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U.S. Department of Health and Human Services

Animal & Veterinary

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FDA Veterinarian Newsletter May/June 2000 Volume XV, No III

The FDA Veterinarian discussed the issue of antimicrobial resistance with Dr. Sharon R. Thompson, CVM's Associate Director for Veterinary Medical and International Affairs. Dr. Thompson is responsible for managing and coordinating national and international activities on antimicrobial resistance related to drug therapy in food animals. The following are questions and answers that came out of that discussion.

Q. FDA's CVM has stated that antimicrobial resistance is its number one priority. Why is FDA so concerned about the role that antimicrobial drug use in food-producing animals plays in the emergence of antimicrobial drug resistant bacteria? Isn't it true that much of the problem in humans is caused by antimicrobial use in human medicine?

A. The Center acknowledges that the bulk of the antimicrobial resistance problem in humans is due to human use of these products. FDA is co-chair with CDC and NIH of an Interagency Task Force on Antimicrobial Resistance that is working on the broad issue of antimicrobial resistance. The Task Force is developing a Public Health Action Plan to serve as a blueprint for Federal agencies to address antimicrobial resistance. A draft plan is being prepared based on input at a public meeting held in July 1999 and is expected to be released for public comment later this year. Most of the plan will deal with human drug issues, which represent the bulk of the human drug resistance problem. However, it is important to recognize that use of antimicrobials in food-producing animals is also of concern. For certain foodborne pathogens, animal use can be a major driver of the resistance that is seen in human medicine. In industrialized countries, the foodborne pathogen Salmonella is infrequently transferred from person to person. In these countries, epidemiological data have demonstrated that a significant source of antibiotic resistant foodborne infections in humans is the acquisition of resistant bacteria from animals via food.

This is not a new issue; we have been concerned about it for about 30 years. FDA first called for several restrictions on antimicrobial use in feed in 1977. That proposal generated several studies and reports. In 1988, the Institute of Medicine (IOM) again reviewed current information about antibiotic resistance. The Committee found a considerable amount of indirect evidence implicating both subtherapeutic and therapeutic use of antimicrobials as a potential human health hazard, but did not find data demonstrating that use of subtherapeutic penicillin or tetracycline directly caused a human to die from salmonellosis. The Committee strongly recommended further study of the issue.

In the early 1990s, several scientists expressed concern that the approval of fluoroquinolones for use in food-producing animals in the U.S. would result in fluoroquinolone resistant foodborne disease in humans. Since then, reports have identified a relationship between the approval of fluoroquinolones for therapeutic use in food-producing animals and the development of fluoroquinolone resistance in Campylobacter in animals and humans. This and other recent epidemiological evidence has highlighted concerns over the human health impact of resistant bacteria acquired from animals via food. As a result of this new evidence, CVM believes that we must address this issue now.

Q. What is CVM doing to address the issue of antimicrobial resistance caused by the use of these drugs in food-producing animals?

A. This is a very complex issue, and the Center has a multi-pronged strategy to address it as follows:

Revising our regulatory approach

Guidance for Industry #78 -- "Consideration of the Human Health Impact of the Microbial Effects of Antimicrobial New Animal Drugs Intended for Use in Food-Producing Animals"

This guidance states that FDA believes it is necessary to consider the potential human health impact of the 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. This guidance document was finalized December 1999.

Framework document -- "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" [ pdf ]

The Framework Document is a conceptual outline of how antimicrobials intended for use in food-producing animals might be regulated.

The Framework Document states FDA’s position that the regulatory system for antimicrobials used in food-producing animals should be modified to address microbial safety concerns. The assessment of microbial safety envisioned in the Framework Document involves a qualitative risk assessment, with the characterization of the risk to include the definition of the hazard and the exposure. The document goes on to articulate the need to determine acceptable levels of resistant bacteria in animal products (thresholds) to ensure that the effectiveness of human antimicrobials would not be compromised.

Risk Assessment

To better estimate the risks posed from the use of antimicrobials in food animals, the Food and Drug Administration’s Center for Veterinary Medicine (CVM) conducted a quantitative risk assessment that modeled the human health impact of fluoroquinolone resistant Campylobacter infections associated with the consumption of chicken.

The draft risk assessment model assumes that resistant bacteria pass through the food supply, infect humans, and are treated in the same manner as susceptible bacteria. The health risk associated with antimicrobial resistant bacteria represents an incremental increase in risk to consumers because resistance to an antimicrobial used in human medicine can compromise the effectiveness of therapy. Using this approach, the incremental human health impact of resistant foodborne disease can be determined without assessing all the factors influencing the cause of the foodborne illness itself.

CVM has contracted for a second risk assessment to examine the indirect transfer of resistance from animals to humans. For this risk assessment, CVM will be modeling the impact of virginiamycin resistance in Enterococcus faecium in animals on the ability to treat E. faecium in humans with the recently approved human antimicrobial, Synercid.

In the April 19, 2000, Federal Register, the Agency requested input from the public on the appropriate design of a risk assessment model, and on the data that should be considered or generated to support the risk assessment. Once the feasibility study is completed, CVM will know whether sufficient data exist to support the risk assessment or whether additional data need to be generated.

The results of CVM’s risk assessments on antimicrobial resistant bacteria will guide risk managers toward more informed decisions regarding the public health impacts of antimicrobial drugs approved for use in food-producing animals. Although each model will address the specific problem outlined, the model generated may be generalized as a guide for future quantitative risk assessments for other antimicrobial products for which transfer of resistance from animals to humans is an issue of public health concern.

Consulting with our stakeholders

We need public input on this complex issue and are using various ways to obtain this input as follows.

Veterinary Medicine Advisory Committee (VMAC) Meeting, January 25-26, 1999. The focus of the meeting was to discuss a proposed framework on how to evaluate the potential public health risk from microbial effects associated with the use of antimicrobials in food-producing animals.

General Public Meeting -- October 4, 1999. This meeting provided an opportunity for stakeholders to give input to CVM on the appropriate issues, experts and agenda items to be included in subsequent workshops related to antimicrobial resistance.

First Workshop -- December 9-10, 1999. This workshop focused on issues related to risk assessment and the establishment of resistance thresholds in food-producing animals.

Second Workshop -- February 22-24, 2000. This workshop was held to discuss the appropriate designs for pre-approval studies to evaluate the microbial effects of antimicrobial drugs intended for use in food-producing animals.

Third Workshop -- Fall 2000. CVM is in the process of planning a workshop on thresholds (levels of resistant bacteria in animal products.)

Improving the monitoring of resistance/surveillance

In 1996, the FDA, the Centers for Disease Control and Prevention (CDC), and the U.S. Department of Agriculture (USDA) created the National Antimicrobial Resistance Monitoring Program -- Enteric Bacteria (NARMS). NARMS was created to prospectively monitor changes in antimicrobial susceptibilities of zoonotic enteric pathogens from human and animal clinical specimens from healthy farm animals and from carcasses of food-producing animals at slaughter.

NARMS is designed to provide descriptive data on the extent and the temporal trends of antimicrobial susceptibility in Salmonella and other enteric organisms from the human and animal populations; to provide timely information to veterinarians and physicians; to prolong the life span of approved drugs by promoting the prudent use of antimicrobials; and to identify areas for more detailed investigation.

NARMS has been expanded each year since its inception. Now, NARMS is monitoring susceptibilities of Salmonella and E. coli isolates to 17 antimicrobial drugs and Campylobacter isolates to eight antimicrobial drugs (azithromycin, chloramphenicol, ciprofloxacin, clindamycin, erythromycin, gentamycin, nalidixic acid, and tetracycline). Animal isolate testing is conducted at USDA’s Agricultural Research Service Russell Research Center. Human isolate testing is conducted at CDC’s National Center for Infectious Diseases Foodborne Disease Laboratory.

Conducting research

FDA's CVM has initiated intramural, extramural, and collaborative research efforts to investigate factors associated with development, dissemination, and persistence of bacterial antibiotic resistance in both the animal production environment and food supply. Both the Agricultural Research Service and the Cooperative State and Research, Education, and Extension Service of the U.S. Department of Agriculture are considering or engaged in research on critically important environmental, mitigation, and product issues relating to the development of resistance to antimicrobials.

Scientists in CVM’s Office of Research are currently conducting or are participating in projects specifically targeted to gather data on such issues as: (1) the background level of bacterial antibiotic resistance that currently exists in retail animal-derived food products; (2) the development and persistence of bacterial antibiotic resistance from aquaculture and animal production environments; (3) characterization of mechanisms of resistance dissemination and transfer among pathogenic and commensal bacteria associated with food-producing animals and aquaculture environments; (4) determining the roles that animal feeds and feed commodities play in the dissemination of antibiotic resistance and pathogen carriage; and (5) co-selection of antibiotic resistance phenotypes associated with the use of sanitizers and other antimicrobials in animals. In addition, CVM is a contributing laboratory to CDC’s PulseNet molecular fingerprinting network involved in the molecular epidemiology of foodborne outbreaks. The CVM laboratory provides the only source of data on animal associated bacterial pathogens into the PulseNet system.

Supporting efforts for judicious use/education

In 1999, the American Veterinary Medical Association (AVMA) formed a Steering Committee on Judicious Therapeutic Antimicrobial Use by Veterinarians. It is to advise the AVMA Executive Board on the means to develop guidelines for judicious therapeutic antimicrobial use by veterinarians and continuing education programs to raise the awareness of the profession to the issue of antimicrobial resistance. The AVMA Board also charged this Committee to work integrally with FDA to develop a scientifically sound framework document. CVM strongly supports this AVMA effort.

FDA has contracted with two outside groups asking them to develop educational material concerning prudent use of antimicrobials. The AVMA will develop written materials, the script for a videotape, and speeches that explain the concept of prudent use to veterinarians. The other group is composed of swine producers. It will develop written material and the script for a videotape that will explain prudent use program to livestock producers, especially swine producers. The projects will be finished in 2000.

During 1999, CVM also started an exhibit program designed to bring the food safety message to livestock producers and veterinarians at their trade shows. The focus of the exhibits is on preventing the risk to public health from bacteria that have grown resistant to antimicrobials following the use of the drugs in food-producing animals.

Q. How does the Center respond to some scientists, consumers, and others who believe all feed use/production use of antimicrobials in food-producing animals should be banned immediately? Why is our approach different from that in some other countries, particularly in Europe?

A. Our approach is different for two main reasons:

  • Differences in the law
    In Europe, laws regulating therapeutic animal drugs differ from laws regulating animal drugs used for growth promotion. These different laws come under different agencies, and this separation makes it easier for the European governments to take different actions on these drugs based on their usage. Thus, the same drug could be approved for use for therapeutic purposes, but prohibited for use in feeds for growth promotion. U.S. law does not separate drugs based on their usage. Also, these drugs are regulated by the same government agency -- FDA's CVM.
  • Differences due to the way we view scientific evidence
    In the U.S., we believe it does not make scientific sense to separate therapeutic and production uses of drugs. For example, we have evidence that fluoroquinolone products used therapeutically can have an effect on resistance. Our Framework document explains how we believe the antimicrobial drugs should be evaluated -- on the basis of importance of the drug or related drug to human medicine and on the potential exposure of humans from resistant bacteria originating from animals. We believe it is appropriate to evaluate risk from all antimicrobial drugs equally. CVM starts with the premise that any product is potentially approvable, but we must evaluate the risks of that proposed use.

Q. How does CVM respond to food animal producers and others who are concerned that the Center is making it too difficult for them to obtain the antimicrobials they need by slowing or making harder for these products to be approved for use?

A. The Center must have adequate data on microbial effects to answer any safety concerns from the sponsors, or antimicrobial products cannot be approved. We acknowledge that there is a delay/slowing in the process as we are working out our regulatory approach. Antimicrobial resistance caused by drug use in food-producing animals is a complex scientific and policy issue requiring a science-based regulatory approach that takes time to finalize. Our approach is to balance the goals of protecting public health and making safe and effective drugs available for animal use.

Q. What about regulation of antimicrobial products that are already on the market? Will the Center reevaluate their safety based on the concepts of the Framework document?

A. Once we finalize our approach to the regulation of antimicrobials used in food-producing animals, we will look at all approved products, and prioritize our evaluation of them on the basis of any public health concern. As mentioned above, we have already initiated a second risk assessment that will model the impact of virginiamycin resistance in Enterococcus faecium in animals on the ability to treat E. faecium in humans with the human antimicrobial, Synercid. Virginiamycin has been an approved veterinary product for about 25 years.

Q. What is CVM's timetable for implementing the concepts in the Framework document?

A. The Center cannot commit to a specific timetable. This is the Center's highest priority area, and we are working as quickly as we can. But, we need to obtain public input before we finalize our regulatory approach on this complex issue, and the resolution of some aspects may require notice and comment rulemaking.