[I]{.underline} [N]{.underline} [D]{.underline} [E]{.underline}
[X]{.underline}

**USE OF ANTIMICROBIAL DRUGS IN FOOD ANIMALS**

**AND THE ESTABLISHMENT OF REGULATORY THRESHOLDS**

**ON ANTIMICROBIAL RESISTANCE**

January 22, 2001

**[Session 1: Introduction and Overview]{.underline}**

***Welcome, Purpose and Objectives of Workshop***

Dr. Claire M. Lathers

FDA/CVM 4

***CVM Approach to the Establishment of Thresholds***

***General Overview***

Dr. Stephen Sundlof

FDA/CVM 8

**[Session 2: Use of Antimicrobial Drugs in Food Animals]{.underline}**

Moderator: Dr. Andrew Beaulieu, FDA/CVM 20

***Animal Husbandry and Disease Control: Cattle***

Dr. Michael D. Appley

American Veterinary Medical Association 23

***Animal Husbandry and Disease Control: Swine***

Dr. Robert B. Morrison

University of Minnesota

College of Veterinary Medicine 42

***Animal Husbandry and Disease Control: Poultry***

Dr. Dennis Wages

American Veterinary Medical Association 64

***Animal Husbandry and Disease Control: Aquaculture***

Dr. John Plumb 85

***Alternatives to Antimicrobial Drug Use in***

***Food Animals: Benefits and Limitations***

Dr. Saeed A. Khan

FDA/NCTR 102

***Human Health Risks Associated with the Use of***

***Antimicrobial Drugs in Food Animals***

Dr. Glenn Morris

University of Maryland

School of Medicine, Baltimore 114

[I N D E X]{.underline} (Contd.)

***Use of Antimicrobial Drugs in Food Animals:***

***Consumer Perspective***

Mr. Richard Wood

FACT 126

***Panel Discussion on Use of Antimicrobial Drugs in***

***Food Animals*** 141

***Public Comment Period*** 206

KEYNOTE: \"\-\--\" denotes inaudible in the transcript.

[M O R N I N G S E S S I O N]{.underline}

(8:40 a.m.)

**[SESSION 1: INTRODUCTION AND OVERVIEW]{.underline}**

***Welcome, Purpose and Objectives of Workshop***

***By Dr. Claire M. Lathers***

DR. LATHERS: Good morning. Please take your seats so that we may begin
our program. I am Claire Lathers, Director of the Office of New Animal
Drug Evaluation at the Center for Veterinary Medicine at the Food and
Drug Administration. Welcome to CVMs public meeting on the Use of
Antimicrobial Drugs in Food Animals and the Establishment of Regulatory
Thresholds On Antimicrobial Resistance.

For those of you who do not have an agenda for this meeting, you will
find copies on the tables in the back. Copies of todays program as well
as tomorrows and Wednesdays are found on the table. In addition to the
agenda, you will find copies of our discussion document entitled An
Approach for Establishing Thresholds in Association with the Use of
Antimicrobial Drugs in Food Producing Animals. We also have for you on
the back table a list of questions which we will be discussing after
each of our sessions. Finally, we do also have copies of [CVM
Update]{.underline} dated January 5th, 2001. Please, if you would like
copies of these materials, do help yourself. For those of you who have
brought portable computers, if you would like to plug them into the
hotel electrical outlets, the tables at the back of the room are
equipped with power and please do use them.

(Slide.)

The public health charge to the Center for Veterinary Medicine gives CVM
the regulatory responsibility of ensuring that use of antimicrobial
drugs in food-animals does not result in adverse health consequences to
humans. Veterinary public health is another frontier in the fight
against human disease with responsibility to determine which antibiotics
are available for use in humans or animals, and the responsibility of
deciding how to categorize the antimicrobial use in animals according to
their importance in human medicine.

(Slide.)

The background for this meeting stems from the Framework Document. This
was published in the [Federal Register]{.underline} on January 6 of
1999. It first introduced the concept of establishing regulatory
thresholds. For today and for the next two days, we will be focusing on
the Threshold Discussion Document, which was made available by CVM on
December 22, 2000. In the threshold discussion document we have outlined
the CVM approach for establishing thresholds.

(Slide.)

The purpose of this meeting is to discuss the risks and the benefits of
antimicrobial drug use in food animals. We will be considering
approaches for establishing regulatory thresholds on antimicrobial
resistance. The objectives of this meeting include the following. CVM
will obtain broad stakeholder input on the use of antimicrobial drugs in
food animals. We will obtain comments on the threshold approach outlined
in the CVM discussion document. CVM will obtain input on the possible
alternatives to CVMs approach.

(Slide.)

Goals for this meeting include: 1) we will listen to public comments; 2)
this meeting will provide an opportunity to consider all perspectives;
3) this meeting will allow us to receive feedback on the CVM approach
and input on panel discussion questions, and the meeting will give us
ideas for alternative approaches; and 4) we encourage discussion of all
relevant concerns.

This Monday morning, January 22nd, we will begin with a general overview
of the CVM approach to the establishment of thresholds. This will be
followed in Session 2 by a discussion of the perspectives on
antimicrobial drug use in food animals.

(Slide.)

Session 2 will include topics related to animal husbandry and disease
control related to cattle, swine, poultry, and aquaculture. We will have
a discussion of the alternatives to antimicrobial drug use. There will
be a presentation on human health risks and we will consider consumer
perspectives.

(Slide.)

This afternoon Session 2 will begin with a panel discussion on
antimicrobial drug use in food animals. During this panel discussion we
will consider the questions related to the presentations. This public
discussion panel will be followed by a public comment period.

Tomorrow, Tuesday January 23rd, we will begin with Session 3,
establishing human health thresholds. The afternoon panel discussion
will address questions related to this topic, and the panel discussion
will be followed by the public comment period.

(Slide.)

Wednesday morning, January 24th, in Session 4 we will begin with the CVM
approach: use of our risk model to establish resistance thresholds. This
will be followed by a panel discussion of resistance thresholds with
questions related to the topic and concluded by a public comment period.
In the afternoon of Wednesday, Session 5 will discuss alternative
approaches to the CVM proposal. There will be a public comment period
and finally the closing comments, summary, and a discussion of the next
steps. I think you can see we have a very full agenda for the next three
days.

(Slide.)

I have several additional comments. The ground rules for this meeting
begin with the fact that the FDA Office of Chief Counsel requires there
will be no discussion by CVM personnel of the pending NOOH, Notice of
Opportunity of Hearing. For this meeting, if you would like to send
comments on the CVM threshold document, please do so by submitting them
to Document #00D-1677. They should be submitted by April 9th, 2001.
Finally, a transcript of this meeting will be available on CVMs website
at a later date. The address for our website is www.fda.gov/cvm.

***[CVM Approach to the Establishment of Thresholds -]{.underline}***

***[General Overview]{.underline}***

***By Dr. Stephen Sundlof***

DR. LATHERS: We will now begin with Session 1. Dr. Stephen Sundlof will
be discussing The Cvm Approach to the Establishment of Thresholds, a
General Overview. Dr. Sundlof is Director of the Center of Veterinary
Medicine at the Food and Drug Administration. He received both his
Doctorate in Veterinary Medicine and his Ph.D. in toxicology from the
University of Illinois. Dr. Sundlof is a diplomat of the American Board
of Veterinary Toxicology. He served on the faculty of the University of
Florida, College of Veterinary Medicine from 1980 through 1994, where he
held the rank of Professor. Dr. Sundlof has published numerous articles
in scientific journals on drug residues and food safety. He has
presented more than 100 invited lectures at national and international
meetings. Dr. Sundlof presently serves as chairman of the WHO/FAO Codex
Alimentarius Committee on Residues of Veterinary Drugs in Foods and is
past president of the American Academy of Veterinarian Pharmacology and
Therapeutics. Please help me welcome

Dr. Sundlof. Steve.

(Applause.)

DR. SUNDLOF: Thank you, Claire. Just a second here to switch. As Dr.
Lathers has, I certainly want to welcome everybody here, especially to
some of our visitors who have traveled across the Atlantic to get here.
We really appreciate your taking interest in this issue that is
extremely important to us. I was asked to give an overview of a document
that turned out to be 40-some pages long in a very short period of time.
So my job today is to try and give some of the insight that went into
developing this document that you have before you.

(Slide.)

Recall as Dr. Lathers has already indicated that the framework document
which was introduced in 1999 did contain the rudimentary elements of the
discussion on setting regulatory thresholds. The agency believes that it
may be possible in certain cases to define the level of resistant
bacteria in animals that would result in no or insignificant transfer of
resistance to human pathogens. The agency believes that this level of
resistant bacteria in animals would need to be determined for each
antimicrobial prior to approval and may vary depending upon human or
animal pathogen of concern, and that was the level of detail that was
given to the issue of regulatory thresholds in the framework document.

Since that time, we have been actively trying to find a way of actually
making that happen, how would thresholds be set, and we went through a
lot of discussion in trying to come up with what we thought would be the
appropriate approach to establishing these regulatory thresholds. We
have tried a whole lot of different approaches, and the one that we
finally came up with I think was the one that we agreed had the best
opportunity for actually being able to implemented and successful.

(Slide.)

Well, why thresholds? First of all, let me just say that CVM will
approve drugs only when and in its best

judgement they meet the standard of reasonable certainty of no harm.
With respect to antimicrobial resistance, CVM would not approve a drug
intended for use in food animals if it had reason to believe that the
emergence of bacterial resistance would be eminent and would impact on
public health. Unfortunately, unlike chemical residues which are
evaluated using a battery of well-established laboratory methods, no
predictive models presently exist to estimate the rate and extent of
bacterial resistance that may emerge from the use of an antimicrobial
drug in food animals. We just dont have the kinds of models that would
allow us to make that kind of determination prior to the approval. So in
the absence of predictive models, CVM is proposing the establishment of
resistance thresholds as an added safeguard to protect public health.

(Slide.)

Lets just talk about what we are talking about when we are talking
about thresholds, and really we are talking about three different things
when we are talking about thresholds. There are three interrelated
parts. You have to have an antimicrobial, obviously; you have to have an
animal species, a food animal species in this case; and a bacterial
species. So all of those three are components to establishing
thresholds. When we are talking about a threshold we are talking about a
drug, an animal species, and a bacterial species, and one or more
thresholds may be established for any specific drug in any given animal
species. Let me kind of explain that.

For instance, if we had two bacterial species in an animal, if it were
something like salmonella and campylobacter, we may have for the same
animal species and the same drug two different thresholds, one for
salmonella and one for campylobacter. Tripping either one of those
thresholds would then result in regulatory action. Or we may have
different endpoints for our threshold. The ones we proposed in the
threshold document are, the two different endpoints are, enteric
infections and systemic infections. So there would be two thresholds for
the same drug in the same animal species. So there may be more than one
threshold, but they all contain these parts, the drug, the animal
species, and the bacterial species.

(Slide.)

Now here is kind of the central premise by which we developed the
document that you have in front of you, and basically the premise is if
we understand the disease itself, if we understand the dynamics of the
disease as it moves from animals to the human populations and causes
foodborne disease, then we ought to have a pretty good idea of the
resistant population looks like as well. So if we understand the disease
itself, we should be able to understand the dynamics of the resistant
disease. Okay? Thats the basic premise.

Although that seems relatively straightforward, when we were developing
and actually trying to develop these concepts, we started from the other
end. We started from, well, we have the resistant population, and tried
to work our way back. After a while I think it became apparent to us
that we were really looking at is a disease. The dynamics of a disease
are fairly clear, whether the disease happens to be resistant or not,
and by understanding that process better we can understand the resistant
part.

Okay. So what is required then? It does require knowledge of the extent
to which bacteria on a given food commodity are transferred to humans
and cause the disease. So we have to understand that process. But by
focusing on the disease rather than the specific drug, only a limited
number of disease models are needed to support a wide variety of
antimicrobial drugs. You dont need to reinvent the model for every drug
that we may have to evaluate. So by understanding what the important
foodborne organisms are and understanding how they transfer from the
food to humans and cause disease, we can use that model for evaluating a
number of different antimicrobial drugs and setting and establishing
thresholds. It has some beauty in the fact that it is relatively
straightforward.

(Slide.)

Here is what the method does not require. It doesnt require predictive
models. It would be difficult to develop and subject to error. That is
trying to project out in the future what the microbial population is
going to be like one year, two years, five years, 10 years down the
road. Those models are extremely complex and generally they have errors
in them that dont adequately predict what would happen, just like
trying to adequately predict the weather or adequately trying to predict
what is going to happen in the stock market over the next five years.

It doesnt require knowledge of complex dose response relationships or
minimum infective doses. It doesnt. All it requires is to know the
relationship between the bacterial population in the animal species of
concern and how that \-- the degree to which that transfers to the human
population and causes disease.

It doesnt require knowledge of the effects of animal husbandry,
transport and processing on pathogen load. It only requires that we know
what that animal species population is contributing to the overall
disease population. So all of these other factors that are important and
potential places for risk management are incorporated in the knowledge
of the dynamics of the disease as it transfers from animals to humans.
It doesnt require knowledge of food handling practices, either.

(Slide.)

What the method does require, the method really only requires two pieces
of information going in. It requires the knowledge of the contribution
of each food animal species that makes to the overall disease prevalence
in humans, and we will go through a little example here in a minute, and
it also \-- the other thing, the only other piece of information that is
needed to know in order to establish these thresholds is the likelihood
that patient will be treated with the antimicrobial drug of concern. If
you know those two things, you can establish thresholds.

All other data that will be needed in order to monitor and calculate
where we are at at any given time are captured in real time through our
surveillance system. So the amount of resistance that we measure in
humans, the amount of resistance that we measure in the animal
populations, those are all captured in real time, but they are necessary
in order to establish a threshold in the first place.

(Slide.)

Let me just walk you through an example of how this might work. These
are all hypothetical examples. We are going to take a fictitious food
animal species, species A we will call it, and we have determined that
10 percent of all salmonella cases can be traced back to food derived
from species A. That is no small task to try and do that, but to try and
determine what that particular species is contributing to the overall
foodborne disease. In this case, in this hypothetical case, 10 percent
of all the salmonella cases in humans can be traced back to food derived
from species A. Okay. If 10 percent of all patients with salmonellosis
are treated with the antimicrobial drug of concern, then up to one
percent of the patients may not respond to treatment. If 100 percent \--
this is the concept of H~max~, if 100 percent of the salmonella were
resistant to the drug as a result of antimicrobial use in species A.
Okay? That is the absolute worst case, and it gives us a boundary by
which we can work backwards to a threshold. Okay? So there is H~max~.

(Slide.)

The next thing is what is the current impact on human health, and then
we give that the designation H(x), and the first bullet is the same
bullet you saw in the last slide. Okay. A maximum of one percent of the
patients may not respond to treatment when 100 percent of the salmonella
are resistant to the drug as a result of the use of the drug in animal
species A.

Okay. Again, that is a hypothetical worst-case situation. When we
measure the population of bacteria of salmonella coming from species A
we find that only two percent of the salmonella from species A are
currently resistant to the antimicrobial drug of concern. The current
human health impact would be 0.02 percent or two out of every 10,000
cases of salmonellosis. That would be the current human health impact of
resistance due to use of that drug in species A. So that is kind of in a
nutshell basically what the concept is. All that 44 pages boils down to
basically that simple concept.

(Slide.)

One of the advantages of using this approach that we proposed is that
resistance thresholds can be periodically adjusted to take into account
changes in food production practices, changes in food processing
practices, food hygiene practices, food consumption and physician
prescribing practices. So that if, for instance, new ways of processing
food are introduced which in effect sterilizes the food, that will all
get incorporated into recalculating the threshold because the human
health impact will be significantly reduced and, if you go through the
mathematics and the algebra, that results in the ability to adjust the
threshold up.

The same thing with if food hygiene practices improve such that food
handling results in fewer cases of foodborne diseases that will have an
impact on the resistance threshold, and it can be recalculated to take
advantage of changes that occur within the industry, but are outside of
FDAs control. Prescription prescribing practices might be another area
in which if physicians rely more heavily on the drug of concern or they
rely less heavily on the drug of concern for treating those particular
diseases, that will be reflected in the threshold.

Food consumption, if we ever get mad cow disease in the U.S. and
everybody quits eating beef, food consumption in beef would go way down
like it has in Europe, and we are seriously hoping that that doesnt
happen. But food consumption practices can change over time, and so that
will have an impact on the thresholds as well. But that is all
incorporated in there, and it is a very simple measure to go back and
recalculate once you have additional information, which we are capturing
through such programs as NARMS and FoodNet, et cetera.

(Slide.)

What are the limitations to the CVM proposal? Well, the proposed
approach does not deal with all the potential issues associated with
antimicrobial resistance, such as multiple drug development \-- or, Im
sorry, multiple drug resistance. The use of one antimicrobial causing
selected pressure for other antimicrobials because they happen to exist
on the same transposon. It doesnt take into account that. It doesnt
take into account indirect transfer of resistance to non-zoonotic
pathogens. We are not there yet. That is even more complicated than the
issue that we are trying to deal with now. I am not saying those issues
arent important. We just havent figured out a way of trying to
incorporate it into this particular method at this time.

But I would just say the failure of the threshold approach to resolve
all of the concerns is not a justification for abandonment of this
approach. This is a good first start, this or something else. I think if
we try and address all of the issues surrounding it at one time it will
result in failure. So I think again we recognize that it is not all
things to all people, but perfection is the enemy of good, and we want
to make sure that we at least are in a place where we can be moving
forward on this part of the issue of antimicrobial resistance.

So my hopes for this meeting are that we can reach some kind of an
agreement on the approach to establishing resistant thresholds, and I
think that is going to take a lot of discussion on everybodys part. I
think people need to engage in this discussion with the idea that by the
end of this meeting we should have reached at least partial agreement on
the approach that we need to go and take to move forward. I think our
failure to reach agreement on this issue will only prolong the
contentious debate which has now lasted for more than 30 years, and the
consequences I believe of our failure to move forward will be equally
negative both for agriculture and the public health.

(Slide.)

So with that, I think we have a little time for questions, if anybody
has any questions. Please use the microphone if you do.

(No response.)

Okay. Thank you very much. We are moving into then Session 2.

**[SESSION 2: USE OF ANTIMICROBIAL DRUGS IN FOOD ANIMALS]{.underline}**

MODERATOR BEAULIEU: Good morning. I am Dr. Andrew Beaulieu from the
Center for Veterinary Medicine, and my purpose here today is to moderate
Session 2 of our workshop. However, I find that I must do more than
that. I find that I cannot in good conscience remain silent on this
issue. So I beg your collective pardon while I lay a few minutes of
personal philosophy on you. This is a point in the program where any FDA
attorneys in the audience start to hold their breath. Joy, if you are
out there, I think were in good shape.

I stand before you today with a new title. I am no longer the Deputy
Director of CVM. I am now the Associate Director for Animal Health
Policy and Operations. There are a number of reasons for this, but among
the most important is that I believe that in all of the legitimate
recent concern for human health associated with a myriad of issues that
have bombarded the Center, including the issue of antimicrobial
resistance, we are in danger of losing our balance with respect to our
statutory obligation to also protect animal health through the products
that we regulate. In essence, there was a perceived need for a position
in the Office the Center Director specially focused on animal health
issues, and I was able to obtain that position.

I found in my 57 years of experience \-- of existence \--

(Laughter.)

MODERATOR BEAULIEU: During which I was accumulating experience I hope,
half of those years working at CVM, that human beings are an amazingly
complex and frequently very self-centered species of animal. I very
strongly believe that humans have a moral obligation to recognize and to
moderate their inherent self-centeredness, their anthropocentricity, in
order to better protect the health, in many cases the very existence, of
the other animal species with whom we share this planet. In short, I
believe that we have a moral obligation to balance our inherent concern
for human health with a concern for animal health. I expect that those
of you in this room today probably share this philosophy, but perhaps to
significantly different degrees.

It may be useful to think of the human health threshold that we are here
to discuss this week as a numerical expression of that balance point
between our concern for human health and our concern for animal health.
I believe that we have an obligation to define that balance point to the
best of our ability, consistent with the existing law. I further believe
that if we collectively conclude that there is a scientifically and
societally acceptable balance point that could be defined, but which
appears to be precluded by existing law, that we have an obligation to
work to change the law to accommodate that point.

I can testify from personal experience that when the Agency is convinced
that the law can be modified in the interest of animal health without
compromising human health, the Agency and CVM will not hesitate to
dedicate the significant amount of time and effort it takes to
accomplish such statutory change. We are already in the process of doing
so with respect to protecting the health of thousands of minor animal
species for which there are no drugs legally available under the current
statute.

I have no doubt that if we can simply find the will to work together, we
can find and maintain an appropriate balance between our concern for
human health and our concern for animal health. That said, to start that
process the next session of our workshop will involve a general
discussion of the perceived benefits and risks of the use of
antimicrobial drugs in food animals and will explore some of the
possible alternatives to their use.

***[Animal Husbandry and Disease Control: Cattle]{.underline}***

***By Dr. Michael D. Apley***

MODERATOR BEAULIEU: Our first speaker who will help us better understand
and appreciate the benefits of antimicrobial use in cattle is Dr. Mike
Apley. Dr. Apley received his DVM from Kansas State University in 1987,
after which he became a general practitioner in Central Kansas for two
years. He completed a Ph.D. in pharmacology at K. State in 1992 and then
worked in a feedlot consulting and research practice in Greeley,
Colorado. During practice he completed Board certification by the
American College of Veterinary Clinical Pharmacology. Dr. Apley joined
Iowa State University in April, 1996, where he is an assistant professor
of beef production medicine in the Department of Veterinary Diagnostic
and Production Animal Medicine. His activities include working with Iowa
veterinarians as well as teaching beef production medicine and
participating in the medicine and clinical pharmacology courses. His
research interests include bovine respiratory disease, food animal
clinical pharmacology, and antimicrobial resistance. Mike will speak to
us about animal husbandry and disease control in cattle.

DR. APLEY: Good morning. I was asked to address antimicrobial use in
cattle, both on the basis of benefits, ways we are working to optimize
these uses and ways we are working to control disease pressure.

(Slide.)

First I would like to start out with two industry models so we are all
on the same page. This would be a model of the beef industry, starting
with the cow. Cows do eventually go to harvest for meat. We produce
calves, which can go to the feedlot through either stock or which is
typically grass phases or backgrounding, and then of course we end up
with meat. Usually 20 or 30 percent of the female calves or heifers
every year end up going back into the cow herd for replacement.

One of the very exciting things for me is the appearance of vertical
alliances, and these have been in the works for years. But I am
participating in one in the design of the health program, and it
involves the cooperation and involvement of the retailer at the consumer
level clear back to the calf. There are significant benefits to the calf
producer for health performance and for the quality of the meat product
at the end. Through this we are able to coordinate health plans
throughout the entire production system, and then also go back to
animals that arent able to maintain satisfactory health status and work
with them to get there, and well go through some ways we are doing
that.

(Slide.)

The dairy industry, the big difference is that there is an immediate
food product from those cows in the form of milk, milk products coming
off during lactation. Those cows will also at the end of their
productive life be harvested for meat. The calves, the vast majority of
the heifers in todays dairy market are going back into the cow

\-- the dairy herds as producing females. The steers will end up going
primarily \-- will end up going to veal or feedlot production.

(Slide.)

So the outline of my presentation will be therapeutic labels, feed
antimicrobial labels, antimicrobial uses that are banned in food
animals, requirements for extra label use and in the efforts to optimize
use of antimicrobials in food animals.

(Slide.)

In words from out west, take a loose rein and a deep seat, because I
want to run through these and give you an idea of exactly what is
available and labeled for use in cattle.

(Slide.)

Be aware that only a subset of these labels are approved for use in
lactating dairy cows. I will point out a few, but not all of these are
approved for use in lactating dairy cows.

(Slide.)

One of our biggest challenges, especially on the beef side where I
primarily work, is bovine respiratory disease. To give you an idea of
our pathogen targets, there are three gram negatives, mannheimia,
pasteurella, haemophilus; and mycoplasma is debated as to its primary
role, but does give us problems at least as a secondary invader.

(Slide.)

So antimicrobials that are approved for use in respiratory disease in
cattle include macrolides of the 14 and 16 member ring groups; beta
lactams with penicillin, two amino-penicillins, an amoxicillin and an
ampicillin, and a cephalosporin in the form of ceftiofur. For
tetracyclines we have chlortetracycline available for feed use, and we
are going to go through that in more detail in a little bit, and
oxytetracycline available in forms for both feed, water, and injectable
use. Florfenicol, a derivative of thiamphenicol, which is a derivative
of chloramphenicol, is also approved.

(Slide.)

We have two sulfas with approvals, sulfadimethoxine and sulfamethazine.
Our sole fluoroquinolone approval in cattle is enrofloxacin for use in
bovine respiratory disease, and as we will state again later, extralabel
use of this compound is prohibited by law. The aminocyclitols
representative is spectinomycin.

(Slide.)

We have two control claims in tilmicosin and florfenicol. Straight from
the label, the claims on the label for example for tilmicosin, For the
control of respiratory disease in cattle at high risk of developing
BRD, or bovine respiratory disease, associated with pasteurella
haemolytica. Florfenicol is similar, although it has more organisms
actually on the label.

I have personally conducted studies and reviewed numerous others that
demonstrate that this use early after arrival at a feeding facility can
help to significantly delay and decrease morbidity, and then to decrease
case fatality rate when morbidity does occur. This is a prescription use
within a valid veterinarian-client-patient relationship, and it is up to
the veterinarian to work with the people receiving cattle to accurately
target this.

(Slide.)

Enteric disease in calves, we encounter E. coli and salmonella. As we
move more into adults we are more likely to see salmonella if it does
occur versus E. coli. Other infectious agents are cryptosporidium,
rotavirus, and coronavirus. The viruses are \-- we have some fairly good
vaccines for those that we aggressively use. Cryptosporidium is one that
we dont have a good antimicrobial for, we dont have a good vaccine
for, and it is one that has forced us to new levels of biosecurity in
thinking about cattle flow, how cattle move through a calving facility.

(Slide.)

So for enteric disease in cattle, approved antimicrobials again are the
sulfas. We do have an aminoglycoside approval in neomycin as an oral
liquid and as a water additive.

(Slide.)

Of the tetracyclines, oxytetracycline and chlortetracycline both carry
approvals for enteric disease.

(Slide.)

In the dairy side, a challenge is mastitis, especially in the month or
so following freshening or having the calf and starting to move into
lactation. To give you an idea of the complexity of this challenge, this
is a list of some of the pathogens that may be encountered.
Veterinarians are very aggressive in trying to diagnose the problem if
it occurs. The level of cattle with this type of condition is monitored.
Milk production is monitored, et cetera.

(Slide.)

So approved antimicrobials for mastitis therapy, there are approvals for
both dry cows, and a dry cow is one that has ceased lactation and is now
going into a typical two-month dry period before lactation again after
the next calf; and then there are lactating approvals where you would
have a withdrawal time for the milk. There are milk withdrawal times and
meat withdrawal times for all of these.

Novobiocin, both alone and in combination with penicillin. There is a
lincosamide in the form of pirlimycin. Of the aminoglycosides,
streptomycin is approved in combination with penicillin.

(Slide.)

Beta lactam approvals for mastitis. All of these are intramammary.
Amoxicillin, again an amino-penicillin; cephapirin, a cephalosporin;
cloxacillin; hetacillin; and penicillin.

(Slide.)

There is a macrolide approval for mastitis, erythromycin in the form of
an injectable, and an intramammary preparation for lactating and dry cow
use.

(Slide.)

Another challenge we face sometimes is footrot or infectious
pododermatitis, in which they get an infection between the claws or
around the hoof. Tetracyclines, some beta lactams, in this case
ceftiofur, is one of them, and ceftiofur is one of these that would be
labeled for use in a lactating dairy cow. Injectable oxytetracyclines,
there are products that have a label claim for approval and a withdrawal
time for use in a lactating dairy cow. Macrolides, we have tylosin and
erythromycin with injectable labels, and then we again have sulfas.

(Slide.)

Another challenge we will run into is metritis, or infections of the
uterus. We may find this more commonly in a dairy cow than we do a beef
cow, and that is because we are \-- one reason is we are much closer to
the dairy cows, much more intense observation for this. It does happen
in beef cows also. Multiple pathogens. There are only really two
products with a label approval for metritis, and that would include
tylosin and oxytetracycline injectable.

(Slide.)

So what other types of label indications do we have? Oxytetracycline has
labels for these infectious diseases that we will run into on an
intermittent basis. So one of the widest set of approvals is for oxytet.

(Slide.)

So specifically lets cover antimicrobial compounds with approvals for
administration in feed.

(Slide.)

For the tetracyclines, chlortetracycline and oxytetracycline both have
labels. We are going to use chlortetracycline as an example of the
multiple applications.

(Slide.)

These are labels obtained from the feed additive compendium and from the
compendium of veterinary products, both of which are based on the
product label. So for calves up to 250 pounds there is an increased rate
of weight gain and improved feed efficiency claim. Then there is also a
label approximately 100 times that for therapeutic use in the face of E.
coli; and that is limited to the use in milk replacers or starter feeds,
and milk replacer is a feed.

(Slide.)

When we get into larger calves, there is another increased rate of gain
and improved feed efficiency claim, and there is also one starting in
cattle 400 pounds and over at a level that is designed to control
bacterial pneumonia. One of the reasons we keep coming back to bacterial
pneumonia in cattle is their lungs are different than ours. The best
model for the human lung in animals is the horse. In cattle, they dont
have the communication between independent lung lobules. So if one
starts to be occluded with debris, there is no way to clear that. It
remains occluded, and we tend to have a lobular appearance of the
pneumonia. So just by the nature of their lung, they tend to give us
more pneumonia problems.

(Slide.)

Here is some that are important to keep in mind, and that is the use of
chlortetracycline for controlling anaplasmosis in cattle. 350 milligrams
per head per day get us through the vector season. Then it is a common
practice to go through \-- collect blood samples, look at titers, and
then individually target carrier animals. Then try to get through the
next year with vector control and not having to use the antimicrobials,
but it is a very important use for us to get through vector seasons.

(Slide.)

And then here is one of the newest or the newest approval as far as I
know, is calves, beef and nonlactating dairy cattle. 10 milligrams per
pound per day for treatment of bacterial enteritis or bacterial
pneumonia. (Slide.)

Chlortetracycline is approved in a feed combination with sulfamethazine,
and that is aid in maintenance of weight gain in the presence of
respiratory disease such as shipping fever.

(Slide.)

Oxytetracycline has some similar claims in a similar range. It also has
a combination approval with neomycin for aid in the prevention of
bacterial diarrhea. Then oxytetracycline and lasalocid, which is an
ionophor. The oxytetracycline is for reducing incidence and severity of
liver abscesses in cattle on feed, and then the improved feed efficiency
and rate of weight gain also involves lasalocid.

(Slide.)

Tylosin, which is a 16 member ring macrolide, has an approval in beef
cattle for the reduction in the incidence of liver abscesses.

(Slide.)

Virginiamycin, which is a streptogramin, has an approval for cattle fed
in confinement for slaughter. There are various dose labels for improved
feed efficiency, reduction of liver abscesses, and increased rate of
weight gain.

(Slide.)

Now we are going to get into the ionophors. This is a class of
antimicrobial compounds which Im not aware of any use in human
medicine, primarily because it would be fairly toxic if done so, and Im
not aware of cross-resistance issues for this compound either.

(Slide.)

When we talk about growth promoting use in cattle, often times this can
be used to inflame the issue by taking the pounds of this compound used
and comparing it to the amount of antimicrobials used in cattle that are
used for growth promotion. It has a feed efficiency and prevention and
control of coccidiosis label. The prevention and control of coccidiosis
is extremely important. There is good work in the literature
demonstrating that coccidiosis can \-- which is a protozoan parasite,
intestinal parasite, can depress the immune system and lead to other
infections. So this is a very valuable tool for us in trying to decrease
other pressures on the animal that might lead to a bacterial disease
weve already discussed, and it is approvrf in confined cattle, pasture
cattle, and mature producing beef cows.

(Slide.)

Lasalocid is another ionophor, similar uses. Laidlomycin, a third one.

(Slide.)

Bambermycins are another compound for growth promotion that Im not
aware of any human use or relation to drugs used in human medicine.

(Slide.)

We do have some extralabel uses that are banned in production animals.
Chloramphenicol is one; clenbuterol is not an antimicrobial;
diethylstilbestrol is not. This is a list of banned compounds.

(Slide.)

Dimetridazole and ipronidazole, all the nitroimidazoles are banned for
use, extralabel use in food animals. Since there is no label, the use is
banned. This is a list that still has approved topical use for
nitrofurazone. That is on its way out. It is not completely out due to
some work where they found that topical use in the eye could lead to
some residues. In lactating dairy cattle, sulfonamide use is restricted
to approved use of these three compounds. The primary one available
would be sulfadimethoxine.

Other uses that are prohibited are, as we mentioned earlier, extralabel
use of fluoroquinolones in food animals. So only approved uses, and then
any extralabel use of glycopeptides which have not been approved for
food animal use in the United States at any time. Any extralabel use is
prohibited, so they wont be used in food animals.

(Slide.)

Veterinarians do have the legal authority now to use antimicrobials in
extralabel use in food animals. There are requirements for this. The
drug must be \-- either have an NADA or an NDA number. So it must be
approved for either human or food animal use, with the primary emphasis
put on the food animal. The use must be within a valid
veterinarian-client-patient relationship, and there is a set of
regulations promulgated to codify the \-\-- that the veterinarian must
work through in a regimented thought process prior to prescribing
extralabel use.

(Slide.)

So the big question is, What happens to this guy? This is a calf at a
feeding facility. Everyone else is up eating. This guy, once you get to
know cattle, this one has a flashing light on his head. He would be what
we call pulled out of the pen.

(Slide.)

And the next step now more and more is becoming this. This is a laptop
carried by the treatment crew at that facility. The program it happens
to have on it is by Infotech. There are several very good programs out
there. This animal has an individual identification number given to it.
Some of them already have them assigned to them. It then goes in. If it
has respiratory disease, it is diagnosed as that. There is a prescribed
treatment regimen on the computer. They go through drug one, how many
ccs for 100 pounds.

Many of our facilities have scales. That is one thing through extensive
research in the veterinary field we found out where we are ahead of the
human medical profession, is we have discovered that all of our patients
dont weigh the same. So just a little advance that we would be willing
to share if we could get on one of those programs.

So we do dose them by weight. Then as a consulting veterinarian, I would
come into this lot, and I do on this one on a routine basis, and we look
at these records and look at case fatality rates, treatment response.
They do have a second and a third treatment regimen that they go to, and
it is very tightly controlled. We do know where every drop of drug on
that facility goes. This is also used to check withdrawal times before
they are able to leave for harvest.

(Slide.)

So thats how we are using drugs now. How are we going about minimizing
disease pressure so that we can decrease our therapeutic use as much as
possible? I talked about vertical integration, and one of the things
this is doing is allowing us to use genetic selection. And with the
individual animal, electronic identification being implemented in some
systems along with the advent of at least three if not more web-based
systems designed to track cattle and be involved in the selling of
cattle from the cow calf producers through the feeding chain, we are
going back and looking at cattle that need some help.

Preconditioning programs are being designed to optimize time of exposure
to vaccines and correct nutritional deficiencies, and the time to do
this in the beef side is before that calf leaves the cow. A rapidly
growing number of producers are bringing calves in to be processed and
receive their first vaccinations about three weeks prior to weaning.
Then they spend the next three weeks back on the cow, so that they are
able to respond to those in a lower-stress environment.

(Slide.)

The biosecurity procedures \-- and I need to emphasize these arent
things we have just discovered. We have been intent on implementing
these for years. The biosecurity procedures Ive listed. One thing down
there, benefits of single injection therapy. From the beef feedlot side,
one reason Im so excited about that is we are able to bring cattle to a
central treatment facility for just a little bit and then set them right
back with their original group. So that we are not spending a lot of
time mixing cattle from individual groups and then sending them back to
their pens as a vector.

Environmental management, we are intent on rodent and fly control.
Calving areas, one of the biggest things to prevent enteric disease in
our beef herds is to get our heifers spread out and get them out on
grass instead of a dry lot. Sanitation, and of course avoiding social
stress for them.

(Slide.)

One thing with the immune system management is that not all immune
modulators are a benefit. One of the things that causes us the most
grief in bovine respiratory disease is when the immune system runs
amuck. It is kind of like starting a bar fight and not calling the cops
to stop it. So actually some immune modulation as far as moderating the
immune response as ancillary therapy can be a benefit.

(Slide.)

Novel approaches to vaccination to allow us to get vaccines to the
animals during phases of production where they are not really
accessible. Sub-unit and gene-deleted vaccines are coming along. We are
looking at competitive exclusion products wherever possible.

(Slide.)

Im really excited about some of our diagnostic methods and the way
theyve evolved. Im particularly excited about some of the extended
range dilution tests thats coming on, and of course alternative
therapies. Education and realization of the need for alternative
therapies. An example is cryptosporidium in calves. If that is
diagnosed, we dont chase a gram negative enteric such as an E. coli or
salmonella. We concentrate on acid base balance and realize that a lot
of times an apparent relapse is not due to the organism coming back or
failure of any other type of therapy. Its because they have gone
acidotic. Sometimes the blood PH is down to 7.05, which is not very
compatible with life. So education and work on that.

(Slide.)

So I would like to finish with an idea of after we have talked about
decreasing disease pressure, when we do need to use antimicrobials
therapeutically, how we optimize their use. I feel the statement there
in white is the absolute truth in both human and veterinary medicines.
There are substantial gains to be made just by making sure every
veterinarian has timely access to the most current information on
antimicrobial use in food animals. I guarantee you if you pull over
your average practitioner in their dirty pickup at 11:00 at night and
tell them, Im from the university, and Im here to help you, they
wont find a body. So what we need to do is give someone in a busy
14-hour day a way in five minutes to get to the most current
information.

(Slide.)

With that in mind, through the support of numerous organizations,
including the American Association of Bovine Practitioners, the AVMA,
the American Association of Swine Veterinarians, the Academy of
Veterinary Consultants, the National Cattlemens Beef Association, and
the National Pork Producers Council, we have achieved startup funding
for the Veterinary Antimicrobial Decision Support System. Myself, Dr.
Virginia Fajt, a recent grad student of mine, Dr. Cory Langston at
Mississippi State, Dr. Jeff Wilcke at Virginia- Maryland.

(Slide.)

What we are doing is developing a database of dosages, amount, frequency
and duration, and we concentrate first and foremost on label uses. That
is always the thing the veterinarian will run into first, but in
practicality a label use may not always be functional. We then want to
correlate dosages with susceptibility information. That is based on
kinetics, dynamics, and clinical data when available.

(Slide.)

The pieces of the puzzle we are using. What concentration of the
antimicrobial does it take to inhibit bacterial growth? How is the
antimicrobial best presented? What are the kinetics in the animal? And
then the final most important thing is to follow through with help for
the veterinarian on how they can tell if our predictions are going to
hold true in practice situations and also confirming them with clinical
trials.

(Slide.)

So our goal is to come up with reasonable doses and target when they do
need to go outside the label. An example is in a dose continuum from
zero to 100 milligrams per kilogram. There are ones that are obviously
unreasonable at the low and the high end. We will be developing doses
for varying MICs of the pathogen from extended dilution, and again we
have no illusion that we can specifically target the absolute best dose
in this animal. This is a population approach, where we give the
veterinarian an idea of for this MIC of that pathogen what percent of
the population would varying doses cover. Then illustrating the benefits
of susceptibility testing, if they are going to treat empirically, we
are going to have to call for quite a little bit higher dose.

I was pleased to see in the plan, the coordinated plan from the
government for addressing antimicrobial resistance, that one of the
biggest \-- one of the big research initiatives was to actually go in
and find out how to build a regimen to decrease resistance development.
We really dont know yet, other than how to optimize therapy through
pharmacokinetic, pharmacodynamic relationships. We really dont know how
to actually suppress resistance. We think we do, but we dont have it
lined up.

(Slide.)

With that, it concludes my remarks. Are we going to take a question, or
wait for the panel?

MODERATOR BEAULIEU: I think we are a little bit behind. We are going to
have an opportunity to talk to all these folks again and ask questions
this afternoon, and then a public comment period also this afternoon.

(Applause.)

***[Animal Husbandry and Disease Control: Swine]{.underline}***

***By Dr. Robert B. Morrison***

MODERATOR BEAULIEU: Our next speaker is Dr. Bob Morrison. While he is
hooking up, I will go ahead and introduce him. Dr. Morrison holds a DVM,
MBA, and PH degrees, and is a professor in the College of Veterinary
Medicine at the University of Minnesota. He is currently President of
the American Association of Swine Practitioners and works closely with
veterinarians across North America. He is also involved in a
family-owned swine farm with 2,200 sows and is part owner of a small
meat processing plant in Southern Minnesota. He consults with small
regional swine farms and large integrated systems in the United States
and around the world. This broad experience in conjunction with his
business training gives him the ability to combine applied science with
the business aspects of pork production. Bob will speak to us about
animal husbandry and disease control in swine.

DR. MORRISON: Thank you very much. I would like to thank you also for
the invitation to be here this morning. I am going to be speaking \-- I
am going to take a little bit different approach than Dr. Apley. Im not
going to really list the antimicrobials that we use. Im going to talk a
little bit more about pig farming and sort of how we raise pigs and how
we try and control \-- prevent diseases other than by antimicrobials. I
hoping that you will understand sort of what the swine industry is doing
as you consider the next two days.

(Slide.)

I want to just read you this excerpt from the official newsletter of the
Land Stewardship Project. It says, The Frantzens used to raise hogs in
closed buildings with concrete floors. The floors had special slots in
them so that urine and feces could drain down into a pit below. All this
liquid manure had to be pumped out and disposed of. Such a system was
bad for the stressed-out animals, and they fought each other and
required lots of antibiotics. In the environment, liquid manure often
finds its way into waterways as well as members of the Frantzen family
who had to work in facilities full of dust and toxic gases. In short,
says Mr. Frantzen, This system treated animals as machines, manure as
waste, and farmers as barnyard janitors. You know, thats the feeling
of Mr. Frantzen.

You know, when we are pig producers, pig farmers are facing many issues
today, antibiotic use being one. Several others being mentioned in this
news letter, and theyre all extremely important to us. Lets just look
briefly at some of these issues.

(Slide.)

On the left side is one perspective and on the right is a different.
Historically pig farming has been quite profitable. You might have heard
it as being the mortgage lifter for the farming family. Recently, and in
particular in 1988 \-- 1998, it was a financial disaster. The more pigs
you had, the worse you suffered. Farming today is an investment. Farming
historically has been a way of life. Many farms today are labeled as
corporate farms, as opposed to, in quotes, a family farm. This is an
issue that you will read about commonly.

Many people believe that manure stinks and pollutes and has no value, as
opposed to pig manure being a resource. Some people think that barns are
large, white and made of steel, as opposed to a more traditional view
perhaps that barns are red and have an adjoining silo. Some people think
intensive rearing is cleaner, efficient and humane. Others would say
that confinement of any type, whether it is stalls, pens, concrete
floors, is inhumane.

(Slide.)

Antibiotics, on one side, we think are needed, valuable, and worth the
risks. On the other hand, some would say that mass medication should be
banned from agriculture. Vertical integration is the marketplace at
work, as opposed to vertical integration is the root of all evil.

Contracts, whether they be market contracts or production contracts,
reduce risk and facilitate growth. Many think contracts are only for the
big and are ruining our industry.

(Slide.)

Intensive agriculture saves land and preserves wildlife habitat. No
person should raise more pigs than is needed to raise a family. Pork is
nutritious, tasty, and can be part of a balanced diet. Others would say
eating meat is unhealthy and immoral. I have great debates with my niece
over that issue.

Pigs are efficient converters of grains to meat. Average three pounds of
grain, lets say \$.21 of value to a pound of pork. Pigs are inefficient
and consume valuable grains better fed to people.

We could take any one of these issues, and we could have a three-day
debate on them with the swine industry and with others who \-- within
the swine industry obviously theres different factions. The Frantzens,
as you read about in that news letter, are facing these in different
perspectives.

One of the things that happens that is not constructive is that we will
try and label an industry, and an author will try and label lets say an
industry as often times a factory farm. A factory farm, in the authors
view, would have any one of those issues on the negative aspect. It
would probably be confined. It would probably be, lets say, vertically
integrated. It would use antibiotics excessively. You know, take any one
of those perspectives and a factory farm would be negative, but I dont
think those labels really are very constructive, at least in some of
these issues that were dealing with that are so confusing and so
difficult to understand.

(Slide.)

I want to just show you here from the website of the Union of Concerned
Scientists. Im a scientist and Im concerned, so this I find a little
bit misleading when it says down below, Animal factories rely on
antibiotics to promote growth. There presumably is a picture of an
animal factory, and that is not true. It is not true that animal
factories, whatever that may be, rely on antibiotics to promote growth.
What is true is that many swine farms use antibiotics to promote growth,
perhaps even most farms, but that is a more constructive statement. Most
swine farms use antibiotics to promote growth.

Let me just explain to you why I think factory farms is misleading. As I
said, or was introduced, I am part owner of a farm, and you might call
it a factory farm.

(Slide.)

Many pigs are raised outdoors. Not so much in the U.S. The U.K. has
moved in the large part to outdoor housing and some parts of Europe, and
there is some in the United States that are raised outdoors, not that
many. They have different issues with regards to disease control than we
do where we raise pigs inside.

(Slide.)

You may recognize this picture, maybe not. Do any of you recognize the
person? Very influential in my profession. That is James Herriot. Dr.
Jim while running around chasing pigs. We dont do too much of that
anymore, because they are confined for the most part.

(Slide.)

So I want to just show you as you \-- again, as you understand
antibiotic use, we are going to walk through my farm, and we will look
at a different way of housing pigs. Whether it is right or wrong, its
probably the most common way in the U.S. These farms are \-- we try and
find a location for a barn where obviously we can get permitted, and
that involves neighborhood, working with the neighbors, et cetera. The
industry is moving more and more to isolated locations, away from people
because of odor. So we also try to find a biosecure location. You
ultimately get the diseases your neighbors have. So the closer you are
to neighbors who have pigs, the more likely you are to get the diseases
that their pigs have. However that transmits in large part we dont
know.

These barns these days will be bird proof, and that is for a variety of
reasons. Salmonella control, several viruses that pigs can carry between
barns, TB. So we try to keep birds away from pigs. Toxoplasmosis. Cats,
we dont let cats in the barn. We dont want access to toxoplasmosis, a
food safety concern. Rodent control, we \-- you know, we probably cant
eliminate them, but weve got very strict rodent control trying to
decrease their access to rodents, again from a food safety control
point.

(Slide.)

This is inside now, what is called a nursery. Pigs are moved into a
nursery. This particular room in a barn would have \-- in our barn, our
farm, now would have about 600 pigs. So you can see they are moved in as
a group. Do I have a pointer? No. Okay. Thats all right. I want you to
just \-- we are going to focus in on a pig that is down in sort of the
right center area, just beside that lamp. So were going to look at him.
You can see him now, and well see him a little closer up. Oh, great.
Okay. Sorry, Steve. (Slide.)

We are going to look at this pig here in just a second. But just before
we do that, we are also going to look up in here, in this area here. But
before we do that, I want to just make the point that when we wean a
group of pigs, we will wean all the females lets say on Thursday, and
we will take all of those pigs and well fill this room at once in an
effort to sort of have a similar health base within that group. Then we
will try to provide high quality diets, and these pipes coming down here
have the feed in it, and these lines down here are the water lines. Then
the other lines sort of hanging down here that you can see is for these
heat bulbs. So we try to keep them very warm. This room will be probably
90 degrees when they are moved in.

(Slide.)

So this pig here, the four things that we have talked about,
biosecurity, we have talked about feeding, and so on and so forth. This
particular pig here you can sort of see, maybe you can see, he is sort
of falling back. What we would want to do is detect these pigs if we can
and move them into what we would call sick pens here. And so here youve
got a group of pigs here, and these pigs are hurting. They have got \--
when I looked at these pigs they had diarrhea. They got a little fever.
They are not feeling well. They are not eating, they are not drinking
well, and so we put them into sick pens so that we can give them here
sort of a mash. They will receive injections of antibiotics, and we will
try and nurse them along to try and bring them back so that they do
better.

(Slide.)

These are two staff people, Rich and Todd, and what theyre doing here
is just getting the bulb. So we try to keep the pigs warm, dry, and
draft free. This is the exhaust fans back here. Up here you can see air
inlets. Lets see. Again, I said these are heat lamps. They just project
heat down to the floor to try to keep the pigs warm.

(Slide.)

Daily attention to provide optimum environment. Now, the pigs are
staying in this room. Ive actually gone to an adjacent room where they
are about three or four weeks older, and you can see the same number of
pigs, but the room is starting to fill up. There is less space in here
for the pigs, and at some point here they are going to obviously outgrow
this space and they move on to what is called a finishing barn.

(Slide.)

When they move \-- this is not our barn, but its just another one that
is very similar. When they move, the previous pigs are moved out as a
group. The barn will be emptied. It will be all powerwashed down,
disinfected and then dried so that the new group can move in. Again,
this is bird proof and rodent controlled. This is a curtain here. This
curtain will drop to let fresh air in. You have got \-- well, I guess
maybe that down there is a fan. I cant quite tell. (Slide.)

Then the pigs move in. This is back to our farm now, and we will move in
that 600 pigs into this room. It could be 1,200. Actually you take two
groups of 600 and make it 1,200, and we will stock this entire room.
They will stay in here for probably, oh, four months, until they grow up
to market weight. At which point the barn is emptied, it is washed down,
and the next group comes in. Okay. If you could see the room here, you
would say, Boy, at least I would say, Theyve got a lot of space.
You see a lot of space here, a lot of space here, a lot of space down in
here. But, you know, they move in as a group, and they are going to grow
up over four months. So what is going to happen is that the density will
increase as these pigs get bigger.

(Slide.)

So at the end, they are sort of looking like this. Same barn, but you
can see now they are getting tighter, you know, getting \-- and they are
going to start going to market now. Okay. We will try and obviously have
fresh feed here, fresh water, fresh air. You can see some circulation
fans here, a heater here for when they move in when its cool, and get
the barn heated up, et cetera.

(Slide.)

Somebody will walk through daily, and this is a veterinarian friend of
mine. A different barn now, not our barn, walking through daily to
identify sick pigs, get them treated, get them moved into a sick pen if
need be.

(Slide.)

So thats a walking tour. An example I like to use with veterinary
students is, A barn full of growing pigs is similar to, and then you
choose one of these three examples. It is either a day care facility, a
residence at a small liberal arts college, or a nursing home. So, you
know, each one of those has its infectious disease control measures that
are very different. Having been through this one, we know what that one
is. You know the parents at home get sick. (Slide.)

But the correct answer here is a residence at a small liberal arts
college. Why? Because we have got a fairly stable population. In other
words, they all come in and they all leave together. So they all go home
at Christmas, and they all come back. Its somewhat isolated. We try not
to have ongoing introduction of new pigs from different sources. We
manage the number of sources. The more sources you have, the more
diseases you have. So we try and have very few sources of pigs coming
into our farm for example. These pigs are, we hope, immunologically
mature and responsive as opposed to either one of these cases, which
would be a very big challenge to control.

(Slide.)

We diagnose a disease problem by evaluating records. We have computer
records. We have hand-kept records. We look at temperature fluctuation
within a barn on a daily basis. We will try and maintain a nice stable,
as I said, warm environment. We look at clinical science. We will draw
blood samples both from cross sections and from serial bleedings. In
other words, we will follow pigs over time and see what they convert,
what infectious agents it looks like they are getting infected with, and
we will conduct post mortems. Often times if it is really a problem, we
will do a sampling of sick pigs and take them to the diagnostic labs
when they are alive, and then euthanize them and do post mortems and not
wait for them to die to try and increase our chances of identifying the
important agents.

(Slide.)

I wanted to just make sure that we all understand that for the diseases
we are dealing with mortality may be and perhaps usually is the tip of
the iceberg. So underneath this iceberg of mortality now we might lose
two percent, for example, of a 1,000 pigs that we moved into a barn. We
might lose two percent of them from mortality. But underneath that two
percent, or lets say 20 pigs out of 1,000, which we dont want to lose,
but we do, is 980 pigs who are vulnerable. What we see in them is that
some of them will become sick and need to be culled, and the rest of
them, a large part, some of them will grow slower and end up lighter at
market. So we have to always consider the population within that barn
when we are talking about disease control.

(Slide.)

I want to just show you this graph to make that point. This is kind of a
confusing graph, so let me explain it to you. Each one of these dots
represents a group of pigs. So a group might be 500, it might be 1,000,
it might be 2,000 pigs. This is a large database, a large database of
groups. So I dont know how many pigs as a whole are in this graph. It
could be a million pigs. Lets say there are 1,000 dots here, 1,000
groups. What you see in this graph is that as mortality goes up within a
group, that is down here, mortality is going up, we would like it to be
down here at zero. The majority of the dots are right in here around
one, and two, and three percent. You get a few really bad groups out
here where you have got 10 and 15 percent mortality, really bad. As you
see mortality going up, you see this parameter, average daily gain,
going down. In other words, that in groups where we have higher
mortality, the pigs that dont die grow slower. I am just trying to make
the point that the mortality is just the tip of the iceberg when were
dealing with many of our infections and diseases.

(Slide.)

Antibiotic use for us is clearly a short-term expense, which we try to
avoid if we dont need it. We are always trying to figure out, Well,
how can we change management so we, you know, optimize our environment
here? Weve talked about air, space, ventilation, flooring. I said we
clean the barns. We minimize sources. This means we try to move all pigs
as groups versus a continuous flow barn. We try to minimize age spread.
We try to optimize density. All of these things here are sort of we
havent really gone into detail, but we manage the sow herds such as we
wean a healthy pig. We will manage immune status. We will vaccinate. Any
of the infections where we think we have to prevent them we will try to
vaccinate. Wean age is important, and finally fresh, available water and
feed. So those are I think the majority of ways by which we try and
manage our pig farms.

(Slide.)

We decide whether to use antibiotics or not based on what the disease
costs, the impact of that disease on the pigs well being, what will
likely happen if I dont treat. Many of these things will go away. Maybe
it will stay the same and it wont get worse, or if it will get worse
and if I think I have to treat, I will go in and treat. Those young pigs
that we saw in the nursery there that had the diahrea, that is not going
to go away by itself. It is not going to stay the same. It is very
likely going to get worse. Not necessarily in those pigs, but in the
group, and it will spread, as you saw, within that room unless I do
something about it. So Im going to aggressively jump on top of that.

(Slide.)

As we think about antibiotics and the pros and cons of antibiotic use,
here are the pros. We clearly reduce pain and suffering of the pigs. We
reduce the incidence of sickness and disease. We reduce manure output in
the big picture. When you look at efficiency in the big picture, it
reduces manure output. It may lower the cost of production thereby
increasing affordability of pork.

The cons are clearly these. Possibility of promoting resistance. The
possibility of having residues in the final product. It clearly adds
costs to our product, and clearly for us we are paying attention
hopefully more and more to our consumers. It is a negative image for
some, perhaps many, perhaps most consumers.

(Slide.)

The antibiotic program is selected based on the following. The presence
of diagnosis, the herd health, the history, the prevalence or incidence
of the disease. This is an important one, compliance of the owner and
staff. What I mean by that is if I come into a farm and they have got a
respiratory disease in the barn, and lets say 30 percent of the pigs
need treating, or 40 percent of the pigs. I go in and I look at them and
I say, Boy, you have got a lot of skinny pigs in here. They are clearly
breathing difficultly. You have already lost four percent of them, and I
see 40 percent of them roughly needing treatment.

He is not going to go and inject them if I ask him to. It might be 1,200
pigs in a barn, it might be 10,000 across a large site. If I ask him to
inject those pigs he will either say he did it and wont, or just wont
do it. Its too many pigs. So they will mass medicate, and they will
either mass medicate in the water or in the feed, depending on the
particular conditions of that disease.

So this issue of compliance is huge, especially in our industry as it is
becoming more intensive. Labor is an issue for us. We will look at the
benefit cost of treatment options. We will consider the laboratory
results. I will incorporate my clinical experience, and I will look at
the antibiotic options available.

(Slide.)

I want to just very briefly, and I will try not to go too long here,
just very briefly go over this AMDUCA regime which were, as Mike said,
we are working with our association, our Association of Swine
Veterinarians very intensively to make sure they understand this and
work through this. This is a flowchart of how you choose what antibiotic
you are going to use, and this is called AMDUCA. I dont remember what
it even stands for. You are either going to inject and/or water
medicate. Then once you have made that decision now, we are going in to
lets say treat or attack a disease problem. You are then either going
to use a food animal drug or not. You are either going to use it at
label or extralabel. You are either going to stop medication, or you may
switch to feed medication. At some point if you switch to feed
medication, you are going to stop feed medication.

Well, how does this process work? First off, you would choose. Well,
your first priority is you are going to look is there a food animal drug
available for this condition; and, if there is, you will go with that.
That is clearly what your first choice is. The next question is, Is
this drug in the proper dosage form? Is it labeled for the indication,
and is it thought to be clinically effective? If it is, you go with it.
If it is not, if it is a food animal drug but it is not labeled, it is
not in the proper dosage form, or it is not labeled for the indication,
or it is not clinically effective, then you go to what is called
extralabel use.

(Slide.)

This extralabel use requires a valid what is called
veterinarian-client-patient relationship, and I will just show you what
that is. It insures adequate withdrawal, it insures animal or a group
ID, and you must have records and labels. Records and labels, by the
way, we are getting requests now to audit farms. Audit farms and audit
farm systems to make sure that what is getting done is what they want to
get down. So this is something new for us that we are getting into.

If there is not a food animal drug for the indication, et cetera, then
we look at non-food animal drugs. If the drug is not prohibited, which
Dr. Apley described, and if we can get an adequate withdrawal time. So
that is sort of the AMDUCA regime that we try and work from.

(Slide.)

What is that valid client-patient relationship? It has the following.
Veterinarian is responsible for making the medical judgement. The
veterinarian has sufficient knowledge of the pigs to initiate at least a
preliminary diagnosis. Which means he has recently seen or makes timely
visits to the premises. Lastly, the veterinarian is readily available in
case of adverse reactions or failure of the treatment regimen. That is
what a valid VCPR is.

(Slide.)

Im winding up now. Medicating the feed or not. Why would we medicate in
the feed? Well, clearly it would give you the broadest coverage of that
group, 1,200, 500, 200, 10,000. Whatever it is, it will give you the
broadest coverage. It clearly is most labor efficient. It is the
simplest for us, but it may be the least \-- and it may be the least
expensive program in the long run. There is the whys. Here is the why
nots. It may be difficult to achieve a therapeutic level in sick pigs.
Why? Because just like us, sick pigs dont eat, or they eat less. They
dont feel like eating. So you are not going to get a therapeutic level
in the pigs if they are already sick. You have got a potential, and this
is huge, for contamination of other feeds. So you dont want, for
example, a medicated feed to have any contaminated \-- any contamination
of feed with pigs that are getting close to market weight, because we
cant afford to have residues from a public perception, from a human
health point of view.

Some pigs that are not sick will receive medication. Clearly, you know,
thats not \-- if only lets say 10 percent of the pigs need it, we
dont want to feed 90 percent of the pigs the drug, and it may be in
some cases the most expensive program. So there is the cons, and we will
try and weigh those pros and cons to feed medication. Whenever we do
feed medicate, it must be under what is called a veterinary feed
directive, which is a written form that has its own set of requirements.

(Slide.)

As I was preparing for this talk, I talked to different veterinarians,
talked to different producers, and in my mind at least there is
generally good awareness and compliance with the guidelines. I wouldnt
say 100 percent, and thats why our association and different pork
producer associations are working hard to make sure we do a better job.

Some veterinarians have detailed protocols for their clients. Product is
based on effectiveness first, cost second. Some veterinarians have
developed spreadsheets for comparing drug costs, different routes of
delivery. I think this system that Dr. Apley described is going to be a
huge advantage for us. Some veterinarians have got spreadsheets and
producers for looking at cost effectiveness of growth promotants.

I think an important principle as we \-- you know, I showed you my farm,
and somebody else could stand up here and show you a different farm, and
it would have different advantages and disadvantages from our farm. The
best way to think of our industry is that this health management is on a
continuum from the lowest level of possible health that you could
imagine. We have some disasters. At the opposite extreme, we have got
some farms with the highest health you can possibly imagine. You know,
the lowest health, down here, would have these sorts of characteristics.
It would have, Well, I bought pigs from 15 different sources. Well,
you know that my pigs are going to sort of go down to the lowest common
denominator of those 15 sources. I have got farrow to finish all and
sort of \-- I wont go into detail, by that will complicate things.

I have continuous flow barns. I have got many barns on one site. Im in
a high pig-dense area. In other words, I get all the diseases ultimately
that my neighbors have. I have got an old wean age. Basically all my
pigs bring in all the diseases that the sows have. Conventional. That
means not a high health sow herd, and Ive got poor biosecurity. Anybody
can come into my facilities on any day. You dont need to shower. You
dont need to anything. No biosecurity, no bird control, no rodent
control. Just come on in.

Our farm is high biosecurity, opposite extreme. Single source is highest
health. Perhaps even no new sources. I close the herd down. All I bring
in is semen. That would be the highest. High health source. This just
means lets have few \-- as little age spread going into that room.
Lets try to have a homogenous group going into a room. We clean and
disinfect barns. We fill and empty the whole site. So if a site or a
barn does have a problem, it all goes to market. It is cleaned, and we
start fresh, and so on.

(Slide.)

I think the point is here that we know these are the highest health,
these are the lowest health. If you looked at our industry as a whole,
this is sort of a frequency distribution. The majority are going to be
in here. You have got a few out here that are really good, and you have
got a few out here that are really bad. What we are trying to do as an
industry is to improve health, move them all down this sort of continuum
such that we have got high health pigs, safe pork going to market,
minimizing the use of antibiotics. Thats where we are headed, and
hopefully Ive given you some thoughts for the next two days or three
days. Thank you very much.

(Applause.)

MODERATOR BEAULIEU: We are almost back on time. We are due for a break
at this point. If we can all be back in our seats and ready to start at
10:30 I would appreciate it.

(Whereupon, a break was taken at 10:10 a.m.)

MODERATOR BEAULIEU: Once again if Dr. Glen Morris or Richard Wood are
present I would like you to join us up here at the podium.

***[Animal Husbandry and Disease Control: Poultry]{.underline}***

***By Dr. Dennis P. Wages***

Our next speaker is Dr. Dennis Wages. Dr. Wages received his DVM from
Kansas State University in 1978 and served a residency in pathology at
Iowa State University. Since 1984, he has been a professor of poultry
health management in the Department of Farm Animal Health and Resource
management at the College of Veterinary Medicine, North Carolina State
University. He is a diplomate of the American College of Poultry
Veterinarians and is currently the Chair of the Drugs and Therapeutics
Committee of the American Association of Avian Practitioners. He has
experience in a mixed animal practice in Nebraska and as a technical
service and research veterinarian at Pfizer Animal Health. He has
authored or coauthored over 100 publications. His current research
interests include antibiotic use in poultry and other food animals,
field investigations of new and emerging diseases, and disease
prevention programs. Dennis will speak to us about animal husbandry and
disease control in poultry.

DR. WAGES: Thank you, Andy, very much. I think like some of the other
speakers, it is difficult to put the years of experience that the
industry has had in disease control and prevention as well as their
experience with antibiotic use into 30 minutes, but we are going to sure
try our best.

(Slide.)

I think we get lumped many times into one big poultry industry, and in
reality we have three industries, much like in cattle where you have got
a beef industry and a dairy industry. We basically have three areas that
make up our total poultry industry, and those are the broiler industry
if you will, turkeys, and layers. I think when you get into the
situation where you are dealing with antimicrobial resistance,
antimicrobial use, and the dealings that we are involved with in these
types of meetings, the meat production is what we will focus on
predominantly in this talk. But many of the things that I do state can
be interpreted for use in the layer industry also.

(Slide.)

Over all years ago in looking at disease prevention management it was
quite evident for a variety of reasons that in food animal production,
specifically in poultry, that companies needed to more closely control
their own destination if you will, and in controlling their own
destination they had to have control over all aspects of production.
This is basically by definition vertical integration. Good, bad, or
indifferent, agree or disagree with it, this is the trend that the
poultry industry has taken probably since the mid 70s. Basically what
it does is the company in this vertical integration process basically
has control of the houses that are built, where they are built, how they
are built; the breeds and breeders, the genetic lines that they wish to
pursue; the feed, all aspects of feed and nutrition, from the
acquisition of the commodities, buying the grain, to mixing it up and
feeding it; live production, and by definition live production is
actually the growth if you will of the meat birds; live haul, the act of
actually picking the birds up and transporting them to the processing
and the processing itself.

The majority of the industry that is integrated has contract growers.
Meaning they have growers come to them, or they go out and acquire
growers and basically furnish the feed, furnish the birds, furnish the
technical expertise to raise those birds for them, and then they are
paid a contract price. There are some areas of vertical integration
where you have company-owned farms. Many times thats where some of the
research and ongoing research that is performed in the poultry industry
is done, in company-owned farms. 95-plus percent, probably it is closely
approaching 97 percent, but anyway greater than 95 percent of the
production in broilers is vertically integrated, and somewhere in the 85
percent range in turkeys. Usually it is either breeders or the
processing end in turkeys that limits their vertical integration.

(Slide.)

Giving you just a little idea of production parameters, broilers are
meat-type chickens. They are small. They are young in respect, somewhere
grown from 45 to 56 days. They will weigh roughly from five to seven
pounds. Again, these are all rough figures. They will either be raised
as straight runs, males and females together usually at the lighter
weights, or the sexes are raised separately, especially when you
approach the eighth week of age.

Feed conversion, the pounds of feed it takes to get a pound of gain, 1.9
to 2.1, depending on the energy density of the ration. We will usually
be tickled to process 95 percent of what we place at day of age. Many
times it is not unheard of for producers to market 97 percent of the
broilers.

Condemnations, to shoot for the percentages is less than a percent at
processing. Many times whole bird condemnations are less than a third of
a percent.

Cost per pound, depending in \-- live production managers and complex
managers would probably just freak looking at this wide range, but
somewhere in that \$.22 to \$.25 per pound range is what it costs to
produce chicken on the live weight. But you also have to add \$.15 to
\$.18 for processing per pound of body weight for your total production
cost, and two-thirds of this cost they eat.

(Slide.)

Turkey hens. Now, in turkeys we do raise the birds separately. Hens are
raised separately because of the automation of processing. We cant
process a 16 pound bird and then right next to it a 50 pound tom coming
through. So they are raised separately. 14 to 16 weeks of age versus
just a few weeks in broilers. 15 to 18 pounds is their projected weight.
About 2.2 pounds or 2.2 on a feed conversion. Livability would be 94
percent. Condemnations less than 1.5 percent at processing, and
somewhere around \$.32 plus processing for production costs.

(Slide.)

Toms, a little older bird. 16 to 22 weeks, depending if they go to the
whole bird market or further processing. 32 to 45 pounds. About a 2.6 on
the feed conversion. Livability is 90 percent. Condemnation is less than
two percent, and our cost for production per pound is \$.35 plus
processing per pound cost.

(Slide.)

Okay. On to prevention management. Other than the vertical integration
that we discussed, companies try to dictate what kind of housing is to
be developed or built by growers. These predominantly or the trend is to
go to environmental control houses, and thats where you can control the
ventilation, the temperature totally environmentally, and many times
computer run buildings. These buildings will approach \$160,000 in their
cost per unit, and they are the expensive housing. They are the positive
controlled. Their ventilation is run based on computerization as well as
static pressure to try to really control the external or the
environment, if you will, of the house. There are curtain-sided houses
that are power ventilated. Not as environmentally controlled as a
environmental house, but they are still present in the industry both in
chickens and turkeys.

One thing that we can talk about a little bit as a success is years ago
we had open type trough watering systems, and especially in chickens. We
found out real quick that most of our respiratory diseases came from
every time a chicken took a drink they inoculated the water for us and
helped to spread the disease. With the closed watering system, the
nipple drinkers if you will, that really minimized many of our diseases,
number one, and plus helped in keeping our litter dry because chickens
and turkeys like to play in water.

So those things have been kind of a success story. Turkeys arent as bad
as ducks, but they do like to play. Thats probably the main reason we
dont have nipple drinkers, effective nipple drinkers at least in the
turkey industry much past six weeks of age. We do have them in the
brooder house, but not in the grow out.

All in all out production is the key for us. We try to place our birds
at the same time period on a farm, and in direct response to that they
are processed at the same time. If a disease comes in and takes
advantage of farm situation where clean-out and long down times are
required, you can effectively do that when you have an all in all out
production. Birds all come in and they go out. When you have multiple
ages on a farm we always say to our students that the farther you go
from an all in all out system you probably 50 percent increase your risk
for disease. So if you have two ages you increase 50 percent. You triple
that if you have three ages on a farm, et cetera. So the broiler
industry at least within a week will place all birds on farms, and that
is pretty much uniform, 100 percent of the broiler industry.

You can take it a step further in the broiler industry and many
companies zone raise. Meaning that a whole area, geographic area, maybe
two to five miles square would all be placed within a week of age.
Again, if laryngo-tracheitis, if an infectious disease that needed to be
controlled by eradication and depopulation, occurred within the
industry, they can remove that whole zone out and keep it void of birds.
Clean it up, disinfect it to minimize disease spread.

(Slide.)

Turkeys more or at least historically have been two-age or a two-stage
production. In chickens, we place the chicks in the same house. We grow
them out in the same house, and then they go to the processing. In
turkeys it is not uncommon to have what they call a two-stage system.
Birds are placed or poults are placed in a brooder house. They grow to
about five or six weeks of age, and then they are transferred on that
farm to a grow-out facility or a grow-out barn. The differences is the
heat required in young birds, ventilation, et cetera in the young bird,
is a different type of house that you need for an older bird. So they
grow these birds in the brooder chamber for five or six weeks of age,
and then they transfer them to grow-out. Then they go from the grow-out
to processing. Very common, and then after each brood the brooder house
is cleaned and disinfected after each group of poults come through.

In broilers, the cleaning and disinfection of a poultry house is really
based on disease incidence. If the bird production parameters are good
and the cost is good and there is no evident disease, they do use
rebuilt or built-up litter in the broiler industry. In the grow-out
facilities in turkeys, again, they use built-up litter, depending on the
disease incidence. If there is no disease there, production parameters
are good and within production standards for the company, they reuse the
litter in the grow-out phase. In the poults, they clean it out every
time.

We are moving toward single stage or an all in all out proposition in
turkeys. We do have what we call brooder hubs and grow-out hubs that
only have young birds or only have old birds and are operated on an all
in all out production.

(Slide.)

Other things we do, we try to control our traffic to and from the farms,
and thats people, thats gas company personnel, thats the feed truck
drivers. We try to know who is coming in our operations and who is going
out. Wild bird and rodent control has been alluded to in both the swine
and cattle presentations, and we are no different. We know that a lot of
our reinoculation, if you will, or introduction of salmonella in our
poultry houses are due to our good friends the rats and mice.

Protective clothing. Depending on the degree of biosecurity companies
have, especially when you have multiple age, the two-stage units in
turkeys, coveralls, boots, bonnets, hair coverings, the whole ball of
wax is utilized quite routinely in the turkey industry to prevent
disease spread, not only within a farm, but between farms.

Dead bird disposal and of course farm isolation I can tell you right now
that in North Carolina farm isolation is not a reality. You can probably
drive in North Carolina in some areas and shut your eyes, stop, get out
of the car, throw a rock and hit a tin roof. Its a lot easier to
isolate a farm as far as poultry density in probably Iowa or Kansas than
it would be in North Carolina, Arkansas, or Georgia. But we do try to
isolate farms, especially our breeders, especially the important birds
that will replace the genetic lines. We try to isolate those farms, and
then we will clean and disinfect farms.

Down time is very important to us. Down time reflects the disease
incidence sometimes as well maybe market changes, but we try to. You
know, the industry would like to see approximately two-week down time
between flocks. Right now you are looking at 20 days in North Carolina
and Georgia. A year ago it was more like seven or eight days. It just
depends. The longer we can keep that farm empty and those bugs not
having a reservoir of a bird to get in, the better off we are. Many of
the companies as well as the National Chicken Council, NTF, the egg
producers, all have best management guides and practices that are
distributed not only to the companies themselves, but to producers that
the companies do embrace and support.

(Slide.)

Vaccination technology, we have a lot of diseases in our birds that we
can vaccinate for and some that we cant. This is just an example. In
breeders as far as chickens we have got 10 or 12 diseases, depending on
the area of the country youre at, and there will be 22 to 25 different
antigens or serotypes going into those birds via live and killed
vaccinations. Turkeys, a little less, but still quite a number of
diseases that we can vaccinate for. In breeder vaccination, not only do
we have to maintain the breeder health, we have got to maintain her
laying eggs, and then a very important concept we learned years ago is
we have got to learn to prime these breeders with \-- to their immune
system to the point that they can deliver an acceptable amount of
maternal antibody so we can target our vaccination in our young meat
birds. Weve done it for years, especially pertaining to the immuno
suppressive virus, and its something that we have been very proud of
and been very fortunate to figure out that we can in fact target
vaccinations and minimize exposure to vaccines in younger birds based on
maternal antibody transfer through the yoke. Then blood testing in our
breeders is standard, usually every 10 weeks to look and see that
immunity is maintained.

(Slide.)

For meat birds, less numbers, less vaccination. You know, vaccines are
all great if animals dont get exposed. So we try to minimize the number
of diseases that we do vaccinate for. Of course, all of you know about
the in-ovo technology for \-\-- disease. It has been kind of advertised
if you will as something done in the poultry industry. That has been
very significant for us in controlling \-\-- disease. Of course a
different avenue, not only do we need to maintain health in our birds,
but we have got to maintain cost per pound. We have got to maintain our
weight gain. We have got to maintain our feed conversion, and these
diseases help us. Of course, in the process we want a healthy bird.

Blood testing again is standard for not only vaccine response, but at
processing to determine if there has been an exposure. Fortunately or
unfortunately we have diseases that we cant vaccinate for. We have
variations of serotypes of bronchitis out there now. Bronchitis is a
corona virus. The evolution of that is about four percent a year now. It
changes. Vaccines that were developed in 1994 are no longer currently
effective against isolates that we call the variants or different
serogroups. So that is problematic for our industry, and that is one of
the reasons E. coli tends to raise its ugly head so much.

(Slide.)

I will get into antimicrobial use, therapeutic disease prevention and
growth promotion, as well as day-old injection and in-ovo
administration.

(Slide.)

E. coli is by far our number one culprit. We also treat clostridial
diseases, both in necrotic enteritis and

gangrenous dermatitis as well as what we call fowl cholera, which is a
pasteurellosis. Those are probably, you know, 80 percent to 90 percent
of what we treat on a daily basis, E. coli being the big boy. It is a
secondary bacterial infection, predominantly due to primary respiratory
infection, but there are enteric diseases that predispose this. Unlike
our mammalian counterparts, E. coli is not a diarheal disease to any
great extent in poultry. It is more of a septicemia; air saculitis,
pericarditis, perihepatitis, splenomegalia, et cetera.

It is troublesome in our hens. We have hundreds of E. coli that we
isolate that cause disease. We have not been real great at finding a
good vaccine for E. coli. Now there are on the horizon somatic antigen
type of vaccines that might in fact give us some broader protection with
E. coli, but right now with \-\-- we just got too many. About anything
that you isolate out there has a potential of causing problems because
it is opportunistic, and I have already given infectious bronchitis. It
is like \-- infectious bronchitis in chickens is like trying to
vaccinate for the common cold in man. Its just very difficult.

We treat predominantly in water. In fact I would say exclusively, but
Im sure there is somebody that does try to go in the feed, but not a
major player in my opinion. The predominance of therapeutic
antimicrobial use is in the water.

Feed grade therapeutics are uncommon. We dont make a living out of
going in with high levels of antibiotics to treat an acute outbreak,
predominantly because we have to have cross-clearances, et cetera. The
feed additive compendium dictates what we can use in the feed, and if it
is not cross-cleared with a coccidiostat we are using lets say, you
cant use it. It is not like we can prescription an antibiotic just
because we want to as veterinarians in the feed. It is pretty much
dictated by the feed additive compendium what we can use and we cannot
use. So water therapy is the most common.

(Slide.)

We currently have about 12 antibiotics as intervention strategies for
our diseases, and the most common ones we use are tetracycline,
streptomycin, neomycin, and bacitracin. Those probably are the common
ones. If you are dealing with necrotic enteritis, if you are dealing
with some E. coli, those are the ones that we will try to use first hand
if our antibiotic sensitivity dictates that.

Less commonly we have got linco that is a good gram positive;
spectinomycin; tylosin, a necrotic enteritis control drug; erythromycin,
a good staph, E. coli, cholera drug used kind of \-- it is not a big
gun. Our big gun is fluoroquinolone, but it is a bigger gun if you will.
Sulfonamides are restricted because of potential residue problems, and
then penicillin.

So we do use them. They just dont treat the diseases that we commonly
see on a daily basis in chickens; and, if we are good at what we do, we
dont see diseases on a daily basis. Now we try to hold fluoroquinolones
in reserve. They are important to poultry as well as humans. They are
costly, and we try to keep them kind of close to hand, because they
represent our ultimate gun. If those dont work, we wont treat E. coli.
Conversely, if those are removed from the market Im sure we will see
some turkeys and chickens die for us.

(Slide.)

We have established guidelines. The American Association of Avian
Pathologists with the AVMA, and those guidelines are used in the
decision process. They are on the AAAP web. They are out there now if
people want to \-- and I have got copies of them.

But one initial thing is a diagnostic evaluation or work-up. We will go
in when there is a half-a-bird or a bird per 1,000, and we will work
these animals up. We will do some cultures on them. We will try to at
that point adjust management, ventilation, the temperature, make sure
they dont get chilled. We dont have the luxury of a lot of IV things,
but we will do oral medications of vitamins and supported therapy if it
warrants in some infections. But we try to wait on those antimicrobial
susceptible \-- well, the culture first, and then the susceptibility
patterns before we go in and start treating.

(Slide.)

So the use is based on diagnostics, mortality, morbidity, the age of the
flock. I mean, you are just not going to go out here and treat a
seven-week old flock of broilers if they are going to go out at 52 days
to processing. You know, you just have to weigh a variety of things.
Its just not a matter of youve got the disease. Theres a lot of
things that go into effect. You look at the farm history, you look at
the culture, historic cultures on that farm, and get together and give
it your best shot on whether you should treat and what with.

All antimicrobials are approved either by veterinarians or the live
production specialist. Integrated companies have their own veterinarians
that do make those decisions. In fact, many companies if in fact
producers treat indiscriminately with antimicrobials, thats potentially
a reason to be not raising chickens for them anymore. Of course, all
extralabel use and fluoroquinolone use is scripted by the veterinarian.

(Slide.)

Records are kept and utilized. The biggest thing is we cant treat sick
chickens and turkeys for a living, and we try to find out why they broke
and prevent that from occurring again. Currently I dont know of a
vaccine out there or an antibiotic that will fix bad management. We
sometimes think that \-- and things get written, and historically as
things get written and they are repeated enough they become fact,
regardless of their origin, but we just \-- we dont have vaccines or
antibiotics that we can put in the feeder and the water that overturns
bad management. Its just not there.

(Slide.)

For disease prevention or growth promotion if youd like, most of these
we utilize are to control necrotic enteritis. Ive got on there the
sub-therapeutic versus low level prophylaxis, and it may be all
semantics. Sub- therapeutic by definition in my mind sounds bad, and I
think in most peoples minds it does. That term got established years
ago because we could prevent diseases with levels that we could not
treat an active infection with. So lets say bacitracin at 50 grams
controlled necrotic enteritis. But if you broke with the necrotic
enteritis, you would have to go to a higher level to treat it. Hence,
the 50 grams had to be sub-therapeutic. I never liked that term, still
dont like it, but it may be a matter of semantics.

The reason we need them at this point in time is coccidiosis. We
routinely use anticoccidials, and these are static, not cidal. They
allow proliferation of coccidia in the gut, which predisposes the gut to
clostridium perfringens infection, which is necrotic enteritis. The
predominance of what we use, virginiamycin, bacitracin, and linco and
tylosin control necrotic enteritis. They are basically gram positive
antimicrobials, and thats why we use them to control that important
infection for us. We are looking closely at different technologies with
coccidia control; vaccinations, aerosoling, eye sprays that may future
minimize our need for necrotic enteritis control. But with coccidiostats
use right now we need them, and we need to use them.

Bambermycin, I have got a little notch there. It is not used in humans
at all and there is no counterpart, but it doesnt really have an
antimicrobial bacteriostatic or cidal effect. It is more of an increased
\-\-- bacteria and enhances certain types of good bacteria versus bad
bacteria to prevent necrotic enteritis.

(Slide.)

Theres things we know and we dont know about the growth promotants.
The ones that are the most common that have the most use in our industry
are virginiamycin, bacitracin, and linco. However tylosin and
bambermycin are used also. We do not use tetracyclines and erythromycin,
and penicillins and sulfas as growth promotants or as disease
prevention. We just dont, folks. The ones I have listed up there is
what we use to control. The other information that is out there I just
dont know who in the poultry industry are using these in low levels if
you are dealing with tetracyclines and penicillins, et cetera.

We have already stated necrotic enteritis control. Theres other things
that they do that we may not have a good handle on as to why, but
increasing breast meat yield, increased hot and chilled carcass weights.
Protein sparing effects has been talked about for years.

(Slide.)

One of the important things that we like is weve got to maintain our
intestinal health because of the automated processing system. When we
eviscerate automatically weve got to have a good intestine. If it is
diseased, we break intestines and get contamination. So it is very
important for us to maintain intestinal health, and these products help
us.

We also get told that in fact this is all economics, its all a numbers
game. But if you just reduce in chickens alone the feed conversion from
2.00 to 1.99, that represents 40 million pounds of feed per year. If you
want to add the costs, again, just for reducing one point in turkeys,
then you are up to 89 million pounds of feed. That is not only a cost to
the industry, but we dont have to mill it, we dont have to gas to run
it. Theres a lot of things that it helps us on.

(Slide.)

The day-old injection or in-ovo, we continually reevaluate this in the
industry and look at it, but it is a biological environment. That egg
comes from the back end of a chicken regardless of how you look at it.
Regardless of how stringent our sanitation and disinfection programs,
and they are quite good in our hatcheries, we get microbiologic
contamination of that egg.

Now, you can say we can sanitize and we can disinfect that egg. If we do
that, we mess up the cuticle, which is the protective covering of that
egg. It is actually the barrier, if you will, mother natures barrier to
antimicrobial \-- or, excuse me, to bacteria penetrating that egg.

A lot of people had controversy for years about the day-old injection,
and when the in-ovo injection came it gave us a window of opportunity to
treat that yoke when it was contaminated. Right, wrong, or indifferent,
it at least if the incubation or the bacteria was contaminated in that
yoke when it was drawn in, an in-ovo deposition of bacteria \-- or of
antibiotic, gave us a shot to control that infection.

(Slide.)

Again, gentamicin and ceftiofur is the most commonly used at this point.
Actually, the only \-- and that is extralabel use. The only labeled
indication for an antibiotic is sarafloxacin, and it of course has not
been used for years and really never was used. The industry didnt want
to use a product as important as sarafloxacin.

(Slide.)

We continually look at competitive exclusion products. We like to look
at dosing based on how much body weight is in the house versus how much
water they drink, but thats an extralabel issue. Processing is
extremely valuable to us, and decrease in bacterial numbers either
through irradiation or certain antibacterial rinses are continually
looked at in our industry. Remember that in our industry antibiotic use
is a salvage procedure. Once we have to treat for active disease we
lose, and we have already lost money as well as the health of the animal
that is at risk.

Got to reiterate that we dont have a vaccine or an antibiotic that
treats bad management, and we try to continually evaluate what we do. I
think one of the things I would leave you with is not everyone agrees
with animal agriculture and the way we do things, but just because
theres disagreement in the minds of experts on how we do things does
not make what we do as labeled as wrong just because there is
disagreement on how things are done. I appreciate the time to speak
here, and Im four minutes over. So I guess there wont be time for
questions.

MODERATOR BEAULIEU: If there is a quick clarifying question we can take
that now. There will be plenty of time for discussion questions after
lunch.

(No response.)

MODERATOR BEAULIEU: Okay. Thank you, Dr. Wages.

(Applause.)

***[Animal Husbandry and Disease Control: Aquaculture]{.underline}***

***By Dr. John Plumb***

MODERATOR BEAULIEU: Our next speaker is Dr. John Plumb. Dr. Plumb
received his Ph.D. from Auburn University in 1972. Prior to going to
Auburn to seek his degree he spent seven years working at the U.S. Fish
and Wildlife Service. Dr. Plumb was employed by Auburn University from
the time of receiving his Ph.D. until his retirement as a professor in
1998. He is currently professor emeritus in the Department of Fisheries
and Allied Aquacultures at Auburn. John will speak to us about animal
husbandry and disease control in aquaculture.

DR. PLUMB: Thank you very much. I get the notion of my antiquity here
when I use slides rather than the Powerpoint systems. Im dragging my
heels as hard as I can into the modern era of communication, but I hope
you can see these.

(Slide.)

Aquaculture in the U.S. has grown tremendously during the last 30 to 40
years. Much of this growth has been due to the tremendous increase in
catfish culture across the southern tier of states. As a matter of fact,
in some of our forest counties in Alabama and Mississippi, that is the
primary industry that is supporting those major economies. But catfish
have grown, also have salmonic culture, trout, and marine salmonids as
well striped bass and tilapia. When we talk to aquaculturists in general
they like to consider that this is a large industry. But when we compare
the production in aquaculture in the United States to that of poultry
and swine and cattle, it is very, very meager, and you will see what I
mean as we go through this. Of course along with this aquaculture has
come the problem of diseases, some old ones and some new ones.

(Slide.)

If we look at the sources of aquaculture you can see that \-- or sources
of seafood rather. You can see that the majority of the seafood
consumption in the United States comes from exports. The aquaculture
imports \-- I am sorry. It comes from imports in the U.S. Currently
there is \$10 billion worth of imports of aquaculture product. We export
\$2 billion. So the trade deficit on aquaculture itself is \$8 billion,
and this is third highest compared to oil and automobiles. Aquaculture,
these data came from 1988, contributes 10 percent of the seafoods that
are consumed in the U.S. Now that is up a little bit to 15 to 20
percent. Wild catch contributes 30 percent, and thats pretty much going
to stay at that level. Its not going to increase. Theres just no more
sources of wild fish out there than can be exploited to increase that
amount. So you can see there is a tremendous opportunity for aquaculture
to get into the seafood business.

(Slide.)

Now when Im talking about aquaculture Im talking about a variety of
groups of animals. Aquaculture can be considered all the way from
growing of brine shrimp to tuna. So its anything that is being grown in
water for a food base or any type of that. We can break this further
down into fish. We have catfish and salmonids, both marine and fresh
water. Other fish are tilapia and striped bass. These have become
extremely popular. Bait fish, a huge industry. Probably all together the
bait fish and ornamental fish industry are larger than our food
production aquaculture is concerned.

Crustaceans, crawfish and shrimp. Shrimp themselves are \-- it is not
cultured a great deal in the United States, but there is a meager almost
embryonic shrimp culture being developed in West Alabama where we have a
salt water aquifer that is quite large. The salinity of that water runs
from five to 25 parts per 1,000, and they are successfully growing
shrimp in West Alabama in ponds receiving that water. Of course oysters
also are contributing to this bit of production.

(Slide.)

And if we look at these various food groups where the production is
coming from, if we look at catfish there are 400 and 525 million pounds
were produced in 1997. If we compare that to 56 million pounds for
trout, 39 million pounds for salmon, crawfish 49 million pounds, others
are 54, and then oysters are 62. So catfish is contributing to the vast
amount of the aquaculture product in the U.S.

(Slide.)

Losses in aquaculture. You know, some of our catfish farmers, they
calculate \-- well, actually its not a calculation. Its actual. From
the time an egg is hatched or produces an embryo until the time that
fish goes to market for sale, they lose 70 to 75 percent of those
animals. In any other animal culture that would be totally intolerable,
but most of those loses are in the early stages where you dont have a
great deal of investment in it. Actually 45 or over 45 percent of these
losses are due to diseases. Predation contributes a tremendous amount of
this loss. \-\-- juvenile fish, cormorants, pelicans, storks, herons,
all of these animals come in. All of these birds come in and feed on
these captive populations of fish in these ponds and raceways.

Low dissolved oxygen and water quality problems contribute to the loss,
and this particular aspect contributes to disease losses. Because as we
will see in a moment in an aquatic environment the disease
susceptibility of fish is very closely tied with that environment
character, and there are other losses contributing to five percent.

(Slide.)

Well, what is the aquaculture approach to disease? For a number of years
we have been trying to emphasize to the aquaculture industry that health
management is a way to go. We can no longer use drugs indiscriminately.
Vaccines are coming into play, and of course thats all part of health
management, the use of those tools. But this goes on the premise that
most clinical diseases of fish result from management or environmental
stress, and actually very few diseases occur as a pathogen, as a primary
etiological agent. If you have a pathogenic agent in those fish and you
have sick fish, they are showing clinical signs, there is probably
something with the environment, some part of the processing of the
aquaculture facility that has influenced that disease. So you have to go
a little bit more deeply into it.

(Slide.)

This is a diagram that we put together to try to illustrate what this
has to do with aquaculture. We put the fish health status in the center,
and all these other aspects, the host, the husbandry, the environment,
the nutrition, the pathogen, and the physiological status of that animal
all plays on the fish health. These are also interrelated. They affect
one another, and there is no more important aspect of this than the
environment, because water quality is the key to successful raising of
fish. If you dont understand the aquatic environment and what role it
plays, then it is very difficult to have an effective process to control
diseases.

(Slide.)

Well, what is this disease prevention? We consider this a proactive
approach, something that aquaculture is doing up front to prevent
diseases, and this is simply herd management. It is the same process,
proper handling. I once heard somebody say that fish are not potatoes,
and they certainly arent. Fish are very delicate animals. They have a
delicate mucus protective layer, and if that mucus layer is disturbed by
handling or for any other reason, then that fish is more susceptible to
infectious organisms that may be present in the environment.

Pond raceway hygiene, this is always important in any of our culture
facilities. Water quality management, here comes the management of the
environment. Water flow, you have to have sufficient water flow. You
have to have enough water on a constant availability to fill ponds and
this sort of thing.

Aeration, with the mechanical aeration that is going on now in pond
culture, this has allowed the catfish industry to develop to the point
that it is now. Much of that technology was developed at Auburn by a
gentleman by the name of Paul Boyd, who pioneered a lot of that work in
the U.S. Algae plant control, alkalinity hardness control, all these are
important in that particular process.

Moderation of stocking density. This is one of the most difficult things
that we have to get over to our fish farmers, that more is not
necessarily better. We were experimentally vaccinating some fish, some
catfish for a bacterial infection a number of years ago with a farmer,
and his immediate response was since were vaccinating these fish and
were protecting them against this X disease that means we can double
our stocking density. Well, it doesnt work that way, and this is the
hardest thing to get over to these people. That just because you can
harvest 5,000 pounds per acre with no difficulty does not mean that you
can go to 10,000 pounds per acre, because it is going to cost you. So
that is hard to get to, but their understanding is some of this from
practical experience when they go out and they find a particular morning
that they have lost 100,000 pounds of fish overnight because of oxygen
depletion, it gets their attention pretty quick.

Feed management and nutrition, of course this is always very important.
Disease resistant-stocks through genetics. This is something that is
coming into play in aquaculture, and it could very well be an important
aspect in the future.

Specific disease-free stocks, the acquisition of seed animals that are
certified or have been inspected to be free of certain disease. Now,
this has been practiced in cold water aquaculture for a number of years,
and its just something thats really coming into play with our warm
water people.

Prophylactic treatments, I do not think that in the United States
anywhere that antibiotics are used as prophylactic treatments. Some
chemicals are, such as formalin, this sort of thing, but not
antimicrobials. Vaccinations, the first fish vaccine came on the market
in 1976, and this vaccination has been credited with the explosion of
salmon culture in Scandinavia. People that produce those vaccines said
that all of this increase in production, the reduction of the
requirements for medicated feed was because of vaccination. But when you
talk to those people that have been involved in that system and that
process, its not vaccination alone. They have gone in and revamped
their management procedure, and vaccination is one of them.

Chemotherapy, a reactive. We try to influence the farmers that if you
have to use an antibiotic it is like locking the barn door after the
horse is gone. The damage is already done, and its not used
indiscriminately. It has been in the past, but I really think there is
very, very little of that that goes on anymore in aquaculture in the
United States. I will talk about that at the end in just a moment.

(Slide.)

I will give you an example of how the catfish industry treats one of the
most serious diseases that it has to contend with. It is a bacterial
infection, enteric septicemia of catfish caused by an edwardsiella
species, and the first and the most effective treatment is to take those
fish off feed. I dont know the mechanism. No one knows the mechanism.
But if you take those fish off feed when that disease breaks, if you
take them off for a week, your survival is better than if you go in and
treat with a potentiated sulfonamide romet 30. So this, taking the fish
off feed, is what is done in production ponds.

When you get down to medicating the feed with Romet 30, say 41 percent,
most of these are fingerling producers that are producing to seed fish
or they have gone through this non-feeding process and it didnt do any
good. Then they may try to come back and use medicated fed. Some of them
just dont do anything. They just keep on feeding the fish and take
their lumps, and take what ends up. Other actions, I dont have any idea
what those are. But that came up in the survey, and I dont know what
they are doing other than the first three.

(Slide.)

If we look at catfish feeds since 1994 and the percent of feeds that
contain antibiotics, and these are some data that were provided by the
Catfish Farmers of America, in 1994 1.5 percent of the catfish feeds
that were sold contained antibiotics. It went up a little bit in 95,
but since that time this has steadily reduced down to .6 percent last
year contained antibiotics. Were talking about not nearly the volume of
feed that occurs with other feed animals.

(Slide.)

Methods of chemotherapy, how do we treat fish? You have to treat them as
a population. You cant treat individuals very easily. Some people dip
them. This is not a particularly good method. You cant handle many
fish. Flush, where you put a chemical in the water and it goes through
very quickly. This is not antibiotics now. These are chemicals,
formalin, this type of thing. Prolonged treatment of minutes and hours,
indefinite. These are in ponds where you put a chemical like potassium
permanganate or formalin in the pond. It deteriorates on its own,
dissipates.

A feed additive, this is where the antibiotics are used as feed
additives and injections. This is not particularly effective in some
husbandry operations, but where we are talking about marine salmonids
where those fish are going to be worth \$3 or \$4 a pound at sometime
down the road, they will spend \$.10 per fish to hand inject and
vaccinate those fish, particularly when they have a multivalent vaccine
that can be used to protect against three, or four, or five diseases.

(Slide.)

Now, FDA registered drugs. In considering what our first speaker talked
about and the drugs that were available to cattle and then to the swine
and then to the poultry, this is all that is approved for use in the
United States in terms of FDA registered drugs. Formalin is used as a
bath treatment for external parasites, all fish, a fungicide on eggs.
Terramycin, oxytetracycline in the feed for systemic bacterial
infections for catfish and salmonids. It is also used a little bit to
tag fish before they are stocked by either emersion or by feed additive,
but there is not very much of that either that goes on. Then Romet 30 as
a feed additive for systemic bacterial infections in catfish, and thats
essentially what is available.

(Slide.)

Now there are two products, two chemicals that are approved by the EPA
to use in plant control and water quality. They are copper sulfate and
potassium permanganate. Now there are inads in place for both of these
to get them so we possibly can use them as a disease treatment.
Currently they cannot be used as a disease treatment. Copper sulfate,
you have to be controlling an algae program problem so to speak, but
its really the only thing we have for ichthyophthirius. If any of you
have aquaria, if you have ever used or worked with aquaria, you have
heard of the parasite ich. That is what we are talking about, and it
can be a devastating parasite. Potassium permanganate is an organic
oxidizing agent in waters with food fish, and it is used as a \-- for
external bacterial and some parasitic infections, an inad is in place to
try and get that approved.

(Slide.)

Drugs under consideration with \-\--, and these are licensing is very
questionable. Some oral antibiotics are enrofloxacin, florfenicol, and
amoxicillin. As I say, the possibility of getting these licensed are
rather slim at the present time, and injection, erythromycin.
Erythromycin is used as an injectable into salmon brood stock before
they spawn to prevent the transmission of bacterial kidney disease to
their offspring, and those fish are not \-- that are injected, once they
spawn, you have to kill the fish in order to spawn them, and they are
disposed off. They do not go into a human food chain.

(Slide.)

Other drugs that are under consideration are fumagillin, chloramine-T,
which is used extensively in Europe for bacterial infections on the
gills and skin, and then hydrogen peroxide, which is used to treat eggs,
fish eggs, as a fungicide.

(Slide.)

Just a brief comment on antibiotics in the U.S. aquaculture. It is not
used nearly extensively as they are in other parts of the word. For
example, Japan has something like two dozen antibiotics that they can
use in their aquaculture systems. South America has more. Europe has
more. All of Southeast Asian countries have more drugs and chemicals
that they can use, but we are pretty well restricted on that list, to
that list that you talked about.

Antibiotics are used only for clinical disease treatments. They are just
not used prophylactically so far as I have been able to determine. As I
mentioned earlier, catfish feeds, only .6 of a percent contain medicated
products last year. Salmonids, I understand there are 37,000 pounds of
oxytetracycline of 20 percent active material are used annually of that
particular drug. Tilapia, striped bass is limited. In talking to the
people that are involved in those cultures, they are taking the
management approach as well.

Some of those systems, particularly with the tilapia, where they are
using circulating systems, high densities, terrible water quality, those
systems just sit on a knife edge all the time. If the fish population
coughs in there, you have got a disease problem. You can use all the
antibiotics you want in those systems. It is not going to correct the
problem until you go back and change the management and the
environmental conditions in which those fish live. Weve seen examples
of that particular aspect.

Marking fish with oxytetracycline by emersion or in feed is limited.
Its not used as much now as it was at one time.

(Slide.)

Further, I really dont think there is much in the way of abuse of
antibiotics in aquaculture in the U.S. Its been restricted. Its
reduced simply because of FDA regulations, concerns for pathogen
resistance. This is not only a concern in the scientific community, but
the aquaculturists themselves, the farmers themselves, understand what
happens. Most of them do anyway, what happens when you prophylactically
treat antibiotic or feed a little bit for a long time. They know what
can result from that, and you dont have many. When you dont have many
antibiotics in your medicine chest anyway, you dont want to eliminate
one before you ever really need it.

Lack of dependable efficacy. This goes back to the Romet 30 problem. It
is not as effective as one would like it to be. Therefore, they are
going to expend that money for something that has a very poor
benefit-cost ratio with them. Disease prevention through health
management is a better approach, and this is something we are getting
across to particularly our warm water aquaculture people. That is a
better approach than dependence on chemicals and drugs.

Implementations of vaccines. I think this is going to become more
important in the future, but here again as the previous speaker said,
there are no silver bullets in these vaccines or in antibiotics. The
aquaculture industry has to know that when you have a vaccine it doesnt
mean you can still indiscriminately ignore the insult on that
environment and other aspects of the culture system.

(Slide.)

Very briefly in conclusion, aquaculture provides only 10 percent of the
seafood market. Its up a little bit now, 10 to 20 percent. When you can
take into consideration that the per capita consumption of seafood in
the United States is about 15.5 pounds per year, and if only 10 percent
of that comes from aquaculture, that is only 1.5 pounds per person. So
there is not very much consumption in that light in terms of our
consumption of seafood. Health management has become more important, and
the use of antibiotics in aquaculture is declining due to the reasons
that we have just mentioned.

(Slide.)

If it comes to pass that antibiotics are indeed eliminated from
aquaculture, I really do not think that it is going to have a
tremendous, devastating effect. It is going to effect them, thats sure,
because it is just another tool that they have to combat these problems.
But I dont think it is going to kill the industry. Now, you might get
some aquaculturists out there that may disagree with that, but with the
emphasis on management, the emphasis on prevention, the emphasis on
these sorts of things, I think well overcome any loss by \-- if
medications are actually eliminated. But at the same time, I think that
the possibilities of this happening and affecting human health from the
aquaculture perspective I think is somewhat limited.

I think it is inappropriate to use data from non-U.S. regions to
evaluate drugs in U.S. aquaculture, because it is totally different. The
approach to it here is totally different from Japan, from Thailand, from
China, from Ecuador, these places where we are getting a lot of our
imported aquaculture products.

Nearly all the shrimp \-- well, 50 to 60 percent of the shrimp that we
consume in this country, come from foreign imports. Either from Ecuador,
other Central American countries, Thailand, and you look at the shrimp
industry in Southeast Asia. 15 or 20 years ago there was a huge shrimp
industry in Taiwan, but they were going through this Push the system,
push the environment, get everything you can out of it. Well control
all of our problems with drugs, antibiotics, and chemicals. Well, after
about six or eight years of that, they couldnt raise shrimp there
anymore. So they went to Indonesia. The same thing happened. The same
investors that were investing in shrimp in Taiwan took the whole system
to Indonesia. They went through the whole system again, and they were
producing \-- I mean, their acreage in shrimp would dwarf our catfish
operation. But they did the same thing, they destroyed the environment
they were trying to raise these animals. So they went to Thailand, and
they are doing the same thing there. They are just doing it in one place
in Thailand, but Thailand is large enough, has enough land mass to
diverse. They ruined it here, they go somewhere else. So its just a
whole process.

So you cant take things that happened in India, happened in Japan, and
apply them to our system as far as aquaculture is concerned, because the
systems are just absolutely different. With that, I will stop. Thank you
very much.

(Applause.)

***[Alternatives to Antimicrobial Drug Use in Food
Animals:]{.underline}***

***[Benefits and Limitations]{.underline}***

***By Dr. Saeed A. Khan***

MODERATOR BEAULIEU: We are running a little late, but not too bad.
Thanks to all the speakers for that. Our next speaker in this session is
Dr. Saeed Khan. Dr. Khan received his Ph.D. from Banaras Hindu
University in 1989. He was involved in post-doctoral studies at the
University of Texas Health Science Center, where he subsequently became
a senior research associate and instructor in the Department of
Biochemistry. Since 1997, he has been a visiting scientist and a staff
fellow at FDAs National Center for Toxicological Research. Dr. Khan is
principal investigator or co-PI on several studies involving
antimicrobial resistance, including potential vancomycin resistance in
competitive exclusion products for quinolone-resistant salmonella in
animals, animal feeds and their environment and for quinolone-resistant
campylobacter in poultry. He hopes to begin work soon on a project
involving the environmental fate and effects of antimicrobials approved
for use in aquaculture. Saeed will speak to us about alternatives to
antimicrobial drug use in food animals, benefits and limitations.

DR. KHAN: Thank you very much. It is my pleasure to come over here and
talk about what we are doing and what are the alternatives to
antimicrobial usage in food animals. (Slide.)

You have heard a lot about the problems associated with the use of
antimicrobials, and then to give you an idea how many different kinds of
antibiotics are used in food animals, about 106 different antibiotic
related products are used in farms animals. Some are used as growth
promoters, while the others are used to treat the infections by
pathogenic bacteria. The most common antibiotics used are
fluoroquinolones, aminoglycosides, and macrolides. The excessive use of
these antibiotics in farm animals is suspected to create a problem of
antimicrobial resistance transfer.

(Slide.)

Last year there was a study that was published from CDC as I will show
you here. They isolated a salmonella strain from a boy who was admitted
in the hospital, and the strain was when it was analyzed, they found the
strain was similar to one that they isolated from cattle.

(Slide.)

We are also doing some work on these antimicrobial resistance transfers.
We isolated several erythromycin resistant staphylococcus aureus
isolates \-\-- isolates could transfer the resistance to human clinical
isolates. So what we did, there are two most common erythromycin
resistance markers, the ERMA and ERMC. What we did, we have the poultry
isolate called the P58 here, and it contains the two, those markers,
ERMA here the top line, and this is the ERMC marker. We got four
clinical isolates. Two of them have the ERMA gene, but they didnt have
the ERMC gene. The two others did not have any of those genes. We wanted
to see if the ERMA and ERMC from poultry isolates could be transferred
to clinical isolates. So after the experiments and conjugation and the
selective \-- and the selection on selective antibiotic plates, we
picked up certain conjugates. When those conjugates were analyzed for
the presence of those markers, here are those conjugates. You can see
the ERMA and ERMC gene both are present in those conjugates, and the
direction of transfer was from poultry isolates to clinical isolates.

Now, we know that there is a problem of drug resistance transfer, and
there are enough groups that it could be transferred from poultry to
clinical or vice versa. What can we do about it? Are there any
alternatives?

(Slide.)

Well, there are a couple of alternatives, and these are use the
prebiotics. These are certain carbohydrates when they use in feed as
additives they stop the growth of certain pathogenic bacteria. Then
probiotics, this could be an organism or a group of organisms that again
do very much the same thing, but they are more effective as compared to
prebiotics.

Then we have the vaccination, phage therapy. In the beginning when the
phages were isolated people thought that they got a cure for bacterial
infections, but somehow it did not work out. But recently there is a
renewed interest in phage therapy. Phages are the bacterial viruses that
grow on bacteria, and they could be used to kill the bacteria. So I
dont know if anybody is using it here in the U.S., but in Georgia,
Russia, they are using the phage therapy for human

\-- to treat human infections. There is only one report here in the U.S.
where they are using the mice as a model. They challenge the mice with
\-\-- and then they injected the \-\-- phages, and they found that the
phages could control the infection process and \-\-- by this method.

There is no alternative for good hygiene. If you maintain the good
hygiene on farms then I think that is also one good step in reducing the
pathogenic bacterial population in those animals.

(Slide.)

None of these alone could prevent the spread of pathogenic bacteria or
the transfer of antibiotic resistance markers. But the probiotics are
gaining more popularity nowadays, and these probiotics are used as
adjunct or replacement for antibiotics. They are currently used to
prevent salmonella contamination in chicks, in chickens. Testing in
swine and cattle is underway. Preempt was recently approved by FDA.

(Slide.)

Now, what are those different kinds of Preempt products that are
available in the market today? There are several of them. They are
Aviguard, Avian Pac, Broilact, Preempt, PCF-1, Ferlac-2. The last two
are used in swine. The others are used in poultry. Most of them are
undefined

\-\-- bacteria, except for the Preempt. The company that produces it
claims they have got 20 different bacteria, well-defined bacteria. But
somebody in our group who is working on this Preempt, he has isolated
the bacteria. There are more than 29 bacteria, and then definitely not
what the company claims.

So that is one aspect to it, and then there is another aspect to this
one. Some of these bacteria are resistant to vancomycin. Now, vancomycin
let me tell you is the antibiotic of last choice. In human clinical
practice when the bugs become resistant to vancomycin, there is no cure
but death. Because there is no antibiotic that can cure those
infections. Now since this contains the vancomycin resistant bacteria,
thats when I got interested into this project. Before I discuss the
results of my studies that I have laid out a little bit, I would like to
tell the mechanism, how this Preempt, or for that matter the probiotics,
work.

(Slide.)

The mechanisms are they reduce the contamination by lowering the pH in
the intestine, low redox potential, they produce inhibitory substances,
and there is a competition for nutrients and they may compete for the
receptor sites.

(Slide.)

Now, the other benefits associated with the use of these competitive
exclusion products are shown in the next slide here. It has been shown
that they can significantly reduce the salmonella infection and
listeria, the two most common food pathogens. Here are the \-- you know,
I have taken the data from this paper. Treated, zero percent; untreated,
seven to nine percent. Same thing here in the case of listeria. Treated,
zero percent; untreated, 13 to 23 percent.

The most important benefit of using the competitive exclusion products
is that the use of antibiotics can be greatly reduced, and that is what
we are probably here to find the ways and discuss the means to eliminate
the use of antibiotics so that the problem of drug resistance transfer
is minimized.

(Slide.)

There are some limitations also with the use of these competitive
exclusion products, and these include as I mentioned before that some of
those competitive exclusion products, most of them are undefined, except
for this Preempt. That also turned out to be a little bit undefined. If
it is an undefined competitive exclusion product it may contain
pathogenic bacteria, and this may defeat the very purpose for which it
was developed. The second one is if the CE product, even if it is
well-defined, they may contain antibiotic-resistant bacteria that would
then assist in the transfer of resistance markers.

There have been several other studies where they have used antibiotics
along with competitive exclusion products, and they have shown that the
competitive exclusion products if they are sensitive to these
antibiotics and if you do the co-treatment using the CE product and the
antibiotics together, that may compromise the efficiency of these
competitive exclusion products.

(Slide.)

Well, at this time I would like to switch some gears and try to tell you
about what we are doing and how many different projects that we have at
NCTR in the Division of Microbiology. We have a couple of these
projects. Most of them are in collaboration with CVM. Two are with the
competitive exclusion product Preempt, and I am associated with one of
them. I am PI on this project.

(Slide.)

So we wrote this protocol in collaboration with Roger Jones of CVM, and
this product as I was telling you before is a mixture of 29 well-defined
bacteria. 11 of the 29 bacteria contain a high level of vancomycin, MIC
being more than 256 micrograms per mil.

(Slide.)

And here the collaborators that we have. Roger Jones from CVM, and some
other colleagues of mine that work there at NCTR.

(Slide.)

Well, we defined certain objectives with this project. What we wanted to
do was develop rapid PCR-based screening methods for vancomycin
resistance markers; plasmid DNA profile and drug resistance transfer;
genetic fingerprinting of vancomycin-resistant organisms.

(Slide.)

We first isolated some vancomycin-resistant bacteria, and they are shown
in the next slide here. We isolated about 10 of those. Most of them are
lactobacilli. There are about three or four \-\-- of these bacteria, and
now we wanted to see how many vancomycin resistance markers are there
and if we can detect them by PCR methods.

(Slide.)

So what are those markers? These are outlined here. They include the
VanA, VanB, C1, C2, C3, DdlA and B genes. These are actually if you look
at the normal cell wall synthesis in bacteria, the bacteria synthesizes
\-\-- peptide. When that is incorporated in bacteria, the bacteria is
sensitive to vancomycin. What these ligases do, they misincorporate
terminal alanine and displace it with D-lactate. When that happens, the
bacteria become resistant to vancomycin. When these ligases are present
you see these resistant \-\-- of bacteria. These van genes are mostly
present in \-\--. DdlA and B mostly present in E. coli and lactobacilli,
but they are also present in \-\--.

Now the sequences of all these genes are known, and they are deposited
in the database. So I picked out the sequence from there and designed
the PCR primers for these individual genes, and we wanted to see if we
can individually amplify all, simultaneously amplify all those genetic
markers.

(Slide.)

So in the next slide, in panel A you will see the individual
amplifications of wild genes. Here is VanA. This is VanB, C1, C2, and
C3. Then we wanted to see whether we can further speed up the whole
process and carry out all these amplifications in just one reaction
tube. So we combined all the primers and templates and carried out a
multiplex PCR, and a multiplex PCR you can see I have all the four genes
amplified in one reaction tube. This is VanA here, VanB, C1, C2, and C3,
and this is another PCR reaction where I have individually amplified the
DblA and B genes. So now we have got this methodology worked out that
could be used for epidemiological screening of all these
vancomycin-resistant markers.

(Slide.)

We have also done some fingerprinting analysis, but because of time
constraint I am probably not going to discuss all those results. Just to
summarize what I have just said, we have this method, individual and
multiplex PCR methods that could be used for epidemiological screening.
We have also done the assay on the bacteria that we isolated from the
Preempt product, and we didnt see any of the Van genes, except for the
DdlA and B genes. Now DdlA and B genes are not known to be transferable.
Among the Van genes, only the A and B are known to be transferable. So
since this product doesnt contain any Van gene markers, especially the
ones that are transferable, it looks like the product is safe. But
probably more studies are needed before we can say with certainty that
this is 100 percent foolproof, and all this data is only for just one
antibiotic. There are other antibiotics that these bugs are resistant
to. So we havent studied the transfer of drug resistance markers for
all those antibiotics.

But in conclusion, I would say that if the CVM, if FDA is interested in
approving these future products, at least they should have \-- they
should be free from pathogenic bacteria and they should not have any
antibiotic-resistant markers that could be transferred. But this product
appears to be, as far as the vancomycin is concerned, appears to be safe
for use in poultry, and at this point I would stop and take any
questions that you have.

(Applause.)

MODERATOR BEAULIEU: A quick question for Dr. Khan?

DR. VOGEL: Yes. This is Lyle Vogel with the American Veterinary Medical
Association. As part of your introduction you had a list of the three
most commonly used antibiotics, and fluoroquinolone was one of those
three. Could you explain the methodology you used to determine the
frequency of use or the amount used and how you determined that
fluoroquinolone was one of the three most commonly used antibiotics?

DR. KHAN: Well, up until now I think fluoroquinolones were commonly
used. We have a lot of poultry farms in Arkansas. They dont use it in
chicken farms, but they use quite commonly in turkey farms.

DR. CARNEVALE: Dr. Khan, Rich Carnevale, Animal Health Institute. You
mentioned that competitive exclusion products would reduce the use of
antibiotics. What did you mean by that? What specific uses of
antibiotics would it reduce?

DR. KHAN: Well, see, when these competitive exclusion products are
sprayed on, you know, chicks, the pathogenic salmonella colonization in
intestine is blocked. Plus you precolonize the chicken intestine with
this Preempt product. So the pathogenic bacteria, they cannot colonize
the chick, and most of the salmonella that have been isolated from these
poultry farms are resistant to antibiotics, multi-drug resistant
salmonella. So if you can block the colonization with these pathogenic
bacteria that are normally resistant to \-- not normally, but because of
the use of antibiotics, they became resistant to antibiotics. So from
that angle I was talking that it will stop the transfer of drug
resistance.

MODERATOR BEAULIEU: Last question.

VOICE: Okay. Dr. Khan, did you \-\-- the PCR product to confirm \-\--
vancomycin-resistant gene?

DR. KHAN: Yes. We have digested these vancomycin-resistant markers with
\-- there are two criteria that I use. First is digesting with certain
\-\-- enzyme that is known to give a certain number of fragments, DNA
fragments when you have these Van markers. The second one is the correct
size of the PCR product that you will get if your PCR amplification is
right.

MODERATOR BEAULIEU: We can pick this discussion up further this
afternoon. Thanks, Dr. Khan.

DR. KHAN: Thank you.

***[Human Health Risks Associated with the Use of]{.underline}***

***[Antimicrobial Drugs in Food Animals]{.underline}***

***Dr. Glenn Morris***

MODERATOR BEAULIEU: Our next speaker is Dr. Glenn Morris. He received
his M.D. and Master of Public Health and Tropical Medicine degrees from
Tulane in 1977, served residencies in internal medicine at the
University of Texas, Southwestern, and at Emory University. He served as
an epidemic intelligence service officer at the Centers for Disease
Control and then came to the University of Maryland School of Medicine
for subspeciality training in infectious diseases. He is Board certified
in both internal medicine and infectious diseases. Dr. Morris joined the
faculty at the University of Maryland in 1984 and is now professor and
chairman of the Department of Epidemiology and Preventive Medicine. He
has published numerous book chapters and articles, has served on three
National Academy of Sciences expert committees dealing with food safety,
and from 1994 to 96 worked with USDAs Food Safety and Inspection
Service on a major revision of food safety regulations while serving as
director of their Epidemiology and Emergency Response Program. He has a
strong research interest in the area of emergent pathogens, maintains an
active laboratory working in the area of molecular genetics and
epidemiology, and serves as co-PI of the CDC Emerging Infections Program
site in Baltimore, Maryland. Glenn will speak to us about human health
risks associated with the use of antimicrobial drugs in food animals.

MR. WOOD: He will as soon as he gets the technical \--

MODERATOR BEAULIEU: Right.

DR. MORRIS: I love Powerpoint slides, but \-- thank you, and my
apologies for the slight technical delay there. (Slide.)

What I would like to talk to you about today are some of the human
health risks which are associated with the use of antimicrobial drugs in
food animals.

(Slide.)

I think there are certain key concepts which I would like to start with.
Basically the idea that emergence of resistance is driven by use of
antibiotics. Resistance can arise in a bacterial strain through a
variety of mechanisms, by mutation and/or be transmitted from another
bacteria, and in particular these are mobile. Many of these are mobile
genetic elements, including plasmids and transposons, and I think
probably the key message is that resistance will arise with sufficient
exposure to antibiotics. It is not a matter of, you know, if. Its a
matter of when. When is it going to happen. In fact thats the problem
which we face on this, is that in human medicine we are facing
significant problems in terms of our ability to use antibiotics.
Antibiotics were the miracle drugs of the later part of this past
century, and I can tell you as a clinician seeing patients everyday \--
again, the reason I was a little bit late was I was looking at my
patients on the ward this morning. Our biggest problem is antimicrobial
resistance and dealing with these patients. It is a substantive and
extremely important problem in modern medicine.

The problem again, as I said, is that resistance will arise. What is
happening is that the window of opportunity during which time we can use
a drug is beginning to narrow. For many of the drugs that have been
standard drugs we no longer have the opportunity to use them because a
significant percentage of the isolates that we are dealing with are now
resistant. For new drugs we are finding that we may have only a limited
life span. Again, as a clinician, our key objective is to try to
lengthen the life span of these antibiotics in human medicine.

(Slide.)

I would point out that antibiotic exposure is substantive in multiple
areas. The numbers here are controversial, I think as many of you are
aware. The ranges I give here, one end of the range is by Animal Health
Association. The other is by the Union of Concerned Scientists, and you
can see that we are dealing with a ten-fold difference in estimates. The
most recent work by the Union of Concerned Scientists suggests that use
of antibiotics in human medicine may be as low as three million pounds
annually, and their estimate is that non-human use may be as high as
30.6 million pounds annually. I imagine the truth is somewhere in
between these. Nonetheless, I would emphasize that there is substantive
antibiotic use, no matter which way you put it in terms of animals
versus human use. I would also emphasize that these high levels of use
have an inevitable impact on the overall levels of resistance in
microbial communities. These may be microbial communities in humans.
These may be microbial communities in agriculture. These may be
microbial communities in the environment. However, we are all in this
together in a single ecosystem, and as we develop antimicrobial
resistance in any one area, inevitably there is spread into other areas.

(Slide.)

In terms of humans specifically, the specific, the primary areas of
concern are direct transmission of resistant pathogenic microorganisms
to humans, and specifically here we are talking about salmonella and
campylobacter, and at a more general level transmission of genetic
material or resistance genes to colonizing microbial flora. Much of the
recent attention in this area has been focused on the enterococci, but
there are also potential concerns, theoretical concerns, in terms of E.
coli and other enterobacteriaceae.

(Slide.)

So who cares if you get a little resistance? Well, in terms of resistant
salmonella and campylobacter, human health consequences fall in several
areas. First of all is the failure of therapy. DT104 strains, which I
think most of you are familiar with, resistant to ampicillin,
chloramphenicol, streptomycin, sulfonamides, tetracycline, are becoming
an increasing problem. In a minute I will show you a slide showing the
numbers. Data from the U.K. suggests increased morbidity and mortality
associated with these strains.

Most recently CDC has identified problems in salmonella with resistance
to ceftriaxone, which is one of our third generation cephalosporins. An
article which just appeared in the [Journal of the American Medical
Association]{.underline}, and there are problems with decreased
quinolone susceptibility. Again I will show a slide in a minute showing
the most recent NARMS data. There is a recent Danish outbreak that was
reported in the [New England Journal of Medicine]{.underline} that noted
the lack of clinical effect of quinolones, even when there was not
outright resistance.

So again, this is a substantive problem. Salmonella is a potentially
serious disease, particularly in young children and the elderly, and the
development of this pattern or resistance which leads to failure of
therapy has a significant impact on human medicine.

(Slide.)

I would also note that transmission of this resistance \-- actually my
slides are slightly out of order. I apologize. The transmission of
resistance can be through several routes. It can be through
contamination of food, such as one would have with salmonella or
campylobacter, through consumption of contaminated food, or probably
most likely through cross-contamination. I would also emphasize that
there can be problems in terms of colonization of farm and
slaughterhouse workers, and finally there are issues related to
environmental contamination with these resistant microorganisms. Both
with resistant microorganisms, but also I think we are becoming
increasingly aware of problems associated with the antibiotics
themselves and antibiotic residues which may persist in the environment.

(Slide.)

Lets switch back a little bit, back to the failure of therapy in terms
of salmonella and campylobacter. With campylobacter, the primary concern
right at the moment is quinolone resistance, and again there are data
including data put out \-- data from CVM that show that quinolone
resistance may be associated with longer duration of diarrhea. A study
from Minnesota, 10 versus seven days. FoodNet data suggests there is a
increase of two days in terms of duration of diarrhea.

Other health impacts of quinolone resistance in campylobacter are not
that well known. There are concerns about special populations.
Campylobacter is a particular concern in immuno-suppressed and in
persons with AIDS, and there are theoretical concerns about the rates of
Guillain‑Barré syndrome. Guillain‑Barré syndrome, as you may well be
aware, is the most severe and most \-- the long-term complication
associated with campylobacter infections which is of most concern. If we
begin to lose the ability to treat campylobacter, the questions is what
impact that may have long-term on Guillain‑Barré rates.

(Slide.)

In terms of other possible human health consequences associated with
resistant salmonella and campylobacter, there are increasing data that
there is \-- the resistance results in increased transmissibility,
particularly in association with prior antimicrobial use. If someone is
already on antibiotics, then there is a much lower infectious dose for
some of these resistant microorganisms. Again, some data coming now from
CDC with a relationship to DT104 strains, and there are also some
concerns about possible increased virulence. Although, again, the data
there still require looking at, and there are still additional studies
that need to be done.

(Slide.)

How significant a problem is this? This gives a feel for the level of
resistance at this point in time in terms of salmonella. These are data
from the NARMS system. What you see here, the total time line is total
salmonella. Typhimurium is yellow. Although they dont serotype to
identify the DT104s, the ACSSuT resistance pattern you can see is
running fairly consistently at around a quarter or so of total
typhimurium isolates. This is a substantive problem in terms of our
salmonella in this country.

(Slide.)

Ciprofloxacin resistance in campylobacter. Actually the title should
have been changed. This includes the 2000 estimates, the preliminary
2000 data which CDC was kind enough to provide to me. You can see that
we are continuing with a resistance level which is around 17 percent,
over 17 percent in terms of cipro resistance in campylobacter. As a
clinician, this is bad news, because we are at a rate where we
effectively cannot use ciprofloxacin as our drug of choice for
campylobacter.

(Slide.)

But I think probably some of the most concerning data are the data in
terms of ciprofloxacin resistance in salmonella. Again, these are the
NARMS data, which include now the preliminary estimates of the year 2000
data. What you see in the yellow is the percent of isolates with an MIC
of \>0.25. Those are strains that are not resistant based on standard
criteria for resistance, but that are showing decreased susceptibility.
So these are a clear concern, because what one sees is from an
epidemiologist standpoint there is a very concerning curve that is
starting to head upward. But I think the other thing that is of major
concern is that the percent of isolates with a MIC of 4.0 which are
strains showing outright resistance is now beginning to climb. So,
again, we seem to be seeing the same things with salmonella in terms of
quinolone resistance that we saw earlier with campylobacter.

(Slide.)

In talking about campylobacter and salmonella, again, I would emphasize
that there we are talking about microorganisms that are foodborne, that
are directly transmitted from the animal to humans, and where again a
sort of nice, smaller model in the sense that we do not get the impact
of human use of these drugs. Because, again, the transmission appears to
be directly from animal to humans.

You get into some of the other microorganisms and the transfer of
resistance genes and the models become much more complex. Again, on day
three of this conference there will be some discussion of some of the
models and potential impact of introduction of these resistance genes
from the agriculture sector into the human sector. But, again, the
concerns, enterococci resistance to vancomycin, the idea that vancomycin
resistance, particularly vancomycin of enterococci, is now a substantive
problem in human medicine. VRE is generally acquired from your own
flora. When you become immuno-suppressed if you happen to be colonized
with vancomycin-resistant enterococci you are at risk for development of
septicemia. So you have a situation where if the genes have been
transferred into the colonizing flora, then at some later point in time
you may be at risk for developing infection with one of these highly
resistant organisms.

If for example you have breast cancer, undergo a bone marrow transplant,
then suddenly you are susceptible to infection to these organisms that
may carry these resistance genes that they may have acquired years
before by transfer from other sources. Again, agriculture is one
potential source.

Resistance to vancomycin is a major concern. There is also ongoing
concern about resistance to the quinupristin, dalfopristin, and at a
theoretical concern \-- at a theoretical level there are concerns about
transfer of resistance in the gram-negative microorganisms.

(Slide.)

How bad a problem is this? Well, I can tell you that antimicrobial
resistance, as I said at the very beginning, is a very major problem in
clinical medicine. These are data from CDC from their Nosocomial
Surveillance System, which is a national surveillance system, and
essentially what they are finding is that about 25 percent of
enterococci are now vancomycin resistant. This represents a 43 percent
increase between 1994 and 1998. In staph, we are seeing methicillin
resistance in 52 percent of strains, a 37 percent increase. Pseudomonas
is simply one example of a gram negative. Imipenem resistance,
resistance to quinolones, third generation cephalosporins, and again you
see the substantive increase.

Why are these increasing? Much of this, in fact virtually all of this
pressure is from human use of antibiotics. This is not agriculture at
this point. The problem is, and again as you will see in some of the
models that are presented later in the meeting, that agriculture
provides potentially a source of resistance genes which if transferred
into human populations may rapidly speed up this process. So again, as
we look at resistance in humans, and again these are very complex models
as we look at them, there must be the recognition that we need to try to
limit the introduction of these genes. Basically to get a resistant
strain you have got to have the antibiotic pressure, but you have also
got to have the resistance gene. So if agriculture is serving as a
reservoir for these genes, then this again may impact on human health.

(Slide.)

To summarize, there are two primary areas of concern or two primary
routes in terms of the impact of resistant microorganisms on humans. The
direct transmission of resistant pathogenic microorganisms to humans,
i.e., salmonella and campylobacter; and secondly the transmission of
genetic material or resistance genes to colonizing microbial flora such
as is being, you know, potential seen with the enterococci and may be
seen with other bacterial species.

There is a clear health impact of resistant strains. There is clearly a
need for further quantitative data and model however. But I think what
we come back to again is this more basic issue, and many of these more
basic issues relating essentially to the inundation of our environment
with antibiotics and this idea that we clearly are overusing antibiotics
in human medicine. Again, as a clinician, I am the first to say that
there is substantive overuse. But at the same time the recognition that
there also is substantive use in agriculture and that all of this
together when one begins to look at the various models and the model
systems has a substantive impact ultimately on development of resistant
organisms and their impact on human health and human medicine. I will
stop there.

MODERATOR BEAULIEU: Any clarifying questions for Dr. Morris?

(No response.)

MODERATOR BEAULIEU: Thank you, Dr. Morris.

(Applause.)

***[Use of Antimicrobial Drugs in Food Animals:]{.underline}***

***[Consumer Perspective]{.underline}***

***By Mr. Richard Wood***

MODERATOR BEAULIEU: Our next speaker is

Mr. Richard Wood, and he is the Executive Director of Food Animal
Concerns Trust, or FACT, which is based in Chicago. FACT advocates
better farming practices to improve the safety of meat, milk and eggs
through its on-farm research projects, its work with federal regulatory
agencies, and its ongoing review of scientific literature. Since 1982,
FACT has worked on behalf of consumers to protect them from foodborne
illnesses. The organization also has a demonstration egg production
project called Nest Eggs, which includes a model salmonella enteritidis
testing and control program.

Prior to joining FACT, Mr. Wood provided staff leadership to consumer
advocacy organizations including Citizens Organizing Project, the
Illinois Stewardship Alliance, and Illinois Impact. Mr. Wood received
both master in theology and doctor of ministry degrees from Wesley
Theological Seminar in Washington, DC, and Richard will provide us with
a consumer perspective on the use of antimicrobial drugs in food
animals.

MR. WOOD: Thank you. I dont have slides, and my computer can barely run
Microsoft Word much less Microsoft Powerpoint. So the lights are on. I
do thank you for the opportunity to respond to the questions on the use
of antimicrobial drugs in food animals. I have appreciated hearing the
presentation of others and learned from those as well.

Question one, what are the benefits for using antimicrobial drugs in
food animals? Guidance document 78 gives consumers a critical framework
by which to enter into the debate on this question, for we dont come to
this question from the same perspective as a producer or as a
pharmaceutical company, or even as a physician. We are not scientists or
risk managers, and yet the guidance document gives all of us including
consumers a concrete way to enter into the debate together over the next
few days.

When this guidance document was first published in 1998, it did not seem
to receive much attention, for everyone was focusing instead on the
framework document to follow. But in fact we felt this was unfortunate,
because the guidance document contains the very kernel of concern for
consumers as we approach the question of antimicrobial resistance. The
guidance asks is there a reasonable certainty of no harm to human health
when antibiotics are administered to food animals to treat disease, to
prevent disease in healthy animals or to enhance growth. As the
threshold document states, the standard is now the yardstick by which
all drug approval decisions are to be measured.

The health and well being of the animal is very important and must be
addressed, but if a producer turns to an antibiotic as the way to treat
a particular disease or if the pharmaceutical develops an antibiotic to
address that animal illness, the first question is not one of animal
health, but human health. Is there a reasonable certainty of no harm? Or
in other words, how effectively or efficiently an animal grows and
finishes is very important financially to a producer. The number of
weeks that it takes to get a hog to be market-ready may impact what kind
of profit if any that the producer experiences. But if the producer uses
antibiotics therapeutically to get that hog or broiler to the market,
the first question is not one of economics or profit. The initial
question is not even one of cheap food for consumers. The first question
is one of human health. Is there a reasonable certainty of no harm?

When we viewed all these management practices that have been laid out so
carefully for us this morning, when antibiotics are involved the primary
question is one of human health. From a consumer perspective that is the
critical question that we all must answer when we discuss the benefits
of antimicrobial use in young, growing, and mature animals, particularly
when the purpose for antibiotic intervention is ultimately one of
economics and not primarily one of establishing an anthropomorphic
balance between animal and human health. We heard that this morning, a
call for that balance, and I must tell you coming from an organization
whose title is Food Animal Concerns Trust that we do have as a primary
goal the health and well being of food animals. But in a system where
economics is the determining factor in antibiotic use and where
maximizing profit determines farm management schemes, the consequence
for human health becomes the measure of its impact.

We all regardless of our perspective can use the standard to measure the
effectiveness of the threshold scheme that CVM is presenting. Just as we
have asked if on-farm antimicrobial use provides reasonable certainty of
no harm, we can also ask if this threshold proposal in itself will
provide that certainty. It is obvious and often stated in the document
that this is the intent CVM is putting forth and has organized the
proposal around.

So where does the threshold document succeed at that point? In our view,
the threshold proposals succeeds when it forthrightly recognizes that,
quote, Food producing animals can become reservoirs of bacteria capable
of being transferred in or on food. Food carrying resistant bacterial
pathogens can cause illness in people consuming the food or contribute
to human reservoirs of resistant bacteria, particularly making human
illness more difficult to treat. Unquote. This is the central tenant of
the threshold proposal around which the entire formulation is shaped. In
the document, the threshold building starts with human health and then
identifies animal resistance levels which respond.

I am delighted today that we have not been consumed by a debate as to
whether or not such a relationship exists, and I have thrown away three
or four pages of my presentation as a result. We need only to heed the
words of another person in another agency in another administration,
Katherine \-\--, who when speaking before the Royal Society of Medicine
said that in essence it is time to put the debate behind us, that debate
behind us, as to whether or not resistance is transferring from animals
to humans and creating such a pool of resistance. It is a time instead
to work together on ways to address the resistance.

The threshold document is based on the potential connection between
resistance and the food animal population and human health. Its appeal
is that it provides a useful method to us by which to consider the
impact of an antibiotic in both humans and animals. Overall, this is
where the threshold document succeeds.

Where does the threshold document fail? I confess to you that I dont
fully understand the threshold document. I have read it a couple of
times, two or three. I have summarized it. I have even gotten on the
phone and talked to epidemiologists and physicians and risk managers and
other people, and I still glaze over. So Im here to learn, and much of
what I offer now I will gladly stand to be corrected, but we do raise
some serious concerns. Some of our concerns will be discussed in the
following days, but it is important to raise them now because they help
to answer our \-- help us to provide an answer to the question on what
kinds of risk management thresholds there should be.

As a consumer group this threshold document has challenged us at the
point of how to respond to medically important antibiotics. For the
important \-- and that is the important antimicrobial drugs in human
medicine for which alternatives are limited. At first we in fact
accepted the implication of the discussion questions that a sliding
scale would work. Perhaps we could support a human health threshold
where no adverse resistance reaction would be allowed, and only
diminishing resistant isolate counts would be acceptable in the food
animal population. Or perhaps we could support the approval of medically
important drugs if they were only injectables, therapeutic antibiotics
not administered through feed and water if they were important to human
medicine and there were no alternatives. But unfortunately it appears to
us that current scientific information simply does not allow the setting
of thresholds with the reasonable certainty that resistance levels will
stay within a threshold and will not constitute harm. So we have had to
turn to look more carefully at this proposal.

For example, we have a concern about the threshold and how it limits
itself only to resistance in foodborne pathogens, specifically
salmonella and campylobacter, but does the threshold document take into
account situations where salmonella infections are contracted because
the person is on an antibiotic to which the salmonella is resistant and
so the person becomes more easily infected with salmonella bacteria, as
Dr. Morris just pointed out. The document seems to deal with an approval
as if there is only one antibiotic with one resistance pattern. But
treating the regulation of all these drugs independently from each other
it seems that CVM may be making a very strong assumption that
cross-resistance is negligible in each case and that the only impact is
a direct one, and we heard Dr. Sundlof this morning speak to the
limitations of threshold proposal at that point.

Second, the document has left undefined the human population that might
be harmed. We believe that to effectively measure the reasonable
certainty of no harm the most vulnerable must become the yardstick by
which the threshold is measured, the elderly, the very young, the
immuno-compromised. A risk analysis that shows 5,000 people in the
general population to be at risk is much different than an analysis that
determines that 5,000 young or elderly will die or be at risk.

Third, we do not have important data defining drug sales or drug use.
Obtaining detailed sales information for animal pharmaceuticals is
critical to any threshold setting scheme. It would provide important
data for monitoring the resistance thresholds and would help provide an
information base upon which mitigating steps can be established when
needed. The threshold document states that such information is needed,
but nothing yet is in place. With this kind of data health officials in
Denmark were able to track an increase in the use of antibiotic as a
growth promoter for broilers and pigs as well as a measure of the
resistance to that antibiotic. Similarly researchers in Sweden were able
to show that the Swedish ban on antimicrobial growth promoters
effectively reduced the prevalence and degree of antimicrobial
resistance. In the U.S., we can measure the resistance, but not the
usage. An important link is missing. Clearly reporting sales and volume
data for antimicrobial pharmaceuticals sold in the U.S. is crucial to
understanding resistance.

Fourth, FACT is also concerned that when it comes to medically important
approvals the threshold scheme may be used to enable an otherwise
dangerous approval decision. The threshold becomes a mechanism to allow
for approvals that perhaps should not have been considered in the first
place. As FACT sees it, this may well have been what happened when the
fluoroquinolones were approved for poultry. FACT was at the VMAC meeting
when the approval was first considered, and we spoke against its
approval due to the importance of the antibiotic to human medicine. But
then the fluoroquinolone was approved, along with a carefully worded
caveat stating that a surveillance system would be established so that
if resistance were to occur appropriate action would follow. Well,
resistance has occurred, and we are still waiting for the appropriate
action. In our view, the surveillance system that was established was
not a safeguard, but rather an enabling action to allow a critically
important antibiotic to be approved for food animal use.

Fifth, the lack of an effective trigger. When it comes to allowing a
sliding threshold scheme with regard to medically important antibiotics
another reason to keep these important health tools of the threshold
table is precisely due to what would happen once the threshold is
reached. The document states that the threshold, quote, Would serve as
the regulatory trigger for initiating immediate withdrawal of the drug
from the animal species that has reached its resistance threshold,
unquote. Then the document goes on to state that we must accept that,
quote, Actually accomplishing such withdrawal takes time because of due
process requirements, and that antimicrobial resistance may continue to
increase during that time, unquote. With medically important
antibiotics we dont have time. When we see resistance isolates rise
from 13 percent one year to almost 18 percent the next, a due process
procedure that takes years to accomplish is simply unacceptable.

But there is a model that may work, and one that does require full
consideration by CVM and the industry and others, and that model was
laid out in the approval of fluoroquinolone for beef cattle where
written into the approval was an agreement that the pharmaceutical would
voluntarily withdraw the antibiotic if resistance were to occur.

Now to the discussion question. We believe that it is not acceptable to
place human health at risk when medically important antibiotics are at
stake. It is still not clear that if resistance were to occur in the
animal population that it could be contained there, and that if
mitigating actions were applied that the resistance could be reduced or
even eliminated. For medically important antibiotics, these are the
critical questions for which in our view conclusive evidence is yet to
come. Therefore, in answer to the question about setting thresholds that
vary, we believe that there should be no threshold setting for medically
important antibiotics where there is no other alternative.

We propose that medically important antibiotics not be approved for use
with food animals and not be included in any threshold scheme. This we
believe is the appropriate response when again the standard asks of this
threshold scheme if it provides reasonable certainty of no harm. This
also includes antibiotics used non-therapeutically if they are also
important to human therapies and no alternative exists. The petition
offered by a number of consumer groups and physicians to remove these
growth promoters from the market is still necessary and requires a
response from the FDA.

However, a threshold base response is useful with regard to antibiotics
that are not medically critical or for which alternatives in human
medicines are available. Even still, setting thresholds for these
antibiotics will only work if there is sufficient data collected through
surveillance and drug sales reporting. In addition, if the threshold
concept is put into place for the medically unimportant drugs, it must
be remembered that the determination as to which drug is important is a
moving target. A prime example is the use of virginiamycin in
agriculture prior to the approval of synercid, which is now the
treatment of last resort for vancomycin-resistant enterococcus I
understand. The FDA will need to constantly monitor for the signals that
a drugs potential medical importance is increasing.

Finally, more emphasis needs to be placed on reducing the need for
antibiotics in food production in the first place. The way this document
is laid out, additional mitigating steps are put into place once
traditional \-- once resistance is found in the food animal population.
We call for aggressive application now of management practices that
would reduce the need for antibiotics and that would then minimize the
spread of resistant bacteria. Here is where the anthropomorphic balance
can be achieved.

If threshold setting is understood to be a part of a larger systemic
response, greater attention needs to be focused on alternatives to
antibiotics to include not just the development of competitive exclusion
products and vaccines, but also effective on-farm management strategies.
A while ago a National Research Council report identified where on-farm
selective pressure is increased. By inference, the list becomes a set of
critical control points where management strategies should be
implemented in order to reduce the need for antibiotic intervention.
These points are: 1) the large concentration of animals with similar
disease susceptibility with the density on that farm in those pens; 2)
the social behavior of livestock which promotes transmission; 3) poor
environmental hygiene which promotes bacterial growth via water, feed,
and bedding; 4) inadequate control over individual antibiotic dose and
treatment; 5) the rapid turnover of animal populations without cleaning
and disinfecting the facilities between groups; and 6) the wide movement
of care animals as breeding and feeding stock. Many of these items we
have already seen on the screen.

The National Research Council also noted the relationship of animal
stress to the shedding of drug-resistant bacteria. Stressful and crowded
housing conditions cause animals to have reduced ability to fight off
disease. Reduce the stress, you reduce the potential for a sick animal
and the need for an antibiotic. The Swedish experience also endorses
improved feed rations as a way to prevent disease and to promote growth.

Taken together, intervention at these critical control points may have
the effect of reducing the need for antibiotics, either in
subtherapeutic or therapeutic doses. Government action by itself will
not succeed in relieving resistance pressure, but as consequence of
on-farm antibiotic use. Producers, veterinarians, the animal drug
industry, government and consumers must each respond as a part of a
larger strategy. Only then will we truly move toward a standard of no
harm. Thank you.

(Applause.)

MODERATOR BEAULIEU: Any clarifying questions for Mr. Wood?

(No response.)

MODERATOR BEAULIEU: Again, we will have opportunity after lunch to hear
from the panel members regarding a series of questions that we asked
them to concentrate on, as well as any other comments they might have to
make about the concept of thresholds. That will start at \-- promptly at
1:30. Then we have an announcement for you before you leave the room.

MS. SINDERLAR: For lunch information there is a flyer at the front desk.
It will cite the specific areas for the local restaurants. There are a
number of them to the right across the street and down at Federal Plaza,
so please stop by the front desk for this additional information. The
speakers, please see Linda Cowatch for lunches that will happen down in
the buffet of Papas Restaurant in the hotel. Please, speakers, see
Linda Cowatch at the registration desk. Thank you.

(Whereupon, a luncheon recess was taken at

12:36 p.m.)

[A F T E R N O O N S E S S I O N]{.underline}

(1:45 p.m.)

***[Panel Discussion on Use of]{.underline}***

***[Antimicrobial Drugs in Food Animals]{.underline}***

MODERATOR BEAULIEU: I think we are going to go ahead and get started. We
are a few minutes late. What we asked the panel, this panel and other
panels to do was to consider a series of questions that we sent out. Im
going to run through those now. So you can see them up on the screen.
There are a different set of questions for each of the panels.

(Slide.)

This panel had three questions to think about. What are the benefits of
antimicrobial use in young/growing food animals? Relative to I would
think mature food animals and there are some issues there about whether
the product use, antimicrobial use, might be in young animals which
would not \-- so that whatever resistance might be developed might not
carry over to the point where that would be a factor when the animals
went to slaughter.

(Slide.)

The second question is, If thresholds are set, should human health
thresholds be consistent for all antimicrobial drugs used in animals, or
should they vary according to the importance of the antimicrobial drug
to human medicine?

(Slide.)

And the third question, If you believe that human health thresholds
should vary, please comment in general terms on whether the levels
should be greater or smaller for the following categories of importance
of the antimicrobial drug to human medicine? The first category,
Important antimicrobial drugs in human medicine for which alternatives
are limited. Second, Important antimicrobial drugs in human medicine
for which alternatives are available. And third, Antimicrobial drugs
that have limited use in human medicine. Then there is a catch-all
question which isnt here, which is, Any other comments that folks
might like to make.

This is a pretty general discussion up to this point, and I dont want
to pin our panel down to just having to answer these particular
questions. So what Im going to do is give each of the panel members an
opportunity to comment upon these questions or any other comments they
might like to make, up to a limit of about 10 minutes. We will go
through the panel in that way, and then we will come back and see if the
panel members have any reaction to anything theyve heard either this
morning or as folks talk. Then well take questions from the floor and
see if we can get some discussion going in that manner.

So with that brief introduction I guess I would like Mike Apley to
start, and then well just follow down the line. If he has any comments
to make at this point, we would appreciate hearing them. Mike?

DR. APLEY: Okay. Starting out with the first question. Dont run off
with those.

MODERATOR BEAULIEU: Sorry.

DR. APLEY: In young, growing food animals again from the cattle side of
primary disease challenges at that time are enteric and respiratory. We
realize there are other things besides just the infectious agents
setting those up, and we are working on those. I think as always we had
mentioned before the economic reasons, and they are very real. Believe
it or not, as veterinarians and producers we still do take into account
animal welfare issues.

One of the things I think is a very, very promising area for research
needs is in these young and growing animals, and some of it is being
done, but it is essentially using pulse dosing as a vaccine to control
exposure or using a lower level to control the disease while the animal
develops immunity. This is to be some very promising work, and that
again goes back to the need for more work on exactly how we can design a
regimen to decrease resistance development.

On to the \-- well, kind of overlapping between the young and growing
animals and mature food animals, there still is a very real place for
well-targeted therapy in a group of animals that is breaking with the
disease. When a significant portion of the population is breaking with
the disease and we suspect that the rest are in that same stage in some
of the higher risk cattle we handle, again, as I stated in my talk
earlier, we can significantly impact \-- oops \-- have an impact on. I
have a graduate student who is an English major. When I use impact as a
verb I get beat up. Have an impact on morbidity in case of fatality
later on.

In \-\-- mature food animals, those either in a production stage as a
lactating dairy cow, or a reproducing beef female, or a feeder animal
nearing harvest we can never forget I feel that with the use of
antimicrobials we can deliver a healthier animal to harvest. We talk
about the effects of the antimicrobials on pathogens that may be in
those animals, but one thing I ask we always keep in mind, too, is that
counter to that is the fact that with the proper uses of some of these
compounds we can decrease dramatically the number of those pathogens
that might be there at harvest.

Another thing getting into this type of use is talking about raising
animals without antimicrobials. It is true that we could take away
strictly growth promotion claims and we would be able to go on and raise
the animals. But once those antimicrobial uses start to impact disease
prevalence and the severity of disease we come into a portion where if
you pull them it is true you can raise some of the animals without
antimicrobials, but I would challenge you to show me a system where you
raise all of them without antimicrobials.

As a matter of fact, some of the antibiotic-free, quote, quote, beef
systems revolve around that, where a certain percentage of the
population ends up getting sold that way, but some of the animals that
have to be treated get pulled off and go through traditional channels.
One of the problems Ive seen with those kinds of systems is where they
are so anxious to sell animals as antibiotic free at a premium that they
let the animals maybe go a little longer in an attempt to see if they
will spontaneously recover. Then we end up with some animals that are
beyond help, and we end up actually treating those for longer. So I
fully realize we can raise some of the animals without antimicrobials.
Again, I challenge you to tell me how we could do all of them and do it
humanely.

The question on if thresholds should be different, weve got another
couple days to talk about those, but obviously yes. The question still
important to me is how we are going to determine importance. Is it going
to be on whats actually prescribed? Is there the \-- the number of
possible alternatives, et cetera, and we will have to work through that.
That becomes a really tough one, because it seems like its the \-- oh,
the game, the Kevin Bacon game. What, six or seven degrees of
separation? Especially if Ive got the right thing in the glass. If we
get to trying to link oxytet like \-- say, okay, your card is link
oxytetracycline resistance to drug X. By the time you find one or two
organisms that has a multiple cassette and go on to some other kind of
thing we might be able to link them. So where do we stop? Thats where
we are going to have to put some reason in, is how tight the association
is going to have to be when we start moving beyond drugs and drug groups
and across resistance issues.

Again, this is a rehash, but we must take into account the effect of
removing a drug use on the prevalence of pathogens at slaughter and the
prevalence of disease. Dr. Beaulieus statement on striking a balance is
well taken by me in the fact that the veterinary profession is very
interested that we maintain the best interest of the animals and of our
clients in mind. Probably as important as different thresholds if it
comes to that is the realization that maybe not all uses of the drug
have to be removed. I mean categorization of uses of it and potential,
and thats one more thing you would have to determine. But I think if we
start just blanket removal of a drug we could throw the baby out with
the bath water and remove some very, very important therapeutic issues.
I go back to the example of the chlortetracycline we talked about this
morning and the different range of feed approvals we have there. Number
three, yes, they should be probably less tolerant for the more important
drugs. The same question goes back on determining importance.

Then just briefly on the other comments to include, I think all the
presenters this morning sat and listened to the other presenters
presentation and thought, Wow. I wish I would have addressed that. But
the thing in Bob Morrisons that really hit me was the continuum slide,
where there is continuum of practices from pretty bad to excellent in
all of these food animal production systems. We are doing the best we
can to move everyone to disease control, biosecurity, and et cetera, but
it takes time. I guarantee you if we knee jerk on some removals before
we get people moved we are going to cause a lot of grief in the
production systems, and were not going to be able to meet the needs of
some of the producers who arent as far into the biosecurity. That
really is a reality of our practice.

Just one other, I wanted to make sure it was clarified from my
presentation this morning, is that I talked about extralabel drug use.
And Dr. Wages mentioned this, and I wanted to make sure it was clear for
those feed approvals in cattle there is no extralabel drug use in the
feed. So everyone is clear on that. The AMDUCA regulations I referred to
apply to the individual animal applied therapeutics and milk replacers
of feed also. So with

that \--.

MODERATOR BEAULIEU: Thanks, Mike. Dennis?

DR. WAGES: Just a couple of quick comments before I address the
questions, and one of the things this morning that may have been a
little bit confusing. When one of the speakers was talking about
campylobacter and salmonella and competitive exclusion products
decreasing the role of antimicrobials in that system, at least in
poultry, you need to recognize that campylobacter and salmonella in
poultry is really not an issue. When you get out of the enteritis table
egg layer situation the percentage of salmonella infections that we
treat in chickens are zero. Very, very limited in turkeys.

Salmonella arizonae and some of the what we call paratyphoid type
salmonellas do kind of hit us in young turkeys less than three weeks of
age, but are usually self-limiting. So we dont \-- any competitive
exclusion type of product, any type of that intervention strategy, is
clearly from a food safety, keeping colonization of salmonella and
campylobacter out of the intestinal attachment of those birds, not
because they are something we would treat. In some areas I wish they
were a problem we could treat and go after them, but when they are kind
of a ubiquitous organism or it gets introduced into the system later on
in production and they are not all vertically transmitted from the hen
down to the chick or the poult, it gets hard to control those.

So the foodborne pathogens really arent a big deal to us as far as us
trying to treat them and causing illness in chickens and turkeys. The
other thing is our antibiotic arsenal is small, but because it is small
doesnt mean we dont need them. The other thing is theres been
percentages thrown out all over the place as far as our use, and our use
\-- lets look at fluoroquinolones, and I think surveys from the NCC,
National Chicken Council, puts its use in the 1.6 or 1.7 percent range,
very low. Probably in turkeys, and I dont have as good of figures, but
probably in the less than three to five percent range. One of the
comments is that Well, if you dont use them much, you must not need
them. Well, I am convinced that theres human drugs, and Dr. Morris can
help me Im sure on this, that they dont use much. But, by golly, when
they need them, theyd sure like to have it on the shelf and know that
thered be some value. So that would be important to us.

Now, to the questions. Our predominant use is in the young animal. Much
like Dr. Apley has said, we focus on disease, either intervention
strategies or through therapy of acute infections, and disease
prevention. Both respiratory and enteric, but the predominant exposure
and prevention that we do, or interventions, are through respiratory.
However, with necrotic enteritis, for example, our disease prevention
goes through that avenue.

We feel that antibiotics not only help us get through day-to-day
production with decreased disease incidence as well as intervention
strategies, I think it gives us, or I personally feel it gives us a
healthier bird at slaughter for processing. If we can keep down the
numbers and the stress and the bacterial proliferation that occurs at
processing or during the processing procedure, load-out, et cetera, then
we have healthy birds. That to me equates to a healthier product to the
consumer.

We have continually looked at our antibiotic use and how we do things,
and even within our own industry we continually evaluate what we do. We
will do that next year and the year after, and the year after and when
Im long gone from this world. Thats good, because things that we did
30 years ago we dont do now. Things that we did 30 years ago maybe we
still do. But at least weve tried to put it through as companies on a
company basis, put it through the system and determine that it in fact
is beneficial for our end product and the consumers.

As far as mature birds being treated, you know, we have some cholera
outbreaks in mature birds, but its very, very limited as far as our
therapeutic or disease prevention in breeders. Probably more in turkey
breeders than it is in broiler breeders, but its very, very minimal in
mature birds. I wont say non-existent, because that gets me in trouble.

The second question is, If thresholds are set, should human health
thresholds be consistent? No. I think the more important the drugs are
in humans, we should look at different thresholds if you will. I guess
one of my concerns is what criteria are we going to use. Are we going to
use, heaven forbid, a mortality? I doubt it, but illness, duration of
illness, duration of therapy, response to therapy? Im sure those
definitions as we get them through the meeting will be outlined, but we
need some very well-defined criteria before we place thresholds.

Wed like to see thresholds that kind of gives us a green light, a
yellow light, and a red light. A light that tells us that were
decreasing in susceptibility toward a threshold so we can do something
about it. So we can look at mitigation strategies and try to thwart the
continued increase development. Some of the concerns of our industry
regarding thresholds is that if company A chooses to irradiate all their
food, and/or further process it through cooking or value-added \-- and I
agree it doesnt eliminate bacteria, but it does a long \-- goes a long
way of providing the ultra in safe product to the consumers. Why should
they not be allowed to continue to use a product, regardless of what the
threshold is? Because they are trying to basically take the bacteria out
of the equation, and I know the arguments that dead bacteria still
transfers the genetic resistance, et cetera. But, you know, irradiation
and cooking product, presenting a cooked product to the consumers is
about the best we can do.

Wed like these thresholds established so we can look at different
mitigation strategies prior to the ultimate of pulling the product.
Theres many of us that are not convinced that you pull the products
tomorrow and it has very little effect on the extent of antimicrobial
resistance in humans. You know, I dont know the answer to that
question. I think we have to be careful on which drug and why is it
important from the human health standpoint. I think we look at experts
like Dr. Morris and would be able to ascertain that, but whats
important in an outbreak in Texas may not be as important as it is up in
Maryland. Also we need to look at thresholds in trying to identify
trends when we have cyclic epidemics in the United States, both in human
infections as well as animal infections.

Answer number three is to me the important antimicrobial drugs in human
medicine where alternatives are limited should have the smaller or lower
threshold it seems to me. I dont know what that number is; and if you
have alternatives, that number should be larger or greater, if you will.
But again, the outbreaks and epidemics, those are difficult to start
identifying trends. Of course, I would defer to the epidemiologists to
help us out on that. So, Mr. Chairman, thats my comments on the
questions. Thank you.

MODERATOR BEAULIEU: Thank you, Dennis. John?

DR. PLUMB: Thank you. Well, just one comment that I would like to make,
is that we dont have a great number of human pathogens that can be
transmitted through fish. There are some, and there are some disease
organisms that infect fish that can also infect humans, but I dont
think there is very \-- in this country at least, there are very few
that are actually transmitted from aquatic organisms directly to humans,
unless that aquatic animal is consumed improperly cooked or raw. Then
you have a real problem with that in some sectors such as oysters and
some fish products.

But generally speaking, in fresh water the microflora of the intestine
or the surface of the fish is going to reflect the microflora of the
water. The microflora of the water is going to reflect what is in the
terrain, soil, drainage that comes into that water. If you have cattle
on that watershed, then you are very likely going to get E. coli in that
water. Then the fish can serve as a carrier, but the fish is not the
problem. The problem is having the cattle on the watershed. So most
farmers have eliminated this.

In the past there have been some \-- not in the United States, but in
foreign countries, where they have had polyculture so to speak where
they actually had hog pens over a pond with fish in it. They would feed
the hogs the debris, and the fecal material would fall into the pound,
produce an algae bloom, and the fish would eat the algae. Well, this is
just a perfect environment to facilitate any transmission of these kinds
of agents. That I believe is no longer done, but in foreign countries
they still use a lot of human waste for fertilizers. Its becoming less
all the time, but there is some still organic farming going on. So many
times the problem is not the fish. It is what is surrounding the fish
and what happens to that fish after its taken from the water in the
processing.

Catfish when they are dressed, from the time that those fish are killed,
from the time that that fillet or fish product is flash frozen is a
matter of minutes. So the opportunities in these kinds of situations for
any transmission of potentially human pathogens is somewhat limited.
After having said that, some people look at a fish pond and think that
its some degree of a cess pole, either minor or severe. Because you are
putting all this organic material in the pond, the fish are eating it
and defecating in it, and so it accumulates when you have too much bio
mass in that pond.

Now, we do see antibiotic resistance in our fish pathogens. Theres no
question about that, but theres several instances where antibiotics
were used extensively. You see the resistance incidence increase, and
when those particular facilities stop using antibiotics, that resistance
declines. So it does occur.

Theres a few parasites that can be transmitted by fish, tapeworm and a
few others, but again it goes back to the condition of the fish when
its consumed. There have been some instances where some of these
microbial disease organisms of fish have really been severely or
seriously implicated in human health. I dont know if any of you
remember, but five years ago there was a case in Canada where a
streptococcus iniae was transmitted from tilapia to humans that were
handling those fish. They were puncturing themselves, and I dont think
there was any \-- well, I guess there was one death, but there was some
other complicating factors in that situation.

But that was just one instance, and all of those fish had come from
aquaculture facilities in the United States. It really affected the
tilapia industry for that period of time and for a period of time
thereafter, but there has been no recurrence of that. No one on these
farms have become infected that handle the fish every day. So usually
its some other factor thats involved with that.

Now, the first question, young versus growing food animals. I think the
antibiotics are certainly more important in the juvenile fish than they
are in production fish that are almost ready for market. This is where
you have the greatest mortality, you have the greatest disease
sensitivity or susceptibility, and this is where they can be used, is in
the young juvenile fish. But once those fish are taken from what they
call fingerling ponds and put into grow-out ponds, they dont have a
great deal of disease problems, and thats when taking the fish off feed
has a beneficial effect. Salmonids is a little bit different, because
there are some diseases, bacterial diseases, that affect the older fish.
Those are effectively medicated with the use of oxytetracycline.

The other point with antibiotics in fish feeds, for example the catfish
industry, almost all of the feed that is fed to those fish is a floating
pellet. If there are medications in it, it is incorporated at the plant.
When that pellet gets into the water, there is minimal leaching of any
antibiotics from that pellet into the water because the fish is going to
consume it almost immediately. If the fish doesnt consume \-- the fish
population doesnt consume the pellets in 10 or 15 minutes after they
are put into the pond, they dont put any more feed in there. So there
is very little chance of accumulation of antibiotics, unless it would
pass through the intestinal track and of course accumulate in other
organisms that are in the pond.

So I think that they are important in young fish, but not necessarily in
older fish. As far as mature fish, brood stocks are concerned, there are
very little antibiotics even used in those fish simply because there are
very few of our infectious agents that affect fish to cause any mass
mortality or large mortality in those adult fish. You very seldom have
what we would really call as an epizootic occurring in those situations.

As far as what thresholds are set, I think there has got to be some
leeway in terms of all antibiotics. I dont think we can put them all
under one particular category.

The third question, certainly I think the emphasis should be placed on
those drugs which there are no or few alternatives as far as human
medicine is concerned. I think thats ultimate. The other two categories
are somewhat less emphasis placed on those, but nevertheless they
certainly, as far as aquaculture is concerned, should be looked at very,
very closely. Thats all I have.

MODERATOR BEAULIEU: Thanks, John. Saeed?

DR. KHAN: Well, as far as the benefits of using the antimicrobials in
young animals is concerned, I think nobody can deny the fact that
antimicrobials, they have been useful in promoting the growth. But at
the same time, we cannot say that the use of all the antimicrobials is
causing the resistance problem. There are certain antimicrobials for
which the resistance transfer doesnt take place. For example, \-\--.
You can easily get the \-\-- resistant bugs in the lab just by streaking
on the \-\-- containing plate, and that is, you know, by the mutation
very \-\--. So that is not transferred.

As far as transferable resistance markers are concerned, for example in
the young, growing food animals, if we apply for example the CE
products, the competitive exclusion products, it is known that if you
apply them when the chicks are a few days old then you get protection
against salmonella. But once they grow out of certain age and then you
apply, the product has a limited use then. When the animals grow big
\-\-- they become mature and then you start using the CE products, it is
not as effective as the use of antimicrobials. So there is a difference
between using the antimicrobials in young animals and the mature ones.

Then the other things about setting the threshold, we need to have some
more data. Since NARMS was established in 1996, we have only four years
of data available. We can probably benefit more from European studies
where say, for example, they have more studies and more data available.
There is a clear link between the usage of avoparein, which is a
structural analog of vancomycin, and the increase in the label of
vancomycin-resistant enterococcal infections in human beings. Once they
withdrew the drug out of the market, then we saw a decrease in the VRE
infections among humans. So there is a clear link.

Now, what we are discussing here, whether are there any other
alternatives to the use of antibiotics, can we completely stop the use
of antibiotics, or it could be minimized by using certain other
alternatives. Well, we cannot completely stop the use of antibiotics
because of various reasons that I just pointed out and many others have
pointed out. So we can probably use a combination effort where we can
use the alternatives along with the antimicrobials.

Now, in terms of setting the threshold, again thats a very grey area
here. So how do we define the threshold? Is there enough data available
so that we can use that data to define the threshold? There is again a
question that says, If thresholds are set, should human health
thresholds be consistent for all antimicrobial drugs? I dont think
that it should be the same yardstick should be applied for all the
antimicrobials, because there are different MIC values for different
antimicrobials. If you look at the NCCLS data and then look at their
approach of defining, if you have a certain area, a certain zone of any
region, then only you can categorize that this particular organism is
resistant or sensitive to. So for different antimicrobials they have
different barometers \-\-- sensitivity of resistance. So for different
antimicrobials we have to have different threshold values.

As far as the antiboiotics that are used in humans and there is no
alternative, we have to be very strict in defining threshold values for
those because there are no alternatives. So we dont want to compromise
the use of antibiotics that are used in animals and the possibility of
drug resistance transfer in humans.

For those antibiotics for which there is an alternative, we can be \--
we can apply a little bit lenient approach. But again, as I said, its a
grey area. We dont know where to set the threshold. For every dose
factor that \-- you know, the modeling. Somebody was talking about
different factors, how to calculate all those values and then define the
threshold. We can probably apply some of those approaches in determining
the threshold values for such antimicrobials.

The antimicrobials that have limited use in human medicine, well, if
they have limited use in human medicine we dont have to worry too much
about those. In other words, if we have the antibiotics used only for
animals and the antibiotics used for human beings. So we are talking two
different things, unless the cross \-\-- and produce the resistance
marker. If they are \-\-- to the antibiotics used in humans, then we
have to be careful in that. But if they have two different mechanisms,
how the resistance is generated, then we can probably take a lenient
approach on that.

In terms of the \-- there is another fourth question I think nobody
asked there, other comments. In other comments I would like to say that
we probably can minimize the use of antibiotics by, you know, using
alternatives to these. Like if there is any antibiotic which is
structurally analogous to the one used in human practice we should be
careful using threshold values for that and setting values for that, and
the alternative approaches that I talked about, the use of competitive
exclusion products, we need more of those products. As long as they, you
know, have two things. First, they should not have any pathogenic
bacteria, pathogenic to the animals as well as to humans. Second, they
should not have transferable drug resistance markers. So if any
competitive exclusion product satisfies these two, at least two minimum
criteria, then we can start looking for those kinds of alternatives.
This has a strong potential in terms of minimizing the use of
antibiotics in farm animals, and that is all I have to say.

MODERATOR BEAULIEU: Thank you, Saeed. Glenn?

DR. MORRIS: Thanks. A couple of comments. Im not going to talk about
young, growing food animals and mature food animals. However, I do have
to get at something here. I think that what concerns me in part in this
are concerns about the total usage of antimicrobials. Again, the problem
is that we dont have good data. Some of you may be familiar with the
recent estimates put out by the Union of Concerned Scientists that
estimate that there may be as much as 27 million pounds of antibiotics
used annually for subtherapeutic applications of agriculture. Obviously
the estimates for how much is really used vary extremely widely. I will
echo what has been said before, is that it would be very helpful if FDA
could put in place an appropriate regulatory structure where we could
get real numbers. In some ways it seems ludicrous. We dont even know
how much antibiotics are really being used, and why cant we get this
simple piece of data? It seems like thats something that should be
fairly quickly admittable \-- or maybe not so quickly admittable, but
something that could \-- data which could be obtained.

But lets go back. Lets say it is 27 million pounds. Thats an awful
lot of antibiotics which is being put into agriculture and into the
environment. I think there is increasing recognition that it is not just
the development of resistance in the animals themselves, but potentially
the fecal matter coming from the animals which may carry resistant
organisms, the antibiotic residues, the intact antibiotic which is going
into the environment. I know EPA is becoming increasingly concerned at
their increasing ability to detect low levels of antibiotic residues
basically in all sorts of environmental settings.

So consequently we are truly inundating our environment with antibiotics
in the agricultural applications, and it is something that we need to
have concerns about. Why do we need to have concerns? Well, among other
things, we are finding increasingly linked antibiotic resistance. So
consequently there is so much antibiotic out there that a lot of
microorganisms now are beginning to acquire a variety of resistance
genes. Those resistance genes are becoming linked. They are being
transferred as linked to resistances. So what happens is that even if
you are using an antibiotic which may, quote, unquote, Not have any
human use, which I will come back to in a minute, you are still
selecting out for a package of antimicrobial resistance which may
include resistances which may have substantive human health impact.

I would also like to briefly mention this idea of, you know, Well, we
dont use very much of a certain drug. So thats probably not a
concern. I think there are also data suggesting that because of some of
the management practices, failure to \-- the fact that bedding is not
changed for extended periods of time for example in poultry, rodent
carriage of resistant microorganisms and the like, that once, for
example in poultry, a flock is dosed that there is long-term impact of
even a single therapeutic dose which extends well beyond the time period
when the antibiotics are actually being given.

Going to question number two, If thresholds are set, should human
health thresholds be consistent for all antimicrobial drugs, or should
they vary according to the importance of the antimicrobial drug to human
medicine? I think thats going to be tough, because in terms of
differentiating, quote, unquote, importance versus importance I can
tell you as a clinician that drugs that we thought were unimportant five
years ago are turning out to be the only thing weve got left.
Antimicrobial resistance is a major problem. Antimicrobial resistance in
clinical medicine is to a large degree a result of doctors
over-prescribing. I will clearly say that. But having said that, the
fact remains that our repertoire, our armamentarium of antibiotics, is
shrinking dramatically.

I think the most striking example of that is the synercid example.
Synercid was a drug which because of its side effect profile,
quinupristin and dalfopristin for those who dont know the trade names,
because of its side effect profile one could five years ago have \-- I
would have five years ago with a great deal of confidence said, This
will never be a human drug. It turns out that its one of only two
drugs which is now active against vancomycin-resistant enterococci. I
use it, and, you know, its a drug I would never even have dreamed of
using. But suddenly this unimportant drug which has no human use is the
only thing weve got left to save patients lives. So again we have as
physicians created this in a way ourselves. But because of this I cannot
say with convictions if there is no unimportant antibiotic.

One interesting concept in this is to think about maybe we should be
judging importance by whether or not a drug already has resistance in
human populations. Maybe the drugs that are not important, and actually
from a practical standpoint the drugs that are not important to me are
the drugs to which I now see high levels of resistance, and maybe those
are the drugs that we should be regarding as unimportant. Thinking about
usage in human first, and when weve exhausted the therapeutic window in
humans flipping them back over to the animal side. An interesting
concept, but actually one that I think you will hear expressed several
times during this meeting, and particularly with some of the modeling
that is being done. It might actually be an interesting alternative to
this concept of trying to designate certain drugs as important and
others as not important.

The third question relates to thresholds, human health thresholds. I
struggle with thresholds. I think in general by the time you reach
detectable levels its too late. These are not heavy metals. This is not
EPA. We arent dealing with the issues that EPA deals with with mercury
contamination where, you know, you hit \-- you creep up toward a
threshold, you hit the threshold, you put in a place for mediation
efforts and you immediately drop back down again. This is a dynamic
system, particularly when were talking about gene transfer. Once the
gene is transferred and is present in human populations and once you
begin to get human use and antibiotic pressure in human populations its
too late. The human usage will continue to amplify and increase the
resistance level.

Again, its get back into some modeling exercises. One of the models you
will hear is Dr. Dave Smiths model. Dr. Smith is on our faculty at
Maryland, and basically what his model shows is that by the time you
reach detectable levels in humans your chance is gone. That by that time
the resistance gene is already introduced, and human use will take it
from there. So consequently human thresholds I think do not have
meaning. Its the too little too late routine, and, you know, were sort
of seeing that with the quinolones, although thats a very special
subset of the overall problem. In this instance were seeing substantive
levels of resistance, and again were struggling with exactly how to
deal with this.

But then come back. What about doing thresholds in animals? Theres some
difficulties there as well. I think specifically for a subset like
salmonella and campylobacter where there is not the human amplification
side then thresholds in animal populations may well make sense. I think
theres still an awful lot we dont understand, and there are a lot of
other issues that surround use of thresholds, even in animals, for some
of these resistance genes. Which, once they are introduced into humans,
again, its too late, and I think Ill stop at that point.

MODERATOR BEAULIEU: Thank you, Glenn. Bob?

DR. MORRISON: Thank you. With regards to antibiotic use in young stock,
the benefits as we talked about this morning are clearly the most
important at decreasing the prevalence and incidence of disease, and the
consequence of disease being, you know, sickness, ultimately mortality,
pain and suffering. So thats basically what disease does to the
animals, and thats the primary use of antibiotics in young stock. That
application is either at the individual level, usually by injection, or
when the incidence and prevalence is high enough the group is medicated,
and thats the application route. First and foremost is the water.
Secondarily is feed when justified.

When we talk about adult stock \-- oh, I should say thats from the pig
well-being sense. There is the other application of antibiotics, which
is from the aspect of efficiency, and it is applied in the production
setting probably, and its cost driven for the most part. When I say
cost driven, the producer is weighing the cost of the antibiotic as
opposed to the benefit that its going to incur in terms of decreased
cost and production. So when the economic setting dictates it, then the
producer will medicate for efficiency. A side benefit of that, less
important perhaps to the producer, but more important to the
environment, is a decrease in the production of manure. So in other
words, if you can expect lets say an eight to 10 percent improvement in
feed efficiency, meaning it takes less corn and soybeans to produce a
pound of pork by eight to 10 percent, that will give you a consequent
decrease in manure production as well. Thats less of an issue than is
the direct economic consequence of lowered cost for that producer.

When we talk about mature animals, were not \-- were usually only
talking about disease at the individual level. So antibiotics are
primarily used on an individual animal basis. It is much less common to
use it at a herd level for lets say a group of females who are
suffering some disease, much less common. So typically in adults its
just individuals who are treated for disease.

On question two with regards thresholds, obviously this is not my area,
but intuitively at least this seems like a reasonable approach. I like
your comment this morning, Dr. Morris, of a substantive amount of
antibiotics. We can debate the pounds, but this seems to me to get to
the endpoint, at least in animals, of resistance. Intuitively it seems
like a reasonable approach. As a colleague of mine said to me this
morning, The devil is in the details, and thats obviously the
difficult part about the development of this process.

One of the aspects of importance when the question is, you know, are all
drugs of equal importance, if they are all of equal importance we will
basically end up I think with none. If they are all of equal importance
to humans, we would have none in animals, and that would be of course a
concern to veterinarians.

One aspect about this threshold approach to me is the modeling, and I
love models. I have studied epidemiology and love application of models,
and models to me are wonderful for showing you what you dont know. You
can then go and find out those components of the model that you dont
know. What worries me a little bit is the application of models where
you are incorporating components of the model where you dont know that
aspect of driving the endpoint. What would concern me a little bit about
thresholds is using models when were not very comfortable with
components of the model. I know thats the whole issue with this
threshold debate, is making these links of the chain and putting it into
an outcome of human suffering.

With regards to question three, I guess it strikes me that all drugs are
not equal, and therefore they should have different thresholds. When
there are limited alternatives it strikes me as logical that there would
be a smaller threshold. When there are available alternatives that
somehow you raise that threshold.

Lastly, my last comment is a general comment. As veterinarians, you
know, we are the guardians of animal well-being, and I think the comment
this morning appealed for a balance between humans and animals. I dont
think a balance necessarily means theyre equal. I think none of us
here, Im guessing, most of us here would say humans are not equal to
animals, although there are some you know who would say that. But I
wouldnt, and Im guessing my association wouldnt. Were just asking or
appealing for the use and application of antibiotics for the well being
of our animals. Were not saying theyre equal to humans. Thank you.

MODERATOR BEAULIEU: Thanks, Bob. Richard?

MR. WOOD: Yes. Ive been told Ive already answered the questions in my
morning address. Ill do it again. What are the benefits? Again, from
our perspective it would be \-- the benefits would be determined through
the application of the standard of reasonable certainty of no harm. That
standard should be developed with an application of the best sciences
available established through a regulatory process that is open and
transparent, as is todays meeting. I know these meetings are difficult
for CVM staff and all to be involved and kind of open up the whole
process to all of us who want to take a look at it, but that is the only
way that it is going to succeed. In the long run, that is the only way
that its going to really have any kinds or levels of protection that
make sense to either the food animal or to human health.

I would hope that we can include in the review of those kinds of
applications identified in question one a review of past approvals as
well. As you know, there is a petition before the FDA that was filed in
March of 1999. We are still waiting for action on that petition that
requires disapproval of drugs used \-- non-therapeutic drugs used as
growth promotion that are medically important.

In the meantime, a commentor here on the panel prompted me to also think
about the need for the FDA, regulatory agencies, USDA, the livestock
industry and other groups as well, for us all to work together on
putting together an infrastructure of support that would help in an
intentional way producers to move away from antibiotics as a method of
responding to their management needs and practices. I come from a rural
community. My family farms, and I know what its like to be at the end
and have things jerked around on me all the time in terms of what I must
do. For this to succeed in an industry that is as broad and as complex
even with the vertical integration that exists today, that it has to
reach down to the grassroots level. I think that industry, the
university system, public health officials, regulatory agencies,
consumer groups, we all need to begin working together and establish a
shared strategy that will move us toward the goal of moving off the drug
and no longer relying on antibiotics to the point where it creates the
resistance that were concerned about today.

In doing that I think I would hope that there would be a primary
emphasis on management strategies. Management strategies that reduce
stress, that reduce the need, that reduce the occurrence of disease,
that would promote growth at the same time, and I think that we need to
be more aggressive in looking at models that would help us to accomplish
that end. I certainly welcome the general willingness that Ive heard
from this panel and others to begin discussing how to move beyond a
reliance on antibiotics.

Then the second question areas has to do with should these thresholds
vary. I did address that this morning. Again, there should be no
thresholds for medically important antibiotics, and I think that has
been underscored by other comments that weve heard today. The stakes
are too high in terms of human health for us to put that kind of
threshold in place. Thank you.

MODERATOR BEAULIEU: These comments \-- thank you, Richard. Have these
comments stimulated any further thoughts on the part of other panel
members or raised points that they would like to react to?

DR. APLEY: Id just like to comment on it seems like we are kind of
evolving towards a caldron model, where instead of a somewhat stylized
trail from food animals to humans we kind of end up with this big pot
thats constantly being stirred with genetics, and the question of the
chicken or the egg \-\-- question comes back of where it came first. I
just want to make sure, and, Dr. Morris, I appreciate your comments
about the reservoirs out there and in the environment, that we have to
be sure that we realize again that we all share, both humans and
animals, in putting into that environment.

That was really brought home to me a couple of summers ago when the
coliform count in the Des Moines River spiked. Of course they
immediately went looking for the evil hog lagoon that had overflown.
About a few weeks later in the back pages of the paper came the fact
that a town up river had had some pump problems in a heavy rain, and
thank you very much. So we do all share in that.

I think there is so much we dont know yet about the birds, wildlife
contributions. I go back to a dairy that had a salmonella problem, and
they fixed it by stopping to mix the feed in an uncovered mixer
underneath a tree that starlings roosted in. There is so much
circulation in the environment that I guess where I have trouble with is
how we reach a logical common ground on realizing that once those
determinants are out in the world and we are expected to basically take
\-- be good husbands of those determinants that are in our neck of the
world, be it human medicine, be it animal husbandry, how we do that.

I think that is the biggest challenge, is we do all need to be
responsible stewards of not only the animals in our possession, but the
animals soon to be food in our possession. Then also realize that some
of the resistant clones that pass around \-- go back to Dale Hancocks
work, where they looked at clones that pop into a production unit, and
you may not even be using that compound in that unit, but they display
resistance and then it will go away. I think it is a big circulating
mess out there, and I personally struggle with how we put a handle on
that without removing some uses in food animals that really benefit both
humans and the animals. I dont know if I would give any, other than I
think that articulates our common problem.

DR. MORRIS: Let me second that also very strongly, and I think some of
the research weve done supports this same concept. I mean, we were the
ones, for example, who reported finding VRE in chicken feed. The VRE
strain that we \-- vancomycin-resistant enterococci strain that we
identified in commercial chicken feed looks like it was probably a
hospital strain. Which, again, I think we need to move away from this
concept of, Its just agriculture. Its just the hospital. I mean,
here we are finding a human strain coming through a commercial chicken
feed manufacturer, and thats a single anecdote, but the problem is that
we are seeing this repeatedly. This concept again that were all in a
common ecosystem.

So obviously in human medicine I will tell you I am involved in
strenuous efforts to reduce antimicrobial use in humans. CDC has a very
aggressive, judicious use of antibiotics program. There is a major
problem with overuse in human medicine. In community physicians, in
hospitals, and again, I could go for hours about this, because this is a
lot of what I do. But I think we need to recognize, again, its all part
of the same system, and as we try to limit it in human populations we
also need to think about total antibiotic use. Thats why I come back to
these somewhat scary figures about total usage, and I struggle with the
same thing that youre saying in that Im not sure how we deal with
this. Except I think there needs to be an appreciation that weve got to
deal with the total amount of antibiotics were putting into the \--
totally into the ecosystem.

DR. APLEY: And the only thing I would follow up is that as we struggle
with how to do that, we need to recognize \-- and I firmly believe there
are some uses we could remove from food animals that would have more of
a deleterious effect from the increased disease incidence or disease
incidence sub-clinical in animals going to slaughter than is gained by
its effect on that big circulating cauldron as it passes through the
food animal. Going back to Dr. Morrisons continuum slide, which I think
was probably one of the most profound of the morning \-- I hate to give
that to a swine guy, but its true.

(Laughter.)

DR. APLEY: Weve got a lot of work in both human and veterinary
medicine. As a consulting veterinarian and as one from the university
Ive been around places and seen some things from veterinarians that
weve cringed and weve fixed, but I also received my first
ciprofloxicin as a handful of free samples from my physician in about
1987. So we both have got some laundry we wouldnt want to hang out by
the highway.

DR. BEAULIEU: Any further comments from the panel? Questions?

DR. MORRISON: Just one comment. If we had the pounds of use, it seems to
me the application for the same drug varies from therapeutic to
sub-therapeutic. It strikes me that simply the pounds of use without
knowing the exact application on every unit could mislead us into
thinking were actually making progress if total pounds are going down,
and yet were not on the real endpoint of resistance. So it just strikes
me that this approach of looking at resistance is a better, perhaps in
the long run, outcome than pounds.

DR. MORRIS: Agreed, but I think without the pound number we dont have
it on there. We have got to know what our total usage is as a starting
point. Because again some of the European data, I think suddenly when
they knew the poundage then the resistance pattern started to make
sense. I think we need to have that information to know why were
starting to see resistance in certain areas, and again, to be able to
figure out the whole system, were missing an absolutely key variable.

DR. MORRISON: Its an interesting question to me. You know, we livestock
people carry a lot of figures around, like you carry normal temperature.
We might carry 50 figures on our fingertips, but I couldnt actually
tell you the amount of antibiotic that our farm uses because it is just
not something that we \-- we will pay attention to different things, and
I might know my total veterinary and animal health and vaccine costs for
example, but not pounds. So its an interesting thing to pay attention
to.

DR. APLEY: Would it be more accurate to say that the pounds or total
consumption versus resistance might give us an association to
investigate further? The concern I have is giving it the allusion of
giving this a cause and effect or a causal relationship which you cant
from that, but it can guide us in areas to look further.

DR. MORRIS: Its a critical component of the modeling. Without that
number were shooting blind. You know, because we dont know what \-- we
dont know how much is out there. We dont. All of the models require an
ability to figure transfer rates of resistance to be able to figure

\-- you know, its just a whole series of variables, and a critical
missing variable is how much drugs are being used. I mean, we dont have
that.

DR. APLEY: Im not downplaying the importance of that information, but
one of the things that is frustrating to me as non-epidemiologist is I
look at these ever-increasing models, and all they seem to serve to do
for me is convince me I dont know more things that need to go into the
model. Finally I get to the point where I go, I dont know 20 things
now instead of not knowing 10. Where have we gotten? So I just throw
that out for thought.

MODERATOR BEAULIEU: Without commenting on the relative importance of
drug use data relative to other pieces of information, I think I can say
that the Agency recognizes that it is an important piece of information
and activity is underway to help us get better information in that
regard. We will hear more about that I think over the course of the next
day or two. Any further comments from the panel?

(No response.)

MODERATOR BEAULIEU: Were open to questions from the floor. If you can
find a microphone and identify yourselves, please.

DR. DOWERSON: Good afternoon. My name is Mike Dowerson. Im a Board
certified toxicologist with Toxicology Excellence for Risk Assessment.
Its a non-profit group. I do a lot of EPA work. So Im going to ask
some naive questions, and I thank you for helping to educate me in this
area.

The first question is to Dr. Morris, or perhaps others, and I will read
the question to you, and then I will tell you what Im intending with
the question. What would the increase in resistance look like in humans
if we sterilized the food before we ate it, irradiation or something
like that, and does any country have good data on this? Because I know
some countries do more sterilization than we do, and then intent of the
question is what proportion of this increase in resistance that you are
seeing in clinical practice, what proportion is due to the resistant
bacteria in the food we eat?

DR. MORRIS: That becomes a very complicated question. I would divide
this into two subsets, if you will. First of all, is the resistance in
enteric pathogens such as salmonella and campylobacter? There there is
very little human amplification. Basically the resistant organism is
coming in directly from the food animal, and there are not
human-to-human cycles. Or at least there are minimal human-to-human
cycles. In those instances, there would appear to be a fairly close
correlation between whats going in terms of development of resistance
in the food animal and the appearance of resistance in humans. Again,
its not an exact correlation. Theres a variety of caveats in all of
this, but thats the simplest. That is the simple model.

When you get into the more complex model, which is simply the transfer
of genetic material which has the capability of encoding resistance,
that gets much more complex. Again actually I think what Im going to do
is defer some of that answer to the presentation that Dr. David Smith is
going to be making \-- what is today, Monday? Wednesday, where he talks
about some of the models he has developed where basically the bottom
line is that the appearance of resistance in animals or animal
resistance has its greatest impact before there is substantive
resistance in human populations. Basically what it does is alter the
window of opportunity during which time the drug has utility in human
populations. But, again, it gets into some fairly complex modeling, and
I prefer to let him describe the models than try to.

DR. DOWERSON: So therefore if we \-- are there countries where they have
had sterilization of food like irradiation where you actually have
resistance in human and now after they sterilize the food you have a
different resistance in the human spectrum?

DR. MORRIS: No. To my knowledge, no. What there are, the European
countries are areas where there has been bans on specific antibiotics
and where there have been the opportunities to watch changes in
resistance patterns in human populations. Basically what you see is a
substantive lag time. I agree with the comment that was made earlier I
think by Dr. Wages that, you know, you can stop it, but you dont see
anything happen for a while. I mean, thats basically \-- you know,
there is a substantive lag time, and some of those data are now coming
up.

DR. DOWERSON: Thank you.

MR. WOOD: We dont have a position. We havent worked on irradiation,
but I just wanted to make \-- to address a question behind that
question, and that is that the sterilization of food products is not \--
we dont see any magic bullet, and the sterilization of food is not a
magic bullet. Just like pasteurization is very important for milk, but
you still have to have a clean product at the beginning of that whole
process. That certainly is true with resistant bacteria in food animals
as well.

DR. DOWERSON: Thank you.

DR. CLOUT: Yes. My name is Buzz Clout, and Im a veterinarian. I work
with chickens, and I have a question and a comment. There seems to be an
awful lot of concern about poundage of antibiotics used in human
medicine and in veterinary medicine, and I thought the concern with this
is exposure of animals to antibiotics. The point Im trying to get at is
that what I think should really be looked at here is usage levels in
herds or flocks. Because we do track our medication usages to farms, and
actually to individual houses, and it should be obvious to everyone that
the amount of antibiotic consumed by a seven-day-old chicken is a lot
less than the amount of antibiotic consumed by a nine-week-old chicken.
I think the same thing holds true for cattle, horses, and I think even
for people like myself.

DR. MORRIS: Absolutely. Poundage is extremely crude and has really no
correlation with reality. I think its a surrogate marker. Ideally we
would have very close records in terms of, you know, specific drugs, how
much is used for different drugs. Again, I think the main thing is to
get at this concept we have got to know what the usage levels are.

DR. CLOUT: I dont question that, and the reason I came back to the
microphone is when you used the word surrogate. Because it seems as
though over the years theres been a lot of like surrogate-like figures
thrown out in meetings like this, and I think this is as groups of
scientists we should try to address specific points as best we can.
Thats why I want to make an issue out of this. Rather than look at a
figure like poundage that can be completely misleading, you should start
looking at the individuals on this thing.

DR. MORRIS: Absolutely.

DR. WALLINGA: Im David Wallinga. Im a physician with the Institute for
Agriculture and Trade Policy in Minneapolis. I think its question two
or three, asks the panel to make some distinction between medically
important \-- sorry, the next one, question three. Between
antimicrobials in human medicine for which alternatives are limited
versus ones for which alternatives are available, and Id like to see
more discussion about alternatives.

Because as a physician I used to treat people who didnt have health
insurance, and whether or not the antibiotic was effective against their
particular infection was only one of the criteria that I would use. I
would also look at things like cost, whether it was a generic drug.
Theres a whole range \-- side effect profile. Theres a whole range of
criteria that one needs to look at, and ideally youd like to have as
big of an arsenal of drugs as you can for that very reason. So Im
uncomfortable putting antimicrobials where alternatives are limited
somehow above another class without looking at that full range of
criteria, and Id like to hear some comments on that point.

DR. MORRIS: Im doing all the talking here. I apologize. I agree
absolutely with you. I think part of this also comes, as I indicated
earlier, to the immediate realities of practice today where, you know,
we are very limited. There may be a lot of antibiotics out there, but
increasingly with patients we are limited to which ones we can use. As
you point out, the whole question of cost, the HMOs, whats on an HMO
formulary. I mean, it starts getting extremely complicated, and its
really not possible to simply sit there and say, Okay. This one is in
class A, this one is class B, this one is class C. Consequently, I
think we need to really look carefully at this whole concept. I realize
FDA has placed a lot of emphasis on this concept in the framework
document.

I guess what Im saying is the reality of todays \-- you know, the
reality of today makes this in some ways an artificial breakdown, and I
think there needs to be careful attention given to this concept, painful
as it may be to think about some alternative approaches. As I said, to
me the only unimportant drug is one that no longer works because the
organism is resistant to it, which may be the way we are going to have
to approach this. But I think this concept is not as cut and dry as we
might have thought it was.

DR. WALLINGA: To use just a real quick concrete example from practice,
to many patients a course of amoxycillin for an ear infection for
example where the course would cost maybe \$5 to \$10 for a generic
prescription is a lot better than a third generation cephalosporin that
might be \$75 to \$80 for the same two-week course. It can range that
much in terms of cost to the patients. Thanks.

DR. BYWATER: My name is Robin Bywater. Im a consultant with Pfizer
Animal Health. I want to just make a point, follow up Mike Apleys
remark about the complexity of the link. We tend to think that we can
easily change something in a species and have an effect on the
resistance in that species, and in the case that were talking about
even in another species, the human one. I would like to just draw
attention to whats happened in Europe. In Europe we dont have
thresholds, but we have had in individual countries surveillance of
resistance over a longer period than the admirable NARMS survey in the
United States. So its possible to go back and see whats happened in
terms of resistance changes in organisms like salmonella in animals.

Theres some intriguing results for the Netherlands and also from
Belgium, where after the introduction of fluoroquinolones in the late
80s sure enough fluoroquinolone resistance among salmonella, and
incidentally pasteurella, was found to be increasing fairly steadily
until about 1992. It reached 15 percent, and I think this was full
resistance, not just a marginal increase or decrease in susceptibility.
Then it departed. It declined so that by 1996 and 97 it was down to a
very low level, at least in terms of greater than four micrograms
resistance.

Nothing particular happened at that time, and in fact when you ask the
companies who were supplying fluoroquinolones had they changed their
pattern of prescribing, had they altered their recommendations, the
answer was no, they hadnt. What had happened was that the organism
strain, 204C, had been replaced by DT104, and DT104, nasty as it is,
doesnt naturally, at least at that time, carry fluoroquinolone
resistance.

This goes back further in the U.K. Weve had 203, a huge surge in the
70s. Lead to lots of concern. It went away, and people then were asked,
What happened? Nothing happened. They were even explaining it by a
calf dealer who died unfortunately in a car accident and had stopped
spreading calves around. Well, it didnt really ring true, and the fact
is these organisms do come and go, and they do come and go with their
resistance at the same time. Theres a great danger that a threshold
will be incorporated into a legislation. It will be operated, and, lo
and behold, something will change, and it will be given the credit for
what has happened. In fact, what has happened would probably have
happened anyway. Any comment, anyone?

DR. BEAULIEU: Looks like we heard you.

(Laughter.)

DR. BEAULIEU: I find it interesting. Thank you. Fred?

DR. ANGULO: Fred Angulo, from Centers for Disease Control. Id like to
focus on this third question, although perhaps not the question, but the
bullets that are under the question, because it appears to be the
opportunity in the agenda to comment on the categorization of the drugs.
I think that its pretty clear that were anxious to move forward on the
categorization of the drugs with all due haste. I think once we
categorize the drugs some of the discussions will be ameliorated in
terms of concerns about being too conservative or too liberal. So I
would hope that we move forward on categorizing the drugs rapidly.

The second part then, though, is when you look at those three reasonable
categories of drugs that are written up there, all three of those usages
still must meet the standard, which is of reasonable certainty of no
harm. I think that the FDA/CVM should be congratulated on the discussion
document that theyve drafted, and it is a novel and exciting approach.

But Im concerned about the definition of the human health threshold,
which Im reading from the executive summary on page four, where it
defines the human health threshold as the unacceptable prevalence of
infections in humans that are treated with the antimicrobial drug of
concern. Thats a loaded clause, treated with the antimicrobial drug of
concern. Because taken to its extreme, you could say that human health
thresholds would only be for those drugs that are used to treat
salmonella and campylobacter infections.

If thats the case, because \-- and of course we know that the current
drugs that are used to treat campylobacter and salmonella infections are
fluoroquinolones and third generation cephalosporins, which clearly are
in category of no alternatives exists. That is the irony of or thats
the evolution where we are in the history of salmonella. Salmonella
infections used to be treated with tetracycline until it became
resistant. Then they were treated with chloramphenicol until it because
resistant. Then there was bone marrow problems, and it was taken off the
market. But resistance emerged to chloramphenicol. Then they were
treated with bactrim, and now they are treated with fluoroquinolones and
third generation cephalosporins in children, and there are not
alternatives with the same pharmacodynamic properties, advantages of
those drugs.

So were at the end of the line. It is not clear what the next class of
drugs for those infections will be. So it could be argued I think fairly
convincingly that fluoroquinolones and third generation cephalosporins
reach \-- are in that first category. The alternatives are limited for
those drugs.

The concern is as we have heard so nicely demonstrated by Dr. Morris is
that \-- my point was that all three of those categories of drugs must
meet the standard, and that is that there be reasonable certainty of no
harm of all three of those categories of drugs. We heard very nicely
from Dr. Morris that there were \-- human health affects of the use of
antimicrobials in food animals is not just treatment failures. It is the
indirect transfer. We talked about that. Dr. Sundlof mentioned that
would be evaluated or there will be ongoing discussion and evaluation of
indirect transfer, and thats good. But there is another human health
affect that this discussion document apparently does not address, and
that is that this concept or the reality of increased transmission as
drugs \-- as salmonella becomes increasing resistant.

Humans are treated with antibiotics for a variety of infections. If a
child is treated with amoxycillin for an ear infection, that child is
exquisitely sensitive to become infected with the salmonella that is
resistant to ampicillin. We have done case control studies at CDC which
demonstrate that human DT 104 infections, the dominant risk factor for
getting infected with DT104, and in fact 40 percent of all DT104
infections in humans can be attributed to people taking antibiotics for
another reason. If DT104 was not resistant to antibiotics that it was
resistant, those 40 percent of infections would not have occurred. So
multi-drug resistance or increase in resistance contributes to increased
transmission. That is another human health affect that isnt addressed
in the discussion document.

DR. BEAULIEU: Thank you, Fred. Over here?

DR. MELLON: My name is Margaret Mellon, and Im with the Union of
Concerned Scientists. I think I heard two of the panelists say that they
believed that the growth promoting use of antibiotics would deliver a
healthier animal to harvest. Id like to know how the healthier animal
is defined in that context and what evidence there is for that
proposition, or even what kind of evidence that you would look for.

DR. WAGES: Yes. I was one that made one of those statements, and I may
not be able to address the concerns in specifics. You will have to be
the judge of that, but anytime that you \-- especially with necrotic
enteritis control. One thing that necrotic enteritis with clustered
infection does is it increases the fragility of the intestine. When we
process we use automation in the processing procedure. The eviscerator
is automated. Its a kind of shell that goes in and pulls out the
intestines. The entire viscera, including the lungs. By preventing the
necrotic enteritis and clustering infections the fragility or the
integrity of the intestine is increased. Its thicker. I cant quote you
the millimeters different, but the intestinal is thicker and it does
withstand more pressure in preventing the breaking procedure. Thats
what I meant with regards to the intestinal portion of decreasing
contamination due to necrotic enteritis control.

DR. MELLON: Thank you. Is there any other response?

DR. APLEY: In cattle my comment was related I believe towards
antimicrobials. If I indicated strict growth promotion claims I
misspoke. Some examples for us would be the tylosin approval for liver
abscess prevention in feeder cattle. There is an incidence of abscesses
in the liver that are capable of rupture at slaughter, and this does
control those and knock them \-- decrease them to a very controllable
level. There is also a low-level approval of oxytetracycline for that.
It was mentioned earlier in feeding that \-- antimicrobials with feed
approvals. They can only be used together with another product if they
are approved for use. With one ionophor you would use oxytetracycline.
With one other you would use tylosin.

Going back to some of the uses, for example, like the anaplasmosis lower
levels we talked about, if were not able to keep those animals under
control during the vector season, towards the end of the season we may
have an animal thats not in as good of shape that can go to slaughter.
Our goal as cattle producers and for the other groups is to have animals
in the highest level of health going to slaughter as we can. Our goal is
to have them go to harvest because its time, not because of a disease
process that has caused their early retirement from production.

DR. WAGES: Maam, were you specifically asking about growth promotion,
low-level and not therapeutic? Is that correct?

DR. MELLON: Well, Im actually interested in the answer to both. I mean,
I guess Im hearing that where there is a disease prevention aspect to
the treatment the instances that you cited would be those that you would
be concerned about, but that there arent instances I gather then where
purely growth promotant uses deliver a healthier animal. Or that is what
Im hearing.

DR. WAGES: Yes. At least in our industry we focus on the disease
prevention that it affords us. Anytime that you take disease out of the
equation it is our hope and intention that it proves out to be they grow
better and there is a growth promotion affect.

DR. APLEY: For example, in ours it gets back into its not a very simple
relationship as weve discussed in a lot of things up here in the panel
today. For example, going back to the ionophors, not linked to a human
use compound, no known cross-resistance. They suppress coccidia.
Coccidia have been demonstrated to suppress the immune system and could
lead to other diseases that then require the use of therapeutic
antimicrobials. So its a pretty tangled web.

DR. MELLON: Well, I will agree with that. Thank you very much.

DR. MORRISON: I didnt list that. I didnt list that for pigs because as
far as I know the benefits of sub-therapeutic levels of antibiotics on
the level of pathogens for humans in the final product have not had
consistent results.

MODERATOR BEAULIEU: Over here?

DR. MELLON: Thank you.

MS. FLORINI: Im Karen Florini, senior attorney with Environmental
Defense. I have a question for you, Dr. Beaulieu. At the outset you
expressed an interest in perhaps moving away from the reasonable
certainty of no harm standard for antimicrobial drug approvals for
animal agriculture. What would you like to see instead?

MODERATOR BEAULIEU: Was that addressed to me?

MS. FLORINI: Yes, it was.

MODERATOR BEAULIEU: I didnt intend to say anything that would \-- well,
what Im saying is \--

(Laughter.)

MS. FLORINI: It sure sounded like it.

MODERATOR BEAULIEU: Well, okay. What Im saying is if we can conclude
collectively that some standard other than that would be scientifically
and societally acceptable, then I think we should not hesitate to change
the statute to accommodate that standard. I dont know what that
standard would be at this point, and Im not advocating any particular
standard in place of the reasonable certainty of no harm standard.

MS. FLORINI: For what its worth, I think it would be rather
controversial to attempt to move in that direction from the perspective
of the environmental health community. Because, after all, we are
talking about animals that are raised for one purpose and one purpose
only, to be slaughtered for food. So this unlike certain other issues
where you are looking at environmental policy and have an interest in
protecting the natural environment independent of an anthropomorphic
interest, this is solely an anthropomorphic interest. We are raising
these animals in order to kill them and eat them, and in that context
moving around from a reasonable certainty of no harm standard in order
to promote what is an economic advantage in food raising would be I have
to say I think highly controversial with a number of members of the
environmental health community.

MODERATOR BEAULIEU: I hear you. Over here?

MS. JOHNSON: Judy Johnson, University of Maryland at Baltimore. I hate
to introduce another level of complexity into this almost
incomprehensible problem anyway, but I felt I had to respond to the idea
that one of the most important things to work on is grouping the
antimicrobials. I havent seen any discussions of what type of organism,
whether you are dealing with a commensal or a zoonotic organism, and the
other major importance for deciding on antibiotic resistance and what
the likely impact of agriculture use is, is the type of resistance
mechanism. Its going to be very different if youre dealing with
something that requires only a point mutation. If youve got a point
mutation that will happen in the human community with human antibiotic
use. If you are talking about something like vancomycin use where you
have to have an intact cassette of several complicated genes transferred
into an organism, then thats a very different picture, and thats
something that needs to go into that discussion.

MODERATOR BEAULIEU: Thank you. Last question.

DR. VOGEL: Okay. At the risk of adding even more complexity, and in
light of Dr. Beaulieus earlier comments about the \-- at least being
open to consideration of changes in the Agency as we look at this
question of variable thresholds based upon the importance to human
medicine, I would also like to add another variable, and thats their
importance to veterinary medicine. Thank you.

DR. WAGES: And that was Lyle Vogel from the AVMA.

(Laughter.)

DR. VOGEL: Oh, thanks.

MR. KEELING: Thanks, Andy. I wanted to revisit the issue of the use data
one time, because \-- oh, Im sorry. Who am I? Thank you. John Keeling
with the Animal Health Institute. Sorry. But revisit that use data
issue, because it seems to me there could be an opportunity there that I
think everybody has alluded to. As most of you know, we collected use
data, and given the recent discussions about use data we have revisited
all of that. We still feel very confident about the numbers that we came
up with, and in fact looking at the Union of Concerned Scientists data
can see some areas in which they overestimated. Not due to their
methodology, but due to their lack of understanding about some of the
production practices that are in place. When you sort it all out, there
may not be a whole heck of a lot of difference in the two numbers.

One missing element is that, as has been talked about here, not every
one of those drugs that we looked for and that we gave numbers for is
important or even useful to human medicine. The ionophors for instance I
think all of us would agree are certainly not even a topic of
discussion. But leaving for a second the argument over the pounds of
antibiotic that may or may not be being used out there, because I dont
think there is really probably as much disagreement as we think, we have
never exactly understood what the ultimate use of the importance of the
data would be, and particularly how it would be applied and what would
be looked at. So I would suggest that there is a real opportunity for us
here to bring all of the stakeholders together under the auspices of CVM
to have a discussion about the type of data that we believe we need, how
that data might be put to use, and where that data might be gathered.
Because it becomes clear to us as you look at this that were going to
have to involve veterinarians, were going to have to involve producers,
because the type of data that generally gets discussed is data that we
cant get, we do not have and our companies do not have access to.

So I would suggest that there is an opportunity for all the stakeholders
to be able to get together and have a very thorough discussion of what
we believe the data needs are, where that data might be gathered, and
how we might begin that process of those of us who are concerned about
human health. And we do know that CVM is in the process of developing
some regulations in that area, but I would suggest to you that now is
the time for us to get together and begin to have that discussion, not
after the regulations are put forward. Because once the regulations are
put forward, it is in effect a very sterile environment because CVM
cant talk to us, they cant talk to other stakeholders. So I would urge
members of the panel and would like your response on whether thats a
good objective, and how we might start in that area and if CVM would be
helpful in that area.

DR. MORRIS: I would concur absolutely, although it is interesting we are
talking about how were going to get the data. It seems like it would be
really nice if the drug companies just simply told us how much they were
producing.

MR. KEELING: We did tell you how much we were producing. Thats what I
just said. We told you exactly. We went back over the numbers. We
agreed. We looked at it. Its in the range of between 17 and 20 million
pounds.

MR. WOOD: But, you know, for that information to be useful I think one
question that is very important is where the repository of that
information is, and that needs to be with the Center for Veterinary
Medicine and available to the public.

MR. KEELING: Thats fine. Lets get together and have that discussion.

DR. ANGULO: Can I comment on this discussion? Just to add to it, we have
formed a small working group at CDC to evaluate this most recent
estimate of use and the previous estimates of use, and I agree that in
fact the animal side may not be that different. They actually might be
very close. They are only 10 million pounds apart. So actually they
might be real close. What is clear is that we dont think that the AHI
human use estimate is nearly accurate and that we do think the Union of
Concerned Scientists estimate is much more appropriate. The AHI estimate
is on the order of 30 million for human use versus the Union of
Concerned Scientists is significantly lower. We are evaluating how we
can get a better human estimate, but the approach made by the Union of
Concerned Scientists is much more reasonable than the approach that was
taken by the Animal Health Institute in terms of human use.

MR. KEELING: Fred, let me \-- we got our human use number from you guys.
So we would appreciate \--

(Laughter.)

MR. KEELING: So we would appreciate you developing a better one if in
fact it is inadequate, and I dont know how the approach taken by the
Union of Concerned Scientists could be better than the approach taken by
AHI. Because our approach was poll our member companies, ask them how
much of the product that they distributed, which I dont know how you
can do much better than that. If you look at the Union of Concerned
Scientists report, I think their methodology and their attempt to
estimate it is valuable. The problem they fell down in is they didnt
understand the industries that they were talking about. Efrotomycin for
example, it is not used. It is approved, but its never been used.
Chlortetracycline, I think Dennis can speak to this, 1,400,000 pounds in
chickens. That use is probably closer to what, Dennis?

DR. WAGES: Zero.

MR. KEELING: So right there you are looking at 1,500,000 pounds that
they clearly overestimated. I agree with you. When you get it back down
the number is not that different. But to say that a survey of the people
that are distributing it is not as good as an estimate of potential uses
is not right. So get us your better number on the human side and I think
you are quite wrong in terms of our estimates. Thanks.

DR. ANGULO: I didnt comment on the animal estimates. I commented on the
human estimates, and I think that your human estimates are incorrect.
Thats all I commented.

MR. KEELING: And you understand where our human estimates came from. The
CDC website.

DR. ANGULO: They were quoted on the CDC website. It wasnt original CDC
data. It no longer \--

MR. KEELING: I dont know where it came from.

DR. ANGULO: It no longer exists.

(Laughter.)

DR. ANGULO: It no longer exists on the CDC \-- it hasnt been on the CDC
website in over six months. When you kindly brought it to our attention
we removed it because it was inaccurate. It wasnt our statement. It
wasnt our data. It actually comes out of \--

DR. MELLON: Well, lets just be very clear.

VOICE: Lets let the folks that put the survey together tell us how \--
they did it.

DR. MELLON: Well, actually I guess I would say I really welcome the
Animal Health Institutes correcting of data and the offering of what it
knows about its industry to \-- in the service of our estimate to
actually calculate usage, but I want to be really clear about why we did
this report. We did this report not because we think that the Union of
Concerned Scientists using publicly available but admitted indirect
methodology can come up with a better number than industry can come up
with. We did it because when we went to look for publicly available
transparent data produced by a methodology, a published methodology, we
basically could not find any such usage data anywhere in the federal
government. We couldnt find it at the CDC. We couldnt find it at the
FDA. We couldnt find it at USDA, with the single exception of the use
data on those antibiotics that are used as pesticides.

Now, the conclusion from our report should not be, you know, is the UCS
data better than the Animal Health Institutes data. It should be lets
get the government to do what it ought to have done long ago, and that
is to compile the data that are needed to address this public health
problem.

There are two kinds of data we need. One is production data. The
industry is quite accurate in saying it knows what it produces. It
doesnt know in a lot of cases how its used. So we need production data
coming from the companies. It needs to be collected by a methodology
that is published, and I will tell you some of the things that we, you
know, didnt know about their methodology. We also need usage data.
Thats data from people who use it, from you folks in the chicken
industry and the turkey industry and the beef industry. How do you use
those antibiotics? How much of it do you use?

We really cant tell by \-- you really cant tell by looking at the AHI
site. I mean, they said they surveyed their members and that 80 percent
of them replied, and that they compiled the numbers. I mean, we assumed,
although no one said, that these numbers include all uses on all animal
systems. Thats minor uses and major uses, therapeutic and
non-therapeutic, companion animal uses, veterinary uses. I mean the
whole \-- everything in order to come up with their number, but they
never said that. They never said whether ionophors are in or out. There
is no published methodology to go with the numbers, and therefore they
are of limited use to the public health community.

So indeed these numbers should be made available by the companies, but
they should be collected, compiled, and made available to the public by
the government so that we have confidence in those numbers. And I submit
that only when they are compiled by the government, which can compel
everybody, not just whoever chooses to provide information, but
everybody in the industry to provide it, will we have the kind of
numbers that we need.

On the human health side I want to be clear that indeed the Animal
Health Institute did not by an indirect or direct methodology attempt to
estimate the human health use of \-- or the medical, human medical use
of antibiotics. All they did was subtract. They took their number,
whatever it was, whatever it represented, it happened to be 17.8 million
pounds, and they subtracted it from this number of 50 million pounds
that has been floating around for the last 15 years now as the total
antibiotic production. So in any case, they \-- and they got a number
of, you know, about 32 million pounds, which is 10 times our estimate
for human medical use. So whatever we need to do as we go forward, we
need to understand that there is no estimate that I think anybody can
rely on for total antibiotic use.

Nobody knows that number, but I think weve actually come up with a
pretty good way of estimating human medical use, and I \-- you know, I
hope the CDC and anybody else in government who would like to go over
our numbers will do that so that we can see whether it is as good as it
could be. But we also know that we have, you know, a number from animal
use that really isnt what we need, and I think that even though there
may not be that much difference between our numbers and their numbers,
it isnt for us to resolve. Its for the government to resolve.

So Id just like to say we need to get on with that. We need to figure
out which element of the government, which agency is the proper one to
collect the data, what kind of authority they need to do it. It is
absolutely essential. I mean, weve agreed what a complex problem that
were facing, and indeed it is. But you cant begin to solve complex
problems without having the fundamental information about how much of
this stuff youre using. I mean, you absolutely cannot begin to solve
this problem.

I keep listening to all these comments people are making. They are
saying, Well, you know, we think that antibiotics might have been
overused in agriculture, but theyre not anymore. Where are the trend
data over the last 10 years that would help you answer that question?
Weve heard, Well, we dont think that. This might have been used for
growth promotion, but we dont think it is anymore. I mean, how can we
possibly evaluate and use those statements if we dont have routinely
collected data provided to us by a government agency in which we can all
have confidence? It just seems to me as a scientist foolish to begin to
solve a complicated problem without having the data we need. So \--

MODERATOR BEAULIEU: I think there is general agreement on that point.
Certainly the Agency agrees with you. Weve had an offer from other
parts of the industry to sit down and talk with you, the Agency, and
other interested people to try to resolve this issue and come to a
methodology that we can all agree on.

DR. MELLON: Well, we accept.

MODERATOR BEAULIEU: The Agency would certainly be willing to do that.

DR. MELLON: Well, we accept. It certainly is time, and I hope all the
folks, not only in the production industry, the people who produce the
antibiotics, but the people who use them will want to be a part of this
disclosure effort. Thank you.

MODERATOR BEAULIEU: Message received. I think weve cut into our public
discussion period somewhat. Lets see if we cant get back after the
break at a quarter to 4:00.

(Whereupon, a break was taken at 3:25 p.m.)

***[Public Comment Period]{.underline}***

***Facilitated by Dr. Aleta Sindelar***

MODERATOR BEAULIEU: Take your seats, folks, so we can get started on the
public discussion period. We are going to get started on our public
discussion section now. I think the program indicates that Mr. Jim
Heslin is going to facilitate that session. Unfortunately Jim had a
conflict at the last minute and he wont be able to be with us, but
Aleta Sindelar has kindly agreed to stand in for Jim and facilitate that
pubic discussion session.

Just before I turn the program over to her I want to do one thing I
failed to do as moderator, and that was I let the panel get away from us
before the break. I would like you to join me in thanking the panel for
all the work they did and the comments that they gave us. Thank you,
panel.

(Applause.)

MODERATOR BEAULIEU: Nice job. We appreciate it. Aleta?

FACILITATOR SINDELAR: Hi. Because we would like to provide an
opportunity for everyone to have a chance to give us feedback on this
meeting and the session, we would like to request that you limit your
comments to five minutes or less. Comments regarding these questions or
any comments about this meeting may be submitted in writing by April
9th, 2001. So if you have a discussion that is longer than five minutes,
please submit that in writing to the docket. The written comments should
refer to docket number 00D-1677 and be submitted to Dockets Management
Branch, HFA305, Food and Drug Administration, 5630 Fishers Lane, Room
1061, Rockville, Maryland 20852. This address of course can be found on
the Q&As that are provided in the back of the room on the table. We have
approximately an hour-and-10-minutes for comments. So I would like to
invite the first commentor.

MS. WALLACE: My name is Deborah Wallace, and I represent Consumers Union
Public Service Project. Im an ecologist and an epidemiologist. Im very
concerned about the modeling on which the threshold is being decided.
Theres a long literature on modeling methodology, both in ecology and
in epidemiology. One of the great cautions has to do with weighing the
simplifying assumptions and their possible consequences. I did not see
that in the discussion document.

This model is based on a large number of simplifying assumptions, many
of which were not made explicit in the discussion document. For example,
that the public health impacts from agricultural antibiotics come only
from food. There are numerous publications such as in environmental and
applied microbiology which show that there is a lot of water pollution
from farms, from animal-rearing farms. The distinction in the enteric
bacteria which are found in the water body thats being sampled between
animal source and human sources made on the basis of the drug resistance
profiles. So we know resistant bacteria are going into the water from
the farms as well as from the sewage treatment plants. When you have an
environmental reservoir the exposure of humans may result in a lag
impact, and that has to be translated mathematically. It is almost
intractable to translate mathematically.

Another example is the assumption that the relationship between the
quantity of animal product with resistant bacteria and human health
impact is linear. It may very well be non-linear, especially if you have
these environmental reservoirs, and if there is a likelihood, a high
likelihood that there is human-to-human transmission after a person
becomes infected even from the food. An implicit assumption is that
socio-geographic variability can be ignored. Socio-geography refers to
socio-economic differences between areas. Now, socio-geographic
variability has always held great importance for contagious diseases and
behaviors. It is quite possible that due to impact of level of
education, stability of residence, simple availability of time and
space, that poor people prepare food in a different way from wealthier
people. It is quite possible that infection from food and transmission
of this infection may occur more frequently in poor, extremely
overcrowded households. This model just blanks all that out. It doesnt
even define what scale, geographic scale, is appropriate to look at this
problem.

Finally, as another example, there is the assumption that the human
health surveillance system will detect changes before we get into
serious trouble.

Dr. Morris addressed this partly, but another consideration is that if
the infections from foodborne resistant bacteria are concentrated in
poor urban neighborhoods the surveillance system may not pick up changes
until they are quite large. Our census bureau cant even count these
neighborhoods properly, even when they have a large, targeted effort.

The inability to detect all cases of reportable diseases is illustrated
by the fact that every year most major cities find some tuberculosis
cases that come to their attention only after autopsy or after the death
certificate comes in. Poor people have less access to medical care than
employer-insured people. They may also avoid seeking medical care
because they cant afford to be sick and because theyre often not
treated well by health care providers. If there is no physician to
report this case, the surveillance system wont pick it up.

So those are just examples of the kinds of assumptions that erode the
credibility of this model. We at Consumers Union would like to see
greater emphasis on reducing the antibiotic load by limiting the dosing
of animals to those who are individual animals who are sick, treatment
of individual animals who are sick. We dont find this threshold concept
as its applied here on humans to be anything but a vast medical
experiment on the American population.

FACILITATOR SINDELAR: Thank you, Ms. Wallace.

MR. CANTOR: May I speak from here?

FACILITATOR SINDELAR: Yes.

MR. CANTOR: From this microphone? Okay. My name is David Cantor. Im
here representing the non-profit organization Farm Sanctuary. Lets see
if I can raise this. I have a very brief written statement that Ill
read, and before I do that I just want to mention that the animal
movement is not based on the idea that animals and human beings are
equal. Its based on the idea that animals have a right to their lives
and to be free from human-inflicted suffering, and they have this right
because they are capable of experiencing a life. Not the exact same way
humans experience a life, but a life with rich \-- thats full of rich
experience and that has \-- thats different based on species and the
environment in which the animals are raised. Its also based on the idea
that equal interests are deserving of equal consideration, which is
often misleadingly stated as being that humans and animals are equal. So
the capacity to suffer makes animals deserving of consideration, et
cetera.

I will just read this brief statement then. Incorporated in 1986, Farm
Sanctuary operates two large farm animal shelters. The shelters give
permanent lifelong care to rescued chickens, pigs, cows, turkeys and
other animals. Farm Sanctuary does not routinely feed animals antibiotic
medicines and will only allow them to be administered for an individual
animals well being. The food industry routinely feeds antibiotics to
animals for reasons other than the animals well being to maximize
profit, and when we talk about \-- most of the discussion today that has
referred to animals well being has not talked really about animals
well being from an animals standpoint. Its about animals well being
vis à vis the ability to maximize profit from those animals, or its
about humans well being vis à vis the ability to get animals to market.
Thats entirely different from whats meant by people who work for
animals.

Operations that do so, that is routinely feed antibiotics to animals,
typically are factory farms where animals are overcrowded and overly
stressed. Without antibiotics, animals at those facilities would have
extraordinarily high rates of disease. With antibiotics many scientists
believe the animals carry increasingly resistant strains of bacteria
that are passed on to human beings who eat the animals. Obviously its
more complicated than that. The present focus on possible regulation of
antibiotics fed to farm animals is surely worthwhile. It is extremely
important to prevent unnecessary antimicrobial resistance. Farm
Sanctuary urges the Center for Veterinary Medicine and the Food and Drug
Administration to end the use of antibiotics in farm animals except to
treat illness in individual animals. Ending the widespread routine use
of antibiotics in animals food will be an important step toward ending
intensive confinement of animals and toward humane treatment of animals.

Since resistance has probably developed in salmonella and other
bacteria, ending routine feeding of antibiotics to animals used for food
is likely to benefit human health significantly. Factory farming is not
a legitimate activity. Although some currently consider it lawful, if
anti-cruelty laws meant in practice what they say on paper, factory
farming would be prosecuted rather than facilitated by government and
animal health professionals. Thank you for considering this important
matter for the American people and her animals, and thank you for the
opportunity to speak at this meeting.

FACILITATOR SINDELAR: Thank you, Mr. Cantor.

DR. DOWERSON: Mike Dowerson, Toxicology Excellence for Risk Assessment.
This is one of probably a half dozen practical ideas that we as a
collective group of people can use perhaps to answer question number
three of this second session, and the question is, If you believe human
health thresholds should vary, please comment in general terms on
whether the levels should be greater or smaller, and you gave three
categories. My background is environmental health, and in the
environmental groups like the Environmental Protection Agency often look
at chemicals that cause cancer, and they give different categories. They
give known human carcinogen, or suspected human carcinogen, or a
probable or a perhaps, and they give these categories various
designations. But an older designation was like an A, B, or a C, and the
International Agency on Research Against Cancer does a similar thing.
Then in USEPA and other groups they talk in terms of quantitative limits
to these carcinogens, as in one times 10. You know, one extra cancer
case in a million, or one extra cancer case in 100,000 or in 10,000, and
regulatory efforts have been usually focused in EPA and state regulatory
agencies with carcinogens on a 10^-4^, 10^-6^ range.

So one quantitative way to approach if you are going to build a
threshold for an antimicrobial and you are going to as a collective
group categorize different uses of these drugs in humans, you might want
to give a 10^-6^ designation quantitatively to an important
antimicrobial drug in human medicine. Then in a second category, an
important antimicrobial drug for which alternatives are available, you
might want to give quantitative designation that might be

10^-5^. Of course these are just suggestions. They are not necessarily
meant to be definitive. For the quantitative designation of
antimicrobial drugs that have limited use in human medicine you might
want to give a different quantitative estimation of the threshold, maybe
10^-4^.

You might want to approach this in a very \-- a less quantitative way,
and in the environmental area there is another less quantitative way to
approach these things, the use of uncertainty or safety factors. There
have been some situations, not necessarily in USEPA, but in other health
organizations in Europe, there are a couple of groups that use this,
that for effects that are severe toxicity a 10-fold extra safety factor
is used. Or if they are not as severe, maybe less than a 10, maybe a
three is used. Or if in effect its considered minimal, maybe you dont
need an extra factor. So you can envision maybe a one-fold factor could
be used.

In like fashion, you might be able to look at your different categories
of drug use, whether they are very important for humans or not as
important because theres many alternatives, with the use of a different
uncertainty or safety factor. Again, this is just some information from
another area of science in regulation. It does have some scientific
support. It has a lot of judgement as well that might be useful here.
Thank you.

FACILITATOR SINDELAR: Thank you, Dr. Dowerson.

DR. WALLINGA: Again, Im Dr. Wallinga. Im a physician with a Minnesota
organization, Institute for Agriculture and Trade Policy, and I find
that the discussion here has often started from the perspective of the
use of these products and then worked backwards to human health. So I
want to start with human health and make that the focus of the
discussion.

I really want to speak in support of FDAs use of the health standard,
reasonable certainty of no harm, but there are some important points to
make. One is apparently earlier this morning there were comments about
somehow balancing the public health standard against other economic
considerations. My organization would not be at all supportive of that.
I really dont understand from a public health standpoint why you would
want to, quote, unquote, balance, which to me is a euphemism for
weaken, a standard that is designed to protect the public health and
instead weaken that standard to provide something less than full
protection of public health.

I am also puzzled by the lack of discussion now teasing out the
difference in uses in agriculture of antibiotics. Weve spoken of it as
a monolithic use when in fact I dont think many here would necessarily
take issue with the importance of veterinarians having effective
antibiotics for treating sick animals. Thats an important use. Its
important for the welfare of the animal. An appropriate concern, but if
we look at the numbers generated by the Union of Concerned Scientists, I
dont even need to look at the total values, the volume of antibiotics
used, but rather at the ratio of what they calculate is used for
non-sick animals versus sick animals. Something on the order 14 times
more antibiotics are used for non-sick animals, in other words,
sub-therapeutic uses, than for sick animals. Well, this suggests to me
that theres plenty of opportunity for us to talk about reducing
antibiotic use in that portion of the agriculture sector without even
touching these important therapeutic uses of antibiotics.

I also think its interesting that if we were in a hospital talking
about the problem of antibiotic resistance we wouldnt start off the
discussion saying, Gee, weve got this really important problem with
antibiotic resistance, but we dont want anyone to change their
behavior. The doctors should keep on prescribing exactly as they have,
but were going to keep worrying about this problem. And yet, isnt
that what were doing here? Were looking at everything but the behavior
of antibiotic use, why its used. Rather, we focus most of the
discussion on which antibiotics are used and what amount theyre used.
Well, I submit that we need to look at that bigger question of how were
using the antibiotics. Is it really necessary to use the antibiotics in
the way that we are in agriculture?

Finally, looking back at reasonable certainty of no harm, from a human
health standpoint there is plenty of science to suggest that people are
different, and harm can be defined with respect to one population that
is completely different than the harm to another population. We need to
acknowledge the risk science on human diversity, the science that shows
us that elderly people, that children, that farmers in some cases who
use more antibiotics or other people that use human antibiotics, all
these populations are probably more vulnerable to getting
antibiotic-resistant infections. Yet this document treats the human
population homogeneously. In fact, the only discussion that I could find
of more vulnerable populations is buried in appendix two, and I want to
read, because it just surprised me.

It says, If an identifiable subpopulation bears a significantly greater
proportion of risk than the general population, it seems appropriate
that they should be the focus of protective measures. Well, Id agree
with that, but the next sentence is somewhat more troubling. It says,
However, this is provided that the defined subpopulation is not able to
avoid or manage the risk. Well, in laymans terms that sounds to me
like FDA is proposing that people with AIDS, transplant patients,
children, the elderly, others who are more vulnerable to
antibiotic-resistant infections should somehow manage their risks by
just not eating chicken, or, you know, staying away from bacteria that
might be harmful to them.

I just dont understand that approach. Rather, I think a reasonable
certainty of no harm standard requires that we set our standards for
antibiotic use in agriculture such that they are protective of the most
vulnerable members of the population, and science tells us who those
are. Those are children, they are the elderly, they are people who have
gone through transplants and other people with compromised immune
systems.

Finally, I just want to reiterate the several things that were said
today about what the science already tells us about thresholds. It seems
to me that there is no scientifically justifiable way that we can have
thresholds for agriculture use of medically important antibiotics at
less than therapeutic levels. Why is that? Because for those really
critical human medicines, any increase in resistance is going to exceed
our public health standard, a reasonable certainty of no harm. In other
words, if there is a bump up in the resistance, by definition we no
longer have a reasonable certainty of no harm. As Dr. Morris said, by
the time you reach a detectable level in people its too late. Since
were really talking about a single ecosystem of bacterial resistance
and there are things like gene transfer, Dr. Angulos point that
exposure to one antibiotic can also increase your susceptibility to get
infected with a different bacteria that is resistant to another
antibiotic, all these things suggest that thresholds just arent going
to provide a reasonable certainty of no harm for that subclass of
antibiotics. That is medically important antibiotics used at less than
therapeutic levels. Thank you.

FACILITATOR SINDELAR: Thank you.

MS. STIFFLER: Good afternoon. I will probably be reiterating a lot of
what Dr. Wallinga just said as well as Dr. Morris this morning. My name
is Terri Stiffler, and Im a staff scientist with Environmental Defense,
which is a non-profit environmental research and advocacy group
established in 1967. I hold a masters degree in environmental
microbiology, and this issue is very interesting to me.

First off I want to say that Environment Defense applauds FDA for
holding this meeting on the important issue of antibiotic resistance and
its relationship to the use of antibiotics in agriculture. We wish to
preface our remarks by recognizing that many farmers have had a
difficult time over the years responding to challenges ranging from
natural disasters to the intense vertical and horizontal integration
within the farming industry. We appreciate their resilience, their
creativity, their hard work, but we believe that the time has come to
put that creativity to work and together with the public, the FDA, drug
companies, the medical community and many others, start implementing
solutions to the emerging public health crisis from antibiotic
resistance.

Many scientists warn that we are approaching an era of post-antibiotics,
where once-treatable diseases are no longer treatable. Im actually too
young to remember the pre-antibiotic era, but I know my grandfather
personally lost two siblings to pneumonia, and he nearly died himself.
Until last year, there was approximately 20 years that had passed since
the development of truly new and novel antibiotics to my knowledge. We
must protect the pharmacopoeia of viable drugs that we have, and I will
explain the use by FDA of thresholds may be part of the needed
protections. But thresholds should not be relied upon as the first line
of defense to protect medically important antibiotics.

We understand the conceptual appeal of thresholds, but this approach
cannot achieve the reasonable certainty of no harm standard, a standard
we strongly support for medical important antibiotics. Theres several
reasons for this conclusion. First, current scientific information
simply does not allow a setting of thresholds with reasonable certainty
that staying within that threshold would indeed constitute no harm. As
alluded to this morning by

Dr. Morris, there are major uncertainties and factors such as potential
cross-resistances, the fitness costs or neutrality of resistance
alleles, and non-foodborne transmission pathways that make the use of
thresholds a shaky business. In addition, existing surveillance and
monitoring techniques are not sophisticated enough to provide timely and
accurate information on whether a threshold is truly being exceeded.

Rather than develop thresholds for medically important antibiotics, FDA
should not approve the use of these valuable drugs in animal
agriculture, especially for non-therapeutic uses. It is simply not
acceptable to jeopardize the efficacy of human medicine for at best
slight efficiencies in animal production. Many flock or herd-wide
applications are questionable as well. We as well do not dispute that
when you have a sick animal you need antibiotics. However, the practice
of flock-wide or herd-wide use of some of these antibiotics is
questionable.

However, a threshold-based approach may be useful for antibiotics that
are not medically important. In that event, it must be remembered that a
threshold approach is only as good as the data that supports it and the
monitoring system that is put into place to collect this data. There are
several variables that must be taken into account when determining an
accurate monitoring system, particularly when you are looking at a
microbiological system. Its not a static system. Its dynamic and its
constantly changing. Some of these variables include, as our first
speaker talked about, it may not be a first-order linear model that
youre looking at. When youre looking at the relationship with a
particular antibiotic it may be second order, and beyond a breakpoint
resistances may accelerate rapidly. So if you set the point at a certain
level, it may just shoot right past that within a year or within quicker
than that, but you dont know. Therefore, it may be advisable to observe
a change versus a static breakpoint value.

Theres also multiple exposure pathways that need to be considered. At
the point with the current methods that are available that resistance is
detected in animals it may have disseminated throughout the environment
via food, via soil, via water, via air, via farm workers, by their
families, et cetera, et cetera, et cetera. Therefore, by the time you
see it in animals it may be way too late, and if you do set this
threshold you need to make it very, very conservative. Or, like I
mentioned before, select for a change in resistance versus just a static
value.

You also have to take into account the bacteria, and their relationships
to antibiotics vary. There are some bacteria like staphylococci,
enterococci, pseudomonas, and salmonella other than the \-\--, and
campylobacter that are very adept at accumulating resistant genes to an
introduced antibiotic. Other bacteria, for example streptococcus
pneumonia at another end of the spectrum, took 30 years to develop
resistance to penicillin. You just dont know.

Theres also issues with laboratory methodology. Theres variations in
techniques from lab to lab. Theres the equipment issues. Theres
background information on the sample, if you dont know the previous
antibiotic use of the animal that you are testing, et cetera. The
identification of the particular species of the bacteria is critical, et
cetera, et cetera.

Finally, in addition, if the thresholds concept is put into place for
the medically unimportant drugs, FDA must keep in mind that the
importance of a drug in medicine is a moving target, as Dr. Wood alluded
to this morning. A prime example of this is the use of virginiamycin in
agriculture prior to the approval of synercid, which is now the
treatment of last resort for vancomycin-resistance enterococcus. FDA
will need to constantly monitor for indications that a drugs potential
medical importance is increasing and should not wait for human use
approval to restrict the use of a drug in animal production. Thank you
very much.

FACILITATOR SINDELAR: Thank you for your comments.

DR. SHRYOCK: Tom Shryock, Elanco Animal Health. Antimicrobial-resistant
foodborne bacteria are indeed a public health concern, but what Id like
to do is offer some perspectives to try to put that \-- put the
magnitude of that problem in a little bit different context.

According to a recent report in the [Journal of Antimicrobial
Chemotherapy]{.underline} in the year 2000, only four percent of the
human antibiotic resistance problem was associated with foodborne or
zoonotic pathogens, salmonella and campylobacter primarily. So it was
based on a limited physician survey in the United Kingdom. To contrast
that without types of mortality rates, the Institute of Medicine
reported that preventable adverse patient events, including
hospital-acquired infections, are responsible for at least 44,000 deaths
annually in the U.S. So just put that in perspective.

In the estimates of total foodborne illness that appeared in the
[Emerging Effects of Disease Journal]{.underline} authored by Mead, 76
million illnesses were attributable or associated with foodborne
disease, 5,000 mortalities. Known pathogens accounted for 14 million of
those illnesses; unknown pathogens, 62 million of those illnesses. If
you break that down further, you get these mortalities, and that doesnt
necessarily have to be the endpoint for our discussion. But just to put
this in perspective, 553 foodborne deaths were associated with
salmonella non-typhoidal, not all of which are antibiotic resistant. 499
foodborne deaths were associated with listeria monocytogenes. None of
those were resistant to my knowledge. 99 deaths with campylobacter
species. Again, not all of those are resistant. 375 deaths were
associated with toxoplasma gondii. None of those are antibiotic
resistant. Just as a comparator on the mortality, I happen to find this
tidbit in [Morbidity Mortality Weekly Report]{.underline}, which in 1998
indicated that 536 persons were killed while trespassing on railroad
tracks. Just as a comparator.

As we continue our discussions through this next several days, we need
to keep in mind that susceptible bacteria will cause disease just like
antimicrobial-resistant bacteria. Thats an important concept to make.
So where are our food safety resources best directed? Is it overall food
safety, including parasites and non-antimicrobial resistant bugs? Or is
it just to the small subset that are easily identified and which are a
smaller subset which include those that might have antibiotic-resistant
genes? It seems to me that the framework and the threshold approach may
well be ignoring the largest part of that iceberg. Thank you.

FACILITATOR SINDELAR: Thank you.

DR. MILLMAN: Is this mike on? Okay. Im Suzanne Millman from the Humane
Society of the United States. Im the Director of Scientific Programs in
our Farm Animals and Sustainable Agriculture section, and I have an
undergraduate degree in animal science and a Ph.D. in applied animal
behavior and animal welfare focusing on poultry. First of all, I would
like to applaud the FDA for taking on the issue of antibiotic
resistance. I think its very important to look at this, and you might
be wondering, Well, what does this have to do with animal welfare? It
ties in on a couple of points.

My take is going to be probably the flip side of that that Karen Florini
just gave from Environmental Defense where she was saying that the
animals really were not that important because ultimately they were
going to be eaten and their welfare was less of an issue. Im going to
argue the opposite. I think that the welfare of these animals is of
critical importance. That we have a responsibility to them precisely
because were going to use them to eat.

Feeding of antimicrobials in animal agriculture has been done in my
opinion in an irresponsible way after reading the scientific literature,
and as far as animal welfare is concerned there are two issues here.
First of all, were compromising the efficacy of these drugs for use
when we really need them in animal agriculture. This is sort of the law
of the commons effect. We do have producers out there that are being
very careful with their management. Theyre minimizing the need for
disease. They are rearing animals in ways that are humane, and these
producers are losing out on the quality of our drugs because of
indiscriminate use by other individuals.

So when I was listening to this talk, one of the first speakers was
talking about taking a less anthropocentric view and maximizing or
balancing human health and animal health, and I thought, Oh, yes. Okay.
Great. There are a lot of people here that are going to be discussing
this from the animal health issue. Then the more I listened, the more I
realized that actually, no, this is not the take that most people from
the industry seem to be taking on this. The industry still is continuing
to perpetuate management practices that are putting animals at risk,
that are not responsible, that are not minimizing diseases, and they are
relying on drugs as a pharmaceutical fix.

Well, for one thing, these drugs belong to all of us as a society, and
its going to be a pretty hard sell to convince the general public that
this is an appropriate use of antibiotics that are so valuable for human
health when public polls show that the majority of citizens actually
oppose current production methods. There was a poll in 1995 by Caravan
Research showing 91 percent of citizens are opposed to keeping pigs in
stalls where they could not turn around. There was a further poll in
1997 showing Oregon citizens where 60 percent were willing to vote for
legislation to control the production practices on commercial
enterprises. Again, 1999, 85 percent of citizens polled opposed
confining farm animals and current agricultural systems.

Citizens are willing to pay more for this. We can see the increase in
production of organic meat, and citizens are also asking for more
regulation. Again, you can see this not just in the polls. People are
actually going and causing change. Most recently, the citizen-lead poll
in Colorado asking for a moratorium on hog farms. So we have a
responsibility to society, and its really unlikely that you are going
to be able to convince the general public that the use of antibiotics to
prop up management systems that are objectionable is going to just fly,
that its going to be fine.

I was a little bit concerned when Dr. Morrison was talking about
prescribing drugs. Im not a veterinarian, Im an animal scientist, and
he was talking about the AMDUCA program. One of the points that he made
was that ultimately the responsibility for drug use on farms was up to
the veterinarian. But just previous to that he was explaining that he
could go onto a farm and say that 40 percent of the animals were sick
and they needed to be treated with a particular antibiotic, but it was
the farmers decision whether to mass medicate or not. Now, to me, that
sounds like a conflict here. I get a little bit concerned when the
veterinarian is offering advice as if they are an AG extension agent for
a really important resource, and ultimately the decision is at the
farmer level. You only have to read last weeks newspaper to find out
about Ohio hogs. What, 300 sows that perished in Ohio just last month?
Apparently the workers forgot to turn the water on. The sows were
without water for 10 days, started dying, and then the farm managers
concluded that the animals were sick. So they went in and started
killing them. I mean, this is \-- if that is the level of care and
attention that were giving to animal health, then we really have
something to be concerned about.

The second big piece, and a piece thats been really missing from the
discussion here, is the term animal welfare and well being. Ive heard
it brought up, but what I havent seen is much discussion about how
animal welfare impacts on immunocompetence. There are a number of
researchers that should have been here to present their information.
Theres USDA researchers, Julie Morrow-Tesch and Don Lai just to name
two, that could talk to you about research that has been done as far as
chronic stress, the effect on glucocorticoids in animals and their
susceptibility to disease. Not just in the immediate animals, but with
animals such as gestating sows, the effect that it has on the piglets in
the next generation.

Its also important to point out that a lot of our current housing and
management systems do not allow the animals to cope behaviorally the way
they have evolved to actually minimize the impact of disease. First of
all, by decreasing their exposure through things like isolating
themselves and thermal regulating, and the choice of materials that they
would forage on. In a current management system the animals are not
provided with bedding. They still are motivated to be foraging. So the
only substrates around for them will be feces and the tails of other
individuals, feather pecking and so on. Thats going to predispose them
to picking up pathogens.

Secondly, the animals have behavioral mechanisms to increase their own
defenses when they are in the situation of immunological stress such as
increasing their rest and even simply thermal regulating. Our current
management systems do not allow for this. We need to rethink it.

In addition, we also need to think about how were managing animals so
that were actually increasing the likeliness that the animals are going
to catch disease. A quick example that hasnt been talked about are
things like the management of dairy calves. Its been put in the
literature for at least 20 years that we know that calves and neonatal
piglets are \-- they dont have strong immune systems at that time, and
yet we continue to move them around, mix them at auction marts, and then
we make it up with dosing them with antibiotics so that they dont get
sick as, quote, preventative measures.

FACILITATOR SINDELAR: Can you please summarize? Thank you.

DR. MILLMAN: Yes. Sorry. Just in conclusion, delighted for the chance to
be here. Its great to hear the different perspectives. If there is
still space at that table that gets talked about as far as setting
thresholds and talking about reporting, the Humane Society would
definitely like to be there.

FACILITATOR SINDELAR: Thank you very much.

DR. MELLON: Im Margaret Mellon, the Union of Concerned Scientists. The
Union of Concerned Scientists is a non-profit organization thats
interested in promoting a healthy food system. Were here today because
we think that the unnecessary and in some cases indiscriminate use of
drugs is contributing to the loss of efficacious treatments for
ourselves, for our children, for our parents, and indeed for animals.

The point I would \-- I guess I would also \-- I want to congratulate
and to thank the FDA and the CVM for taking on this issue. I think, you
know, youve done it and youve done it in a very serious way that
deserves all of our gratitude. Especially for the fact that you have
tried to bring a good deal of scientific effort and credibility to the
issue.

But with that in mind, my comment is that the threshold document is
still aimed as far as I can tell only at future approvals of
antibiotics; and if this \-- if the FDAs approach is indeed to be
science-based, it must take into account that the majority of the risk
from the use of antibiotics is as a result of those antibiotics used as
a result of existing approval. So to focus on future approvals rather
than our existing antibiotic use is looking at a little mouse and
ignoring the 800 pound elephant in the tent. If this is to be
scientifically credible I think some of that scientific creativity has
to be focused not only forward into the future, but at our existing
uses.

With that in mind, I would like to actually report on the results of the
study that UCS did on antibiotic usage. We did find that there are 25
million pounds of antibiotics currently in use in cattle, swine, and
poultry for non-therapeutic purposes. Thats only in three species, and
only for non-therapeutic purposes. About 4 million pounds in cattle, 11
million in swine, 10 million is in poultry. We cannot ignore that really
surprisingly huge use of antibiotics. By contrast the report finds that
only three million pounds of antibiotics are used in human medicine.
Thank you.

FACILITATOR SINDELAR: Thank you very much.

DR. KLEIN: Hi. My name is Dr. Pat Klein. Im a veterinarian working for
the Humane Society of the United States. Actually in a former life I was
a poultry veterinarian as well. I worked in both a state diagnostic
laboratory, and I was a field veterinarian for a poultry company,
integrated poultry company. Im also a Boarded member or diplomat of the
American College of Poultry Veterinarians. So I have worked in the
field, and I have a sense and experience in the poultry practice, and
Ill limit my comments to that area of my expertise.

I want to reflect on a few comments that Ive heard throughout this
morning and this afternoon from the various speakers. A comment by Dr.
Morris this morning regarding the development of antibiotic resistance
in human medicine due to overprescribing, and it certainly was a very
candid comment, and I would offer up as a veterinarian a similar candid
comment that we, too, seem to be in the same situation throughout
various practices of veterinary medicine and overprescribing
antibiotics. It often is a very convenient and easy approach to disease
treatment, but just keep that in mind.

I do believe that because of that it is incumbent upon us as
veterinarians in whatever walks of life were in to insure that there is
judicious use of these antibiotics, therapeutic uses of antibiotics to
treat diseases where they are warranted. Unfortunately, I think we find
ourselves in various situations where we are compromised into using
antibiotics as a bandage for poor management practices, and I have
worked in the poultry industry for some period of time, and I have seen
both the good and the bad in that. Ive seen at the bad end where those
situations were using antibiotics to bandage bad management practices.

There is this whole concept of the range of low health versus high
health, and I would encourage my colleagues, those who are still in the
food animal industry, to not necessarily support or prop up the low
health end of life, but to try to encourage those situations where
management practices are at fault to improve those management practices.
That truly would be disease prevention, and not necessarily have to
default to the use of antibiotics, which may be the quicker and the
easier path.

That befalls the question of how do we change human behavior, and I
think thats a big issue that has been touched on periodically. Because
this all really does relate back to human behavior issues, whether it is
as the corporate level or its at the individual level. We need to
change our behavior practices in order to manage animals better.

Dr. Khan mentioned in his lecture as well that there is no substitute
for good hygiene, and I think we need to go back to the basics.
Unfortunately we live in a situation in a world of high technology, and
I think that is part of the problem, is that the food animal industry is
just that. It is an industry, and its foundation however is working
with biological systems. Its not working with mechanical parts like in
a car industry. Its working with animals, and they are biological
systems. Yet the technology advances, both for the good and for the sort
of not so good, are trying to push the limits of those biological
systems. Theres a breaking point in that situation.

Animals have evolved to a certain homeostasis if you will, but were
trying to push that. Push it for better production, for faster
production, for more protein sources, for more economics, for being able
to feed people. But they are, after all, biological systems, and the
systems have their genetic and their immunological and their
physiological limits, which cannot necessarily meet those demands of
technology. Men meet the demands of intensive agricultural practices.
Someone just mentioned recently, another speaker mentioned briefly, this
whole syndrome of chronic stress. Thats what were dealing with in that
situation. There are pathological consequences to chronic stress and
stressors, and thats what these animals are under.

Those of you who remember back in I guess the late 80s the lovely
situation of salmonella enteritidis when it raised its ugly head. Well,
then the poultry producers really had to address this issue of SE and
salmonella, not so much for the actual health of the animals themselves,
but for the public health concerns; and it was. It was the toxic egg
commercials for those of you who go back in those days with me. We all
remember toxic egg commercials, which were really damning. But the
public health concerns drove the market, which drove the industry to
improve their management practices and to intensify their disease
surveillance.

Again we are faced with another public health issue and a concern about
antibiotic resistance. Im hoping that in this case the industry and the
veterinarians who work within the industry will look at this past
experience that weve just survived and lived through with salmonella
and this time be proactive and try to make those changes now ahead of
the situation or before it becomes much worse, and before you have sort
of federal mandates that will dictate how you are to practice. I do
encourage my colleagues, my veterinary colleagues, and I actually
empathize with you because as I remember my experience were often in
middle management situations in industry. Were not at the policy making
level. Those decisions are made, and we have to figure out how to make
the system work. Oftentimes we are limited in what we can do. I
encourage you to try to become a better part of the policy making
decision in your companies in your industry and to try and better
management practices rather than be complacent about using antibiotics.

We all remember the overcrowded houses. We all remember how the
genetics, the animals that have been genetically engineered to grow
faster produced more eggs. We have all those issues of the large toms
that cant even stand on their legs anymore because their muscle mass is
so large that they cant support \-- their skeleton cant support their
bodies. We see that there are benefits to some of those situations in
the food producing economics of that, but there are also detriments to
the animal health.

So work on the better management practices. Try and get those houses
cleaned out every time if possible. Theres no reason why birds should
go out one door and the new chicks come in the next and there is no down
time, and I know that that happens. Also there is an issue of
overvaccination, but that goes on to another subject. I think we need to
all be concerned about that. It certainly is in the human end a concern
now these days about how much vaccination is out there and what that
antigenic load may be doing to compromise immunity. Thank you.

FACILITATOR SINDELAR: Thank you.

DR. BROWN: Hello. My name is Scott Brown. Ive been sent here by the
American Veterinary Medical Association, but in request of having
completely an open discussion I also work for Pharmacia Animal Health.
That is also the company that has most recently approved that one
compound that is a new generation of antimicrobial agent that now can be
used for vancomycin-resistant enterococci. So I let you know that my
entire company is very interested in this whole issue.

A comment that Mr. Wood brought up from the Food Animal Concern Trust.
His question was does threshold proposal provide certainty of no harm.
Perhaps he didnt mean it in this particular context, but I would like
to perhaps provide you with a tangible example of what might have been
the case about 20 years ago should we have had this conversation back
then. This is in effect an example of mitigation in action.

Prior to 1984, there was a tetra-resistant salmonella typhimurium. It
was an ASSUT. At that time for another reason completely irrelevant to
the antimicrobial resistance issue, chloramphenicol was banned for use
in the United States. There was an extensive monitoring and surveillance
process put in place to insure that chloramphenicol use was not being
done to any extent at all in veterinary medicine in food animals, and in
fact there was quite a heavy penalty should that have been done. So that
was done in about 1983 or 1984. Ive forgotten the exact date and year,
but it was in that range.

The next florfenicol approval was in 1997. So there was approximately a
13-year period during which time there was very little if any selective
pressure in the food animal community for chloramphenicol-related
resistance. However, during that time, the ASSUT tetra-resistant
isolates were replaced by ACSSUT, with chloramphenicol resistance being
noted and increasing in prevalence.

How could this be the case, because chloramphenicol was banned by the
Food and Drug Administration for use in food producing animals? One
possible conclusion is that there was a clonal dissemination of this new
ACSSUT, this penta-resistant salmonella typhimurium, through the lack of
biosecurity at key control points in the production cycle. One example
that has been provided by an epidemiologist, not myself, by Dr. Dale
Hancock, was potentially the calf rearing area and the fact that in the
calf rearing management that currently is in place there are calves from
a variety of sources that come in and are commingled and are raised, and
then are distributed to a wide variety of destinations. So one calf that
might have had that penta-resistant salmonella could have come in,
disseminated that penta-resistant isolate to a variety of others, and
then that would have been proliferated through the process. It really
highlights the fact that biosecurity is a very important factor that we
may be overlooking if we go solely to the threshold assessment.

Now, lets take for example the concept that we had set a threshold and
chloramphenicol had been banned at that point. We have erroneously
concluded that chloramphenicol resistance would have developed had we
not removed chloramphenicol. But in that case in fact the penta
resistance occurred in spite of the fact that there was no selective
pressure.

The other point I would like to make has to do with the multi-drug
resistance, which is a terribly difficult issue, and Dr. Sundlof noted
that there was not an effort in the threshold document to be addressing
that. Id like us to think carefully about whether mitigation by removal
of one drug in a clonal or cassette resistance modality would likely
have any effect. The transfer in cassettes of resistance is going to be
impacted by all the antimicrobials that are within that cassette. The
control must be then by a decreased transfer from animal to animal, or a
decreased transfer through the feed to the animals, or a decreased
commingling of the animals.

This speaks very clearly to the biosecurity issues and the management
issues that have been raised previously. This requires a careful
collaboration by all the stakeholders. Mr. Wood was quite right when he
said it requires the FDA, it requires the USDA, it requires the
pharmaceutical industry, it requires the consumer groups, it requires
the producers, and it requires the veterinarians. We have the
opportunity as our system of food animal production has become more
vertical to have the opportunity to impact not only at the tail end
where the animals become food, but at the early end where the animals
still are young and fairly far removed from that time when they do
become food. In the vertical operation, there is then that management
oversight through the entire process that lends itself to enhance
biosecurity and added value for that enhanced biosecurity.

FACILITATOR SINDELAR: Thank you for your comments.

DR. HERSHAFT: Good evening. My name is Alex Hershaft. I hold a Ph.D.
from Iowa State University, and Im the national chair of the Great
American Meatout. The reason for the Great American Meatout has been for
the last 17 years to protect the American public from the various
assaults of the meat and other animal food industries. Primarily they
are environmental, economic and health assaults.

Now, some of these assaults are easier to dismiss than others. For
example, we can say, Well, it doesnt matter that public funds
subsidize the meat industry. Because after all the government wastes so
much more money on other useless activities. So what the heck? Whats
another \$10 billion, \$20 billion? You can make a similar claim for
the environment. You can say, Well, okay. So weve ruined our rivers
with runoff from concentrated animal feeding operations. So well just
swim in swimming pools, and well just purify our water before we drink
it. For long term health affects, heart disease, stroke, cancer, you
can always say, Well, if you dont like to die of those diseases you
have a choice. You dont have to eat animal products.

However, when it comes to the antimicrobial resistance, there is no
escape. I as a citizen of this country, even as a resident of this
country, I cannot run away from it. This is something that affects every
single person in this country. Therefore it is incumbent upon the FDA to
make sure that whatever the cost to industry may be, this is an assault
on the public health thats A) of sufficient gravity, and B) so
unavoidable by an individual that it must be stopped.

FACILITATOR SINDELAR: Thank you for your comments.

MR. HANSEN: Yes. My name is Michael Hansen. Im with Consumer Policy
Institute, which is part of Consumers Union of the U.S. Someone else
from Consumers Union spoke earlier, but I just want to make a very quick
comment. It will be very short, and that is we also support the fact
that the FDA and CVM is looking into this whole issue of antimicrobial
resistance. We also very strongly support the reasonable certainty of no
harm as being the appropriate standard.

With the opening comments or some of the comments that were heard at the
opening that maybe there could be some other standard that might be
agreed upon and the fact that the first question deals with benefits we
are worried that if there is any movement to move away from a reasonable
certainty of no harm, which is a health-based standard, if there is any
movement toward another standard which would allow actually considering
other things besides human health, such as balancing off with economic
benefits or something else, we would consider that to be very important,
and there would be a very strong response I think from the consumer
community. We would fight this very much.

So I just want to say that we believe that the reasonable certainty of
no harm is the appropriate standard that should be used, and it should
be simply a health-based standard. This is just like, I mean
conceptually, antibiotics or pesticides. Because they are designed to
kill a pest. The pest is bacteria. There was a fight for over 20 years
to reform our pesticide laws to get them to be not a cost benefit, but
to be a health-based standard, which is what the Food Quality Protection
Act is.

We would also like to point out that just like FQPA, that reasonable
certainty of no harm should be toward the most vulnerable segments of
the population, children, elderly, and those with immune-compromised
systems. Thank you.

FACILITATOR SINDELAR: Thank you.

DR. BARLAM: Hi. Im Tamra Barlam with Center for Science in the Public
Interest, and Id actually like to speak as an infectious disease
physician. I was in practice in infectious disease for 17 years before I
joined CSPI. I just want to emphasize the importance of all these
antibiotics that are used in humans that are currently used in animal
medicine, even ones that we gloss over such as tetracycline for example.
And I actually disagree with Dr. Morris that we can afford to say that
some are \-- there is enough resistance that we should basically offer
those up as sacrificial lambs in a sense and not consider them in the
process of whether or not we should try to start looking for alternative
ways in animal husbandry so that we dont have to use them.

In medicine now we dont just treat infections that come up in the
course of normal human events, but we are using very intensive therapies
that are causing us to get infections with things that we never had
infections with before. The transplantation program, some of the
chemotherapy programs, some of the very invasive surgeries have
basically made a population of patients who are getting infected with
organisms that were never considered pathogens before. They were
considered so-called commensals, so-called colonizers. But now these
same organisms that were considered to be safe and part of the normal
flora are causing some very serious infections and occasional fatal
infections in these very immuno-compromised patients.

So I as an infectious disease doctor am loathe to say that I dont want
to at any point in the future go back to some of these antibiotics that
maybe we dont use as often now such as the tetracycline. In the
documents of the \-- and I also applaud the FDA and the CVM for all the
work theyve done and support a lot of what they are doing; but, as Fred
Angulo mentioned, if you take a very narrow view of the statement of the
human health threshold which talks about in humans treated with the
antimicrobial drug of concern associated with bacteria resistance to the
drug concerned and for which the resistance is attributed to the use of
antimicrobial drugs in animals I hope that were not just speaking about
salmonella and campylobacter infections for example where were really
then just talking about fluoroquinolone, cephtriaxone and the macrolides
for campylobacter and very few other drugs besides that.

Its as if to say that because weve overused tetracycline so much in
agriculture and human medicine that now 40 percent of animal isolates
are resistant to tetracycline and 50 percent are resistant of \--
salmonella typhimurium are resistant to tetracycline. A previously
useful therapy is no longer useful. Therefore, it is not on the table,
and I really dont think that we can afford not to at least put all the
medicines on the table.

So in addition to the new medicines or the medicines that are in fact
used for these infections I think we have to consider all of these
antibiotics that are used in human medicine. The CSPI does not therefore
include drugs like the ionophors or \-\-- which we feel dont have a use
in human medicine and therefore it is not really what our major concern
is, but we would like all the drugs put on the table because we have a
different population of patients now. We never know when we want to use
those antibiotics in the future.

FACILITATOR SINDELAR: Thank you very much. We still have a few minutes
left if anyone would like to make any additional comments.

DR. ANGULO: Fred Angulo from the Centers for Disease Control. Id like
to publicly acknowledge and applaud the FDA for this approach and to for
the record provide the full endorsement of CDC for the framework
process. We dont see \-- were unaware of other feasible alternatives,
and we applaud this approach, and we look very much forward to moving
forward with its implementation.

To put it in perspective, I think that view is shared by other members
of the Interagency Taskforce on Addressing Antibiotic Resistance because
that Interagency Taskforce listed the implementation of this framework
process as one of the top 12 high priority items to address antibiotic
resistance in this nation.

FACILITATOR SINDELAR: Thank you, Fred. We still have a couple of
minutes. There are two additional public comment periods, one tomorrow
and one on Wednesday. So should you have any additional comments. We are
closing our Session 2. We will begin tomorrow at 9:00 a.m. in the
ballroom. Thank you very much.

(Whereupon, the meeting was adjourned at 4:58 p.m. to reconvene January
23, 2001, at 9:00 a.m.)