the veterinary profession and is also commonly reported in human medicine [49-51] where it relates to a failure to consider bodyweight, although disease and obesity may also impact on circulating concentrations of any particular drug [52-54]. In equine medicine, dosing is further impaired by inconsistencies between licencing authorisations and published evidence. The study by Hughes et al. [2] defines the correct dose as the dose indicated in the marketing authorisation. However, the term ‘correct’ in this setting is arguable. For example, 70% of prescriptions using the trimethoprim potentiated sulphonamides were indicated as being ‘overdosed’, whereas evidence shows that once daily use of these products, as indicated in the marketing authorisations, does not provide appropriate therapeutic concentrations [55-57]. As such, 70% of respondents actually dose responsibly, while dose rates indicated by manufacturers may be inappropriate and may promote antimicrobial resistance. Best practice in evidence-based medicine requires that the practitioner stratify the quality of evidence using an established hierarchy. Well-designed experimental studies that stand up to the scientific rigour of the peer review process should come well above the sources of evidence used by most respondents in this study. The British Equine Veterinary Association have provided an extensive range of scientific resources to help practitioners develop local guidelines for dosing that is based on this evidence.

There is clear evidence of the need for a change in our relationship with antimicrobials. It is up to individuals whether they are motivated by the ethics of future human and animal health or by the selfish desire to respond to threats from legislation. However, irrespective of motivation, change is still needed. It is time to end the practice of blaming others but look at what we can learn from them. We need to identify examples of best practice and consider how these can be applied to us, while sharing our experiences and ideas. We need to act responsibly, as well as being seen to act responsibly [58]. Currently, the companion animal and equine sector are trying to do just this and our organisations are putting their efforts into promoting responsible use. These first steps are evidence of our desire to change, to show the world that we can be trusted as responsible guardians of these essential therapeutic agents. Those sectors of the profession that wish to respond to this challenge by simply blaming others jeopardise these efforts. That does not mean the equine sector should not bother, we should continue to strive for excellence and if we cannot change the views of the farm animal sector then we need to differentiate ourselves from them and show that collectively the companion animal (including equine) sector should be treated differently by the legislators.

Ancillary