The Use of Drugs in Food Animals

Benefits and Risks




Committee on Drug Use in Food Animals

Panel on Animal Health, Food Safety, and Public Health

Board on Agriculture

National Research Council

Food and Nutrition Board

Institute of Medicine



NATIONAL ACADEMY PRESS
Washington, D.C. 1999


Preface | Acknowledgements | Contents | Executive Summary




NATIONAL ACADEMY PRESS · 2101 Constitution Avenue, NW · Washington, D.C. 20418

NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance.

This report has been reviewed by a group other than the authors according to procedures approved by a Report Review Committee consisting of members of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine.

This material is based upon work supported by the U.S. Department of Agriculture, Agricultural Research Service, under Agreement No. 59-0700-1-141, the Department of Health and Human Services, Food and Drug Administration under Agreement No. 1-R13-FDO1495-01, and the Pew Charitable Trusts under Agreement No. 90-02372-000. Partial support was provided by the American Veterinary Medical Association and the American Feed Industry Association. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the author(s) and do not necessarily reflect the view of the organizations or agencies that provided support for this project.

Library of Congress Cataloging-in-Publication Data

The use of drugs in food animals : benefits and risks / Committee
on Drug Use in Food Animals, Panel on Animal Health, Food Safety,
and Public Health, Board on Agriculture, National Research Council.
p. cm.
Includes bibliographical references and index.
ISBN 0-309-05436-6 (hardcover : alk. paper)
1. Veterinary drugs. 2. Antibiotics in veterinary medicine. 3.
Food animals—Diseases—Chemotherapy. 4. Veterinary drug residues.
5. Food of animal origin—Contamination. I. National Research
Council (U.S.). Board on Agriculture. Panel on Animal Health, Food
Safety, and Public Health. Committee on Drug Use in Food Animals.
SF917 .U74 1998
363.19'2—dc21
98-58111

About the cover: The background of the cover is an electron micrograph of Staphylococcus aureus and its secretion of a polysaccharide that increases the virulence of this microbe. When these bacteria secrete this matrix, they can decrease the ability of immune cells like neutrophils to attack and destroy them. Credit for the picture is given to Dr. Albert Guidry, Dr. William Wergin, and Mr. Eric Erbe, all associated with the U.S. Department of Agriculture, Agricultural Research Service at Beltsville, Maryland.

©1999 by the National Academy of Sciences. All rights reserved.

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COMMITTEE ON DRUG USE IN FOOD ANIMALS


PANEL ON ANIMAL HEALTH, FOOD SAFETY, AND PUBLIC HEALTH


BOARD ON AGRICULTURE


FOOD AND NUTRITION BOARD


1Served through August, 1995
2Served through May, 1995


The National Academy of Sciences is a private, nonprofit, selfperpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Bruce Alberts is president of the National Academy of Sciences.

The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. William A. Wulf is president of the National Academy of Engineering.

The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Kenneth I. Shine is president of the Institute of Medicine.

The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy's purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Bruce Alberts and Dr. William A. Wulf are chairman and vice-chairman, respectively, of the National Research Council.


Preface



The raising of livestock for meat, milk, and eggs has been an integral component of the food production system in this country since its first settlement in the 1600s. The U.S. capacity for food production is tremendous and remarkable, considering that now less than 2 percent of the population is genuinely vested in the raising of food for the rest of the country. Pressures for land development and the vast increase in population have commanded a shift in food-raising practices and the efficiency of food-animal production is testimony to the successful implementation of scientific discoveries in breeding, genetics, nutrition, and animal health on the farm.

Veterinary drugs are a critical component of food-animal production. They provide many benefits related to animal health, animal welfare, and economic return for the industry. Since the benefits of subtherapeutic use of antibiotics in enhancing growth and feed efficiency in animals were first observed almost half a century ago, the number and use of these products has increased. In fact, the discovery of the benefits of subtherapeutic use of antibiotics is often credited with the move toward more intensive animal production management systems, thereby allowing fewer people to produce greater quantities of food.

For decades, the quality, efficiency, value, and safety of food production in the United States has been exceptional; it has served as a model for the rest of the world. However, the U.S. food production system must continuously improve if our country expects to be successful in today's highly competitive global market and if producers hope to deliver animal-derived foods that meet the ever-increasing expectations of the consuming public.

A totally risk-free system of food production is an unreasonable and fundamentally unattainable goal. Actual human health risks associated with food-producing animals are most immediately brought into focus in reviewing the number of cases of human illness that occur from food contamination with microorganisms of animal origin. The magnitude of this risk is somewhat difficult to assess. In terms of tracing the origin of an illness directly back to the animal, a complicated intertwining of farm, wholesale­retail, and consumer practices exists that create opportunities for disease to emerge. However, because many aspects of the risk are known and acknowledged, it could be thought of as manageable, because logical courses of action can be applied. The potential risk to human health directly associated with the use of antibiotic drugs in food animal production is a more nebulous issue but still of great concern because of what is not known, what could occur, and a general attitude that control and management of the situation need to be improved.

The gains that have been made in food production capacity would not have been possible were it not for the ability of reliable agricultural chemicals to contain the threat of disease to crops and animals. The health of food-producing animals is intrinsically linked to human health. That is to say, factors that affect food-animal health will, in turn, affect human health. The logic is, if you improve the health of our animals, the health of the human population should not be compromised. The use of animal drugs, antibiotics in particular, is considered by some to pose an increased health risk to the people who consume the products from those animals. The use of all drugs (in humans as well as animals) creates both benefits and risks. With proper controls, the benefits should exceed the risks, and "new" risks will replace the "old" risks at a lower level of threat. For example, the risk of suffering from an antibiotic-resistant bacterial infection is considered acceptable when compared with the risk of dying from the bacterial infection left untreated.

Public attention today focuses primarily on the favorable and unfavorable effects of animal drug use on human health. For livestock producers and veterinarians, attention also is focused on the favorable and unfavorable effects of animal drug use on animal health and on the consequences of the inadequate numbers of approved drugs available for use. Antibiotic agents are one class of drugs used extensively in food-animal production therapeutically and subthera-peutically. By far the most important concerns among stakeholders today are microbial resistance to these compounds and residues of these compounds in the food supply. In addition, significant concerns have come to the forefront from manufacturers, producers, and veterinarians that the ever-increasing cost and length of time to approve new drugs have produced a crisis in drug availability. These issues have already generated legislative activity on two occasions, in the Animal Medicinal Drug Use Clarification Act, which was passed in 1994, and in the Animal Drug Availability Act, which was signed into law October 9, 1996. There is reason to believe that, in the near future, these issues will be joined by others, particularly those related to genetic engineering technology.

As a result of these concerns and the conflicting interests surrounding them, the Panel on Animal Health, Food Safety, and Public Health, jointly sponsored by the National Research Council's Board on Agriculture and the Institute of Medicine's Food and Nutrition Board, initiated a project to contemporize the understanding of the issues and relevant information concerning use of drugs in food animals and to establish recommendations regarding a new approach to addressing the problems pertaining to availability and the effective and safe use of drugs in food animals. The Panel on Animal Health, Food Safety, and Public Health convened the Committee on Drug Use in Food Animals to address these issues. Specifically, the committee was charged with examining the benefits and risks associated with drug use in food animal production and to prepare a report with recommendations that:

The committee commissioned background papers to provide an historical perspective on the role of drugs in animal production, a status report of the animal health industry, and an historical perspective on the regulatory approval process for animal drugs. The committee met four times and, on two of these occasions, held open sessions and a workshop to gather detailed information from federal regulatory agency personnel concerning the new drug approval process, procedures for setting residue tolerance levels, and drug residue testing. Representatives of the various livestock, poultry, and aquaculture organizations provided information concerning current husbandry and production practices and quality-assurance programs.

During the evaluation process, it became evident that the existing system that encompasses the total spectrum of drug development, regulation, and use is in part paralyzed by politics and perceptions. The need for a more coordinated, flexible system for tactical decision making and for strategic planning related to policies affecting animal drug use is striking. Issues attendant to drug use in food animals will continue to evolve. Thus, there is a need for a process for evaluating needs and risks in the uses for human and animal drugs that continuously updates the issues and restructures decisions rather than one that periodically resolves crises.

As the committee pursued its work, four primary objectives were identified. The unifying theme among these goals is to offer to policy makers, consumers, the communications industry, food producers, drug manufacturers, and other audiences our recommendations for needed improvements related to:

In addressing its charge, through these four areas, the committee developed a line of logic, which guides the elaboration of this report, as follows:

Chapter 1 provides an overview of the use of drugs in food animals and some of the controversy that has existed concerning this practice for the past 30 years. It also sets the stage for examining the perceptions of the risks associated with antibiotic use in food animals and the complexity of the intertwining of food production economics, animal health, industry drug development, and consumer preferences. Chapter 2 provides an overview of current production practices in the major food-animal species and describes the industry-initiated quality-assurance programs in place for cattle (beef and dairy), swine, and poultry producers. Chapter 3 discusses the primary benefits and hazards to human health of the use of drugs in food-animal production. Chapter 4 presents issues related to development of new drugs, the current approval process, and issues related to new developments in the approval process that are attempting to relieve some of the time lag and expense of developing new drugs. Antibiotic approval is the most pressing aspect of this process. Recommendations are offered to focus resources on public health risks. Chapter 5 summarizes the pertinent features of the drug-residue-monitoring program in the United States, explaining that an effective system is the critical assumption upon which all other strategies rest. In recent years significant interest has emerged, as has fear, in the development of antibiotic resistance in human and veterinary health arenas. The importance of this area of concern cannot be understated, and the specifics of this topic are presented in Chapter 6. The effects of therapeutic and subtherapeutic use of antibiotics on resistance in animals are discussed, as are the mechanisms through which resistance can develop. Finally, new data are presented that underscore much of the controversy in views regarding the approval of new antibiotics for general use in food animals with particular reference to the class of antibiotics called fluoro-quinolones targeted to the development of resistance in Salmonella. Chapter 7 describes the economic implications of eliminating subtherapeutic drug use in food animals, and Chapter 8 discusses alternative strategies to reduce the need for drug use and highlights promising areas for further research.

Successful food-animal production management systems are continuously changing as advances are made in biomedical and agricultural science. Furthermore, consumer trends shift, and multiple factors alter the priorities and practices of the food production and pharmaceutical industries as well as of public health and health care policy makers.

Capitalizing on opportunities and solving problems pertaining to food-animal production systems now and in the future will be best accomplished through an integrated process that continuously assesses the strengths and weaknesses of the total system, rather than the various components separately, and uses the expertise of all stakeholders. This will be successful only if the various stakeholders define the best long-term solutions instead of short-term wins and losses and have access to information that is relevant, comprehensive, and accurate.

Since the committee began its deliberations, movement has indeed begun in this direction, as indicated by the alliance of food-animal producers, veterinarians, the animal pharmaceutical industry, and the Center for Veterinary Medicine of the Food and Drug Administration to work out a solution to accelerate the approval process for needed new animal drugs.

James R. Coffman, Chair
Committee on Drug Use in Food Animals






Acknowledgments



The committee would like to acknowledge the generous support for this study provided by the U.S. Department of Agriculture Agricultural Research Service, the Department of Health and Human Services Food and Drug Administration, and the Pew Charitable Trusts. In addition, the committee appreciates the support provided by the American Veterinary Medical Association and the American Feed Industry Association.

The committee wishes to thank Theodore H. Elsasser and Michael J. Phillips for their dedication and untiring efforts in seeing this project through to completion. In addition, the committee thanks Lester Crawford, Harold Hafs, and John Welser for the preparation of commissioned papers important to the committee's deliberations. Appreciation is also given to Juliemarie Goupil, Shirley Thatcher, Lucyna Kurtyka, Melinda Simons, Charlotte Kirk Baer, Suzanne Patrick, and Anne Kelly for their assistance with the report preparation, and to Mary Poos for her work in the early stages of the project.

This report has been reviewed by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council (NRC) Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the authors and NRC in making the published report as sound as possible and to ensure that the report meets institutional standards for objectivity, evidence, and responsiveness to the study charge. The content of the review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their participation in the review of this report: Dale Bauman, Cornell University; Charles Carpenter, Brown University; H. Russell Cross, IDEXX; John Dowling, Harvard University; Johanna Dwyer, New England Medical Center; D. Mark Hegsted, Southborough, MA; Larry Katzenstein, Bronx, NY; Kirk Klasing, University of California; James Peters, Alpharma, Inc.; Eileen van Ravenswaay, Michigan State University; H.E. Umbarger, West Lafayette, IN; and Judi Weissinger, Weissinger Solutions Inc. While these individuals listed above provided many constructive comments and suggestions, responsibility for the final content of this report rests solely with authoring committee and with NRC.

During the course of the study, committee member R. Gregory Stewart changed employment to became affiliated with a pharmaceutical firm that has a drug approval application pending before the Food and Drug Administration for a fluoroquinolone antibiotic. As a result, Dr. Stewart has excused himself from the committee discussion and deliberations pertaining to this class of antibiotics.


Contents



Tables and Figures



TABLES

1­1 Summary of Previous Major Reports on Food-Animal Antibiotics

2­1 Coccidiostats Approved for Use in Broilers, Turkeys, and Layers
2­2 Major Claims of Antibiotics Approved for Use in Chickens and Turkeys
2­3 Cost of Drug and Vaccine Use in Broilers from 1989 to 1994
2­4 Turkey Medication and Vaccine Cost Analysis
2­5 Cost of Medication and Vaccination Used for Turkeys and Broilers in the United States
2­6 Major Claims of Antibiotics Approved for Use in Hogs
2­7 Major Claims of Chemotherapeutics Approved for Use in Hogs
2­8 Intramammary Antibiotics Approved for Dairy Cattle
2­9 Distribution of Health Costs per Cow by Functional Category
2­10 Estimated Annual Losses Caused by Mastitis
2­11 Major Claims for Systemic Antimicrobials Approved for Use in Beef and Dairy Cattle
2­12 Steroid Products Labeled for Improved Growth and/or Feed Efficiency in Cattle
2­13 Major Claims of Antibacterials Approved for Use in Sheep
2­14 Major Claims for Drugs Approved for Use in Minor Species
2­15 FDA-Approved New Drugs for Use in Aquaculture

3­1 The Effect of Implementation of a Veterinary Preventive-Medicine Scheme on Offal and Carcass Rejections from 12 Finishing Farms

4­1 Food-Animal Populations in the United States
4­2 Comparative Value of FDA-Regulated Industries
4­3 Annual Sales of Animal Drugs

5­1 FSIS Animal Drug Residue Test Results
5­2 Drug Residue Analysis Results for Grade A and Non-Grade-A Milk
5­3 Survey Report of Microbiological Hazards in Swine
5­4 Survey Report of Microbiological Hazards in Cattle
5­5 Survey Report of Microbiological Hazards in Lamb
5­6 Survey Report of Microbiological Hazards in Poultry

6­1 E. coli Resistance to TMP-SMX
6­2 Resistance of TMP-SMX-Resistant E. coli Isolates to Other Antimicrobial Agents
6­3 Antimicrobial Resistance of E. coli Strains Isolated from Enteritis in Calves in the United States, Canada, and France
6­4 Antibiotic Resistance in Salmonella from Animals, Percentage of Cultures Showing Resistance
6­5 Antibiotic Resistance in Salmonella typhimurium from Animals, Percentage of Cultures Showing Resistance

7­1 Approximate Annual Costs of a Ban on Subtherapeutic Antibiotic Use in Four Domestic Retail Markets

8­1 Efficacy of Recombinant Bovine IFN- against E. coli Mastitis
8­2 Effect of GCSF on Blood and Milk Leukocyte Profiles and Efficacy against Staphylococcus aureus Mastitis
8­3 Blood Selenium, GSH-Px, and Serum Vitamin E of Cows from Low-and High-SCC Herds

FIGURES

4­1 CVM Organizational Structure
4­2 Comparison of the Traditional and Re-Engineered Approval Processes
4­3 Effect of Re-Engineering the Approval Process on the Time to Approve New Animal Drug Applications
4­4 Trends in Animal Drug Approvals since 1990

5­1 Seasonality of Reported Cases of Food-Borne Disease as Monitored Across the Seven Sentinel Organisms at All Locations

6­1 Salmonella DT-104 Ciprofloxacin-Resistant Human Isolates Confirmed in the United Kingdom




Executive Summary



Americans cherish the availability and affordability of a vast food supply. At the same time, we expect the foods we choose to buy and eat to be clean, fresh, and not contaminated with debris, chemicals, or organisms that cause sickness or discomfort. Many of our foods come from "food animals" or "food-producing" animals raised specifically to provide meat, milk, and eggs. These animals serve primarily as a rich source of protein and protein-related products, vitamins, and minerals, some of which are not readily available from nonanimal sources.

Food animals convert one form of nutrient (usually grain or lignocellulosic feed such as grass, hay, or silage) to another form that differs in amino acid content, nutrient composition, and general nutritional benefit. Chickens can be raised at remarkable rates of weight gain and great metabolic efficiency to yield lean white meat. Laying hens provide a useful protein source in the eggs they produce. It takes longer for a steer to mature to a size that is marketable for beef or for a cow to mature to the point of providing milk. However, ruminants are unique in the human food chain in that they convert low-quality protein and plant-derived feed that is fundamentally indigestible by humans into meat and milk that are readily used by humans. Similarly, swine, fish, and minor species contribute to the supply of available and affordable animal-derived food.

In current agricultural practice, raising animals for food depends heavily on the use of pharmacologically active compounds: drugs. The use of drugs in food animals is fundamental to animal health and well-being and to the economics of the industry. However, their use also is associated with human health effects. There are two sides to the issue of how drug use in food animals affects the health of humans: Reported benefits are derived largely from the maintenance of good animal health and, therefore, the reduced chance that disease will spread to humans from animals. But drugs used in food-animal production and residues of those drugs could enter human food and increase the risk of ill-health in persons who consume products from treated animals. Moreover, the use of antibiotics in food animals could contribute to the emergence of antibiotic-resistant microorganisms in animals that could be transmitted to humans and result in infections that could be difficult to treat.

There are five major classes of drugs used in food animals:

There are also compounds used to modify gastrointestinal environments to reduce the likelihood of rumen foaming and bloat in cattle, organic and inorganic water treatments that reduce the chances of infection in aquaculture, and miscellaneous substances used with the advice of veterinarians to treat specific conditions. Noticeably absent from the list is a specific class of drugs for treating pain and discomfort in food animals.

In response to growing public concern over food safety in relation to the use of drugs in food animals, the U.S. Department of Agriculture (USDA) and the Center for Veterinary Medicine (CVM) of the Food and Drug Administration (FDA) asked the National Research Council to form a committee to examine and review the benefits and risks associated with drug use in the food-animal industry. The National Research Council assigned the task to the Board on Agriculture, which, through the Panel on Animal Health, Food Safety, and Public Health—a joint panel with the Institute of Medicine—convened the Committee on Drug Use in Food Animals. The committee was charged with reviewing, evaluating, and making recommendations related to the need for drugs and their availability and accountability in agriculture, the benefits and risks to human health and food safety associated with food-animal drugs, the development of food-animal drugs and the process of approval of their use, and the emerging trends in animal health care and the availability of alternative management practices for raising food animals. In particular, the sponsors stressed the importance of evaluating the class of drugs known as antibiotics.

The committee's report summarizes the current state of the science concerning the relationship between food-animal drug use and public health, reviews the rationale and process under which food-animal drugs are developed by industry and approved by the federal government for use, addresses alternative measures that might be considered in food-animal production strategies to lower use of and dependence on drugs—specifically antibiotics—and summarizes the basic strategies and practices used in modern animal production. Risks and benefits to human and animal health and to animal production economics and efficiency are identified but because quantitative information was insufficient or confounding, not objectively ranked.

THE COMMITTEE PROCESS

The committee reviewed the major classes of drugs used in food animals, focusing on the potential effect of drugs used both for human and for animal health. The committee conducted a review of the scientific literature; heard testimony on animal-drug-related issues; and reviewed federal regulations that provide guidelines and list mandatory practices for drug use, monitoring capabilities for drugs and residues in foods, veterinary oversight in prescription drug use, rates of violations, and instances of documented health problems. The committee concluded that most drugs used and most drug residues found in animal-derived foods pose a relatively low risk to the public so long as the drugs are used responsibly and in keeping with label instructions.

There were, however, concerns about the effects of antibiotic use in food animals. Effects on human health were not related to food contamination from the use of antibiotics or from antibiotic residues. Rather, the concern was narrowed to the effect of antibiotic use on the emergence in food animals of populations of microorganisms that become resistant to the biochemical mechanism by which an antibiotic drug kills or severely restricts the proliferative capability of microorganisms. For example, a review of the scientific literature found that studies focused on antibiotic resistance in human health outnumber those related to drug and chemical residues by almost 10 to 1. In addition, there has been a notable increase in reported cases of human illness associated with antibiotic resistance and an increase in documented resistance patterns from veterinary microbiological surveillance data.

Based on that information, the committee decided to focus on the potential for antibiotic resistance as the main food-animal drug issue. The committee updated and consolidated the most recent findings and opinions that address the human health risk or shape perceptions of the risk. It also summarized the science behind the process by which bacteria become resistant to antibiotic drugs and the ramifications for animals and humans.

FOOD-ANIMAL DRUG USE

Intensive production practices in the modern farming industry have created a new set of management concerns and interactions. Animal-to-animal contact is often closer, less space is available, and preventive-health measures are much more important than are therapeutic ones. Antibiotic use with prescription or veterinary oversight is assumed to be, in general, highly accountable. As with many human drugs for which adequate directions can be written for the lay user, some food-animal drugs can be purchased over the counter without a prescription, usually from distributors of animal feed and other animal production supplies. Accountability of use is improved when producers follow industry quality-assurance guidelines and, with the assistance of veterinarians, document the instances of drug use and the practices associated with drug use.

Most drugs used in food animals have a specific purpose: to treat cuts and abrasions, to enhance growth, to fight parasites. Antibiotics are among the few classes of drugs used in food animals both therapeutically to treat disease and subtherapeutically to increase production performance, to increase efficiency of use of feed for growth or product output, and to modify the nutrient composition of an animal product. Therapeutic use generally occurs after diagnosis of disease, and treatment is governed by label instructions. Subtherapeutic use, defined in the United States as the use of an antibiotic as a feed additive at less than 200 g per ton of feed, delivers antibiotics that have therapeutic effects but at dosages below those required to treat established infections. In most cases, subtherapeutic drugs are given to animals in feed or water.

Antibiotics used to improve the health of animals can increase growth rates and thus offer an economic benefit. When antibiotics stabilize animal health, food animals are able to use nutrients for growth and production rather than to fight infection. Subtherapeutic drugs are used in a range of concentrations, which vary with the type of antibiotic, the food-animal species, and the purpose of treatment. The bacterial species affected also vary with the drug used, so the potential for drug use to affect resistance and human disease varies from drug to drug, from dose to dose, and from animal species to animal species.

There is substantial food-animal industry concern that the unavailability of approved antibiotics compromises food-animal production practices in the United States. Many producers believe that, without more antibiotic choices, current production capacity and economic return might not be maintained, animal well-being could decline, and human health could be affected. The human medical community has the same concern about the lack of development of newer antibiotics to treat antibiotic-resistant bacterial infection in people. The human health care community also calls the use of these drugs in food animals into question because of the possibility that drugs used in animals will become ineffective in treating human diseases as a result of drug resistance in pathogens.

APPROVAL AND OVERSIGHT OF FOOD-ANIMAL DRUGS

New developments and FDA regulations have begun to offset the perceived shortage of drug choices for veterinarians to treat food animal diseases and other problems. CVM has authority for approving new food-animal drugs and feed additives and for regulating, tracking, and monitoring their use and their residues. A considerable portion of the monitoring activity, particularly for detecting drug residue violations, is done by FDA in cooperation with the Food Safety Inspection Service of USDA. CVM's mandate, through the Food, Drug and Cosmetic Act, is to make public health its paramount responsibility.

In the opinion of several organizations, regulatory decisions aimed at protecting people, animals, and the environment from harmful food-animal drugs have also produced delays in the approval of effective new drugs. The cost of production has increased for drug developers and frustration with the process has increased as communication between CVM and drug developers has become strained. Some organizations have used the term "crisis" to describe the present lack of choice of pharmaceuticals to administer to food animals when traditional therapies prove ineffective. The crisis reflects the fears inherent in conflicting concerns and the fears that arise when the choices and practices of one stakeholder are restricted by those of other stakeholders.

CVM has responded to industry concerns and to the enactment of new laws by reorganizing many of its operations and streamlining procedures to expedite drug approval even as it continues to meet the federal mandate to protect the public health. When no approved drug is available or when higher-than-approved dosages of approved drugs are needed, veterinarians must use their professional judgment regarding the benefits and risks to sick animals associated with extra-label use of drugs. Extra-label use for analgesic purposes is common because few animal-specific drugs have been approved for the relief of pain and suffering. Extra-label use also is common in the therapeutic treatment of minor species (goats, deer, llamas, fish, exotic pets) of food and companion animals of which the per capita use or consumption is relatively low; drugs approved for common food-animal species are typically used.

Legislative reform occurred in 1996 with the passage of the Animal Medicinal Drug Use Clarification Act (AMDUCA). AMDUCA legalized some aspects of extra-label drug use by giving veterinarians latitude in prescribing drugs for nonapproved species or dosages. Extra-label drug use is allowed only when a well-defined veterinarian­client­patient relationship is established, when drug use is accurately documented, and when accountability is ensured. A national database called the Food Animal Residue Avoidance Databank (FARAD) provides a valid and needed reference for practicing veterinarians with regard to the implementation and success of AMDUCA. Through FARAD, veterinarians can obtain information on specific veterinary and nonveterinary drugs for treating sick animals and recommend appropriate dosing and withdrawal times.

A second law aimed at streamlining the approval process is the Animal Drug Availability Act (ADAA), which was also signed into law in 1996. ADAA was developed to remove barriers in the drug approval process by reducing the stringency of requirements for proof of efficacy, by making clear early in the process which data CVM would require for approval, and by providing more flexible labeling to permit a range of dosages within a given species. Final FDA regulations based on ADAA are anticipated to be available by 1999.

There is still a need in the food-animal industry for FDA to approve more drugs for specific uses, but progress has been made in legalizing the use of medications for food animals under the guidance of veterinarians.

MONITORING OF DRUG RESIDUES

Drug residues in animal-derived food products are an important consideration for consumers. Residues of drugs used in the food-animal industry threaten human health by being acutely or cumulatively allergenic, toxic, mutagenic, teratogenic, or carcinogenic. There is inconclusive evidence that antibiotic residues transferred to humans through food might set up a biological milieu that favors the emergence of microbial strains within a host.

The processes for identifying drug residues and stopping their entry into the food chain were evaluated by the committee on the basis of drug-residue-screening data. There is always a need to increase the specificity and accuracy of screening and testing, and increased research in this regard would facilitate improvements in the monitoring process. Erring on the conservative side, regulatory agencies do find some degree of false-positive drug residue infractions. Food-animal producers generally use drugs responsibly and in keeping with manufacturers' labels. In the view of the committee, residue-monitoring procedures must be and are deployed effectively to protect consumers against possible adverse effects of ingesting small or trace amounts of drug residues. With an effective monitoring and enforcement system in place, an efficient and accountable regulatory system is freer to provide more rapid approvals and greater availability of drugs. However, only the legal use of food-animal drugs can be accounted for; with the availability of some food-animal drugs as over-the-counter preparations, prescription drug use offers the greatest accountability. (Illegal drug use in food animals and its inherent problems were largely outside the charge to this committee.) To judge by the few detected incidents of illegal drug residues in milk, eggs, or meat, the health risk posed by drug residues in foods is minimal and specific.

RESISTANCE TO ANTIBIOTIC DRUGS

With an effective residue-monitoring system in place, the dominant issue in the use of drugs in food animals is the microbial acquisition of resistance to antibiotics. This issue dominates both the drug approval process and the risk­benefit aspect of drug use in food animals, and therefore it was central to the committee's response to its charge.

Microorganisms can mutate to develop or acquire resistance to antibiotic drugs. Several questions determine whether this resistance will result in an increased hazard for humans: First, is the microorganism zoonotic; that is, can it cause a human disease by moving from the animal to a human? Second, are there missteps in the normal safety procedures for processing and handling animal-derived foods that are intended to reduce the risk of transmission of zoonotic microorganisms to humans, whether they are resistant to antibiotics or not? Third, if transmitted to humans from an animal source, is the microorganism more virulent than in its less-antibiotic-resistant form? Fourth, if the microorganism is zoonotic, is the zoonosis treatable with other antibiotics? Finally, are there enough new antibiotics in development to substitute for antibiotics to which microorganisms have become resistant? How these questions are answered determines the extent of hazard to humans.

The committee's findings on antibiotic resistance for food animals are as follows:

CONCLUSIONS

The committee concludes that the use of drugs in the food-animal production industry is not without some problems and concerns, but it does not appear to constitute an immediate public health concern; additional data might alter this conclusion. The greatest concern is associated with the use of antibiotics in food animals in such a way that there is a potential for antibiotic resistance to develop in or be transferred to pathogens that can cause disease in humans. This report acknowledges that there is a link between the use of antibiotics in food animals, the development of bacterial resistance to these drugs, and human disease—although the incidence of such disease is very low. A substantial change in the human health risk posed by antibiotic use would affect not only how animal drugs are reviewed, approved, and used, but also how food animals are produced. It should be noted that antibiotics are still effective for their intended purposes at the recommended dosages.

Bacterial resistance to antibiotics will be the most important motivating factor in the development of new drugs to fight infections and in the modification of processes by which drugs are approved. Regulatory agency approval practices have improved in recent years and continue to do so. Reasonable balance in accountability, oversight, and veterinarians' access to alternative drugs has increased with the passage of ADAA and AMDUCA. However, those are only temporary solutions to a continuing problem. Unless new antibiotics become available, even the extra-label use of antibiotics is expected to become ineffective. There is a great need to understand better both the magnitude of the risk and the options available to minimize the risk while maintaining the benefits these drugs confer on agriculture. Constant vigilance in monitoring trends in antibiotic resistance in farm animals and humans is strongly encouraged.

New antibiotic drugs are needed to combat emerging animal diseases that do not respond to traditional drugs and so threaten public confidence in animal agriculture and human medicine. Professionals in human health care should be concerned that they do not have enough specialty antibiotics to treat resistant and emerging infections in humans, as should veterinarians. The question is, should newly discovered medications be held in reserve for human or animal use only? Antibiotics should be available to treat specific human and animal diseases with proper accountability and oversight of the drugs used.

Information gaps hinder the decision- and policy-making processes for regulatory approval and antibiotic use in food animals. A data-driven scientific consensus on the human health risk posed by antibiotic use in food animals is lacking.

MAJOR RECOMMENDATIONS

Development, Approval, and Availability of Food-Animal Drugs

• The committee recommends that the Center for Veterinary Medicine continue procedural reform to expedite the drug approval review process and broaden its perspective on efficacy and risk assessment to encompass review of data on products already approved and used elsewhere in the world.

• The committee recommends that, to improve drug availability, worldwide harmonization of requirements for drug development and review be considered and further enhanced among the federal agencies that are responsible for ensuring the safety of the food supply.

• The committee recommends that the Center for Veterinary Medicine base drug use guidelines on maximal safe dosage regimens for specific food animals, consider greater emphasis on the pharmacokinetics of drug elimination from tissues that are consumed in large quantity, and set drug withdrawal times accordingly.

• The committee recommends increased funding for basic research that explores and discovers new or novel antibiotics and mechanisms of their action, including the development of more rapid and wide-screen diagnostics to improve the tracking of emerging antibiotic resistance and zoonotic disease.

Resistance to Antibiotic Drugs

• The committee recommends establishment of integrated national databases to support a rational, visible, science-driven decision-making process and policy development for regulatory approval and use of antibiotics in food animals, which would ensure the effectiveness of these drugs and the safety of foods of animal origin.

• The committee recommends that further development and use of antibiotics in both human medicine and food-animal practices have oversight by an interdisciplinary panel of experts composed of representatives of the veterinary and animal health industry, the human medicine community, consumer advocacy, the animal production industry, research, epidemiology, and the regulatory agencies.

Alternatives to Drug Use in Food Animals

• The committee recommends increased public- and private-sector research on the effect of nutrition and management practices on immune function and disease resistance in all species of food animals.

• The committee recommends increased public- and private-sector research on strategies for the development of new vaccination techniques, on a better understanding of the biochemical basis of antibody production, and on genetic selection and molecular genetic engineering for disease resistance.


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