HHS Response to House Report 106-157- Agriculture, Rural Development, Food and Drug Administration, and Related Agencies, Appropriations Bill, 2000
Human-Use Antibiotics in Livestock Production
The Committee is concerned about the potential human health risks associated with the use of human medicines, such as antibiotics in livestock production, including the development of antibiotic resistance in foodborne and other bacteria. The House directs a report by January 2000 on human health risks associated with the uses of approved antibiotics in animals in the U.S. and on the status of FDA’s development of regulations on data submission requirements for electronic database entry on the use of antibiotics in animals that may compromise human therapies in the U.S.
We asked for and were given an extension until April 28, 2000, for the filing of this report to the House. This extension allowed us to incorporate the findings of the Campylobacter draft risk assessment and consider comments from the public meetings held in December 1999 and February 2000. These inputs were essential factors in our writing of a comprehensive report.
Food and Drug Administration
Center for Veterinary Medicine
April 28, 2000
Executive Summary
Risk Assessment
Data Submission Requirements for Electronic Database Entry
Background
1960 Netherthrope Committee
1969 Swann Committee
1970 FDA Task Force
1977 FDA Proposal
1980 NAS Study
1984 NRDC Petition
1984 King County Study
1987 FDA Report
1988 IOM Review
1995 ASM Report
1997 WHO Meeting
1998 WHO Meeting
1998 CSPI Report
1998 NRC Report
1998 EU Action
1999 GAO Reports
Current Work in FDA-CVM
Framework Document
Risk Assessment
A Public Health Action Plan to Address Antimicrobial Resistance
Partnerships and Implementation
Data Submission Requirements for Electronic Database Entry
The issue of antimicrobial use in food-producing animals has been controversial for more than three decades. However, recent scientific evidence has highlighted concerns over the human health impact of resistant bacteria acquired from animals via food. A recent draft risk assessment examining the human health impact of antimicrobials used in food-producing animals demonstrated quantitatively that resistance development in food-producing animals does impact on human health. We are a long way from having all the answers but we are gathering data, building the science, and managing the risk.
The FDA first called for several restrictions on antimicrobial use in feed in 1977. That proposal has generated several studies and reports. Definitive answers about the safety of antimicrobial use in animals remain scientifically challenging, but we are continuing to uncover more truths and, more importantly, have begun updating FDA’s process for determining whether antimicrobial products can be safely used in food-producing animals.
In 1988, the Institute of Medicine (IOM) again reviewed all the information available on the human health risk of antibiotic use in animal feed. 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 1999, the General Accounting Office (GAO) published two reports on antibiotic resistance. These are FOOD SAFETY The Agricultural Use of Antibiotics and Its Implications for Human Health (GAO/RCED-99-74 Food Safety) and ANTIMICROBIAL RESISTANCE Data to Assess Public Health Threat From Resistant Bacteria Are Limited (GAO/HEHS/NSIAD/RCED-99-132).
In the FOOD SAFETY report, GAO notes that the use of antibiotics in agriculture is only one of several factors that contributes to antibiotic resistance in humans for pathogens that are not foodborne and that the debate extends to antibiotics used on plants.
Since 1988, The Food and Drug Administration’s (FDA) Center for Veterinary Medicine (CVM) has approved new therapeutic antimicrobials for use in food-producing animals as prescription-only products. This prescription-only policy is based on the need to assure the proper use of antimicrobials through precise diagnosis and correct treatment of disease to minimize animal suffering and to avoid drug residues in food. Antimicrobial products for use in animals must meet FDA’s standards for safety, efficacy, and quality to be approved in the U.S.
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. In the U.S., ciprofloxacin-resistant Campylobacter were recently isolated from 20% of domestic retail chicken products sampled. (For reference, see Smith, K., Besser, J., Hedberg, and C., et al. Quinolone-Resistant Campylobacter jejuni Infections in Minnesota, 1992-1998. NEJM. 1999. 340(20); 1525-1532.) Molecular subtyping revealed an association between resistant Campylobacter jejuni strains from chicken products and C. jejuni strains from domestically acquired human cases of campylobacteriosis.
To better estimate the risks posed from the use of antimicrobials in food-producing animals, CVM conducted a quantitative risk assessment that modeled the human health impact of fluoroquinolone resistant Campylobacter infections associated with the consumption of chicken. Data for the risk assessment were obtained from National Antimicrobial Resistance Monitoring System (NARMS), from the Centers for Disease Control and Prevention’s (CDC) case control studies, FoodNet, and other sources. The draft assessment was released in December 1999, and it was the subject of December 9-10, 1999, public workshop. A revised draft report was posted to the CVM Homepage on February 9, 2000.
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 the 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.
The model estimates that in 1998 approximately 2 million people in the U.S. acquired a Campylobacter infection. Although Campylobacter infections are usually self-limiting, antibiotic therapy is used for patients: 1) who demonstrate symptoms of high fever, bloody diarrhea, or more than eight stools in 24 hours; 2) who are immunosuppressed; 3) who have bloodstream infections; or 4) who have symptoms that worsen or persist for more than one week. Antimicrobial therapy can reduce the median duration of illness.
The model estimates that in 1998, the mean number of people infected with fluoroquinolone resistant Campylobacter from consuming chicken and receiving fluoroquinolones as therapy was about 5,000. The model gives a 90% confidence interval for the mean of about 2,600 to 8,600 culture confirmed cases. The model is based on the assumption that all individuals with a fluoroquinolone resistant infection treated with a fluoroquinolone would experience a longer illness due to a decrease in effectiveness of the drug.
The benefits of this assessment include a review of how surveillance data are collected and the identification of what measurements are most relevant for linking the impact of resistant foodborne pathogens to human health. Significantly, this draft risk assessment links resistance development in food-producing animals to an impact on human health.
Risk management decisions that are discussed in the draft risk assessment include defining the target population(s) that need protection and the identifying the appropriate level of protection for the identified population. The latter issue is linked to the need to clearly articulate the risk standard that will be applied. The measure of risk changes from 1 in 61,093 to 1 in 32 depending on whether the denominator is the total U.S. population or persons with campylobacteriosis seeking care and prescribed an antibiotic. The interpretation of this finding is discussed in detail in Section 5 of the draft risk assessment report.
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, quinupristin/dalfopristin. As a first step in 2000, CVM has initiated a feasibility study for the risk assessment on virginiamycin resistant E. faecium.
As part of the feasibility study, 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, (see Federal Register April 19, 2000 (65 FR 20992)). Once the feasibility study is completed, CVM will know if sufficient data exist to support the risk assessment or if 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 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.
At this time, the available data are insufficient to permit a scientifically valid comparison of risk from on-farm and non-farm uses of antimicrobial drugs. Even if these data become available in the future, it is not clear whether a risk assessment model could be constructed to quantitatively evaluate this complex issue.
Data Submission Requirements for Electronic Database Entry
CVM is planning to propose regulations that would require the submission of detailed drug sales information by sponsors of antimicrobial drug products intended for use in food-producing animals. Information about sales and volume of animal pharmaceuticals sold in the U.S. is crucial to a complete understanding of the antimicrobial resistance issue. Drug use information will facilitate more direct correlation between loss of susceptibility or increasing resistance trends observed in NARMS with the actual use of both individual drugs and drug classes. This information will also allow more effective implementation and assessment of any intervention or control strategies to be initiated in response to finding trends of decreased susceptibility or increasing resistance over time.
The FDA first called for several restrictions on antimicrobial use in feed in 1977. That proposal has generated several studies and reports. Definitive answers about the safety of antimicrobial use in animals remain scientifically challenging, but we are continuing to uncover more truths and, more importantly, have begun updating FDA’s process for determining whether antimicrobial products can be safely used in food-producing animals.
The use of antibiotics to treat disease in food-producing animals started in the mid-1940s. The introduction of antibiotics in commercial feed for cattle, pigs, and chickens started in the early 1950s. Soon after livestock producers began using antimicrobials in food-producing animals, scientists began studying the possible effects of long-term use of antibiotics.
In recent years, concerns about the use of antimicrobial products in food-producing animals have focused on human food safety because foods of animal origin are identified as vehicles of foodborne disease in humans. As a result of treating animals with antibiotics, foodborne bacteria may also be resistant to the antibiotics used to treat human disease. These concerns have led to a number of studies.
The following is a brief review of the studies and reports to date.
It was formed in the UK to consider possible human health implications from the use of subtherapeutic antibiotics in livestock and concluded that there was no evidence of a human health hazard associated with the use.
Also formed in the UK, the committee reported no hazard to humans or animals from the use of antibiotics in poultry or swine. However, it linked an outbreak of salmonellosis in humans to the therapeutic use of antibiotics in sick calves. The committee recommended:
1. Antibiotics used in animals should be divided into "feed" or "therapeutic" classes.
2. The "feed" antibiotic class should not include drugs used therapeutically in humans or animals.
3. "Therapeutic" antibiotics should be available only by prescription.
The task force report, "The Use of Antibiotics in Animal Feeds," concluded:
1. The use of subtherapeutic amounts of antimicrobials favored the selection and development of resistant bacteria.
2. Animals receiving antimicrobial treatment may serve as a reservoir of antibiotic resistant pathogens that can produce human disease.
3. The prevalence of multi-resistant bacteria in animals has increased due to the use of antimicrobials.
4. Resistant bacteria are present in meat and meat products.
5. There has been an increase in the prevalence of antimicrobial resistant bacteria in man.
Based on the report’s recommendations, FDA-CVM began requiring microbiological safety studies for non-therapeutic uses. The focus of these studies was to preserve efficacy and safety of antibiotics for animal uses, and the safety evaluation included an evaluation of human health concerns.
In 1977, FDA proposed to withdraw the subtherapeutic uses of penicillin and the tetracyclines from animal feeds when used alone or in combination. These two drugs were chosen because of their importance in human medicine. The proposal was criticized at the time because of a lack of epidemiological evidence to show that the drug-resistant bacteria of animal origin are commonly transmitted to humans and cause serious illness. Critics argued that, while antibiotics used in animals select for resistant bacteria, the transfer of these bacteria from animals to humans is rare. Also, the critics said, no evidence showed that "any transferred organisms actually survive or cause disease in humans." The critics argued instead that the increased antibiotic resistance of bacteria found in humans was a result of the use of antibiotics in human medicine.
As a result of the 1977 proposal, several studies were started. In 1978, FDA began to work with the National Academy of Sciences (NAS) to study the issue. In 1979, the Congress required FDA to spend $1.5 million of its appropriations for a study of the antibiotic issue, to be conducted by NAS. The NAS study was finished in 1980. It concluded that existing data had neither proved nor disproved the potential hazards to human health from subtherapeutic antimicrobial use in animal feeds.
In 1984, the Natural Resources Defense Council, Inc., (NRDC) petitioned the Department of Health and Human Services (HHS) to immediately suspend the approval of the subtherapeutic use of penicillin and tetracyclines in food-producing animals by invoking the imminent hazard provision of the Act, 21 U.S.C. Sec. 360b(e)(1). That provision authorizes the Secretary of HHS to suspend approval of an application for the use of a new animal drug if an imminent hazard exists to the health of man or to the animals for which the drug is intended. NRDC based its case on several studies, two by Holmberg, et al., at the Centers for Disease Control and Prevention (CDC) in Atlanta, GA, and one published by Thomas O'Brien, et al., in the New England Journal of Medicine. However, in November 1985, HHS denied the petition on the basis that an "imminent hazard" had not been demonstrated. This decision was based on an analysis of the NRDC’s evidence as well as scientific evidence, information, and opinions coming out of the January 1985 public hearing and other relevant data collected and analyzed by FDA.
The House Appropriations Committee provided money in the early 1980’s, to FDA for a definitive epidemiological study of the antibiotics in animal feeds issue. The Committee stated that FDA should hold in abeyance any implementation of the proposed withdrawal of the subtherapeutic uses of penicillin and the tetracyclines, pending completion of the studies and reevaluation of FDA's concerns. FDA contracted with the Communicable Disease Control Section of the Seattle-King County Department of Public Health to review the possibility of the movement of bacteria from chickens to humans. The study focused on poultry workers, slaughterhouse workers, and consumers. The 1984 report, "Surveillance of the Flow of Salmonella and Campylobacter in a Community," stated that C. jejuni was more common than Salmonella on poultry. Also, it stated that C. jejuni "does appear to flow from chickens to man via consumption of poultry products." The report stated that the "isolates from human cases and those from retail poultry had similar antibiotic susceptibility patterns, including prevalence of 29.7% and 32.8%, respectively, for tetracycline resistance, which was found to be plasmid-mediated."
In its report, "Antibiotics in Animal Feeds: An Assessment of Scientific Data Concerning Their Safety," FDA concluded that the therapeutic use of antibiotics would not significantly contribute to the frequency of resistant organisms because of the pattern of use of these products. Therapeutic use is typically for a select number of animals and for a short duration, situations that are not likely to lead to antibiotic resistance, the report said.
In 1988, the Institute of Medicine (IOM) again reviewed all the information about the antibiotic resistance issue available. An expert Committee was convened to determine the human health risks associated with the practice of feeding subtherapeutic levels of penicillin and tetracyclines to animals for growth promotion, feed efficiency, and disease prevention. In the report, "Human Health Risks with the Subtherapeutic Use of Penicillin or Tetracyclines in Animal Feed," the Committee developed a risk-analysis model, using data only on Salmonella infections that resulted in human death. 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.
The American Society of Microbiology (ASM), which includes members who specialize in medical and animal microbiology, issued a report in 1995 that cited grave concerns about both human and animal antibiotic use and the rise in antimicrobial resistance. The report advocated a significant increase in resistance monitoring in the U.S., more education about the use and risks of antimicrobials, and more basic research designed to develop new antimicrobials and vaccines and disease prevention measures. The report criticized overuse of antibacterials in human medicine, but also pointed out the large use in food production, which was partly attributed to the consolidation of farms to facilities with large numbers of confined animals. The report made it clear that the antibiotic resistance problem is global. The ASM report was a precursor to involvement by the United Nation’s World Health Organization (WHO).
In October 1997, WHO convened a meeting of experts in Berlin, Germany, to review the question of whether the use of antimicrobials in animals leads to antimicrobial resistance in humans? The experts sought to define potential medical problems that could arise from antimicrobial use in livestock and to recommend actions that the WHO should take. The group of experts recommended against using antimicrobials for growth promotion if those antimicrobials are also used in human medicine or can induce cross-resistance to antimicrobials used for human medical therapy. The group also recommended that research be conducted on non-antimicrobial growth-promoters and urged that the risk to human health from use of antimicrobials in food-producing animals be accurately assessed. The group called for enhanced monitoring of resistance among isolates of enteric bacteria from food-producing animals and food of animal origin. In addition, the group recommended managing risk at the producer level through the judicious use of antimicrobials.
In June 1998, the WHO held another meeting, this time in Geneva, Switzerland, to specifically address the use of quinolones in food-producing animals. The participants agreed that the use of antimicrobials will cause resistance to develop and that there is a potential human health hazard from resistant Salmonella, E. coli, and Campylobacter organisms transferred to humans through the food supply. However, the experts also agreed that antimicrobial drugs, including quinolones in certain instances, are needed to treat sick animals, and urged more research on the possible human health effects from the use of these drugs in animals.
In May 1998, the Center for Science in the Public Interest (CSPI), in a coalition that included 15 other health and consumer groups, produced a comprehensive report on the antibiotic resistance problem. The focus of the report was on human antimicrobial use; however CSPI made several recommendations regarding the use of antimicrobials in veterinary medicine. The report recommended that FDA ban all subtherapeutic uses of antimicrobial agents that are used in human medicine or might select for cross resistance to antimicrobials used in human medicine. The organization also expressed concerns about new human antimicrobials that may be at risk due to use of the same class of drugs in agriculture, at either subtherapeutic or therapeutic levels. Development of resistance to certain classes of drugs that are considered vital in human medical therapy, such as the fluoroquinolones, would cause particular concern. For this reason, CSPI recommended that FDA withdraw approval of fluoroquinolones in poultry and allow additional approvals of fluoroquinolones only if the drug sponsor can show that food-producing animal uses would not reduce the drug’s effectiveness for human medical therapy.
In July 1998, the National Research Council (NRC) produced a report reviewing antimicrobial resistance issues in broad terms. The NRC recommended establishing national databases to support scientific process and policy development for approval and use of antibiotics in food-producing animals. The NRC also recommended that FDA use interdisciplinary panels of experts so that "…further development and use of antibiotics in both human and animal medicine have oversight by an interdisciplinary panel of experts composed of representatives of the veterinary and animal health industry, the human medicine community, consumer advocacy groups, the animal production industry, and the regulatory agencies."
The European Union (EU) recently took action to minimize the agricultural use of antimicrobial drugs. In December 1998, health ministers for the EU voted to ban four antibiotics that are widely used at subtherapeutic levels to promote animal growth. The ban on using bacitracin zinc, spiramycin, tylosin, and virginiamycin in animal feed became effective for the fifteen member states of the EU on July 1, 1999.
In April 1999, the General Accounting Office (GAO) published two reports on antibiotic resistance. These are "FOOD SAFETY The Agricultural Use of Antibiotics and Its Implications for Human Health", (GAO/RCED-99-74 Food Safety) and "ANTIMICROBIAL RESISTANCE Data to Assess Public Health Threat From Resistant Bacteria Are Limited", (GAO/HEHS/NSIAD/RCED-99-132).
In the FOOD SAFETY report, GAO notes that the use of antibiotics in agriculture is only one of several factors that contributes to antibiotic resistance in humans for pathogens that are not foodborne and that the debate extends to antibiotics used on plants. GAO acknowledges the complexity of the antimicrobial resistance issue and reports that FDA recently proposed a framework for evaluating the safety of antibiotics used in food-producing animals. GAO encouraged the Departments of Agriculture and Health and Human Services to work together to develop and implement a plan with specific goals, time frames, and resources needed for determining the safe use of antibiotics in agriculture.
In the ANTIBIOTIC RESISTANCE report, GAO states that the full extent of the antibiotic resistance problem remains unknown. While a number of federal and federally funded agencies are collecting information about different aspects of antibacterial resistance, there is little information about antibacterial use, particularly in animals, and antibacterial residues in places other than food.
Since 1988, CVM has approved new therapeutic antimicrobials as prescription-only products for use in food-producing animals. This prescription-only policy is based on the need to assure the proper use of antimicrobials through precise diagnosis and correct treatment of disease to minimize animal suffering and to avoid drug residues in food. Antimicrobial products for use in animals must meet FDA’s standards for safety, efficacy, and quality to be approved in the U.S.
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 1990s, several scientists raised concerns about the therapeutic use of fluoroquinolone antibiotics in food-producing animals. The scientists said the use could lead to enteric disease in humans associated with fluoroquinolone-resistant foodborne pathogens. Adding to that concern were reports of a temporal association between the approval of fluoroquinolones for therapeutic use in poultry in Europe and the emergence of a fluoroquinolone-resistant Campylobacter spp. from humans.
To further investigate the public health concerns regarding the potential impact of fluoroquinolone use in food-producing animals and to determine whether the 1987 FDA report (which concluded that therapeutic antimicrobials used for short duration were safe) was still valid, FDA held a Joint Advisory Committee meeting in 1994 that included the CVM Veterinary Medicine Advisory Committee (VMAC) and the Center for Drug Evaluation and Research’s Anti-infective Drugs Advisory Committee. The joint committee recommended that fluoroquinolones for poultry be approved, but that 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.
CVM created a Fluoroquinolone Working Group to address the points raised by the joint committee. The Working Group offered seven recommendations, all of which were accepted by CVM, and subsequently the use of fluoroquinolones was approved for poultry. As suggested in the recommendations, the sponsors agreed to provide baseline susceptibility information and to conduct continuing monitoring of target animal pathogens through the post-approval monitoring program.
More recently, scientists have detected a new multi-resistant pathogen, Salmonella enterica serotype Typhimurium Definitive Type 104 (DT104). The organism carries chromosomally integrated resistance to ampicillin, chloramphenicol, streptomycin, sulphonamides, and tetracycline. This chromosomally integrated resistance is unique and raises concerns about the establishment of a reservoir of multi-drug resistant organisms that are foodborne enteric pathogens that may become endemic in food-producing animal microbial populations. In addition to the chromosomally borne penta-resistance, the organism seems to be losing its susceptibility to quinolone and trimethoprim antibiotics and has been recently shown to carry additional florfenicol and spectinomycin resistance.
A report from the UK suggests that infections caused by DT104 may be associated with greater morbidity and mortality than other infections by Salmonella. An association has been noted between loss of susceptibility to fluoroquinolones among DT104 isolates and the approval and use of a fluoroquinolone for veterinary therapeutic use in the UK. This organism has also been identified in livestock and poultry in the U.S. Human disease caused by DT104 in the U.S. has been associated with unpasteurized dairy products and direct contact with livestock.
DT104 is currently epidemic in human and animal populations in Great Britain and has been isolated from most countries in Europe. The organism more recently has been found in the U.S. The most notable outbreak of zoonotic DT104 occurred on a dairy farm in Vermont.
The DT104 findings caused FDA to move ahead aggressively with plans to change its regulatory approach for approving antimicrobial products. The discovery of DT104 was a turning point for FDA and led to the development of a proposed regulatory course for the Agency.
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 20% of domestic retail chicken products sampled. Molecular subtyping revealed an association between resistant C. jejuni strains from chicken products and C. jejuni strains from domestically acquired human cases of campylobacteriosis.
FDA’s concept of an appropriate regulatory approach for antimicrobial approvals was made public in 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"). It is available on the CVM Home Page at http://www.fda.gov/cvm/antimi18.html or http://www.fda.gov/cvm/Documents/antim18.pdf.
To assist in evaluating the human health impact of antimicrobial use in animals, CVM contracted with a quantitative risk assessment expert to develop a quantitative risk assessment model. The risk assessment was intended to determine the feasibility of estimating risk to human health from resistant foodborne pathogens associated with the use of antimicrobials in food-producing animals. Specifically, a mathematical model was derived to relate the prevalence of fluoroquinolone resistant Campylobacter infections in humans associated with the consumption of chicken to the prevalence of fluoroquinolone resistant Campylobacter in chickens. The model could become a regulatory tool for assessing such risks in the future.
The use of fluoroquinolones in chickens and the development of resistant Campylobacter in chickens were of concern for several reasons. First, chickens are reservoirs for many foodborne pathogens including Campylobacter and Salmonella. For example, chicken carcass contamination measured in the processing plant indicates that 10.3% of broiler chickens from large plants and 16.3% broiler from small plants (data available at http://www.fsis.usda.gov/oa/background/salmtest5.htm) are contaminated with Salmonella and more than 80% are contaminated with Campylobacter. Consumption of food contaminated with these bacteria can lead to illness in susceptible individuals. Second, Campylobacter is the most common known cause of bacterial foodborne illness in the U.S. Sporadic cases of Campylobacter account for approximately 99% of all Campylobacter cases. Epidemiological investigations of sporadic infections have indicated that chicken is the most common source of human infection. Also, slaughter and processing of chickens may result in bacterial contamination on the carcass that can survive on retail product and result in human exposure during food preparation and consumption. Third, Campylobacter has been reported to develop resistance quickly when fluoroquinolones are used in both human and veterinary medicine. Fourth, fluoroquinolones are used in human medicine empirically to treat gastrointestinal infections, such as campylobacteriosis, and are important for use in many other therapeutic indications in human medicine.
Although Campylobacter infections are usually self-limiting, antibiotic therapy is used for patients: who demonstrate symptoms of high fever, bloody diarrhea, or more than eight stools in 24 hours; who are immunosuppressed; who have bloodstream infections; or who have symptoms that worsen or persist for more than one week. Antimicrobial therapy can reduce the median duration of illness. Empiric treatment of patients with enteric disease seeking treatment is the norm because when treatment is delayed (e.g., until C. jejuni infection is confirmed by a medical laboratory), therapy may not be effective. Fluoroquinolone drugs are frequently used in the empiric treatment of patients presenting to a physician with gastrointestinal symptoms because they exhibit good activity against most enteric pathogens.
While the safety assessments for food additives, veterinary drugs, and pesticides are standardized and accepted internationally, microbial risk assessments are relatively new, with no formal procedures. Microbial food safety problems are generally extremely complicated, and assessment requires a great deal of data. To date, about a half-dozen microbial risk assessment models have been published that attempt a full quantitative assessment of the public health risks of microbial contamination. These models use only specific products and limiting assumptions and have not been used by regulatory agencies to set limits on the amount of bacterial contamination permitted in food. Under FSI, the charge to government Agencies with respect to risk assessment was to develop better data and modeling techniques to help characterize the nature and size of risks to human health associated with foodborne hazards.
The draft risk assessment model developed assumes that resistance in food-producing animals is attributable to drug use, and 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 disease itself.
To limit the complexity of the assessment, only the human health risk associated with the use of fluoroquinolones in chickens was assessed.
Although the predominant interest to readers of the draft risk assessment may be to quantify the risk, it is important that the level of risk be viewed in context. This risk assessment has provided insight into the strengths and limitations of the data available to assess the impact of fluoroquinolone resistant Campylobacter associated with consumption of chicken on human health. While assembling the data to be used in the risk assessment, numerous scientific limitations were raised and were addressed as data gaps where issues were considered relevant. Some issues were considered less relevant to determining the measurable impact of risk because methods have not yet been developed or are not practical due to cost or time considerations. The benefits of this assessment are that it has resulted in a review of how surveillance data are collected and identified what measurements are most relevant for linking the impact of resistant foodborne pathogens to human health.
The strengths of this model include the fact that it is mathematically simple and can be updated, as new data become available. The model has limitations. It does not directly link the level of resistance in bacteria from food-producing animals to drug use in particular animals. However, the Agency believes it is justified in assuming that the presence of resistant Campylobacter on the animal carcass was due to antimicrobial drug use in the animals rather than the transfer of resistant Campylobacter from people who had been treated with a fluoroquinolone.
The draft risk assessment model was discussed at a public meeting held December 9-10, 1999, in Rockville, MD. At this meeting, scientific experts gave the Agency their comments on the strengths, limitations, and data gaps associated with the model. The Agency will consider these comments, as well as comments submitted to the public docket, in finalizing the draft risk assessment.
The Agency has also contracted for a second risk assessment to look at the indirect transfer of antimicrobial resistance from animals to humans. The use of antimicrobials in food-producing animals leads to the development of resistance in foodborne pathogens in other bacteria associated with the animal. These non-pathogens, often referred to as commensals, can be passed to humans via the food supply and colonize in the human gastrointestinal tract or transfer their resistance genes to bacteria that colonize in the human gastrointestinal tract. Under the right conditions, some bacteria in the human gastrointestinal tract can cause infection either in the gastrointestinal tract itself or in other organs. When antimicrobial use in food-producing animals leads to the development of resistance to antibiotics used to treat these infections, human therapy could be compromised.
Recently there have been several papers reporting that the use of antimicrobials in food-producing animals increases the level of resistance to antimicrobials used to treat enterococcal infections in humans. While enterococci transferred from animals to humans do not appear to colonize the human intestine directly, these bacteria can transfer resistance genes to enterococci normally present in the human intestine. In immunosuppressed patients, enterococci can cause life-threatening illness. While there are no data to support a significant acquisition or transmission of antimicrobial resistant enterococci outside the health-care setting in the U.S., reports from Europe suggest that vancomycin-resistant enterococci (VRE) are present in animals. VRE could be transferred from animals to humans via the food or by direct contact. The use of avoparcin as a growth promoter in food-producing animals has been reported to be an important factor in the development of VRE in the human community in Europe. Avoparcin is not approved for use in the U.S.
VRE infections in the U.S. are associated with human use of vancomycin, and recently FDA has approved another antimicrobial -- quinupristin/dalfopristin -- to use in VRE cases. However, there are concerns about the emergence of resistance to the drug in the U.S. because quinupristin/dalfopristin is structurally related to virginiamycin, an antimicrobial that has been used in the U.S. agriculture for more than 20 years.
Unlike the fluoroquinolones, where the major hazard associated with their use in animals is the selection of resistant foodborne pathogens, the major hazard associated with the use of virginiamycin in food-producing animals is the selection of resistant enterococci. It is not likely that these resistant bacteria will colonize in humans directly. However, resistant enterococci can contaminate food and enter the human gastrointestinal tract. In the gastrointestinal tract, enterococci may pass their resistance genes to enterococci present in the human intestinal microflora. The presence of virginiamycin-resistant enterococci is of concern now since quinupristin/dalfopristin has been approved for use in human medicine. Quinupristin/dalfopristin can be used in humans to treat enteroccal infections for which there are no other antimicrobial therapies available.
To assess the risk associated with the continued use of virginiamycin in animal agriculture, a quantitative risk assessment framework is needed. This framework will quantify the probability, uncertainty, and variability associated with several factors including the likelihood that:
The results of this risk assessment will guide risk managers toward better decisions regarding the public health impacts of antimicrobial drugs approved for use in food-producing animals. The results will also indicate areas where data are missing and where research is needed. Although this model will address the specific problem outlined, the model generated can be generalized as a guide for future quantitative risk assessments for other antimicrobial products for which indirect transfer of resistance is an issue.
The Agency initiated a feasibility study for the risk assessment on virginiamycin and enterococci in first quarter of 2000. As part of the feasibility study, the Agency requested input from stakeholders on the appropriate design of a risk assessment model and on the data that should be considered or generated to support the risk assessment. The Agency intends to conclude its feasibility study by the end of the second quarter of 2001. At that point, the Agency should be able to report on the timeframe to complete a risk assessment on this issue, or if sufficient data are not currently available, should be able to identify the additional data that needs to be generated to support the risk assessment.
The Agency will also be considering whether additional risk assessments should be conducted on other antimicrobial and foodborne pathogen combinations. Additional public discussion is planned on microbial safety issues relating to the regulation of antimicrobials used in food-producing animals. The Agency held a public workshop on February 22-24, 2000, to discuss the appropriate design for pre-approval studies to evaluate the microbial effects of antimicrobial drugs intended for use in food-producing animals. Such studies should address the rate and extent of resistance development and changes in the number of enteric bacteria in the animal's intestinal tract that cause human illness (pathogen load). At this workshop, the Agency sought scientific input from experts on these issues. The Agency is also considering the need to hold additional scientific workshops on risk management issues relating to the regulation of antimicrobials used in food-producing animals.
A PUBLIC HEALTH ACTION PLAN TO ADDRESS ANTIMICROBIAL RESISTANCE
The Federal Government can play a special role in supporting and coordinating the national effort to address the threat of antimicrobial resistance, bringing together stakeholders from medicine, public health, health care delivery, scientific research, environmental protection, and the pharmaceutical and biotechnology industries. Federal agencies can work with these partners to find ways to overcome technological, economic, and behavioral obstacles to achieving the public health goal of preventing antimicrobial resistance emergence and spread.
Partnerships and Implementation
An interagency Task Force on Antimicrobial Resistance is developing a Public Health Action Plan to Combat Antimicrobial Resisance. The Task Force is co-chaired by the CDC, FDA, and the National Institutes of Health. Members include representatives from the Agency for Health Care Policy and Research, the Department of Agriculture, the Department of Defense, the Department of Veterans Affairs, the Environmental Protection Agency, the Health Care Financing Administration, the Health Resources and Services Administration, and from FDA Centers.
The Public Health Action Plan is to reflect a broad-based consensus of Federal Agencies on actions needed to address antimicrobial resistance, with input from consultants from state and local health agencies, universities, professional societies, pharmaceutical companies, health care delivery organizations, agricultural producers, consumer groups, and the public. This plan is to be finalized in the summer of 2000.
Data Submission Requirements for Electronic Database Entry
CVM is planning to propose regulations that would require the submission of detailed drug sales information by sponsors of antimicrobial drug products intended for use in food-producing animals. Sales and volume data for animal pharmaceuticals sold in the U.S. is crucial to a complete understanding of the antimicrobial resistance issue. Drug use information will facilitate more direct correlation between loss of susceptibility or increasing resistance trends observed in the NARMS with the actual use of both individual drugs and drug classes. This information will also allow more effective implementation and assessment of any intervention or control strategies to be initiated in response to findings of decreased susceptibility or increasing resistance trends over time.
If the Agency proceeds with its plan to revise the regulations, it will obtain public input through notice and comment rulemaking. The Agency will also issue any necessary guidance on this matter with appropriate public input.
The resources for the creation of an electronic database entry program will be included in a request for a future appropriation. At this time, FDA proposes that the detailed sales information described above must be submitted on paper, with the capability for electronic submission to follow. The submitted hard copy information will be maintained in an electronic database.
April 16, 2000
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