Questions and answers

LATHERSVETERINARY MEDICINE IN PUBLIC HEALTHCOMMENTARY COMMENTARY

Role of Veterinary Medicine in Public Health: Antibiotic Use in Food Animals and Humans

and the Effect on Evolution of Antibacterial Resistance

Claire M. Lathers, PhD, FCP

VETERINARY PUBLIC HEALTH: A FRONTIER IN THE FIGHT AGAINST HUMAN DISEASE

Veterinary public health is another frontier in the fight against human disease.1 The veterinary public health scope includes the control and eradication of zoonoses, diseases that are naturally transmitted between verte- brate animals and man. These diseases pose a continu- ous hazard to the health and welfare of the public.

There are more than 100 diseases categorized as zoonoses, including salmonellosis. For example, ap- proximately 20% of U.S. broiler chickens are contami- nated with Salmonella, while more that 80% are con- taminated with Campylobacter.2 The veterinary public health scope, in addition to the control and eradication of zoonoses, also includes the development and super- vision of food hygiene practices, laboratory and re- search activities, and education of the public.

ANTIBIOTIC USE IN FOOD ANIMALS AND HUMANS AND THE EFFECT ON EVOLUTION OF ANTIBACTERIAL RESISTANCE

Antibiotic Use in Food Animals: Therapeutic and Subtherapeutic

It is important to understand how antibiotics are used in humans and in food animals and how these uses af-

J Clin Pharmacol 2001;41:595-599 595

From the U.S. Food and Drug Administration (FDA), Center for Veterinary Medicine, Rockville, Maryland. This commentary represents the opinion of the author and does not reflect policy of the FDA or the U.S. government. Presented at the American College of Clinical Pharmacology Teaching Fo- rum, chaired by David M. Benjamin, “Educational Issues in Clinical Phar- macology: Updating the Curriculum for the New Millennium: Who Are Our Audiences and What Are Their Specialized Needs? One Specialized Need: Understanding the Role of Veterinary Medicine in Public Health,” September 19, 2000. Address for reprints: Claire M. Lathers, PhD, FCP, Director, Office of New Animal Drug Evaluation, Center for Veterinary Medicine, Room 390, HFV-100, 7500 Standish Place, Rockville, MD

Veterinary public health is another frontier in the fight against human disease. The veterinary public health scope includes the control and eradication of zoonoses, diseases that are naturally transmitted between vertebrate animals and man. These diseases pose a continuous hazard to the health and welfare of the public. More than 100 diseases are categorized as zoonoses, including salmonellosis. It is im- portant to understand how antibiotics are used in humans and in food animals and how these uses affect the evolution of antibacterial resistance. Appropriate use of antibiotics for food animals will preserve the long-term efficacy of existing antibiotics, support animal health and welfare, and limit the risk of transfer of antibiotic resistance to humans. An under- standing of the epidemiology of antimicrobial resistance al- lows development of preventive strategies to limit existing

resistance and to avoid emergence of new strains of resistant bacteria. Risk assessments are being used by the Center for Veterinary Medicine at the U.S. Food and Drug Administra- tion as regulatory tools to assess potential risk to humans re- sulting from antibiotic use in food-producing animals and to then develop microbial safety policies to protect the pub- lic health. The veterinary public health scope, in addition to the control and eradication of zoonoses, also includes the development and supervision of food hygiene practices, laboratory and research activities, and education of the public. Thus, it may be seen that there are many ways in which veterinary medicine plays a very important role in public health.

Journal of Clinical Pharmacology, 2001;41:595-599 ©2001 the American College of Clinical Pharmacology

fect the evolution of antibacterial resistance. An under- standing of the epidemiology of antimicrobial resis- tance allows the development of preventive strategies to limit existing resistance and to avoid emergence of new strains of resistant bacteria.3 Food animal produc- tion in the United States currently uses large amounts of subtherapeutic doses of antibiotics for disease con- trol. Aarestrup and Wegener4 conclude that the use of large amounts of antibiotics for disease control in food animal production results in the spread and persis- tence of antimicrobial-resistant zoonotic bacteria. A heavy antimicrobial drug-selective pressure in over- crowded populations of production animals creates fa- vorable environments both for the emergence and the spread of antibiotic resistance genes.5 Wierup, of the Swedish Animal Health Service, recently published a paper6 in which he emphasized that antibiotics should be an integral part of other disease-preventive methods and employed only when other methods have failed. He concluded that antibiotics should not be included in the first line of action. Pedersen et al7

emphasized that appropriate use of antibiotics for food animals will preserve the long-term efficacy of existing antibiotics, support animal health and wel- fare, and limit the risk of transfer of antibiotic resis- tance to humans.

These conclusions are in agreement with those made by the Food and Drug Administration (FDA) in 1977, when the agency first called for restrictions on the use of antimicrobial agents in feed. The FDA pro- posed to withdraw penicillins and tetracyclines, alone or in combination, from animal feeds since both of these pharmacological agents were then very impor- tant in the human medical field. Critics of the FDA pro- posal based their arguments on the lack of epidemio- logical evidence to support the fact that drug-resistant bacteria of animal origin were commonly transmitted to humans and contributed to serious illness. Those op- posing the FDA’s proposed withdrawal concluded that although the use of antibiotics in animals may select for resistant bacteria, the actual transfer of these bacteria from animals to humans is rare. In 1978, Congress man- dated the FDA to allocate $1.5 million of its monies to support the National Academy of Sciences National Research Council to study the questions surrounding the use of subtherapeutic antibiotics in animal feeds. The conclusions of this study were that the existing data did not prove or disprove that subtherapeutic antimicrobial use in animal feeds contributed to seri- ous illness in humans. Thus, the subtherapeutic use of antimicrobial agents continued in the United States, in part, because Congress interceded in the FDA-

proposed withdrawal of penicillins and tetracyclines, alone or in combination.

The FDA request for data on the subtherapeutic use of antibiotics has generated a number of studies and re- ports over the ensuing years. In November 1999, U.S. Congressman Sherrod Brown introduced a bill, co- sponsored by Representatives Henry Waxman and Louise Slaughter,8 to ban harmful subtherapeutic anti- biotic use in animal feed since antibiotics used in this manner can contribute to the development of antibi- otic-resistant bacteria. Brown emphasized the impor- tance of protecting the public health so that when peo- ple do become ill, the antibiotic medicines available for use in treatment will indeed be effective. He noted that young children and the elderly are especially at risk be- cause they have weaker immune systems. Brown’s bill would deny approval of subtherapeutic use of antimicrobial drugs in livestock if the data provided by the applicant do not sufficiently prove the drug will not harm human health. The bill requires previously ap- proved drug use to be proven safe within 2 years. Brown included two reports as supporting evidence for his bill. The first report cited was the April 1999 Gen- eral Accounting Office report9 of resistant strains of Salmonella, Campylobacter, and E. coli, microbial or- ganisms that cause illness or disease in humans, being linked to the use of antibiotics in animals. The second report cited by Brown as evidence to support his bill was the World Health Organization’s conclusion10

that antibiotics used to treat humans should not be used to promote animal growth. Brown concluded, “This bill would stop the misuse of antibiotics. It will not prevent farmers and livestock factories from the safe, effective use of antibiotics in animal feed. It will not prevent short-term use of antibiotics to treat ill an- imals. Our goal is to protect people from building up a resistance to drugs they might need some day to stay healthy.”

Cause-and-Effect Relationship between Use of Antibiotics in Food Animals and Treatment Failures in Human Disease Are Challenged by Variable Methods of Data Collection

Shryock11 notes that studies attempting to establish a cause-and-effect relationship between the use of antibi- otics in food animals and treatment failures in human disease are challenged by the variable methods of data collection used. Some studies focus on antibiotic usage data, while other studies examine in vitro determina- tions of antibiotic susceptibility of animal and human

596 J Clin Pharmacol 2001;41:595-599

LATHERS

isolates or data obtained in controlled animal experi- ments or epidemiological data. It is difficult to recon- cile these different approaches because the data used in the analyses are often of disparate origin. The best as- sessment of the degree of contribution to human antibi- otic resistance from animal use will result from com- prehensively organizing these different approaches in a coordinated science-based effort. Such an approach should ultimately minimize and contain the devel- opment and spread of antibiotic-resistant bacteria as- sociated with food animals. In addition, Kla and Tollefson12 stressed the importance of quality assur- ance programs designed to ensure food safety and qual- ity, including the control or reduction of pathogen load. Pathogen load is defined as the number of enteric bac- teria in the intestinal tract of the food animal that causes human illness.

NATIONAL ANTIMICROBIAL RESISTANCE MONITORING SYSTEM

Tollefson et al13 have recently described the develop- ment, implementation, and objectives of the National Antimicrobial Resistance Monitoring System to pro- spectively monitor changes in antimicrobial suscepti- bilities of zoonotic-enteric pathogens from human and animal clinical specimens, from healthy farm ani- mals, and from carcasses of food-producing animals at slaughter plants. The resulting data will guide the redirection of antimicrobial drug use, if needed, to diminish significant development and spread of resistance.

INTERAGENCY TASK FORCE ON ANTIMICROBIAL RESISTANCE

The FDA is a participating member of an inter- agency task force14 on antimicrobial resistance that is cochaired by the Centers for Disease Control and Pre- vention, the FDA, and the National Institutes for Health, and it also includes the Agency for Healthcare Research and Quality, the Department of Agriculture, the Department of Defense, the Department of Veterans Affairs, the Environmental Protection Agency, the Health Care Financing Administration, and the Health Resources and Service Administration. The task force charge is to work on the broad issue of antimicrobial resistance by developing a Public Health Action Plan to serve as a blueprint for federal agencies to address antimicrobial resistance. The task force has drafted a plan based on a public meeting held in July 1999 and

the Federal Register notice announcing the plan was just published in June 2000. The plan addresses con- cerns related to both human and animal use.

FDA FRAMEWORK DOCUMENT

In addition, the FDA has developed a framework docu- ment, “A Proposed Framework for Evaluating and As- suring the Human Safety of the Microbial Effects of Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals,”15 which presents an outline of how antimicrobials intended for use in food- producing animals may be regulated, based on qualita- tive risk assessment, to characterize risk in terms of hazard and exposure. An antibiotic resistance thresh- old mechanism is proposed to establish the acceptable level of resistant bacteria in animal products to provide for continued effectiveness of human antimicrobials. The Framework Document was published in the Fed- eral Register on January 6, 1999. The FDA response to comments on the proposed framework is found on the FDA/Center for Veterinary Medicine (CVM) home page at http://www.fda.gov/cvm/fda/infores/vmac/ FDAResp4_PDF.

FDA GUIDANCE FOR INDUSTRY #78

The FDA’s Center for Veterinary Medicine recognizes that the primary contributory source in the overall re- sistance problem is use of antimicrobials in human medicine.16 Nevertheless, it is important to understand the role of using antibiotics in food-producing animals. For certain food-borne pathogens, animal use can be a major driver of the resistance seen in human medicine. In industrialized countries, the food-borne pathogen Salmonella is infrequently transferred from person to person. Epidemiological data demonstrate that a signif- icant source of antimicrobial resistance to food-borne infection in humans is acquisition of resistant bacteria from animals via food. The FDA’s Guidance for Indus- try (no. 78)17 states that it is necessary for the potential human health impact of microbial effects associated with all uses of all classes of antimicrobial new animal drugs intended for use in food-producing animals when approving such drugs. Study designs to develop new drugs in food-producing animals may have to ad- dress separate but related issues.2 First, the rate and ex- tent of development of antimicrobial drug- resistant enteric bacteria formed in the intestinal tract after ex- posure to the antimicrobial may have to be determined. Second, the changes in the pathogen load may have to be characterized. See the FDA’s Guidance for Industry

COMMENTARY 597

VETERINARY MEDICINE IN PUBLIC HEALTH

(no. 78)17 at www.fda.gov/cvm/fda/TOCs/guidad78. pdf.

QUANTITATIVE RISK ASSESSMENT TO MODEL THE HUMAN HEALTH IMPACT OF FLUOROQUINOLONE-RESISTANT CAMPYLOBACTER INFECTIONS ASSOCIATED WITH CONSUMPTION OF POULTRY

To address the necessity of considering the potential human health impact of microbial effects associated with the use of fluoroquinolines in food-producing animals, the CVM conducted a quantitative risk assessment to model the human health impact of fluoroquinolone-resistant Campylobacter infections associated with the consumption of poultry. A draft version of the risk assessment has been posted on the FDA/CVM home page (www.fda.gov/cvm).18 The CVM intends to publish a final risk assessment in the near fu- ture. Campylobacter is the most common known cause of bacterial food-borne illness in the United States.2

The model assumes that resistant bacteria pass through the food supply, infect humans, and are treated in the same manner as susceptible bacteria. However, resis- tant bacteria may impair the effectiveness of therapy. The model allows assessment of incremental human health impact of resistant food-borne disease but does not require that all contributing factors be evaluated. The draft risk assessment estimates that the risk for the average U.S. citizen appears small (i.e., 1 in 61,093 peo- ple were affected in 1998). Most of the U.S. population consumes chicken, and the consumption of a fluoroquinolone-resistant Campylobacter-contami- nated chicken product or consumption of another food item contaminated by chicken, such as salad, is a ran- dom process. The result is that most people are ex- posed to the risk, and the randomness of the event means that most people are not in full control of the risk.

The draft risk assessment estimates that the risk for U.S. citizens with Campylobacteriosis contracted from chicken was 1:521 in 1998. The individuals in this group will potentially seek medical care and may be prescribed a fluoroquinolone. The risk for U.S. citizens with Campylobacteriosis obtained from chicken and seeking medical care was 1:63 in 1998. Thus, individu- als in this group are “sufficiently ill that they decide they need help” from their physician. These individu- als may be more susceptible to Campylobacter than most. The risk in U.S. citizens with Campylobacteriosis seeking medical care and prescribed an antibiotic was 1:32 in 1998. Individuals in this group are considered

ill both by themselves and by their physicians. This group includes those most seriously at risk from the failure of fluoroquinolone therapy. A detailed descrip- tion of the risk assessment, including two interactive versions of the model, is available on the FDA/CVM homepage. The estimates provided are based on a U.S. population of 270,298,524. The other denominators used in estimating the probability of a health impact (e.g., the number of people with Campylobacteriosis seeking care and prescribed antibiotic) are estimated with each specific iteration of the model.

RISK ASSESSMENT TO EVALUATE IMPACT OF VIRGINIAMYCIN RESISTANCE IN ENTEROCOCCUS FAECIUM IN ANIMALS ON THE ABILITY TO TREAT E. FAECIUM IN HUMANS WITH THE HUMAN ANTIMICROBIAL AGENT SYNERCID

Huycke et al19 noted that Enterococci faecium is a spe- cies more likely to be resistant to antibiotics of last re- sort and emphasized that effective control of multiple- drug-resistant enterococci will require a better un- derstanding of the interaction between E. faecium, the hospital environment, and humans; prudent antibiotic use; better contact isolation in hospitals; and better sur- veillance. The CVM will model some or all of these fac- tors in a second, more complex risk assessment20 de- signed to examine the indirect transfer of resistance from animals to humans. The impact of virginiamycin resistance in Enterococcus faecium in animals on the ability to treat E. faecium in humans with the human antimicrobial agent Synercid will be evaluated.

CONCLUSIONS

Both the Campylobacter and E. faecium risk assess- ments may be used by the CVM as regulatory tools to assess potential risk to humans resulting from antibi- otic use in food-producing animals and to then develop microbial safety policies to protect the public health. Thus, it may be seen that this is one way in which veter- inary medicine plays a very important role in public health.

REFERENCES

1. Tacal JV: Veterinary public health: a new frontier in the fight against human disease. J Philippine Med Assoc 1965;41:361-367. 2. U.S. Food and Drug Administration: Antimicrobial resistance doc- uments available. FDA Veterinarian 2000;15:1-2. 3. Guillemot D: Antibiotic use in humans and bacterial resistance. Curr Opin Microbiol 1999;2:494-498.

598 J Clin Pharmacol 2001;41:595-599

LATHERS

4. Aarestrup FM, Wegener HC: The effects of antibiotic usage in food animals on the development of antimicrobial resistance of impor- tance for humans in Campylobacter and Escherichia coli. Microbes and Infection 1999;8:639-644. 5. Franklin A: Current status of antibiotic resistance in animal pro- duction. Acta Vet Scand Suppl 1999;92:23-28. 6. Wierup M: The control of microbial diseases in animals: alterna- tives to the use of antibiotics. Intl J Antimicrobial Agents 2000;14: 315-319. 7. Pedersen KB, Aarestrup FM, Jensen NE, Bager F, Jensen LB, Jorsal SE, Nielsen TK, Hansen HC, Meyling A, Wegener HC: The need for a veterinary antibiotic policy. Vet Rec 1999;145:50-53. 8. Brown S, Waxman H, Slaughter L: Introduced a bill “To direct that essential antibiotic drugs not be used in livestock unless there is a reasonable certainty of no harm to human health: preservation of es- sential antibiotics for human diseases act of 1999.” Referred to Sub- committee on Commerce Health and Environment. November 17, 1999. 9. General Accounting Office: Report of Resistant Strains of Salmo- nella, Campylobacter, and E. coli, Microbial Organisms That Cause Illness or Disease in Humans, Being Linked to the Use of Antibiotics in Animals. Washington, DC: GAO, 1999. 10. World Health Organization: The medical impact of the use of antimicrobials in food animals. Report of a WHO meeting, WHO/ EMC/ZOO/97.4, Berlin, Germany, October 13-17, 1997. 11. Shryock TR: Relationship between usage of antibiotics in food- producing animals and the appearance of antibiotic resistant bacte- ria. Intl J Antimicrobial Agents 1999;12:275-278. 12. Kla J, Tollefson L: Producer quality assurance programs. Vet Clin North Am Food Anim Pract 1999;15:197-208.

13. Tollefson L, Fedorka-Cray PJ, Angulo FJ: Public health aspects of antibiotic resistance monitoring in the USA. Acta Vet Scand Suppl 1999;92:67-75. 14. Interagency Task Force on Antimicrobial Resistance: A Public Health Action Plan to Serve as a Blueprint for Federal Agencies. U.S. Food and Drug Administration, U.S. Department of Agriculture, En- vironmental Protection Agency and Center for Disease Control and Prevention, 1999. 15. U.S. Food and Drug Administration: A proposed framework for evaluating and assuring the human safety of the microbial effects of antimicrobial new animal drugs intended for use in food-producing animals. Federal Register 1999;(January 6). 16. Thompson S: Update on CVM activities in antimicrobial resis- tance. FDA Veterinarian 2000;15(3):4-5. 17. U.S. Food and Drug Administration: Guidance for Industry: Consideration of the Human Health Impact of the Microbial Effects of Antimicrobial New Animal Drugs Intended for Use in Food- Producing Animals. CVM guidance document 78. Rockville, MD: FDA, 1999. 18. U.S. Food and Drug Administration: Risk Assessment of Fluoroquinolone Resistant Campylobacter Infections in Poultry [Online]. Available: http://www.fda.gov/cvm/fda/infores/vmac/ FDAResp4_PDF. 19. Huycke MM, Sahm DF, Gilmore MS: Multiple-drug resistant enterococci: the nature of the problem and an agenda for the future. Emerg Infect Dis 1998;4:239-249. 20. U.S. Food and Drug Administration: Modeling the impact of virginiamycin resistance in Enteroccus faecium in animals with the recently approved human antimicrobial, Synercid. Federal Register 2000;(April 19).

COMMENTARY 599

VETERINARY MEDICINE IN PUBLIC HEALTH