FOOD AND DRUG ADMINISTRATION
CENTER FOR DRUG EVALUATION AND RESEARCH
ANTI-INFECTIVE DRUGS ADVISORY COMMITTEE
9:05 a.m.
Thursday, January 9, 2003
Grand Ballroom
Marriott Washingtonian Center
9751 Washingtonian Boulevard
Gaithersburg, Maryland
ATTENDEES
COMMITTEE MEMBERS:
JAMES E. LEGGETT, JR., M.D., Chairman
Associate Professor of Medicine
Oregon Health Sciences University
5050 NE Hoyt, Suite 540
Portland, Oregon 97213
TARA TURNER, PHARM.D., Executive Secretary
Advisors and Consultants Staff, HFD-21
Center for Drug Evaluation and Research
Food and Drug Administration
5600 Fishers Lane
Rockville, Maryland 20857
DAVID M. BELL, M.D.
Assistant to the Director for Antimicrobial Resistance
National Center for Infectious Diseases
Centers for Disease Control and Prevention
1600 Clifton Road, N.E. (C-12)
Atlanta, Georgia 30333
STEVEN EBERT, PHARM.D.
Consumer Representative
Department of Pharmacy
Meriter Hospital
202 South Park Street
Madison, Wisconsin 53715
CELIA J. MAXWELL, M.D.
Assistant Vice President for Health Affairs
Office of the Vice President for Health Affairs
Howard University
2041 Georgia Avenue, N.W., Suite 6000
Washington, D.C. 20060
JAN E. PATTERSON, M.D.
Professor of Medicine and Pathology
University of Texas Health Science Center
at San Antonio
Division of Infectious Diseases
Mail Code 7881
7703 Floyd Curl Drive
San Antonio, Texas 78229
ATTENDEES (Continued)
COMMITTEE MEMBERS: (Continued)
ELLEN R. WALD, M.D.
Chief, Allergy, Immunology and Infectious Diseases
Children's Hospital of Pittsburgh
3705 Fifth Avenue at DeSoto Street
Pittsburgh, Pennsylvania 15213
ACTING INDUSTRY REPRESENTATIVE (non-voting):
KENNETH R. BROWN, M.D.
Independent Consultant on Vaccines,
Antibiotics, and Tropical Medicine
8111 Winston Road
Philadelphia, Pennsylvania 19118
CONSULTANTS (voting):
JOHN S. BRADLEY, M.D.
Director, Division of Infectious Diseases
Children's Hospital and Health Center
3020 Children's Way, MC 5041
San Diego, California 92123
JANET D. ELASHOFF, PH.D.
Director, Division of Biostatistics
Cedars-Sinai Medical Center
8700 Beverly Boulevard
Los Angeles, California 90048
JUDITH R. O'FALLON, PH.D.
Cancer Center Statistics, Kahler 1A
Mayo Clinic
200 First Street, S.W.
Rochester, Minnesota 55905
DONALD M. PORETZ, M.D.
Infectious Diseases Physicians, Inc.
3289 Woodburn Road, #200
Annandale, Virginia 22003
ATTENDEES (Continued)
CONSULTANTS (voting): (Continued)
L. BARTH RELLER, M.D.
Professor of Medicine (Infectious Diseases)
Director of Clinical Microbiology
Duke University Medical Center
Box 3938
Durham, North Carolina 27710
MARK E. RUPP, M.D.
Associate Professor, Infectious Diseases
Medical Director, Department of Healthcare Epidemiology
984031 Nebraska Medical Center
Omaha, Nebraska 68198
GUEST SPEAKERS (non-voting):
RICHARD CARNEVALE, D.V.M.
Vice President
Scientific, Regulatory, and International Affairs
Animal Health Institute
1325 G Street, N.W., Suite 700
Washington, D.C. 20005
MICHAEL D. APLEY, D.V.M., PH.D.
Associate Professor
Department of Veterinary Diagnostic and
Production Animal Medicine
Iowa State University
1452 S. 16th Street
Ames, Iowa 50011
FOOD AND DRUG ADMINISTRATION STAFF:
RENATA ALBRECHT, M.D.
MARY BARTHOLOMEW, PH.D.
MARK GOLDBERGER, M.D.
JEAN MULINDE, M.D.
JOHN POWERS, M.D.
LINDA TOLLEFSON, D.V.M., M.P.H.
ATTENDEES (Continued)
ALSO PRESENT:
TOM BURKGREN, D.V.M., M.B.A.
American Association of Swine Veterinarians
TONY COX, JR., PH.D.
Cox Associates
STEVE PROJAN, PH.D.
PAUL SUNDBERG, D.V.M., PH.D.
Assistant Vice President, Science and Technology
National Pork Board
C O N T E N T S
AGENDA ITEM PAGE
CONFLICT OF INTEREST STATEMENT
By Dr. Tara Turner 9
OPENING COMMENTS
By Dr. Mark Goldberger 12
OVERVIEW
By Dr. Linda Tollefson 14
EXPLANATION OF ANTIMICROBIAL RISK ASSESSMENT
By Dr. Mary Bartholomew 25
RANKING OF ANTIMICROBIAL DRUGS RELATIVE TO
THEIR USE IN ANIMALS
By Richard Carnevale 44
RELATING FOOD ANIMAL AND HUMAN ANTIMICROBIAL USE
By Dr. Mike Apley 71
PROCESS OF RANKING DRUGS BY IMPORTANCE IN
HUMAN MEDICINE
By Dr. John Powers 105
OPEN PUBLIC HEARING PRESENTATIONS:
By Dr. Paul Sundberg 124
By Dr. Tom Burkgren 133
By Dr. Tony Cox 138
By Dr. Steve Projan 146
SUMMARY AND CHARGE TO THE COMMITTEE
By Dr. Mark Goldberger 150
COMMITTEE DISCUSSION 153
CONCLUDING COMMENTS
By Dr. Mark Goldberger 202
P R O C E E D I N G S
(9:05 a.m.)
DR. LEGGETT: I'd like to welcome you to the Anti-Infective Drugs Advisory Committee meeting regarding the ranking of antimicrobial drugs according to their human importance in human medicine. I guess that's human importance or importance.
Let's start off by going around the table and having everyone here tell us who they are and where they're from. Dr. Brown, would you like to start off?
DR. BROWN: Ken Brown. I'm retired from industry and I teach at the University of Pennsylvania.
DR. PORETZ: Don Poretz. I'm a practitioner in infectious diseases in Fairfax, Virginia.
DR. WALD: Ellen Wald, infectious diseases, Children's Hospital of Pittsburgh.
DR. BRADLEY: John Bradley, pediatric infectious diseases, Children's Hospital, San Diego.
DR. RUPP: Good morning. Mark Rupp, infectious diseases, University of Nebraska.
DR. ELASHOFF: Janet Elashoff, biostatistics, Cedars-Sinai and UCLA.
DR. EBERT: Steve Ebert, an infectious disease pharmacist at Meriter Hospital, clinical professor of pharmacy, University of Wisconsin.
DR. PATTERSON: Jan Patterson, medicine infectious diseases, University of Texas-San Antonio.
DR. LEGGETT: Jim Leggett, infectious diseases, Providence Portland Medical Center and Oregon Health Sciences University.
DR. TURNER: Tara Turner, Executive Secretary for the committee.
DR. O'FALLON: Judith O'Fallon, Cancer Center Statistics, Mayo Clinic.
DR. RELLER: Barth Reller, adult infectious diseases, meta-microbiology at Duke University Medical Center.
DR. MAXWELL: Celia Maxwell, adult infectious diseases, Howard University.
DR. BELL: David Bell, National Center for Infectious Diseases, Centers for Disease Control and Prevention in Atlanta.
DR. BARTHOLOMEW: Mary Bartholomew, biometrics team, Center for Veterinary Medicine, FDA.
DR. TOLLEFSON: Linda Tollefson, Center for Veterinary Medicine, FDA.
DR. MULINDE: Jean Mulinde, medical team leader, Division of Anti-Infective Drug Products, FDA.
DR. ALBRECHT: Renata Albrecht, Director, Division of Special Pathogen and Immunologic Drug Products, FDA.
DR. POWERS: John Powers, lead medical officer, antimicrobial drug development and resistance initiatives, in the Office of Drug Evaluation IV at FDA.
DR. GOLDBERGER: And Mark Goldberger, the Office of Drug Evaluation IV, FDA.
DR. LEGGETT: Thank you.
Tara.
DR. TURNER: The following announcement addresses the issue of conflict of interest with respect to this meeting and is made a part of the record to preclude even the appearance of such at this meeting.
The topics of today's meeting are issues of broad applicability. Unlike issues before a committee in which a particular product is discussed, issues of broader applicability involve many industrial sponsors and academic institutions.
All special government employees and federal guests have been screened for their financial interests as they may apply to the general topics at hand. The following participants have reported no current financial interests with regards to pharmaceutical companies: Drs. James Leggett, Jr., David Bell, Barth Reller, and Judith O'Fallon. Dr. Mark Rupp reported a financial interest in a pharmaceutical company covered under CFR 2640.202(b), de minimus exemption.
The following participants have reported interests in pharmaceutical companies and the Food and Drug Administration has granted general matters waivers to the following SGEs, which permits them to participate in today's discussions: Drs. Ellen Wald, Alan Cross, Steven Ebert, Celia Maxwell, Jan Patterson, John Bradley, Donald Poretz, and Janet Elashoff.
A copy of the waiver statements may be obtained by submitting a written request to the agency's Freedom of Information Office, room 12A-30 of the Parklawn Building.
Because general topics impact so many institutions, it is not prudent to recite all potential conflicts of interest as they apply to each member and consultant. FDA acknowledges that there may be potential conflicts of interest, but because of the general nature of the discussion before the committee, these potential conflicts are mitigated.
With respect to FDA's invited guest speakers, there are reported interests which we believe should be made public to allow the participants to objectively evaluate their comments. Dr. Michael Apley is a scientific adviser to Schering, Intervet, Farnam, and Novartis. He lectures for Novartis, Intervet, Pharmacia, Pfizer, and Merial. Dr. Apley is a member of the Beef Cattle Advisory Boards for Elanco, Ft. Dodge, and Intervet, and has received funds from Pharmacia, Pfizer, and Elanco for drug-related research.
In addition, we would like to disclose that Dr. Kenneth Brown is participating in this meeting as an acting industry representative acting on behalf of regulated industry. Dr. Brown owns stock in Merck and has stock options in the firm. As of July 2002, his 401(k) owns shares in Genentech, Johnson & Johnson, and Pfizer. During the summer Dr. Brown has been visiting scientist at Gordon College. The college has a contract with Merck that is currently inactive. He is a consultant to Wyeth and works at Merck two days a month. Dr. Brown has been an expert witness for Merck.
In the event the discussions involve any other products or firms not already on the agenda, for which FDA participants have a financial interest, the participants' involvement and their exclusion will be noted for the record.
With respect to all other participants, we ask in the interest of fairness that they address any current or previous financial involvement with any firm whose product they may wish to comment upon.
Thank you.
DR. LEGGETT: Thank you. Dr. Goldberger, would you like to give us some opening comments?
DR. GOLDBERGER: I'd like to welcome everybody here to the second day of this advisory committee, to what should be an interesting and important day.
Some of us within the Center for Drugs have been helping the folks in the Center for Veterinary Medicine over the last few years with their efforts to provide better information about approaches to the development of antimicrobial drugs for veterinary use. What we were asked to do was to provide information that would sort of provide a basis for looking at the importance of antimicrobial drugs in human medicine.
I want to make just a couple of observations about this.
One is, this is really not explicitly a part of our normal regulatory process when we approve new antimicrobials for human use. That is not to say that we don't try to get a sense of what their added value is, particularly if there is, as an example, an unexpected toxicity or safety signal. But there is no requirement that a drug -- for instance, a new antimicrobial -- offer added value or be particularly important. It simply needs to be safe and effective. So this is a function that we've done to help the folks at CVM, but it's not a normal part of our day-to-day process.
Second thing that's important to note, and we made this clear from the outset, that we were doing this totally from the perspective of their importance in human medicine and the potential importance in treating patients. We recognize that ultimately -- and this is underway now -- this type of approach and the information that we've provided needs to be integrated into a larger approach to provide guidance about how to proceed, and that obviously a number of other factors need to be taken into account.
But what we were asked to do, and the information that we provided, really focused on the issue of what is the importance of antimicrobial drugs in human medicine, and what kind of elements go into making that determination. The questions that we'll be talking about this afternoon really are to allow you guys to give us some additional advice in that area.
We are very pleased that there will be representatives from both the producer and the veterinary communities who will be giving talks as part of this meeting, both planned talks and additional talks in the open public hearing. Although, as I indicated, our goal was really from the CDER perspective to focus on the importance in human medicine, we realize that it's extremely important that people on the committee have a broader understanding of what this overall process is, and these talks, as well as the talks by the folks from the Center for Veterinary Medicine, as well as John Powers, will hopefully provide that broad perspective which may also be important should additional scientific questions have to come before this committee, or perhaps a meeting of this committee and the CVM committee to outline and deal with some of the other scientific issues that come up in making this type of advice available to the veterinary community.
I think I'll stop at that point.
DR. LEGGETT: Thank you. Dr. Tollefson, would you like to start us off with an overview?
DR. TOLLEFSON: Good morning. I want to express my appreciation and thanks to the advisory committee for taking the time to provide us with your expertise and just good advice on trying to deal with this issue. We really do appreciate your input on the issue of ranking drugs for importance in human medical therapy.
Ranking the drugs is a very important component of a new draft guidance from the Center for Veterinary Medicine that provides a pathway to evaluate the safety of animal antimicrobial drugs with respect to their ability to cause resistance and thereby decrease the risk that resistant pathogens will affect humans by contaminating the food supply.
I want to cover several parts, and I want to do a brief background of the issue on the scope of the new guidance for industry, which I just mentioned, spend some time on the components of the qualitative antimicrobial resistance risk analysis, which is a key part of the guidance. This is going to be rather confusing. We recognize that you are busy people, you have limited time. We did not expect you to go through the guidance in detail. We've been through it, of course, several times and it still can be confusing to us.
So what we've decided to do is have Dr. Mary Bartholomew at the Center walk you through the guidance using a hypothetical example, and we're hopeful that this will clear up some of the mechanics of the guidance in more detail.
The overall human food safety evaluation of antimicrobial new animal drugs includes consideration of several things, not just the resistance issue. The residues of animal drugs in food, the effects of the animal drug residues on human intestinal microflora, and then the microbiological effects of animal drugs on bacteria of human health concern, the antimicrobial resistance issue.
This last point is relatively new. It was not considered for all classes of antimicrobials until approximately late 1998. At that time we changed our policy to include in the pre-approval evaluation process the potential human health effects resulting from the emergence of bacterial resistance due to that use of the antimicrobial in animals, in food animals specifically.
Just to make sure that everybody is on the same page in terms of the hazard or the risk, what we're dealing with is the issue that antibiotic-resistant food-borne pathogens may be present in or on animals. By "in" we're referring to the enteric system, so it's really on animals as a result of drug use in animals. Then those resistant pathogens may contaminate carcasses at the slaughter plant and be transmitted to humans through consumption of contaminated food and also handling of contaminated food and cross-contamination issues.
Then when these resistant bacteria cause an illness that needs treatment, medical therapy may be compromised if the pathogenic bacteria are resistant to the drug or drugs used for treatment.
We've been working on various aspects of our strategy to address the issue of antimicrobial resistance for the last four years. It's multi-faceted. It includes this revised pre-approval assessment. That's the focus of the new guidance to industry. We've also spent a great deal of effort on improved surveillance activities, looking at development of resistance and changes in resistance. We've supported judicious use principles for food animal veterinarians, and we've also undertaken expanded research activities. Also we're part of the federal public health action plan to combat antimicrobial resistance and many of these activities fall under the scope of that broader issue.
What the committee has been asked to consider is one component of this revised pre-approval assessment, the ranking of the drugs based on importance in human medical therapy. The pre-marketing approval assessment takes the form of a draft guidance for industry, a copy of which we provided to you. The status of that is such that we are now addressing comments received on the document, as well as this ranking, which is an important part of the document, both written comments and comments that we received at a public meeting in October, where we went through the guidance in a lot of detail.
We plan to revise the guidance based on these comments as well as the discussion with you today. Guidance for industry, unlike a regulation, is much more easily changed to reflect new science, additional comments, and so on. So even when the guidance is finalized we consider it an ongoing work in progress and we can make changes based on new information.
Now, the focus of the guidance is primarily on human exposure to antimicrobial-resistant bacteria, or resistance determinants through ingestion of animal-derived food. We recognize that the emergence, spread, and persistence of antimicrobial resistance is complex and involves many pathways. We believe that the food-borne pathway is the most significant and most directly linked to antimicrobial drug use in animals, but that isn't to say that it's not the only pathway.
The guidance is applicable to both therapeutic and non-therapeutic antimicrobial drugs intended for use in food-producing animals. Drugs in food animals are used to treat disease, prevent and control disease, and then also can enhance performance, growth, feed efficiencies.
The components of the risk analysis consist of a hazard identification, a qualitative antimicrobial resistance risk assessment, and then risk management strategies to deal with any potential risk to humans. The identification of the hazard is the first step of the process and it's really outside and separate from the qualitative antimicrobial resistance risk assessment. The hazard here is defined as human illness that is caused by a specified antimicrobial resistant bacteria, is attributable to a specified animal-derived food commodity, and is treated with a human antimicrobial drug of interest.
The three main elements of a qualitative risk assessment are the likelihood of whether use of the drug in food-producing animals will first cause bacteria to become resistant, that humans will be actually exposed to the resistant bacteria, and that exposure will have a human health impact. We've elected to do a qualitative risk assessment because we anticipate that limited information will be available when a new drug is brought forward to us to be approved. If more quantitative data are available, they would certainly be used and would take precedence over the qualitative risk assessment.
Now, the release assessment describes the probability that factors related to the animal drug and its use in animals will result in emergence of resistant bacteria or resistant determinants in the animal.
Then the exposure assessment describes the likelihood of human exposure to the resistance determinant of human health significance that arises in a food-producing animal as a consequence of the use of the drug in that animal.
The exposure assessment also provides a qualitative estimate of the probability of this exposure occurring, and Dr. Bartholomew will illustrate that, as well as the components of this qualitative antimicrobial resistance risk assessment in more detail using an example.
The components of the qualitative risk assessment then consist of the release, the exposure, and the consequence, which is Appendix A in your document. The consequence is the ranking of the drugs based on human medical importance. It's entirely the same thing; it's equivalent. So therefore, it accounts for one-third of the estimation of risk, but it's very important to point out that it does not equate to risk and does not equate to a categorization of drugs that I'll describe a little bit later. In other words, because it's high-consequence, it doesn't necessarily mean that it's going to come out as a category 1 drug which carries the most restrictions on use.
We asked the Center for Drug Evaluation and Research to rank all drugs, not just those used in food-borne disease treatment. We recognize first that many human drugs are used to treat enteric disease. And of course, we wanted to base the ranking on the best available science, which demands that we consider cross-resistance between classes as well as within classes, also factors related to drug efficacy. Dr. John Powers will describe this in more detail in his presentation, which will go through the factors. There are 10 factors that were used to come up with the ranking of the drugs.
Then we'll be asking for your comments on these factors and whether there should be more weight placed on certain factors. For example, that which concerns the treatment of food-borne disease. Or, are there a subset of factors that should drive the ranking because they more clearly concern a connection to the use of the drugs in animals?
The next component of the guidance is a risk estimation which then integrates the release, exposure, and consequence assessments. This qualitatively, because it's based on a qualitative risk assessment, characterizes the potential for human health to be adversely impacted by the emergence of resistance associated with the drug used in animals, in food-producing animals.
The risk estimation is the point which leads to the ranking of drugs according to risk. Sorry, I didn't mean to use the word "ranking" because that's very confusing. It leads to the placement of drugs according to the risk to humans, and in turn these risk-based categories are associated with certain risk management strategies that we can take to control the risk. These parts of the process are where the veterinary medical aspects of the drug are considered mostly. There are other areas too.
Now, the risk management categories are very simple. There are three of them. Category 1 equates to a high risk estimate and we intend to approve the drugs only on strictly limited use conditions. I'll describe those in a little bit. Category 2 then is medium, and it's intermediate restriction, and category 3 would be the least restriction on drug use. This may be the case where drugs could be used, possibly with no restriction or on a large number of animals for non-therapeutic purposes.
Now, we attempted to draft the guidance document so that all veterinary antimicrobials would be potentially approvable in food animals by using risk management strategies. We do not intend to dampen the development of veterinary antimicrobials, but rather develop a more reliable and predictable process for approval.
The risk management strategies are somewhat self-evident. One would be limitations on marketing. For certain antimicrobial drugs, we feel that veterinary involvement is important for ensuring safe use. The categories available to us are prescription, over-the-counter, or something that we term a veterinary feed directive, which for your purposes should be considered as a prescription product.
The extent of use and conditions of use of antimicrobial drugs influences the selection pressures for resistance development. So restricting use can be a risk management tool to determine the safe conditions of use of the drug for a food-animal drug. Specific drug use limitations are found in table 4 of the guidance document. Basically they concern restricting both the duration of use and the method of administration.
The possible risk management steps are summarized in table 5 in the document, and they're stratified by the category of concern. Category 1 would only carry prescription marketing status. Category 2 would also only carry prescription status. However, in category 2 use of the drug in animal feed could be allowed, depending on the other parts of the evaluation.
We have the ability in veterinary medicine to restrict extra-label use or off-label use. And the extent of use I just describe, and those are described as categories again of low, medium and high. Unfortunately, we couldn't get away from that.
Post-approval monitoring refers to the surveillance system. It's called the National Antimicrobial Resistance Monitoring System that is a three-armed system of animals at slaughter plants, which is run by the U.S. Department of Agriculture; humans ill with food-borne disease, which is done by the Centers for Disease Control and Prevention, the National Center for Infectious Diseases; and then retail meat, which is done at the Center for Veterinary Medicine. Then, of course, advisory committee review is another option that we always have.
To summarize, we feel the draft guidance outlines a risk-based approach for evaluating these antimicrobial resistance concerns. Ranking of the drugs according to human medical importance represents approximately one-third of the qualitative risk assessment process. Our goal is to provide for the safe use of antimicrobials in food-producing animals, while ensuring that significant human antimicrobial therapies are not compromised or lost due to the use of these drugs in food animals.
The risk to humans, then, is managed through application of drug use limitations and restrictions to maximize the availability of antimicrobials for animal therapy. That's our theoretical approach. That's how we wrote the guidance to accomplish that goal.
We very much look forward to continuing working with CDER and the public and the industry and other valued stakeholders to successfully address this very complex health problem. I thank you very much for your attention.
DR. LEGGETT: Thank you. Are there any questions for Dr. Tollefson?
(No response.)
DR. LEGGETT: Very good. Thank you.
The next speaker will be Dr. Mary Bartholomew, who will give us an explanation of antimicrobial risk assessment.
DR. BARTHOLOMEW: Good morning. I too would like to take this opportunity to thank the committee for their time, and I'd also like to thank Carol Andrus and Bill Flynn for their work on condensing this presentation from three presentations that we made at our public meeting in October.
Now that Dr. Tollefson has provided you with a general overview of the risk assessment process, I'd like to take the opportunity to run an example of a hypothetical drug through the risk assessment process in hopes of helping us understand the process.
First, as outlined in the draft guidance, the risk analysis process is intended to organize and integrate an array of relevant information and to provide guidance as to how this information may be used to manage risk. As mentioned earlier in Dr. Tollefson's discussion of the qualitative risk assessment process, it's composed of the hazard identification process, the qualitative antimicrobial resistance risk assessment, which has three parts, release assessment, exposure assessment, consequence assessment, and the integration of the three parts in the risk estimation process. Also the risk management steps.
Prior to initiating the risk assessment, we must identify the hazard and the conditions that influence the occurrence of the hazard. By definition, the hazard is human illness that is caused by a specified antimicrobial resistant bacteria, is attributable to a specified animal-derived food commodity, and is treated with the human antimicrobial drug of interest.
As stated in the guidance, we recommend that the hazard identification step of the risk assessment include drug product information, and that would consist of information for the example such as miraclemycin is the name of the drug. Its trade name is Miracin. It's in the class, second generation, curalloside, with a CAS number of 2002.
Its use information, we're going to talk about dosage regimen. It's intended to be administered as an oral solution in drinking water for 5 days. It's going to be given for the treatment of swine respiratory disease, and the target species, of course, then would be swine.
In addition to the drug-specific information, we need information about bacteria, resistance determinants information, including antimicrobial susceptibility testing methodology, as well as any data gaps or emerging science related to the particular drug-bug combination.
The release assessment describes the probability that factors related to the antimicrobial new animal drug and its use in animals will result in the emergence of resistant bacteria or resistance determinants in the animal. That was defined before as the probability that resistant bacteria or resistance determinants are present in the target animal as a consequence of the antimicrobial new animal drug use. That probability would be expressed, since this is qualitative risk assessment, as low, medium or high.
The boundaries of the release assessment span from the point the new antimicrobial drug is administered to the food-producing animal to the point the animal is presented for slaughter or animal-derived food is collected.
For the purposes of this risk assessment, a number of relevant factors are suggested for consideration. They're listed here on the slide. Some of them overlap with those in the hazard identification set. They are: product and drug substance description, mechanism and type of action, spectrum of activity, PK/PD, resistance selection pressures, prevalence of resistance, resistance mechanisms, resistance transfer, other relevant information.
So the sponsors may consult with FDA -- in fact, we encourage them to do so -- to determine the specific factors that are most relevant to the new animal drug in question. The sponsor or FDA may consider additional factors to take into account any specific considerations pertinent to the drug and its proposed conditions of use.
The relative significance of any one of these particular factors among all factors pertinent to the release assessment may vary, depending on the specific new animal drug under consideration. Therefore, certain factors may carry greater weight than other factors when determining the overall release assessment ranking.
So we turn to our example of Miracin. In the interest of time, I will not provide an in-depth explanation related to each of these criteria for this particular example. Rather, this background information will be handed out after my talk to the committee, and it was presented in our October meeting so that you can visit our web site and see the slides from the presentation in which this was done in a series of several slides with more explanation.
I will move directly to the outcome comments and conclusions for each of these criteria.
Miracin is a bactericidal drug with some activity against Gram-positives. Campylobacter exhibit low MICs. The PK/PD parameters are favorable for minimizing resistance release. It has rapid absorption and high distribution to the tissues, and the serum concentration greater than the MIC for 6 hours makes for minimizing resistance release. And the in vivo post-antibiotic effect is about 3-and-a-half hours.
The transfer of resistance is infrequent. There's a low baseline resistance and a low mutation rate.
The FDA recommends that the sponsor use the conclusions obtained from assessing all relevant factors to derive an overall qualitative ranking for the release assessment, and in this particular case, the release assessment conclusion for Miracin would be that there is a low probability of release.
Let me turn to the third component of the assessment. Well, let me say a few more words about that.
The overall conclusions are expressed as low, medium and high, and as we mentioned, this is just one of the three. So it's intended to estimate the probability that resistant bacteria or resistance determinants will occur in animals as a consequence of the proposed drug use in animals.
It's also important to note that if sufficient information regarding a factor is not available or has not been generated for the assessment, the most conservative significance of the particular factor may be assumed. That is, the factor would be assumed to have a high likelihood of contributing to resistance emergence. And that's one of these factors. So if a number of those would turn out to -- would be unknown, we would assume high likelihood, and that would tend to bump up the overall release assessment probability.
The next component is the exposure assessment. The exposure assessment describes the likelihood of human exposure to the hazardous agent through particular exposure pathways. And again, the strict definition from the guidance document was that the exposure assessment is the probability for humans to ingest the resistant bacteria or resistance determinants in question from the particular relevant food commodity.
The exposure assessment describes the likelihood of exposure to the hazardous agent through particular exposure pathways, and at this time assessing human exposure to the hazardous agent is focused on food-related pathways. FDA believes that human exposure through the ingestion of resistant bacteria from animal-derived foods represents the most significant demonstrable pathway for human exposure to resistant bacteria or resistance determinants as a consequence of drug use in the food-producing animals. As we say, it's the most significant.
The probability for exposure is also qualitatively determined to be low, medium, or high.
The exposure assessment may be accomplished by integrating information that characterizes the probability for humans to be exposed to given bacteria via a particular food commodity. We're not talking about resistance at this point. This is just being exposed to the bacteria. Then the probability that the bacteria of interest to which the humans are exposed are resistant to a particular antimicrobial drug or possess associated resistance determinants.
Returning to our example, the probability for humans to be exposed to a given bacteria via a particular food commodity is independent of drug use, and may be estimated by considerations of per capita consumption of the food commodity. And this example was pork. Now, this information is available from several sources.
The probability of contamination of the pork by bacteria of interest, and in this case we're looking at the example of Campylobacter.
While it's acknowledged that other factors such as food preparation practices can affect exposure, the above two considerations can provide a qualitative indication of the magnitude of the probability of human exposure. Survey data of both food commodity contamination and per capita consumption may be submitted to support a qualitative ranking of probability of human exposure to the given bacteria via a particular food commodity, and examples of such sources of data are shown on the slide.
Appendix B of the guidance document contains examples of how such information may be integrated, and we'll run through that for the example.
According to current consumption data from the USDA Economic Research Service, we see that 47.7 pounds of pork are consumed per capita per year, which will give a qualitative ranking of high. From Food Safety and Inspection Service data, we also note that there's a 32 percent prevalence of Campylobacter contamination of market hogs, which results in a high ranking relative to other contamination levels.
Next, the consumption and contamination rankings are merged to derive the qualitative ranking for the probability that a human is exposed to Campylobacter on pork. Looking at our table of outcomes, the per capita consumption being high and the probability of food commodity consumption being high, then we see that the overall ranking results in a high probability of human exposure to the given bacteria. Now, this is not completion of exposure assessment because we haven't discussed resistance to this point.
So finally, overall exposure assessment ranking is derived by integrating the ranking for the probability of human exposure through food to the bacteria in question -- high from the previous slide -- with the probability that the bacteria will be resistant to the antimicrobial drug in question, which we saw was high from the previous slide, and with the probability that the bacteria will be resistant to the antimicrobial drug in question. That comes from our release assessment, and that was low.
So looking at our table of possible outcomes, we see that a high probability of human exposure to a given bacteria and a low probability of the bacteria of interest being resistant will result in a medium overall exposure ranking. So that completes the second of our third components.
Now we move on to the consequence assessment. Now, in the third component, we note that the consequence was the probability that human exposure to resistant bacteria determinants results in an adverse human health consequence. That was based on the medical importance of the antimicrobial drug under review, and is also ranked low, medium or high.
Returning to our example, then, we find that in Appendix A the antimicrobial drug ranking developed by CDER determined that Miracin is high, of great importance in treating of human disease. However, I'll reiterate what Dr. Tollefson mentioned. This does not equate to a high potential risk to humans or to a category 1 drug. This is not the completed risk estimation, as the two other assessments, the release and the exposure, have not yet been integrated.
We will move forward then to this process of integrating the release, the exposure, and the consequence assessment, and that will provide a result as high, medium, low risk for human health to be adversely impacted by emergence of antimicrobial resistance associated with the use of the drug in animals.
How is this integration done? The risk estimation is low if all three are low, or if two are low and one is medium. It's high if all three are high, or there are two highs and one medium. And otherwise it's medium. The thinking behind this integration scheme is that the presence of one medium along with two lows would not raise the estimate to a medium. Similarly, the presence of one medium along with the two high assessments would not decrease the risk to medium.
These three rankings relate to the level of concern for human health impact potential of the new drug. Each level of concern corresponds to a category of risk management steps. Category 1 management options or steps are applicable to situations where the risk estimation result is high. Conversely, category 3 management steps are applicable when the risk estimation result is low. Dr. Tollefson showed the table of risk management steps in her talk and we will display it again shortly in context of the example.
Recalling again in our example for the release assessment, we had a low. For the exposure assessment, we had a medium. For the consequence assessment, we had a high. From the general rule for integrating the three assessments, we note that the risk estimate is medium, which is associated with category 2 risk management steps.
Category 2 risk management option or steps permit therapeutic application to selected groups of pens or animals for short durations.
Returning to the example, Miracin oral solution for swine, we note that the sponsor is proposing that the drug be used by prescription only, administered as a therapy to select groups of pens or animals, and that it be limited to 5 days of administration. In this instance the use conditions for the proposed drug are those of a therapeutic drug rather than those of a non-therapeutic drug. Also, note that the proposed use is consistent with conditions of use deemed appropriate for category 2 drugs on the previous table, the risk management steps.
Therefore, based on the risk assessment and the drug application as a whole, FDA concludes that the antimicrobial new animal drug Miracin is safe. That is, there is a reasonable certainty of no harm when the drug is approved under the defined use conditions.
That completes the explanation for the example. Are there any questions?
DR. LEGGETT: Do you have a question, Steve? Otherwise, I have a few.
Thank you for the example. It has a great name, too.
On your slide on page 3 of the example, the release assessment of Miracin, are all of these data currently provided for new drugs when they are brought before the FDA? In other words, is this data available for drugs now?
DR. BARTHOLOMEW: If there are data gaps, as we mentioned, what we would tend to do would be to make the assumption that that factor corresponds to increasing the probability for release.
DR. LEGGETT: I realize that. I'm down to nuts and bolts. Do you know the mechanism of activity, the spectrum, the kinetics, the dynamics, the resistance when the drug is brought before the FDA? Or is this all theoretical?
DR. BARTHOLOMEW: A lot of the development work is brought forward and has this information in the submission. A lot of the times, yes.
DR. LEGGETT: My second question is, on the slide on page 5, you were talking about exposure assessment. It sort of made me think, are there data available to test this sort of qualitative mathematical model already? In other words, are there data from outbreaks, epidemics, that sort of thing, that are available to sort of look at how -- it's a quasi-mathematical model of the various risks.
DR. BARTHOLOMEW: For the major food-borne pathogens, Foodnet has a lot of epidemiologic data about exposure to the bacteria.
Now, about the exposure to the resistance, of course if you were looking at a new animal drug that's not been out there, then there will not be information about resistance, about that particular --
DR. LEGGETT: Right. I'm getting at the model testing. You've sort of got X times Y percentage times Z percentage in terms of figuring out just whether somebody eats it. Are there any data for drugs currently available for outbreaks that have occurred of animal-associated illness in humans? Do we know if low, medium and high are logs apart in terms of the risk, or just how good are these assessments? Or are we sort of floating free?
DR. BARTHOLOMEW I'll try to answer that and then I'll see whether somebody else from the panel wants to.
But we have information from the Economic Research Service on how much of all the different food-animal products are consumed. We have FSIS data on what the levels of contamination are. Those permit us to look at broad bands and say that some of them cluster above a certain percent, so that's a high rate of contamination. And some cluster low. So yes, it's based on real information from FSIS about contamination levels.
DR. LEGGETT: And my final question is about the risk assessment. Say it's pork for Campylobacter. How do you compare a pork chop with ground pork? I mean, even though the rate of contamination of the animal may be the same, the transmission to people may be different, much like the E. coli 0157 would be for steak versus hamburger.
DR. BARTHOLOMEW: Right, and a lot of the products are looked at in terms of ground product and whole product. I think that our approach probably would be to be more conservative. If one product were highly contaminated, I mean that would be a route of exposure that we would go with the more conservative process.
DR. LEGGETT: Steve.
DR. EBERT: Probably just a comment. It appears from the assessment that you've done that the release assessment is actually being used twice in the analysis. You're using the release assessment by itself and then you're also modifying the exposure assessment based on the release assessment. Is that an accurate statement?
You initially said that the exposure was high, but then when you take into account the release, that got downgraded to medium so that the ultimate result was medium. So you're really using that in two different ways.
DR. BARTHOLOMEW: That's accurate in terms of we need to decide during the exposure what the rate or the prevalence of resistance in that exposure is. And it may be that there are some data -- for instance, we frequently get proposals to add to existing claims. And then there might be some information out there, but if not, you just use the information straight out of the release assessment. You might, in fact, have more information to bring to bear on that.
DR. EBERT: The reason that's of concern to me is, at least from my initial reaction, of the three it seems as though the release assessment is the most subjective in its analysis. For example, some of the things that are included in there, the drug has a time above MIC of 6 hours. It has a PAE of 3 hours. What does that really mean? Is there any real clear-cut relationships between some of these measures and the likelihood of resistance? Maybe that will be discussed later in the day.
DR. LEGGETT: Ellen.
DR. WALD: This is a small point, but the word "release" just seems like a funny word for this assessment because at least it doesn't relate to anything that I can think about, whereas the other terms are sort of meaningful. Could you think about changing that to like probability of emerging resistance or something where the description would be relevant to what you're talking about? It would have helped me understand the documents.
DR. LEGGETT: Mutant escape.
(Laughter.)
DR. BARTHOLOMEW: I'll take that comment forward. However, that term comes out of an OIE, Office of International Epizoides, paper in which a formulation for risk assessment for resistance determinants was proposed, and that's where the term arose. I guess we can take that under consideration.
DR. LEGGETT: Go ahead, John.
DR. BRADLEY: The model looks very nice, and as a pediatrician there are lots of data on day care centers' spread of resistant organisms, and I sort of see a feed lot to be analogous to a day care center.
(Laughter.)
DR. BRADLEY: There are lots of new colonization studies which show introduction of a resistant organism into a day care center and how quickly it spreads. In addition, in the release assessment, once you eradicate a certain set of organisms with an antibiotic, there's a chance that you can get colonized with resistant organisms of a different type because you lack colonization interference at that time.
So my question is, are there data in feed lots or herds or flocks -- I have no idea -- on how rapidly a resistant organism can spread under conditions of antibiotic therapy.
DR. BARTHOLOMEW: I'll defer to some other people on that -- we have some veterinarians and veterinary epidemiologists in the audience -- about the studies for the prevalence of rate of spread in herds.
DR. LEGGETT: Hopefully we'll remember to bring that up later in the discussions.
DR. BARTHOLOMEW: That's fine.
DR. LEGGETT: Yes, Mark.
DR. RUPP: I don't know if this is the appropriate time to bring this up. I suspect there will be a lot more discussion on this. But, for instance, in the document you provided us, in Appendix B, where you're trying to figure out the risk of exposure based upon the prevalence of this antibiotic being in animals, and you've cited some data where you go and sample ground chicken or ground turkey. It seems like you've got some really high percentages there, 40, 50 percent levels, that you've only graded as sort of a medium risk. I'm wondering how you break that down, low, high and medium, based upon the prevalence of bacteria found in these food items. 40 percent prevalence seems real high to me.
DR. LEGGETT: That's the table B-2 where we broke it down to less than 5, 5 to 25, and greater than 25 percent in terms of the prevalence.
DR. BARTHOLOMEW: Right. Well, I think that we just looked and sort of saw a clustering and made what was out there. It's relative to what the other products had. If they only range from 0 to 15 percent, then 15 percent is going to be high relative to others. If they range from 25 to 75, then 75 is going to be high relative to others. It's not an absolute.
DR. RUPP: Right, so it's a relative scale, but it would seem to me that again if 40 percent of your broilers have Salmonella in it, you have a very high risk of exposure, even though 40 percent is only in the middle of that rank, or what-have-you.
And then another question would be, in the tables that you've shown you proposed certain policies based upon your assessment, and I guess my biggest concern is use of antibiotics in animal feed. And for instance, in a medium-risk situation like this product, it would be allowed to be used in animal feed, it sounds like. How did you decide where you were going to draw those lines of, gee, you're going to restrict it only to therapeutic use versus non-therapeutic use in animals?
DR. BARTHOLOMEW: In this whole process the upper end and the lower end are the easier things to discern. Then when you get toward the middle, yes, there's an issue about where you make your cutoffs. I'm trying to go back to that risk management slide. I guess the rationale was -- and somebody can correct me if I'm wrong -- that Rx or a veterinary feed directive -- this is still on your prescription of a veterinarian. So that's medium. It's still being controlled there by a veterinary feed directive. So it would take the input of a veterinarian to make that decision.
DR. RUPP: So as a feed directive you're still using this drug therapeutically, not as a growth-enhancer?
DR. TOLLEFSON: That's correct.
DR. LEGGETT: Any further questions at this point?
(No response.)
DR. LEGGETT: Great. Thank you very much.
DR. BARTHOLOMEW: Thank you.
DR. LEGGETT: The next speaker is Dr. Richard Carnevale, who will talk to us about the ranking of antimicrobial drugs relative to their use in animals.
DR. CARNEVALE: Thank you, Dr. Leggett. I appreciate that pronunciation.
DR. LEGGETT: My wife's Italian.
(Laughter.)
DR. CARNEVALE: It is indeed a pleasure for me to be here, and first let me say I appreciate the invitation from Dr. Tollefson and Dr. Powers of CVM and CDER to come and present to you today the AHI, the Animal Health Institute's concerns about this categorization issue.
Before I begin, though, I'm happy to see someone in the audience -- Dr. Brown from the committee is at the University of Pennsylvania. I'm a proud graduate of the University of Pennsylvania veterinary school on Spruce Street. However, I will not reveal when I did graduate from that school because it's too many years ago.
In any case, what I'd like to do is talk a little bit about why we're here. We, of course, are the representative of the major animal health companies in the U.S. We are a small PhRMA, the Pharmaceutical Research and Manufacturers Association, and we're quite a bit smaller than them.
We are pleased that CDER and CVM have asked this committee to take a look at the categorization issue. We think the advice of this committee is going to be very important and very critical to the practice of veterinary medicine and animal production in the future with regard to the use of important therapeutic products.
The FDA regulatory approach will affect new and existing antimicrobial drugs for food animals. This document will apply retroactively to existing products as well, so this risk assessment process that is underway will be applied to existing products on the market, which of course have been on the market for many years in some cases for a range of uses.
Infectious bacterial, fungal, viral diseases are very big problems in food animal production, as you can expect. And antimicrobials are a vital product line with many of our members. Antimicrobials, anthelmintics are probably the two biggest pharmaceutical products and feed additive products that our companies manufacture.
Of course, we are members of the larger human health companies, and being members of those larger companies they are greatly concerned about the resistance development not only with animals, but of course how it might affect human health. Of course, this issue has been around for many, many years. Probably in the late 1970s the concern first came up with regard to the use of antibiotics in feed particularly, and now it's extended also to the use of therapeutic antibiotics, which this document would mainly apply to, although as I said it does apply in a more broad fashion to existing feed use antimicrobials as well.
As with human medicine, availability of a wide variety of products in veterinary medicine is very important. A range of products reduces resistance pressure on the few compounds that may be available, and timely and effective treatment of animal diseases does improve not only human health but food safety as well. There is some research that is underway that actually indicates that by not treating many animal diseases, you can have an increase in pathogens in the food supply. I think evidence in Europe is coming out that there is increased animal disease over there and possibly a concomitant increase in food safety problems.
The FD&C Act applies the same standards to antimicrobials as with human products. There is a very rigorous approval process that is required. There is an additional burden over and above safety and efficacy to the patient that residues that are left in the animal, any drug residues that might remain in the food when an animal goes to slaughter is safe. And of course, that's been a process that's been underway for many years.
Resistance concerns are a bit newer, and as Dr. Tollefson mentioned, the concerns that CVM has for resistance will now apply to a whole range of products that are on the market. Originally the concerns were with feed use, continuous use feed use antimicrobials, and there were some standards applied in the 1980s for those. But this document will now apply a risk assessment process and additional standards to all antimicrobials.
We certainly support a strong FDA and rigorous standards. I mean, without a strong FDA I think that the consumers don't have the assurance that these products are safe. But, of course, industry must rely on science, and we hope that the agency operates on a basis of science and not on supposition or emotion. Unfortunately, this issue, antimicrobials in animals, has been driven to a large extent -- not necessarily the agency, but certainly in the media and other places -- by an emotional reaction to the concerns that some people think animal drugs contribute to human health.
We rely on a predictable process. We want strong standards, but they need to be reasonable standards so that we can invest in new products. Without an assurance that the agency is operating in a predictable, transparent fashion, the industry is going to be hard-pressed to invest new monies into new products that may, in fact, benefit resistance in the long run.
Now, this qualitative risk assessment process has been described to you this morning, and it's really to determine the risk to human health. I want to talk this morning just talk about the categorization issue. I know there are a lot of questions that came up with regard to the release and consequence assessment, but maybe others can speak to that. I'd really like to focus on the categorization issue.
As Dr. Tollefson and Mary Beth Bartholomew mentioned, food-borne zoonotic infections are considered the most likely route of transmission driving this risk-assessment process, and we certainly agree with that. However, we are concerned that there is a reference to commensal organisms, commensal enteric bacteria in the animal, transferring resistance to non-commensal bacteria, which is driving a lot of the concern about the impact on human health. I will be addressing that later.
Most of the drugs in Appendix A are ranked as of high importance based on meeting one or more of 10 different criteria, as has been discussed with you. We feel that most of the criteria don't have a lot to do with how drugs are used in animals or the infections veterinarians are treating. For example, macrolides are rated as high because of their usefulness in treating Legionella, but Legionella to my knowledge is not a zoonotic pathogen. I'm hard-pressed to find a connection between animal use and Legionella.
So that's the concern we have, and it was mentioned that the categorization was done irrespective of its connection with animals. I hope to present some information to you to put that in context.
If, in fact, this risk assessment process goes forward and many drugs are categorized in the high risk category, as has been described to you, because of concerns for its importance to human health, which will drive a lot of that final ranking, then this could really mean very few if no new animal drug approvals, and we think that's going to be a detriment to veterinary medicine.
What is our concern? Well, the underlying assumption by the agency appears to be that there is resistance gene transfer between commensals and non-enteric bacteria. Certainly we have no argument, or little argument with the fact that food-borne transmission of zoonotic pathogens such as Salmonella and Campylobacter and possibly E. coli are a concern, but this commensal to non-commensal transfer we find difficult to understand because we know of no documented in vivo evidence. There certainly have been in vitro studies showing that you can transfer resistance genes, but in vivo we don't know of any.
In fact, there are two studies that I would reference here, one that attempted to colonize humans with Enterococcus faecium, and that a was very transient colonization, about 2 weeks in duration, and they fed very high doses of Enterococcus faecium, somewhere in the range of 10 to the fifth to 10 to the sixth organisms, and they really did not get permanent colonization of that.
Also there's a study in the literature that shows the reverse, taking human pathogens and trying to colonize animals was not successful. So it's questionable whether there is actually in vivo resistance transfer.
We do believe that the majority of infections that are critical for antimicrobial treatments in humans aren't going to be jeopardized by animal use, and we want to put this in context. The ranking of importance, therefore, should factor in whether there is real evidence of an animal connection and not just theoretical evidence. We can't operate on theory. We need to operate on evidence.
The Appendix A ranking, therefore, is double jeopardy for our companies. One, it is the sole criteria for the consequence assessment portion. If the drug is considered important in human medicine, it will drive the approval for new products. It also will drive the evaluation of currently approved antibiotics. So both existing products and new approvals will be jeopardized by how Appendix A finally comes out.
I'd like to present three pieces of information. I don't want to call them evidence because they're really opinion surveys, if you will, in some cases. But there are three pieces of evidence that I hope puts this whole issue of animal use of antibiotics and human health in context.
The first is a study published in the Journal of Antimicrobial Chemotherapy in 2000 by Bywater and Casewell, assessment of the impact of antibiotic resistance. What they did is they went out and surveyed practicing physicians and microbiologists in the UK and other countries, some in the U.S., on major human antibiotic resistance problems. They developed a seminar. They designed a list of organisms or developed a list of organisms that they thought were the major contributors to resistance. And then they sent this questionnaire out to a number of experts in the field. They originally tried to get 25 or 26 experts. They ended up getting 16 replies.
They asked what was the burden of ill health resulting from this bacterial species in a ranking of 1, negligible, to 5, major. What is the impact of resistance on treatment choices? Again, 1, rare, to 5, resistance is common. And what they thought the contribution of animal sources to human resistance for all the particular species they were looking at, 0 being of no consequence and 5 being the main source.
The bacteria in the survey are listed here, things like methicillin-resistant staph, Mycobacterium tuberculosis, on down to some of the food-borne pathogens such as Salmonella and E. coli.
So what they first came up with is the contribution of individual species to the total resistance problems in humans. I don't think it would surprise any of these committee members to note that MRSA is sort of the leading candidate for resistance problems in humans. And on down the list we have Pseudomonas aeruginosa, Klebsiella. And then down towards the right-hand side of this scale we have non-typhi Salmonella, Campylobacter, E. coli 0157 of a lower importance to the contribution of resistance.
Then when you overlay this on their estimation of what animal source might be contributing to these, as you can see, down in the areas of Enterobacter, Salmonella clearly, Salmonella non-typhi, Campylobacter, there is some contribution that clearly was felt to be due to animal sources, but overall a fairly low percentage of contribution.
So the analysis of this questionnaire, certainly this was to my knowledge the first time that the relative impact of individual organisms was quantified. Clearly MRSA is the biggest problem. The opinion of these experts was that animal sources were resulting in less than 5 percent of the total human resistance problems, and furthermore, the enterococcus, the growth promoter link, which has been the big issue particularly in Europe over the last 5 or 10 years, was less than 1 percent contributing to antibiotic resistance problems in humans. So for what it's worth, that's one study that was published.
I'd like to cite another source of information, a 1999 European Union Scientific Steering Committee. These sets of slides come to me by way of Dr. Herman Goosen, who is a physician in the Netherlands, who was part of the steering committee in Europe. I'll briefly run over this just to give you a context for what the steering committee looked at.
They were charged with evaluating the current position regarding the prevalence of resistance. They examined the implications of human and animal health, and they looked at factors contributing to the present situation. They also looked at ways they could influence or control resistance. They made recommendations, and they advised on monitoring of the outcome of measures and considered the implication of the advice.
They looked at a range of bacteria. Mainly they focused on the enteric food-borne bacteria, enterococci, E. coli, Salmonella, Campylobacter, the common food-borne organisms. They also looked at other bacteria. They also looked at a range of uses for animal drugs in food-producing animals, such as the growth promoter, performance-enhancing use, the prophylactic use, drugs that are used to prevent or control disease that might occur, or that are occurring. And then finally the true therapeutic use when animals are clinically ill and there's a need for high-dose, short-term treatment.
They looked at a range of antibacterial feed additives of concern, and I think the important thing in this slide is that there are many, many of these drugs that are used in the feed of animals that really don't have any analog to human health. Clearly there are some. A number of these drugs were removed from the market in Europe, not on the basis of good science but on the basis that they were concerned about the potential effects in animals, but in fact many of the drugs that are used in animal feed don't have a clear connection to any real human health care product.
The important part of their discussion also looked at infections in humans, and they looked at the same kinds of bacteria that the Bywater-Casewell study examined -- staphylococcus, Citrobacter, Pseudomonas, staph, strep, Salmonella -- and they looked at evidence for a link with antibiotic use in animals. The important thing with this slide, which agrees with the previous survey, is that at least for vancomycin and enterococci they saw some link. Clearly for Salmonella and Campylobacter with the fluoroquinolones there was potential link. But for most of the other bacteria there was really little evidence that there was a connection between animal use and human health.
The same thing with hospital-acquired infections. Clear evidence for antibiotic use and resistance problems with these bacteria, but again, enterococcus, vancomycin possibly was the only one that might be linked with a human health problem.
To round it out, the human community-acquired infections, the same kind of situation where Salmonella and Campylobacter, maybe fluoroquinolones had some connection, but not too much of a connection with the others.
The third piece of information I'd like to provide to you comes to me by way of Dr. Ron Jones, who runs the SENTRY program. Many of you, I'm sure, are familiar with it. This is a program that was established in 1997, funded by SmithKline Glaxo. It looks at antibiotic resistance patterns around the world from a number of pathogens. It's a very large database, collects thousands of clinical isolates in a statistically designed fashion, and it has international networks of sentinel hospitals which supply isolates to the SENTRY program for both nosocomial and community-acquired infections.
This is a chart Dr. Jones developed in consultation with us. He looked at the risk of animal pathogens occurring in human medicine and he looked at them by pathogen, by infection type, and he first classified them in three categories. One, respiratory tract infections, both community-acquired and hospital, skin and soft tissue infections, and urinary tract infections.
In his estimation these are the main contributors to respiratory tract infections in humans, and he believes that 75 percent of all prescribed antibiotics go for those particular infections. Skin and soft tissue infections, Staph. aureus, Pseudomonas, E. coli, and enterococcus are contributors to those problems, and urinary tract infections, E. coli and enterococcus.
In his estimation the animal-related risk, none of these respiratory tract pathogens have any animal-related risk or any evidence that we know of that there's a connection between animal use and these pathogens. Only with regard to enterococci with these other infections is there a possible connection, and that's not clear what the connection is. But clearly enterococcus has been linked to some degree with animal use. But clearly the majority of these infections in his estimation don't have a lot to do with animal use.
I also included a paper -- I hope that it was made available to the committee -- called "Contemporary Patterns of Antibiotic Resistance in Humans" that Dr. Jones prepared this fall for us. I think that should be in your package.
The references supporting that previous slide are listed here. You have those. If you want to look up those references, they are all SENTRY program references.
So what does this all mean and why did I present all this data? Well, we certainly believe that antibiotics are important to human health and food safety and we don't want to do anything that would limit the ability of veterinarians to continue to be able to treat our food supply. It is very important obviously to human health that our food supply remains safe.
Veterinarians do need a wide variety of products, as do physicians, to combat bacterial disease and reduce selection pressures on existing antibacterials.
We don't believe -- it is our opinion that the vast majority of antimicrobial use in food animals will have much consequence to human health, and we certainly support the FDA assessing that and trying to do that in a realistic and as scientifically accurate as possible.
We need to stimulate research and development so that safer and more effective antimicrobials can be put on the market. Therefore, we need a rational approach to assessing the risk.
Current ranking criteria in Appendix A, we believe, will tend to over-estimate the risk to human health, and we think that the current way drugs are ranked and categorized is important to human health. It will certainly push many, many animal drugs, as you heard before, into the high- or medium-risk category, which will in fact prevent many of those drugs from being approved or will greatly restrict their uses.
So we believe that absent evidence of an actual connection between antimicrobial use in animals and non-enteric human disease, as I've talked about here, only those antimicrobials that are really important for treating food-borne disease should carry a high risk ranking. So we would appreciate this committee taking this information into consideration in their advising the agencies on how to proceed in developing this document.
I do appreciate your time this morning. I'll try to answer any questions that you may have. Thank you.
DR. LEGGETT: Thank you.
Are there any questions? Dr. Maxwell.
DR. MAXWELL: I just have a question on your next-to-last slide, the one that says risk of animal pathogens occurring in human medicine. It lists E. coli as possibly having a related risk.
DR. CARNEVALE: You're talking about this slide?
DR. MAXWELL: Yes.
DR. CARNEVALE: Actually you probably can't see it on the slide. There's an asterisk right there, which says possible. The way he prepared this slide, it is a bit misleading. It looks like all these organisms have a possible link, but really what he has done is put an asterisk next to enterococci. I don't believe he feels that there is a connection between E. coli skin and soft tissue infections and animal use.
DR. MAXWELL: Okay.
DR. CARNEVALE: I know it's a little confusing on the slide, but if you look at the asterisk you'll see.
DR. LEGGETT: Dr. Wald.
DR. WALD: The chart entitled Antibacterial Feed Additives of Concern on page 13, is that a pretty comprehensive list of all the current antimicrobials that would be found in feeds? And are those the same that might be used for growth promotion?
DR. CARNEVALE: I would say that is a relatively comprehensive list. I can't guarantee that every single one is on there, but it's relatively comprehensive, yes.
DR. WALD: I guess I'm asking, are there important ones that aren't on there?
DR. CARNEVALE: Well, offhand I don't see any.
DR. TOLLEFSON: I don't see any that aren't on there. I would point out that it includes Monensin. It includes some what we wouldn't consider an antimicrobial. They are used for growth promoting. Those are approved for use in growth promotion.
DR. CARNEVALE: Right. And things like Monensin and olaquindox and Salinomycin are mainly anticoccidial compounds. They're mainly used for coccidiosis, although they are technically classified as antimicrobials. They don't have any, to our knowledge, use in human medicine and don't have any cross-resistance selection pressure. But they are used in some cases for growth promotion. For example, Monensin is used for growth promotion in cattle.
DR. LEGGETT: Dr. Bell.
DR. BELL: With reference to the SENTRY methodology, I'm trying to remember that methodology, but I am inclined to take issue with your statement that this is statistically designed. It's certainly not population-based. It relies on a group of sentinel hospitals that sort of agree to participate. And I believe that the isolates virtually always come from that hospital laboratory, which means that it's going to be mostly, if not almost all, hospitalized patients. So a lot of these pathogens cause community-acquired infections and I think would not be captured necessarily, and certainly not proportionately so in the SENTRY database.
DR. LEGGETT: Dr. Patterson.
DR. PATTERSON: As a clinician, of course, with the perspective of human health and someone who's been interested in both hospital and community antibiotic resistance for some time, I just had some observations from the presentation that I think could be misleading.
One is from the slides on page 6, where you make the case that there's no evidence of resistance gene transfer between animal organisms and human organisms. While that may be true that the particular gene hasn't been documented to be transferred, there are clearly a number of instances where there have been well-documented outbreaks of actual organisms going from food from animals to humans, not the least of which includes Salmonella and hemorrhagic E. coli. So I think that is sort of missing a point.
Then on page 9, you have the slides there, those two graphs. You make the case that food-borne pathogens like Salmonella, hemorrhagic E. coli and Campylobacter -- resistance in these organisms are of lower importance in the overall picture of resistance. However, these are of the most importance in terms of food-borne concerns of resistance, which is what we're here to talk about today. I think in the context of that, that the potential impact for prevention in a setting where we can do something about resistance in food-borne pathogens makes them quite important for our discussion today.
Obviously, these other pathogens that you cite are primarily nosocomial, and we continue to work on infection control and antibiotic utilization programs in hospitals to control them, but in terms of food-borne pathogens, these are quite important for public health. I think it's somewhat irresponsible to state that they're not important.
Then on page 15, you have a slide indicating that E. coli/UTI being a primarily community-acquired infection, although it can be hospital-acquired also, that there is no link with animals in the slide, and that is in conflict with your slide on page 16, where in Ron Jones' opinion E. coli is linked with resistance in animals. I think that that in fact is true, that the potential for emergence of resistance in E. coli with regard to urinary tract infections in humans is a concern, particularly now that there has been such an emergence of resistance in trim-sulfa, which was our previous drug of choice for UTI's, that the drug of choice now in most cases is fluoroquinolones, and we know that increase in fluoroquinolone use is, in fact, linked with increase in resistance. I think that is indeed a concern, and your slides there I think appear to be in conflict.
DR. LEGGETT: Dr. Bell.
DR. CARNEVALE: Can I address --
DR. LEGGETT: Yes, Dr. Carnevale.
DR. CARNEVALE: First of all, I didn't say that food-borne illness was not important. What we're trying to present here is in context with all the problems that occur in human medicine with regard to resistance and what the connection to animal use is. The current category or Appendix A categorization categorizes many drugs as very important to human medicine, but we fail to see a link between animal use.
Clearly food-borne pathogens, there is a link, zoonotic food-borne pathogens there is a link. There can be a link with animal use. That's the point I was trying to make, not that food-borne pathogens are not important.
Furthermore, I don't think Dr. Jones' opinion conflicts with the previous one. As I mentioned, if you look at the chart, and I'm sorry that it's a bit misleading but he did not believe that skin and soft tissue infections are due to E. coli or related animal use. Now the possible down there at the bottom is really starred, and he's got enterococci as possible.
DR. PATTERSON: Your slide on page 15, the top slide there says E. coli/UTI, fluoroquinolones, evidence for link with antibiotic use in animals, you have negative there in that column, and that appears to conflict. Yes, that slide right there.
DR. CARNEVALE: This is from the European Union. This is not my data. I didn't develop this. This is the European Union Steering Committee for Antibiotic Resistance that came up with this.
DR. PATTERSON: I'm just pointing out that it's in conflict with your slide on page 16.
DR. CARNEVALE: If it is, I apologize for that.
DR. LEGGETT: I think I'd just let it drop there.
Dr. Bell.
DR. BELL: Yes, I just wanted to bring up a couple of other things. For the E. coli, there actually is documentation of transfer of resistance determinants from an antibiotic used in animal agriculture to strains causing urinary tract infections. This was in East Germany back in I think it was the 60s or 70s. There was a streptothricin class of antibiotics that were used only in animals, and it turned out that the resistance genes were spread and ended up in E. coli that actually was isolated from people with urinary tract infections. This class of drugs was only used in animals. So this is documented. It does happen.
It's certainly easy to understand because we're talking about gut flora, and you didn't, I don't believe, state the contrary, but I just wanted to add that this actually has been documented.
Also, many times bacteria that are pathogenic in humans are really only commensals in animals. Salmonella, for example, is not always, not necessarily pathogenic in animals, but can be in humans. The issue of enterococci, certainly they can be both commensals and pathogens in humans. I'm not sure if they're pathogens in animals. But it's noteworthy that we now have two documented cases in the United States of fully vancomycin-resistant Staph. aureus and the resistance gene, the resistance elements were transferred from enterococci that happened to be in a contiguous site.
DR. CARNEVALE: Vancomycin has never been used in animals. Not in the U.S.
DR. BELL: No, I understand, but yes, in parts of Europe. Vancomycin is not used in the U.S.
But the point I'm making is that a resistance determinant from enterococcus can transfer to Staph. aureus that is not necessarily in the gut. Now, in this particular case I'm not attributing the VRSA to any sort of animal drug use, but I'm just making the point that enterococci are present in gut flora in both animals and humans, and the vancomycin-resistant Staph. aureus that we've seen has acquired genetic material from enterococci. So the possibility has to be entertained that the drug-resistant element that is generated or spread through agricultural use could be transferred to humans and then transferred across to a Staphylococcus aureus in humans as well.
DR. CARNEVALE: Well, David, certainly no one is going to discount the possibility. But again, we need some real evidence for that happening in order for these companies to be regulated in appropriate fashion. You can't operate on the theoretical. Certainly these things are possible, but unless you have real evidence that there's a connection. If you raise theoretical concerns with every case, then you might as well not approve anything for animal use if there's a potential connection out there. So that's all we ask, is evidence.
DR. BELL: Obviously, this is a controversy that's been going on for decades.
And I think that my understanding of what the committee is being asked to address is, fortunately, a pretty narrow aspect here, which is the ranking of the antibiotics that are listed in terms of their importance in human medicine. I would just hold out that antibiotics that are viewed as critical in treating Staph. aureus, which is not normally food-borne infection, we do have to bear in mind that there is documented precedent for Staph. aureus to acquire resistance genes from bacteria that are essentially gut flora.
There are many factors that enter into this complicated FDA guidance that address the issues of how frequently, what would the connections be to the actual use on the farm, but the particular narrow aspect that we're looking at is should a drug for Staph. aureus be ranked very highly in this list that CDER gives to CVM.
We're going to have more discussion this afternoon.
DR. LEGGETT: Yes, let's go on to the next point. Dr. Bradley and then Dr. Rupp.
DR. BRADLEY: On page 6 of the handout, I just wanted to comment on the ranking of importance should factor in whether or not there's real evidence of an animal connection. Dr. Tollefson's original presentation highlighted how complex this whole antibiotic resistance problem is, and it's very multi-factorial and certainly I don't think we're going to come up with a single solution to the problem today.
To say that there is no real evidence is not the same thing as to say that there's not a problem. In each situation I think if there's an investigation which shows that there's no problem then that certainly is the scientific evidence you're looking for. But until there's actually an investigation to look at, once an antibiotic is introduced into a herd, what is the actual risk that a resistance determinant will go into a human, I think one can't really say whether there's a problem or not.
So it appears as though we're dealing with a lack of information, and theoretical concerns about antibiotic resistance are very real, but I agree with you that we need further study in order to show whether those theoretical concerns are actually important or not.
DR. CARNEVALE: That's been the problem. It's been very, very hard to design such studies. That's been the difficulty.
DR. LEGGETT: Dr. Rupp.
DR. RUPP: I guess I would just voice agreement with the previous two comments, and I think that overall your presentation seemed to try to place these organisms and conditions in a very static manner, particularly that last material on classifying things as hospital-acquired, community-acquired organisms put into these silos. I think it's a very, very dynamic process. We're seeing this all the time in human medicine, the crossover between community-acquired, hospital-acquired. I think there is good evidence to suggest that antibiotic resistance traits do transfer from pathogens to commensals. I think there is good evidence to suggest that these organisms, particularly food-borne organisms, get from animals into people and I think it's a major concern.
DR. LEGGETT: Dr. Carnevale, a couple of points. I think what you're hearing in sort of your statement that you wanted scientific evidence, the committee is sort of raising their hackles a little bit in that I think the sense is that the data that you tried to use didn't really seem to be all that scientifically neutral. It was sort of a pick and choose, as in sort of a survey in the JEC, and then the use of the SENTRY data, which is not population-based, as Dr. Bell.
And in the chart, for instance, on page 16, where Dr. Jones comes up with a list of skin and soft tissue infections where he put Staph. aureus first and Pseudomonas aeruginosa second. Come on. It's group A strep that's 90 percent. Staph. aureus is maybe 10 percent, and all the other things don't even exist. And in that slide there's nothing about GI infections, which is the major cause, as you mentioned.
So it would be nice for us, I agree, to come up with some data. It would be also nice, in terms of coming up with our program, to get some input from both AHI and the CVM about what do we know about which pathogens are in animals that didn't move to people.
While we state that food-borne illness is the only transmission, we also -- off the top of my head right now, Rhodococcus equi from horses, we didn't know about it until we got AIDS. So there's lots of things that we don't know that we may find out.
I think the committee is taking the standpoint of if there's a risk, let's think about that as opposed to when the cat's already out of the bag, the horse out of the barn, or whatever the heck it is. So look at all the things we're doing about smallpox, which doesn't even exist in the world. So I think that's why you sense some of us bristling.
But I think your point is well taken that we should certainly think of those pathogens from animals that are of the main consequence to humans. I think everybody would agree with that point. It's just how do we come up with refining that list of the things we really want to concentrate on.
If there are no further questions, I thank you very much for your presentation.
DR. CARNEVALE: Yes. Well, that was my point, thank you. And hopefully Dr. Apley can add some further context to this discussion after the break. Thank you.
DR. LEGGETT: Thank you.
So why don't we take a break a little bit early and come back at 11:00 o'clock.
(Recess.)
DR. LEGGETT: If we could please reconvene.
Our next speaker will be Dr. Mike Apley, who will talk to us about relating food, animal, and human antimicrobial use. Dr. Apley.
DR. APLEY: Thank you. Well, good morning. On behalf of the American Veterinary Medical Association, I would like to thank the committee for the opportunity to speak with you this morning.
And in the hope of stimulating some questions and discussion after my brief presentation, I'd like to give a little bit of my background. I've been a general practitioner in central Kansas, spent four years as a feed lot practitioner on the high plains, and since then I've been teaching antimicrobial clinical pharmacology and beef production medicine at Iowa State University.
On the comments on day care and feed lots, as a father of a past child care child and now two in grade school, I've often commented on the similarities also, and I think we could get together and work out a mutual model type deal.
(Laughter.)
DR. APLEY: The difference is in the feed lot the outbreaks occur about two to three weeks after the stress of shipment, and in the day care it's just the stress of Easter, Christmas, and Thanksgiving, I think.
(Laughter.)
DR. APLEY: Another big difference is when they start to break, we round them up and re-vaccinate them. So I have often looked at that.
(Laughter.)
DR. APLEY: Another question was on looking at some of these pathogens, rate of transfer, spread, around for example a feed lot, there's been a lot of work done on that, especially for pathogens that affect our animals, the ones we're very, very concerned about treating. For example, in feed lots we look at some of the respiratory disease cases, et cetera. A lot of the ones that would involve the zoonotic pathogens such as Salmonella or indicator organisms such as E. coli have been like a cross-sectional single time study with looking at prevalence more than actual spread within the operation.
There was an epidemiological investigation, getting to be 8 or 10 years ago now in the Pacific Northwest that dealt with Salmonella that was being found in some cattle in a feed lot, and they traced it back to our central, what we call the hospital facility. That was stopped by applying hygiene principles.
So to go back to our topic of choice this morning. The AVMA has presented written and public comments concerning the guidance for industry No. 152. This morning in the context of this discussion, we'll concentrate on the ranking process.
The AVMA does have a significant concern with the ranking of these drugs as it now stands. There are some reasons why the AVMA has some concerns, and one of them is that we do rely on preventive and therapeutic strategies to maintain the health of food animals. Within these strategies, antimicrobials are essential for addressing disease in food animals in order to relieve animal suffering and conserve livestock resources. In our oath veterinarians pledge to be responsible for both animal and human health, and we believe that healthy animals are the basis for a healthy food supply.
The point of my presentation here this morning is that we feel we need to be very careful that we don't bias the decision process so heavily towards protecting any potential theoretical effects on human health that we remove vital tools for protecting human health through maintaining animal health. I think that would be a reasonable agreement for most in the room and what it comes down to as we start talking about some of the details and where the break is from a problem to no problem.
The antimicrobial ranking section of Guidance 152 is especially critical. The hazard identification that's mentioned in there, it's not near as critical, of course, as the consequence assessment, which has been very nicely discussed in previous presentations.
Guidance 152 does have multiple required input categories that must be categorized as being of low, medium, or high risk, and for many of the primary categories there's really no defined method to determine that degree of risk. An example is mechanism spectrum, pharmacokinetics, dynamics, resistance mechanisms, et cetera. The criteria for calling them low, medium or high is really not there, so you tend to go towards a more conservative approach. We feel that by some of the methods that are being used to put some of these antimicrobials in a high ranking might further bring about this potential to have an overly conservative approach.
Within each one of these, and going along that conservative approach, if the FDA determines there is inadequate information, then the most conservative assessment of high risk is assigned. Now, this next statement, I'm not implying that this was the CVM's intent in any way, but we do feel it is an outcome of some sections of the document that if we do not have the evidence to argue that, hey, this is low rather than medium, or medium rather than high, then we end up going to the more conservative or higher approach, which gets to the issue of proving there's not a problem or proving that there is.
We realize the concern that nothing be let slip through, that a potential problem not be missed, but on the other hand, we ask that the committee consider that by going too far to the side of saying there is a potential problem, let's really err on the side of conservative, that the potential adverse effect of that is to take away a valuable tool for use in veterinary medicine.
The context within which these drugs should be ranked is defined or we feel they should be ranked as defined in Guidance 152. For example, in the hazard definition "is attributable to a specified animal-derived food commodity," and again, in the risk definition "is attributable to a specified animal-derived food commodity." There has been discussion today on just how hard it is to say exactly probably what attributable means. How many steps removed from a potential resistance genetic transfer do you need to be? That's really one of the issues.
So they're related. Food, animal, and human antimicrobial use in this document are related through a specified animal-derived food commodity. So we believe that the antimicrobial drug rankings in this guidance document should consider only those bacteria or resistance determinants that are food-borne.
In other words, antimicrobial drug rankings justified on the importance for treatment of other than food-borne bacterial disease or disease involving food-borne resistance determinants should not be included as part of the final outcome determination in this document.
Now, what we would ask for is justification, and I look back at this and that's probably a more combative word than I wanted to use, but justification of antimicrobial rankings based on the following disease organism combinations in a document intended to address resistance relationships through food-borne channels. Our goal in asking for this is to be able to evaluate and understand the reasons for each ranking and then to be able to comment on what the degree of evidence is or potential links that may exist as specified for reasons for ranking.
So these are examples of some of the ones that you can read in the slides, rather than me go through them, that were either mentioned at the public meeting or come out of Guidance 152. Again, we are not saying that you are incorrectly ranking these for importance in human medicine. That's not our intention at all, but rather we're asking what could be the potential outcome on the final classification of this guidance document by using these types of applications to come up with the ranking of the antimicrobial drug for use in the consequence assessment. So these are in your slides and ones that we'd be interested in discussing and seeing comments on. Are these related to a food-borne context?
As it stands right now, the guidance document does not provide specific disease justifications for the rankings of each drug. There are examples given in the document. We would be very interested in seeing these actually linked to the drugs so we could evaluate those, and there is a degree of subjectivity in them. I think that's why it's really important that the ability to comment on them be given.
An example of one of the antimicrobial situations we would have questions about, which was discussed at the public meeting, is the ranking of the natural penicillins is high. And what this would do is say that in the first two sections of the document you were to have low and low, the consequence assessment ranking of penicillin G is high would move this up into the medium category and puts us into a whole other set of situations.
The AVMA recognizes and supports the need to preserve human health and our part in that. We also have an obligation to do everything we can to make sure we have the tools available to protect and address animal health. We feel that by taking this document to the direction that the consequence section is based on food-borne, either pathogen or resistance determinant, links that we would better serve the interests of both parties.
With that, I would conclude my comments and be open for questions or comments from the committee.
DR. LEGGETT: Are there any immediate comments?
Just in terms of examples, when I read the guidance document, I thought those were just examples, not that they were supposed to be set in stone. So I may have misunderstood. It seems you also interpreted those as set in stone, but I read them as examples.
I certainly personally agree that rankings need to be justified scientifically and in a transparent fashion.
You mentioned penicillin and neurosyphilis. It doesn't take me long to go from penicillin in animal feed in the United States to potential emergence of resistance. That doesn't seem to be too many links apart. Can you explain, first of all, how penicillin is used currently? Is it therapeutically used in animals or also as growth promoters? And how that wouldn't have an impact on human illness.
DR. APLEY: I'm aware of one growth promotion claim for penicillin G, could not speak to the extent of use of that. Therapeutically it's very important to us for treatment of diseases. It's got a label for respiratory disease. The problem with the label of procaine penicillin G is that the labeled dose is ineffective, so we then go within the constraints of the Animal Medicinal Drug Use Clarification Act and use it in extra-label fashion. And we get withdrawal information from Food Animal Residue Avoidance Data Bank for that use.
It's used in cattle for indications such as infectious pododermatitis, or foot rot, therapy of some types of pneumonia. It's important in swine for some respiratory --
DR. LEGGETT: Right. What I'm saying is, penicillin is mostly used therapeutically. I don't think the committee -- at least my interpretation of the way things are going -- that's not where the concern is. The concern is the huge numbers. The way that we think of emergence of resistance is, for instance, in an intensive care unit where you've got the sickest patients, just like the sickest animals, and you put them all together and then they have a very high pressure to develop resistance. The other way you do it is you give a little bit to a sea of people, so the population part of it brings up your resistance.
I think that my concern in trying to come up with these rankings that we're going to try this afternoon to sort of get our fingers around, is how do you attack the problem as we know it in terms of the processes of the emergence of resistance. So I think everybody's goal is to come up with something that everybody can understand.
Dr. Rupp.
DR. RUPP: I guess I would just again point out this is a very dynamic process, and it's extremely difficult to predict the potential significance of an agent sometimes now based upon what's going to happen. I guess the best example of that would be the situation currently with virginiamycin. Ten years ago nobody cared that virginiamycin could have been used in animal use or animal feeds. Now we have a huge degree of cross-resistance of enterococci with a therapeutic agent, Synercid, that was not developed and there was no need for it at that time. That's clearly use of antibiotics in animals that is now influencing human disease. Nobody would have been able to know about this a few years back.
DR. APLEY: I recognize and respect your concern about that. I think the other side of that, in my view, is where we draw the line in pursuing those concerns. I messed around with applications one day, and if you start thinking if you can name one organism that perhaps has a cassette carrying four different ones, or if you think about potential class cross-resistance, or you think about potential uses, you could come up with reasonable possible problems with almost any compound. The question is how far you go in requiring some level of evidence to establish that that's a likelihood.
And again, we're not saying let's just go on with no consideration for human health. What we're saying is we need to go back and forth on the criteria that are being used, so we can strike a ground where we retain the ability to address therapeutic concerns in our patients and you do also.
DR. LEGGETT: Dr. Brown?
DR. BROWN: I think some of us in human health feel like we're in a quagmire of ignorance because we don't know the relative importance of the use of these antibiotics in feed lots versus the amount of drug which is used in therapy, versus the amount of drug which is used for human use. Could somebody give us that perspective in some order of magnitude?
DR. APLEY: I can speak to the feed lot aspect. Are you talking about drugs that would be labeled for therapeutic or growth promotion purposes?
DR. BROWN: I don't think we have a good feel for either volume or which drugs are used largely in feed lots. So I think we're sort of ignorant right now.
DR. APLEY: The volume comes to be quite a contentious issue. I believe -- Dr. Tollefson, I'll put you on the spot -- that there are regulatory processes, or in development, to address reporting to that?
DR. TOLLEFSON: Amount used is a problem. Essentially we don't know. But let me answer the question in a different way.
Many of the drugs are approved for subtherapeutic or growth promotion use as well as therapeutic. So the example of penicillin, we have a number of approvals for growth promotion use of penicillin. Many of these are also in combination with other growth promoters.
It very much varies by species also. Feed lot cattle are not going to be seeing a lot of growth promoters. There are non-antimicrobial drugs like hormones and so on that can be used.
The issue of amount. There are more of the penicillin, tetracyclines, virginiamycin type of drugs, growth promoters, used for growth promotion simply because of the number of animals and the length of time that they are administered. So the therapeutic use is going to be naturally much smaller.
There have been some estimates. One group of estimates is something done by the Animal Health Institute, where they surveyed their members and were given rough estimates anyway. I don't know if Rich could speak to that.
But I don't think the amounts are going to mean anything to you other than the fact that it's a big number. There are a lot of animals. We slaughter, what, some 9 billion chickens a year. They live 42 days. So they're all getting fed growth promoters, virginiamycin primarily in that case.
DR. LEGGETT: Basically what we're trying to say is that for us to have the maximum valid input this afternoon in discussion, it would help us a lot to put this in context, if not at this meeting, certainly before the next meeting. We have to come up, I think, as I stated earlier, with a more mathematically tenable and testable hypothesis or way of getting about this model.
DR. TOLLEFSON: One thing that I elected not to show in my presentation is Table 4 in the guidance document, which addresses use, limitations on use, and how we came about assigning risk categories to that issue.
DR. LEGGETT: Page 25.
DR. TOLLEFSON: Page 25, Table 4. When we speak to the extreme right column, flocks or herd of animals, this is where all the animals in any kind of a confinement facility are getting treated with that drug. So it would be all chickens in a house. Not all chickens in a flock. They're divided up into houses, but it could be 30,000 birds, up to about 100,000, I think. It would also be maybe all swine within one building.
See, part of the problem is it varies very much by the kind of production unit it is. It could be 500, it could be 1,000, it could be any number I think.
Then we had the duration of use in combination with that, to get at the question of what are the animals seeing, selected for pressure.
DR. LEGGETT: As an example or follow-up, can you tell us what of these antibacterial food additives that Dr. Carnevale talked to us about would be typically used in chickens and would be typically used in swine?
DR. TOLLEFSON: The antimicrobials that Dr. Carnevale talked about?
DR. LEGGETT: On page 13, he talked about the antibacterial food additives. Then you talked about table 4, and you had this category of high where flocks or herds or animals were used. And I just want you to fill out the example for us.
DR. TOLLEFSON: Got you, okay. For example, carbadox is -- I wouldn't consider that. Erythromycin is the first one. Avoparcin is not approved. The erythromycin is the first one. That's almost exclusively used in swine as Tylosin as a growth promoter. Yes, feed lots to a certain extent.
DR. LEGGETT: How about lincomycin?
DR. TOLLEFSON: Lincomycin is a swine drug. And poultry too?
DR. LEGGETT: As growth promoters? No?
DR. CARNEVALE: No, mostly therapeutic.
DR. TOLLEFSON: Yes. That's mostly therapeutic.
Penicillin is approved in all classes of animals for all uses -- growth promotion, prophylactic, therapy. In general, the old drugs, penicillin, tetracyclines, sulfa drugs are approved for everything.
DR. APLEY: Yes. I think just in cattle there wouldn't be a growth promotion penicillin.
DR. TOLLEFSON: No. That's an injectable.
DR. APLEY: Poultry and swine.
DR. TOLLEFSON: Right.
DR. WALD: Which one of those is a sulfa drug?
DR. TOLLEFSON: Oh, I'm sorry. Sulfa drugs are used in combination in growth promotion. Sulfa methazine -- anybody from 157 here? Sulfa methiazole.
DR. WALD: So it's not on this list?
DR. TOLLEFSON: No, you're right, it's not. There is no single sulfa drug used as a growth promotion. Correct? I don't think so. So they use it in two- and three-way combinations.
I think the point is that the way we tried to address the issue was through table 4, and then if you look at the risk management table, that's strictly limited to category 3. Growth promotion uses would only be available on category 3, the least category of concern.
DR. LEGGETT: Dr. Wald.
DR. WALD: Yes, I think it's easy for us to agree that healthy animals are the basis for a healthy food supply, and to be sympathetic about the use of antimicrobials for either treatment or even prophylaxis when there is illness in some of the animals in a herd.
I guess for me the big question would be as growth promotion, and I'm sure that this is a controversial issue. But there must be areas in the world where these things are not added to the food that animals eat. And I wonder what are the data that they are essential for growth promotion, and could we hear some discussion of that.
DR. LEGGETT: Do you want to try in 30 seconds or less?
(Laughter.)
DR. APLEY: That's one that I'm surely not the resident expert on. There may be some others later who would be willing to comment. A lot of that goes around the Danish experience or what's gone on in that area of the world with withdrawal of these. The key thing that rests in my mind is the total amount has gone down due to removal of those products. We've seen therapeutic use go up.
Let's say that is a two-hour deal. It would be something that if this committee would be interested in, there would be the availability of having someone come and present on that because, as usual, there's data that can be interpreted in several ways.
DR. TOLLEFSON: Yes. We have a fair amount of data on that. What tended to happen -- and I've got to say from a personal point of view I thought the way the European Union handled the issue was a little draconian, in that they just removed them. So they did find animal health problems in the use of therapeutic antimicrobials rose.
When all the dust settled over a period of time, the Danes and the Swedes are getting along pretty well. They have some problems with predictable areas, like weanling pigs. When the baby pig is removed from the sow and put into the first growth phase, that's still an issue. They do have disease rates that they need to treat with therapeutic drugs, and for a relatively short period of time. But they do need to use antimicrobials. I think the experience has shown that you can't raise animals without antimicrobials. In general you can't.
DR. LEGGETT: Dr. Poretz.
DR. PORETZ: Although we occasionally see advertisements for hormone-free and antibiotic-free animals in the food stores, what percentage of chickens and what percentages of cattle, swine that are sold commercially are given antimicrobials of any type?
DR. TOLLEFSON: Most of them. Antibiotic-free animals are antibiotic-free. The companies raise the animals, and if they need antimicrobial treatment for health reasons, they'll divert them to regular commercial channels. Hormones are only given to cattle, pretty much in this country. Poultry don't have hormones at all, but they do have growth promoters. So pretty much all animals see antimicrobials -- that's true -- at some point in their life.
DR. LEGGETT: Dr. Maxwell.
DR. MAXWELL: I don't see it on the list, but I just wondered, are any quinolones used for growth promotion?
DR. LEGGETT: Absolutely not. It's approved. There are very limited approvals. There are approvals in poultry. All are therapeutic and under veterinary prescription. The poultry one is highlighted because the FDA has decided to go through the process of removing that approval. Yes, we are in the middle of the process of doing that, and it's long and involved.
There are also therapeutic fluoroquinolones for use in cattle and in swine, and those are both injectable.
DR. APLEY: No, there's not one for swine. A fluoroquinolone isn't.
DR. TOLLEFSON: Just approved.
DR. APLEY: Oh, okay. I didn't read that one. The two for cattle are respiratory disease only.
DR. TOLLEFSON: Oh, the other one's a Bayer product and another one for cattle. I'm sorry. Yes, that's right.
DR. APLEY: Yes, okay. That was a new one to me. There's danofloxacin and enrofloxacin. They're approved only for use in bovine respiratory disease and any extra-label use is prohibited.
DR. MAXWELL: I just had an additional question. I don't know anything about it, but I know that I have heard that some people access animal drugs for human consumption. Do you have any comment on that?
DR. APLEY: The one that made the news recently was individuals going into pet stores and acquiring them through that. If that does occur in the veterinary chain, it would surely not be intentional. They're controlled and dispensed for animal use. But that was going in and buying aquarium caplets and using them as an example.
We had the question about how are drugs used in the production setting. I could give you a two- or three-minute rundown of exactly how you'd see it in a feed lot, how they're used, if that would interest you.
DR. LEGGETT: Yes, I think so.
DR. APLEY: What we do is on arrival the animals are processed, put into pens. There are compounds that may be used in the feed. One of the ionophores is very typically used in cattle, and that would include Monensin and Lasalocid. They're used as a coccidiostat and used as a performance enhancer, altering rumen flora. Tylosin may be used as a liver abscess preventive.
There was an article in the New York Times about the --
DR. BELL: That's a macrolide.
DR. APLEY: That's a macrolide, a macrolide not used in human medicine, but it is a macrolide.
DR. BELL: In case everybody didn't necessarily know that Tylosin was a macrolide, I just wanted to mention that.
DR. APLEY: There was a New York Times article about the vats of hormones that were put in the feed. We don't put any hormones in the feed. If they are given a growth promoting hormone, it's an in-ear implant.
For animals that display signs of respiratory disease, we have labeled products that include the two fluoroquinolones discussed. We have a macrolide in erythromycin, Tylosin. Tilmicosin is a macrolide labeled for respiratory disease. We have a third generation cephalosporin, Ceftiafur, which is labeled for the use in respiratory disease and in foot rot, infectious pododermatitis. We also have a thiamphenocol derivative, florfenicol, which is approved for that.
Of those drugs, we have two of them that are also labeled for -- we use the term "metaphylaxis" -- high-risk animals on arrival that are considered to be in the early stages of respiratory disease, and that is the case in feed lots, where we may apply a drug in an injectable format to the entire group of cattle, a pen of cattle coming in, or a load.
Then we also have other drugs approved for respiratory disease. We have some sulfa dimethoxine, sulfa methazine. We have oxytetracycline.
In the feed we have oxytetracycline and chlortetracycline as individual agents, and then we have a combination tetracycline-sulfa agent that can be used in the feed for therapeutic prevention of respiratory disease. They have defined periods. I think they're all less than 14 days or so.
When animals are detected in the pen as having respiratory disease, which is about 70 percent of our morbidity and about 50 percent of our mortality, we usually -- respiratory disease case fatality rates will run 5 to 10 percent in highly stressed cattle down to 1 percent in cattle that are not. When they are identified, they are typically brought to a central treatment facility where they are treated. Some hospitals keep them there, some take them back.
I work with feed lots up to a 100,000-head capacity. That translates to about 21 miles of feed bunk in that facility. We had each animal individually identified with a tag, and they were entered into a treatment computer, and as a consultant I'd start my day there every day, when we came there twice a month, analyzing treatment response. We would perform necropsies on all the animals so we could go back and see what exactly was happening.
So with the larger units and the progression of the industry, we're actually progressing towards tighter and tighter veterinary control of the therapeutic agents than we've ever had before. In this case we've got 100,000 head of cattle in a two-square mile area that each have their own individual identification number, and if they're treated, their response is tracked on computer.
DR. LEGGETT: A question. They're still in the herd when they're being treated? They're not sort of ostracized or isolated?
DR. APLEY: Yes. The problem is when you isolate them in what we call our hospital facility, then you mix cattle from different groups. That happens somewhat. Some facilities have gone so far as to treat them and quickly return them to the home pen so that they're not exposed to whatever others might have. This is a case where one of our biggest management procedures is preventing viral effects, bovine viral diarrhea, IVR, which is a herpes virus. And it's just like in human medicine. It hides out and comes back under stress. We try to address those in a lot of our successful programs. By addressing those viral etiologies, we drastically decrease their need for antimicrobials.
That in a nutshell is how we use it.
DR. LEGGETT: Could either Richard or you give us an example of, for instance, you say 50 percent of the mortality in cattle would be respiratory, so we could sort of think of those antibiotics that you're using there. What are the illnesses for which swine are most often treated therapeutically? What antibiotics would most likely be used, do you know?
DR. CARNEVALE: I'd prefer to turn to some folks in the audience who are swine specialists to answer that question. Paul?
DR. LEGGETT: Please identify yourself.
DR. SUNDBERG: I'll ask you to restate the question too.
I'm Dr. Paul Sundberg. I'm with the National Pork Board and I'm asked to be part of the open comments this afternoon as well, so maybe we can address some of those then. But again, specifically your question?
DR. LEGGETT: Trying to get a handle on what would be typical antibiotics used therapeutically for the major causes of mortality. Dr. Apley just said it's mostly respiratory, for which there would be fluoroquinolones and the sulfa things. What would be the correlate in swine?
DR. SUNDBERG: In pork production, there are really two times of primary risk for disease. One is as a neonate and a young animal. That's diarrhetic diseases. Those are diarrheas. So you use those antimicrobials that would be effective on diarrhetic disease. It happens in the feed lot too, if I understand correctly.
As the animal gets older, then that risk from diarrhea transfers over to a risk of respiratory disease. So you see little diarrheas during the older stages of the animal's life and more of the respiratory disease and the antimicrobials that would be used for that.
For example, Tylosin, penicillin, tilmicosin. Those could be used for respiratory diseases in pigs. Chlortetracycline. The tetracyclines are used commonly, both for prevention and for treatment.
DR. LEGGETT: And in the diarrhea?
DR. SUNDBERG: For the diarrhea, it's Tylosin again. Some of the Gentacin, for example, is labeled for diarrhea in neonatal pigs.
DR. LEGGETT: Any cephalosporins?
DR. SUNDBERG: Not for diarrhea.
DR. LEGGETT: Thank you.
Dr. Maxwell.
DR. MAXWELL: Just a general question. What percentage of respiratory illness is of viral etiology?
DR. APLEY: This is an excellent question that we continue to ask for the final question -- actually in the bovine respiratory disease we call it the complex. We think that viruses are a big part of setting it up. We treat animals with elevated temperatures, displaying signs of depression and appearing to be suffering or in danger of not making it if not treated. For those animals, when we do deep nasal swabs, et cetera, there are varying percentages who are able to recover something. I couldn't give you a good percent of how many are involved. There's a possibility that in a lot of the cases it was laying somewhere in there as one of the instigators, although there's a bacterial cause now.
And along that line, which I think the question is probably leading to, are there any ways of trying to avoid putting antimicrobials in animals that are just viral. One of the things we do is in the yards I've worked with is we institute what we call a non-eater treatment, and in that treatment the animal is identified in the pen as displaying signs of respiratory disease, being depressed, off feed, nasal-ocular discharge, et cetera. If, when they get to our hospital facility, we find that their temperature is not elevated to a sufficient amount and they've stopped displaying the signs of lethargy, et cetera, some places may revaccinate, some may give them some oral vitamins, some hydration but don't put an antimicrobial in. It's been very successful. We've found in those programs that our case fatality in the ones that are just treated as an observe or a non-eater is actually less than the ones treated for true respiratory disease.
And that's one of the reasons we watch our case fatality so closely. If we get a case fatality of almost 0 percent, that tells us there are a lot of animals being treated that don't need to be, and we go back and change our treatment criteria.
DR. LEGGETT: Would you estimate that the number, the percentage of veterinarians who give antibiotics for viral illness is as high as it is among doctors who give antibiotics for viral illness?
(Laughter.)
DR. APLEY: I don't know how to answer that and win.
(Laughter.)
DR. APLEY: I will tell you that veterinarians are extremely concerned about this. I do a lot of continuing education, and one of the reasons is because I talk on antimicrobial resistance, prudent antimicrobial use, case definitions, and applying those in production settings. Veterinarians are very interested in that and there are two reasons. One is there's an obligation to animal and public health. The second is the profit margins for our clients are really narrow.
For example, on our feeder cattle, to use some of those antimicrobials I talked about could take $15 to $20 per animal. Over the long haul, people would hope to make $15 or $20 per animal, over the long haul feeding those animals.
That's another reason is economically this -- in the New England Journal of Medicine, that editorial about we'd rather just lace them with antibiotics instead of applying management -- that's so wrong. That is so unbelievably wrong, not just because of our ethics and our obligations but because we can't afford to do that. The food animal sites, the food animal segments within the industry that think they can rely on antimicrobials to cover up management practices are not going to stay in business. We don't want to do it and we can't afford to do it.
DR. LEGGETT: Dr. Goldberger.
DR. GOLDBERGER: Could you talk a little bit about the current threat areas in terms of not having available or adequate therapy, the things that are driving the need for new antimicrobials in animals?
DR. APLEY: I think we're finding some of the same areas, and that there are some Gram-positives giving us some fights. We see some streps that are tough to deal with with the drugs we have available. We see enteric disease similar to you. Some of the enteric diseases that are moving around in some of the neonates are very tough to treat and we've always focused on prevention and it brings a newer emphasis to it.
Some of the Gram-negatives, the enterobacteriaceae can give us a really big challenge. There are some Actinobacillus that are starting to show up with some resistance. A lot of the enteric disease, the same as in human medicine, gives us a real fit.
DR. GOLDBERGER: Are most of the examples you're using, individual or small numbers of animals treated, or are some of these situations where you might end up having to treat large numbers of animals for some of those infections?
DR. APLEY: For some enteric outbreaks, there would be the need to address a pen or a room or a group of animals. On the cattle side, our enteric disease is almost all individual animal, and our enteric disease usually takes place out on the pasture. Then as Dr. Sundberg stated, in swine it would be earlier on.
Most of our enteric disease occurs the furthest away from going to the slaughter facility as possible. It occurs early on in the animal's life, so there's quite a little time between there and harvesting the animal.
The respiratory cases, depending on the species, in the same way. They may require addressing the whole group, or they may require individual animals.
One thing we've found is that if we delay in some of these cases and wait for individual animal therapy -- for example, in what we call the high-risk cattle -- that we end up having to use a lot more antimicrobials on the one we treat later.
DR. LEGGETT: Could you clarify? By threat areas, do you mean bacteria that are resistant to current antibiotics, just so we're all clear on that?
DR. APLEY: Yes. We'