The increasing evidence linking use of antimicrobials in food animals with resistance developing in zoonotic enteric pathogens has led to the need for a new regulatory approach in the US to the approval of antimicrobials for food animals. FDA's proposed new regulatory approach is explained in what has been termed the 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"). This document sets out a risk-based framework for evaluating the human safety of the microbial effects of antimicrobial drugs for the use in food animals. The Center for Veterinary Medicine (CVM) is conducting a risk assessment that evaluates the risk to human health from resistant food borne pathogens associated with the use of antimicrobials in food producing animals. Specifically, the risk assessment models the risk of increased duration of illness due to resistant Campylobacter infections attributable to the use of fluoroquinolones in chickens. This risk assessment is the first of several that will be done by CVM. CVM will be developing a second risk assessment model to assess the transfer of resistance determinants to human pathogens from enterococci originating in animals. CVM plans to hold a series of public meetings to discuss the important issues related to antimicrobial resistance (AR) in food-producing animals. Three sequential public meetings are planned for October 4, 1999, December 9-10, 1999 and February 22-23, 2000. The purpose of these meetings and the issues to be considered will be discussed.

The issue of antimicrobial use in food animals has been controversial for more than three decades. The US Food and Drug Administration (FDA) first called for restrictions on antimicrobial use in feed in 1977. That proposal generated several studies and reports over the subsequent years. Definitive answers about the safety of antimicrobial use in animals remain scientifically challenging, but we are continuing to uncover more truths and have begun updating FDA's regulatory process for evaluating antimicrobial drugs intended for use in food-producing animals.In the United States, FDA is the primary Federal agency responsible for ensuring the safety of the food supply. While the Center for Food Safety and Applied Nutrition regulated the vast majority of human food, FDA's Center for Veterinary Medicine (CVM) ensures that animal drug products are safe and effective for animals and that edible products derived from treated animals are safe for consumers. The U.S. Department of Agriculture (USDA) is responsible for testing the meat supply for microbiological contamination and animal drug residues.Although the use of antimicrobial products in food-producing animals raises various efficacy and safety concerns, in recent years these concerns have focused on human food safety because foods of animal origin are often identified as the vehicles of foodborne disease in humans. As a result of treating a food-producing animal with antimicrobials, food borne pathogens may become resistant to antimicrobials used to treat humans.When antimicrobial products are intended for use in food-producing animals, safety considerations include the evaluation of data to ensure that residues in food derived from treated animals are safe for human consumption. In the past, microbiological safety studies were required only for antimicrobials to be used in feed for more than 14 days. These studies examined resistance patterns and pathogen load.In the 1990's, several scientists raised concerns about the therapeutic use of fluoroquinolone antimicrobials in food-producing animals. The scientists said the use could lead to enteric disease in humans associated with fluoroquinolone-resistant zoonotic pathogens. At least part of this concern was prompted by the fact that the search for new antimicrobial drugs and other novel agents to combat bacterial pathogens had decreased in recent years, leaving fluoroquinolones as the last class of therapeutic agents available to treat some resistant organisms.To further investigate the public health concerns regarding the potential effect of fluoroquinolone use in food-producing animals, FDA held a Joint Advisory Committee meeting in 1994. The meeting included the CVM Advisory Committee and the Center for Drug Evaluation and Research's Anti-infective Drugs Advisory Committee. The joint committee recommended that fluoroquinolones be approved, but that the use of the drugs should be limited to prescription only, that no extra-label use should be allowed, and that resistance should be monitored after the product was approved.More recently, scientists have detected a new multi-resistant pathogen, Salmonella typhimurium DT104. The organism carries chromosomally integrated resistance (penta-resistance) to ampicillin, chloramphenicol, streptomycin, sulfonamides, and tetracycline. This chromosomally integrated resistance is unique and raises concerns about the establishment of a reservoir of multi-drug resistant organisms that are zoonotic enteric pathogens that may become endemic in food-animal microbial populations. In addition to the chromosomally borne penta-resistance, the organism seems to be losing its susceptibility to quinolone and trimethoprim antimicrobials and has been recently shown to carry additional florfenicol and spectinomycin resistance.A report from the United Kingdom suggests that infections caused by DT104 may be associated with greater morbidity and mortality than other infections caused by Salmonella. An association has been noted between loss of susceptibility to fluoroquinolones among DT104 isolates and the approval and use of fluoroquinolone for veterinary therapeutic use in the UK. Human disease caused by DT104 in the U.S. has been associated with unpasteurized dairy products and direct contact with livestock. DT104 has been found in livestock and poultry in the U.S. and appears to be increasingly prevalent in both domestic and wild animals. The most notable outbreak of DT104 was on a dairy farm in Vermont.Reports from the scientific and public health communities, both domestically and internationally, have identified concerns about the relationship between the approval of fluoroquinolones for therapeutic use in food-producing animals and the development of fluoroquinolone resistance in Campylobacter. The approval of these drugs in food-producing animals in the Netherlands, the UK, and Spain temporally preceded increases in resistance in Campylobacter isolates from humans. Despite several restrictions placed on the use of the two approved poultry fluoroquinolone products in the U.S., ciprofloxacin-resistant Campylobacter were recently isolated from domestic retail chicken products. Molecular subtyping revealed an association between resistant C.jejuni strains from chicken products and C. jejuni strains from domestically acquired human cases of campylobacteriosis.The increasing evidence linking use of antimicrobials in food-producing animals with resistance developing in zoonotic enteric pathogens has led to the need for a new regulatory approach in the US to the approval of antimicrobials for food producing animals.

FDA's proposed new regulatory approach for antimicrobial approvals is explained in what has been termed the 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"). The document is available on the CVM Home Page, www.fda.gov/cvm. The document was released to the public December 9, 1998, and the comment period closed April 6, 1999.The Framework proposes three tiers for ranking antimicrobials according to two factors: the importance of the drug in human medicine and the potential for human exposure to resistant bacteria acquired from food-producing animals. The ranking of the antimicrobial for the two factors would then be combined to determine what actions would be considered necessary to assure the safe use of the drug in animals.Under the Framework, antimicrobial drugs would be placed in Class I, the level with the greatest approval requirements, if:

They are needed to treat a serious or life-threatening disease for which there is no satisfactory alternative therapy, and

They are important for the treatment of foodborne diseases.

Drugs that can select for cross-resistance to Class I human agents would also be listed in Class I, unless the sponsor could demonstrate that animal use did not result in the induction of resistant pathogens or the transfer of resistant elements to human pathogens.Drugs would be placed in Class II if:

FDA would put products into Class III if they do not meet any of the requirements of the other two classes.FDA's implementation of the framework will require the development of guidance documents and perhaps new or amended rules. All such guidance or rules would be developed with public input, and FDA will consider any needed change as a high priority.

CVM now believes that the safety assessment of antimicrobials must include evaluation of resistance concerns with the conduct of pre-approval studies and post-approval monitoring programs, which are aided by the National Antimicrobial Resistance Monitoring System (NARMS).NARMS was proposed by CVM to monitor the emergence and spread of resistance in enteric bacteria and to help ensure the continued safety of veterinary antimicrobials. In 1996, the FDA, CDC, and the USDA created NARMS 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. Non-typhoid Salmonella was selected as the sentinel organism. The NARMS has been expanded each year since its inception. At the present time, NARMS is monitoring susceptibilities of Salmonella and E.coli isolates to 17 antimicrobials 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 Agriculture Research Service Russell Research Center. Human isolate testing is conducted at the Centers for Disease Control and Prevention's National Center for Infectious Diseases Foodborne Disease Laboratory. Seventeen State and local health departments (CA, CO, CT, FL, GA, KS, Los Angeles County, MA, MD, MN, NJ, New York City, NY, OR, TN, WA, and WV) submit human clinical isolates of non-typhoid Salmonella and E.Coli. Eight health departments are submitting human clinical Campylobacter isolates, and in addition MN, GA, MD, and OR are submitting Campylobacter isolates from poultry retail samples. A pilot study involving MN, GA, MD, and OR to monitor the resistance of human and poultry Enterococcus isolates to 27 antimicrobials was begun in 1998.The goals and objectives of the monitoring program are to provide descriptive data on the extent and temporal trends of antimicrobial susceptibility in Salmonella and other enteric organisms from the human and animal populations; provide timely information to veterinarians and physicians; prolong the life span of approved drugs by promoting the prudent use of antimicrobial drugs; identify areas for more detailed investigation; and guide research on antibiotic resistance. Annual reports summarizing the data are available through the CVM Website.The NARMS was substantially expanded during 1998. Veterinary diagnostic lab sentinel sites were enrolled as well as additional sites to gather human isolates, and the number of Salmonella isolates collected from slaughter plants was increased.Also in 1998, follow-on epidemiology research and investigations augmented the program. Collaborative molecular genetic studies have begun at FDA's National Center for Toxicological Research in Arkansas to identify regions of fluoroquinolone resistance in zoonotic enteric organisms. This information will be applied to enteric and environmental bacteria to provide improved monitoring for resistance emergence and transfer. Case-control follow-up investigations of human cases of salmonellosis and campylobacteriosis with losses in susceptibility to quinolones were begun in 1998. Also in 1998, two projects on prudent drug use activities were initiated in California and Michigan.

CVM believes it is critical that prudent use of antimicrobials be emphasized in order to minimize the development of antimicrobial resistance and to ensure the continued efficacy and availability of antimicrobial products for use in food-producing animals. To promote this concept, CVM and CDC facilitated a meeting on Prudent Use held in May 1998 in Rockville, Maryland.The objective of the meeting was to develop a plan to promote the Prudent Use of therapeutic antimicrobials in veterinary medicine. At the meeting, the American Veterinary Medical Association announced that it would be forming a Steering Committee on Judicious Antimicrobial Use. This Committee is now coordinating the development of judicious use guidelines in the US. FDA participates as a liaison member on the AVMA Steering Committee on Judicious Use. The AVMA recently finalized general guidelines on judicious use principles. Work is ongoing to develop species specific guidelines which will include recommendations to reduce disease transmission on the farm.

The Center for Veterinary Medicine (CVM) is conducting a risk assessment that evaluates the risk to human health from resistant food borne pathogens associated with the use of antimicrobials in food producing animals. Specifically, the risk assessment models the risk of increased duration of illness due to resistant Campylobacter infections attributable to the use of fluoroquinolones in chickens. A mathematical model was derived to relate the prevalence of resistant Campylobacter infections in humans due to chickens to the prevalence of resistant Campylobacter in chickens. In deriving the model, the risk modeler contracted by CVM for the project incorporated the uncertainties about the information in the data that had been gathered.The risk assessment is the first of several that will be done by CVM. The model used in this assessment is a prototype for assessing risk due to the transfer of resistant food borne pathogens from animals to humans. CVM will be developing a second risk assessment model to assess the transfer of resistance determinants to human pathogens from enterococci originating in animals.To develop the risk assessment on fluoroquinolone resistant Campylobacter, data on the prevalence of Campylobacter in both chickens and humans were needed. CVM used prevalence data in chickens from the National Antimicrobial Resistance Monitoring System (NARMS) database. The FoodNet, an active surveillance system for food-borne pathogens maintained by the Centers for Disease Control and Prevention (CDC), and associated databases and published journal articles were sources for the human prevalence and other epidemiological data.

The Center for Veterinary Medicine is funding several research projects under the Food Safety Initiative to investigate the linkage between antimicrobial drug use in animals and emerging resistance in humans. FDA is developing the ability to evaluate sources of zoonotic pathogens, to describe the extent of the problem on farms and in production facilities, and to assess the impact of management and drug therapies on reduction of animal-carried pathogens.

CVM plans to hold a series of public meetings to discuss important issues related to antimicrobial resistance (AR) in food producing animals. Three sequential public meetings are planned for October, 4, 1999, December 9-10, 1999, and February 22-23, 2000.

General Public Meeting, October 4, 1999

This meeting is intended to provide an opportunity for stakeholders to give input to CVM on the appropriate issues, experts and agenda items to be included in two subsequent workshops related to antimicrobial resistance. The Center will consider comments received at this general public meeting in the further planning of the following two scientific workshops.

Risk Assessment and the Establishment of Resistance Thresholds Workshop, Dec. 9-10, 1999

This workshop will be held to discuss the CVM's risk assessment model to evaluate the risk to human health from resistant foodborne pathogens associated with the use of antimicrobials in food-producing animals. The meeting will also discuss the Center's current thinking on the use of this model to establish resistance and monitoring thresholds in food-producing animals.

Pre-Approval Studies on Antimicrobial Resistance, February 22-23, 2000

This workshop will be held to discuss the Center's current thinking on the appropriate design of pre-approval studies in food-producing animals to model the rate and extent of resistance development.

CVM's duty is to protect the public health. CVM has the additional duty to approve the use of antimicrobials in food animals, when the approval is appropriate. Establishing a science-based regulatory framework to ensure the safety of antimicrobial drugs used in food animals is a high priority for the Agency.To address these responsibilities, CVM developed the Framework Document. It gives CVM a way to protect public health and consider future approvals of antimicrobials for food animals. Many of the details about the framework are yet to be worked out. CVM will use open forums and public comments to gather the best science to settle those issues.