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



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The Use of Drugs in Food Animals: Benefits and Risks 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

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The Use of Drugs in Food Animals: Benefits and Risks 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. No part of this book may be reproduced by any mechanical, photographic, or electronic process, or in the form of a phonographic recording, nor may it be stored in a retrieval system, transmitted, or otherwise copied for public or private use without written permission from the publisher, except for the purposes of official use by the U.S. government. Printed in the United States of America.

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The Use of Drugs in Food Animals: Benefits and Risks Committee on Drug Use in Food Animals JAMES R. COFFMAN, Chair, Kansas State University JOHN AUGSBURG, American Cyanamid Company, Princeton, New Jersey1 GEORGE W. BERAN, Iowa State University HARVEY R. COLTEN, Washington University School of Medicine, St. Louis, Missouri CONNIE GREIG, Little Acorn Ranch, Estherville, Iowa JEAN HALLORAN, Consumers Union of U.S. Inc., Yonkers, New York DERMOT HAYES, Iowa State University JOHN B. KANEENE, Michigan State University ALEXANDER MACDONALD, Pharma Science, Inc., North Caldwell, New Jersey2 KRISTEN MCNUTT, Consumer Choices, Inc., Winfield, Illinois DAVID L. MEEKER, Ohio State University STEPHEN C. NICKERSON, Hill Farm Research Station, Louisiana State University THOMAS SEAY, Atlanta Cancer Care, Atlanta, Georgia R. GREGORY STEWART, Bayer Animal Health, Inc., Watkinsville, Georgia Panel on Animal Health, Food Safety, and Public Health JOHN A. SHADDUCK, Chair, Heska Corp., Ft. Collins, Colorado KENNETH BERNS, University of Florida MICHAEL P. DOYLE, University of Georgia HOLLIS N. ERB, Cornell University JOHN FERRY, Adams, New York JERE E. GOYAN, Alteon, Inc. Ramsey, New Jersey WERNER HEUSCHELE, San Diego Zoo HELEN H. JENSEN, Iowa State University FRANKLIN M. LOEW, Medical Foods, Inc., Cambridge, Massachusetts JOY A. MENCH, University of California, Davis HARLEY MOON, Iowa State University WILSON G. POND, Cornell University, Ithaca, New York R. GREGORY STEWART, Bayer Animal Health, Inc., Watkinsville, Georgia Staff MICHAEL J. PHILLIPS, Program Director THEODORE H. ELSASSER, Project Director SHIRLEY THATCHER, Senior Project Assistant JULIEMARIE GOUPIL, Project Assistant MARY I. POOS, Program Director (through April 30, 1997) DEBORAH FAISON, Senior Project Assistant (through July 30, 1995) DENNIS BLACKWELL, Senior Project Assistant (after July 30, 1995) 1   Served through August, 1995 2   Served through May, 1995

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The Use of Drugs in Food Animals: Benefits and Risks BOARD ON AGRICULTURE DALE E. BAUMAN, Chairman, Cornell University JOHN M. ANTLE, Montana State University SANDRA S. BATIE, Michigan State University MAY R. BERENBAUM, University of Illinois LEONARD S. BULL, North Carolina State University WILLIAM B. DELAUDER, Delaware State University ANTHONY S. EARL, Quarles & Brady Law Firm, Madison, Wisconsin ESSEX E. FINNEY, JR., Mitchellville, Maryland CORNELIA FLORA, Iowa State University GEORGE R. HALLBERG, The Cadmus Group, Inc., Waltham, Massachusetts RICHARD R. HARWOOD, Michigan State University T. KENT KIRK, University of Wisconsin, Madison HARLEY W. MOON, Iowa State University WILLIAM L. OGREN, University of Illinois GEORGE E. SEIDEL, JR., Colorado State University JOHN W. SUTTIE, University of Wisconsin JAMES J. ZUICHES, Washington State University Staff J. PAUL GILMAN, Executive Director MICHAEL J. PHILLIPS, Director

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The Use of Drugs in Food Animals: Benefits and Risks FOOD AND NUTRITION BOARD CUTHBERTO GARZA, Cornell University JOHN W. ERDMAN, University of Illinois LINDSAY H. ALLEN, University of California BENJAMIN CABALLERO, Johns Hopkins School of Hygiene and Public Health FERGUS M. CLYDESDALE, University of Massachusetts ROBERT J. COUSINS, University of Florida MICHAEL P. DOYLE, University of Georgia JOHANNA T. DWYER, New England Medical Center SCOTT M. GRUNDY, University of Texas Southwestern Medical Center CHARLES H. HENNEKENS, Harvard Medical School JANET C. KING, University of California SANFORD A. MILLER, University of Texas Health Science Center ROSS L. PRENTICE, Fred Hutchinson Cancer Research Center A. CATHARINE ROSS, Pennsylvania State University ROBERT E. SMITH, R.E. Smith Consulting, Inc. VIRGINIA A. STALLINGS, Children’s Hospital of Philadelphia VERNON R. YOUNG, Massachusetts Institute of Technology Staff ALLISON YATES, Director BERNADETTE MARRIOTT, Project Officer

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The Use of Drugs in Food Animals: Benefits and Risks The National Academy of Sciences is a private, nonprofit, self-perpetuating 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.

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The Use of Drugs in Food Animals: Benefits and Risks 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 funda-

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The Use of Drugs in Food Animals: Benefits and Risks mentally 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, wholesale–retail, 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 subtherapeutically. 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.

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The Use of Drugs in Food Animals: Benefits and Risks 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: review the role of drugs in food-animal production, including accessibility and accountability in their use; summarize available knowledge on human health effects of drug use in food animals; evaluate the approval and regulatory process and delivery systems for animal drugs; and assess emerging trends, technologies, and alternatives to drug use in food animal production. 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,

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The Use of Drugs in Food Animals: Benefits and Risks the communications industry, food producers, drug manufacturers, and other audiences our recommendations for needed improvements related to: drug resistance monitoring; drug residue monitoring; drug use and alternative strategies; and an integrated, continuous, decision-making process with shared responsibilities of all stakeholders to enhance availability of needed drugs and to move toward global harmonization of this process. In addressing its charge, through these four areas, the committee developed a line of logic, which guides the elaboration of this report, as follows: The residue-monitoring process is critical to the protection of the consumer’s health—it must be effective and match the patterns of use for all classes of drugs in animal production systems. The drug approval process is critical to the availability and accountable use of all classes of drugs used in animal production systems, and in the future this will include emerging issues such as genetic design strategies. If the drug-residue-monitoring system is effective, then the remaining risk–benefit issue of major proportion is microbial resistance to antibiotics. Based on this line of logic, and because of the urgent nature of this matter, it is treated more extensively than any other topic in this report. 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

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The Use of Drugs in Food Animals: Benefits and Risks 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 fluoroquinolones 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

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The Use of Drugs in Food Animals: Benefits and Risks 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

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The Use of Drugs in Food Animals: Benefits and Risks 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.

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The Use of Drugs in Food Animals: Benefits and Risks Contents     EXECUTIVE SUMMARY   1      The Committee Process,   3      Food-Animal Drug Use,   4      Approval and Oversight of Food-Animal Drugs,   5      Monitoring of Drug Residues,   6      Resistance to Antibiotic Drugs,   6      Conclusions,   9      Major Recommendations,   10      Development, Approval, and Availability of Food-Animal Drugs,   10      Resistance to Antibiotic Drugs,   11      Alternatives to Drug Use in Food Animals,   11 1   DRUGS USED IN FOOD ANIMALS: BACKGROUND AND PERSPECTIVES   12      The Role of This Report,   13      Review of Previous Reports,   15      The Antibiotic Issue,   19      A Possible Scenario,   20      The Emergence of Antibiotics in Our Lives,   20      Food-Animal Antibiotic Resistance and Human Health,   22 2   FOOD-ANIMAL PRODUCTION PRACTICES AND DRUG USE   27      Overview,   27      The Poultry Industry,   29      An Integrated Industry,   30      History and Trends in Drug Use,   31

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The Use of Drugs in Food Animals: Benefits and Risks      Routes of Drug Administration,   34      Feed,   34      One-Day-of-Age Injection,   34      Water Medication,   34      Growth Promotion,   38      Disease Control,   38      Salmonella Control,   38      Escherichia coli Control,   39      Clostridium Control,   39      The Swine Industry,   40      Disease Control and Use of Drugs and Chemicals,   41      Growth and Metabolic Performance,   42      The Dairy Industry,   44      Disease Control and Prophylactic Treatments,   45      Therapeutic Treatment of Disease,   45      Antibiotic Drug Use,   47      Production Enhancers,   48      The Beef Industry,   48      Disease Prevention,   50      Trends in Drug Use,   50      Therapeutic Drug Use,   51      Vaccinations,   53      The Veal Industry,   53      The Sheep Industry,   54      Minor Species,   56      The Aquaculture Industry,   56      Quality-Assurance Programs and Animal Health Maintenance,   60      Poultry Quality-Assurance Programs,   60      Pork Quality-Assurance Programs,   61      Dairy Quality-Assurance Programs,   63      Beef Quality-Assurance Program,   67      Summary of Findings,   68 3   BENEFITS AND RISKS TO HUMAN HEALTH   69      Overview,   69      Prevention,   71      Treatment,   72      Benefits of Antibiotic Use,   73      Possible Hazards of Antibiotic Use,   75      Antibiotic Resistance as a Human Health Risk,   76      Antibiotic Resistance Trends,   78      Human Health Risks from Drug Residues in Foods,   81      Antibiotic Toxicities,   83      Allergenicity,   84

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The Use of Drugs in Food Animals: Benefits and Risks      Relative Risks: Residues versus Microbial Contamination,   85      Summary of Findings,   86 4   DRUG DEVELOPMENT, GOVERNMENT APPROVAL, AND THE REGULATORY PROCESS   88      Overview,   88      Restructuring the Regulatory and Approval Process,   91      Reforming the Regulatory Process,   95      The Animal Medicinal Drug Use Clarification Act,   96      The Animal Drug Availability Act,   99      Human Health Risk, Residues, and Approval,   100      Perspectives on Developing Drugs,   101      Worldwide Harmonization of the Animal Drug Approval Process,   104      Summary of Findings and Recommendations,   106      Recommendations,   107 5   DRUG RESIDUES AND MICROBIAL CONTAMINATION IN FOOD: MONITORING AND ENFORCEMENT   110      Drug Residue Standards and Screening,   111      Tracking Drug Residues in Food,   113      Drug Residues in Meat and Poultry,   115      Drug Residues in Fish and Seafood,   119      Drug Residues in Milk,   119      The Grade A Pasteurized Milk Ordinance,   121      Drug Residue Testing in Milk,   122      Drug Monitoring in Milk,   124      Unresolved Dairy Testing Issues,   125      Food-Borne Pathogens and Contamination of Food,   126      Determination of Pathogens,   127      A Nine-Year Survey of Reported Food-Borne Illness,   133      Integrating Issues of Residues and Microbial Contamination,   137      Summary of Findings and Recommendations,   140      Recommendations,   141 6   ISSUES SPECIFIC TO ANTIBIOTICS   142      Development and Functionality of Antibiotic Drugs,   143      Identifying and Screening Antibiotics,   145      Bacterial Resistance,   148      Antibiotic-Resistant Bacteria and Animal Management,   150      Subtherapeutic versus Therapeutic Use of Drugs,   153      Human and Veterinary Clinical Implications of Antibiotic Resistance,   161      Cases to Test the System,   166      The Fluoroquinolones Issue,   168      The Virginiamycin Issue,   175

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The Use of Drugs in Food Animals: Benefits and Risks      Summary of Findings and Recommendations,   176      Recommendations,   177 7   COSTS OF ELIMINATING SUBTHERAPEUTIC USE OF ANTIBIOTICS   179      Considerations in Determining the Effect of a Ban,   180      Definition of Subtherapeutic Use,   180      Measurement Choice,   180      Viable Antibiotic Substitutes,   182      Total Versus Partial Ban,   182      Consumer Behavior,   183      Results of Economic Analysis and Conclusions,   184      Appendix,   186      Technical Notes for Table 7–1,   186      Chicken Data,   186      Turkey Data,   187      Beef Data,   187      Pork Data,   187 8   APPROACHES TO MINIMIZING ANTIBIOTIC USE IN FOOD-ANIMAL PRODUCTION   188      Animal Management,   190      Ambient Temperature and Heat Stress,   190      Overcrowding and Behavioral Stress,   193      Vaccination Strategies to Prevent Disease,   193      DNA Vaccination,   195      Beneficial Microbial Cultures, Probiotics, and Competitive-Exclusion Alternatives,   195      Biosecurity,   197      Fly Control,   199      Moisture, Mud, and Manure,   199      Enhancing Natural Mediators of Immune Function,   200      Killed Bacterial Adjuvants: Biomodulation of Cytokine and Immune Function,   202      Nutrition,   202      Disease Eradication   206      Genetics,   207      Recommendations,   208     REFERENCES   210     ABOUT THE AUTHORS   235     INDEX   239

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The Use of Drugs in Food Animals: Benefits and Risks Tables and Figures TABLES 1–1   Summary of Previous Major Reports on Food-Animal Antibiotics,   16 2–1   Coccidiostats Approved for Use in Broilers, Turkeys, and Layers,   32 2–2   Major Claims of Antibiotics Approved for Use in Chickens and Turkeys,   32 2–3   Cost of Drug and Vaccine Use in Broilers from 1989 to 1994,   35 2–4   Turkey Medication and Vaccine Cost Analysis,   36 2–5   Cost of Medication and Vaccination Used for Turkeys and Broilers in the United States,   37 2–6   Major Claims of Antibiotics Approved for Use in Hogs,   42 2–7   Major Claims of Chemotherapeutics Approved for Use in Hogs,   43 2–8   Intramammary Antibiotics Approved for Dairy Cattle,   45 2–9   Distribution of Health Costs per Cow by Functional Category,   46 2–10   Estimated Annual Losses Caused by Mastitis,   47 2–11   Major Claims for Systemic Antimicrobials Approved for Use in Beef and Dairy Cattle,   52 2–12   Steroid Products Labeled for Improved Growth and/or Feed Efficiency in Cattle,   53 2–13   Major Claims of Antibacterials Approved for Use in Sheep,   55 2–14   Major Claims for Drugs Approved for Use in Minor Species,   57 2–15   FDA-Approved New Drugs for Use in Aquaculture,   59

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The Use of Drugs in Food Animals: Benefits and Risks 3–1   The Effect of Implementation of a Veterinary Preventive-Medicine Scheme on Offal and Carcass Rejections from 12 Finishing Farms,   76 4–1   Food-Animal Populations in the United States,   102 4–2   Comparative Value of FDA-Regulated Industries,   102 4–3   Annual Sales of Animal Drugs,   103 5–1   FSIS Animal Drug Residue Test Results,   118 5–2   Drug Residue Analysis Results for Grade A and Non-Grade-A Milk,   121 5–3   Survey Report of Microbiological Hazards in Swine,   128 5–4   Survey Report of Microbiological Hazards in Cattle,   130 5–5   Survey Report of Microbiological Hazards in Lamb,   132 5–6   Survey Report of Microbiological Hazards in Poultry,   134 6–1   E. coli Resistance to TMP-SMX,   163 6–2   Resistance of TMP-SMX-Resistant E. coli Isolates to Other Antimicrobial Agents,   164 6–3   Antimicrobial Resistance of E. coli Strains Isolated from Enteritis in Calves in the United States, Canada, and France,   165 6–4   Antibiotic Resistance in Salmonella from Animals, Percentage of Cultures Showing Resistance,   165 6–5   Antibiotic Resistance in Salmonella typhimurium from Animals, Percentage of Cultures Showing Resistance,   167 7–1   Approximate Annual Costs of a Ban on Subtherapeutic Antibiotic Use in Four Domestic Retail Markets,   185 8–1   Efficacy of Recombinant Bovine IFN-γ against E. coli Mastitis,   201 8–2   Effect of GCSF on Blood and Milk Leukocyte Profiles and Efficacy against Staphylococcus aureus Mastitis,   201 8–3   Blood Selenium, GSH-Px, and Serum Vitamin E of Cows from Low- and High-SCC Herds,   204 FIGURES 4–1   CVM Organizational Structure,   90 4–2   Comparison of the Traditional and Re-Engineered Approval Processes,   92 4–3   Effect of Re-Engineering the Approval Process on the Time to Approve New Animal Drug Applications,   93 4–4   Trends in Animal Drug Approvals since 1990,   94

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The Use of Drugs in Food Animals: Benefits and Risks 5–1   Seasonality of Reported Cases of Food-Borne Disease as Monitored Across the Seven Sentinel Organisms at All Locations,   137 6–1   Salmonella DT-104 Ciprofloxacin-Resistant Human Isolates Confirmed in the United Kingdom,   173

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