Antimicrobial prescribing guidelines for dairy cattle

Antimicrobials are one of the most important medical developments of the 20th century and are used to safely treat many common infections in humans and animals. Antimicrobial resistance (AMR) occurs when the microorganisms that cause infection, such as bacteria and viruses, become resistant to medical treatment with antimicrobial agents. Australia was one of the first nations to embark on a comprehensive reform process aimed at protecting humans and animals from the harmful effects of AMR and has remained at the forefront of antimicrobial stewardship globally.

AMR is recognised as a global health priority due to its adverse effects on public health, animal health, welfare and production, and the economy. Inappropriate use of antimicrobials in humans and animals has accelerated the process. A shared One Health approach, working across the human, animal and environmental health sectors, and promoting antimicrobial stewardship across a range of industries, is a key component of how we address AMR.

As a major exporter of high-quality food products, Australia has taken a proactive approach to managing food safety issues, including the use of antimicrobials. Antimicrobials are an essential tool for dairy farmers and veterinarians to ensure the health and welfare of animals in their care. Overall, the Australian dairy industry has very low antimicrobial usage compared to other countries and holds a favourable reputation for low levels of AMR. The industry is, therefore, well-placed to play a leading role in how we address AMR more broadly across the animal health sector. The dairy industry's “as little as possible, as much as necessary” method is particularly commendable and demonstrates their commitment to using antimicrobials responsibly.

In closing, I would like to recognise the important stewardship role dairy cattle veterinarians play in promoting the appropriate use of antimicrobials on dairy farms. These best-practice, evidence-based prescribing guidelines have been developed specifically for the dairy industry and will help attending veterinarians make good decisions about their use (or otherwise) of antimicrobials. I extend my sincere thanks to everyone who contributed to the development of these guidelines and urge all dairy cattle veterinarians to apply this advice. In doing so, you will help safeguard the ongoing, long-term efficacy of antimicrobials, deliver best practice veterinary service, and play an integral role in the global response to AMR.

Dr Mark Schipp

Australian Chief Veterinary Officer

John is Associate Professor of Livestock Health and Production and Head of The Livestock Veterinary Teaching and Research Unit at the University of Sydney. He is a registered specialist in livestock medicine with a keen interest in veterinary clinical practice and dairy cattle management. He completed a Bachelor of Science and Bachelor of Veterinary Medical Science at Murdoch University in 1986, became a Diplomate of the American College of Veterinary Internal Medicine in 1994 and completed a PhD in Veterinary Comparative Pathology at the University of California in 1997. As a clinical academic, he gets to apply the diversity of skills and resources available in the School of Veterinary Science at the University of Sydney to investigate individual animal and herd level problems. Clinical interests include animal husbandry, medicine, surgery, and reproduction. He enjoys utilising herd records to benchmark performance and investigate herd problems. His main research areas relate to the diagnosis, treatment, management, and prevention of infectious diseases.

Matt completed his veterinary degree from the University of Sydney in 2004, and after spending a few years working in mixed dairy practice on the south coast of NSW, he returned to Sydney University of Sydney to undertake a residency in Ruminant health and production. Matt completed a Masters degree in the field of neonatal calf diarrhoea in 2009 and became a fellow of the Australian and New Zealand College of Veterinary Scientists in the field of dairy cattle medicine and management in in 2012. Matt is one of the few registered veterinary specialists in dairy cattle in Australia.

Since completing his residency, Matt has worked in large dairy practices in Victoria and Tasmania. Matt is a member of the Apiam Animal Health Antimicrobial Stewardship Working Group and has been active in the development of on farm treatment protocols.

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 the 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), 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 publication¹ 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.

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.

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.^{2, 3}

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).⁵

Third-generation cephalosporins are very important in the treatment of severe and invasive infections in humans and are listed as being of high importance by ASTAG (2018).⁶ Therefore, the potential for animals to act as reservoirs of organisms resistant to this category of drugs needs to be considered seriously.

All of these products are registered for the treatment of respiratory tract infections in cattle. Despite this, ceftiofur has been used empirically for other conditions, including the treatment of footrot, metritis, septic arthritis and salmonellosis.

Importantly, the following label information is an example of a prudent use statement approved by the APVMA (see APVMA 84894):

PRUDENT USE:

Indiscriminate use of ceftiofur can contribute to the development of antibiotic resistance. Culture and sensitivity tests should be performed when appropriate to determine susceptibility of the causative organism(s). Empirical therapy can be instituted before results of susceptibility studies are known; however, once these results become available, the antibiotic treatment should be adjusted accordingly. It is also advised ceftiofur should be reserved for the treatment of clinical conditions which have responded poorly or expected to respond poorly (refers to very acute cases when treatment must be initiated without bacteriological diagnosis) to first line treatment.

Not to be used for any purpose, or in any manner, contrary to this label unless authorised under appropriate legislation.

One of the factors behind the off-label use of ceftiofur is the zero-milk withholding period (WHP) for treated animals. This has several advantages in dairy production, as treated animals contribute to saleable milk, rather than milk being discarded, and there is no risk of an antibiotic residue penalty due to the accidental addition of milk from a treated animal to the bulk milk. However, from a prudent antimicrobial use standpoint, neither factor amounts to an acceptable rationale for use.

For each of the off-label uses for ceftiofur outlined above, there are alternative treatments, including several efficacious antibiotics with a lower ASTAG importance rating that could and should be used. These are described in these guidelines. Ceftiofur should only be used in situations where culture and susceptibility testing has been performed and there are no other registered antimicrobials that are likely to be efficacious. The most likely scenarios where this will occur is in bovine respiratory disease in lactating animals due to Mannheimia haemolytica (for which ceftiofur is registered) and multi-drug resistant salmonellosis. Extreme care must be taken in treating multi-drug resistant salmonellosis with ceftiofur, as there is a significant zoonotic risk for in-contact humans and all necessary infection control precautions should be undertaken when handling these animals (Table 1).