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eBriefing

Antimicrobial Resistance in Food Animal Production: Minimizing the Risk

Antimicrobial Resistance in Food Animal Production
Reported by
Hallie Kapner

Posted February 07, 2019

Hallie Kapner is a freelance writer in New York.

Presented By

The New York Academy of Sciences

Elanco Animal Health

Overview

The Centers for Disease Control and Prevention estimates that 2 million people in the United States alone contract antibiotic-resistant infections every year, at an annual cost of $20 to $35 billion. While the sources of infection vary, the rise in prevalence of resistant organisms over the past several decades has triggered global public action to minimize the spread of antimicrobial resistance and reduce the use of antibiotics in humans and food production animals. On September 28, 2018, Elanco Animal Health and the New York Academy of Sciences presented Minimizing the Risk of Antimicrobial Resistance from Food Animal Production, a daylong symposium to discuss the drivers of antimicrobial resistance in food animal production; identify pathways for transmission of resistant organisms and methods for controlling transmission; explore alternative treatment approaches; and discuss consumer demands and beliefs surrounding food safety and the use of antibiotics in the food supply.

Speakers

Heather Fowler, VMD, PhD, MPH, DACVPM
Heather Fowler, VMD, PhD, MPH, DACVPM

National Pork Board

Jason Gill, PhD
Jason Gill, PhD

Texas A&M University

Karin Hoelzer, DVM, PhD
Karin Hoelzer, DVM, PhD

The Pew Charitable Trusts

Tim Johnson
Tim Johnson, PhD

University of Minnesota

Laura Kahn, MD, MPH, MPP, FACP
Laura Kahn, MD, MPH, MPP, FACP

Princeton University

Paul Morley, DVM, PhD, DACVIM
Paul Morley, DVM, PhD, DACVIM

Colorado State University

Amy Pruden, PhD
Amy Pruden, PhD

Virginia Tech University

Donald Ritter, DVM, ACPV
Donald Ritter, DVM, ACPV

Mountaire Farms, Inc.

H. Morgan Scott, DVM, PhD
H. Morgan Scott, DVM, PhD

Texas A&M University

Matthew Salois, PhD
Matthew Salois, PhD

American Veterinary Medical Association

Natalie Seymour
Natalie Seymour, MS

North Carolina State University

Shabbir Simjee, PhD
Shabbir Simjee, PhD

Elanco Animal Health

Randall Singer, DVM, PhD
Randall Singer, DVM, PhD

University of Minnesota

Session 1. Setting the Stage

Speakers

Antibiotic Resistance: Background and Spread

The 1940s mark the beginning of what H. Morgan Scott, of Texas A&M University, called “the age of antibiotic discovery.” From 1942, when penicillin was discovered, until 1968, new antibiotics and antibiotic classes were discovered and introduced at a pace that remains unmatched. More than 30 years have passed since a new antibiotic was introduced for use in food animal production. As Scott explained, a lack of new antibiotics for both human and animal use, as well as widespread overuse of existing drugs, has contributed to antimicrobial resistance (AMR), an issue characterized by the World Health Organization (WHO) as a “threat to global health security.”

While the mechanisms of antimicrobial resistance have existed in nature for as long as antimicrobial compounds themselves, Scott described how the “incubators” of food animal production and human medical care have dramatically expanded resistance elements, forcing those who use antibiotics at scale to consider and address the problem. “We have moved from the age of antibiotic discovery to the age of concern, and now we are in the age of antibiotic action,” Scott said.  He suggested that antibiotic susceptibility can be considered a public good, and that those who are in position to protect the susceptibility of pathogenic organisms have a responsibility to “act ethically in the present.”

New antibiotics were introduced at a rapid pace for more than 30 years, but no new antibiotics have been approved for us in food animals since the 1980s

New antibiotics were introduced at a rapid pace for more than 30 years, but no new antibiotics have been approved for us in food animals since the 1980s

Judicious Use and Acceptable Risk

The decision to use antibiotics in food animals necessitates that producers balance the need to prevent, control, and treat animal diseases against the risk of encouraging resistant organisms that could threaten human health if they move from farm to community. A meta-analysis of randomized trials of antibiotics to treat bovine respiratory disease illustrates the difficulty of setting a baseline for judicious antibiotic use. The analysis revealed that the number needed to treat in instances of acute disease was 2:1—for every two sick animals treated, one is saved. In metaphylaxis, or disease control, that ratio jumps to 5:1, and in disease prevention, some estimates place the ratio as high as 20:1. “Nobody argues about 2:1 or even 5:1, but when is it a morally justified decision to treat 20 animals to save a single animal, given the potential risks to public health?” Scott asked.

Data from the Netherlands, where mandatory cuts have resulted in a 50% reduction of antibiotic use in food animals since 2009, highlight yet another area of quandary in establishing responsible antibiotic use protocols. The Dutch data show that while poultry can be raised without antibiotics, other species, such as veal calves, are impractical targets for an antibiotic-free approach.

Setting a baseline for an “acceptable ” prevalence of resistant organisms in food animals is also deeply challenging. In the United States, cattle coming off pasture have low levels of antibiotic resistance, yet once they enter intensive feeding, resistance levels in indicator bacteria often jump 20%–30%. A baseline of “zero resistance” is thus unrealistic; but Scott acknowledged that farmers’ efforts to decrease antibiotic use may be thwarted by a complex regulatory environment that strictly mandates “on label” antibiotic use. Paradoxically, this often leads to greater dosing, even in instances when experiments have shown that fewer or lower doses are equally effective.

Scott set the stage for a day of debate and discussion, signaling the need for assessment and change throughout the food animal production chain— from potential legislative shifts; to defining judicious use and acceptable risk; to developing novel biological approaches for minimizing the spread of resistance and preserving bacterial susceptibility. He positioned AMR as a “One Health” issue, referencing the philosophy that the health and well-being of humans, animals, and the environment are inextricably linked, and that addressing the issue will require a multisectoral, collaborative approach.

Sustainability Implications for Raising Animals Without Antibiotics

Matthew Salois, of the American Veterinary Medical Association, explored the sustainability implications of raising food animals without antibiotics, emphasizing that strategies to address antimicrobial resistance cannot be created in a vacuum, and must be considered alongside other global challenges.

A soaring population and growing middle class are projected to drive demand for animal protein up 60% over the next 30 years. Meeting this demand sustainably will require, among other actions, minimizing food waste—a large percentage of which comes from a surprising source. More than 20% of food animals are lost to disease, a fact that Salois refers to as “the greatest untold story of food waste.” “If we’re going to deliver food for a growing population, control animal morbidity and mortality, and be good stewards of the environment, we’re going to need to be efficient, and learn to do more with less,” he said. Reconciling consumer demands with the economic and environmental realities of feeding a growing global population is a challenge that looms large in addressing antibiotic use policies and practices.

Efficiency and Sustainability Issues in Poultry Production

The richest source of data on animals raised without antibiotics (RWA) is the poultry sector, where nearly half of all broiler chickens in the United States are produced in RWA programs. Salois reviewed broiler mortality trends, noting that 2013 marks the first mortality increases since 1920. While he cautioned against presuming causality, he noted a connection between rising mortality and the implementation of RWA programs by several large poultry producers.

Further analysis of health indicators among broiler chickens raised without antibiotics compared to conventionally raised broilers reveals higher rates of morbidity and mortality among RWA cohorts. Negative health indicators including foot lesions, eye burns, and airsacculitis occur more frequently in birds raised without antibiotics, although these conditions can be controlled with proper management.

Raising poultry without antibiotics is more resource-intensive and comparatively less efficient than conventional production. Birds in RWA programs require more feed, take longer to reach a target weight for harvest, and require lower stocking density. A modeling exercise simulating the impact of a 100% conversion of U.S. broiler production to an RWA approach revealed that between 680 and 880 million more birds per year would be required to meet current demand. The additional demands of increased production are significant, and include approximately 5–7 million additional tons of feed and 2–3 million gallons of water per year, as well as the environmental impact of an estimated 4.5–6 million tons of additional bird waste annually.

An economic model simulated the increases in feed, water, and land needed to produce the same amount of protein to meet current demand

An economic model simulated the increases in feed, water, and land needed to produce the same amount of protein to meet current demand

Consumer Viewpoints and Market Demand

Salois reviewed the marketplace for broiler chickens, highlighting gaps between production volume and market demand for RWA broilers. Despite the fact that 50% of broilers are RWA, conventionally raised chicken dominates 89% of sales by dollar, and represents 94% of the volume of chicken sold in the United States. And while consumer demand appears to be a major driver of RWA production, most consumers harbor significant misperceptions about the care and raising of chickens for food. For example, in a 2017 nationally representative survey of 1,000 consumers who purchase chicken, 76% believed that most chicken meat contains added hormones and steroids, and 75% believed that antibiotics are present in most chicken meat. Additionally, 71% of consumers surveyed affirmed the belief that most chickens are genetically modified to increase growth.

Consumers believe they are knowledgeable about chicken production, but misperceptions are common

Consumers believe they are knowledgeable about chicken production, but misperceptions are common

Critically Important Antibiotics in Veterinary Medicine

Shabbir Simjee, from Elanco Animal Health, concluded the session with a review of guidelines surrounding the use of critically important antibiotics in food animal production. Simjee clarified the definition of “critically important,” explaining that antibiotics are classified by WHO and other international health organizations as either “non-medically important,” meaning they are not used in human medicine, and “medically important,” indicating that at least one molecule in an antibiotic class is important for human health. Within the medically important category is a short list of drugs considered “critically important,” and it is the use of these medications in food animals that has sparked controversy.

In 2017, WHO released guidelines for the use of medically important antimicrobials in food animals.  Recommendations include an overall reduction in the use of these medications; a complete restriction of medically important antibiotics for animal growth promotion; complete restriction of medically important antibiotics for prevention of undiagnosed animal infections; and complete restriction of critically important antibiotics in animals for disease control or treatment.

Simjee explained that while the first two recommendations are widely accepted, the restrictions of medically important antibiotics for prevention are clouded by conflicting ideas about what actually constitutes prevention. WHO specifies prevention as the administration of antibiotics in the absence of a diagnosed infection, whereas Simjee explained that farmers often administer antibiotics during times of stress—prior to transporting animals, for example—to prevent subclinical infections from becoming fulminant. “Farmers don’t consider this prevention, they consider it control. If they wait for symptoms to appear, it’s too late,” Simjee said. The WHO recommendation for complete restriction of all critically important antibiotics in food animals also presents logistical and ethical issues. Simjee explained that the veterinary counterpart to WHO, the World Organization for Animal Health (OIE) maintains its own list of critically important antibiotics, many of which overlap with the WHO list.

In an attempt to reconcile potential conflicts in guidance, WHO has recommended that countries develop their own critically important antibiotic lists for human medicine based on local resistance patterns and availability of drugs in each region. The United States, Japan, Europe, and Australia have already created these lists. Simjee described how some countries subdivide certain molecules within classes in an attempt to restrict some drugs just for human use, while freeing up others within the class for veterinary use. “The lists aren’t static, and shouldn’t be,” said Simjee. “Surveillance of emerging AMR patterns over time will dictate which drugs are critical, and which aren’t.”

Speaker Presentations

Antibiotic Resistance: Background and Spread


H. Morgan Scott (Texas A&M University)

Sustainability and Antimicrobial Use in Animal Agriculture


Matthew Salois (American Veterinary Medical Association)

The Urgent Need for Harmonized Definitions in Addressing Antimicrobial Resistance in Veterinary Medicine


Shabbir Simjee (Elanco Animal Health)

Further Readings

Salois

Karavolias J, Salois MJ, Baker KT, Watkins K

Translational Animal Science. 2018; 2(4):337-348

Salois MJ, Cady RA, Heskett EA

Journal of Food Distribution Research. 2016; 47(1):79-80

Food and Agriculture Organization of the United Nations

2013

Session 2A. Reducing Buildup of Resistance

Speakers

The Role of Animal Husbandry in Reducing the Need for Antimicrobials

Animal husbandry—the discipline of caring for and breeding animals for food— is essential to reducing disease risk thereby reducing the overall need for antimicrobials. As Heather Fowler of the National Pork Board explained, animal husbandry focuses on raising food animals safely, humanely, and efficiently, while minimizing psychological and environmental stressors. Fowler reviewed the key areas of animal husbandry, outlining how protocols in each category support efforts to maintain animal health and reduce the need for antibiotics.

Food production animals were once primarily raised outdoors, and farmers often raised multiple species. As farmers have moved toward specialization, care and housing practices for food animals has shifted and become more customized. Covered barns, lighting and noise control, tailored nutrition by life stage, vaccinations, and appropriate stocking densities to avoid aggression and stress all contribute to a reduction in the prevalence of disease across species. Additionally, advances in genetics and breeding have helped farmers select for traits associated with both physical heartiness and desirable nutritional attributes­.

Animal monitoring protocols and biosecurity measures are among the most important practices linked to reducing disease prevalence and spread. According to Fowler, farmers across the food production spectrum are encouraged to develop daily observation routines to identify and manage sick animals and implement herd health plans—which may include vaccinations or defined courses of antibiotics. To prevent the introduction of pathogens, modern farms implement strict biosecurity protocols, which include visitor control and restrictions on items brought onto the farm, the use of protective clothing, and an “all-in, all-out” approach for animals, which dictates that animals enter and leave the farm en masse, allowing for thorough sanitation of farm facilities between herds or flocks.

Lastly, routine disease surveillance provides critical insight into both the presence of pathogens in food production animals, as well as those organisms’ susceptibility to antimicrobials. Animal and environmental samples are routinely sent to veterinary diagnostic laboratories, which publish antibiograms for industry reference.   

Vaccinations as Antibiotic Alternatives

Vaccines are a primary form of disease prevention in humans and animals, however, the food animal sector needs more effective vaccines to prevent common diseases that currently require antibiotic treatment. Karin Hoelzer from The Pew Charitable Trusts reviewed the latest research to determine whether vaccines are viable alternatives to antibiotics in food animals and described the hurdles to developing practical and effective vaccines for use in this sector.

Multiple proof-of-concept studies show that vaccines can reduce the need for antibiotics, and studies of swine and salmon farms reveal that antibiotic use and mortality can drop significantly when vaccinations are introduced. “Vaccines are among the most feasible and cost-effective alternative to antibiotics,” said Hoelzer, yet they are currently under-used as primary prevention for several reasons.

In the poultry sector, for example, a small number of diseases drive the bulk of antibiotic use. Yet many of the vaccines currently available to prevent these conditions have limited efficacy, are impractical to administer, are costly, or have unintended consequences. “It’s a big challenge to incentivize producers to choose vaccines instead of antibiotics if the vaccines are comparably more expensive,” Hoelzer said.

Currently available veterinary vaccines are often ineffective or impractical, although progress is being made in several important areas

Currently available veterinary vaccines are often ineffective or impractical, although progress is being made in several important areas

Advances in several key areas will increase both the effectiveness and practicality of using vaccines as an alternative to antibiotics in the foreseeable future. Hoelzer highlighted the need to boost vaccine efficacy, noting that many current commercially available vaccines require multiple doses. “The ideal is a safe, single-dose vaccine that provides robust immunity, even in very young animals,” she said. Ease of administration is also a critical factor, as many of today’s animal vaccines are injectable, making their use wholly impractical in some production agriculture settings.

Very promising research efforts are underway to design effective and affordable oral vaccines to avoid these challenges and effectively prevent common diseases in food production animals; however alternative therapies using for instance prebiotics, probiotics, and antimicrobial peptides should not be overlooked. While these approaches are less effective than antibiotics and have a narrower spectrum of activity, Hoelzer explained that they may serve a complementary role in disease prevention, particularly as their mechanisms of action become better understood.  “As antibiotic use becomes more restricted in the United States and elsewhere, this creates increasing demand for alternatives, and that demand is not currently being met,” said Hoelzer.

Speaker Presentations

The Role of Animal Husbandry in Reducing the Need for Antimicrobials


Heather Fowler (American Pork Board)

Vaccinations as a Means to Reduce the Need for Antibiotics


Karin Hoelzer (The Pew Charitable Trusts)

Further Readings

Hoelzer

Cameron A, McAllister TA

J Anim Sci Biotechnol. 2016 Dec 12;7:68

Hoelzer K, Bielke L, Blake DP, et al.

Vet Res. 2018 Jul 31;49(1):64

Session 2B. Reducing Buildup of Resistance

Speakers

Microbiome Manipulation: Probiotics and Prebiotics

Tim Johnson, from the University of Minnesota, continued the discussion of how to fulfill the need for antibiotic alternatives with an update on research efforts to develop targeted probiotics for animal agriculture. Less is known about the animal microbiome than the human microbiome, a fact that Johnson believes is partially responsible for the skepticism surrounding the use of antibiotic alternatives in food animals. Yet studies indicate that much like the human microbiome, the animal microbiome can be manipulated by specific strains of commensal bacteria or combinations of pre- and probiotics.

The animal microbiome is thought to be as complex and diverse as the human microbiome, which contains more than 1,000 species in the gut alone, and includes niche-specific sets of bacteria, viruses, and fungal species throughout the body. While these colonies are “difficult to study and even more difficult to manipulate,” Johnson says that gene sequencing has helped identify many of the species that comprise human and animal microbiomes, revealing unexpected findings about how the microbiome varies among members of the same species.

Human microbiomes vary due to differences in environment, diet, and lifestyle habits. Johnson reports that same-species food production animals boast similar variability despite uniformity in their environment, diet, and genetic makeup. “Even with this level of control, the microbiomes are different and complex,” said Johnson, explaining that animals raised just miles apart have different microbiomes. Age and season are also drivers of change in the microbiome.

These variations dictate the need for tailored, species-specific antibiotic alternatives, an approach which Johnson believes is “the future of animal agriculture.” Rather than a one-size-fits-all approach to developing probiotics, researchers are profiling specific animal microbiomes with an eye toward identifying bacterial strains tied to desired phenotypes, such as performance or reduced disease susceptibility. Experiments in turkeys show that host-adapted probiotics can induce positive changes in the microbiome that mimic those of a common antibiotic, bacitracin. Positive effects have also been achieved by using a tailored approach to prebiotics, selecting compounds targeted to feed the desired probiotic strain.

More research is needed to develop antibiotic alternatives, including building a repository of baseline microbiome data from different species and regions; implementing guidelines to enable cross-study comparisons; and eventually, developing technologies for product development and commercialization.

Prospects and Challenges of Using Bacteriophages in Animal Production

The idea of using bacteriophages for bacterial control dates back to the early 1900s. But little research was done to advance the concept until the 1980s, when interest in developing phages as antibiotic alternatives began to gain traction, according to Jason Gill, of Texas A&M University. Today, phages are utilized to control foodborne pathogens, yet there are no commercially-available phage-based therapeutics.

The “top predators of bacteria in nature,” phages are appealing alternatives to antibiotics. As Gill explained, phages are the most abundant organism in the biosphere. Found in soil, water, and food, they are non-toxic to humans and animals and are supremely targeted in their activity. Unlike antibiotics, phages infect only particular strains of bacteria, leaving other flora unharmed.

However, phage specificity can be a “double-edged sword,” said Gill, as multiple phages may need to be used in tandem to treat or control infection. Bacteria can also mutate to develop resistance to phages, and while phage resistance is unrelated to antibiotic resistance, this too complicates the development of phage-based therapeutics. Gill and other researchers have worked to identify phages with broad host ranges and to understand the mechanisms of phage resistance.

Bacterial resistance to phages is unrelated to antibiotic resistance, and often results from the loss of surface receptors that allow the phage to bind to bacteria

Bacterial resistance to phages is unrelated to antibiotic resistance, and often results from the loss of surface receptors that allow the phage to bind to bacteria

Phage therapy has been studied in many species of food animals, with promising results.

Experiments show that phage therapy can significantly reduce bacterial load in swine challenged with Salmonella Typhimurium, and chickens infected with avian pathogenic E. coli show reduced mortality when treated with phages. Phase I and II clinical trials of phages for medical applications in humans are also underway.

Yet hurdles remain to bringing phage therapy from the lab to the market, and Gill described the difficulties of developing these therapeutics in today’s pharmaceutical development pipeline. Phages are products of nature with high specificity and the potential to become ineffective in the presence of bacterial resistance. This limited potential for patent protection and narrow spectrum of applications hampers investment in research and development. However,  engineered phages—which may encode toxic genes that kill bacterial cells or CRISPR systems targeting resistance genes—are  better candidates for intellectual property protections.

Gill also explained that phage research has been largely academic thus far, and most published experiments are proof-of-concept studies using different phages with little standardization and no follow-up. He believes a common set of criteria is essential to guiding the future of phage selection, including whole genome sequencing; determination of which bacterial surface receptors a particular phage utilizes; immunogenicity; and knowing whether a particular phage promotes bacterial DNA mobilization. Gill envisions that these criteria and others could be included in a library of phages to guide the design of new therapeutics.

Speaker Presentations

Microbiome Manipulation: Probiotics and Prebiotics


Tim Johnson (University of Minnesota)

Bacteriophages in Animal Production: Prospects and Challenges


Jason Gill (Texas A&M University)

Further Readings

Johnson

Gill

Wall SK, Zhang J, Rostagno MH, Ebner PD

Appl Environ Microbiol. 2010 Jan;76(1):48-53

Carvalho C, Costa AR, Silva F, Oliveira A

Crit Rev Microbiol. 2017 Sep;43(5):583-601

Wernicki A, Nowaczek A, Urban-Chmiel R

Virol J. 2017 Sep 16;14(1):179

Session 3. Assessing Risk

Speakers

A One Health Perspective on Antimicrobial Resistance

Use of antibiotics in food animals is often blamed for the rise of resistant bacteria, but as Laura Kahn from Princeton University explained, the sources of antimicrobial resistance may be less obvious. Kahn described the process by which health officials around the world worked to contain the spread of a resistant strain of E. faecium in humans and animals—a path that led to an unexpected culprit and highlighted the need for wider surveillance.

In 1988, the first cases of vancomycin-resistant Enterococcus faecium (VRE) presented in European hospital patients, and surfaced shortly thereafter in food animals. Experts blamed widespread use of avoparcin, a glycopeptide similar in structure to vancomycin and used for animal growth promotion. Within a decade, the European Union banned its use in food animals. Kahn reported that while the ban resulted in a precipitous drop in animal VRE infections, rates remained high in hospital patients, puzzling physicians and policymakers alike.

Rates of VRE in farm animals dropped following the avoparcin ban, yet there was no corresponding decrease in hospital cases, indicating a disconnect between the two sources of infection

Rates of VRE in farm animals dropped following the avoparcin ban, yet there was no corresponding decrease in hospital cases, indicating a disconnect between the two sources of infection

During that same time period, VRE had emerged as an epidemiological mystery in the United States, where avoparcin had never been approved for use in farm animals, yet thousands of hospital patients were acquiring VRE every year. Adding to the puzzle, tests of poultry and swine in the United States revealed no incidence of VRE—the first clue that perhaps food animals were not the source of infection.

A Likely Answer 

In 2009, whole genome sequencing suggested that the organisms responsible for the VRE outbreaks in humans and animals were genetically distinct, and the human strain emerged from an unexpected animal: the companion dog. “It’s those furry little bioterroists who live in our homes,” joked Kahn, explaining that although vancomycin is not used in dogs, ampicillin is widely prescribed. Up to 25% of companion dogs harbor an ampicillin-resistant strain of E. faecium that is the genomic precursor to the VRE clone that became endemic in hospitals. “Companion animals are invisible in this entire debate,” Kahn said, as virtually none of the AMR surveillance systems include them. “They aren’t responsible for the rise of all resistance, but they do play a role.”

This case illustrates the importance of challenging preconceived notions about the sources of resistance and highlights the need for genomic studies of resistant organisms. “AMR surveillance must include whole genome sequencing, otherwise we make conclusions that might not be true,” Kahn said. “Each organism has its own ecosystem that needs to be studied and tracked.”   

Characterizing Antimicrobial Resistance

Efforts to reduce antimicrobial resistance in food animals hinge largely on the hypothesis that resistant organisms jump from farm to community and cause infections in humans. Paul Morley, of Colorado Statue University, doesn’t dispute that this hypothesis may be accurate, but noted that all the evidence to support it exists on the “ends of the chain,” with little to support the intermediary steps. “It’s too easy to say that because we see problems with resistant infections in people and we use antibiotics in food animals, that there’s a causal linkage,” he said. “We need to figure out which uses in animals lead to risk in humans.”

Just as antibiotics have different modes of action, they also have different modes of resistance. Morley described how a phenotypic response—such as decreased sensitivity or total resistance to an antibiotic—can be conveyed through one of several resistance mechanisms. The complexity of resistance is not well appreciated outside of scientific circles, and Morley believes that even within the research community, methodologies for monitoring and characterizing resistance underrepresent the full range of the resistome. 

A Metagenomic Approach

Most studies that aim to characterize antimicrobial resistance focus on marker bacteria—non-pathogenic bacteria that are intended to represent the animal microbiome. Morley questions the utility of this approach, noting that the presence of resistance genes in non-pathogens is unlikely to augment our understanding of the risk resistant pathogens pose to humans. Completing the chain of potential linkages between resistant organisms in animals and infections in humans requires a metagenomic approach—an examination of resistance genes across the microbiome, not just in select organisms.

Metagenomic studies can upend long-held beliefs and previous findings about the emergence of resistance genes. For example, Morley described a study that demonstrated that with few exceptions, all classes of resistance genes actually decrease during the time cattle spend on the feedlot. Another study of cattle treated with a macrolide drug upon entering the feedlot showed few differences between the fecal microbiome and fecal resistome of treated and untreated cattle on either the day of treatment or 11 days later, but the resistome and microbiome in both cohorts changed over that timeframe. Both studies indicate that age, time, and environment exert strong influence in the development of resistance, and in some cases may be more influential than antibiotic use itself. Understanding the development and mechanisms of resistance throughout the microbiome is considered a key step in relating resistance measures in animals to health outcomes in humans.

The abundance of resistance genes in feedlot cattle decreases over time, despite antibiotic exposure

The abundance of resistance genes in feedlot cattle decreases over time, despite antibiotic exposure

Tracking Antimicrobial Resistance from Agroecosystems to Fresh Produce

Amy Pruden, of Virginia Tech University, shared the results of her studies examining the pathways through which antibiotic resistance genes (ARGs) move from “farm to fork.” While there is some evidence of transmission of ARGs through animal meat, much less is known about the environmental pathways that may serve as conduits for resistant organisms, including land-applied manure, wastewater used for irrigation, and even fresh produce. Pruden’s research aims to understand those pathways and provide practical guidance to limit the spread of resistance genes through the food chain.

Pruden described experiments to track the presence and abundance of resistance genes in the manure of a control group of cows and a group that received in-feed antibiotics. The manure of each cohort was collected and applied directly to various soil microcosms, as well as composted and then applied to the soil microcosms.

Metagenomic sequencing showed that ARGs decreased overall in all samples after composting, but individual analysis of several known anthropogenic indicator ARGs showed increased prevalence after composting. “It appears that composting has some benefits in reducing some ARGs, but we need to get a handle on which ARGs are meaningful for human health,” Pruden said. Studies of soil microcosms treated with either compost or manure showed similarly mixed results. ARGs were most prevalent in manure from antibiotic-treated cows at the start of the experiment, and while overall ARG abundance decreased in these samples after 120 days, some populations rose during that time. Additionally, some soil types appear to enhance the persistence of manure-based ARGs.

These findings also translate to the greenhouse, where radishes grown in different types of soils amended with either manure, compost, or fertilizer show higher numbers of ARGs in certain soil types as well as in radishes grown using manure from antibiotic-treated cattle.

Pruden emphasized that the simple presence of ARGs does not necessarily correlate with clinical relevance, and that more work is needed to understand which ARGs have the greatest potential impact on human health. She also noted that machine learning and advanced data analytics tools are transforming efforts to identify new ARGs and understand the “resistome risk” of environments that are potential pathways for ARGs to enter the community, such as hospital effluent streams, wastewater treatment plants, or farm lagoons. “Our hope is to identify critical control points for farmers so we can keep the antibiotics we depend on for human and animal health working for as long as possible,” Pruden said.

Speaker Presentations

A One Health Perspective in Antimicrobial Resistance


Laura Kahn (Princeton University)

Characterizing Antimicrobial Resistance: Molecular vs. Microbiological Approaches


Paul Morley (Colorado State University)

Tracking Antimicrobial Resistance from Agroecosystems to Fresh Produce


Amy Pruden (Virginia Tech University)

Further Readings

Kahn

Kirst HA, Thompson DG, Nicas TI

Antimicrob Agents Chemother. 1998 May;42(5):1303-4

Willems R, van Schaik W

Future Microbiol. 2009 Nov;4(9):1125-35

Kahn L.

One Health and the Politics of Antimicrobial Resistance

2016

Morley

D'Costa VM, King CE, Kalan L, Morar M

Nature. 2011 Aug 31;477(7365):457-61

Mollenkopf DF, Stull JW, Mathys DA, et al.

Antimicrob Agents Chemother. 2017 Jan 24;61(2). pii: e01298-16

Mollenkopf DF, Mathys DA, Feicht SM, et al.

Foodborne Pathog Dis. 2018 Jun;15(6):372-376

Benedict KM, Gow SP, McAllister TA, et al.

PLoS One. 2015 Dec 3;10(12):e0143995.

Lakin SM, Dean C, Noyes NR, et al.

Nucleic Acids Res. 2017 Jan 4;45(D1):D574-D580

Noyes NR, Weinroth ME, Parker JK, et al.

Microbiome. 2017 Oct 17;5(1):142

Noyes NR, Yang X, Linke LM, et al.

Elife. 2016 Mar 8;5:e13195

Weinroth MD, Scott HM, Norby B, et al.

Appl Environ Microbiol. 2018 Jun 18;84(13)

Pruden

Arango-Argoty G, Garner E, Pruden A, et al.

Microbiome. 2018 Feb 1;6(1):23

Martínez JL, Coque TM, Baquero F.

Nat Rev Microbiol. 2015 Feb;13(2):116-23

Oh M, Pruden A, Chen C, et al.

FEMS Microbiol Ecol. 2018 Jul 1;94(7)

Session 4. Communicating Risk

Speakers

Raising Animals Without Antibiotics: Opinions and Experiences

Randall Singer from the University of Minnesota opened the final session of the conference with a discussion of soon-to-be-published results from a 2018 survey about RWA production programs. The study revealed stark disconnects between veterinarians’ and producers’ opinions about the impacts of RWA programs on animal welfare and food safety, and their beliefs about customer perceptions of RWA production.

The study queried veterinarians and producers across five commodity groups—broiler chickens, turkeys, beef, pork, and dairy, and included two groups of respondents—those with current or prior experience with RWA programs, and those with no experience raising animals without antibiotics.

Singer reported that client and customer demand surfaced as a primary factor influencing producers’ decisions to raise animals without antibiotics, while concerns about animal welfare dominated the rationale for conventional producers to maintain their approach.

Both groups of respondents reported believing that raising animals without antibiotics has either no impact on food safety or that it slightly to significantly worsens food safety.  Yet they also overwhelmingly stated that they believe customers would say the opposite— that RWA production significantly improves food safety.

A similar disconnect appears in questions about how respondents personally feel about the impact of RWA production on animal health and welfare. Regardless of whether the respondent had personal experience with RWA or not, the majority reported the belief that RWA production worsens animal health and welfare. A majority of respondents also reported believing that their customers think that RWA improves animal health.

When asked if maintaining the RWA label had ever taken priority over herd or flock health, the majority of RWA producers and veterinarians across every commodity agreed or strongly agreed. Most respondents across all groups also agreed upon the need for more auditing and assessment of the impact of RWA production systems on animal health and welfare.

“One of the big conclusions here is that pursuing the RWA label seems to be about economic incentive, and not about decreasing resistance or decreasing the use of medically important antibiotics,” Singer said. He identified several research needs, including studies directly examining customer perceptions and beliefs about RWA products. Additionally, Singer called for the development of metrics to evaluate the impact of RWA production on animal health and welfare.

An Alternative Approach to Food Labels

“We have created a lot of the confusion, conundrum, and controversy when it comes to antibiotic use and food labeling,” said Donald Ritter of Mountaire Farms, Inc., describing the dizzying number of antibiotic-related label claims on meat sold in the U.S, and proposing a new approach for the future.

Supermarket shelves around the country are testaments to what Ritter refers to as the “good/better/best” approach to marketing meat, one that appeals to customers’ values and beliefs as often as it does to their health concerns. On one end, Ritter places the niche products that follow what he refers to as “extreme” production practices, including organic or raised without antibiotics. Conventionally raised meat occupies the other end of the spectrum. Production schemes that adhere to responsible antibiotic use practices do exist in the middle, but they are far less visible. “We don’t have a Budweiser-type standard in commercial agriculture,” said Ritter. “What we’re missing is a mass market brand that satisfies the needs of most consumers.”

The retail stratification of meat by production method—complete with dozens of label claims touting various attributes—reinforce consumer confusion about animal production and food safety, according to Ritter, who notes that surveys often confirm significant consumer knowledge gaps when it comes to food production, including the use of antibiotics and the risks of contracting resistant foodborne pathogens.

Producers can use a wide variety of label claims regarding antibiotic use

Producers can use a wide variety of label claims regarding antibiotic use  

The Perfect and the Good

Ritter introduced a new concept for a cross-commodity animal production standard called One Health Certified. Based on the One Health concept and encompassing three pillars of that philosophy—animal well-being, antibiotic stewardship, and environmental sustainability—the One Health certification is an interdisciplinary effort spearheaded by a coalition representing food animal producers across all commodities, government advisors, non-governmental organizations, and scientists.

Ritter says the One Health Certified label epitomizes the notion of “not letting the perfect get in the way of the good,” creating a production and labeling standard that has both meaning and value to consumers while simultaneously promoting animal welfare and judicious antibiotic use. Participating producers will be guided by a set of benchmarks and core principles, including biosecurity measures; an animal health plan including treatment for sick animals; responsible antibiotic use; a third party-audited animal welfare program; and environmental measurements. “It’s meant to be a living standard that we improve over time,” said Ritter, who estimates that the first One Health Certified products will appear in markets mid-2019.

Customer and Consumer Perceptions and Demands

Natalie Seymour, of North Carolina State University, reiterated the importance of understanding consumer perceptions and beliefs in the final presentation of the conference. “The entire food industry is driven by consumers,” she said. “These are the people who will drive innovation, policy, and demand, so we have to figure out where they are with these issues and what they think.”

Seymour expounded on the difficulties of communicating scientific topics to the lay public, acknowledging the “information vacuum” that often exists between research and public perceptions. Conflicting sources of information complicate the problem, especially in the Internet age, where misinformation and evidence-based reporting often exist side-by-side and can be difficult to distinguish for non-scientific audiences. Consumers seek opinions from trusted sources when making decisions and evaluating risks, and Seymour explained that the most common sources are news outlets, friends and family, and social media. Within this context, it is unsurprising that misconceptions about complex issues, such as the use of antibiotics in food animals, are rampant.

Science is dynamic, and new findings often alter previously issued guidelines and practices. While those within the scientific community may view emerging research as exciting signs of progress, shifts in recommendations or opinions can erode public trust in science— a hurdle Seymour advocates addressing through clear messaging, proactive responses to public concerns, and simple language.

“Food is a complex issue—it’s physical, it’s social, it’s emotional, and eating is something we do multiple times a day,” Seymour said. “We’ve talked a lot today about the fact that we’re probably not communicating about these issues as well as we can, so let’s figure out what people believe, what they think the issues are, and how we can communicate the facts in a way that reaches them.”

Speaker Presentations

Agricultural Antibiotic Use: Tradeoffs and Usage Strategies


Randall Singer (University of Minnesota)

Antibiotic Use Food Labels and an Alternative Approach


Donald Ritter (Mountainaire Farms, Inc.)

Customer and Consumer Perceptions and Demands


Natalie Seymour (North Carolina State University)