Antimicrobial prescribing guidelines for sheep

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These Guidelines and any recommendations presented in the Guidelines: Persons involved in the preparation of the Guidelines accept no responsibility or liability (in contract, tort including negligence or otherwise) for any consequence, damage, cost, expense, claim or loss (including indirect loss, consequential loss, special loss, loss of profit or loss of business opportunity) arising in any way out of: Antimicrobial resistance (AMR) is a growing global threat that presents a serious risk to human and animal health. Resistance to antimicrobials occurs naturally in microorganisms. But it can be amplified by antimicrobial overuse, underuse, or poor management. Hence, the effective stewardship of antimicrobials—through appropriate and judicious manufacture, administering, dispensing, prescribing and disposal—is critical. Here, in Australia, the veterinary profession and food producing animal industries have a long history of addressing AMR, working diligently to ensure the safe and continued efficacy of antimicrobials. Their previous and ongoing work—a result of partnerships across the animal sector—has resulted in demonstrated low levels of antimicrobial resistant bacteria in food producing animals. It is encouraging that, in the United Kingdom's 2015 O'Neill Review into Antibiotic Resistance, Australia was ranked the fifth lowest for antibiotic use in agriculture among the 29 countries examined. Strict regulation on antimicrobial registration, high levels of biosecurity and extensive farming systems that do not favour bacterial disease also contribute to the low risk of AMR development from animals in Australia. With the recent release of Australia's National Antimicrobial Resistance Strategy–2020 and Beyond (2020 AMR Strategy), the veterinary profession will continue to play a critical role in how we minimise AMR. The antimicrobial prescribing guidelines for sheep seeks to "ensure that coordinated, evidence based antimicrobial prescribing guidelines and best practice supports are developed and made easily available, and encourage their use by prescribers". These practical guidelines for Australian sheep veterinarians are designed to be a useful resource. They have been developed specifically for the Australian sheep industry and contain best-practice information to help clinical veterinarians make appropriate decisions when prescribing antimicrobials. They encourage veterinarians to first pause and consider the need to use antimicrobials in the situation and whether there are effective non-antimicrobial alternatives. Prevention and control of infections through strict on-farm biosecurity minimises the need to use antimicrobials. Vaccination may also be available to control several important sheep diseases. If antimicrobial use is indicated, practitioners should consider the five rights—right drug, right time, right dose, right duration and right route. Using a lower rating or narrow-spectrum antimicrobial is the preferred approach, and you can also refer to the Australian Antibacterial Importance Ratings to help with these decisions. I commend the work of all involved in the development of these guidelines and urge every sheep veterinarian to use this advice. In doing so, you'll help safeguard ongoing access to antimicrobials, ensure their long-term efficacy, deliver the best possible veterinary service to the Australian sheep industry, and play your role in the global response to AMR. Dr Mark Schipp Australian Chief Veterinary Officer President of the OIE World Assembly For much of a 50+ year career as a veterinarian, Ray has been involved in a range of professional activities associated with sheep. This has included research on caseous lymphadenitis and ovine meat inspection standards, international projects, as a rural practitioner or consultant to individual producers, and as an adviser to service or support organisations of the sheep industry. From teaching and working in both medical and veterinary microbiology, Ray developed a special interest in applying laboratory antimicrobial susceptibility testing to appropriate clinical use. Appointment to a state reference group developing control of use regulation fostered an ongoing interest in managing risk from administering veterinary chemicals. This extended to undertaking investigations on behalf of and providing advice to a veterinary chemical company supplying products registered for sheep. Ray has been convenor of continuous professional development for SCGV and its predecessor ASV, as well as presenting at national and international conferences and publishing in refereed scientific journals. Paul Nilon graduated in veterinary science in 1983 and completed a Masters with the Mackinnon Project in sheep and beef production in 1986. Since then, Paul has worked in rural practice in 3 states, and for the last 15 years as a full time health and production adviser to sheep and beef clients in Tasmania, as well as the occasional gig with sheep and beef R & D corps, research projects with universities and pharmaceutical companies and some training and surveillance with the Tasmanian government. Paul has been a member of state steering committees for footrot and OJD. He was a member of the Paraboss technical committee and contributes monthly to the Paraboss website. Paul has been trained to represent Wool Producers Australia on the CCEAD in the event of an exotic disease incursion. Paul was the president of the ASV and a committee member. Paul cites the collegiality of a small, dedicated group of government and private vets and ag scientists as being an essential element to providing animal health and welfare, biosecurity, and production advice to the sheep industries in all states. Jacqui is Professor of Veterinary Microbiology and Infectious Diseases and Head of School and Dean of the Sydney School of Veterinary Science, at the University of Sydney. She is a registered practicing veterinarian and is passionate about practical research projects and education programs for veterinary professionals, animal breeders, and animal owners. Her main research areas include: (1) Development of diagnostics and treatments for companion animal viral diseases; (2) Q fever; (3) Multidrug resistant (MDR) Staphylococcus species; (4) Infection prevention and control in veterinary practices; (5) Chronic renal disease in domestic and zoo Felids and 6) Factors influencing antimicrobial prescribing behaviour of vets and health professionals. She is a co-founder of the AMR Vet Collective (www.amrvetcollective.com). Stephen is a consultant veterinary clinical pharmacologist and toxicologist and founder and sole director of Advanced Veterinary Therapeutics–a consulting company that provides advice on appropriate use of veterinary medicines to veterinarians, veterinary organisations (Australian Veterinary Association, World Veterinary Association, World Organisation for Animal Health), state and national government departments and statutory bodies (APVMA, Department of Agriculture, Department of Health, US Environmental Protection Agency), and global organisations (OIE, FAO, Chatham House). He is a member of the AVA Antimicrobial of Resistance Advisory Group (ARAG), a member of the ASTAG committee on antimicrobial prioritisation; in 2017, he became President of the ANZCVS Chapter of Pharmacology, and is a Stephen is a consultant veterinary clinical pharmacologist and toxicologist and founder and sole director of Advanced Veterinary Therapeutics–a consulting company that provides advice on appropriate use of veterinary medicines to veterinarians, veterinary organisations (Australian Veterinary Association, World Veterinary Association, World Organisation for Animal Health), state and national government departments and statutory bodies (APVMA, Department of Agriculture, Department of Health, US Environmental Protection Agency), and global organisations (OIE, FAO, Chatham House). He is a member of the AVA Antimicrobial of Resistance Advisory Group (ARAG), and a member of the ASTAG committee on antimicrobial prioritisation; in 2017, he became President of the ANZCVS Chapter of Pharmacology, and is a member the World Veterinary Association Pharmaceutical Stewardship Committee. He has more than 100 publications on which he is author or editor, including chapters on antimicrobial stewardship, clinical pharmacology, adverse drug reactions, use of antimicrobial agents in livestock, and antimicrobial drug discovery and models of infection. He has been a teacher and facilitator of courses at the University of Sydney on food safety, public health and antimicrobial resistance since 2003. He is regularly invited to speak nationally and internationally at a broad range of conferences and symposia, especially on the subjects of antimicrobial use, antimicrobial stewardship, and risk assessment. He gave his first presentation on veterinary antimicrobial resistance and stewardship at the AVA Conference in Perth in 2000 and remains passionate about improving the use and effective life span of antimicrobial agents. Glenn Browning is Distinguished Professor in Veterinary Microbiology, Director of the Asia-Pacific Centre for Animal Health and Director of Research at the Melbourne Veterinary School at the University of Melbourne. He completed a Bachelor of Veterinary Science with First Class Honours at the University of Sydney in 1983, a postgraduate Diploma of Veterinary Clinical Studies in Large Animal Medicine and Surgery at the University of Sydney in 1984 and a PhD in Veterinary Virology at the University of Melbourne in 1988. He was a Veterinary Research Officer at the Moredun Research Institute in Edinburgh from 1988 to 1991, investigating viral enteritis in horses, then joined the staff of the Faculty of Veterinary Science at the University of Melbourne, and has been a member of teaching and research staff there since 1991. He teaches in veterinary and agricultural microbiology. He is a Life Fellow of the Australian Veterinary Association, a Fellow of the Australian Society for Microbiology and Chair of the International Organisation for Mycoplasmology. He is a co-author of 280 peer reviewed research papers and book chapters, has edited two books on recent progress in understanding the mycoplasmas, and has co-supervised 60 research higher degree students. His research interests include the molecular pathogenesis and epidemiology of bacterial and viral pathogens of animals, the development of novel vaccines and diagnostic assays to assist in control of infectious diseases, and antimicrobial stewardship in veterinary medicine. Derived from: Page S, Prescott J and Weese S. Veterinary Record 2014;175:207–208. Image courtesy of Trent Hewson, TKOAH. While the published literature is replete with discussion of misuse and overuse of antimicrobial agents in medical and veterinary situations, there has been no generally accepted guidance on what constitutes appropriate use. To redress this omission, the following principles of appropriate use have been identified and categorised after an analysis of current national and international guidelines for antimicrobial use published in the veterinary and medical literature. Independent corroboration of the validity of these principles has recently been provided by the publication (Monnier et al 2018) of a proposed global definition of responsible antibiotic use that was derived from a systematic literature review and input from a multidisciplinary international stakeholder consensus meeting. Interestingly, 22 elements of responsible use were also selected, with 21 of these 22 elements captured by the separate guideline review summarised below. Apply appropriate biosecurity, husbandry, hygiene, health monitoring, vaccination, nutrition, housing, and environmental controls. Use Codes of Practice, Quality Assurance Programmes, Herd Health Surveillance Efficacious, scientific evidence-based alternatives to antimicrobial agents can be an important adjunct to good husbandry practices. Make clinical diagnosis of bacterial infection with appropriate point of care and laboratory tests, and epidemiological information. Develop outcome objectives (for example clinical or microbiological cure) and implementation plan (including consideration of therapeutic choices, supportive therapy, host, environment, infectious agent and other factors). Consider other options first; antimicrobials should not be used to compensate for or mask poor farm or veterinary practices. Culture and susceptibility testing Utilize culture and susceptibility (or equivalent) testing when clinically relevant to aid selection of antimicrobials, especially if initial treatment has failed. Spectrum of activity Use narrow-spectrum in preference to broad-spectrum antimicrobials whenever appropriate. Extra-label (off-label) antimicrobial therapy Must be prescribed only in accordance with prevailing laws and regulations. Confine use to situations where medications used according to label instructions have been ineffective or are unavailable and where there is scientific evidence, including residue data if appropriate, supporting the off-label use pattern and the veterinarian's recommendation for a suitable withholding period and, if necessary, export slaughter interval (ESI). Dosage regimens Where possible optimise regimens for therapeutic antimicrobial use following current pharmacokinetic and pharmacodynamic (PK/ PD) guidance. Duration of treatment Minimise therapeutic exposure to antimicrobials by treating only for as long as needed to meet the therapeutic objective. Labelling and instructions Ensure that written instructions on drug use are given to the end user by the veterinarian, with clear details of method of administration, dose rate, frequency and duration of treatment, precautions and withholding period. Target animals Wherever possible limit therapeutic antimicrobial treatment to ill or at-risk animals, treating the fewest animals possible. Report to appropriate authorities any reasonable suspicion of an adverse reaction to the medicine in either treated animals or farm staff having contact with the medicine, including any unexpected failure to respond to the medication. Thoroughly investigate every treated case that fails to respond as expected. Retain an objective and evidence-guided assessment of current practice and implement changes when appropriate to refine and improve infection control and disease management. Each of the core principles is important but CORE PRINCIPLE 11 Extra-label (off label) Antimicrobial Therapy can benefit from additional attention as veterinarians, with professional responsibility for prescribing and playing a key role in residue minimisation, must consider the tissue residue and withholding period (WHP) and, if necessary, export slaughter interval (ESI) implications of off-label use before selecting this approach to treatment of animals under their care (Reeves 2010; APVMA 2018). An example of the relationship between the maximum residue limit (MRL) and tissue depletion following administration of a veterinary medicine. In a healthy animal (A), tissue depletion to the MRL often occurs at a time point shorter than the withholding period (WHP) that has been established for the 99/95th percentile of the population. In such an individual animal, if the dose is doubled, tissue depletion (B) should only require one more half-life and would most likely still be within the established WHP. However, if the half-life doubles due to disease or other factors, depletion (C) would now require double the normal WHP and may still result in residues exceeding the MRL (adapted from Riviere and Mason, 2011) APVMA. Residues and Trade Risk Assessment Manual. Version 1.0 DRAFT. Australian Pesticides and Veterinary Medicines Authority, Kingston, ACT, 2018. Craigmill AL, Riviere JE, Webb AI. Tabulation of FARAD comparative and veterinary pharmacokinetic data. Wiley-Blackwell, Ames, Iowa, 2006. Monnier AA, Eisenstein BI, Hulscher ME, Gyssens IC, Drive-AB. WP1 group. Towards a global definition of responsible antibiotic use: results of an international multidisciplinary consensus procedure. J Antimicrob Chemother 2018;73:3-16. Reeves PT. Drug Residues. In: Cunningham F, Elliott J, Lees P, editors. Comparative and Veterinary Pharmacology. Springer Berlin Heidelberg, Berlin, Heidelberg, 2010:265-290. Riviere JE, Mason SE. Tissue residues and withdrawal times. In: Riviere JE, editor. Comparative Pharmacokinetics Principles, Techniques, and Applications. 2nd edn. Wiley-Blackwell, Oxford, UK, 2011:413-424. Nationally and globally, there is close examination of animal production practices that might contribute to the transfer of antimicrobial resistance (AMR) to human pathogens, and the effects that interventions to reduce antimicrobial use in food-producing animals might have on the level of antimicrobial resistant organisms in humans and animals.1 Most of the AMR problems in human medicine are not related to AMR in animals, and the World Health Organisation (WHO),2 having commissioned two meta-analyses of available published literature,1, 3 concluded that the quality of evidence supporting recommendations on reducing antimicrobial use (AMU) in animals to mitigate AMR in human pathogens is low to very low. Nevertheless, it is clear that antimicrobials should only be used when necessary. Using antimicrobials in sheep production systems increases the likelihood of resistance developing in ovine pathogens or commensals, with an associated potential for transfer to human pathogens or to pathogens in other animal species. Sheep production practices intersect with human health and the emergence of resistance from the use of antimicrobials in sheep production may also result in environmental contamination, particularly when treatment is implemented at flock level, especially when confinement feeding is practiced or when sheep are aggregated in saleyards or prior to live-export. Antimicrobial stewardship (AMS) programs are one way that the animal production community can demonstrate its commitment to producing food and fibre in a way that mitigates risk to the environment or human health, while ensuring that our shared antimicrobial resource continues to be available when needed to protect animal health and welfare. It is not the intention of AMS programs to develop animal production systems that never use antimicrobials. This is not yet possible with current knowledge and resources, although a substantial proportion of sheep are likely to be produced in this way. However, it is possible to substantially refine and reduce AMU, with the overall aim of reducing selection pressures favouring resistant organisms and securing the use of antimicrobials for the future. To achieve these objectives for the sheep industry requires an understanding of the factors that may determine the occurrence of infectious disease in individual enterprises, as well as across the industry. In Australia, sheep enterprises are conducted across a diverse range of geographic and climatic regions within limitations imposed by the quality and quantity of available fodder or water throughout the year. This is substantially influenced by large variations in climate, season, and soil. Predation or risk of specific diseases also tend to restrict sheep production to certain parts of the country. There is a historical differentiation between wool and meat enterprises, although it is now generally accepted that meat production as lamb, hogget, or mutton is a significant contributor to most sheep enterprises, with a major proportion of meat and offal being exported. Sheep production is generally based on extensive grazing systems with continuous access to pasture and appropriate supplementary feeding. Less frequently, sheep may be kept intensively and fed commercially or locally mixed rations for a range of commercial objectives. The routine use of specifically targeted antimicrobial agents is very unlikely in Australian sheep enterprises, although it may be necessary for veterinarians to prescribe treatment to individuals or groups of animals on farms when specific bacterial diseases, such as dermatophilosis or mastitis, are unresponsive to other interventions. Local circumstances, combined with the production system, define what constitutes best practice sheep production, with a lack of uniformity across the country in several key aspects that affect the occurrence or consequences of infectious disease, including stocking rates and whether animals are regularly moved to fresh areas for grazing (generally described as rotational grazing). In some regions, best practice may include ewes or weaned lambs being congregated in temporary feedlots or at high stocking rate (confinement feeding) for short periods as determined by seasonal factors. High-value animals may also be housed and fed for variable lengths of time, including during critical growth periods, during preparation for and during exhibition, for the collection of semen or embryos, or for the production of ultra-fine wool. The live export industry uses large sheep feedlots close to ports and there may be significant environmental contamination if antimicrobials are used in these feedlots. Clinical conditions other than infectious disease tend to be the principal causes of morbidity or mortality in commercial sheep flocks, particularly parasitic, toxicological, and nutritional diseases. The treatment of infectious disease with antimicrobials may often require that concurrent non-infectious conditions also be addressed. However, specific diseases, such as virulent ovine footrot, may be a significant recurring challenge for some sheep enterprises or in some climatic regions. In commercial sheep enterprises, the timing of regular annual husbandry events, such as mating, lambing, and weaning, and procedures such as crutching and shearing, is frequently determined by anticipated seasonal constraints, or by other farming priorities, such as the demands of cropping. Husbandry procedures associated with increased risk of infectious disease on many farms include tail docking, castration, mulesing, and dipping, which tend to be performed within a restricted time period after regular events such as lambing or shearing. In some remote areas, the difficulties of mustering may affect the timing of or age at which some procedures are performed, and this may affect the likelihood of infectious disease events. Many bacterial or protozoal infections may be endemic or recur sporadically in individual flocks because of subclinical infection, such as with coccidia, Dermatophilus congolensis and salmonellae, or may originate from environmental contamination or sources, as is seen with Erysipelothrix rhusiopathiae. Normal microflora, such as Streptococcus bovis, may also contribute to the infectious disease burden due to the impact of high starch intake on the ruminal microflora when individual sheep or flocks consume substantial quantities of grain. are the most frequent reasons for veterinarians prescribing antimicrobial treatment within individual sheep enterprises (unpublished data). In addition to this general survey, interviews were conducted in late 2019 across five Australian states with veterinarians who regularly treat sheep. The results were used to determine the impact on sheep enterprises of a range of conditions or circumstances that may or may not necessitate prescription of antimicrobials (unpublished data). Participating veterinarians were asked to score the importance or urgency of the situation when a client sought advice on each nominated condition and indicate how often they were consulted about animals with each condition. The impact of each condition in the meat/wool and the dairy sectors was calculated as importance x frequency, although only two of the veterinarians were involved in the dairy sector. The median of these scores was the basis for ranking conditions as having moderate to high importance or occurring with medium to high frequency, as shown in Table 1. For the meat/wool sector, these data summarise priority conditions across mainland Australia and thus present an overall view of likely requirement for antimicrobial treatment. However, these semi-quantitative median values do not adequately reflect that there may be substantial state, regional, or local variations in the importance or frequency of some conditions. While 19 conditions were deemed by veterinarians to be of moderate to high importance or urgency if encountered in dairy and/or meat/wool sheep enterprises, the median frequency of veterinarians being consulted was low for the majority (15/19 or 79%) of these. This supports the conclusion that the prescription and use of antimicrobials are likely to be infrequent in sheep enterprises, including for high impact diseases. It should be noted that, in this context, frequency refers to how often individual veterinarians encounter a disease, rather than overall prevalence or percentage of enterprises in which the disease occurs. For example, caseous lymphadenitis (CLA) is a relatively common infectious disease of sheep, but veterinarians are infrequently consulted about it. However, the results from the interviews suggest that CLA is important on those infrequent occasions when veterinarians are consulted, whether for individual cases or advice about a high prevalence of disease. The substantial difference in impact between the meat/wool and the dairy sectors of some conditions, such as acute ruminal acidosis and interdigital trauma, suggests that prescribing veterinarians are required to take account of the enterprise type when a specific condition occurs or is diagnosed (see Table 2). Targeting treatments at the specific diseases or condition of concern helps preserve the efficacy of more important antimicrobials, the drugs of high or critical importance by reducing their use in situations where they are not needed. This concept is well developed in human medicine, where a wide range of antimicrobial agents is available for use. With relatively few medicines registered for use in sheep to prioritise, these guidelines provide advice principally on whether antimicrobial agents are required and the recommended primary treatment, but not on secondary or tertiary recommendations for treatment. The Australian Strategic and Technical Advisory Group4 (ASTAG) on AMR importance rating was used in developing these recommendations as the most relevant to the Australian situation. This rating ranks antimicrobials as having high, medium, or low importance for use in humans. There are two other categories of minimum human use (MHU) or no human use (NHU). The WHO5 list is numbered from one to five, from highest to lowest in importance, and varies from the ASTAG list, as it aims to address global issues, rather than the Australian context. First-line treatments, for example, those initiated while waiting for laboratory results, should use the lowest rated medications that are likely to be effective. In Australia, registered veterinarians are permitted to prescribe a medication for sheep if it is approved by the Australian Pesticides and Veterinary Medicines Authority (APVMA) for use in sheep or other food animals in Australia. Veterinarians are also permitted to prescribe a medication approved for use in sheep at levels and durations that vary from those on the label if a suitable withholding period (WHP) can be applied, the prescription can be justified scientifically, and provided that the use does not contradict a restraint statement on the label. It is likely there will be no label meat WHP for such drugs or elevated dose rates in sheep, and it is therefore the responsibility of the prescribing veterinarian to determine a suitable WHP. The treatment priority list is outlined in Table 3. An effective, approved antimicrobial is preferred over "off-label" prescription. Although there may be only one or two first-line treatments listed, in most situations, medications classified as low importance, NHU or MHU can meet this criterion. The higher importance rating of lincomycin, spectinomycin, and trimethoprim/sulfonamide should be noted. Trimethoprim/sulfonamide combinations are recommended as a first-line treatment only for specified conditions, though it should be recognized that trimethoprim may not be a suitable antimicrobial agent for sheep as it has a very short elimination half-life. Fusobacterium Necrophorum Trueperella (Actinomyces) pyogenes Parenteral: Procaine or penethmate penicillin. Oxytetracycline LA Long acting penicillin Topical: Cloxacillin Fusobacterium necrophorum Dichelobacter nodosus Trueperella pyogenes Antimicrobials generally not prescribed Parenteral: Procaine penicillin LA oxytetracycline Parenteral: Oxytetracycline LA Erythromycin Procaine penicillin 42 mg/kg Efficacy of antimicrobial treatment enhanced by leaving sheep on concrete or boards for 12–24 h post injection. Erythromycin particularly useful if a short WHP needed. Antimicrobial treatment confined to four scenarios: For a review of prevention, control and eradication of virulent footrot.7 Septic arthritis: suppurative6, 7 E. Coli Fusobacterium necrophorum Trueperella pyogenes Histophilus somni Actinobacillus seminis Staphylococcus. Spp. Streptococcus spp. Parenteral: Oxytetracycline LA Procaine penicillin or penethamate Parenteral: Oxytetracycline LA Erythromycin Parenteral: Procaine penicillin or penethamate LA penicillin Oxytetracycline LA Parenteral: Oxytetracycline LA Procaine penicillin or penethamate LA Parenteral: Procaine penicillin or penethamate Penicillin LA Oxytetracycline Parenteral: Oxytetracycline Erythromycin Staphylococcus. Aureus Mannheimia haemolytica Mannheimia glucosida Actinobacillus spp. Strep