David C. Speksnijder, Stephen W. Page, Jaap A. Wagenaar, and John F. Prescott There has been an explosion of interest and action in antimicrobial stewardship (AMS) in food‐producing animals over the past decade, which continues to expand, develop, and consolidate. How antimicrobials are used in food‐producing animals has undergone a dramatic paradigm shift that continues to be refined. It is hard to capture the unprecedented breadth, depth, and dynamism of these developments, which are embedded in broader global activities addressing the antimicrobial resistance (AMR) crisis, epitomized at the international level by the multiple actions of the United Nations, the World Health Organization (WHO), the World Organisation for Animal Health (WOAH, formerly OIE), and the Food and Agriculture Organization of the United Nations (FAO) (Chapter 21). There has been more than a 30% decline in use of medically important antimicrobials in the United States and more than a 45% decline in total antimicrobial use (AMU) in the European Union (EU) in food‐producing animals over the last decade (European Medicines Agency, 2022a; US Food and Drug Administration, 2022). For the 80 countries that reported data to the WOAH each year from 2017 to 2019, an overall decrease of 13% (expressed as mg antimicrobial/kg biomass) was observed. The 66 participating countries reporting antimicrobials only for veterinary medical use experienced an overall decrease of 37%, while the remaining 14 countries, reporting antimicrobials for veterinary medical use and growth promotion, experienced an overall decrease of 9% (WOAH, 2023). The unrestricted use for growth promotion provides no substantial health benefit, as discussed further below. Antimicrobials should only be used where the benefits are both clear and substantial, and with minimal negative consequences for human and environmental health. A One Health approach to addressing AMR (Chapter 20) and development of a stewardship mindset are prominent global themes in promoting AMS in food‐producing animals. The detailed practices of AMS in food‐producing animals, including the development of global standards (Chapter 21), are still developing but the core elements are clear and include the guiding “5R” principles of Responsibility, Reduction, Replacement, Refinement, and Review (Lloyd and Page, 2018). In stark contrast to companion animal medicine (Chapter 22), antimicrobial use in food‐producing animals is frequently a political battleground between intensive animal agriculture and forces critical of meat consumption in general, for reasons such as animal rights and climate change, with criticism of AMU being a major focus of this dispute. Not only does improving AMS in food‐producing animals contribute to the One Health approach in addressing the AMR crisis and its existential threat to modern medicine, it is important for modern animal agriculture and corporate social responsibility, with global trade implications (George, 2019). Changing long established practices and behaviors in AMU in food‐producing animals is an often slow participatory process, which can suddenly change direction unexpectedly, requiring careful management. AMU is a source of conflicting views and interests between individuals and groups, sometimes including misleading analyses of complex issues. Different countries and jurisdictions with different production animal agricultural systems are at varying stages in development and implementation of AMS programs (Chapter 21). This is associated with marked variation in the commitment to and pace of change of existing practices as well as the introduction of different regulations and practices to modify AMU. For example, changes in AMU in food‐producing animals in North America have generally lagged behind those in several European countries and the evolving animal production systems of fast‐growing economies are facing a different set of challenges to those of the well‐entrenched food animal production systems in highly developed countries (Prescott, 2019). The greater focus on AMU in production rather than companion animals is also a result of the larger quantities of antimicrobials used and the potential for widespread dissemination of resistant bacteria to people through the food chain and the environment. This chapter will review the basic elements of successful implementation of AMS programs in food‐producing animals that have emerged in recent years in various countries and animal sectors. Improvements will continue to emerge in the light of research into best practices and other aspects relating to AMR in food‐producing animals. Given the global diversity, not only in animal agriculture and environmental characteristics but also in the governance and cultures of different countries, there is no “one size fits all” approach. Without being prescriptive, because of this global variation, this chapter will emphasize and provide examples of what is working successfully in different countries and may be appropriately adapted for adoption more broadly. The practices of AMS in food‐producing animals are at different levels in different countries and production systems so that considerable improvement can be anticipated in the coming years. The general principles of AMS in food‐producing animals according to the 5Rs framework have been summarized in Table 20.1 and are elaborated further for companion animals in Chapter 22. The general principles of appropriate AMU in food‐producing animals, highlighting where AMU and AMS practices could be improved, are summarized in Table 23.1. A critical AMS principle is that AMU in all animals must be under the oversight of a veterinarian (or suitably trained paraveterinary professional where veterinarians are not available) who has a genuine veterinary/client/patient relationship with the animals and herd or flock owner, as usually defined by national veterinary authorities. A further critical principle in production animal AMS is the hierarchy of antimicrobial agent importance as set out by the WHO, including the category of Highest Priority Critically Important Antimicrobials (HP‐CIAs), categorized as “Restrict” by the EU (European Medicines Agency, 2019), which are highly focused targets for reduction of use in food‐producing animals. The ranking of antimicrobials for animal use according to their medical importance is a difficult and often contentious task, complicated by the dynamic nature and complexity of resistance. Table 23.1 General 5R principles of appropriate antimicrobial use specific to food animals (see also Table 20.1). The initial development of the List of Critically Important Antimicrobials for Human Medicine (WHO CIA List) occurred in 2005, following discussions at FAO/WOAH/WHO expert meetings in 2003 and 2004. The WHO CIA list has been based upon two criteria relating to (1) whether an antimicrobial class is the sole or one of limited available therapies, to treat serious bacterial infections in people, and (2) whether the antimicrobial class is used to treat infections in people caused by either (a) bacteria that may be transmitted to humans from nonhuman sources, or (b) bacteria that may acquire resistance genes from nonhuman sources. Following several revisions, with the sixth revision in 2019 (WHO, 2019), the CIA list has been replaced by the Medically Important Antimicrobial (MIA) list (WHO, 2024). This seventh revision of the WHO MIA list has been developed by the WHO Advisory Group on Critically Important Antimicrobials for Human Medicine (AG‐CIA), and now presents three major classes of antimicrobials: (1) authorized for use in humans only, (2) authorized for use in humans and animals, and (3) not authorized for use in humans. For example, carbapenems, third and fourth generation cephalosporins with beta‐lactamase inhibitors, fifth generation cephalosporins with or without beta‐lactamase inhibitors and glycopeptides such as vancomycin are now human use only. The shared class of antimicrobials is then subjected to categorization according to the criteria described above plus the use of prioritization factors related to human importance and existing evidence of resistance transmission from nonhuman sources. Antimicrobial classes classified as HP‐CIA include cephalosporins (third and fourth generation), quinolones (including fluoroquinolones), polymyxins, and phosphonic acid derivatives (notably fosfomycin). In parallel, the WOAH has developed the List of Antimicrobials of Veterinary Importance (WOAH, 2021; Pinto Ferreira et al., 2022) which shows extensive overlap with the WHO CIA list. The WOAH list was based on a global survey in 2005 of AMU in member states and is regularly updated, allowing categorization into different definitions of importance of antimicrobials based on current use in the treatment of serious infections in animals where there was a lack of sufficient alternate drugs (Gehring et al., 2023). Inspired by the WHO process and using the WHO CIA and MIA lists as a benchmark, many countries, or jurisdictions, developed or continue to develop their own list of (critically) important antimicrobials for the purpose of risk assessment and risk management and for the development of regulations associated with AMU in food‐producing animals (Scott et al., 2019). Yet, there is sometimes huge variation in categorization terms and the actual categorization of antimicrobial classes between countries or jurisdictions (Table 23.2) which variously focus on importance to either human health or animal health and welfare (Gehring et al., 2023). Table 23.2 Selected antimicrobial drug categorization, with examples from different organizations or countries. a Highest priority critically important (HP‐CIA); Critically important (CIA) ; Highly important (HIA); Important (IA). b World Health Organization, 2024; European Medicines Agency, 2019; Australian Strategic and Technical Advisory Group on Antimicrobial Resistance (ASTAG), 2018; Government of Canada, 2009; US Food and Drug Administration, 2003; Food Safety Commission, 2014. # Not registered for use in production animals (except for topical polymyxin B ointment). The European Medicines Agency (EMA) has prepared scientific advice to classify antimicrobial drugs for use in animals into four categories (Avoid, Restrict, Caution, Prudence) which can be used by member states for their national policy. The “Avoid” category antimicrobials should not be used in food‐producing animals in the EU and only under exceptional circumstances in companion animals (European Medicines Agency, 2022b). Antimicrobials categorized as “Restrict” should be considered only for the treatment of clinical conditions when there are no alternative antimicrobials in the categories of “Caution” or “Prudence” that could be effective. Particularly for this category, use should be based on the results of antimicrobial susceptibility testing, whenever possible. Separate from the EMA categorization, on request of the European Commission, a list has been developed of antimicrobials that should be reserved for use in humans only, and not allowed to be used in animals, under any condition (Schmerold et al., 2023). Despite differences among these lists (Table 23.2), there is general agreement that CIAs are those: (1) used for the treatment of serious bacterial infections in humans where there are no, or virtually no, alternatives, and (2) where resistant bacteria or their resistance genes can reach humans from animals treated with these drugs. A third consideration for CIAs (and “Reserved” antimicrobials) is that they are not essential for the health and welfare of animals (European Medicines Agency, 2022b). Although there is some inevitable variation in the lists of different countries based on national considerations, the concept of importance categorization is now well entrenched in human and veterinary medicine as an important consideration in AMS and is increasingly incorporated into public or private controls of the use of the most critically important antimicrobials in human medicine in food‐producing animals in different countries. The drugs of particular current focus, that for the purposes of this chapter will be referred to as HP‐CIAs, include third‐ and fourth‐generation cephalosporins (3&4GCs), fluoroquinolones, and polymyxins (colistin). The terminology around antimicrobial growth promotion (AGP), subtherapeutic and preventive (prophylactic) use is complex and confusing, but it refers to approved uses of antimicrobials, often dating to regulatory authorization in the 1950s as feed additives, without the requirement for veterinary prescription (Prescott, 2018). Antimicrobials have historically been used prophylactically in food‐producing animals to prevent the development of infections within apparently healthy herds or flocks, and to promote growth via improved feed efficiency, particularly in intensive animal production. Despite 50 years of AGP use, recent reliable data on their effect on productivity are scarce and there is growing evidence that they do not have as much economic benefit as previously observed, especially in countries with advanced farming practices and under proper biosecurity conditions (Aarestrup, 2015; O’Neill, 2015; Council of Canadian Academies, 2019; Tang et al., 2019). Studies conducted before the 1980s reported an improvement as high as 5–15% in the growth rate and feed efficiency of intensively reared livestock fed subtherapeutic antimicrobials (Cromwell, 2002) but more recent studies in Denmark, Sweden, and the United States indicate statistically either insignificant effects or between 1% and 3% improvement (Sneeringer et al., 2015). Similar findings of a nonsignificant effect on performance are reported in a recent study from India (Paul et al., 2022). The reason why the growth response of farm animals to antimicrobials has declined over time is likely that many aspects of animal health and herd management practices such as nutrition, genetics, hygiene, and biosecurity measures have improved significantly over the decades (Aarestrup, 2015; Laxminarayan et al., 2015; O’Neill, 2015). Recent experiences of several European countries demonstrate that reducing AMU does not have major effects on productivity and animal health when coupled with good herd management practices. Laxminarayan et al. (2015) used a Computable General Equilibrium economic model to estimate the potential loss to global meat production if AGPs were banned worldwide, projecting that a ban would decrease global annual meat production by between US$14 billion and US$44 billion (worst‐case scenario). Such an apparent global benefit of AGPs and preventive antimicrobials must be weighed against the immediate and long‐term adverse impacts on human, animal, and environmental health and the fact that improved husbandry practices appear to replace the benefits previously associated with the AGPs. With an increasingly unfavorable benefit–risk ratio, there is no justification for continued routine and uncontrolled use for these purposes. For many years, The Netherlands has had the lowest consumption of antimicrobial drugs in human medicine in Europe. Paradoxically, the consumption of antimicrobials in farm livestock appeared to be the highest in a comparison made between 10 European countries in 2007. Where human methicillin‐resistant Staphylococcus aureus (MRSA) was successfully controlled in hospitals through an intense “search and destroy” approach, it appeared unexpectedly in 2005 that livestock‐associated MRSA was widespread in the Dutch pig industry with occupational transmission to humans, sensitizing the general public to the adverse effects of AMU. This led a Task Force on Antibiotic Resistance in livestock to develop action plans for reduction of AMU in the major food animal production chains. The action plans involved monitoring AMR, monitoring detailed AMU at the herd and flock level, separating responsibilities for antimicrobial prescriptions between veterinarians and farmers, and developing farm treatment plans and farm health plans. This, however, did not substantially affect AMU in the following year (Speksnijder et al., 2015). The discovery in 2009 of extended‐spectrum beta‐lactamase (ESBL)‐producing bacteria on poultry meat with evidence strongly suggestive of transmission from poultry and retail chicken meat to people and causing bloodstream infections (Leverstein‐van Hall et al., 2011), coming on top of earlier public concern about the human health impacts of animal farming generally and AMR specifically, led to a firestorm in the national media and intense debate in the Dutch Parliament. This resulted in a 50% reduction target in veterinary AMU by 2013 mandated by the government and supported by all the stakeholders in the major livestock sectors. In 2010, the national Veterinary Medicines Institute (SDa) was established as a public–private partnership between the government, the livestock industries, and the veterinary association. The task of the SDa was to collect reliable usage and prescription data from all farms and veterinarians and to set annual targets for AMU in the different livestock sectors and their subcategories and to differentiate (benchmark) moderate, high, and very high users (farmers) or prescribers (veterinarians) with the ability to sanction very high users and prescribers (Speksnijder et al., 2015). Additional measures were taken by the livestock sectors and the government in the subsequent years to better fine tune AMU in animals. Antimicrobials for veterinary use were divided into first, second and third choice based on the WHO classification (third choice) or potential selection for ESBL and AmpC‐producing bacteria (first and second choice). This included a ban on the use of 3&4GCs and fluoroquinolones for preventive and (systematic) group treatment of animals and a complete ban on newer antibiotics like carbapenems. In 2011 the government introduced a ban on all preventive use of antimicrobials in food‐producing animals. The position of veterinarians as gatekeeper was strengthened by regulating the distribution of antimicrobials only through the official farm veterinarian. Additionally, private quality labels introduced extra‐legal specific regulations for AMU in their production chains. Important and relatively easy management changes implemented by farmers included abandoning routine preventive AMU, shifting towards individual treatments instead of group treatments, improving feed and water quality, increased attention on biosecurity and housing conditions, uptake of different vaccination schemes, and the increased use of supportive therapies instead of antimicrobials (Bergevoet, 2019). As a result, a 56% reduction in AMU was achieved between 2007 and 2012, with a 92% and 59% reduction in use of 3&4GCs and (fluoro)quinolones respectively between 2009 and 2012 (Speksnijder et al., 2015). In 2013 the government raised the target for AMU reduction to 70% by 2015 compared to the 2009 baseline. This target was met in 2022 with a 77.4% reduction in sales of antimicrobials for use in livestock (Autoriteit Diergeneesmiddelen, 2023). Additionally, the use of HP‐CIA classes had been very limited for years. Moreover, AMR rates declined in indicator Escherichia coli isolated from cecal samples of healthy food‐producing animals at slaughter and a clear reduction in the proportion of animals positive for ESBL/AmpC‐producing E. coli was observed and believed to result from a direct effect of the AMU measures taken since 2010 (MARAN, 2022). Since 2016, the focus has shifted to specifically address the high users and prescribers. In several research projects initiated by the government, attempts were made to study critical success factors for low AMU (farms) and low antimicrobial prescription levels (veterinarians). These studies revealed a relatively large attribution of psychological characteristics of the farmer and/or veterinarian on the level of AMU. The distilled success factors are currently applied in (mandatory) coaching sessions for high users in different livestock sectors. The objective of the AMU policy changed over the years from reducing AMU on all farms towards encouraging as many farms as possible to enter the lowest benchmark category, defined as an “acceptable” level of AMU (Autoriteit Diergeneesmiddelen, 2023). The case study in The Netherlands presents an example of successful changes in AMU in food‐producing animals, with a corresponding reduction in AMR in indicator bacteria (Hesp et al., 2019). It also shows how AMU can be drastically reduced at a national level without jeopardizing animal health and welfare and the economic position of farmers (Bergevoet, 2019) when coming from a relatively high baseline AMU. The Danish approach in the livestock sector has shown similar outcomes where several consecutive national initiatives implemented by the government and private sectors have led to a remarkable reduction in AMU since 1994 without compromising the economic competitiveness of farmers (DANMAP, 2022). Key success factors of the Dutch approach were the common concern of the public, government, and private sectors about the extensive veterinary AMU and risk of AMR transmission, the clear reduction targets set in combination with transparency in use and prescribing, and the joint efforts undertaken by the private sectors and the government. These are important examples of thinking through the processes required in making significant improvements and provide an important model for other countries to follow. The more notable of the numerous lessons to be drawn from these experiences are summarized in Table 23.3. To be effective, AMS in food‐producing animals requires political commitment and a coordinated national (or transnational) approach which involves several integrated and interacting elements, summarized in Figure 23.1. The figure is based on analysis of lessons learned from multiple effective actions advocating AMS in food‐producing animals promoted by individuals and by numerous countries (particularly the high‐income countries), and by transnational jurisdictions or responsible agencies in recent years. Table 23.3 Major lessons from the Dutch experience in making substantial reductions in AMU and AMR levels in food animals (2009–2017). Figure 23.1 Description of the different elements of successful national approaches to veterinary antimicrobial stewardship in food‐producing animals. A critical component is that the preferred approach must be national and involve high‐level political commitment, coordination, regulation, leadership by both veterinarians and producers, surveillance, benchmarking, and measurement, set within the context of One Health approaches and of international commitments to addressing antimicrobial resistance. See also Figure 20.2 for a summary of additional elements of stewardship. Evidence has established that AMU in food‐producing animals selects for resistant pathogenic and commensal bacteria, or their resistance genes, reaching people through the food chain or environment (see Figure 3.3) with the potential to make infections with such resistant organisms more difficult to treat. The precise scale of AMR transmission is difficult and maybe impossible to quantify due to the complex epidemiology of AMR (Chapter 3). Some classic examples of AMR selection (e.g., selected nontyphoid Salmonella enterica serotypes, MRSA strains, fluoroquinolone‐resistant Campylobacter jejuni, vancomycin‐resistant Enterococcus faecium) have been described in Chapter 3
23
Antimicrobial Stewardship in Food‐producing Animals
Introduction
General Principles of Antimicrobial Stewardship in Food‐producing Animals
Critically Important Antimicrobial Drugs (CIAs)
Theme
Principle
Application to food animals
Responsibility
There is national commitment to the regulation and to monitoring of the use of antimicrobials in food animals.
This is focused especially on food‐borne zoonotic pathogens and on “indicator” enteric bacteria that enter the food chain.
There is commitment to understanding both the need for, and adoption of, antimicrobial stewardship practices, including the 5Rs of responsibility, reduction, replacement, refinement, and review of Good Stewardship Practice (GSP).
Leadership at all levels with championing of GSP and antimicrobial guardians.
Antimicrobials should only be used in the context of a valid veterinarian/client/patient relationship.
All antimicrobial use in food animals should be under the genuine oversight of a veterinarian or a paraveterinary professional accountable to a veterinarian.
Antimicrobials should only be used when there is reasonable likelihood that a bacterial infection is present or at high risk of developing, and antimicrobial intervention will benefit the disease outcome in the treated animals.
A critical general principle applicable to all antimicrobial drug use. The use of treatment guidelines and point‐of‐care diagnostics can aid in on‐farm clinical decision making.
An antimicrobial stewardship mindset should be a guiding principle of antimicrobial use in food animals.
A stewardship mindset is a collaboration between farmers, veterinarians, and advisors, as well as industry‐led policy.
Antimicrobials of critical importance in humans that are described as Category A (“Avoid”) in the European Union should never be used in food animals.
Examples are the carbapenems and the glycopeptides.
Reduction
There is a national targeted commitment to reduction and improved use of antimicrobials in food animals.
National policies and standards are pursued by animal sector industries and implemented by farm level practices.
Methods to reduce the risk and incidence of infection should be emphasized to decrease the need for antimicrobials.
Proper biosecurity, immunization procedures, housing design, early diagnosis, and husbandry practices are important aspects of good stewardship.
Antimicrobials should only be used for disease prophylaxis under restricted circumstances.
Antimicrobials should only be used where bacterial infection is known or extremely likely to be present, and antimicrobial use benefits clinical outcome.
Reduction without affecting production and welfare involves multiple interventions.
Identifying the different potential reduction intervention points involves individual farm management analysis.
Replacement
Alternatives to antimicrobials should be pursued wherever possible and where there is sound evidence of safety and effectiveness.
Supportive therapies in many instances can abate the need for antimicrobial treatment. For example, activated charcoal and oral fluid therapy is a useful approach to treating some neonatal diarrheas in calves and piglets.
Refinement
Antimicrobials that are important for treating refractory or serious infections in humans should be used sparingly and only after careful consideration.
The WHO High Priority Critically Important Antimicrobials are a highly important target for reduction of use in food animals, that requires laboratory validation before use.
Antimicrobial therapy should never be used as a substitute for good infection control, medical and surgical practices, and animal husbandry.
Antimicrobials should not be used for growth promotion or routine prophylaxis in food animals.
Antimicrobials should be used for as short a time as possible and in as few animals as possible.
Long‐term disease preventive use should be avoided.
Improved early detection of animals with infections should be implemented.
Rational indicators for stopping treatment should be investigated and included in treatment guidelines.
Food animal veterinarians need to know and follow national or veterinary association regulations and guidelines relating to antimicrobial use.
Use of antimicrobial drugs in food animals should be subject to national regulation.
Animal welfare considerations are critical in assessing the need for antimicrobial drug use.
“Raised without antibiotics” in animal production must never become “Raised without welfare.”
Review
Measure, benchmark, quantity, and quality of use.
A critical aspect of the 5Rs of good stewardship.
Continuous improvement is fundamental to good stewardship.
Stewardship actions are evaluated and documented regularly.
Potential benefits of introducing new interventions should be evaluated.
The target should be the best possible practice of AMS.
Categories and examples
World Health Organizationb
Proposed European Unionb
Australiab
Canadab
United Statesb
Japanb
Categoriesa
HP‐CIA; CIA; HIA; IA
Avoid; Restrict; Caution; Prudence
High;
Medium;
Low
Very high; High; Medium
CIA; HIA;
IA
CIA;
Highly important; Important
Examples
Aminopenicillins
HIA
Caution
Low
High
HIA
High
Cephalosporin, third–fourth generation
HP‐CIA
Restrict
High
Very high
CIA
CIA
Glycopeptides
Humans only
Avoid
High
Very high
CIA
CIA
Macrolides
HP‐CIA
Caution
Low
High
CIA
CIA 15‐membered
Polymyxins
HP‐CIA
Restrict
High#
Very high
Critical
CIA
Fluoroquinolones
HP‐CIA
Restrict
High#
High
CIA
CIA
Tetracyclines
HIA
Prudence
Low
High
High
High
Antimicrobials as Livestock Feed Additives
Case Study: The Dutch Experience and Its Lessons
Lessons Learned
Elements of National Veterinary Antimicrobial Stewardship Programs in Food‐producing Animals
Commitment: Incentives and Motivation for Change
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