Alleviating Risks of Feeding Cattle Nontherapeutic Antimicrobial Cattle Feed
Public Health Rep. 2012 Jan-Feb; 127(1): 4–22.
A Review of Antibiotic Use in Food Animals: Perspective, Policy, and Potential
Timothy F. Landers
aThe Ohio State University, College of Nursing, Columbus, OH
Bevin Cohen
bCenter for Interdisciplinary Research to Reduce Antibiotic Resistance, Columbia University School of Nursing, New York, NY
Thomas E. Wittum
cThe Ohio State University, Department of Veterinary Preventive Medicine, Columbus, OH
Elaine L. Larson
bCenter for Interdisciplinary Research to Reduce Antibiotic Resistance, Columbia University School of Nursing, New York, NY
SYNOPSIS
Antibiotic use plays a major role in the emerging public health crisis of antibiotic resistance. Although the majority of antibiotic use occurs in agricultural settings, relatively little attention has been paid to how antibiotic use in farm animals contributes to the overall problem of antibiotic resistance. The aim of this review is to summarize literature on the role of antibiotics in the development of resistance and its risk to human health. We searched multiple databases to identify major lines of argument supporting the role of agricultural antibiotic use in the development of resistance and to summarize existing regulatory and policy documents. Several lines of reasoning support the conclusion that agricultural antibiotics are associated with resistance, yet most public policy is based on expert opinion and consensus. Finally, we propose strategies to address current gaps in knowledge.
Antibiotic resistance is a looming public health crisis. While once believed to be the province of hospitals and other health-care facilities, a host of community factors are now known to promote antibiotic resistance, and community-associated resistant strains have now been implicated as the cause of many hospital-acquired infections.1 , 2 An inherent consequence of exposure to antibiotic compounds, antibiotic resistance arises as a result of natural selection.3 Due to normal genetic variation in bacterial populations, individual organisms may carry mutations that render antibiotics ineffective, conveying a survival advantage to the mutated strain. In the presence of antibiotics, advantageous mutations can also be transferred via plasmid exchange within the bacterial colony, resulting in proliferation of the resistance trait.4 The emergence of drug resistance has been observed following the introduction of each new class of antibiotics, and the threat is compounded by a slow drug development pipeline and limited investment in the discovery and development of new antibiotic agents.5 – 7
International, national, and local antibiotic stewardship campaigns have been developed to encourage prudent use of and limit unnecessary exposure to antibiotics, with the ultimate goal of preserving their effectiveness for serious and life-threatening infections.8 , 9 In practice, however, clinicians must balance the utilitarian goal of preserving the effectiveness of antibiotics with ethical obligations to patients who present with conditions that are unlikely to be harmed and may benefit from antibiotic use. There is also considerable debate in veterinary medicine regarding use of antibiotics in animals raised for human consumption (food animals). The potential threat to human health resulting from inappropriate antibiotic use in food animals is significant, as pathogenic-resistant organisms propagated in these livestock are poised to enter the food supply and could be widely disseminated in food products.10 – 15 Commensal bacteria found in livestock are frequently present in fresh meat products and may serve as reservoirs for resistant genes that could potentially be transferred to pathogenic organisms in humans.16 , 17
While antibiotic use in food animals may represent a risk to human health, the degree and relative impact have not been well characterized. Given divergent stakeholder interests and inadequate research to date, public policy discussions of this issue are often contentious and highly polarized. The aim of this review is to examine the scope and nature of antibiotic use in food animals and summarize its potential impact on human health. We also review key national and international policies on use of antibiotics in food animals. Finally, we propose future directions for research and monitoring of the agricultural use of antibiotics.
METHODS
We searched three online databases of medical and scientific literature citations—the National Library of Medicine's MEDLINE®, the U.S. Department of Agriculture's National Agricultural Library Catalog (known as AGRICOLA), and Thomson Reuter's Web of Science—for English-language documents from 1994–2009 containing the keywords "antibiotic," "antibiotic resistance," "antimicrobial," "antimicrobial resistance," "agriculture," "livestock," "food animal," "farm animal," "pig," "swine," "cattle," "cow," "poultry," and "chicken." Two authors reviewed the references and selected exemplary original research articles examining the association between antibiotic use in food animals and antibiotic-resistant bacteria in humans. We also performed searches of the ROAR Commensal Literature Database (part of the Reservoirs of Antibiotic Resistance [ROAR] project, coordinated by the Alliance for Prudent Use of Antibiotics and funded by a grant from the National Institute of Allergy and Infectious Diseases) and the World Health Organization (WHO) website to identify research articles and policy documents pertaining to antibiotic use in food animals. An online search engine was used to locate policy statements published by governmental agencies.
RESULTS
In our review, we found that the use of antibiotics in food animals is widespread, yet poorly characterized. Furthermore, in existing studies, neither the risks to human health nor the benefits to animal production have been well studied. We also found a lack of consistency in national and international policies.
In the following sections, we review the current literature on the nature and scope of antibiotic use in food animals, and on the epidemiologic links between use of antibiotics in food animals and resistance in humans. We then provide an overview of the complex risk analysis framework required to understand this problem. Finally, we review key national and international policy and regulatory recommendations.
Literature on the nature and scope of antibiotic use in food animals
The high population density of modern intensively managed livestock operations results in sharing of both commensal flora and pathogens, which can be conducive to rapid dissemination of infectious agents. As a result, livestock in these environments commonly require aggressive infection management strategies, which often include the use of antibiotic therapy.
Antibiotics are used in food animals to treat clinical disease, to prevent and control common disease events, and to enhance animal growth.18 The different applications of antibiotics in food animals have been described as therapeutic use, prophylactic use, and subtherapeutic use. Antibiotics can be used to treat a single animal with clinical disease or a large group of animals. However, these various uses are frequently indistinct; definitions of each type of use vary, and the approaches are often applied concurrently in livestock populations.19 For example, 16% of all lactating dairy cows in the U.S. receive antibiotic therapy for clinical mastitis each year, but nearly all dairy cows receive intramammary infusions of prophylactic doses of antibiotics following each lactation to prevent and control future mastitis—primarily with penicillins, cephalosporins, or other beta-lactam drugs.20 Similarly, 15% of beef calves that enter feedlots receive antibiotics for the treatment of clinical respiratory disease, but therapeutic antibiotic doses are also administered to 10% of apparently healthy calves to mitigate anticipated outbreaks of respiratory disease.21 Forty-two percent of beef calves in feedlots are fed tylosin—a veterinary macrolide drug—to prevent liver abscesses that negatively impact growth, and approximately 88% of growing swine in the U.S. receive antibiotics in their feed for disease prevention and growth promotion purposes, commonly tetracyclines or tylosin.22 Most antibiotic use in livestock requires a veterinary prescription, although individual treatment decisions are often made and administered by lay farm workers in accordance with guidelines provided by a veterinarian.23 , 24
Despite the widespread adoption of antibiotic use in food animals, reliable data about the quantity and patterns of use (e.g., dose and frequency) are not available.25 Quantifying antibiotic use in food animals is challenging due to variations in study objectives—investigators may measure only therapeutic uses, only nontherapeutic uses, or a combination thereof, depending on their outcome of interest—and lack of clarity surrounding the definitions of therapeutic vs. nontherapeutic uses.26 Although limited, the available data suggest that food animal production is responsible for a significant proportion of antibiotic use. In 1989, the Institute of Medicine estimated that approximately half of the 31.9 million pounds of antimicrobials consumed in the U.S. were for nontherapeutic use in animals.27 More recent estimates by the Union of Concerned Scientists, an advocacy group that supports reduced agricultural antimicrobial use, suggest that 24.6 million pounds of antimicrobials are used for nontherapeutic purposes in chickens, cattle, and swine, compared with just 3.0 million pounds used for human medicine. Calculations by the pharmaceutical industry-sponsored Animal Health Institute are more conservative, suggesting that of 17.8 million pounds of antimicrobials used for animals, only 3.1 million pounds are used nontherapeutically.26 Twelve classes of antimicrobials—arsenicals, polypeptides, glycolipids, tetracyclines, elfamycins, macrolides, lincosamides, polyethers, beta-lactams, quinoxalines, streptogramins, and sulfonamides—may be used at different times in the life cycle of poultry, cattle, and swine.25 While some of the antimicrobials used in animals are not currently used to treat human disease, many, such as tetracyclines, penicillins, and sulfonamides, are also used in the treatment of infections in humans.26 The WHO has developed criteria for the classification of antibiotics as "critically important," "highly important," and "important" based on their importance in the treatment of human disease.28 , 29
However, other classes of antimicrobials used in agriculture have not led to concerns about dissemination of resistance in humans. For example, some of the most frequently used antibiotics in ruminants are ionophores, a distinctive class of antibiotics that alter intestinal flora to achieve increased energy and amino acid availability and improved nutrient utilization. Most beef calves in feedlots and some dairy heifers receive this drug routinely in their feed. Because of their specific mode of action, ionophores have never been used in humans or therapeutically in animals. While some bacteria are intrinsically resistant to these drugs, there is currently no evidence to suggest that ionophore resistance is transferable or that co-selection for resistance to other classes of antimicrobials occurs.30
Literature suggesting epidemiologic evidence of an association between antibiotic use in food animals and antibiotic resistance in humans
Evidence that antibiotic use in food animals can result in antibiotic-resistant infections in humans has existed for several decades. Associations between antibiotic use in food animals and the prevalence of antibiotic-resistant bacteria isolated from those animals have been detected in observational studies as well as in randomized trials. Antibiotic-resistant bacteria of animal origin have been observed in the environment surrounding livestock farming operations, on meat products available for purchase in retail food stores, and as the cause of clinical infections and subclinical colonization in humans. Figure 1 outlines a sampling of prevalence studies, outbreak investigations, ecological studies, case-control studies, and randomized trials whose results suggest a potential relationship between antibiotic use in food animals and antibiotic resistance in humans.
Literature on the risks and benefits of antibiotic use in food animals
To understand how antibiotic use in agriculture might impact the emergence of antibiotic resistance, it is essential to consider the complex interaction of elements in the physical environment (e.g., air, soil, and water) with social exchanges (e.g., between animals within a herd, farmers and animals, and domestic poultry and migratory birds), in processing steps (e.g., farming activities, transportation, and storage), and in human use patterns (e.g., food preparation, meat consumption, and susceptibility to infection) (Figure 2). Antibiotic use in animals can have direct and indirect effects on human health: direct effects are those that can be causally linked to contact with antibiotic-resistant bacteria from food animals, and indirect effects are those that result from contact with resistant organisms that have been spread to various components of the ecosystem (e.g., water and soil) as a result of antibiotic use in food animals (Figure 3).
Figure 3.
Examples of direct and indirect effects of antibiotic use in food animals on human health
Given the multitude of factors that contribute to the pathways by which antibiotic use in food animals could pose risks to human health, it is not surprising that a wide variety of methods has been used by researchers in various disciplines to approach the problem. In general, risk assessment models in veterinary medicine emphasize animal health and treatment of diseases in animals, food scientists' studies focus on the safety of human food supplies and the presence of antibiotic-resistant bacteria on food products, clinicians and epidemiologists investigate human outbreaks caused by resistant infections for which animals are identified as primary sources, and molecular biologists examine relationships between resistant strains and the prevalence of specific resistance genes in human and animal bacteria. It is unlikely that any single study will be able to fully and accurately quantify the relationship between antibiotic use in food animals and infections in humans. At best, only crude estimates of the etiologic fraction or "impact fraction" can be made for specific links in the ecologic chain.31
Several mathematical models have been proposed to quantify the overall risk associated with antibiotic use in animals, typically by estimating the prevalence of infection with a specific organism and its associated morbidity, and then multiplying by the proportion of these infections believed to be attributable to antibiotic use in food animals. While models of this nature have been rightfully criticized for failing to include indirect risk and, consequently, underestimating total potential risk, felicitous risk assessment strategies must also consider the potential benefits of antibiotic use in food animals. Even though agricultural antibiotic use carries a demonstrated risk, there are likely benefits to the agricultural use of antibiotics as well. For example, reducing animal microbial load and shedding could lead to safer, more affordable food. However, many of the claims of benefit have not been fully demonstrated in large-scale trials, and other trials have shown that the overall impact of the short-term benefit is poorly described.
The U.S. Food and Drug Administration (FDA) requires manufacturers of new antibiotics to perform risk assessments to demonstrate that new drugs are safe and effective for use in animals and that "there is reasonable certainty of no harm to human health from the proposed use of the drug in food-producing animals."32 To evaluate potential human health consequences, the FDA employs a qualitative framework to classify as "low," "medium," or "high" the probabilities that bacteria in the animal population will acquire resistance, that humans will ingest the resistant bacteria in food products, and that ingesting the bacteria will result in adverse health outcomes (Figure 4). Drug approval decisions are based on these risk estimations, along with information about proposed marketing status (e.g., prescription, over-the-counter, or veterinary feed additives), extent of limitations on extra-label use, and intended use patterns (e.g., duration of use and administration to individual animals vs. select groups of animals vs. flocks or herds of animals). "High-risk" drugs may be approved if the FDA determines that human health risk can be mitigated. "Medium-risk" drugs could be approved if appropriate label restrictions are required.
In addition to the direct risk assessment model, the FDA has developed guidance to determine the risk of antibiotic residues remaining on food products.32 This guidance recommends determining the impact of antibiotic residues on normal human intestinal flora and the presence of resistance in these strains, and it provides guidelines for the calculation of Acceptable Daily Intake (ADI) for antibiotic residues that pose an appreciable risk to human health.
Guidelines and recommendations on the use of antibiotics in food animals
Given the importance of antibiotic resistance as a public health problem, many governments and professional societies have reviewed existing scientific evidence and developed recommendations to limit all types of antibiotic use, including use in food animals. Depending on the nature and jurisdiction of each group, the findings may provide best practice guidelines for antibiotic use, prioritized agendas for research on the emergence of antibiotic resistance, recommendations for legislative action to regulate drug approval and surveillance processes, or enforceable laws on the manufacture, distribution, and prescription of antibiotics. Figure 5 summarizes recommendations directly related to use of antibiotics in food animal production for a sample of national and international guidance and policy documents.
DISCUSSION
Despite increasingly widespread recognition that antibiotic use in food animals is an important contributor to human infections with antibiotic-resistant bacteria (Figure 1), there remains a significant need for scientific evidence of the antibiotic use practices that create the greatest human health risk. Our goal with this article was not to propose specific solutions to the problem—in part because we believe there are no easy, specific answers—but rather to reiterate and summarize the importance of this issue and to suggest some general policy directions that are indicated. As the importance of the problem and complexity of the issues are increasingly appreciated by the public, policy dialogue, focused research, and informed regulatory action can be undertaken. To facilitate further research and timely action in response to emerging knowledge on this issue, we propose the following measures, which are in concert with WHO's global strategy for the containment of antimicrobial resistance, the U.S. Interagency Task Force on Antibiotic Resistance's public health action plan to combat antimicrobial resistance, and the Infectious Diseases Society of America's call to action.33 – 35
Develop a scientific agenda to recommend appropriate study designs and specific aims related to antimicrobial use in food animals
A coordinated plan is needed to identify missing scientific data and to specify research designs and methods to address these needs. Although rigorous studies have been conducted in some disciplines, there has been a lack of serious and harmonized interdisciplinary effort to expand on the corpus of knowledge, which should be used to inform public policy. To result in a useful and complete list of research priorities, the agenda must include contributions by experts in basic sciences (e.g., genetics and microbiology), clinical sciences (e.g., veterinary medicine and human medicine), public health (e.g., epidemiology and nursing), social sciences (e.g., anthropology and sociology), economics (e.g., health and agriculture), and public policy (e.g., legislative and regulatory). Research goals put forth in the agenda should be reflective of methodological weaknesses identified in the existing literature. For example, definitions of antibiotic uses in food animals (e.g., therapeutic and subtherapeutic) should be standardized and designed to reflect specific goals (e.g., improving production or preventing economic loss from unrestrained disease); the terms should be recognized across disciplines and used to classify the potential effects of different types of antibiotic use on human health. Another potential focus could be whether to approach research on the development of resistance narrowly (i.e., the causes and effects of specific drug-organism combinations) or broadly (i.e., the causes and effects of all antibiotics used in animals on microbial flora) to develop public health recommendations.
Fund agricultural research that reflects the priorities identified by the research agenda
Inadequate funding for agricultural research has likely contributed to the lack of sufficient scientific evidence necessary for informing public health decisions. For example, in the United States, it was recently estimated that the $101 billion in combined governmental and biomedical industry research funding represents almost 5% of national health expenditures each year.36 In 2007, the U.S. Department of Agriculture provided more than $32 million in external research funding, representing less than one one-thousandth of 1% of annual U.S. livestock and poultry sales.37 In contrast, one single Institute within the National Institutes of Health—the National Institute of Allergy and Infectious Diseases—directed more than 20 times this amount to antimicrobial resistance research (more than $800 million) in the same year.38 Given the scale of the antibiotic resistance problem and the demonstrated role of agricultural antibiotic uses in this impending public health crisis, adequate support for research specific to the role of agricultural uses of antibiotics in the development of resistance must be a national priority. Considering that the U.S. funds 70% to 80% of biomedical research worldwide, the need for appropriate levels of funding is especially acute.36
Urgently address barriers to the collection and analysis of antimicrobial use data
Complex political, economic, and social barriers limit the quality of data on the use of antibiotics in food animals. Currently, such data are provided on a voluntary basis, and the methods used to collect and compile reports are not standardized or fully transparent. While voluntary industry compliance with antibiotic reporting is commendable, the long-term effectiveness of nonbinding auditing programs is unproven. Effective surveillance of veterinary antimicrobial production and administration to food animals is a key first step toward ascertaining realistic estimates of the full scope of antibiotic use. These data will be useless, however, unless an agency with adequate analytic, regulatory, and enforcement capabilities exists. Because the commercial interests of antibiotic manufacturers must be appropriately balanced with the public health urgency for development of new antibiotics, any agency tasked with monitoring antibiotic resistance must operate independently of commercial influences when releasing data to the public and drafting evidence-based regulations to safeguard human health.
CONCLUSION
It is evident that at present, the resources devoted to studying the role of antibiotic use in food animals—both in terms of funding and scientific inquiry—are insufficient. It is now critical that agricultural use of antibiotics be recognized as one of the major contributors to the development of resistant organisms that result in life-threatening human infections and included as part of the strategy to control the mounting public health crisis of antibiotic resistance.
Footnotes
During portions of this project, Dr. Landers was supported by a training grant from the National Institute of Nursing Research, National Institutes of Health (Training in Interdisciplinary Research to Reduce Antimicrobial Resistance; T90 NR010824).
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