Minimizing the Risk of Antimicrobial Resistance from Food Animal Production

The roles that antibiotics have played – and continue to play – in selecting for antimicrobial resistance (AMR) among commensal and pathogenic enteric bacteria of animals and humans are the focus of a great deal of scientific investigation and debate. The relationship between antibiotic use and AMR will be considered over time periods extending back long before before antibiotics were discovered, through the ‘golden age’ of antibiotic discovery of the 1940s to 1980s, and into the present beginnings of a post-antibiotic era. The specific roles that food animal uses of antibiotics have played in negatively impacting public health will be discussed, along with the quality of evidence that supports such viewpoints. Opportunities to intervene by mitigating previous and ongoing emergence, spread, propagation and persistence of acquired bacterial resistance are exemplified by several US and international efforts. These include the recently enacted Guidance for Industry (GFI) 209/213 in the United States and the efforts over the past decade in the Netherlands to reduce antibiotic use in food animals by up to 70%. Evidence to support such efforts is difficult to compile; however, several analytical approaches to doing so in the short, medium and longer-term offer some promise. These include consideration of temporal dynamics of bacterial populations during and immediately following treatment, the medium term effects of these cumulative treatments in food animal facilities as mediated through environmental spread, and longer-term shifts in populations reflecting evolutionary fitness changes and large-scale spread and propagation of mobile genetic elements under intensive use and rearing conditions.

Rising consumer interest in how food is produced has resulted in the expansion of farm animals raised under a raised-without-antibiotics (RWA) program. The RWA classification is most prominent in the poultry/broiler industry as several producers and retail-chain companies have moved their marketing in that direction. The rapid expansion of the RWA program has raised questions regarding their potential sustainability across the three pillars of environment, economics, and animal welfare. This presentation takes a data-driven approach to assessing the potential outcomes of RWA broiler production on animal health effects, environmental resource impacts (land, feed, water, and manure), and economic consequences.

Animal health effects are assessed using a data set on broiler health covering conventional and RWA broilers looking specifically at three disease states that are important indicators of broiler welfare: corneal eye burns, foot pad lesions, and airsacculitis. The environmental impacts are estimated using a model that simulates broiler production in the U.S., examining differences between average survivability, space requirements, days to grow-out a defined sized bird, and days between production cycles. Finally, the economic consequences are reviewed using industry data on trends in broiler production and performance comparing across different production regimes (e.g., conventional, RWA, and those that allow access to ionophores).

The topic of antimicrobial resistance is both broad and extremely complex, with intricate terminology. A fundamental issue that arises in discussions between different stakeholders is how terms are defined and this leads to confusion and misinterpretation.

Multiple organisations have attempted to define terms related to antimicrobial resistance and this has only lead to further confusion. For example, the simple term ‘prevention’ is defined differently by the WHO, Codex and OIE. In fact, WHO and Codex confusingly interchange ‘prevention’ and ‘control’ whilst the OIE specifically addresses ‘prevention’ in the strictest sense. This has resulted in some cases where antimicrobials are inappropriately administered under a ‘prevention’ claim.

At a fundamental level, there remains a great deal of confusion over even the basic of terms i.e. what is a ‘non-medically important antibiotic’ vs. ‘medically important antibiotic’. Of greater concern is that a number of institutions are confusing ‘medically important antibiotics’ as being ‘critically important antibiotics’.

Confusion in definitions leads to confusion in policy documents and interpretation of regulations. Such confusions can have detrimental effects when interpreting guidelines and legislations and indeed misinterpretation due to lack of clear definitions can, in some instances, lead to animal welfare issues.

This paper discusses the urgent need for clear definitions in regards to antimicrobial resistance and the international efforts currently being undertaken to harmonise definitions at a global level.

Antimicrobial resistance is an emerging global health issue that affects people and animals alike. Drivers of resistance are multifactorial and span the sectors of human, animal, and environmental health. Given the broad reach of this phenomenon, a One Health approach is needed to protect antimicrobial efficacy. Practices that reduce the overall need for antimicrobials are often considered the most effective at curbing the trend of resistance. In the U.S. animal agriculture industries, animal husbandry practices meet this objective by preventing disease introduction, impact, and spread. This presentation will provide a brief overview of the preventative strategies implemented in food animal production to reduce the need for antimicrobials.

Any use of antibiotics contributes to the growing global threat of antibiotic resistance, so minimizing their use is essential. Vaccines and other antibiotic alternatives have the potential to prevent infections in food animals and various studies have demonstrated their ability to reduce the need for antibiotics. This holds promise for efforts to decrease reliance on antibiotics. To be widely used in food animals, vaccines have to be safe, effective, easy to use, and cost-effective. Many current vaccines fall short in one or more of these respects, although focused research and development efforts will help overcome these challenges and bring promising new vaccines to the veterinary market. This presentation will provide an overview of the field of vaccines as antibiotic alternatives today and tomorrow.

The microbiota of plays an intrinsic role in the health and performance of food animals. Efforts to reduce antibiotic use in food animal production have led to a search for alternative products mimicking their effects. Combinations of prebiotics and probiotics, also referred to as synbiotics, hold great promise as one such alternative approach. However, this field is in its infancy and much work is still required for the development of products conferring consistent and reproducible effects. Traditionally, synbiotics have targeted pathogen reduction on food animals. Recently, more focus has been directed towards modulation of the microbiome by synbiotics and, subsequently, enhancement of animal performance. Most of the work in this area thus far has targeted defining the baseline microbiota of food animals, and how this baseline shifts during disease. The future of synbiotic development will include the identification of animal-specific and context-specific products that positively modulate the microbiota towards performance enhancement. The ultimate goal of these efforts is to mitigate antibiotic resistance through reducing the need for antibiotic use. Such efforts will only be successful if they consider the entire toolbox, not just one specific alternative product type. Furthermore, resistance to alternative products such as synbiotics also needs to be considered and mitigated so that history does not repeat itself.

There is increasing pressure to reduce antibiotic use in animal agriculture while maintaining or improving animal health and the microbiological safety of animal products.  Bacterial pathogens can reduce production yields and impact public health by their transmission to humans.  A number of non-antibiotic strategies to control bacterial pathogens in agricultural systems are under development, and the use of bacteriophages (phages) represents one such avenue.  The current antibiotic resistance crisis has revitalized interest in phages, bacterial viruses, as an antibacterial strategy for foods, animal health and in human medicine.  Phages are ubiquitous and highly successful natural predators of bacteria, and resistance to phages is generally unlinked to antibiotic resistance.  They are highly specific for their bacterial targets, which reduces collateral damage to beneficial members of the microflora but also poses challenges for producing broadly effective treatments.  Phages have shown efficacy in controlling a variety of pathogens in animal production systems, including Salmonella, E. coli, and C. perfringens.  While phage-based products designed for food safety applications have been commercially available for some time, commercial adoption of this technology in animal production has been limited.  This talk will discuss the current state and future directions of phage use in animal production systems.

Worsening antimicrobial resistance (AMR) threatens the practice of modern human and veterinary medicine. For decades, medicine and agriculture have blamed each other for the rise of resistant microbes. Widespread use and misuse of antibiotics in both medicine and agriculture have contributed to the problem, but metagenomics studies suggest that antimicrobial resistance genes are ancient and ubiquitous. Widespread use by humans has increased their prevalence and expression. The rise of vancomycin-resistance Enterococcus faecium (VRE) in the European Union (EU) led to the ban of avoparcin, an antibiotic chemically related to vancomycin, an antibiotic used in human medicine. In the years post ban, VRE surveillance data of EU hospitals showed no obvious reduction in VRE rates. The United States (US) never approved avoparcin, yet VRE has been an enormous problem in its hospitals. AMR surveillance data showed zero rates of VRE in US livestock. Genomic data suggests that VRE might have evolved from ampicillin-resistant Enterococcus faecium from dogs. Companion animals have been completely ignored in the AMR debate and should be included in AMR surveillance systems. Whole genome sequencing surveillance should be conducted in hospitals, veterinary hospitals, farms, and slaughterhouses, and it should become the gold standard in AMR surveillance systems.

Antimicrobial resistance (AMR) is one of the greatest challenges facing public health in the 21^st century.  As scientists work to improve our understanding of the scope and drivers affecting this important issue, it is critical to be able to appropriately characterize the nature of this problem.  Thus, a key question is: how do we best describe the occurrence of AMR?  For decades, scientists have relied on in vitro estimates of phenotypic expression for reduced susceptibility to antimicrobial drugs (AMDs).  However, similar phenotypic appearance of AMR can be driven by a myriad of different genetic determinants of antimicrobial resistance (genes).  Just as understanding the epidemiology of specific pathogens is aided by differentiating different strains, an improved understanding of the dissemination and propagation of AMR will be obtained through differentiating AMR that is associated with specific GDAR.  Some previous and ongoing research has focused on pathogens of humans and animals, but research has just as commonly investigated AMR in “marker” bacteria such as E. coli and Enteroccus spp. as representatives of Gram-negative and Gram-positive fecal flora, respectively.  Use of marker bacteria has relied on the assumption that these bacterial species can be broadly representative for AMR found in pathogens and other microbiota, not only in feces, but also in other microbial niches (e.g., respiratory, skin, environment).  However, these target species represent a minority of the microbiome, and AMR in these organisms has not been proven to correlate with resistance in specific pathogens or in the broader microbiome.  Increased use of molecular methods is needed to more fully characterize the ecology of AMR in entire microbial ecological systems.

The importance of pre- and post-harvest management practices in the production of fresh produce are of well-established importance for prevention of food-borne illness.  Such practices include composting of manure before application as a soil amendment, wait periods between application of manure to soil and harvest, produce washing practices, and packaging and preservation conditions.  However, little is known about how management practices during crop production may be adapted to minimize chances for the spread of antibiotic resistance.  Mitigating antibiotic resistance requires a distinct paradigm from traditional pathogen control because it is important to more broadly consider avoiding conditions that select for antibiotic-resistant strains or stimulate evolution and transfer of antibiotic resistance genes (ARGs), including from non-pathogenic microbiota to pathogens.  With the advent of next-generation DNA sequencing, it is now possible to comprehensively track ARGs, along with mobile genetic elements contributing to their transfer, through food production ecosystems and other environments.  This is advantageous because it provides a holistic microbial ecological view on the potential for antibiotic resistance to spread, and not just individual target microbes.  Here we will demonstrate the use of deep-learning and assembly-enabled bioinformatics tools for tracking ARGs through various pre- and post-harvest barriers in the production of radishes and lettuce.  Notably, even far upstream practices, such as use of antibiotics in the livestock producing the manure composted for soil amendment, can be detected in the metagenomes of the microbiota colonizing the surfaces of corresponding vegetables.

Antibiotic use in animal production is not considered a precompetitive issue in the United States as it is in other countries such as the European Union. Thus the way that antibiotics are used – or not used - during the raising of animals is becoming an integral part of the marketing strategy used to sell meat and poultry products by many producers. Unfortunately, most consumers are unfamiliar with animal agriculture and are increasingly confused by food labels related to antibiotics and animal production practices. The meanings and implications for consumers and animals of antibiotic related labels used by the food industry such as “No Antibiotics Ever” and “Responsible Antibiotic Use” will be discussed. There are unintended consequences and tradeoffs to these single attribute labels that are part of a package based labeling system.  An alternative approach to food labels is a program or systems based certification process that does not require diversion of product. A balanced multi-point standard that addresses several important areas in animal agriculture, including responsible antibiotic use that is respectful of animal welfare, may be a better solution to provide an affordable and sustainable labeled alternative for meat and poultry that will satisfy the needs of many consumers.  A new cross commodity animal production certification program currently in development based on the principles of one health will be discussed.

Ensuring the safety, health, and overall well-being of animals raised for food is both an ethical obligation and a critical component of providing safe food products. The use of antibiotics for maintaining animal health has come under scrutiny in recent years due to the rise of antibiotic resistance globally. Some U.S. producers, especially in the poultry industry, have responded by eliminating their antibiotic use. Restaurants, grocers and other retailers of meat, egg, and dairy products have implemented programs centered on providing proteins sourced from animals that received no antibiotics throughout their lives. The number of animals raised without antibiotics (RWA) is growing in the U.S., but there are concerns that RWA practices might negatively impact animal health and welfare. This presentation will discuss a survey we conducted to investigate the impacts of removing antibiotics from animal production on key parameters such as animal health and welfare, food safety, consumer demand, and cost of food production.

Antimicrobial resistance (AMR), and the impacts of animal food production is a concern amongst consumers While there are many steps in place to mitigate the risk and prevent public health impacts, many consumers have developed perceptions that animals raised with antibiotics produce foods are unsafe to eat for various reasons including antibiotic consumption and exposure to AMR microorganisms. In addition, AMR concerns have moved into other foods and water sources. In a situation like this, where trust is low and uncertainty (from a consumer’s perspective) is high, employing best practices for risk communication is important. Being open and transparent, evidence-based and acknowledging what is not known is important to further discussions. Current communication methods have fallen short in delivering accurate, information about risks and what is being done by stakeholders to impact public health. Development of effective communication around antibiotic use in animal production should begin with an understanding of current consumer information sources and incorporate risk theory strategies to craft and evaluate messages.