Number range CHAPTER**Cover Page**

**Official Meeting of the**

**Veterinary Medicine Advisory Committee**

**New Drug Microbial Safety Review Under Guidance #152**

**September 25, 2006**

***[Members Present]{.underline}:***

Arthur L. Craigmill, Ph.D., Chairperson

Corrie Brown, D.V.M., Ph.D.

John R. Glisson, D.V.M., MAM, Ph.D.

Sam Groseclose, D.V.M., M.P.H.

Gregory Jaffe

John J. McGlone, Ph.D.

Mark G. Papich, D.V.M.

M. Gatz Riddell, Jr.

Richard A. Sams, Ph.D.

***[Invited Consultants]{.underline}:***

James E. Leggett, Jr., M.D.

L. Barth Reller, M.D., D.T.M.&H.

**Official Meeting of the**

**Veterinary Medicine Advisory Committee**

**New Drug Microbial Safety Review Under Guidance #152**

**September 25, 2006**

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

**[PAGE]{.underline}**

***Opening Remarks***

by Steven F. Sundlof, D.V.M., Ph.D. 5

***Welcome and Introductions***

by Steven F. Sundlof, D.V.M., Ph.D. 7

***Background of Today's Discussion***

by Steven D. Vaughn, D.V.M. 11

***Use and Importance of Cephalosporins in Human Medicine***

by John H. Powers, M.D. 15

***Importance of Cephalosporins in Veterinary Medicine with a Focus
on***

***Cattle Production Systems***

by Kelly Lechtenberg, D.V.M., Ph.D. 39

***Introduction to Cefquinome and Overview of the Microbial Safety
Assessment***

by Carl Johnson, D.V.M. 64

***Fourth-Generation Cephalosporin Use: Experience in Europe***

by Andre Bryskier, M.D. 81

***CVM Response***

***Presentation***

by Jeffrey M. Gilbert, Ph.D. 98

by David White, Ph.D. 100

***Public Comment Session***

by Patricia Griffen, M.D. 111

by Dr. Edward Belongia 121

by Dr. Richard Carnevale 129

by Steven Road 139

by Susan Prolman 142

***Questions of Public Comment Session Speakers*** 149

**[I]{.underline} [N]{.underline} [D]{.underline} [E]{.underline}
[X]{.underline} - (Cont'd)**

**[PAGE]{.underline}**

***Questions Presented to VMAC***

by Jeffrey M. Gilbert, Ph.D. 184

***VMAC Deliberation***

by Arthur L. Craigmill, Ph.D., Chairperson 185

***Question Number 1*** 186

***Question Number 2*** 198

***Question Number 3*** 210

***Concluding Remarks and Next Steps***

by Arthur L. Craigmill, Ph.D., Chairman 216

**Keynote: "\-\--" indicates inaudible in the transcript.**

**Keynote: "(\*)" indicates phonetic spelling in the transcript.**

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

(8:43 a.m.)

***[Opening Remarks]{.underline}***

***by Stephen F. Sundlof, D.V.M., Ph.D.***

DR. SUNDLOF: Good morning everyone. Well, we are still missing one
member of our Committee, but I am sure he will be able to catch up. So,
I think in the interest in making sure we get through this meeting in
time for folks to catch their planes and such, that we will start the
meeting.

So, I want to welcome everybody. And before I deliver some of my opening
remarks, Aleta Sindelar has some housekeeping information for us.

MS. SINDELAR: Thank you, Steve. I am just going to go over these very
separate issues.

Parking, for those of you who have driven here, there is construction
going on underneath the building. So if you have a car that is located
downstairs, please check on your car, or move your car at lunch because
the crews will be coming in to work.

So, all you need to do is check at the front desk, get a certificate
that they will put in the front of your car for free parking at any of
the surface areas.

If you cannot find a surface area parking, the SIMS location behind us
has a large parking area, so please feel free to park there because they
have a cooperative agreement. And if you have any questions, please come
see me with any issues.

For the purposes of transcription, could we please turn off all
Blackberry's and cell phones. Even for the vibration, so we can have the
clearest transcription.

There are two written public comments which came in very recently.
Copies have been made of those two written comments. They are located
over here on the table for you as well.

I will be reading the conflict of interest statement prior to the
meeting. The Z-Tech representative, Drennan Lindsey(\*), will be here
for any reimbursement issues for those of you who have traveled here
under the contract. She will be here from 11:30 a.m. until 12:00 noon,
out here at our registration table.

And I would like to remind you that we also have certificates outside at
the registration table for continuing education credit from the Maryland
Department of Agriculture. It is one hour, but please feel free to take
a certificate with you and for it to be signed.

I would like to invite Drs. Vaughn, Powers, and Lechtenberg to the table
at this time so we can begin our meeting.

(Pause)

MS. SINDELAR: Please bear with me as I read the Conflict of Interest
Disclosure Statement on particular matters.

("Conflict of Interest Disclosure Statement " read)

MS. SINDELAR: Thank you. I would like to turn the mic over to Dr.
Sundlof.

***[Welcome and Introductions]{.underline}***

***by Stephen F. Sundlof, D.V.M., Ph.D.***

DR. SUNDLOF: Thank you Aleta. And, again, welcome. Thank you all who
have come to this meeting today. We at CVM convened this meeting to get
input from the Veterinary Medicine Advisory Committee on the Agency's
assessment of microbial food safety of a proposed new antimicrobial
cefquinome for the proposed use in food-producing animals.

This request is for an outside review and is, in part, part of our
antimicrobial food safety that we developed with input from all the
stakeholders. This has been a multi-year endeavor to reach agreement on
what is the proper regulatory pathway. And, to meet our goals of
protecting public health, but also protecting animal health as well.

(Slide)

So, first of all, I would like to introduce to everybody the VMAC
members. And we start with our Chair, Dr. Arthur C. Craigmill, from the
University of California, Davis. And Dr. Craigmill, his area of
expertise is veterinary toxicology.

Also, we have sitting next to Dr. Craigmill, Dr. Corrie Brown, from the
College of Veterinary Medicine at the University of Georgia, who
represents pathology on the VMAC.

(Slide)

John Glisson, from the Department of Avian Medicine at the University of
Georgia, and he is representing Avian Medicine on the VMAC.

Dr. Sam Groseclose, Chief of Statistics and Data Management Branch,
Division of STD Prevention, National Center for HIV/STD/TB Prevention,
Centers for Disease Control and Prevention \-- I would hate to have to
write that out every time I signed my name \-- with expertise in public
health and epidemiology.

(Slide)

Dr. Sherman W. (Skip) Jack could not make it today because the travel
Gods conspired against him and he was unable to get a plane out of
Mississippi. The only other plane was over-booked, so he would not be
able to get here today, so he will be with us in spirit only. His
expertise was in minor use, minor species veterinary medicine.

Greg Jaffe is Center for Science and Public Interest. And Greg
represents our consumer representative on the Committee.

(Slide)

Dr. John McGlone, Professor and Director of Pork Industry Institute,
Department of Animal Sciences and Food Technology at Texas Tech
University, Health Sciences Center. He represents animal science on the
Committee.

Dr. Mark Papich, Department of Molecular Bio-Medical Sciences, College
of Veterinary Medicine, North Carolina State University, with expertise
in Pharmacology.

(Slide)

Dr. Gatz Riddell \-- who we assume will be here shortly \-- and Dr.
Riddell is the Executive Director of the American Association of Bovine
Practitioners. And he represents food animal medicine on the Committee.

Dr. Rick Sams, Professor and Director of the Ohio State University
Analytical Toxicology Laboratory and the College of Veterinary Medicine
at OSU. And he represents chemistry on the Committee.

(Slide)

In addition to the VMAC members, we are very happy to have some invited
consultants from the Center for Drug Evaluation and Research consultants
in infectious disease. So, from their committee, we have Dr. James
Leggett, Associate Professor of Medicine at Oregon Health Sciences
University.

And Dr. Barth Reller, Professor of Medicine and Pathology, Director of
Clinical Microbiology at Duke University Medical Center. Thank you both
for attending this meeting.

(Slide)

So, let's go to the purpose of the meeting then. CVM called this meeting
to get input from the Veterinary Medicine Advisory Committee on the
Agency's assessment of the microbial food safety of a proposed new
antimicrobial drug, cefquinome for use in food-producing animals. It is
an extended spectrum beta-lactam in a fourth-generation cephalosporin,
intended for use in beef cattle.

The concept of a review by outside experts is contained in our
antimicrobial guidance for industry, which we finalized in 2003, and
this will be the second VMAC Committee in which we have addressed a new
antimicrobial.

The guidance that I am talking about came before this Committee on
several occasions, and the guidance established a regulatory pathway,
based on the concepts of risk assessment and risk management.

The drug sponsors could use this to demonstrate microbial food safety of
an antimicrobial used in food-producing animals. And you may recall that
this meeting, again, is the second such meeting. In October 2004 we held
another VMAC meeting to evaluate Pfizer's Tulathromycin for use in
cattle and swine.

The VMAC's work was an important part of CVM's review of all aspects of
the drug, including the effectiveness, target animal safety,
environmental safety, user safety, and the quality of the manufacturing
process, as well as the food safety component. CVM later, following the
VMAC's recommendation, approved that drug.

(Slide)

CVM does not bring all pending antimicrobial applications to VMAC for
review, however, but we are asking for the VMAC's evaluation of the
microbial food safety aspects of this drug. Cefquinome is the first of
its class, a fourth-generation cephalosporin to be considered in use in
food-producing animals in the United States.

Fourth-generation cephalosporins are important to human medicine, but
also because cefquinome is a cephalosporin, its use could affect
third-generation cephalosporins, which are drugs that FDA has classified
as critically important to human medicine.

Our guidance for industry, therefore, indicates that an outside review
of the microbial food safety aspects of this drug is an appropriate
risk-management step.

(Slide)

So, in closing then, I want to thank all of you for coming, and we will
get the meeting started. I will turn it over to Dr. Steve Vaughn.

***[Background of Today's Discussion]{.underline}***

***by Steven D. Vaughn, D.V.M.***

DR. VAUGHN: Good morning, welcome. I want to thank the Committee for
taking time out of your busy schedules to be here today. It is very
helpful to the FDA to have your insights and your expertise, and we are
very grateful to you.

We are here today to discuss the microbial food safety of an
antimicrobial new animal drug with respect to antimicrobial resistance.
Food-producing animals are reservoirs of food-borne pathogens, such as
Salmonella, Campylobacter, E. coli, 157, and there is a potential for
antimicrobial resistant pathogens to be present in food-producing
animals as a result of these animals being treated with antimicrobial
drugs.

We know from our surveillance monitoring that the antimicrobial
resistance pathogen contaminates carcasses in retail meat, thus,
exposing humans to these organisms transmitted through food. Therefore,
the Agency is reviewing the microbial food safety of all uses of all
antimicrobial drugs used in food-producing animals\...

(Slide)

\...with published guidance for industry No. 152 in October of 2003,
outlining an approach for assessing microbial food safety prior to
approval. The guidance uses a qualitative risk assessment process to
arrive at an overall estimate of the risk to humans.

(Slide)

The complete qualitative risk assessment has, essentially, three
components; all of which are treated equally in terms of the risk. The
first is the release assessment that assesses the probability that the
use of the drug will result in the emergence and selection of
antimicrobial resistant bacteria. Second, the exposure assessment
addresses the likelihood of human exposure to the pathogen.

And, finally, the consequence assessment addresses the importance of the
antimicrobial drugs human medical therapy; and, thus, the consequence to
humans of loss of a treatment option.

The criteria for developing the ranking of drugs that we use for the
consequence assessment was developed by the Center for Drug Evaluation
and Research, with a great deal of help from the Anti-Infective Drugs
Advisory Committee.

(Slide)

The three components are integrated into an overall risk estimation,
which comes out qualitatively as low, medium, and high. Once we have an
overall risk estimation, then there are specific risk-management steps
that may be implemented to manage the estimated risk.

One of those risk-management strategies is a Veterinary Medical Advisory
Committee review. Today, we have included members of the Anti-Infected
Drugs Advisory Committee. And it is important for members of that
committee to lend us their knowledge of the importance of individual
antimicrobials and antimicrobial classes to the Committee's
deliberations.

This morning, we will hear presentations on the importance of
fourth-generation cephalosporins in human medical therapy, and in
veterinary medicine.

The sponsor, Intervet, will be presenting their microbial food safety
risk assessment for the use of cefquinome sulfate in cattle for the
treatment of bovine respiratory disease, and we will also hear about
experiences with fourth-generation cephalosporins in Europe in both
humans and animals.

Finally, this morning we will briefly review the Agency's assessment of
Intervet's proposal, and we will briefly discuss the current resistance
picture as captured by our NARMS program.

In the afternoon session, there will be an open public hearing period,
where interested parties can comment on the proposed use of cefquinome
sulfate. We will ask a series of questions for the Veterinary Medical
Advisory Committee to provide their thoughts on:

> 1\. Whether the findings presented in the sponsor's assessment
> demonstrate that cefquinome is safe with respect to the potential for
> the transfer of antimicrobial resistant organisms to humans;
>
> 2\. Whether there are other issues to consider relative to this class
> of antimicrobial agents fourth-generation cephalosporins; and
>
> 3\. If the risk management options we discuss are appropriate, should
> they be modified, or are there other risk-management options that we
> should consider.

Again, I want to express our appreciation to the Committee members, and
we look forward to hearing what you all have to say. If I can be of
further assistance to the Committee, or participants, please feel free
to catch up with me during the day.

And we will begin today's program by hearing from Dr. John Powers from
FDA's Center for Drug Evaluation and Research, who will talk to us about
the use and importance of fourth general cephalosporins in human
medicine. I will turn the mic over to Dr. Powers.

***[Use and Importance of Cephalosporins in Human
Medicine]{.underline}***

***by John H. Powers, M.D.***

DR. POWERS: Thanks, Steve. All of that delay because there is three
little references on the bottom of this in 2. font. You are not even
going to be able to read, but we had to get this information cleared
that I am going to show you about usage of cephalosporins in humans.

(Slide)

So, what I would like to go over with you today is a little bit of
background on cephalosporin antimicrobials. And looking through other
folks' slides, it appears that you are going to get a lot more of this,
so I tried to keep this as small as possible in my talk.

And then, talk a little bit about the uses of cephalosporins in human
medicine, both what they are FDA approved for, and then we actually went
and got some usage data on what they are actually being used for out in
the United States.

Then, talk a little bit more about, in addition to what Steve said about
the background on the ranking process of the ranking of these drugs,
according to their importance in human medicine, according to Appendix A
in Guidance 152, and then apply that ranking process to the
cephalosporins, both the third and the fourth-generations.

(Slide)

This is an interesting story of how cephalosporins were discovered.
Giuseppe Brotzu was a professor of public health in Cagliari in
Sardinia. And he was a pretty smart guy, and he was investigating two
things, malaria and typhoid-fever. And he was doing what had been done
with cholera almost a century before, he was trying to figure out where
the hot-spots of typhoid-fever were.

So, in doing this, he tried to culture the effluent from sewer water in
various parts around Sardinia. And what he noticed was that one of these
sewers in particular had a decreased concentration of Salmonella in the
water.

So, rather than just assuming this was due to dilutional effects \--
because as a smart guy, he realized, well, why wouldn't it be diluted in
all the other places too? He then took that water and actually put it on
culture plates and saw what he called, Virgin Patches \-- what we now
call zones of inhibition \-- on a petri dish.

And I am going to bring this up again because the initial organism he
was looking into was Salmonella typhi. And that becomes an important
consideration in what the drug may be used for as well.

So, the other interesting part about this was he discovered this in
1945, realized that he had something very important on his hands, a
product that he called, Myceton(\*), and then it took him 20 years to
find enough funding to be able to do anything with it. Does that sound
familiar to anybody?

And I am kind of bringing this up because I know Dr. Leggett and Reller
have been in our discussions about antimicrobial development on the
human side. And this is an article by [BO]{.underline} in the Clinical
Microbiology and Infection in 2000. And there is a quote from Brotzu
when he was talking to one of his colleagues where he was trying to get
funding. And he said:

> "He devised plans and projects for research and, in vein, sought the
> financial support of various institutional bodies. His quote was,
> 'They didn't even answer me,' he once confessed bitterly."

So, he ended up going into research with Florey Abraham in Oxford, and
then finally was able to develop cephalothin, which was the first
cephalosporin which was put into clinical use in 1964.

(Slide)

All of the cephalosporins have a very similar bicyclic ring structure.
The square ring on the left side is the beta-lactam ring. And, again,
you will see more of this than from me. But if this ring is \-\--, the
drugs lose their activity entirely. The second ring is a six membered
ring, which usually contains a sulfur atom at the one position.
Although, some of the cephalosporin-related molecules, like loracarbef,
have substituted a carbon in that spot.

The places that are most likely changed \--that change these molecules
\-- are the seven position and the three position, where various side
chains are added. Changes in this seven position changes this side chain
and causes stearic hindrance of that beta-lactam ring and makes it
harder for beta-lactamases to cleave that ring; and then, therefore,
allows the drugs to maintain their stability to that enzyme.

So, in other words, changes in that position change the spectrum of
activity of the molecule. The other changes that occur here are out at
the three position, and most of those, in general, affect the
pharmacokinetics of the drug, whether it penetrates into the cerebral
spinal fluid, et cetera.

So, there have been a number of these drugs then that have been
developed based on changes in that basic molecule structure. The
mechanism of action is that these drugs bind to penicillin binding
proteins and, therefore, inhibit formation of the cell wall of the
organisms.

Which is probably an incredibly over simplistic view of how these drugs
actually work. If all you do is inhibit the cell wall, the bugs don't
die. So there must be a second step that occurs, some people think that
these are enzymatic \-\-- that occur inside the cell that sort of
destroy the cell by suicide.

(Slide)

The mechanisms of resistance are related to those particular mechanisms
of action. The first one is changes in the penicillin binding proteins,
or the target of the drugs themselves.

And a good example of this would be methicillin resistant Staphylococcus
aureus, which is certainly in the news almost everyday these days. In
these organisms, the penicillin binding proteins have changed so that
the cephalosporins no longer bind to them.

The second one, which is rather uncommon, for cephalosporins is lack of
access of the drug to that target of the penicillin binding proteins.
One kind may be efflux pumps, where the drug gets inside the cell of the
organism, but gets pumped right back out again.

And an example of this would be the efflux pump in Pseudomonas
aeruginosa. There is also a multi-drug efflux pump in E. coli, which
seems to affect penicillins more than it does cephalosporins.

The second way of lack of access may occur is that there is decreased
permeability of the cell wall itself. The drug never gets in. And that
is less common for cephalosporins as well. But the major mechanism of
resistance for cephalosporins is alteration of the drug itself.

And the most common way this happens is hydrolysis of the drug by
beta-lactamase enzymes that cleave that four membered ring that I showed
you in the previous slides. The numbers and types of these
beta-lactamase enzymes have been increasing over the years, and these
can be either chromosomally mediated, or extra-chromosomally mediated on
plasmids.

And you will hear some more about this in other people's slides, so I
won't go into this in detail. The only important issue is that these
extra-chromosomally mediated forms of resistance are more easily
transmitted than the chromosomally related ones, and they can be passed
on even to entirely different organisms. Commensal organisms in people's
mouths, so that they can really become wide-spread.

The issue there is because of the ability of that resistance to spread,
resistance to one cephalosporin can result in resistance to the others,
depending upon that particular mechanism of action.

(Slide)

The other issue is that since all of the beta-lactam drugs, like
penicillins, all act in the same way, by binding to penicillin binding
proteins, resistance to cephalosporins cannot only confer resistance to
other cephalosporins, it may confer resistance to other beta-lactam
drugs as well.

(Slide)

Cephalosporins have been divided into generations for convenience, and
this is to the consternation of every medical student on the face of the
planet. Because the generation name has nothing to do with the chemical
structure of the drug, and they are very loosely related to spectrum of
activity. But that doesn't even really fit when you actually go through
it.

And this gave me fits when I was a medical student because every one of
the drugs begins with ceph-, and so it is very hard to put all these
together in your head. And there is folk-lore around the FDA that the
term generation was actually devised by a drug company in terms of
trying to say our drug is better than the one that went before it. So it
wasn't even something invented by us.

There are currently four generations of cephalosporins, but which
generation a particular drug belongs to is even a matter of debate. So
there is a wide generalization that with the increasing generations, as
you go from first, to second, to third, to fourth, that the activity in
the test-tube, at least against gram positive organisms goes down, while
the activity against gram negatives goes up.

That is a gross over-simplification, and it may be that the potency
changes, but actually differences in those in terms of clinical trial
data in patients is, actually, pretty lacking.

(Slide)

The first-generation cephalosporins \-- and I will show you some data on
this \-- are some of the most commonly used drugs out there in the
out-patient setting. They are also very commonly used on the in-patient
setting as well for surgical prophylaxis. They have both oral and
intravenous forums and, for the most part, they have in vitro activity
against E. coli, Klebsiella, and Proteus, which tells you pretty much
where those things are used.

They are mostly used for skin and soft tissue infections, urinary tract
infections, and respiratory tract infections. There are so many of these
that I thought I would spare you putting them all on a slide and just
put up the generalizations.

The second-generation cephalosporins had increased activity against some
of the beta-lactamase producing organisms, like Haemophilus influenzae,
and therefore, are used more in respiratory tract infections. And then
here is where the generational scheme starts to fall apart.

There are drugs that are really not even cephalosporins, per se, called
cephamycins, like cefoxitin, that have activity against beta-lactamases
producing Bacteroides fragilis that can be found in the human gut. So
those are commonly used either to treat or to prevent inter-abdominal
infections in terms of treating or surgical prophylaxis.

The third-generation cephalosporins, again, kind of defy this
generational scheme in that there are two classes within it. There are
those that do not have in vitro activity against Pseudomonas aeruginosa,
such as ceftriaxone and cefotaxime.

And the major benefits of these drugs were their changes in
pharmacokinetics, which allowed them to penetrate the cerebral spinal
fluid. So these drugs were used in acute bacterial meningitis.

The second group within the third-generations is anti-pseudomonal drugs,
which do have in vitro activity against Pseudomonas aeruginosa. And an
example of those would be ceftazidime, which are commonly used for
pneumonia in the hospital or empirical therapy in neutropenic patients
where Pseudomonas is an important organism.

In the United States, there is one fourth-generation cephalosporin drug
approved, and that is called cefepime. You will hear in a later talk
that there is also one called cefpirome, that is licensed for use in
Europe as well.

(Slide)

I thought I would try to give you a little bit, again, of a historical
background in terms of how important cephalosporins have been in human
medicine. And this is as far back as we can go, which is 1980. It
becomes much more difficult to track FDA approvals prior to that in
human drugs.

If you look on this, this is a color coding of all the new molecular
entities approved, or antibiotics approved since 1980 until the present
in human medicine.

And the one thing to look at is that all that yellow that shows upon
there are all beta-lactam class drugs. So you can see that during the
1980s the vast majority of that graph is yellow. So, there were between
1980 and 1990, there were 27 new molecular entities approved for human
use. Of those, 23 of the 27 are beta-lactam drugs, and 14 of those are
cephalosporins.

So you can see that the 1980s were kind of the age of cephalosporins,
and that a number of both intravenous and oral drugs became available
for use in human medicine. And again, one of the reasons was, as we went
up the generations, there was improved spectrum of activity, improved
pharmacokinetics where these drugs could be used in different
situations.

There were a number of oral drugs, however, that had very similar
activity as well. And you can see that even into the 1990s, the yellow
continues to pop up, and there were a number of cephalosporins still
developed.

We do sort of get into the age of the quinolones here in 1990s, where
they become the most common drugs. But five more cephalosporins were
approved in the 1990s as well.

If we then just look at amongst the beta-lactam drugs, what you will see
up here is the yellows are the penicillins, and you see they start to
trickle off in the beginning of the '90s, and all of this green is all
of the cephalosporins that have been approved since 1980s.

The reds are penam drugs, three of which have been approved since 1980
as well. So, again, you can see the vast majority of this is related to
cephalosporin usage.

(Slide)

I know this is hard to read, but I thought it was very apropos because
that is the way it is in labeling, everything is in 8. font, and it is
kind of hard to read. All I wanted you to actually look at here was the
indications for which the fourth-generation drug cefepime is approved
for humans in the United States.

So it is approved for pneumonia, moderate to severe. And this is, again,
usually since this is an intravenous drug only \-- this is usually used
in the hospital setting in seriously ill people.

And the additional benefit here is that this drug is approved for
Pseudomonas aureginosa. And as I will show you, the third-generation
drugs are not. It is approved for empiric therapy for febrile
neutropenic patients, and it is actually one of the only drugs of any
class that is approved for that indication. It is approved for
uncomplicated and complicated urinary tract infections, uncomplicated
skin and skin structure infections, and complicated intra-abdominal
infections as well.

(Slide)

I just put as an example up here, ceftriaxone as an example of a
third-generation cephalosporin. And the reason I wanted to do that is it
actually has a number of indications. And there is also a lesson in
this. And that is that cefepime was approved in 1996, ceftriaxone almost
a decade earlier.

And you can see how labels change over time. Instead of listing the
specific types of pneumonia, we now have just general grouping of
lower-respiratory tract infections for ceftriaxone. It is also approved
for acute bacterial \-\-- media. Again, this is before we divided up
skin and skin structure infections, and to complicated and
uncomplicated.

So, it has this one generic indication. Urinary tract infections and
uncomplicated gonorrhea. It is also approved for pelvic inflammatory
disease. And here is an indication that we don't even grant any more
called, bacterial septicemia. And I think Barth, you were even on the
advisory Committee where we decided that this really wasn't a legitimate
indication because all of these things occur in relationship to one of
these other infections that are listed in the label.

It is also approved for bone and joint infections, intra-abdominal
infections. And here is the major difference for this class of drugs
from the ones that preceded it. It is approved for acute bacterial
meningitis, due to a number of organisms. It is also approved for
surgical prophylaxis as well.

So you can see there was a wide usage of third-generation
cephalosporins. When this drug was approved, I was in my residency where
it was referred to as Vitamin C, since it was used so commonly. And it
has a number of advantages in terms of this is one of the only drugs
that is liver metabolized instead of renal metabolized and doesn't need
to be adjusted for renal insufficiency.

(Slide)

So, how are these drugs actually used? That is what it is approved for
in human medicine. And you will notice something is missing from that;
which I, actually, found very interesting when I went looking through
this. Even though Brotzu's first looking into these drugs, or
discovering of them, was in relationship to typhoid fever and
Salmonella. That is no where on the indication. Even though we know that
that is what people use these drugs for in a lot of indications.

And I think that brings up another issue for us in human medicine, and
it is one of, how do we get people to study these serious infections
where we really need the drugs, and try to focus on those areas.

So, beta-lactam antibiotics make up 40 percent of the total
prescriptions of antibiotics in the out-patient setting. The most
commonly used drug in the out-patient setting is still, good old
Amoxicillin. So, despite our issues with resistance, it is still used a
tremendous amount of the time.

Cephalosporins make up 14 percent of the total out-patient antibiotic
prescriptions, which accounts for over 50 million prescriptions per
year. And just a little background on how this is done, this is data
from Verispan where we, actually, get data on how many prescriptions are
written. Did people actually take all of these? We don't know, but it is
our best estimate of what is going on out there in the community.

The cephalosporins, when we look at the usage of what they are used for
in these prescriptions are mostly commonly used to treat out-patient
indications of pneumonia, skin and soft-tissue infections, sinusitis,
urinary tract infections, and otitis. So, of those most of those are not
lethal infections, except pneumonia has the potential to be in that
particular setting.

(Slide)

On the other hand, in the in-patient settings, cephalosporins are
diagnoses associated with billing, most often with a diagnosis of
pneumonia. And this is a different database, and this is what I said, we
had to change these slides because \-- if you can read that, good luck,
but that is what we had to add at the bottom of these slides.

And this is from the Premier database, which actually looks at ICD-9
billing codes. And, again, we don't know, if you have a billing code,
how well does that correlate with what the person actually has, but this
is our best estimate.

So, again, pneumonia in the hospital setting is, certainly, a severe and
life-threatening infection.

We looked at data from January of 2000 to December of 2005. Actually,
the most common drug, cephalosporin used in the in-patient hospital
setting, was cefazolin, which is a first-generation cephalosporin, and
is very commonly used as surgical prophylaxis. With approximately 37
million projected discharges receiving the drug.

The reason this is projected discharges is they look at a sample and
then expand it out numerically to look at the total population in the
U.S.

The third-generation cephalosporin cephtriaxon, had approximately 16
million projected discharges; and, again, with pneumonia being the most
common usage.

And the fourth-generation drug, cefepime, had approximately two million
projected discharges, with pneumonia being the most common billing
discharge for this drug, in approximately 157,000 projected discharges.

(Slide)

So the third and the fourth-generation cephalosporins \-- again, these
drugs are all intravenous, and they are used primarily in the hospital
setting in seriously ill patients, for serious and life-threatening
diseases. And many of these diseases are due to organisms that, although
they may not be transmitted by food, they are organisms that reside in
the gastrointestinal tract. \-\--, E. coli, Klebsiella, and other
Enterobacteriaceae.

These also are the drugs of last resort for serious infections, due to
food-borne pathogens, like Salmonella and Shigella. And, again, as I
mentioned, they are not FDA approved for those indications; however,
they are commonly used for those.

And the reason is is that these organisms may be resistant to other
classes of drugs other than cephalosporins and quinolones. But
quinolones may be effective in this setting, but they are usually
avoided in children due to their potentials for cartilage, joint
toxicity, et cetera.

And the one thing that is interesting about quinolones, is as we learn
more about them, we realize that, perhaps, as a class, there are safety
issues associated with them that are not present in the cephalosporins.

So, for instance, there have been 12 quinolone drugs approved since
1980, 5 of those are now off the market in humans due to toxicity
issues. And that is not the case with cephalosporins. So, in children we
may have only the third-generation cephalosporins left as a potential
treatment for serious Salmonella infections.

(Slide)

So how does this relate to Guidance 152? Well, in Guidance 152, the goal
is to preserve the usefulness of antimicrobials of greatest importance
in the treatment of human disease. So, Guidance 152 categorized the
drugs, based on their relative importance in human medicine.

And the drugs are ranked in Appendix A of that document as either
critically important, highly important, or important in human medicine.
And, again, notice we consider every drug as important in human
medicine, it is just a matter of relative importance.

And we looked at several factors to try to do that. And this is only one
factor in the hazard identification and consequence assessments in the
overall assessment of the drug within that risk assessment.

This Appendix A was developed by a Center for Veterinary Medicine and
Center for Drugs team that went through this criteria together to try to
categorize the drugs. And we thought that it was important to develop
criteria first, and then apply the criteria, rather than looking at the
drugs and coming up with a gestalt, and then trying to fit the drug to
the criteria. And that way, we could assure some fairness and a lack of
bias.

And there are some surprising things sometimes when you look through it.
Because when you really go through the indications of what the drugs are
looked for.

(Slide)

This criteria is presented in an open public meeting in October of 2003,
and at an Anti-Infective Drugs Advisory Committee in January of 2003.
And the criteria were refined based on the suggestions that we got at
both of those meetings.

And, again, as Dr. Sundlof pointed out \-- I was saying to Steve Vaughn,
it seems like yesterday that we were in this room, only rotated by 45
degrees \-- when we talked about this for a drug in 2004 and tried to
apply this criteria.

So, what are these criteria? There are five of them.

(Slide)

The first is that the antimicrobials used to treat enteric pathogens
that cause food-borne disease. So that means we are talking about an
illness that is actually transmitted in a food-borne manner. The second
is that it is the sole therapy, or one of few alternatives to treat
serious human disease, or the drug is an essential component among many
antimicrobials in the treatment of human disease.

This is not linked to food-borne pathogens in any way, but one of the
pieces of advice we got at the advisory committees was there are drugs,
like rifampin, that are used to treat tuberculosis \-- which, if we lost
those, would be an incredible public health issue. So that is why this
was put in there as a separate criteria all together.

The third is that the antimicrobials are used to treat enteric pathogens
in non-food-borne disease. So organisms like E. coli that are
transmitted by food, also cause things like urinary tract infections,
neonatal sepsis, meningitis. Even though those are not directly caused
by ingestion of food.

The fourth is that the drug would be more important if there was no
cross-resistance within the drug class, or an absence of linked
resistance with other drug classes.

And, unfortunately, that is becoming less and less common now-a-days,
where you see \-- or, co-resistance is probably a better word to call
it, where you have, for instance, resistance to a quinolone and there is
also resistance to a cephalosporin as well.

And then the fifth criteria would be the drug would be more important if
there was no cross-resistance within the drug class \-- oops, actually,
I repeated that one.

(Slide)

So, what would make something important? Drugs that meet both criteria 1
and 2 are considered critically important. Those that meet criteria 1 or
2 are considered highly important.

So, for instance, our rifampin example with tuberculosis would make a
drug highly important, even though that is not a drug we commonly use to
treat food-borne illness. And drugs that meet any of the criteria, 3, 4,
or 5, would be considered important.

(Slide)

So, how does this apply to fourth-generation cephalosporins? Well, the
fourth-generation cephalosporins are one of the sole therapies approved
for empirical therapy in febrile neutropenic patients. These are people
with cancer whose chemotherapy has knocked out their white blood cell
count, who are at risk for getting infections from any number of
gram-negative organisms from their own intestinal tract.

So, that meets criteria number 2. Criteria number 3 is these are used to
treat diseases that are due to enteric pathogens even in the
non-food-borne setting. For instance, E. coli pneumonias. So, since it
meets both criteria 2 and 3, these drugs are considered highly
important.

And, again, these are not often used \-- specifically, do we use
fourth-generation cephalosporins to treat gastrointestinal diseases, or
food-borne illnesses. The issue, however, becomes about the issue of
cross-resistance between third and fourth-generation cephalosporins.

The third-generation cephalosporins are used to treat, at least in the
practice setting, used to treat typhoid fever and gastrointestinal
illness due to Salmonella and Shigella. Although, again, as I mentioned,
they are not FDA approved for that indication. And they would be one of
the only therapies for that usage in children who would not be able to
take quinolones.

They are the sole or limited therapy to treat serious diseases, such as
acute bacterial meningitis. And, in fact, there are few other
alternatives at all in human medicine to treat meningitis due to
gram-negative organisms.

They are also one of the sole therapies to treat disease due to
Salmonella or Shigella in children, as we mentioned. Also, these are
used to treat diseases due to enteropathogens in non-food-borne
situations, such as, again, gram-negative meningitis, or complicated
urinary tract infections that could be caused by E. coli.

So, these drugs meet criteria 1, 2, and 3, and, therefore, they are
considered critically important. Basically, based because they meet
criteria 1 and 2.

(Slide)

The issue here, and you will hear some more about this today, is that
resistance to fourth-generation cephalosporins may confer resistance to
all of the other cephalosporins, including third-generation
cephalosporins. And, in addition, resistance to those may also confer
resistance to other members of the penicillin class as well.

So, it could have a much more far-reaching effect than just that
particular fourth-generation cephalosporin class.

(Slide)

So, just to sort of put another note on this, after Guidance 152 was
issued, the World Health Organization convened a meeting, to which
members of CDC and FDA attended, to rank the drugs according to
importance in human medicine on a global basis.

And this effort used a different, but related, set of criteria. It took
the same tack of coming up with criteria first and then applying it, but
came up with some different criteria. The two criteria were that the
drug was the sole therapy, or one of few alternatives to treat serious
human disease. So this criteria doesn't have this direct linkage to
food-borne disease at all.

Or, that the antibacterial is used to treat diseases caused by organisms
that may be transmitted via a non-human source, or diseases caused by
organisms that may acquire resistance genes from non-human source. So,
this criteria has a much broader reach.

It is taking into account this issue of cross-resistance and saying,
even if the E. coli in the human intestine didn't come from an animal,
if it could get resistance determinants from an animal, that would be an
important issue for human health as well.

So, meeting both criteria defined the drug as critical, and meeting one
or the other defined it as highly important. And then this document also
outlined the organisms that we should be most concerned about that could
meet those criteria. Namely, E. coli, Salmonella, Campylobacter,
Pseudomonas, and Enterococcus, but makes a notation that it doesn't
exclude other organisms as well.

So, based on these criteria, both the third and the fourth-generation
cephalosporins are ranked as critically important in the WHO ranking
document.

(Slide)

So, in conclusion then, cephalosporins are one of the most widely used
drug classes in the United States and world-wide. And one of the most
common out-patient drugs that are used. And, again, they are also
commonly used in the in-patient setting for serious diseases, like
pneumonia.

The mechanisms of resistance, which you will hear more about today, to
cephalosporins, may also confer resistance to other beta-lactam agents
as well; including, other generations of cephalosporins, and other
penicillin-like drugs.

The ranking of the fourth-generation cephalosporins as highly important,
and third-generations as critically important in Guidance 152. They are
both considered critically important according to the WHO criteria.

And the ranking of antimicrobials accordance to human medicine is one
factor in considering an overall risk-management strategy for drugs in
animals, according to Guidance 152.

It is always interesting to me that when you give one of these talks,
you show one slide, it goes by in about 20 seconds. And then you start
to realize how much work went into putting all those numbers up on the
slide. So, those two slides I showed you with drug usage took a lot of
work from a lot of people that I wanted to thank.

Our Office of Surveillance and Epidemiology in CDER was very helpful in
putting this information together. Rosemary Johann-Liang is the Deputy
Division Director there, and Vicky Borders-Hemphill; Laura Governale;
and Carol Pamer were the medical officers who were exceedingly helpful
in helping us put this information together. Thanks.

(Applause)

***[Importance of Cephalosporins in Veterinary]{.underline}***

***[Medicine with a Focus on Cattle Production Systems]{.underline}***

***by Kelly Lechtenberg, D.V.M., Ph.D.***

DR. LECHTENBERG: Good morning. Mr. Chairman, esteemed members of the
Committee, and guests, I would like to thank you for giving me the
opportunity to come visit with you this morning about the importance of
cephalosporins as a drug class in veterinary medicine.

My comments this morning will be quite specifically about feedlot
medicine, which is where I live, in my are of expertise. My name is
Kelly Lechtenberg. I come to you from Oakland, Nebraska, where I operate
a feedlot consulting practice, and have a small cattle-feeding
operation.

Part of our business is also involved in assisting the vaccine
manufacturers and pharmaceutical industries to help bring products
through the approval process by creating data that is used for those
approvals. And I am having a little trouble with advancing here. Maybe I
am just not patient enough. Thank you. Got it.

(Slide)

So we will be talking a bit about the U.S. cattle production systems
this morning. Quite specifically, about certain feedlot diseases that we
track and encounter in our production of livestock. Most particularly,
bovine respiratory disease \-- which you will hear me refer to by the
acronym BRD \-- how we manage the disease processes that we are
encountered with; how cephalosporins are used in our practice situation;
and quite specifically, how they are used to treat bovine respiratory
disease; and then pull together some concluding comments for you.

(Slide)

I grew up on a small family farm in North Central Nebraska, the last of
seven children. A Jeffersonian environment that doesn't exist very
commonly anymore. We had about 300 Hereford cow herd that we finished
those offspring through the fat-market.

We had about 50 sows we farrowed twice a year, and finished fat hogs as
well. Milked about a half a dozen cows. We even had about 300 layer hens
that I remember producing eggs for the family, in addition to selling
eggs in town.

So that doesn't happen very commonly anymore at all, to my knowledge,
and my family farm is now just a \-- my parents are still on it, it is
just a cattle ranch.

The production agricultural system that America has grown up with has
changed dramatically through the '60s and '70s, and has become much more
integrated in many sectors. This picture represents a success story to
me in the life that I lead now.

This is a pen of pretty uniform, healthy Angus steers that are getting
ready to head into the next part of producing the safe, wholesome food
supply which we enjoy an abundance of in this country. But the
production systems that cattle come through are quite different
philosophically from what poultry and swine production systems have come
through.

And we will talk a bit about how those sectors have developed
differently, and how those present unique challenges, depending upon the
part of meat production that you are discussing.

(Slide)

Beef cattle production systems remain quite segregated. We have cow/calf
producers, stocker operators, feedlot operators, and packers. And at
each one of those interfaces, cattle physically change locations and
move. And that represents stressors to the cattle and risk factors for
disease.

It exists that way because we have high equity business inputs in all of
those different sectors. There are traditionally profit opportunities
and challenges between those sectors, but most importantly, because our
first input to beef cattle production, you know, the baby calf, if you
will, is produced predominantly on cow/calf operations that have less
than 40 cows per herd.

That is because our grassland in this country, the grazing opportunity
to produce these cows is quite geographically distributed. So what that
means is our cattle feeding operations are going to have animals coming
to them that have geographic and genetic and immunologic diversity by
definition of our production system.

Take that a bit further, and what that means is consolidation of those
resources is quite unlikely over time; at least, in my foreseeable
future in my professional career. And the net result is also pretty
predictable. We have cattle who are co-mingling as virtually assured. In
other words, the coming together of animals from very diverse locations
into a common area for finishing, that also assures the pathogen
exposure, i.e., horizontal transmission amongst animals when they come
into these cattle feeding operations is assured.

I discuss this with my clients as similar to when children are coming
back to school in the fall of the year. If you want to place a bet on
when there is going to be a lot of illness present, it is going to be
about three or four weeks after school starts in the fall. And it is
like that in these cattle feeding operations, and it is like that pretty
much everyday of the week because we always have cattle coming in, and
we always have cattle going out.

Suffice to say, infectious disease will remain one of our major
challenges in the feedlot business.

(Slide)

If you look at a brief schematic, and this speaks to integration, and to
some extent, it speaks to animal movement. To the far right, the poultry
industry is quite integrated. There are multiple players in the market
but, generally, one person or one company has control from start to
finish, from the egg all the way, in some cases, to the fresh meat
counter, or to the frozen meat counter.

The pork industry, the commonality, there is integrator operations in
place, there is some segregation inasmuch as animals do move some in
these systems but, generally, the amount of horizontal transmission, the
stress on these animals, and the movement on these animals is very
limited today compared to what it was 20 years ago. And it is very
limited today, compared to the beef cattle industry.

The movement of the beef cattle industry hasn't significantly changed,
and for the reasons we have mentioned, I suspect it won't significantly
change. We have cow/calf operations. In our particular feedlot
operation, we tend to purchase a lot of our feeder cattle out of
Kentucky, Tennessee, the Carolinas. And they come to Nebraska to feed.
Well, they are originating on relatively small cow/calf operations.

And for us to have any opportunity for efficiency to provide the proper
care for those animals, we are going to group them into large groups so
that they are manageable in the feedlot sector. And then, ultimately,
there is one final transportation on to the packers. So, structurally,
there is some innate challenges and opportunities in our production
systems.

(Slide)

When we try to get a feel for the scope of morbidity and mortality that
we face, I have just a little bit of definition to do for you. A pull,
albeit slang, it is the common word that would be recognized in the
cattle industry. That speaks to an animal that is recognized in its pen
of contemporaries as being sick and has to be pulled from the pen and
come to the hospital. So that is usually a guy on a horse sorting a calf
out of a group of other cattle, one at a time, taking them to the
hospital.

A dead is pretty self-explanatory. That is a mortality for us.

The "Y" axis here represents a percent of inventory per month. So if you
hear later in this presentation, we talk about having morbidity rates of
12 to 20, to 50 or 60 percent, depending upon the cattle, the difference
between this scale and that scale is you just multiply that by how many
months the cattle happen to be in the feedlot; which is also somewhat
variable.

So let's not get caught too much up in the numbers, but recognize that
illness and death loss are part of our life year-round. This data is
feedlot cattle that our operation sees, primarily Nebraska and Kansas.
And this represents an average of about 16 years worth of data. So there
is some seasonality to disease, but there aren't any times that we get
to take a break and just stop going through cattle. It is a 365 day a
year process.

(Slide)

We will talk a little bit about the most common reasons cattle get
pulled from the pen. This chocolate colored cross-bred steer is having a
bad day. You may or may not recognize that, depending upon your
experience and your perspective. But this guy has got droopy ears, kind
of a dull eye.

If you were to walk in that pen of cattle, he is not going to move away
from you, he has changed his flight zone, if you will. He is not feeling
well. Normal temperature for cattle is around 102 to 103, this guy may
well be at 106 or 107 degrees rectal temp.

He has acute fibrous pneumonia starting. If proper antimicrobial therapy
is put into place soon, we'll expect that calf to have reduced fever and
probably be at the feedbunk by tomorrow morning. If not, we would expect
that five, or six, or seven, or eight days later, he might succumb to
pneumonia and die. Or, he may continue to get a little worse, and a
little worse, and a little worse until ultimately he succumbs to the
infection.

So this is our most common cause of morbidity in the feedlot. This is
bovine respiratory disease. If this were a live footage, you could see
this guy is breathing kind of hard.

(Slide)

The second most common category for the reasons that we pull cattle from
the feedlot pens are lameness. Just for example, we are looking at the
bottom of a feedlot cow's foot that has been cleaned up. And you can see
that we have got kind of a nasty infection going here between his toes.
We call it infectious pododermatitis, or foot rot. It is not the only
cause of lameness, but it is one cause of lameness and lame/injury is
our second most common category; but still very small compared to BRD.

(Slide)

The third categorical reason that cattle become sick and/or die is a
digestive or metabolic disease, as exhibited by various different
sequelae. This picture happens to represent a slice of liver that has
small areas of focal necrobacillosis. That is a sequelae of
rumenacidosis, the digestion process where the gut becomes accessible to
this particular anaerobic bacterial infection.

Laminitis, or founder, other sequelae also exist, but as a categorical
reason to pull cattle, that comes in number three in our data-set. So,
if we look at those graphically, again, same type of chart, months of
the year, 16 year summary, the blue bars represent cattle that are
pulled and treated because of bovine respiratory disease.

As a percent of all the cattle pulled, you can see that the
preponderance of reasons that we are going through those cattle on
horseback every day is to find these guys. We are trying to have an
early intervention opportunity to prevent the development, and the
continued progression of respiratory disease, the suffering, the death
that goes along with that.

(Slide)

I have a slide entitled BRD by the numbers. To recognize that the beef
industry is terribly important to this country, U.S. consumer spending
tops \$70 billion. That is notable. The cost of BRD has been estimated
to exceed \$1 billion, just on cattle here in the U.S.

Estimates of cost-per-head, \$13.90, or somewhere around \$400 million
on the 29 million head of cattle that we feed. And this particular
journal publication by [Animal Science]{.underline}. And that excludes
the cost of labor and handling costs, and all those other costs that
make up the different between this math and this math.

So it is a very important disease to us, not only for care of the
animals, but also financially for our industry.

(Slide)

Why do we have BRD? The etiology. We have some major viruses that are
involved in BRD. You will hear the disease referred to as BRD complex
also because it does involve a complex of factors. Often times, those
start with viral infections, infectious bovine rhinotracheitis is a
herpes virus infection. And it acts in these animals, much like herpes
virus infections in humans do with their effect on respiratory tract in
this case.

Bovine virus, diarrhea virus, types I and II are immunosuppressive
viruses. The most common corollary I would come up with, from an
immunologic perspective, these are the AIDS viruses of cattle; although,
they are cleared fairly easily, and the animals respond. With time, will
heal from those viruses. They are very immunosuppressive and they can
set these animals up for bacterial pneumonias.

The major bacterial pathogens of interest are Mannheimia haemolytica,
Pasteurella multocida, and Histophilus somni, tend to develop
consolidative acute, potentially fatal, pneumonia in these cattle. But
it is also important to recognize that the bacteria, in order to set up
what we'll recognize as clinical disease, often stress is a part of
that. Much like it is in human medicine.

The stressors that inhibit our body's immune system, and our ability to
respond to the challenges are very important to these cattle. So, we do
everything we can from a management perspective to minimize that stress.

(Slide)

Our patients don't get brought in the back of the mini-van, we have to
go find them. This is a picture taken from the saddle of a horse in the
process of going through these cattle, asking the question, who is not
feeling well today? Who has dyspnea, signs of depression, muscle
weakness that are telltale signs of BRD?

And our goal is to find those animals, confirm the presence of
respiratory disease with ancillary diagnostics that might be as simple
as taking the rectal temperature of those cattle, but case definition is
extremely important to us. So, a tremendous amount of my life is spent
training our animal healthcare people, the feedlot cowboys, if you will,
how to and continue to retrain so that we get this process right.

And the reason that we want to get it right is therapeutic efficacy
isn't about using the right drug, it is not that simple. It is early
detection of the calves that need therapy, early access, getting those
cattle out of the pen so we can get them to the hospital and get
antibiotic into them.

Early therapy. I should say early effective therapy. And then what might
fall as unrecognized is extremely important, and our cattle producers
know it is important. And that is successful therapeutic support. We
bring those cattle to the hospital, we put them in an environment that
is less competitive for the feedbunk and the water tank. And better
bedding, better housing, better everything we can do to help these
animals respond to their infection.

(Slide)

We have several products available to us. Ones that I have classified as
"older." Pick a number, I used 10 years. If you use 10 years and you
look at cattle approvals, we have had these products around as a group
for quite awhile. Beta-lactams that include the penicillin and its
derivatives, and ceftiofur sodium.

Ceftiofur is a third-generation cephalosporin that was launched just
shortly after I got into veterinary practice, when I graduated. We have
sufonamides, tetracyclines, macrolides, erythromycin, tylosin,
tilmicosin. So all those are products that have been around awhile, and
still find use.

Newer injectable products, and we are talking about injectable
therapeutic, single-treatment regimented administrated products where we
are not discussing things that would be administered through water or
feed. But these are all therapeutics.

Beta-lactams, we have two new formulations of ceftiofur, and the
hydrochloride, and the crystalline-free acid form. We do have two
fluoroquinolones approved in this country, danofloxacin and
enrofloxacin. We also have florfenicol, spectinomycin as the
aminocyclitol, and a relatively new macrolide, which you held a VMAC on
here not too long ago, and that is tulathromycin.

(Slide)

I mentioned that we have these products available, and so the process of
selection is the job of the veterinary consultants caring for the
cattle. Recognize there are differences in the feedlot operations
because they tend to feed different classes of cattle. It is not a
situation of what is the best drug in 2006 to use for BRD. That is the
best drug for that class of cattle.

Based on our response rate, as you would probably have guessed, the
industry has become quite technical. Computerized record systems are the
norm, where we have tracking and the ability to know specifically which
animal is treated on which day, what their rectal temperature was.

In some cases, how clinically severe did they present in terms of a
scoring system. We can, and do, analyze that data with respect to
response rates, so this is not anecdotal, gee, doc, what do you think is
working today? There is an increasing level of science going into that
assessment.

There are also product attributes that affect our product decision.
Without going into detail, if the wind-chill is 20 below that day, it
doesn't do me a lot of good to use a product that is so cold you can't
get out of the bottle if you have been out in the chute for awhile. So
there is product attributes that go beyond just response rate.

Safety of the product, the antimicrobial spectrum, relative to what we
have, what we are dealing with in that particular group of cattle. Their
route of administration, the dose volume, how easy it is to administer,
because we are talking about animals that might be 1,000 pounds. You
know, 500 to 1,000 pounds, so we want something that we can handle and
do this easily.

The withdrawal period needs to be appropriate for how long those cattle
are going to be in the feeding operation with us. And then availability
of products.

I have, personally, had experiences where we have had treatment regimens
in place that are serving us very well, had a staff trained and
comfortable with the process, only to have products become unavailable.
And you can imagine, there is various reasons, other than we forgot to
order some more, or the products might become unavailable.

In this particular situation of which I speak, it was several months
that we went without a drug class that we would like to have been using,
and justifiably, had in a regimen. So that is from a practical
standpoint, that is an issue for us.

(Slide)

So what factors affect how well the cattle respond? You will recognize
our trophy cattle over here, kind of the goal. I also want to show you a
notch worse. This isn't just about economics. As veterinarians, you
know, we commit to an oath of animal care, and humane treatment.

This is a calf that looked normal yesterday. BRD can be rapidly
progressive. This guy is sunken flanked, he is showing signs of
dehydration. He is, obviously, depressed. If you look at his headset and
his earset, we need effective therapeutic antibiotics for our practice
of veterinary medicine in these animals.

(Slide)

So what factors effect that response? We have talked a bit about the
diversity that we see in age and quality of the cattle. The shipping
stress \-- and when I say that I mean, did these cattle load on a ranch
in Western Nebraska at 2:00 in the afternoon after the sale, and arrived
at a our feedyard at 5:00 that evening, or 6:00 that evening, and we
have them available for our processing procedures?

Or, did they go through marketing channels somewhere further distance,
and have it be two or three days before they actually arrive at the
feedlot?

Did their truck get caught in a snowstorm in what should have been a 12
hour truck ride, turned into a 36 hour truck ride? There are certainly
many stressors that are beyond our control and our ability to manage,
but we are still challenged with doing the best that we can do.

What kind of a nutritional program did these cattle have on the ranch or
the background, or that they came from? How diverse was their immune
status? What is the stage of the disease before we actually get to
administer therapy to a calf? That is not a matter of just being a good
pen rider, or a bad pen rider. Some of these cattle, God made them
pretty fractious and wild, and some he made pretty docile.

The wild ones are pretty stoic, they don't show you they are sick until
they are very sick. And so there are processes that occur that affect
the stage of disease which we are able to access and treat these cattle.
And that is all part of the training process and the things that are
challenges to us in the business.

(Slide)

I hope this slide projects well enough. This is what we are talking
about inside the animal. This is a consolidated hemorrhagic, large
portion of this calf's lung, with a nice fibrous, what will be
eventually an adhesion on the surface between that lung and the rib
cage, if you will. That is acute fibrous bronchopneumonia.

And if we have to assess our response by looking at very many of these,
the answer is we are not doing a very good job. But, certainly, looking
at mortality and doing autopsies, or necropsies, as we call them, is an
important part of our assessment tool.

The most common though is to look at the hospital pen and how cattle
have responded to our therapy in the days following therapy. What is our
mortality rate, what percent of these cattle fail initial therapy that
have to come back and become what we call retreats or re-pulls?

(Slide)

A gentleman that I have a lot of respect for that many of you probably
know is Dr. Bob Smith. Bob compiled some comments for a publication in
'96. That might sound a bit dated, but it is pretty accurate still.

Response rates in some yards of high-risk cattle might be as low as 55
to 86 percent of first therapy. That is cattle that were treated and
never have to come back to the hospital situation again. So that is
single therapy successes.

Yearling cattle tend to be quite a bit higher than that, but in
high-risk cattle, that is pretty representative. The difference is, and
this is an important comment that I agree with, were not due to
antibiotic failure. And what he means is, it is not a susceptibility
issue, it is more a timing issue as he paraphrased by saying how long it
took to put cattle together. Accumulate them and get them to the
feedlot.

(Slide)

He goes on to state the cattle that died within four days of initial
therapy were probably late pulls. So it is a progressive disease, and
early intervention is critical for us.

Cattle treated within five days of shipping \-- in other words, if they
get sick as soon as they come off the truck, they have a higher chance
of relapse and being mortalities than animals that have been with us
much longer before they become sick. And that really supports what we
have been saying.

If we can shorten that exposure process before we have a good assessment
tool, we and the cattle are much better off.

Case fatality rates, and in that particular paper he talks about being
six to eight percent, that is the percent of cattle that die relative to
those that become treated. The numbers that you will see in our data-set
are smaller \-- or that you have seen in our data-set \-- are somewhat
smaller than that. That is accumulation of all young cattle and older
cattle, placed on feed, so it tends to get diluted a bit.

The point is there is a tremendous amount of variation within groups of
cattle that come through this process.

(Slide)

If we shift gears a bit and talk about cephalosporin use in veterinary
medicine, we do have some first-generation products available.
Cefadroxil in dogs and cats, cephapirin is an intra-mammary infusion in
dairy cows.

Then we jump to third-generation cephalosporins. Cefpodoxime is an oral
for dogs. And then kind of the topic of the day, if we get back into a
product that has application for use in feedlot medicine, ceftiofur in
its different formulations, sodium hydrochloride, and the
crystalline-free acid. So those are where our uses are.

(Slide)

And then when we look at NAHMS, National Animal Health Monitoring System
data, this is the most recent data available through NAHMS, it is 1999.
Discussion and the survey was done on 12 major cattle feeding states,
with 520 feedlots; which is about 85 percent of the total U.S. feedlots
and represent about 96 percent of the fed cattle. So, a very broad
survey.

And you will notice again that 29 million head of cattle on feed
supported our previous comments and our data, that bovine respiratory
disease is the most common cause of illness, regardless of the size of
feedyard.

(Slide)

When asked if feedlots use antibiotics for metaphylaxis, just a little
over 40 percent said yes they do. And that involved about 10 percent of
the cattle. Now, metaphylaxis is early therapeutic intervention. This is
the FDA's control claim for certain antimicrobials. And the idea is,
because we have talked about stoic cattle, or wild cattle that don't
show signs of illness yet, are highly at-risk. And this is an assessment
of the veterinarian. At risk of becoming ill.

When you see the word metaphylaxis, that is what the reference is to.
So, when asked the same question about therapy, 100 percent of the
feedlots said that they used antibiotics for therapy of BRD. And that
involved about 14.5 percent of the calves, of the total population in
that survey.

(Slide)

Drilling down a bit further, talking specifically about cephalosporins
and the metaphylaxis question, the response was about eight percent. So
about eight percent of the feedyards in that survey are using
cephalosporins for metaphylaxis involving about five percent of the
cattle placed on feed.

From a therapeutic treatment standpoint, about eight percent of the
feedyards were using cephalosporins in their treatment regimen. About
six percent as their first-line or their primary therapy. And you will
also see that there is some utilization for re-pulls and retreat data.

(Slide)

Similar data, 2002 NAHMS data in weaned dairy heifers. Twenty-one major
dairy states, these represent about 83 percent of the dairy operations,
and about 86 percent of the dairy cows. The dairy cows, the
representation, this data is on weaned heifers coming through those
operations, however.

And we are talking the pool size of discussion, it is about 3.8 million
head of heifers.

(Slide)

When asked questions about BRD and their therapy, about 95 percent say
they will use antibiotics as BRD therapy. And because the management and
the handling and the movement of dairy heifers is much, much different
than beef cattle, you will recognize that a much smaller percent of
these animals need to have therapy; although, when they need therapy,
almost 100 percent of them use antibiotics to treat it.

(Slide)

Again, the cephalosporin questions. Primary antimicrobial therapy in
just under five percent of the dairy operations. In that part of the
survey, just the way the questions get asked, it comes back to about 5.6
percent of the weaned heifers. So, regardless of whether it is 4.7 or
5.6, the point is these are not commingled, they are fairly low-stress,
pretty highly managed, and we don't need relatively nearly the amount of
antimicrobial therapy in those weaned dairy heifers as we do feedlot
cattle.

(Slide)

So, from a personal perspective, one of the reasons that I like, and I
use cephalosporins \-- you know, the first two are a given. Because we
are talking about approved products that have come through the approval
process. We know they are proven safe for animals, we do target animal
safety studies to document that. Human safety, the residue studies to
document that, but also user safety is very important.

And at least with respect to the cephalosporins that I am aware of in
veterinary medicine, these are safe products for our people to handle.
And then that is part of our charge as well, as we have some roles in
management recommendations in these feedyards.

(Slide)

Looking specifically at the use of cephalosporins for BRD, looking a bit
at labels, ceftiofur sodium, tradename Naxcel, and Ceftiofur
hydrochloride is EXCENEL. These are labeled for \-- and you will
recognize the genus and species names of radiology for BRD, but also for
Fusobacterium necrophorum and Bacteroides melaninogenicus for footrot.
That infectious foot rot slide that we saw. Short withdrawal products,
very easily used in our feedlot environment.

(Slide)

There is a new label claim, crystalline-free acid, a tradename of
Excede. Again, a BRD claim, with a slightly longer withdrawal.

(Slide)

In conclusion then, I would like to leave you with a few comments. BRD
remains a major health threat to our U.S. cattle industry. I suspect for
the rest of my professional career, that is going to be the main topic
of conversation. And I believe that because the production dynamics of
cattle in the U.S. almost mandate that that be the case.

Early diagnosis and effective treatment for BRD is critical to achieve a
positive clinical outcome. So, we need safe, effective antimicrobials to
help care for these animals.

(Slide)

Safeguards are in place to provide and document the use of these
antimicrobials, that they are safe. And when I talk about safeguards, I
am talking about the data capture systems, the computerized
recordkeeping that we do. The fact that we don't have to wonder if our
patients took their antibiotic today.

We don't send them back to their pen with a packet and say, you know,
once a day for 10 days. I would argue that our compliance with dosing is
something that isn't that common on some of the other antimicrobial
uses. So, dosage compliance is an important part of that safeguard.

I am proud of our industry's challenge to be prudent stewards of the
antimicrobials that we have been entrusted with. I am a member of the
NCBA's Beef Quality Assurance Task Force, and a tremendous amount of
effort goes into training and documentation. The willingness of our
producers to embrace the technologies and the training programs is
pretty impressive, so I am proud to be part of that process.

(Slide)

Cephalosporins have a proven safety record in veterinary medicine, and
they share a significant part of our BRD market. I think it is important
that we have a competitive range of cephalosporin class products that
will allow veterinarians to decide on specific therapeutic regimens, and
also to help ensure product compound availabilities in the class.

And I thank you for your time and attention this morning.

(Applause)

MS. SINDELAR: Thank you everyone. Let's take a 10 to 15 minute break. So
that makes, what do I have here, by 25 after 10:00.

(Whereupon, a short recess was taken)

MS. SINDELAR: If everyone could please come in and have a seat.

(Pause)

MS. SINDELAR: We can begin. We have Drs. Johnson and Bryskier up here.
Could I please have Drs. White and Gilbert. Let's see, do we see Dave
White? He is out there.

(Pause)

MS. SINDELAR: Thank you. Here he comes. Dave, could we please have you
up at the podium? Thank you.

So we will lead off with the second portion of this mornings' meeting
with Dr. Carl Johnson, Director of Product Development and Regulatory
Affairs at Intervet. And he will be followed by Dr. Bryskier,
Consultant, Infectious Diseases. Thank you.

***[Introduction to Cefquinome and Overview of the Microbial Safety
Assessment]{.underline}***

***by Carl Johnson, D.V.M.***

DR. JOHNSON: Mr. Chairman, members of the Committee, other interested
parties, thank you for this opportunity to discuss with you a new
antimicrobial that Intervet is developing for veterinary medicine in the
U.S.

(Slide)

My objective this morning is to introduce you to cefquinome, a
fourth-generation cephalosporin for use in cattle, and to provide you
with an overview of the microbial safety assessment of this compound,
following FDA's CVM Guidance for Industry #152, which has been reviewed
already by the agency as you are aware.

Following my presentation, Professor Andre Bryskier here to my left will
give you a perspective of fourth-generation cephalosporin use in Europe,
where these compounds have been used concurrently in both human and
veterinary medicine since the early '90s.

(Slide)

In this slide, we have an overview of the molecular structure of those
cephalosporins available in veterinary medicine in the U.S. Without
getting into the detail, and I think you have seen a little of this
already, the key thing to note here are the importance of the
side-chains that are adjacent to the cephalosporin core, which as you
have learned, improve the spectrum of activity of the drug, provide
pharmacokinetic advantages, and reduce the potential for resistance
development.

Structural similarities, similarities in spectrum of activity have,
between various cephalosporins, have lead them to this loose grouping of
compounds, referred to as generations.

(Slide)

Here is another view of the molecular structure of a fourth-generation
cephalosporin. And what is important to note here, and what is different
from its predecessors, is this zwitterionic nature of the molecule.
Where you have opposing positive and negative charges in this side-chain
here.

This non-polar feature of fourth-generation cephalosporins convey
specific advantages.

(Slide)

The non-polar zwitterionic structure of fourth-generation cephalosporins
results in a faster penetration of the outer-cell membrane of
gram-negative bacteria, a lower affinity for beta-lactamases, and a more
rapid binding to penicillin binding proteins.

The net result is enhanced antimicrobial activity of fourth-generation
cephalosporins.

(Slide)

Cefquinome is a fourth-generation cephalosporin that has been developed
exclusively for veterinary medicine. In Europe, it has been on the
market since 1994 in cattle, followed by swine in '99, and horses now in
2005.

In the U.S., there are pending applications for the treatment of bovine
respiratory disease with two different injectable formulations by
prescription only.

(Slide)

Cefquinome will not be developed for applications via the feed or water.

(Slide)

This schematic provides a visual display of the mode of action of
beta-lactams in general. And you have heard a little of this already,
but as mentioned earlier, what distinguishes cefquinome from first or
third-generation cephalosporins is the relative ease it has in
penetrating the outer membrane protein, via these porin tunnels.

A lower affinity for beta-lactamases in the periplasmic space, which can
inactivate other beta-lactams or cephalosporins. And a more rapid
binding to penicillin binding proteins of the cell wall.

And once cell wall synthesis is compromised, cell death occurs.

(Slide)

I would like to shift now and move to giving you an overview of the
microbial food safety assessment we have done for cefquinome. So now,
with a little better understanding of fourth-generation cephalosporins,
and cefquinome, in particular, I would like to take you through the
microbial safety assessment pertaining to the intended use of cefquinome
in cattle.

Please note, that this qualitative risk assessment closely follows
Guidance #152 for industry and, specifically, addresses only
fourth-generation cephalosporin use and not cephalosporin use in
veterinary medicine in general.

Following now, established methodology for conducting risk assessments,
we begin by defining the hazards and the conditions that influence its
occurrence. And once in agreement with CVM regarding the hazard
characterization and the described in Guidance #152, the process then
moves on to a release assessment; which characterizes the probability of
emergence of resistance resulting from the antimicrobial use in the
animal.

This is then followed by an exposure assessment, which describes the
probability of human exposure to the bacteria of concern, via food-borne
transmission; which is then followed by a consequence assessment, which
characterizes the potential that human exposure to resistant bacteria
results in adverse human health consequences. Which, in Guidance #152,
is determined by the medical importance of the drug class in humans. And
you have seen that already this morning.

The overall risk estimate then is an integration of the individual
assessments for which Guidance #152 characterizes the potential for an
adverse human health impact of the proposed veterinary use of the
antimicrobial in question.

(Slide)

To characterize the hazard, we first need to define the food-borne
pathogens of concern. And this is defined in the Guidance as the
antimicrobial resistant bacteria attributable to an animal derived food
commodity, and treated with human antimicrobial drugs of interest.

In this risk assessment, non-typhoidal Salmonella species are the
relevant food-borne pathogens of interest. And this is based on NARMS
survey data for which Salmonella is the sentinel organism. And the fact
that enteric salmonellae are susceptible to cefquinome.

While E. coli is considered in the release assessment, most E. coli, as
you know, is not associated with food-borne disease in humans. With the
rare exception, of course, of E. coli 0157:H7, for which antimicrobial
therapy is controversial.

Other well recognized food-borne pathogens, for instance, Campylobacter,
Enterococcus are not considered in this assessment since cefquinome is
not active against these pathogens to begin with.

(Slide)

To summarize the hazard characterization, consider the following
hypotheses: First, that the use of cefquinome may cause resistance in
Salmonella or E. coli present in the gut of the treated animal. Second,
that resistant Salmonella may contaminate the carcass and then be
transferred to humans via the food. And third, that resistant Salmonella
may cause infections in humans, and when treated with a
fourth-generation cephalosporin, the effectiveness of the drug is
compromised.

(Slide)

Skipping now to the final outcome, are reviewed by CVM and in agreement
with Intervet, the overall risk estimate is medium, or this is known as
a Category #2 drug in the assessment, for the proposed veterinary use of
cefquinome.

Note, that for antimicrobials assessed in Guidance #152, the risk
estimate will be shown to be high, medium, or low. The proposed risk
management measures then that follow will minimize this risk and reflect
prudent use guidelines. And there is, furthermore, reasonable certainty
of no harm to public health given the proposed use.

Now I would like to provide you with a brief summary of how we arrived
at this final outcome.

(Slide)

Following the steps in Guidance #152, we will look first at the release
assessment which was shown to be medium. In the release assessment, four
key facts support, at most, a medium release assessment ranking.

First, conditions of the proposed cefquinome use are limited. This is
intended for individual animal parenteral, short duration therapy for
sick animals.

Second, fourth-generation cephalosporins are active against most common
beta-lactamases found today. Those are the AmpC-type.

Third, fourth-generation cephalosporin resistance is very rare. To
achieve this, you need an outer membrane protein mutation, plus enhanced
beta-lactamase activity, or the presence of extended spectrum
beta-lactamases.

It is important to note that ESBLs, or these Extended Spectrum
Beta-Lactamases have not been identified in isolates from livestock in
the U.S.

And fourth, U.S. and European surveillance data, both from human and
animal isolates, continues to show a high-level of susceptibility of
food-borne pathogens to fourth-generation cephalosporins.

(Slide)

Data generated in development work with the compound is shown that only
a small amount of cefquinome enters the gut of treated cattle. And
furthermore, there is inactivation of the compound when it presents
itself in the gut.

Also, given the prescription-only status of the product in the short
duration of therapy, only limited exposure of enteric pathogens to
cefquinome is possible.

(Slide)

As described earlier on, fourth-generation cephalosporins remain active
against pathogens which harbor many common beta-lactamases, such as the
CMY-2 and AmpC-type beta-lactamases associated most often with
Salmonella and E. coli from livestock.

CMY-2 inactivates most beta-lactam drugs, including third-generation
cephalosporins, but not fourth-generation cephalosporins, or
carbapenems.

Furthermore, cefquinome does not induce AmpC-type beta-lactamase
resistance. In the case of extended spectrum beta-lactamases, which are
known to be associated with fourth-generation cephalosporin resistance
in humans, ESBLs have not been found, as mentioned earlier, in isolates
of Salmonella or E. coli from livestock in the U.S.

And then to summarize, fourth general cephalosporins are active against
the predominant beta-lactamases, and do not select for these. ESBLs are
not associated with enteric pathogens of livestock.

(Slide)

Also, with respect to resistance development, high-level,
fourth-generation cephalosporin resistance requires either, as mentioned
earlier, a combination of a non-transferable chromosomal mutation in the
outer membrane protein, and enhanced beta-lactamase activity.

Or, the specific presence of certain extended spectrum beta-lactamases
that confer fourth-generation cephalosporin resistance.

Such conditions are rare, and as mentioned earlier, since ESBLs are not
found in the livestock, Salmonella and E. coli isolates in the U.S., the
likelihood of development of fourth-generation cephalosporin resistance
is remote.

This statement is supported by surveillance data, which we will look at
next.

(Slide)

Intervet has been actively supporting the collection of enteric
Salmonella and E. coli susceptibility data for both cefquinome and its
surrogate fourth-generation compound in human medicine, cefepime, from
both animal and human isolates.

From animals, human isolates have been tested in the EASSA survey, after
several years of being on the market. And you will hear more about this
from Professor Bryskier following my presentation.

And in a research study separate from the official NARMS Program, U.S.
isolates have been tested using NARMS Salmonella slaughter isolates, and
this work has been ongoing since the year 2000. Intervet also has
conducted a susceptibility survey of E. coli isolates from U.S. feedlots
in 2002.

A glimpse then at this U.S. data in the next slide will clearly show
that there continues to be a high-level of susceptibility to cefquinome.

(Slide)

Now I would just like to bring your attention to this number here. This
needs to be 0.15 instead of 0.05.

This table summarizes the data generated from the NARMS slaughter
isolates for Salmonella that was included in the microbial food safety
assessment for cefquinome.

I would like to mention that this work was conducted in the USDA labs of
Dr. Paula Fedorka-Cray, and fully funded by Intervet. Furthermore, it is
separate from the official NARMS Program, and was conducted with the
full knowledge of CVM.

You will see here that both the MIC50 and MIC90 for cefquinome remains
very low and oscillates at most by one dilution step between years.
Outside of what was available at the time, the microbial safety
assessment was reviewed in the year 2003, this surveillance work
continues on and more recent isolates reflect the same high-level of
susceptibility.

(Slide)

Turning now to human Salmonella and E. coli isolates of U.S. origin,
data generated by the Century Program and by the TSN Program now Focus
Bio-Inova, demonstrate much the same. Greater than 98 percent of the
human enteric Salmonella and E. coli isolates surveyed are susceptible
to cefepime, the only fourth-generation cephalosporin used in human
medicine in this country.

As was the case for animal isolates, outside of what was considered in
the microbial safety assessment reviewed by the agency, surveillance
data from human isolates continues to be compiled, and the picture also
has not changed.

(Slide)

To summarize then a rather extensive review of the potential to develop
resistance to fourth-generation cephalosporins from the targeted use of
cefquinome in cattle, I would like to say that exposure of enteric
pathogens in the gut of cattle to cefquinome is limited, at best, that
cefquinome does not select for the most prevalent beta-lactamase
resistance mechanisms. And the much less common extended spectrum
beta-lactamases are not associated with food-producing animals in the
U.S.

Selective pressure then to develop fourth-generation cephalosporin
resistance is minimal, which is again, supported by surveillance data
from both humans and animal isolates.

While this portrayal of fourth-generation cephalosporin resistance
continues to look very promising, Intervet and the Center for Veterinary
Medicine agree that the release assessment should be conservatively
ranked as medium; which is based more on the potential to see resistance
develop in the future, rather than what we have demonstrated from past
and current data.

(Slide)

Returning now to the next step in the microbial safety assessment
process, we will briefly review the exposure assessments. According to
Guidance #152, the probability of human exposure to food-borne
Salmonella is assessed by considering both the contamination rates of
the food commodity, and the estimate of human consumption of that
commodity.

And to do this, we have looked at beef and milk as potential food-borne
sources of Salmonella. Due to pasteurization, a highly effective means
of hazard control, milk as a source of commodity contamination was not
considered further. So our focus narrowed to beef.

And from the table, based on USDA FSIS surveillance data, beef
commodities are all ranked low. Less than five percent in terms of
contamination rates. And I would like to note here that this is data
that was current as of the assessment through 2001. My understanding is
that these rates have actually decreased further.

Also, from Guidance #152, beef consumption in the U.S. is ranked high,
based on USDA economic research service data.

(Slide)

Together then, contamination rates and consumption data are integrated
in this table from Guidance #152 and yield a medium exposure assessment
ranking.

It is important to note here that Guidance #152 provides no further
refinement within this assessment category.

(Slide)

This conservative design of this qualitative risk assessment, therefore,
provides an extra measure of protection that is inherent in this
exposure categorization scheme, which is based on limited data.

And to illustrate this, for any beef or pork related commodity for that
matter, Salmonella exposure is fixed at medium. In spite of the low
prevalence of Salmonella, irregardless of serotype, the high variability
of consumption rates, which is a number based on total U.S. population,
and the fact that American cook their beef and pork before the consume
it.

(Slide)

Now on to the last assessment, that being the consequence assessment \--
or, in this case, the potential for resistant Salmonella to have a
negative human health impact.

Guidance #152 proposes that the consequence assessment can be
qualitatively assessed by simply ranking the relative importance of the
human drug of the same class. And you saw that this morning from Dr.
Powers.

Following Appendix A of this Guidance document, cefepime, also known as
Maxipime, developed by Bristol-Myers Squibb, is the only
fourth-generation cephalosporin approved for humans in the U.S. It is
administered IV for the treatment of multiple indications, including
respiratory disease, urinary tract infections, skin and skin structure
infections.

However, a relevance to this risk assessment are the indications for
monotherapy of neutropenic fever associated with nosocomial infections,
and its indication to treat non-food-borne related intra-abdominal
infections.

(Slide)

This chart summarizes the criteria considered for cefquinome, and all
fourth-generation cephalosporins from Appendix A. And which the human
drug classes are, as you heard earlier, ranked either critically
important, highly important, or important.

And for fourth-generation cephalosporins, cefepime in this case, the two
relevant criteria have yielded a highly important ranking. And this is
in contrast to third-generation cephalosporins, fluoroquinolones,
macrolides, potentiated sulfas, which are all ranked critically
important to human medicine, and all have been approved for use in
veterinary medicine.

(Slide)

Even so, the highly important ranking for fourth-generation
cephalosporins might be considered conservative, as there are multiple
approved antimicrobials used to treat Salmonella and E. coli infections
in humans, according to the Sanford Guide. And you can see that was
listed in this table.

(Slide)

Now, to conclude this part of the risk assessment exercise, the overall
risk estimation, as previously indicated, determined by this Guidance
document, is achieved by combining the results of the constituent
assessments. So, for release we have a medium ranking, for exposure we
have also a medium ranking. For consequence, we know the drug is highly
important to human medicine, yielding a net result or risk estimate of
medium, or a Category-2.

Intervet is in agreement with the agency on this ranking, which we
believe is conservative on the basis that the design of the Guidance
document is conservative by nature, the release assessment is based on
the future possibility of resistance development, and not what current
data supports, and there is a range of alternative therapies for human
conditions, for which fourth-generation cephalosporins might be used.

(Slide)

Now that we have a risk estimate, let's look now at risk management
considerations for Category-2 drugs. These drugs, as you can see by this
chart \-- again, taken from Guidance #152 \-- are marketed by
prescription, or by veterinary feed directive use only.

In some cases, extra-label use may be restricted. And this is stated
here in the footnote below that in such cases where the human drug of
the class is ranked critically important, and the proposed veterinary
use is ranked high for release or exposure.

Furthermore, the extent of use of these drugs is generally considered
low or medium. Post-approval monitoring will be instituted generally
through the NARMS Program, and a review of VMAC in certain cases may be
warranted. Usually, the same footnote you see below.

(Slide)

Looking now at specifically at cefquinome, and its two injectable
formulations under consideration in this microbial safety assessment
then, the drug will be marketed only by prescription, and there will be,
as you have heard earlier, individual animal parenteral use only for
therapy, and for short duration.

And this will result in a net extent of use as low, as we have seen.

(Slide)

Resistance development potential and human consequence potential are
both conservatively ranked as medium and highly important respectively.
Cefquinome will continue to be tested against NARMS slaughter isolates.
And this microbial safety assessment has, as you know, been critically
reviewed by CVM and agreed to.

And it is, furthermore, consistent with 152 and extra-label use
limitations are unwarranted.

(Slide)

In final summary, we have heard that the microbial food safety risk
estimate is ranked medium for cefquinome. The conditions of use and
proposed risk management measures are appropriate to minimize this risk
and consistent with proven use guidelines. And there is reasonable
certainly of no harm to public health with respect to the proposed
therapeutic use of cefquinome in veterinary practice.

Thank you very much for your attention, and at this point, I will turn
the podium over to Professor Andre Bryskier, who will give you his
perspective from Europe in terms of fourth-generation cephalosporin use
in humans and animals. Thank you.

(Applause)

***[Fourth-Generation Cephalosporin Use: Experience in
Europe]{.underline}***

***by Andre Bryskier, M.D.***

DR. BRYSKIER: Good morning Mr. Chairman and dear colleagues. First of
all to thank you to invite me as French and European person to share
with you our experience with so-called fourth-generation cephalosporin
in Europe.

(Slide)

For more than a decade, we are using so-called fourth-generation
cephalosporin in human and in veterinary medicine in Europe. Our
concern, like you will have, is how this type of drug will impact the
resistance of the difference on \-\-- or even \-\-- in your country. And
I will share with you what is happening in Europe.

(Slide)

First of all, we have to remember what is exactly the \-\--
cephalosporin. You know, the beta-lactam antibiotics is extremely used
family of compound. And Dr. Power showed you this morning how many drugs
were registered in 20 years in the U.S. It is exactly the same in Europe
and, perhaps, a little more because we take into account since the
\-\--.

So, this \-\-- now is for cephalosporin have more than hundred compounds
and in \-\-- of compound. This group could be divided in four: Penams
for penicillin; Cephems with cephalosporin; Cephamycins, Cephamycin is a
\-\--, Oxa-1-cephem is moxalactam, and carbacephem, \-\--, and isocephem
only recharge drug.

The third one is monocyclic beta-lactam with monobactam and one drug is
\-\--. The fourth class is penam, with two type of compounds. It is a
\-\--, which \-\--, and carbapenem, and carbapenem with \-\--, \-\-- in
the U.S. In Japan, there are four or even six compounds.

(Slide)

What is exactly the so-called \-\-- cephalosporin. On the chemical
point-of-view, they are classified as a C-31 quaternary ammonium cephem.
I will explain you in a few minutes what the difference.

And for everyday, I would say, \-\-- cephalosporin or extended spectrum
cephalosporin like for the \-\-- generation cephalosporin. But, as
pointed out earlier, Dr. Powers, you can say that generation is
extremely difficult in reality to \-\--. But, for the clinician, it
means something. In chemistry, not.

(Slide)

If you look at the shot, this shot seemed complicated, but in reality,
cephalosporin could be divided into three groups. The first one here is
so-called monoanionic cephem. And what does monoanionic cephem, that
means that you have only one shot \-\-- the group. And this global, you
have for human cefotaxime, ceftriaxone, and in veterinary, ceftiofur and
a derivative of ceftiofur, ceftriaxone, which is exactly the same
bacter, we just \-\-- less.

And, you have as pointed out previously, that the so-called \-\-- could
be divided into two. So you have this part, and the second part is with
\-\--, which is a dianionic cephem. And this dianionic cephem of good
property, especially, they have nitrogen here. And due to this nitrogen
chart, you have \-\-- against \-\--.

The third one of the so-called fourth-generation cephalosporin, here you
have a positive charge, and a negative charge. And these compound are
\-\-- compound. Inside, you have Cefepime, available in the U.S. In
Europe, we have Cefpirome. And in veterinary, \-\--. All share these
chemical structure, and all compound having this chemical structure are
considered a fourth-generation cephalosporin.

It is not only for a chemist, there is also some property behind this
denomination. First of all, all the cephalosporin, as explained
previously, bind on PBP. That is a basic. Now we try for recharge to
have the same type of compound that is for \-\-- with another additional
mechanism \-\--, giving more activity of \-\-- resistance.

And in the case of \-\-- compound, you have a different philosophy for
the outer membrane. You can cross to outer membrane very quickly, and
the \-\-- space also. That is totally different for Cefotaxime and
Ceftriaxone.

So what is our interest? Okay, for micro-releases \-\-- in practice, you
can avoid this beta-lactamase because you go very quick. And secondly,
that is a consequence of recharge. We add molecule with low affinity for
beta-lactamase. So the drug goes in very quickly the \-\-- space, \-\--
beta-lactamases usually idolize the beta-lactam. And for these reasons,
they arrive through the \-\-- safe through the PBP, and they can block
the cell walls biosynthesis.

(Slide)

The indication for fourth-generation cephalosporin in human medicine in
Europe are very close to those in you have for cefepime in the U.S.
Respiratory tract infections, so we still have bacteremia and
septicemia. We have complicated urinary tract infection, biliary tract
infection, and empiric therapy for the neutropenic patients. And this
compound was introduced in clinical practice in '93, so almost in a
decade. All of both \-\-- injectable for hospital.

(Slide)

For cefquinome, if you look in the \-\--, the first was also introduced
a decade before. For respiratory tract infection in cattle with other
indication. And as you can see, the second more important indication is
probably the foot infection in cattle, that I totally understood from
the previous talk.

We have also a few years after introduction in pig, also for respiratory
tract infection and others, and recently in horses for FTI also.

As far as the mechanics of \-\-- sense is concerned, you could had three
possibilities. \-\-- the efflux of the drug, or to have very high \-\--
of the drug. So, if out membrane \-\-- ability is one of the problem,
but is an \-\-- problem really. Except \-\--. And, usually, you don't
have this problem for \-\-- except for some \-\-- bacter, but not
always.

The real problem is beta-lactamases. I will come back on this one. And
the \-\-- is mainly a problem of gram positive is modification of PBP
with additional PBP like for \-\--, or modification of PBP, you have a
Strep pneumo. Perhaps, \-\-- investigated. So, it is a gram positive
problem.

(Slide)

Okay, difficulty to raise is to classify beta-lactamases. This is a
really a \-\--, and I think that the people who are working in
beta-lactamases want always to make difficult simple things \-- which
are very simple. For me, you can divide these type of compound proteins
in four classes. Class A with the so-called broad spectrum
beta-lactamases already known as a TEM-1 or SHV-1, for which cefotaxime
or ceftriaxone were synthesized.

And also, now the new extended broad spectrum beta-lactamases, ESBL,
with at least three classes. Three main classes. TEM, SHV, and CTX-M.
Others could be added but are very, for the moment, minor classes.

Class B, especially, directed against carbapenem, and these
metalloenzymes are extremely difficult to overcome.

Class C, with the \-\-- cephalosporinase, now has the name of AmpC, with
many, many different type of compound proteins.

And Class D, oxacillinase, more or less, directed against \-\--. I say
more or less could be in other books, of course.

So, in clinical practice, the two most important classes are ESBL and
also AmpC enzyme.

(Slide)

The \-\-- are not exactly the same from both. ESBL is mainly for old
beta-lactam antibiotics, with difference between them for the affinity
due to the chemical structure. This chemical structure \-\-- with the
different affinity.

AmpC, mainly for all beta-lactam, except the fourth-generation
cephalosporin and carbapenem. And they idolized both the \-\--
penicillin the \-\--. NeuroSpectrum cephalosporin may need the
first-generation cephalosporin. And for AmpC also, they idolize the
so-called third-generation cephalosporin, the oxyamino cephalosporin.
And most important \-\-- cephamycins that means cefoxitin and cefotetan.

(Slide)

I don't know what has happened.

(Pause)

DR. BRYSKIER: I just want to give props for me on the \-\--. The
so-called fourth-generation cephalosporin were synthesized. At the
beginning, the people started to want to have a very easy way to
synthesize alpha-amino cephalosporin \-- oral cephalosporin.

And they discovered because \-\-- was this oxyamino, and they discover
cefotaxime. But Cefotaxime as \-\-- power \-\-- of a lack of \-\-- and
the lack of \-\-- AmpC. And all \-\-- research for the two or three
years was directed against this problem and they discovery as \-\-- when
you have a zoonotic cephalosporin you can overcome both problem,
Pseudomonas and AmpC is originally \-- it is totally different. And now,
of course, we know that there are other types of cephalosporin. So,
people will ask, I am sure, of six, seven generation, \-\--.

Today this fourth-generation cephalosporin was really designed for the
problem of AmpC and for clinical use in human \-\--.

Okay, so now we are back to the computer.

(Slide)

If we look as mechanics for \-\-- resistance and the prevalence of AmpC
and ESBL in Europe in general. If you scan all the literature, there is
two conclusions. First of all, the diversity \-- and I will show you a
slide in a few minutes \-- the diversity of enzyme in human, and also
the number of publication is very high. But sometimes the same people
are giving two, three, four times the same publication to have a lot of
publication to have a better position in the university or somewhere
else.

So it is extremely difficult to follow, because they put their name in
another place on publication. So I am very bad to say that, but I review
so many papers that I know.

So, what is the real \-\-- of this shot. Simply that you offer many,
many AmpC, a different type of AmpC in human. For E. coli, for \-\--,
for antibacterial, all of the type of \-\-- bacilli. For Salmonella
\-\--, you have also AmpC in human, was described in human in Europe.

For vet, it is totally a different approach. We have really few sporadic
cases described, even in highly available report of good quality for
AmpC in E. coli, in Salmonella. Only a few.

I know for Salmonella, there is only three \-- if I remember well \--
three countries describing Salmonella and each time one or two cases.
One in France for ulcers, for meat. One for turkey in U.K., and other in
Denmark for bovine. We eating \-\-- everyday. So it is very rare.

(Slide)

For ESBL it is exactly the same. You have a lot of ESBL in human, in
Salmonella as well, and nothing in livestock. Of course, you can find if
you are looking for, you will find, but very rare.

(Slide)

This shot is more interesting. You can see that the diversity in human.
In human, you have so many different type of enzyme for the \-\--, more
than a 158 if I think now. Everyday you have publication, people are
looking for a new amino-acid. Some of them are of importance for
clinical use and most are only important for publication.

The same from SHV, you have a lot of SHV. For CTX-M, you have around \--
if I remember, well around 45 or something like this. But in vet, you
have very few and probably is a difference of the way human are to get
very concentrate and cattle probably are more spaced in the field. I
don't know, it is my hypothesis, but it is probably that.

And present for SHV, in \-\-- you have only one SHV. You can find
SHV-12. For TEM, you have two. And for CTX-M, you have three or four.
And for \-\--, you have a lot. For CMY, exactly the same. You have CMY-2
you can find; perhaps, CMY-3 also, but it is very rare in vet. In human,
you have more.

(Slide)

So, in the conclusion of this \-\-- for resistance. We can say that ESBL
or AmpC are broad spectrum beta-lactamases. The difference is between
bovines \-- AmpC doesn't idolize due to the poor affinity in-vivo,
idolize the fourth-generation cephalosporins. That is a main difference.

All are identified since I would say late '90s, or early '80s or '90s.
It is 20 years we are knowing that, and we are living with such an
enzyme.

In human, you have a high diversity of enzyme, but some are more
predominant and \-\-- probably \-- I don't say \-- you have clinical
problem. Most of them are more publication. And in vet, as a part, you
have very rare. You have but rare and sporadic cases of described for
the cases in livestock of these different type of enzymes.

(Slide)

Now, I will change a little bit the topic, we will go from what exactly
is happening in the field. So, there is not so many susceptibility
surveillance program dealing with fourth-generation cephalosporin.
Today, there is I will say three programs, two in human, one in
veterinary.

In program, it is a T.E.S.T. program, used by Tigecycline, and they have
tested cefepime. The SENTRY Program, the SENTRY was built for cefepime,
so we are testing cefepime. And there is one program for veterinary.

The second part is could be a program funded by the European Union. One
in blood stream infection, and another in gastrointestinal infection.
Unfortunately, they are testing only the so-called third-generation
cephalosporin. They didn't test cefepime.

But, it is of interest because if you have a strain susceptible to
third-generation cephalosporin, you can expect it will be susceptible to
fourth-generation cephalosporin. \-\-- resistant to third, is not always
resistant to fourth, due to the difference between the AmpC and both
type of cephalosporin.

(Slide)

So, to go into detail, the T.E.S.T. is a Tigecycline surveillance
program, was initiated by \-\-- of Tigecycline. And they use cefepime as
a comparator. The SENTRY Program now is funded since more than a decade
by BMS, and they of course are testing cefepime. And the European
Antimicrobial Susceptibility Surveillance Program in veterinary is also
including cefepime as a comparator.

(Slide)

So, if we look in global as a result on enteric bacilli for the T.E.S.T.
Program, \-\-- bacteria \-\-- for cefepime, you have around six percent
of resistance. Unfortunately, we don't know if it is an ESBL or
something else, but it is probably due to ESBL.

In E. coli, we have only four percent. And I think the difference is
probably due to ESBL, which is more important in Enterobacteriaceae or
in \-\-- than in E. coli.

(Slide)

In the SENTRY data, they have analyzed a lot of \--

MS. SINDELAR: Dr. Bryskier, please excuse, they are doing construction
here. So can we please speak a little bit louder into the mics?

DR. BRYSKIER: Okay.

MS. SINDELAR: There you go.

DR. BRYSKIER: Okay, I will think that I have a cigar now.

First of all, in the SENTRY Program, we have to see one thing. The
difference between the number of E. coli strain collected and the
Salmonella. Salmonella in human are not a real problem, except in
gastrointestinal. And in gastrointestinal infection, they are
self-limiting, and no compound is given, no antibiotics, except when you
have elderly or immunocompromised patient, children you need to give, or
if you have some very specific Salmonella.

First of all, Salmonella is ranked 15 in the U.S. as a bug. In Europe,
11. So that means that it is not a real, real problem, it represents
less than one percent of the bugs isolated among gram-negative bacilli.

I think it is important to note that the Salmonella is not a real
problem, except for typhi, and we don't have so many non-typhoid
infection in human. And for me, what is important is invasive infection.

Except in some countries in the world, like in Taiwan, where you have a
lot of \-\-- or sometime \-\-- but is exceptional, as those give less
than one percent of invasive \-- as published by \-- and a lot of work
was done in the U.K. with such work.

It is not so important as for \-\-- or other bugs as those producing
AmpC, which are very big problem in some worlds.

(Pause)

DR. BRYSKIER: Thank you. Sorry for these moments, but it is good we had
a relax two minutes.

(Slide)

So, if we look at the charts, we see that resistant to cefepime is not
so high.

(Slide)

In the SENTRY Program, the resistant to cefepime is around two percent,
and they didn't find any Salmonella resistant to cefepime. But we are
not \-\-- about that.

(Slide)

If you look at the data now of the veterinary surveillance program, you
can see that between four years, there is no difference in MIC against
E. coli and Salmonella, in cattle, pigs, and chicken. All are in the
same range.

This means that probably this MIC-90 shows that no resistance is
occurring during this period among E. coli and Salmonella issued from
cattle, pigs, and chicken.

(Slide)

Now the European Funding Program. This program is for all around EU, and
they add some countries which will join you in two, or three, or four
years. That means that some countries like Romania, Bulgaria, will join
the country, the EU system in a few years.

And all were found for by EU in order to look at the resistance around
the continent. The first is devoted for blood stream infection mainly.
We add some meningitis, but it is not so frequent. And the second is
totally devoted for the gastrointestinal infection. They are collecting
mainly Salmonella, and E. coli, with E. coli producing toxin and
Campylobacter. The last was published a few times ago in a specific
review of this EU Program.

(Slide)

So, to summarize this, it is extremely difficult to summarize, but among
30,000 isolates collected, the average rate is around three percent, so
it is very \-- for cefepime is very low. No, third-generation
cephalosporin, so it is very low.

The only problem really arise that the breakpoint is not uniform in all
Europe. It will come, but not yet. And we can always discuss about \-\--
four percent, five percent, two, percent, one percent, it is depending
other sorts of breakpoints.

And one country didn't join the system is U.K. But others, all of them
are \-- and, of course, all this part of Europe, but they have something
else to do. They are fighting each other, so all this was \-\-- so they
didn't join to this system.

(Slide)

And now if we compare the data for Salmonella in gastrointestinal tract
infection, you can see that for ampicillin, the level of resistance is
more or less stable, is around 20 or 25 percent. So they reach a
plateau, they never move.

But if you look now for cefotaxime with a breakpoint, a very
conservative breakpoint of one. So it is very, very low. Now is a new
breakpoint proposed by the CSLI and, perhaps, approved these around
four. So, it is a very conservative one, and we have less than five
percent of that two or three percent of resistant. So it is very, very
low.

(Slide)

For E. coli including those producing this toxin, this viral toxin, in
2005, we have no strain resistant to cefotaxime or ceftriaxone. No one
\-- that we know \-- so no strain resistant to cefepime. In the first
quarter for 2006, also we have no strain resistant.

(Slide)

So, in conclusion, for the resistance of extended spectrum
cephalosporin, after I would say a decade or more of used of this type
of compound, we have approximately three to four percent of E. coli
isolated in \-\-- infection resistant to the extended spectrum
cephalosporin. The resistance rate for Salmonella is less than one
percent.

I read in the last paper from \-- I think [SENTRY]{.underline} is the
one that is around 08 percent. So it is nothing. If you consider also
that you have less than one percent as Salmonella isolators, it is
really a pinpoint. And also, nothing was found in E. coli producing
toxin.

(Slide)

So, the fourth-generation cephalosporin is not only I will say a name
easy to carry and to say. I have the fourth-generation cephalosporin
now. Fourth-generation cephalosporin is also a structure by itself. The
structure was designed to overcome some really important problem. AmpC.
So you have low affinity for AmpC to most of beta-lactamases of AmpC
class.

For instance, if you have \-\-- against the bugs harboring, and in AmpC,
you have an MIC sometime around 128. With CMY-2, you have around all 25
or less. So you have a real activity against this type of bugs carrying
this type of enzyme.

Resistance of ESBL, which \-\-- around two decades ago, and you have a
\-\-- evolved. And for some time, people say, oh, it is very important
now, it is increasing. But I think it is not increasing really. So, for
\-\-- now, we are detecting it, so it is totally different. And we are
looking at it.

And the CSLI, the former \-\-- have given tool, for instance, in this
country to look if there is or not ESBL. So, people are looking for and,
of course, when you look for something, you find.

Secondly, all the ESBL in vet, or AmpC, are really sporadic in Europe.
They are very sporadic cases. You cannot avoid. If you eat strawberries,
you also have allergy, you cannot avoid these things. This is the
nature. And we have.

No fourth-generation cephalosporins resistance in E. coli and Salmonella
in animal be reported at slaughter. Usually, those are reported in sick
animals. In sick bird, or in sick cattle, or in sick \-- I don't know,
animals. That is published. And in Spain they have these few cases, but
in sick animals.

So I think that this type of cephalosporin, cefquinome or \-\--, and
cefepime, did not induce so many resistance. First of all, they are not
used as large as cefotaxime, so it is a first.

And second, I think that they didn't really promote any resistance, a
special resistance, for the moment and we don't have any big problem
with them.

Okay, thank you very much for your \-- how I say, to listen to me and
for your welcome.

(Applause)

***[CVM Response]{.underline}***

***[Presentation]{.underline}***

***by Jeffrey M. Gilbert, Ph.D.***

DR. GILBERT: Good morning everyone. Considering the jet noise, and the
hibernating computer, I have cut my talk to three slides. So we will get
through it pretty quick.

I am the team leader for microbial food safety, the group that actually
did the review of the cefquinome.

(Slide)

For a narrative, I guess Carl did a pretty good job, so I guess I could
just say we agree, but I will just go back through here.

Carl went through all the release points and we arrived at the same
conclusion, that that would be categorized as medium for exposure,
considering the consumption of beef and the contamination rates, and the
way that integrates, that also is medium.

And then our human health consequence ranking in Guidance #152, Appendix
A, has fourth-generation cephalosporins as highly important. And when
you take those three from the sub-assessments and integrate them
together, you come out with a risk estimation of medium.

(Slide)

And which for all intents purposes, fits nicely into the Category 2,
category of concern for risk management options. And as pointed out
earlier, the marketing status, extra-label use restricted in some cases,
extent of use, low-medium. Post-approval monitoring in NARMS and, in
certain cases, an Advisory Committee meeting.

I would point out to you there under Category 1, we have some of those
things in place, actually, with this particular product. The marketing
status will be RX. Extent of use we believe will be low.

It is being looked at in NARMS now in the second-tier plate, and
Advisory Committee, we are having that today. As far as the agency's
response, we are in agreement with Intervet on how they categorize the
drug.

And with that, what I would like to do is turn it over to my colleague
and friend, Dr. Dave White, from the Office of Research. He is the
manager of our NARMS Program, and he is going to share with you today
some of the data, sort of the current picture, of resistance with some
of the drugs we have been talking about this morning. So, Dave, come on
up.

***[Presentation]{.underline}***

***by David White, Ph.D.***

DR. WHITE: I think we are okay, it's just hibernating. And as Jeff said,
I thought for a sec we had some fighter jets over our hotel, wondering
what the heck was going on.

What I would like to do is just take 10 to 15 minutes and just share
with you some more NARMS data; in particular, some of the retail data as
the NARMS Program. For those of you not familiar with it, it has three
arms to it: An animal arm headed up by Dr. Paula Fedorka-Cray; a retail
arm headed up by Dr. Pat McDermott; and a human arm headed up by Dr. Tom
Chiller.

For those of you who don't know, the NARMS stands for the National
Antimicrobial Resistance Monitoring System. As I mentioned, this is a
national collaborative network between FDA, CDC, and USDA. It was
developed to monitor changes in susceptibility of select zoonotic
pathogens and commensal organisms.

In particular, for today, Salmonella \-- to antimicrobial agents of both
human and veterinary importance. And as I mentioned, the three testing
sites: Office of Research in Laurel, Maryland; \-\-- unit in Athens,
Georgia; and the CDC in Atlanta, Georgia.

(Slide)

In terms of the retail meat \-- this is going to be some of the data I
am presenting. For those of you not familiar with the retail meat arm,
there are 10 food net sites are involved. There is a random sampling
scheme where each site purchases 40 meats per month, 10 pieces of
chicken breast, 10 ground turkey samples, 10 pork chops, and 10 \-- what
did I miss here? \-- ground turkey, sorry.

And approximately about 4,800 meats per year are being looked at in this
program. All 10 sites culture for Salmonella and Campylobacter, and due
to the large numbers of Enterococcus and E. coli recovered, we only have
four sites looking at those two bugs. The isolates are sent to the FDA
Office of Research in Laurel, Maryland.

(Slide)

Just to give you some numbers, in terms of the number of meats being
looked at in this program, it started in 2002. It is the most recent
addition to the NARMS Program. It started off with about 2,500 meats. As
of 2005, we are up to almost 4,800 meats being looked at per year; which
is a very significant number of meats.

(Slide)

Looking at the prevalence of Salmonella, in particular, over these four
meat commodities over the past four years, you can see the majority of
the Salmonella isolates are being recovered from poultry, either chicken
breast or ground turkey. And much lower prevalence rates in pork chop
and ground beef. With ground beef today of interest, each year being
below two percent.

(Slide)

If we look at some of the antimicrobials that have been mentioned today,
the third-generation cephalosporins, in particular, ceftriaxone and
ceftiofur. If we look at the total number of Salmonella isolates being
collected in the program from '02 to '05, we have approximately 1,044
Salmonella isolates.

With regards to the percent resistance, 0.7 percent resistant to
ceftriaxone, which translated to seven isolates. And those isolates were
approximately one ground beef from 2002, one ground beef from 2003, four
ground turkeys from 2005. So, very limiting number of isolates resistant
to ceftriaxone.

And, again, this is looking at it by the meat commodity. CB standing for
chicken breast; GT, ground turkey; GB, ground beef; and PC, pork chop.
And, again, it is the seven isolates and the majority of those were
isolated from ground turkey, the other two are from ground beef.

(Slide)

If you look at ceftiofur, which is the third-generation cephalosporin
being used in vet med, we have a few more isolates, 138 isolates of
Salmonella, were greater than eight microgram per mil. And that is a
breakpoint we borrow from Salmonella \-\-- for ceftiofur.

So, approximately 13.2 percent of the Salmonella isolates from the NARMS
retail exhibited resistance to ceftiofur.

(Slide)

If we look at again by meat, you can see that the largest number is
chicken breast, in CB in blue. Very little from ground beef. Particular,
I think, from ground beef we had two isolates.

This was mentioned earlier in terms of the beta-lactamases, there is
really two of significance. That, of course, should be a beta not an
eyeglass.

(Laughter)

DR. WHITE: The CTX and CMY beta-lactamases are the ones really of public
health significance. The CTX give you the resistance to the
fourth-generation cephalosporins, and in terms of the United States or
the \-\-- are the ones we are seeing that give you third-generation
cephalosporin resistance.

(Slide)

So here is the breakdown of the isolates. Of the 138 isolates that have
exhibited MIC's greater than eight microgram per mil, the breakdown, as
we said, overwhelmingly was poultry: 98 chicken breasts; 29 ground
turkey; 8 isolates from ground beef. And when we do PCR looking for
these two beta-lactam, not a single ESBL was found. No CTX-M genes were
found. Of 138 isolates, 132 were positive for the \-\-- gene.

(Slide)

If we look at ceftiofur versus cefquinome MIC distributions \-- and this
is a study we have ongoing with NARMS looking at ampicillin resistant
isolates going back to 2002. These are all ampicillin resistant
isolates. If we compare them to cefquinome, you can see that in red, it
really doesn't affect the cefquinome MIC distributions. It is pretty
much a bell-shaped curve. However, some of these Amp resistant isolates
are ceftiofur resistant, as you can see by this population out here.

(Slide)

And if we compare these side-by-side, we break it down by those isolates
that are resistant to ceftiofur at eight microgram per mil or higher,
and those that are less than eight microgram per mil or higher, we are
actually seeing two populations present. And of interest in blue, are
all your ceftiofur susceptible isolates.

And they have a MIC distribution from less than, or equal to, 0.06 to
.5. And the ones that are actually ceftiofur resistant that were shown
to have the \-\-- gene, are a little bit skewed to the right by one or
two dilutions.

Still, much below the cefepime resistant breakpoints of 8, 16, and 32,
which is susceptible, intermediate, and resistant. So even though we see
shifts up to two, they are still well below the breakpoints for the
fourth-generation cephalosporin cefepime.

(Slide)

We also look at E. coli from the NARMS retail and we get a lot of
isolates here. So just to give you an idea again, the number of meats we
are looking at as of 2005, we are almost up to 2,000 meats being
sampled. The prevalence is much higher with E. coli. Again, this is why
we only do four sites, because we find high prevalence rates, almost 70
percent or greater on all the meats except for pork chops.

So, if we had all 10 sites, I think you could agree that we would be
looking at thousands and thousands of E. coli per year.

(Slide)

If we look at ceftriaxone MICs against the E. coli in the program \--
and we only did 2002 to 2004, as the 2005 data is not vetted yet \-- but
we are talking almost 3,700 E. coli isolates. And in terms of percent of
resistance to ceftriaxone, we have zero percent resistance to
ceftriaxone.

(Slide)

If we look at ceftiofur \-- I am sorry, again, that was by year. If we
look at it by meat, of course, there is zero so it is not going to be
anything. If you move onto ceftiofur, we are going to see few more
isolates. Again, much like the story with Salmonella, 2.4 percent of E.
coli isolates exhibiting resistance to greater than 8 microgram per mil.
There is not really any increases over the years between 2002 and 2004.
It is all about two percent each year.

(Slide)

And if we break it down by meat, again, you can see we are seeing
primarily the ceftiofur isolates from chicken breasts. Very limited from
ground beef. In fact, from ground beef we have four isolates.

(Slide)

Again, much like the Salmonella, we did the E. coli isolates, there were
ceftiofur resistance for this \-- via PCR for the CTX in the CMY genes.
Again, of the 89 isolates resistant to ceftiofur at eight microgram per
mil or higher, none of them had a CTX-M gene. Eighty-two of them did
have a bla(CMY) gene. So, you can see in both populations, there are
several isolates that do not have the bla(CMY), so we are going to try
to figure out what exactly those beta-lactamases are.

(Slide)

So, in summary, NARMS currently monitors susceptibility to several
beta-lactam antimicrobials, including cefoxitin, ceftiofur, and
ceftriaxone. Among the thousand Salmonella recovered from retail foods,
approximately 13 percent resistant to ceftiofur at 8 microgram per mil
or higher, 0.7 percent ceftriaxone resistant. Among the approximately
3,700 E. coli recovered from retail foods between '02 and '04, 2.4
percent ceftiofur resistant, zero percent ceftriaxone resistant.

As Jeff mentioned, we do have a NARMS secondary ESBL plate. This is a
plate we developed this past year where anything that is \-- we are
proposing that any Salmonella or E. coli isolate that displays
resistance to ampicillin will be put onto the secondary plate, and what
is on the secondary plate is cefquinome and cefepime, as well as several
other third-generation cephalosporins.

With regards to detection of beta-lactamases, again, no CTX-M
beta-lactamases were detected. The CMY, the bla(CMY) genes were the most
commonly identified. They are not currently associated with resistance
to fourth-generation cephalosporin.

However, they were associated with shifts in cefquinome \-\-- to a less
susceptible population. Again, well below the cefepime resistant
breakpoint of 32.

(Slide)

And in summary, NARMS will continue to monitor any shifts in deceased
susceptibility to cefquinome and other cephalosporins of animal and
human health significance.

And with that, I think you very much.

(Applause)

MS. SINDELAR: Thank you everyone. We will save our questions until this
afternoon. I have still some general housekeeping here. We will have a
copy of the public statement from the Infectious Diseases Society of
America on the table over here. Dr. Belongia will be referencing this
statement during his presentation during the open public hearing.

(Housekeeping matters discussed)

MS. SINDELAR: We will reconvene at 1:00 p.m. and they will be serving
downstairs an ala carte menu for the members. And, Dr. Sundlof, if we
could travel as a group downstairs, the hostess will have us seated. We
will be seated separately with the hostess of the Double-Tree.

So, thank you very much and we will see you back here at 1:00.

(Whereupon, a luncheon recess was taken)

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

(1:21 p.m.)

MS. SINDELAR: Welcome back everyone. Let's get started with the
afternoon session and, in particular, the open public hearing portion of
the meeting. So, if everyone could have a seat.

(Pause)

MS. SINDELAR: The plan for this afternoon is that we will invite the
open public hearing registered speakers to come up to the chairs in
front, for them to provide their presentations.

We will hold the questions from the Committee until all have had a
chance to present their views; after which, we invite the Committee to
ask questions of them.

Following the Q&As from the OPH speakers, we will then have the morning
speakers come to the podium and have the morning speakers available to
answer any questions that you might have.

So, we will have our break at 3:00, Dr. Craigmill will read the open
public hearing announcement for product-specific meetings, and after you
read that, I will invite the speakers to the podium. Thank you.

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

DR. CRAIGMILL: Good afternoon. Both the Food and Drug Administration and
the public believe in a transparent process for information gathering
and decision-making. To ensure such transparency at the open public
hearing session of the Advisory Committee meeting, FDA believes it is
important to understand the context of an individual's presentation.

For this reason, FDA encourages you, the open public hearing speaker, at
the beginning of your written or oral statement to advise the Committee
of any financial relationship that you may have with any company, or any
group, that is likely to be impacted by the topic of this meeting.

For example, the financial information may include the company's or a
group's payments of your travel, lodging, or other expenses in
connection with your attendance at the meeting. Likewise, FDA encourages
you at the beginning of your statement to advise the Committee if you do
not have any such financial relationships.

If you choose not to address the issue of financial relationships at the
beginning of your statement, it will not preclude you from speaking.

MS. SINDELAR: Great. Thank you, Art.

At this time, could we have Dr. Patricia Griffen, Dr. Edward Belongia,
Dr. Richard Carnevale, Mr. Steven Roach, and Susan Prolman.

(Pause)

MS. SINDELAR: Are we ready? Okay. At this time, I would like to invite
Dr. Patricia Griffin to begin her presentation. She is from the Center
for Disease Control. Thank you very much, Patricia.

***[Comments]{.underline}***

***by Patricia Griffen, M.D.***

DR. GRIFFEN: Good afternoon. Just before I start my talk, I want to say
something about pathogens themselves, not resistant. And that is because
for the past almost two weeks I have been working night and day on an
outbreak of E. coli 0157 infections from spinach. It has mobilized a lot
of us at CDC. We are in the Director's Emergency Operation Center,
working through weekends on this.

We now have 173 confirmed illnesses, 28 people with kidney failure, 1
confirmed death, and 2 under investigation. We have done estimates on
how many true cases of E. coli 0157 there are when we get a confirmed
case. When we apply those estimates, we could estimate there are about
3,500 people ill in this outbreak.

What I want to remind everyone is that cattle are the major reservoir
for E. coli 0157. The organism doesn't just get into beef, it gets into
the cattle manure and from there it spreads to the environment;
including, to leafy green vegetables that are consumed raw.

So, the big picture is not just pathogens in beef, it is pathogens in
our environment that we humans, and our children, and the elderly are
exposed to. Whether they are resistant or whether they are susceptible.

(Slide)

The National Antimicrobial Resistance Monitoring System for enteric
bacteria, or NARMS, objectives are to monitor antimicrobial resistance
among enteric bacteria from humans, food, and animals. We conduct
surveillance in all 50 states. We focus intervention efforts to decrease
the emergence and dissemination of antimicrobial resistance, and we
provide a platform for studies, such as field investigations, and
studies of resistant mechanisms.

Can anyone who can't hear me well raise their hand?

(Show of hands)

(Slide)

DR. GRIFFEN: Okay, human isolate sampling in the CDC portion of NARMS is
conducted in the following way bacteria are isolated in clinical labs
and sent to state health department labs for characterization. And then
isolates are sent directly to CDC from those state health department
labs. And this includes every 20^th^ Salmonella, Shigella, and E. coli
0157 that is isolated, all Salmonella typhi, all Listeria, and all
Vibrio, and a representative sample of Campylobacter from \-\-- food net
sites.

(Slide)

Well, what has surveillance shown? We found an increase in multi-drug
resistant Salmonella. For example, Salmonella Typhimurium DT104 and
Salmonella Newport now have a high proportion of strains that are
resistant.

There is a spread of genetic material, usually plasmids, containing
genes coding for resistance to multiple serotypes. We have also found
the emergence of resistance to antimicrobial agents that are important
in human medicine. These include resistance to third-generation
cephalosporins, we see resistance to these in Salmonella and E. coli,
and resistance to fluoroquinolones in Campylobacter, Shigella, and
Salmonella, including Typhi.

Anyone having trouble hearing me, raise your hand.

(No response)

DR. GRIFFEN: Okay. A few words of Salmonella. It is a leading cause of
food-borne illness in the United States. We estimate that there are 1.4
million infections each year, 16,000 hospitalizations, and nearly 600
deaths. Salmonella accounted for 13 percent of food-borne disease
outbreaks reported to CDC the last time we analyzed this data.

Most infections are self-limited, but antibiotics are essential for some
serious infections. Fluoroquinolones, such as ciprofloxacin, and
third-generation cephalosporins, such as ceftriaxone, are commonly used
for treatment of severe Salmonellosis. Third-generation cephalosporins
are the primary treatment for severe illness in children.

(Slide)

Resistant Salmonella caused more severe infections than susceptible
Salmonella. Resistant Salmonella strains cause an increased risk of
invasive illness in death, compared with susceptible strains; and
increased risk of blood stream infection in hospitalization compared
with susceptible strains; and an increased rate of hospitalizations
compared with susceptible strains.

(Slide)

Third-generation cephalosporin resistance in Salmonella is what I want
to talk about now. This resistance is most commonly caused by a plasmid
containing resistance genes. We formed a definition of MDR, multi-drug
resistant, AmpC resistance. And this group means resistance to at least
ampicillin, chloramphenicol, streptomycin, cephathlamoxicillin(\*),
tetracycline, which we call ACSSuT, and resistance to third-generation
cephalosporins, and amoxicillin clavulanate.

Between 1998 and 2001, we observed a five-fold increase in the
proportion of human Salmonella strains resistant to third-generation
cephalosporins. And this increase was primarily due to emergence of MDR,
AmpC, Salmonella, Newport.

(Slide)

Well, where is this third-generation cephalosporin resistance coming
from? As you have heard, with the MDR AmpC resistance carry a plasmid
with genes coding for the CMY2 enzyme. And the CMY2 enzyme mediates
resistance to third-generation cephalosporins. Plasmids that carry genes
for the CMY2 enzymes are spreading to other Salmonella serotypes and
other bacteria. For example, E. coli.

The spread of plasmids may be related to antibiotic pressure from the
use of third-generation cephalosporins, particularly ceftiofur, which is
the only third-generation cephalosporin used in food animals.

Or, it could be related to the use of other drugs. For example, giving
tetracycline to an animal or a person carrying an MDR AmpC resistant
Salmonella will select for survival of strains that are resistant to
both tetracycline and third-generation cephalosporins.

(Slide)

This graph shows the proportion of Salmonella Newport strains resistant
to at least ACSSuT. The "X" axis shows years, the "Y" axis shows percent
resistant. Look first at the blue bars, this shows the proportion of
Salmonella serotype Newport strains that were resistant to ACSSUT in
some county surveys that we did beginning in 1980.

The orange bars show data from NARMS, and you can see that we began
seeing MDR AmpC, which includes third-generation cephalosporin
resistance in 1998. And now, you can see some tiny blue bars at the
bottom of the orange bars. Those are the strings that are only resistant
to ACSSUT. Most of those ACSSUT strains are also MDR AmpC resistant, so
are colored orange.

(Slide)

I want to tell a story about Salmonella Newport. Salmonella Newport MDR
AmpC infections in Massachusetts. In November of 2000, the Massachusetts
State Lab called us because they had noted four Salmonella Newport MDR
AmpC isolates. They were screening with chloramphenicol, and were able
to find these strains. Two of them came from little dairy cows, and two
from ill persons. It is one of those labs that just by serendipity,
unfortunately, was testing isolates from both humans and animals.

And one of the isolates from an ill person was from a child who attended
a daycare center on a dairy farm.

We sent a team to Massachusetts and risk factors for human illness
included contact with cattle, and consumption of bovine products,
including ground beef and unpasteurized cheese. So, the risk factors
were both direct contact, and food exposures.

(Slide)

The team reviewed cattle isolates in Massachusetts and neighboring
Vermont, and they detected Salmonella Newport MDR AmpC in the stools of
both ill and well cattle. Some dairy farms with Salmonella Newport MDR
AmpC strains often had illness and deaths in cows. And on one farm,
there were ill persons and milking cows with the same strain. And many
cow strains had the same PFG pattern as human strains

(Slide)

Here is another story about Salmonella Newport MDR AmpC, this time in
horses. More recently, in 2004, there was a Salmonella outbreak at the
prestigious new Bolton Center, a veterinary hospital in Pennsylvania.

The cause was Salmonella Newport MDR AmpC. There was a high mortality in
the horses and the hospital had to close for three months.

(Slide)

So look at the bottom graph. It shows the percentage of all Salmonella,
not just Salmonella Newport with MDR AmpC resistance between 1996 and
2004. So the "X" axis shows the year, the "Y" axis the percent
resistant. If you look at the light blue bars, you will see the
proportion of Salmonella Newport that are resistant to MDR AmpC.

But the point of this graph is to show \-- you have already, basically,
seen that data \-- but I want to show you the purple and the \-- I don't
know, that is sort of a dark green color \-- bars that show you that
that there are other serotypes besides Newport that also are exhibiting
this resistance pattern.

And the little insert graph is, basically, the same as the big graph,
except removing those light blue bars and just showing you resistance in
other serotypes.

(Slide)

So this is taking that data on the serotypes other than Newport, and
showing you the cumulative number of Salmonella serotypes with MDR AmpC
resistance, beginning in 1996 and going through 2004.

This is not number of strains, or number of isolations, this is number
of different Salmonella serotypes in which we found MDR AmpC resistance
in humans.

So, by 2004, 14 different serotypes, Newport, Typhimurium, and 12
others, had been found that carried the MDR AmpC resistance. MDR AmpC
resistance has also jumped to E. coli 0157.

(Slide)

In 2000 and 2001, six E. coli 0157 strains were isolated for humans that
have the MDR AmpC plasmid.

(Slide)

I want to talk now about fourth-generation cephalosporins in non-human
use. And as you have heard earlier today, in February of 2005, WHO
convened a panel of experts to determine critically important
antibacterial agents for human medicine for risk-management strategies
of non-human use. And fourth-generation cephalosporins were ranked as
critically important.

(Slide)

Fourth-generation cephalosporins are widely used in food animals in
Europe. They are the most commonly used extended spectrum cephalosporin
in Europe. Very little third-generation cephalosporin is used in Europe;
although, it is used. And fourth-generation resistance has developed in
Salmonella in Europe.

There, the resistance is due to the CTX-M gene enzyme that is carried on
its own plasmid. Resistance is not due to CMY2 present in the United
States.

(Slide)

So in comparison, third-generation cephalosporins are used in food
animals in the United States. Resistance is mediated by CMY2 enzymes and
coded on a plasmid. Fourth-generation cephalosporins are widely used in
food animals in Europe, and resistance is mediated by CTX-M enzymes and
coded on a plasmid.

(Slide)

Our belief is that resistance will develop to fourth-generation
cephalosporins. The question is, how and where? Some possibilities are
that the genes in coding the CMY2 enzyme in MDR AmpC Salmonella may
mutate to confer resistance to fourth-generation cephalosporins. And, in
fact, this has already been done in-vitro.

Or, it is possible that as in Europe, we may find Salmonella strains
with plasmids carrying the genes for the CTX-M enzyme.

To understand and control emergence, we need to know where and how
fourth-generation cephalosporins are used in food animals.

(Slide)

CDC strongly supports the continued use of FDA's Guidance #152. CDC
agrees with the sponsors medium risk estimation based on current
guidelines. However, the risk estimation could increase should
fourth-generation cephalosporins be judged of critical importance in
humans.

(Slide)

CDC recommends extra-label prohibition of cefquinome use in food
animals. Off-label use could lead to emergence and dissemination of
resistance from unknown uses.

(Slide)

Surveillance is needed to monitor for the emergence and dissemination of
fourth-generation cephalosporin resistance. CDC NARMS does not currently
screen human Salmonella strains for fourth-generation cephalosporin
resistance.

CDC could add testing plates to monitor for this resistance. Current
resources, however, only allow for continuation of existing NARMS
activities.

(Slide)

Information on the quantity of fourth-generation cephalosporins used by
animal type should be available on an ongoing basis in a format suitable
for public health surveillance purposes, including information on
off-label use.

Thank you for your attention.

MS. SINDELAR: Thank you, Dr. Griffen. Dr. Edward Belongia of the
Infectious Diseases Society of America. And I think you will need to
speak loud and clear, you will be challenged.

***[Comments]{.underline}***

***by Dr. Edward Belongia***

DR. BELONGIA: Okay, thank you. Can everybody hear me okay?

(Members nodding heads)

DR. BELONGIA: My name is Ed Belongia, I am an infectious disease
epidemiologist in Wisconsin at the Marshfield Clinic Research
Foundation, a non-profit research organization affiliated with the
Marshfield Clinic.

I am here today though representing the Infectious Diseases Society of
America, or IDSA. IDSA represents \-- oh, before I forget, I have no
financial relationship with any commercial entity that has any interest
in this topic in any way.

IDSA represents 8,000 physicians and scientists devoted to patient care,
education, research, prevention, and community health in infectious
diseases. IDSA members care for patients of all ages with serious
infections, including antibiotic resistant bacterial infections,
meningitis, pneumonia, food-borne infections, AIDS, and people with
cancer or transplants who have life-threatening infections caused by
unusual pathogens.

IDSA is the principal organization representing infectious disease
physicians in the USA. Cephalosporins are essential drugs that are
widely used to treat serious and life-threatening human infections. As
we heard this morning, the FDA has classified fourth-generation
cephalosporins as highly important in human medicine because they are
the sole therapy, or one of few alternatives, for serious human disease.

Cefepime is a fourth-generation cephalosporin that has a broader
spectrum of activity compared to third-generation cephalosporins, and it
is often effective against organisms that are resistant to cefotaxime or
ceftazidime. Currently, there are no fourth-generation cephalosporins
used in food-producing animals in the U.S., but as we heard, they are
used in Europe. Cefquinome, in particular.

Now, resistance to third and fourth-generation cephalosporins can be
mediated by extended spectrum beta-lactamases, and I will refer to them
as ESBLs in gram-negative organisms. ESBLs are an important cause of
treatment failure in patients receiving cephalosporins.

A specific family of ESBLs, known as cefotaximases, or CTX-M, as Dr.
Griffen mentioned, has rapidly expanded in the past decade to include
Europe, Africa, Asia, and Latin America. The CTX-M gene is located on
plasmids, which allow rapid and efficient spread of CTX-M mediated
resistance to other organisms.

Even more concerning is the fact that CTX-M producing isolates often
exhibit co-resistance to other drug classes, including fluoroquinolones.
For example, ciprofloxacin resistance was strongly associated with the
presence of CTX-M in a recent Canadian surveillance study. And the odds
ratio for that was 14. And as an epidemiologist, I can tell you that an
odds ratio of 14 is a very impressive association.

This raises the concern that a fourth-generation cephalosporin use could
select for co-resistance to fluoroquinolones. In the United Kingdom,
surveillance for CTX-M producing isolates from out-patient and
in-patient sources, identified an epidemic strain with multiple
resistance to fluoroquinolones, trimethoprim, tetracycline,
aminoglycocides.

And we had a number of copies of the written IDSA statement here, and
references for these studies are included at the end of that statement,
for those who are interested.

Most ESBL mediated resistance has been reported from hospitalized
patients. However, there is growing evidence that ESBL producing
organisms, and CTX-M producers, in particular, represent an emerging
problem in the community.

For example, data from Spain indicate that the rates of ESBL producing
isolates increased significantly in both hospitalized patients and
out-patients from 1991 to 2003. In that study, CTX-M enzymes accounted
for over 60 percent of the ESBL isolates.

Despite the rapid emergence of CTX-M in Europe and other regions, CTX-M
producing organisms appear to be uncommon in the United States. We are
not aware of any published reports of community onset disease caused by
CTX-M producing isolates in this country, and there has been only a
single report of nine E. coli isolates with CTX-M mediated resistance
from patients in five states.

ESBL producing E. coli with CTX-M genes have recently been detected in
food-producing animals in the United Kingdom, Denmark, and Spain. CTX-M
genes have also been found in Salmonella enterica isolates from
food-producing animals in Spain.

There is a legitimate concern that food-producing animals may serve as a
reservoir for ESBL producing human pathogens, and that resistance genes
may be transferred to humans through the food supply and, ultimately,
cause treatment failure in patients receiving cephalosporin therapy for
serious infections.

And I just want to emphasize this point, that the concern is not just
the direct transfer of resistant pathogens, which is what much of the
focus was this morning, but the transfer of resistance genes, transfer
of DNA through mobile genetic elements even if the original organism
that was in the animal is not what is actually causing the infection in
the human.

FDA Guidance #152 outlines the recommended procedures for a qualitative
risk assessment to evaluate the microbial food safety of
fourth-generation cephalosporins in animals. And that was gone through
in quite a bit of detail this morning in terms of assessing the risk of
release exposure and consequences.

I would just like to point out that for the exposure assessment, the
probability of human exposure is determined by the prevalence of
Salmonella and Campylobacter contamination in various food commodities,
and the amount of that food that is consumed by the general public. And
using that framework, cefquinome is best classified as medium risk for
human exposure, as was reported this morning.

And since fourth-generation cephalosporins are currently classified as
highly important for treating human infections, the overall level of
risk is appropriately classified as medium, or Category 2, based on
Table 6 of Guidance #152.

IDSA supports Guidance #152 and the overall FDA risk assessment
approach. However, we note that in this case it fails to consider the
human risk posed by horizontal gene transfer, or clonal spread of ESBL
producing E. coli. In Europe, resistant E. coli with CTX-M have been
detected on farms where fourth-generation cephalosporins were
administered to livestock.

The risk to human health has not been defined and there is much that we
do not yet understand about the epidemiology. But, the potential for
selection and horizontal transfer of CTX-M genes from food-producing
animals to human pathogenic bacteria must be taken seriously.

We also note that many infectious disease specialists would consider
fourth-generation cephalosporins to be critically important rather than
highly important for treating human infections.

The fourth-generation cephalosporins fail to meet the FDA criteria for
critically important only because they are not routinely recommended for
treating enteric pathogens that cause food-borne disease.

However, IDSA treatment guidelines recommend third and fourth-generation
cephalosporins for complicated, high-severity, intra-abdominal
infections, as well as for other serious infections and people at-risk
for multi-drug resistant pathogens.

Extended spectrum cephalosporins are also important for treating
invasive Salmonella infections in humans. We, therefore, believe the FDA
should re-evaluate the criteria used to classify the importance of
cephalosporins for human health.

And I also note, that has been mentioned a couple of times today, is
that the World Health Organization has classified fourth-generation
cephalosporins as critically important for human health.

If cefquinome is approved for use in U.S. food-producing animals, IDSA
strongly recommends that FDA implement the following measures to
minimize selection pressure for ESBL producing organisms, and to monitor
the public health impact of the new drug.

1\. Limit the marketing status to prescription only, which is what has
been proposed.

2\. Prohibit extra-label use of the product. And this differs from the
recommendations that were made this morning.

3\. Limit the extent of use to low, meaning that the drug will be
administered only to individual animals rather than to groups or pens of
animals.

4\. Require post-approval surveillance for resistance in NARMS and
provide sufficient funding to include the new drug in the NARMS panel.

5\. Require the manufacturer to report the volume of products sold or
distributed in the U.S. each calendar year. And the FDA should establish
a standard criteria for reporting this information. If the drug is ever
used in species other than cattle, the volume should be reported
separately for use in each species; including, poultry, swine, or any
other where it is eventually used, as well as the total volume sold for
use in all food-producing animals. These data should be publicly
available to support epidemiologic and microbiologic research on the
impact of fourth-generation cephalosporins in food-producing animals.

6\. And, finally, we recommend that FDA provide funding for molecular
epidemiology studies \-- and I want to emphasize the epidemiology part,
as well as the molecular part \-- to evaluate the impact of cefquinome
use in livestock and the associated risk of CTX-M transmission to human
pathogens and commensal flora through the food supply. And I really view
this as applied research that is best done through an RFP mechanism so
that the right questions are posed and the right answers are provided.

I will stop my comments at that point, and thank you again for the
opportunity to comment on the issue.

MS. SINDELAR: Thank you very much. Dr. Rich Carnevale please. Loud and
into the mic.

***[Comments]{.underline}***

***by Dr. Richard Carnevale***

DR. CARNEVALE: All right. Thank you. Good afternoon to the regular and
specially invited members of this Advisory Committee. I am Dr. Richard
Carnevale, the Animal Health Institute, Vice President for Scientific,
Regulatory, and International Affairs. We represent the manufacturers of
animal pharmaceuticals, feed additives, and biologicals.

I have no direct financial interest in Intervet or its products;
however, Intervet, as a member of AHI does partially fund the operations
of AHI through payment of its dues, like all the rest of our members.

We are pleased to comment at this Advisory Committee proceeding on
behalf of our member companies; and, in particular, Intervet. Intervet
has been an important member of AHI, committed to the needs of the
animal health community. And I know it takes stewardship of its products
very responsibly.

Antimicrobials have been used safely for many years to prevent and treat
livestock and poultry diseases, and to enhance production.
Antimicrobials are strictly regulated by FDA for safety and
effectiveness, as this proceeding today demonstrates.

AHI member companies must meet high standards for assuring the human
safety of animal drugs used in food-producing animals. The standards
have covered both safety testing for residues in foods, and for the
transfer to humans of antimicrobial resistant bacteria through the food
supply.

There have been numerous documents that have been made available to the
industry by CVM over the years, which has guided this testing. Guidance
for Industry #152, which we heard discussed this morning, is the latest
such document to specifically address the resistance issue for the
approval of antimicrobials in food animals.

It represents a risk assessment process for the determination of the
potential for human medical impacts from the use of antimicrobials in
food animals. AHI has long endorsed the application of data-driven risk
analysis as an effective tool in rendering public policy decisions, in
lieu of decision-making, based on inference or popular opinion.

We support the FDA's approach to determining risk of animal drugs on the
basis of sound risk analysis principles. The topic of this Committee
today is focused on the evaluation under #152 of a specific
antimicrobial product, cefquinome, and how it may affect human health
through potential selection of resistant enteric bacteria during the
treatment of respiratory disease in cattle.

The selection for resistant bacteria by the use of an antimicrobial is,
of course, a possibility during the treatment of infections in humans
and animals. However, whether or not selection of resistance occurs, or
is likely to result in harm to animal or human health by compromising
treatment, is the real question. And we believe is best answered through
an iterative science-based process of risk assessment.

That is why AHI endorses the principle that each antimicrobial product
must be evaluated on an individual basis to address these concerns,
taking into account the specific antimicrobial compound, the intended
species, the conditions of use, and the specific food-borne bacteria
that could be of concern to human health through risk assessment and
estimating the probability of harm.

And I think that was demonstrated this morning in the presentation.
Regarding the specific topic of this meeting, the Committee should take
into account that cephalosporin antibiotics have been used safety for
many years in food-producing animals. There is no evidence that their
use has contributed to adverse consequences in the treatment of
infections and humans.

Data presented by the sponsor indicates cephalosporins important to
human medicine continue to be effective against enteric food-borne
pathogens, with a low incidence of resistance. The evidence presented
today supports the conclusions that administering cefquinome to cattle
for treatment of respiratory infections will not compromise treatment of
human bacterial infections.

It is critical that veterinarians have available to them a wide-range of
antimicrobials to prevent and treat animal disease. This is important,
not only for maintaining the health of livestock and poultry, resulting
in a more wholesome and safe food supply, but also important in
mitigating resistance by reducing selection pressures from the over use
of the limited number of antimicrobials.

The Committee also needs to be aware that there are now multiple layers
of protection, safeguarding human health from the use of antimicrobials
in animals, beginning with a stringent FDA review process, to efforts by
the American Veterinary Association and veterinary practitioner groups
to develop prudent use, antimicrobial guidelines, through the USDA
pathogen reduction performance standards in raw meat and poultry.

The Center for Disease Control and Prevention continue to report
decreasing rates of food-borne illness that they attribute in large part
to decreasing overall rates of pathogen contamination in animal
carcasses after processing. If overall pathogen load is reduced, it
follows that specific antimicrobial resistant pathogens will also be
reduced, lessening the likelihood that they can impact human health.

This was the conclusion in a recent Institute of Food Technologist's
report, IFT, which examine the implications of antimicrobial resistance
to food safety. The National antimicrobial Resistance Monitoring System
has been also used to establish and monitor the frequency and nature of
antimicrobial resistant bacteria in animals, humans, and retail meat
products.

As you heard this morning, data indicates low and stable rates of
resistance for newer antimicrobials important to both human and animal
medicine.

We appreciate the opportunity to comment on this very important
proceeding, one that continues to aid in formulating a sound,
scientific, and risk-based approach to dealing with the potential
concerns for transfer of antimicrobial resistance. We trust the
Committee will provide sound guidance to the agency so that the
availability of safe and effective animal health products will be
maintained while adequately protecting public health. Thank you.

MS. SINDELAR: Thank you, Rich. Mr. Steven Roach, please. Food Animal
Concerns Trust.

Do you want me to pass those out? There are two different ones.

***[Comments]{.underline}***

***by Steven Road***

MR. ROACH: Hello, I am Steve Roach, I am with Keep Antibiotics Working.
And I am handing out my presentation, and there is also a graph that I
will refer to in my presentation. So that is a separate handout.

Keep Antibiotics Working appreciates this opportunity to provide
comments on the proposed approval of the fourth-generation cephalosporin
class of antimicrobials in food and animals. I am Steven Roach, Director
of Food Safety Programs for Food Animal Concerns Trust, a member
organization of Keep Antibiotics Working.

Keep Antibiotics Working is a coalition of health, consumer,
agricultural, environmental, humane, and other advocacy groups with more
than nine million members working to protect public health through the
promotion of the responsible and appropriate use of antibiotics in
animal agriculture.

If you are looking at my text, I am going to drop part of it, just to
move us on a little bit more quickly. Today, you are being asked to
consider the approval of a class of drugs that has never been used in
food animals in the U.S. Unsurprisingly, given the lack of selection
pressures through drug use, resistance to this class of animal
antimicrobials has not been detected in the U.S. in farm animals.

During the presentation this morning, that was given as evidence of that
this won't happen in the future. But I don't think that that is a very
sound conclusion. We haven't used it, so it is not surprising that we
haven't found resistance. What we need to know is what happens when we
actually do use it.

There is, however, evidence that an animal \-\-- to such resistance. For
instance, in Europe, where cefquinome has already been approved under
the brand name Cobactan, resistance to this and other classes of
cephalosporins have been detected among Salmonella and E. coli bacteria
isolates from food-producing animals on farms where Cobactan has been
used.

Resistance in these isolates is conferred by the extended
beta-lactamases of the CTX-M family. And we heard about that earlier
today.

Again, this family of enzymes has not been detected in livestock in the
U.S. While extended spectrum beta-lactams have been detected in U.S.
patients, as the Intervet Risk Assessment noted, the U.S. currently has
the lowest rate of this type of resistance in the world.

We should try to maintain this low rate, and you, the members of the
VMAC Committee play an important role in assuring that this approval
does not lead to an increase in resistance in farm animals, the
community, and sick patients.

The Intervet Risk Assessment plays down the potential for cefquinome use
to select for resistance in gram-negative bacteria, such as E. coli and
Salmonella. Their argument, partially based on a claim that levels of
the drug are too low when they got to select for resistance in enteric
bacteria.

Despite this argument, there own data described on page 20 of the report
shows that cefquinome use in an actual field trial did lead to a
reduction in numbers of E. coli, and to reduce susceptibility to
cefquinome in E. coli and treated animals.

The Intervet Risk Assessment states that cefquinome in this respect is
similar to the third-generation cephalosporin, ceftiofur. However, there
is good evidence that ceftiofur use in cattle has lead to increased
ceftiofur resistance in cattle isolates. And I provided a chart based on
the NARMS data system. Just looking at the cattle slaughter isolates.

And if you look at for Salmonella \-- so this is all the slaughter
isolates for Salmonella from 1997 when we started collecting data, from
2003 when the last year that we have data, at least, published.

So, you have an increase from zero in 1997 when we started looking, up
to 20 percent of the Salmonella isolates from cattle slaughter are
resistance to ceftiofur. This is exactly what should be avoided with
cefquinome.

Okay, KAW believes that the Food and Drug Administration should update
Appendix A of Guidance #152, based on the more recent work of the World
Health Organization. They are finding that fourth-generation
cephalosporins should be considered critically important. And on the new
information about the role of food and transmitting organisms causing
urinary tract infections.

So, at the time, and I am thinking in 2003 when the FDA finalized
Guidance #152, there wasn't as much evidence that food-borne \--
actually, urinary tract infections can be food-borne. But, there has
been several studies that strongly suggest that there is a role of food
in the spread of urinary tract infections since that point.

It is also important to acknowledge that the use of this drug can select
for bacteria containing extended spectrum beta-lactamases, which confer
resistance to third-generation as well as fourth-generation
cephalosporins.

So, it is important to look at each drug in its own, but the problem is
is that this drug \-- it causes a risk to resistance to the
third-generation. It doesn't make sense to say, well, we can't look at
that. We know that the CTX genes provide resistance, both to third and
fourth-generation cephalosporins, and also a bunch of other drugs.

So that is a risk. You can't just ignore it because it is in a different
class if it selects for resistance of both. And third-generation
cephalosporins are considered by FDA to be critically important.

You the members of the VMAC Committee have been asked to answer three
questions related to the approval of this drug. And the first questions
is, do the findings presented in the sponsor's risk assessment
demonstrate that cefquinome is safe with respect to the potential
transfer of antimicrobial resistance?

The answer to this first question must be no. What does safety mean in
the context of new animal drug approval? The standard required by the
FDA for safety is reasonable certainty of no harm.

Keep Antibiotics Working believes, in this particular case, the sponsors
have failed to meet the FDA safety standards; specifically, because they
have failed to account for the likely and predictable risk for the use
of this drug in livestock to select for extended spectrum
beta-lactamases in gram-negative bacteria. Particularly, those in the
CTX-M class.

Such selection could internally do treatment failure with both third and
fourth-generation cephalosporins. Given the failure of the assessment to
address this risk, we recommend that the drug has not been approved.

To state that we haven't found this type of resistance in the United
States in animals before the drug has been approved should not give you
any evidence one way or the other. Because you wouldn't expect to find
resistance to the drug until it has been approved.

KAW believes that denying approval is also consistent with Guidance
#152. Under Guidance #152, the first decision to be made is to determine
whether the drug has been shown to be safe. Grounds for denial include
the determination that there is insufficient information as to whether
the drug is safe. Without a more thorough consideration of the potential
for livestock use of cefquinome to select for extended spectrum
beta-lactamases, this risk assessment does not meet that standard.

Keep Antibiotics Working also believes that if this drug is approved, it
will almost certainly be used metaphylactically to treat groups of
animals at risk for bovine respiratory disease, despite any label claim
for individual animal treatment.

This type of use would be inappropriate for critically important drugs
under Guidance #152. Keep Antibiotics Working acknowledges the
importance of drugs to treat animal disease, but feels that in this the
risks to human health are too great unless more information is
forthcoming about the potential risks of the extended spectrum
beta-lactamases, and more information about how this drug is likely to
be used.

That being said, if cefquinome is approved, Keep Antibiotics Working
recommends that it be approved for prescription only with an extra-label
prohibition. There must also be a commitment from FDA to both monitor
resistance to fourth-generation cephalosporins, including E. coli from
cattle, which is not currently done in a consistent manner. And to
collect data on how this drug is used so that resistance data can be
interpreted.

The extra-label restriction should be comprehensive, covering both other
species and other indications in cattle. Given the likely short
withdrawal period of this drug in both milk and meat, it could be used
in sick dairy cattle the day before slaughter, not the 60 days before
slaughter mentioned in the Intervet risk assessment.

So, we haven't heard anything about the expected withdrawal time, but if
it is similar to other cephalosporins, it could be very short. So you
could, basically, treat a dairy cow that is not doing well, send it off
to be slaughtered before, actually, the antibiotic wears off on it.

The current risk assessment only considers the safety of this drug in
cattle. But without an extra-label restriction, it could be used
flock-wise in poultry as well. The third-generation cephalosporins,
ceftiofur, commonly use extra-label in hatcheries. And this is a likely
cause of ceftiofur resistance detected in Salmonella isolates from
chicken.

Thank you for your attention. I was also asked by the American Medical
Association to read a little bit from their letter, if that is okay. I
don't think I will read the whole thing, but I was requested by them. So
now I am just going to read from the letter by the American Medical
Association, because they wanted you all to hear from them.

Okay, I have five minutes, so that is fine. Okay, and the letter was in
the back, but they are also going to \-- there is a correction in it.
But I will read it.

The American Medical Association respectfully submits the following
comments for consideration by the Veterinaries for Center \-- regarding
approval of the fourth-generation cephalosporins. The AMA notes that no
fourth-generation cephalosporins are approved for use in food animals in
this country.

I am trying to see if I can skip part of it.

(Pause)

DR. ROACH: I will just skip to the conclusion. For these reasons, the
AMA opposes the use of fourth-generation cephalosporins in food animals
\-- so the American Medical Association.

Furthermore, if fourth-generation cephalosporins are approved for such
use, the AMA strongly recommends that public health safeguards be put in
place. Minimally, these must include \-- the same things we have heard
before \-- enhanced national surveillance to include data on the
quantity of fourth-generation cephalosporins used in food animals.
Currently, no drug reporting is available.

Enhanced national surveillance to include monitoring for emergence of
the CTX-M mechanism, and enactment of extra-label prohibition to ensure
that fourth-generation cephalosporins are used only according to label.

Thank you for considering the AMA's concerns.

MS. SINDELAR: Thank you. Susan Prolman, Union of Concerned Scientists.
And you just have to speak right into it.

***[Comments]{.underline}***

***by Susan Prolman***

MS. PROLMAN: Thank you, Aleta. Hi, my name is Susan Prolman, I am here
on behalf of the Union of concerned Scientists. And I want to start out
saying that I have no financial relationship with any company that will
be impacted by the outcome of this meeting.

I also want to note that the Union of Concerned Scientists is a member
of Keep Antibiotics Working, and we endorse KAW's comments, but think
that this issue is so important, we also wanted to add our own as well.

This is a precedent setting application. As evidenced by the interest of
the medical community in this application, fourth-generation
cephalosporins are drugs of vital importance to human medicine. If
approved, cefquinome would be the first fourth-generation cephalosporin
approved for use in animal agriculture in the United States.

Widespread use of this important drug in animals could undercut the
efficacy of the fourth-generation cephalosporins and related drugs, and
lead to more severe and more expensive diseases in U.S. hospitals and
clinics. In an area of rampant loss of drug efficacy due to resistance,
CVM should think hard before taking this step.

For this reason, we applaud CVM for convening this VMAC meeting to
consider the important issues raised by this application. We also
commend the agency for continuing to approach the approvals in the
context of Guidance for Industry #152.

We strongly support the agency for using this scientific framework to
assess potential harm from resistance, resulting from the veterinary use
of antibiotics; although, reduce the opportunities for improvements and
updates to Guidance #152.

It is our view that fourth-generation cephalosporins should not be
approved for the treatment of bovine respiratory disease in cattle. We
fully support the approval of veterinary antibiotics to treat sick
animals; however, we are cautious regarding drugs that will be used
prophylactically to treat large numbers of animals, as we expect will be
the case with these formulations.

We believe that a proper analysis of this use under Guidance #152 in
response to the FDA's questions support this position.

In response to VMAC's question number one, we answer no. The basic
question before the Committee is whether cefquinome formulations are
safe in respect to their potential for transferring antimicrobial
resistant organisms to humans.

We think that the risk estimation failed to adequately assess the
following two critical pieces of information: First, the European
experience. The fact that data from Europe, where fourth-generation
cephalosporins are used in animal agriculture, show that this resistance
to fourth-generation cephalosporins is on the increase, while resistance
in the United States where the drugs are not used, is uncommon. We think
that this should be a red flag for the United States.

Secondly, the cross-resistance of third and fourth-generation
cephalosporins. The use of fourth-generation cephalosporins could select
for traits that will not only confer resistance to fourth-generation
drugs, but also cross select for third-generation cephalosporins. This
fact affects the consequence assessment of fourth-generation
cephalosporins because third-generation cephalosporins are considered
critically important by the FDA.

The FDA's standard for safety is reasonable certain of no harm. Unless
both of these lines of evidence are satisfactorily addressed in the
assessment, the sponsors cannot meet the burden of demonstrating that
resistance is reasonably certain not to develop.

To question number two, the Union of Concerned Scientists answers yes.
Guidance #152 sets forth the framework for the qualitative assessment of
the harm of resistance that assessed three elements: release, exposure,
and consequence. UCS believes that the FDA should update the
categorization of drugs used in its consequence assessment to reflect
the current state of knowledge.

Especially in the field of antibiotic resistance, CVM should have a
mechanism for reassessing the importance of antibiotics to human
medicine over time.

Guidance #152 currently lists fourth-generation cephalosporins as highly
important drugs, one-level below critically important drugs. The
categorization is based on years old data and new development suggests
are outdated.

For example, the World Health Organization's 2005 analysis lists
fourth-generation cephalosporins as critically important. New
information has also arisen indicating that fourth-generation
cephalosporins are used to treat a wider class of diseases than were
taken into account in the Guidance #152 classification.

In particular, the public health community now views urinary tract
infections as food-borne illnesses. Indeed, the sponsor acknowledges
that a fourth-generation cephalosporin is used, among other things, to
treat urinary tract infections in humans. The fact that scientists have
linked urinary tract infections in humans to cattle-based, food-borne E.
coli calls into question the claim made in the sponsor's risk estimation
that cefepime is not indicated for the treatment of food-borne
pathogens.

All E. coli infections, including urinary tract infections, Septicemia,
and Meningitis are potentially food-borne. The sponsor acknowledges that
this drug is also used to treat intra-abdominal infections. The broader
spectrum of diseases treated by fourth-generation cephalosporins argue
for their greater importance in medicine, and supports the argument that
they should be categorized as critically important.

On the exposure component of the assessment, UCS questions the sponsor's
contention that these formulations of cefquinome are intended to be used
in individual animals only. We believe that VMAC and CVM should consider
this proposed use, which can be expected to involve routine injection of
possibly millions of cattle, to be of herd-wide use, and not individual
use.

In any case, VMAC should not proceed with this application until it has
from the sponsor reliable information on the number of cattle each year
that will receive an injection of each of these formulations.

If VMAC proceeds with this application, it should ask CVM to take
concrete steps to ensure that the drug will be used only for therapy,
and not for prevention of respiratory diseases in cattle. The
respiratory diseases at issue are endemic due to the conditions in which
the cattle are transported, housed, and fed. The drug could be used for
prophylactic compensatory purposes in millions of animals.

If the application is approved, it should be restricted to narrowly
delineated treatment of bovine respiratory disease only in beef cattle.
VMAC should recommend that these drugs are never used in dairy cattle,
poultry, swine, aquatic species, or any other species of food animal.

VMAC should recommend that if the drugs are approved, there should be
strong prohibitions on extra-label use. UCS believes that approval of
these formulations are not needed for two reasons. First, the other
drugs can address bovine respiratory disease associated with shipping.
And, second, shipping fever in cattle is wide-spread because of poor
management practices that should be addressed before resorting to drugs.

And, finally, to question three, the Union of Concerned Scientists
answers no. We oppose the approval of these drugs; although, we do note
that if CVM does approve these drugs, the drugs should be administered
only to treat animals diagnosed by a veterinarian with a disease, or
others at immanent risk of contracting the disease. And only to
individual animals and not to whole truck loads, herds, pens, or other
groups of animals.

Moreover, if the application is approved, it will be essential to
monitor microbial populations for evolution of resistance. This will
require increased surveillance through the NARMS Program. Significantly
increased NARMS funding must be a pre-requisite to FDA approval for the
use of these cefquinome formations, or any fourth-generation
cephalosporin use in animal agriculture.

Requirements for detailed, timely drug use reporting should accompany
any FDA approval for use of these formulations, or any fourth-generation
cephalosporins used in animal agriculture. Without reliable, meaningful
data on the quantity of use, the purpose of use, the type, number, and
location of animals treated, it will be exceedingly difficult to
interpret fluctuations in rates of resistance.

UCS recommends that all such information be made available to the public
at the same time that it is shared with the FDA.

I want to thank you very much for your consideration of our comments,
and turn the microphone back over to Aleta. Thank you.

MS. SINDELAR: Thank you everyone. What we will do is turn over to the
VMAC at this time for any questions directed towards the open public
hearing participants.

***[Questions of Public Comment Session Speakers]{.underline}***

DR. LEGGETT: John, go ahead please.

DR. MCGLONE: I have some specific questions. I don't know whether it is
for the sponsor or for the FDA. Can you give us some idea \-- probably
from the sponsor \-- what the withdrawal will be? I really have really
three questions for, perhaps, the sponsor.

DR. LEGGETT: John, I think we are going to ask questions of the open
hearing \--

MS. SINDELAR: Open public hearing participants.

DR. LEGGETT: \-- participants right now, and then we will get to those
questions for the speakers from this morning in a minute or two.

DR. MCGLONE: Oh, okay.

DR. LEGGETT: Okay.

MS. SINDELAR: So, if you have any questions for the open public hearing
speakers, please ask now. Sure, Dr. Leggett.

DR. LEGGETT: There was some data presented that there was a five-fold
increased risk of Salmonella by the CDC from, I believe he said 1997 to
2001. But then I noticed that that has since dropped. And I wondered how
\-\-- could explain what is going on.

And then there is the cattle slaughter data that talked about a 20
percent rate. What is the discrepancy? Is it just different animals,
different sub-sets? Or, what is going on?

DR. GRIFFEN: Well, surveillance data is just what it is, we just test
the resistance of isolates that we get from people, and unless we do
ancillary field studies, we don't have along with that data, an
explanation of why it is increasing or decreasing.

If you would like, I could speculate, but the possible reasons I would
give would not be based on particular studies that we have done.

(Members not speaking into microphones)

MR. ROACH: Yes, what I presented was cattle slaughter data. What you
would have to think is that what human Salmonella isolates are going to
be from other sources as well. So you wouldn't expect the resistance. So
I would assume \-\-- the assumption is the bulk of the Salmonella in
humans actually comes from poultry. So you wouldn't expect the same
percentage of resistance in human isolates as in the cattle isolates.

DR. LEGGETT: Is it also a difference in techniques in terms of you only
look at cattle that were slaughtered so it looks like a much higher
number than an actual use? So, maybe it is less than one percent if we
sampled intestines or feces from all cattle?

MR. ROACH: Yes, I am actually not sure about that. What I used is
slaughter isolates, is because what we have with NARMS is we have
diagnostic isolates for animals. Or, the slaughter of the bulk of them,
and I think the slaughter ones are the most consistent over time.

DR. GRIFFEN: Could I try to help you with that question a little bit
more than I did?

DR. LEGGETT: Sure.

DR. GRIFFEN: Okay. So, again, we don't know the reasons for the change,
but remember I described what was happening in Massachusetts and Vermont
in 2000. And we went up and there were sick people, but there were also
quite a number of farms that have sick animals. And I think what bovine
practitioners could tell you better than I could, but we have seen with
a number of pathogens is when they first emerge, we detect them in
humans, they are just the unexpected, unintended host. But they have
emerged in animals in sort of a big way, making animals sick, which is
very unusual for Salmonella. And they seem to rip through these herds,
causing a lot of morbidity and some mortality.

And after awhile, the pathogen seems to settle down a bit. And, perhaps,
when it settles down, there are fewer animals excreting the pathogen and
maybe less getting into the slaughter isolates.

MS. SINDELAR: Can I take a moment to remind you to please state your
name before your question, and your response, for purposes of
transcription. And try to speak as directly into the mics, I am sorry
about the noise. Yes, Rich.

DR. CARNEVALE: Yes, could I suggest that Dr. Paula Cray, who is in the
audience and runs the NARMS Program comment on the slaughter data? The
question about the slaughter data. If you would, Paula.

DR. CRAY: May I?

MS. SINDELAR: Yes.

DR. LEGGETT: Please, go ahead.

MS. SINDELAR: Dr. Paula Cray.

DR. CRAY: My name is Dr. Paula Cray, and I am the Director of the animal
arm of the NARMS Program. And the differences that you are going to see,
first of all, NARMS collects isolates from diagnostic isolates, from
diagnostic sources which are presumed to be from ill animals that many
of whom have already succumbed to some disease \-\-- were actually
isolating our isolates from tissues.

Then we have the slaughter data, which is based on the FSIS compliance
testing. And those are presumed to come from healthy animals. And then
we have also an on-farm component. And the biggest differences that you
are going to see between some of these sets of data have to do with
serotypes. So the serotypes that you get from cattle isolates will be
different from the serotypes in large part that you get from chicken,
that you get from turkey, that you get from swine. And those, in turn,
are going to have variability in comparison to the isolates that you see
with the human; although, there is some overlap.

And what you are going to find is is that, in large part, multi-drug
resistance, in particular, or resistance to certain antimicrobials is
driven by serotype. So, any time you look at these data, you have to
look down to the serotype level, and you also have to look by regional
and seasonal differences, because you will also see that discrepancy
too.

What we haven't seen though is an increase in any DT-104 over a period
of time. Nor have we seen an increase in MDR AmpC and our isolates that
we are seeing. And we have done molecular work on these isolates, and we
have not found any ESBL yet.

DR. LEGGETT: Thank you.

MS. SINDELAR: Thank you.

DR. MCGLONE: Okay, to this group. I wonder if the last two speakers
could comment on the humane aspect of your recommendation? That is, to
withhold a new class of antibiotic to animals that are sick;
particularly, those that are carrying bugs that are resistant to the
third-generation.

MS. PROLMAN: Well, speaking on behalf of the Union of Concerned
Scientists, you know, we believe that the prevalence of shipping fever
is really problematic and points to poor management practices, which are
a major humane problem. And we advocate for better management practices
so that these \--

DR. MCGLONE: Sorry, I can't hear.

MS. PROLMAN: We advocate for better management practices in terms of the
way that the animals are housed and transported to prevent the spread of
disease from being so wide-spread.

MR. ROACH: I would also like to respond by saying that there are already
14 other antimicrobial in 8 classes approved for this indication. So,
there are other options to treat with this, so we already have 14 drugs,
if you count the different ceftiofur forums, and you would have even
more drugs for the same indication.

So, it is not like something that has not \-- and what I would say is if
the problem is multi-drug resistance as why we need a new drug, then we
really need to think about how do we address the problem of resistance
and its impact on animal health.

MS. SINDELAR: All right.

DR. LEGGETT: Jim Leggett. A question for anybody. A comment was made
about multi-drug resistant AmpC, and then, perhaps, that tetracycline, I
think, was given as the example, but it could have been aminoglycosides,
it could have been anything else that are also given to animals.

Is there any data that says that a use of a fourth-generation
cephalosporin is going to drive more emergence than any of the other
co-drugs in the plasmid? Especially, since we see that ESBLs are sort of
this pan-resistant thing. So, I don't know of any data. Does anybody
know of any data that says it is more likely to be this drug than, say,
the tetracyclines that are used commonly, from what I understand, with
cattle?

(No response)

DR. LEGGETT: Do you know of any?

(Panel nodding their heads "no")

MS. SINDELAR: This looks like a negative response. If I can say that.

DR. CRAIGMILL: Anyone from this morning that would like to chime in on
that question?

(No response)

MS. SINDELAR: Okay, let's move on.

DR. CRAIGMILL: Okay, thank you very much. We appreciate your
participation and input. I would like to ask this morning's speakers to
please come forward, those that are still here.

MS. SINDELAR: Those speakers include Drs. Gilbert, Lechtenberg, Johnson,
Bryskier, and White. And Dr. Powers had to leave.

(Pause)

MS. SINDELAR: What we will do is answer any Q&As from this morning, and
then Dr. Gilbert will address the questions to the Committee and clarify
any questions regarding the VMAC questions at that time.

So, first, Q&As regarding any of the this morning's presentations.

DR. CRAIGMILL: And with that, Dr. McGlone.

DR. MCGLONE: I can hardly wait. Could, perhaps, the sponsor answer these
three questions for me please? What is the proposed withdrawal in days,
or whatever units you want to use? Will you be recommending \-- sorry
about the noise \-- individual animals be treated, or groups of animals?
I noticed in the report it said that it is not suitable for use in
water, so I know from that statement that that could not be a round of
application \-- but pens or individuals? And then, finally, the number
of doses you would propose.

And I know this may change in the regulatory process, but you are
talking about one dose a-day for three days, or one every 12 hours, or
whatever.

DR. JOHNSON: Thank you, Dr. McGlone, those are good questions. I will
start by responding to your first one regarding withdrawal time. Both
formulations of cefquinome that are currently indicated for bovine
respiratory disease are still in the development process. These
withdrawal times, therefore, have not been finalized. There is no final
label at this point.

But, I think you can expect that, being of cephalosporin class, probably
this will not be a long withdrawal.

DR. CRAIGMILL: Long as in?

DR. JOHNSON: Well, we expect less than a week total in duration.
Probably less for one formulation versus the other.

DR. CRAIGMILL: Oh, less than a week.

DR. JOHNSON: Yes.

MS. SINDELAR: Let me just remind this new group here that if you could
please speak loud and directly into the mic and state your names for
purposes of transcription. Thank you.

DR. JOHNSON: Getting to your second question regarding the conditions of
use. As I have indicated in my presentation, this will be indicated for
individual animal use only. We have no plans to develop any kind of
formulation of cefquinome for use in groups of animals. And as also
indicated, the drug is really inappropriate for use via feed or water.

DR. CRAIGMILL: And the number of doses?

DR. JOHNSON: And number of doses, as I mentioned again, we have two
different formulations in development. One will be a single injection
product, which will be, basically, it in terms of its therapeutic
regimen. The other will be a daily injectable for two to three to four
days, potentially.

DR. CRAIGMILL: Thank you.

DR. LEGGETT: Jim Leggett. A follow-up question regarding the dosing,
because I saw very little \-- at least at most a scant \-\-- data in
here, so some of these may be really silly.

In the report, cefquinome was compared to cefepime, so I would assume,
therefore, that the kinetics are like cefepime? And then following along
that line, I assume your one-time dose is a sustained release
preparation, and the once-daily dose is also somewhat sustained in order
to get your adequate serum levels to actually be effective?

DR. JOHNSON: Carl Johnson with Intervet. Yes, with regard to the dosing
regimen, and your question regarding kinetics, obviously, that is
species dependent. So we really have no data for cefquinome in humans.
We do have this injectable, single injection product, which is one of
the formulations that was reviewed.

And this does provide a therapeutic blood levels that has been
demonstrated to be effective for the indication.

DR. CRAIGMILL: Dr. Riddell.

MR. RIDDELL: Gatz Riddell, VMAC. For either the sponsor or for Dr.
Lechtenberg, have there been any trials done with this product in a
metaphylactic frame?

DR. JOHNSON: I will answer that one, Kelly. No. This will not be labeled
for metaphylactic use, for treatment of animals at high-risk. It will be
indicated only for individual sick animal use.

MR. RIDDELL: And will there be a claim for lactating dairy cows?

DR. JOHNSON: That is, as you have seen from the claims for cefquinome in
Europe, there are some indications for dairy animals. We, certainly,
have that potential here in the U.S. At this point, we have to evaluate
the need and the development costs and risks. Whether or not we elect to
develop this for dairy is really beyond the scope of this meeting. And
at this point, we are looking at strictly a BRD claim for non-lactating
dairy and beef.

DR. LEGGETT: Jim Leggett, again, for the sponsor. What are the
susceptibility patterns for the bacteria that you put on your slide
about the ones that cause bovine respiratory disease? I recognized
\-\--, but I didn't really recognize the others. Is there any resistance
that is used now that would require this new thing? Or couldn't we just
use Ampicillin?

DR. JOHNSON: Yes. Carl Johnson, again, with Intervet. Your question is
in reference to target pathogens for which the drug is being developed.
And, yes, we do see a high degree of efficacy, in-vitro, as well as
in-vivo, in these clinical trials. We have not tested the product
head-to-head, or against a third-generation cephalosporin like
ceftiofur.

DR. LEGGETT: Sorry, I didn't make myself clear. What I wanted to know is
do any of those target pathogens have resistance to Ampicillin, or
cefazolin, or tetracycline, or other drugs that are already on the
market?

DR. JOHNSON: To answer that question, probably a little bit more
directly, I am going to call on a colleague of mine from Intervet.
Marcus, would you be able to respond to that? This is Dr. Valerie Tomma
with Intervet.

DR. TOMMA: Valerie Tomma from Intervet, microbiologist. We have some
resistance in the \-\-- for the older antibiotics, indeed. I can speak
from the \-\-- program we are doing in Europe and we have some
resistance rates \-\-- for the older antibiotics.

DR. LEGGETT: They are on the level of what, do you know? Is it just to
Ampicillin or a bunch of things?

DR. TOMMA: Oh, it is also to tetracycline too, but it depends on the
person, it is depending on the antibiotics.

DR. LEGGETT: And you said you just studied Pasteurella, you didn't study
the other pathogens?

DR. TOMMA: Pasteurella \-\-- and we have less \-\-- in Europe.

DR. LEGGETT: Okay, thank you.

DR. RELLER: Dr. Barth Reller. In follow-up to Dr. Leggett's question,
specifically, are there data of ceftiofur, the currently licensed third
in this country, resistant target pathogens? The principal ones listed
for bovine respiratory disease? Dr. Walker, behind, is shaking his head.
Dr. Robert Walker knows, a veterinary microbiologist.

DR. WALKER: As far as I know, and I haven't been in that arena for a few
years, but ceftiofur, there are no Mannheimia haemolytica, Pasteurella
multocida, or Histophilus somni that are resistant to ceftiofur.

DR. RELLER: This would fit in the expected resistance, in that there are
a few \-- at least in human disease, the one that we see most often, is
Pasteurella multocida that may have the simpler beta-lactamases present.
But to have a third-generation cephalosporin resistant among those, I
would think, would be surprising in that it sounds like there is general
agreement that that has not been recognized or, at the most, very
uncommon, if it occurs at all.

So the reason I wanted to pursue this question was for Dr. Lechtenberg,
in a way, the same question from a slightly different direction. You
cogently pointed out in giving the relative risk factors for bovine
respiratory disease, the quality of the animal, the realities of
shipping management that was addressed by the Union for Concerned
Scientists.

And in this equation, I think we, perhaps, now have the answer. I wanted
to know where in the scale of risk, or the scale of potential benefit,
weighing the benefit or efficacy, if you will, versus the risk? And in
the context of this discussion, most of the risks that we are talking
about in what are generally recognized as safe antibiotics, both in
humans and animals, has to do with the risk for development of
resistance.

So, in the scheme of things, the quality of the animal, the realities of
the shipping, what might or might not be addressed with better
management practices, where does the inability to treat only to
resistant organisms uniquely susceptible to fourth-generation
cephalosporin in veterinary medicine come in for the diseases that we
are talking about? And I would infer from the comments made that that is
not an issue. That is, it may work, but there is not a need for it from
the standpoint of resistance.

DR. LECHTENBERG: From a standpoint of resistance, if we make the
assumption that we have ubiquitously available access to the antibiotics
that are approved, one could make that argument. Also, as part of my
presentation this morning, you might recall my personal experience of
not having access to an entire drug class of antimicrobial. And given,
yes, we do have three labeled cephalosporin products available to us,
but the fact is, they are all one chemical entity.

One could imagine various issues, which might include manufacturing, or
some other things that might cause this single chemical entity to become
unavailable to us.

And I am glad that you also brought up the management issues. I was
either not convincing, or not understood, but management and the
appropriate care of these animals is extremely important to our
industry. And I would be doing a disservice to the veterinary medicine
community, and to the cattle producers if I left here without saying
once again, for the record, proper care, proper management, doing
everything we can possibly do to minimize the amount of antimicrobials
that we need to use for therapy is foremost.

In that same vein, I would be very remiss if I didn't address the
comment that suggested that no matter what the label says, we are going
to use these products as we choose to in practice. That is not true.

We take this process very seriously in the cattle industry, and I think
this is a wonderful forum. And I would like to assure the people in
attendance here today that if products are approved and labeled, the
vast majority of our industry will do everything they can do to make
sure they are used according to those regulations.

DR. CRAIGMILL: Dr. Leggett.

DR. LEGGETT: A follow-up on that. I was turning from your slides 20
through the next ones, where you talked about the percentage of cattle
that were actually treated for BRD et cetera. And I was trying to figure
out what the percentage of all antibiotic use was due to the
cephalosporins. And of that, what was due to ceftiofur rather than the
other? Or is ceftiofur the only cephalosporin?

Okay, so what is the percentage currently? It looks like it is 40 or 50
percent of all the antibiotic use is the ceftiofur. But I am not sure I
have enough of your percentage down here to figure that out.

DR. LECHTENBERG: Good question. Appreciate, that is 1999 data and time
has probably changed. The cephalosporin usage in treatment of bovine
respiratory disease \-- I believe the slide you are referring to talks
about the number of operations that will use cephalosporins in their
toolbox, so-to-speak. And that number was about 40 percent for therapy.

So, the number of cattle treated, and I am working from memory here
also, but it is considerably less than that as far as the actual number
of therapeutic doses that in that survey are relying on cephalosporin as
the drug that we are going to pull into the bottle to administer.

DR. LEGGETT: Yes, the numbers I was trying to get at is the 14 percent
of cattle developed BRD, and of that, 6 percent \-- well, no, 5.4
percent of the cattle were treated metaphylactically. In other words,
take 5 divided by 14 \-\-- and come up with another number.

And then what are \-- you said, sometimes you don't have an antibiotic
available. What are the other antibiotics that are commonly used for
BRD? People have tossed around tetracycline products, the
fluoroquinolones, et cetera.

DR. LECHTENBERG: Good question. This is Dr. Kelly Lechtenberg again. The
most commonly used classes of antimicrobials for BRD therapy today
include macrolide class antibiotics, both tilmicosin and tulathromycin.
They include fluoroquinolone class antibiotics. They include
cephalosporins. As a group, those are the most common.

Appreciate that there are differences because of what we have talked
about this morning, and differences of class of cattle. It is not a
matter of here is the best antibiotic to use September 25^th^, today,
but based on the history, and the response rate in the cattle, the
choices will vary from region-to-region in the country.

Did I answer that to your satisfaction?

DR. LEGGETT: Yes, thank you.

DR. CRAIGMILL: Yes, Dr. Sams.

DR. SAMS: Richard Sams. Dr. Johnson, what routes of administration and
formulations are proposed for this product?

DR. JOHNSON: Carl Johnson with Intervet. Dr. Sams, the routes of
administration are both subcutaneous \-- I am sorry, what was the second
part of that question?

DR. SAMS: Formulations.

DR. JOHNSON: Oh, formulations. Yes, there is a reconstitutable powder
formulation and also a long-acting suspension.

DR. SAMS: Was that suspension?

DR. JOHNSON: Yes.

DR. SAMS: And will those be marketed in single-use vials?

DR. JOHNSON: No. They will be marketed in multi-use vials, as is
convention with antimicrobials for food animals.

DR. SAMS: Are there any formulation factors, and I don't know what those
might be, that would tend to cause the product to be used as you have
proposed, as opposed to other uses?

DR. JOHNSON: Well, it is perfectly obvious you are not going to use a
sterile injectable formulation for oral administration. We also know
that absorption from the gut is very limited, if at all. So, the
likelihood that these formulations will be used in other routes of
administration is \-- well, I can't imagine one that would have any
significance.

DR. SAMS: Thank you.

DR. CRAIGMILL: I would like to follow-up, just on that question. One of
the indications, apparently, in Europe is for E. coli mastitis. Is that
a systemic treatment or intramammary approved overseas?

DR. JOHNSON: That would be a systemic treatment with an injectable
product.

DR. JOHNSON: Okay.

DR. PAPICH: Dr. Papich. The approved breakpoint for ceftiofur is less
than two micrograms per ml. And for cefepime, for human use, it is eight
for susceptible. I know it is premature to make you guys pick a
breakpoint, but do you have an idea where in relation to at least those
two extremes, where the breakpoint might fall for this drug?

DR. JOHNSON: Carl Johnson with Intervet. Dr. Papich, good question. You
are probably aware that it is the CLSI group is evaluating most new
antimicrobials, including cefquinome, generally, after approval of the
compound. There is a fair bit of work involved in that process, and we
are currently in that process.

So, in terms of the actual breakpoints, which establishes susceptibility
or resistance, those have not been established yet. We have used in some
of our surveillance work the surrogate cefepime breakpoint to describe
whether these fourth-generation cephalosporins are sensitive or
resistant, but it has not been established at this point for cefquinome.

DR. PAPICH: That was going to be my follow-up. This is Dr. Papich again.
So, reporting resistant versus susceptible, any data that has been
reported so far, it is using the cefepime, eight micrograms per ml
breakpoint. Correct?

DR. JOHNSON: Correct. Yes, and I believe \-- and, Andre, correct me if I
am wrong, that was at \-\-- 32 for resistance.

DR. BRYSKIER: Yes.

DR. JOHNSON: Yes.

DR. BRYSKIER: But today, I think everything is sensing because the CLSI
sense and you are going to \-\-- it. In Europe, they changed the
breakpoints for cephalosporin for the \-\-- and \-\-- fourth-generation
cephalosporin. Perhaps, \-\-- know better than I because we don't \-\--
through the \-\-- for so many years. So, it is a lot of discussion now
to change. And the reasons this morning I point out, doctor, we have
breakpoint between 1 and 32, and depending on the country. It is
sometimes difficult to really assess the reality. But in global, it is
\-\-- E. coli between three to four percent. Change, not a lot.

If you look \-\-- the population distribution, the change so many for
the moment.

DR. MCGLONE: John McGlone. This is for either Dr. Lechtenberg or
Johnson. I was a little bit confused when I first started reading this
because the application is for respiratory disease, and all the
objection seems to be for enteric problems. Completely different
microbes, and present at a different time.

Could you describe what you think might be the most typical application
of this product, relative to when the animals arrive and when they go to
market? And, therefore, some address the risk involved with secondary
non-target micro-organisms.

DR. LECHTENBERG: This is Kelly Lechtenberg. The majority of bovine
respiratory disease, for which the intended claim is being discussed
happened early in the feeding period. If you are looking at calves
coming into feed yards, in that say 500 pound range, they will be on
feed about 200 days. And the preponderance of naturally occurring BRD
will happen within the first 30 days on feed.

So, while we do have some straggle along the graphs that I presented
this morning, we are talking about a feedlot population, and didn't
really clearly bring that out. But if we graph BRD incidents over time
for a pen of calves, you see a peak very early in the feeding period.

And that tails off and it quite common to not have any BRD therapy for
the last 50, 60, 100 days on feed. So, you do bring up a good point in
terms of where that selection pressure relative to time occurs.

DR. CRAIGMILL: And then for adult animals, would adult animals be
covered by the label? Maybe there is some situation, I don't know if it
is a dairy cow or a mother beef cow that might be treated, and then she
still stays in the herd for years, perhaps?

DR. JOHNSON: Carl Johnson with Intervet. Yes, I mean, this product will
be approved for adult cattle. It will not be approved for use in veal.
Or veal calves. So, cattle of all ages, as long as they are beef cattle
and non-lactating dairy, with these two indications, that is what the
label will read.

DR. CRAIGMILL: Dr. Leggett and Dr. Riddell.

DR. LEGGETT: Would it be possible to ask this question of Dr. Sundlof,
because I don't see John Powers here?

DR. SUNDLOF: Sure.

DR. LEGGETT: And it involves the FDA regulations for this guidance. In
other words, I heard many times from the people that spoke before, and
around here that, oh, we should limit extra-label use, we should make
sure that going forward that --- the question is, is this a highly
important antibiotic, or a critical, you know, those sort of things.
What is the next process? Does the FDA have to stay put with what is on
the paper now, or can you go back and look at it scientifically again
and make modifications without open hearings, and that sort of thing?

DR. SUNDLOF: I will try and answer that. And you are talking about
prohibition on extra-label use, is that the part you are talking about?
The prohibition on extra-label use requires a change in regulation. In
other words, there is a formal process by which we have to publish a
notification that these drugs are now prohibited from extra-label use.
And that prohibition can be very specific, or it can be very general. In
other words, all extra-label use, or extra-label use in certain animal
species.

In order to do that, there has to be a determination made. A scientific
determination made that the extra-label use in that particular situation
that we are concerned about \-- and let me just give you an example of
that.

We recently published a prohibition of the use of Phenylbutazone in
lactating cows. And we didn't prohibit in other species because we were
aware that there was significant extra-label use in lactating cows, and
it may have been a public health issue. So, that is a case.

But the burden is on the FDA to establish that the extra-label use of
the drug may present a risk to public health. So that is a process that
we will have to go through if we are to issue an extra-label use
prohibition.

And that must be based on evidence or a very credible threat that the
extra-label use will pose a threat to public health. Let me give you an
example of the latter.

We recently published a prohibition on the use of antivirals of the
Tamiflu variety for use in chickens and turkeys and ducks, I believe, in
the United States. To our knowledge, there has never been any
extra-label use of those products in poultry in the United States. There
had been in another country, China. And in order to prevent what we saw
had actually occurred in China, and that is that the emergence of
resistance of the H5N1 virus to these antivirals did occur, and we were
able to make a scientifically credible case. And, therefore, now have a
prohibition on that use.

So it is not something that the Committee can recommend, and that the
FDA can automatically do. There is a process involved in making a very
strong, credible case that it does pose a risk.

DR. CRAIGMILL: Dr. Riddell.

DR. RIDDELL: I guess that was for either Dr. Lechtenberg or Dr. Johnson.
Have there been any acute studies done on the enteric pathogens
immediately following therapy and, possibly, some chronic follow-up to
see what happens with the enteric pathogens?

DR. JOHNSON: Carl Johnson with Intervet. To my knowledge, we have no
data to evaluate. I just want to clarify the question here, you asked
about acute studies?

MR. RIDDELL: Yes. They would have to be done pre-treatment and then
immediately post-treatment to see if there is a change in enteric
pathogens.

DR. JOHNSON: Well, if we haven't done that specifically, we have
generated that type of data because of other needs within the
development pathway. Would someone of Intervet's \-- the Intervet group
there, care to?

MR. : \-\-- from Intervet. What we can say is that we did not do any
pathogen load studies for cefquinome, for example, if someone to test
for Salmonella increase by giving the drug to livestock. We have not one
that.

MR. : Could I get you to repeat that?

MR. : We did not do any pathogen load studies for cefquinome, because it
is not necessary in the approval, in the registration process. So we did
not do that, it was not required.

DR. JOHNSON: I would like to add to that. Carl Johnson, again, with
Intervet. As part of Guidance #52, we did establish the microbial safety
of drug residues, where you are looking at enteric pathogens in models.

MR. RIDDELL: I have one more question that I would like to address,
probably, to Dr. Bryskier. We have heard from a couple of our invited
public speakers that there is an increasing incidence of resistance to
the fourth-generation cephalosporins being noted in Europe. And that
seems to be in contrast to some of what you were presenting. I wondered
if you would comment on this?

DR. BRYSKIER: I think, first of all, the number of studies and
surveillance studies concerning the fourth-generation cephalosporin are
very little. So, it is extremely difficult to say that there is high
incidence now, or an increase in incidence, of resistant to cefepime, or
cefpirome first.

Secondly, if we \-\-- release \-\-- it is always the same people
publishing in five or six different journals who have a mass of papers.
So, it looks like it is very important \-\-- of resistance. At the end,
it is always the same thing, publishing one strain.

So, in global for the moment, we have only two or three studies showing
what is really ongoing in Europe. You have the study of \-- I showed two
studies \-- and probably there is another one, was the Mystic Study. But
also difficult to interpret because there are more carbapenam oriented.

So, if you have an increase of ESBL, you will have an increase of
resistant to fourth-generation cephalosporin. That you cannot escape.
But, you will not have an increase probably for the moment to resistant
to cephalosporinase.

So, it is really different. But, you know, each time you introduce a new
antibiotics, you have resistance and you cannot escape that. If you look
in the time, human \-- two generations in 50 years. And bacteria is
1,500 generations. So, we cannot compete. That is all, the mutation is
very quickly. You cannot do anything against that. The only things is to
use properly the antibiotics in our end and you try to use it for
nothing, and everything for nothing.

\-\-- inter-friction when we have probably resistance, but for all
antibiotics, the same. You cannot escape. Perhaps, in 50 years from now,
but I will not be there.

MR. RIDDELL: Thank you. And then one for Dr. Johnson. Basically, this
drug has been approved in the European Union for more than 10 years. Is
the use pattern in the EU the same as what is being proposed in the
United States?

DR. JOHNSON: Carl Johnson with Intervet. No, the use pattern will be
different. And with regard to this specific microbial food safety
assessment that you have had an opportunity to review, the use pattern
will be very limited to simply BRD in beef and non-lactating dairy.

What we do in the future will probably be even \-- I mean, there are
certainly opportunities, as mentioned earlier. Just where we take those
is really a complex set of decisions that depend on a lot of risk, and
cost, and need. So, will the use patterns be the same, very likely no.
And there are a number of reasons for that.

MR. RIDDELL: And then the answer to the use pattern is being different,
is the use pattern in Europe much broader than \-- this is a much more
narrow one that is proposed here? It is a much broader use in Europe, is
that correct?

DR. JOHNSON: That is correct. Yes. And in Europe, as you saw, it is
approved for use in cattle, swine, and horses now, with multiple
indications, clinical indications for each species. In the U.S., we will
probably keep it, at least, for the foreseeable future, to cattle for
respiratory disease. And with the potential of expanding that label
prudently where the need exists.

DR. GROSECLOSE: Sam Groseclose. Just a question on the use in other
species in Europe. Was that done at the same time, or was that a
sequential introduction to different species?

DR. JOHNSON: No, that was a sequential introduction. I believe the
cattle claim \-- at least the initial claim appeared in 1994. They were
probably extensions to that label in the succeeding years for that
species. And as you saw, I think swine indications were approved in
1999, and the horse now, just a year ago, in 2005.

DR. GROSECLOSE: And another question, if I could. Sam Groseclose. The
issue of metaphylaxis or the use in that manner, would it be prohibited?
While you indicate that it is to be used for therapeutic purposes, would
it be contraindicated for metaphylaxis?

DR. JOHNSON: Carl Johnson with Intervet. It wouldn't be contraindicated
for metaphylaxis. It certainly would not be labeled for metaphylactic
use. To label your drug for that, you have to show the agency that the
drug works in that condition. In these formulations, we may not have the
ideal formulation to use that way, therefore, we are proposing that it
be used for therapeutic use only.

DR. BROWN: Corrie Brown, VMAC. I think this question is for FDA. If this
drug is approved, how and when will it be incorporated into the NARMS
surveillance?

DR. WHITE: This is Dave White, CVM FDA. I think I can answer that. It
actually already is. We actually already have it on our secondary panel.
The secondary panel is not used as much as it could be.

Right now, what we are trying to envision is how to use it for 2007. And
we have to evaluate current resources to see how it can be used. But,
currently, it is on the second panel already.

The choices would be to move it to the primary panel. If we do that, we
have to get rid of another drug, because there is only 97 wells on the
panel. So, to add that, we have to get rid of something, or we start
moving to a secondary panel, which then, of course, would increase the
costs. So we will just have to start evaluating how we are going to do
that.

DR. GROSECLOSE: Sam Groseclose. A follow-up question on that. It sounded
like it is not \-- you have three arms to NARMS. Apparently, it is not
in the human surveillance activity?

DR. WHITE: This is Dave White again, DVM. The plates have been made
available to CDC. They probably just do not have the data yet for '04
-'05 yet. This is a brand new plate that we just instituted this year.

We have been making use of it at CVM, as we also had the research arm -
the Office of Research, where we do studies \-- tagged along with NARMS.
As the CDC and USDA as well. So, we hope to really start going in '07
with this plate.

And I think Dr. Griffen has a comment as well on that.

DR. GRIFFEN: As I said in my presentation, that is correct. We at CDC
have not begun testing for fourth-generation cephalosporins on human
isolates. And we don't have the ability now to do it even if we got the
plates, along with what we are doing right now with our current
resources that we have.

DR. CRAIGMILL: Dr. Riddell.

MR. RIDDELL: Gatz Riddell. I guess a question for Dr. Johnson. Are there
any other formulations approved and marketed in Europe, other than the
two you are proposing for the United States?

DR. JOHNSON: Yes. Carl Johnson with Intervet. Yes, there is a 2.5
percent solution approved. That is also an injectable. And there is also
an intramammary formulation approved.

DR. GROSECLOSE: Several of the public commenters mentioned this issue
about getting access to usage data, drug usage information. And I
noticed Dr. Powers presented data from what appeared to be third-party
data sources. Can someone from NARMS comment on how you can access drug
usage data now? And do you have any plans underway to improve your
access to drug utilization?

DR. WHITE: Dave White, CVM FDA. That information is not currently
collected under NARMS at this point.

DR. GROSECLOSE: How can you access that information?

DR. WHITE: I would turn that over to Dr. Sundlof to answer that
question.

DR. SUNDLOF: Thank you, Dr. White.

(Laughter)

DR. SUNDLOF: We have some sources of \-- public sources of information
that we do have access to, and we have accessed them in the past. There
is a Doanes Database that has some of that information.

We also require drug companies to report the total amount of drugs that
they manufacture and sell every year, but it doesn't give us the
specific kind of information that I think we would need to do a more
thoughtful epidemiologic study.

We have initiated the process of re-writing regulations to ask for more
of that information, but based on the amount of other pressing issues
that we have had before us, that has not advanced as far as we would
have liked it to. But that initiative has been started, and if we
determine that it is necessary to get the information \-- if we can't
get it from other sources, at some point, we may have to publish these
regulations which would make it then a requirement.

DR. CRAIGMILL: John McGlone.

DR. MCGLONE: John McGlone. This may be my last question for this group.
We have this letter from Dr. Peter Collignon from Australia \-- I don't
know if you have seen this \-- but I just wanted you to comment on one
part of a sentence that he has in this letter.

And I will just read you part of what he says:

> "People in the community" \-- I guess that is all of us \-- "are
> carrying resistant bacteria" \-- speaking of ESBLs \-- "for which
> third-generation cephalosporins in cattle and other food-producing
> animals is the most likely explanation."

Is that the most likely explanation, or is overuse in human medicine a
more likely explanation?

DR. JOHNSON: Could you rephrase that question for Dr. Bryskier?

DR. MCGLONE: Do you think that the resistance that if found among people
is \-- to third-generation cephalosporins \-- comes from cattle, or does
it come from overuse of antibiotics in the hospital among people?

DR. BRYSKIER: It is difficult to answer. From my opinion, I am not sure
that the cattle are \-\-- give resistance to human. I think the human
will be resistant to animals. That is totally different. This is my
personal opinion.

But it is difficult to answer because today, we don't have real good
studies showing who is given that. But if you see the balance between,
for instance, dogs and \-\--, and if you read on \-\-- you can see that
a lot of dogs acquire \-- they make a gene for human. And the resistance
is in human. Look at the diversity.

So I am not so sure. And it is a lot of discussion in Europe between us,
we don't know. And I think it is the same in the U.S. Who know really
who transfer from whom?

But, of course, if you go in the hospital, you have more resistance.
Bugs \-\-- in the communities, that is for sure. I don't know if the Dr.
Reller have an opinion, because he is probably more aware of what is
happening in humans in the U.S.

DR. RELLER: I don't know. Professor Collignon is a respected scientist
from Australia, and I think it might be easier to understand on some of
the organisms that don't, under ordinary circumstances, persist in
humans a long time. For example, outside of HIV, humans harbor
Campylobacter a very short time.

I think our resistance in Campylobacter is coming from food. My
suspicion is that there are enough ample precedents for the problem of
resistance in food stuff, directly or indirectly, as Dr. Griffen pointed
out earlier, that it is an important consideration. Though, I certainly
don't have the data to say which direction.

Some of these things are more associated with animals. Staph. aureus is
more of a human pathogen. So one could see how it could go one direction
with one species of bacteria, and more commonly other directions, with
other organisms. What is, I think, incontrovertible, is the facility
with which in the broad category of Enterobacteriaceae, and enteric
pathogens, the capacity to pass resistance in closely related species,
and even across species that are not intrinsically closely related, but
harbor the same milieu; namely, the gut.

Would you accept that?

DR. GLISSON: This is John Glisson. There has been several of the
speakers addressed, or recommended that the product be restricted and no
off-label use. And I think some of the concern would be other animal
industries using it, frankly.

And the one that I am most familiar with is the poultry industry. Would
either of these formulations even be in such a form that they could be
used in the poultry industry? Or, more importantly, priced at a level
where you could stick it in a chicken?

DR. JOHNSON: Carl Johnson with Intervet. Good question, Dr. Glisson.
Neither formulation really is appropriate for use in the poultry
industry. And I think you hit on a couple of reasons why. One is cost,
one is the way in which it is administered. And as I have indicated
earlier, it is completely inappropriate to use the drug orally.

So, will it likely be used there? We can't prevent the absolute use at
times but, certainly, this is something that we as a company would
discourage and would not promote.

DR. CRAIGMILL: Any further questions from any other member of the VMAC?

(No response)

DR. CRAIGMILL: If not, we will take a 15 minute break and then come
back. I will turn it back over to Aleta though.

MS. SINDELAR: Thank you. After the break, we will just reconvene, 10 to
15 minutes, and Dr. Gilbert will answer any outstanding questions for
VMAC.

(Whereupon, a brief recess was taken)

MS. SINDELAR: Excuse me, if we can all take a seat and we will begin the
last portion of the VMAC meeting today.

(Pause)

MS. SINDELAR: As we planned, Dr. Gilbert will recite the questions as on
the screen, and then Art will proceed with the questions to the
Committee. Dr. Gilbert.

***[Questions Presented to VMAC]{.underline}***

***by Jeffrey M. Gilbert, Ph.D.***

DR. GILBERT: Thank you, Aleta. I think everybody has heard part, or all,
of these questions in some of the comments we have gotten, but I wanted
to go back over these questions one more time for the VMAC.

Question Number 1: Do the findings presented in Intervet's Qualitative
Risk Assessment demonstrate that cefquinome is safe with respect to the
potential for transfer of antimicrobial resistant organisms to humans?

Question Number 2: It has a few parts to it. Are there other issues to
consider relative to this class of antimicrobial agents, that is, the
fourth-generation cephalosporins? Are there other species for which it
should or should not be approved? What about routes of administration
that may or may not be acceptable? Are there indications that are or are
not appropriate? Are there any other relevant issues on this?

And then, finally, Number 3, are the risk management recommendations
appropriate or should they be modified? You will remember, we
categorized this as a medium in a category two. However, as I pointed
out earlier, they are following some of the Category 1 risk management
considerations.

So, those are the questions we would like to pose to VMAC today for your
discussion, and I am going to turn it over to Art and let him take over.
Thank you, Art.

***[VMAC Deliberations]{.underline}***

***by Arthur L. Craigmill, Ph.D., Chairperson***

DR. CRAIGMILL: Okay, thanks very much. I think what we will do today is
that we will just address these questions one at a time and go around
the group. But rather than do it just in a linear fashion, I will do it
in a slightly chaotic format, which will please Dr. Sundlof enormously.

(Laughter)

DR. CRAIGMILL: And in order to do that, I will ask Dr. McGlone if he
would please like to give the first opinion on Question Number 1.

***[Question Number 1]{.underline}***

DR. MCGLONE: Thank you, Dr. Chairman. I guess you probably thought I had
a long-winded answer. Which I do. The answer to the question requires
just a little bit of background.

First, this product is proposed for respiratory disease, and
respiratoriality, and a lot of talk has been about enteric pathogens,
and I am not sure why that would be, and why the focus wouldn't be on
respiratory \-\-- occasions that might have antibiotic resistance. And,
perhaps, there are not any that are both those things.

I think also that the antibiotic resistant data points quite often to
people contaminating each other. And then my area is animal science,
which includes the welfare of the animals, and I need to make a point
about the welfare of the cattle. Data presented by keeping antibiotics
working, and by the CDC, show that the percentage of animals, cattle \--
slaughter cattle \-- resistant to third-generation cephalosporin has
gone up, which, to me, means that we need another tool. A different tool
to improve the health of these really very sick animals. When an animal
has BRD and is taken out of the pen, these are not the animals with a
little hack, or a little cough, they are animals that are suffering.

And I was surprised to see that some of the humane groups that are part
of some of the groups that talked, particularly, the HHUS being opposed
to providing a therapy to cattle, who are very ill and suffering. So,
with all of that in mind, I didn't see a lot of evidence for any
documented risk, and I think that the level of medium suits me as being
conservative. So, I think the product is safe with respect to the
potential for antibiotic resistant organisms' transfer to humans.

DR. CRAIGMILL: Thank you, Dr. McGlone. Dr. Leggett, may I call on you
next?

DR. LEGGETT: Sure. Dr. Reller is in the long habit of putting me on the
spot, so I am glad you are following up. My first caveat is that I am
infectious disease physician and know, basically, nothing about animals,
other than our pet blind cat, so.

And I think my comments about Number 1 are going to sort of a nuance
response. And I would like to make the comments as much for the VMAC, or
the FDA, to sort of think about as they come up with their response as
we go forward.

I don't, for one thing, think that the current practice of just sort of
saying we have "X" percent of resistance at this point in time tells us
enough since emergence of resistant correlates, generally, the tonnage
of antibiotic use as we go through. And it can be a long process, and
you can have the sudden emergence of a clonal epidemic strain, et
cetera. There is a lot of other things that we don't have a very good
way of looking at so far.

My major concern about Number 1 is if we have no susceptibility problem,
why do we need one more new drug since a minimal risk outweighs any
benefit whatsoever of a not necessary drug?

The second point in this process is we have scant, as I mentioned
before, PT data that I have seen that doesn't allow me to tell if there
is optimally active drug, nor that the drug pressure couldn't lead to
the emergence of resistance in the gut. There was a drop in the E. coli
in the gut on page 20 of the presentation that tells me there is some
drug pressure of being applied. And, moreover, it is not just E. coli I
am worried about.

The presence of ESBLs is much more common in Klebsiella Enterobacter
aerogenes, and those are also in the gut. So it is not just the two
organisms that were looked at.

The next point I think is that I am not sure that it is true that there
are two mechanisms necessary, as was in the paper for fourth-generation
to become resistant, because the CTX-M is also a plasma mediated
process, so it is not only a CMY2 process, it is going to be a simple
thing. It is not going to require two things, I don't think.

In humans, which I know a little bit more about, we try to limit these
newer, broader, antibiotics for therapy of known resistant strains,
trying to save these drugs as long as possible. And I think that the
drugs that are used in the lung does not mean that the drugs don't also
go to the gut. That where we have seen that the most recently is the
fluoroquinolone question. The newer fluoroquinolones are supposedly only
for respiratory tract infections, yet, the explosion and tonnage of
fluoroquinolone use in people has lead to a single or double-digit
emergence of resistant E. coli; especially, in places like Southern
California.

So I don't think that just where the drug is supposed to have an effect
dictates all the parts of the body that see that drug. So, I think I
will shut up there for Number 1.

Oh, final thing. In the data that was published, the lack of resistance
that was shown in limited numbers of isolates, and I think there were 73
isolates that were questioned, means very little to me when we are
talking about the emergence of a two percent, three percent, four
percent development of resistance that can then go forward. Zero and
seventy is nothing, it is not a valid sample.

DR. CRAIGMILL: Could I clarify one thing Jim?

Dr. Leggett: Sure.

DR. CRAIGMILL: Was that a no?

DR. LEGGETT: Yes, that was a no.

DR. CRAIGMILL: Okay, thank you. Greg Jaffe, if I could call on you at
this time.

MR. JAFFE: Thank you very much, yes. I am also not an expert in
veterinary medicine, but my answer to this question is going to be a
qualified no also. And I guess I want to explain that. My background is
as a lawyer, and one of the problems with this question is I really
don't understand the second portion of the question. You know, the how
safe is safe?

We are not really given a definition of safety, as safety with respect
to the potential transfer of antimicrobial resistant organisms to
humans, does that mean we won't have any transfer of any microbial
resistant organisms to humans? Will we have just a small amount that is
not significant, or what are we talking about here? To me, safety is
more relative and this question doesn't tell us to take into account
what risk management measures would be done at the same time. And that
seems to be difficult to me, to look at safety in an absolute sense here
without looking at it in terms of what are the potential risk management
measures.

So, if I look at them in terms of what the sponsor has provided, in just
the risk manage of measures that they have provided, I think that it
isn't safe. They haven't met that burden of showing safety because I
think everybody has agreed that it is at least a medium risk. And I
think that that the WHO and others have considered this class of drugs
to be critically important. Which, if the FDA Guidance took that into
account, wouldn't even potentially make this into a high-risk category.

And so, to me, it doesn't seem to me that the medium risk that has been
identified here \-- it is overly conservative, and if there is a medium
risk of transfer of an antimicrobial organism to humans, then to me,
that is not saying that something in here is safe.

DR. CRAIGMILL: Thank you. Dr. Riddell.

MR. RIDDELL: Thank you. All things considered, and I did miss the
presentation that commented on the World Health Organization. However,
we operate under the Guidance #152, and I think we need to remember
that.

Though, with that in mind, and with the understanding of how the drug as
inactivated in the gut, how it works as far as rapidity of getting into
the bacteria, how it may not be as susceptible to resistance mechanisms.
Also, knowledge of human medical treatment decisions regarding cases of
diseases which may be related to food-borne pathogens, which we really
have to be most impressed with here rather than other pathogens that
humans deal with. Because we really need to deal with food safety.

I would have to say my answer is, yes, it is safe.

DR. CRAIGMILL: Thank you, Dr. Riddell. Dr. Reller.

DR. RELLER: I will be crisp at the off-set, and my vote is no. Why? As I
heard the presentations, the most compelling therapeutic need for this
drug \-- or, at least the proposed use \-- is for bovine respiratory
disease. There were other potential uses, but in looking at their
microbiology, you know, one wonders why a fourth-generation
cephalosporin would be uniquely needed.

And then, the numbers that I heard were approximately something in the
order of 10 percent of therapeutic use for this entity was with a
currently approved \-- whether it would be today is another matter \--
but currently approved third-generation cephalosporin. And that the
added need for a fourth-generation cephalosporin, to me, logically would
be based on demonstrated resistance required to save animals with the
introduction of a new agent of approved efficacy.

We don't have that. There is a difference between showing that something
is safe, and showing that the existing evidence doesn't show that it is
harmful. And I allow that we don't have all the data. In a way, we are
put in the unfortunate position of looking ahead, prophesying, if you
will, as to what will happen.

And there, based on these two cardinal principals of efficacy and
safety, and I think all would recognize that safety nowadays, of the
genre of drugs that we are talking about, is that antimicrobial
resistance in human disease, not that it isn't important in animal also,
but in human disease is a big safety public health issue.

And as a consequence, where there is no demonstrated need, then I, like
Dr. Leggett, thinks that one can tolerate next to nil risk. And I,
actually, think there is a risk, given the complicated dynamics. Can I
prove it? Do I have data in hand to show that it is not safe? No. But I
do not see the compelling public health in the broadest sense need, and
consequently, I think we cannot tolerate the risk that I recognize is
medium by the constraints that we are bound to. Though I, in fact, think
that the emergence of resistance to fourth-generation cephalosporins is
actually a very high-risk situation.

And we have an opportunity to forestall that. That is why I vote no,
unequivocally.

DR. CRAIGMILL: Thank you, Dr. Reller. Dr. Brown.

DR. BROWN: Okay, I would vote no, but for different reasons. And this
question reminds me a little bit of the question, when did you stop
beating your wife? Because there are actually two basic premises in the
question, and one is pharmacologic. Is cefquinome safe regarding
antimicrobial resistance? And I think that has to do with it is used in
a respiratory tract infection, how much of it gets into the intestinal
tract and modifies organisms there that are then shed out into the
environment?

And then the second part of that question up there is, what is the
potential for transfer of antimicrobial resistant organisms from this
large volume of fecal material to humans? And that is not a
pharmacologic question. That is a question about ecology and husbandry.

So, that is it.

DR. CRAIGMILL: Very short. Dr. Glisson.

DR. GLISSON: I struggle also with the word safe, because I basically
don't think that anything is safe, including this. But I think I
understand what we mean here is that safe, relative to other things.

Being a scientist, I always like to run experiments. And these are the
kind of questions that you have to make decisions without running
experiments. And I can tell you, if I could foresee the future, I
wouldn't be working for a living.

But, in this particular instance, there has been an experiment run, and
that is in Europe. And the data from that experiment is fairly
encouraging, I would say. That if we see the same sort of response in
North America that was seen in Europe, that 10 years from now, this will
be a small to non-existent issue; which is, essentially, what the
European literature that was presented to us indicates.

So, my vote would be yes.

DR. CRAIGMILL: Dr. Groseclose.

DR. GROSECLOSE: My vote is no. And based on many of the same rationales
that have been provided by other speakers as well. I think some of the
information is not available. You know, the U.S. data, for example,
there is insufficient time and, perhaps, insufficient use of the agents
to detect any resistance patterns there. And there appear to be unique
resistance patterns emerging in Europe.

Also, in the absence of any qualifications, I guess, as to management of
this risk post-approval, I have some concerns in that area as well. And
while I agree that I think Guidance #152 is a good framework, there
appears to be, as all guidance, it will need to be revisited at times.
And today, it does classify this agent as having medium risk. And I
accept that, but vote no, nonetheless.

DR. CRAIGMILL: Dr. Sams.

DR. SAMS: My vote is no. I also struggle with this question about
safety. It has been before this Committee before and I have struggled
with it every time.

But what I have heard today is that there is a considerable amount of
evidence from Europe, particularly, with the 12 years of experience with
this product in cattle. Evidence that the drug doesn't result in a large
increase in antimicrobial resistance.

But, I have concerns about differences between production practices in
the U.S. and in the European Union. I have concerns about differences in
the use patterns that this drug would undergo in the U.S.; particularly,
in view of the fact that there are at least 14 different products
already approved for treatment of bovine respiratory disease in the
United States. There are other cephalosporins available.

I have concerns about the emergence of CTX-M mediated resistance as a
result of exposure to a fourth-generation cephalosporin. And, finally,
there is very little data about the secretion of this drug or its
passive transfer into the GI contents and its effects on micro-organisms
at the point that it is excreted or passively transferred.

It is a totally different situation when you look at feces and activity
of the drug in feces. That is not what is important. What is important
is what is going on at the point at which the drug enters the GI tract.
Thanks.

DR. CRAIGMILL: One of the nice things about being Chair is you get the
last word. At least on one question.

(Laughter)

DR. CRAIGMILL: At every VMAC meeting I have been to, there has always
been a question about whether something is safe. And as a toxicologist,
I, like Dr. Glisson, do not believe anything is safe. It is a question
of relative risk and acceptable risk.

So, the question to me is whether this is an acceptable risk and whether
it has been demonstrated that it is acceptable. I will also take this
opportunity to pass one further pot-shot at the way the process goes
through.

And that is the idea of having something called a qualitative risk. Risk
is a probability, so how do you have a qualitative number? It sounds a
little bit to me like Sesame Street. You know, one is a good number, and
less than one is not such a good number.

So, with all those little shots said, I appreciate all the concerns. I
also appreciate the fact that in the animal health industry, there are
very few antibiotics that come along and they take an awfully long time
to get approved.

In the animal health industry, economics is a major concern; whereas, in
the human health field, economics is usually covered by insurance, at
least for many people. So I, personally, feel like Dr. Riddell that
having another one in the armamentarium is going to be a good thing.

I also feel that the experience in Europe has shown that there is an
acceptable risk. And when we get to the management guidelines, that
those will probably allow us to utilize this and make sure that there
are no major accidents.

So, my vote is yes in that regard, even though I still don't like the
term safety.

***[Question Number 2]{.underline}***

So, let's move on to question Number 2. Since Dr. Leggett said Dr.
Reller always puts him on the hot seat, would you like to put him on the
hot seat for this one first? Dr. Reller, would you like to begin with
this Number 2 question, or would you prefer to \--

DR. RELLER: Sure. For those who don't know the background, I had the
opportunity to chair the Anti-Infective Advisory Committee, on which Dr.
Leggett served, and then he asked me to continue to serve under him as
chairman. That is why the back and forth, when he chaired the committee.

I sense that there was, if not uniform, at least wide-spread, support
for if this drug were to be approved. And I find the language that is
used interesting. Those who say when it is approved, and those \-- and
myself being included \-- that always maintains at these advisory
committee meetings the subjunctive form of the verb.

But one of the reasons that I voted no was tactics and an understanding
of what I perceive as the following twin reality. That many people who
have been made such conscientious statements from all of the people who
presented would like to see this compound not used at all for any
off-label use as a further constraint on preventing resistance.

And I also heard what the regulatory constraints \-- in fact, without an
arduous process of being able to do that with under the context of #152,
a medium list drug. I voted no for 1, and 2 becomes then superfluous.
Because I think it would be very difficult if this drug is approved when
\-- the major reasons that I have heard for approval is the need for
having an additional drug in the "armamentarium." I didn't realize that
was one of the criteria on which the FDA could approve a drug, and
secondly, the unavailability of drugs from time to time.

Dr. Leggett and I were discussing earlier the dilemma that clinicians
faced not so long ago when penicillin was not available. But those are
marketplace and supply issues that I don't think also are in the
statutes in terms of when to consider that a drug should be approved, or
not approved.

So, quite honestly, I think it would be very difficult were this drug to
be approved, to put the constraints that many who would otherwise like
to see the drug would, in fact, like to have in place but from a
regulatory standpoint, current rules, regulations, difficult to put into
place.

And I think in the aggregate, this is one of the reasons, because of the
practical difficulties of what one can do to constrain use, for example,
prohibition of off-label use, as the Union of Concerned Scientists, and
others, called for. And even some who voted yes, I think from the
comments, at least, would favor.

I think it adds, the reality adds to, in fact, the risk that lead me to
vote for no for 1. So, that is what I feel about 2. I mean, I don't want
it at all, and 2 becomes a superfluous. But there is more than simply I
don't have to say anything about 2 because I think that that is a real
issue about what kind of constraints realistically, given what the
regulatory process is.

DR. CRAIGMILL: Thank you. Dr. Glisson.

DR. GLISSON: Same concerns. I think that the worry is that drugs are, or
could be, used off-label in other food animals. I think that is a
serious concern. I think what Intervet has proposed here is a relatively
innocuous way to use this compound, but there are other ways out there
that aren't so innocuous.

And my personal worry is that people will misuse it. I understand the
limitations on what FDA could do, but the purpose of this Committee, I
guess, is to say what we think. And I think the idea of putting
extra-label use restrictions on this compound, that idea should not be
forgotten, and it should be pursued.

DR. CRAIGMILL: Thank you. Dr. Riddell.

DR. RIDDELL: I guess I will have to step back to the first question just
a little bit, and possibly I didn't voice some answers to some questions
that were asked here earlier. And maybe the panel kind of missed this. I
think it needs to go on record that just because we have 14 antibiotics
that treat BRD, that doesn't mean that there aren't classes of animals
that encounter health crises that a 15^th^ might not be valuable for.

We are dealing with groups of animals that represent a lot of classic
animal variability. And just the fact that we have effective products
now doesn't mean we need to stop the search for science, or the use of
science to find more.

Also, as a veterinarian, I have to look at something like this, having a
product, in my opinion, come this close to fruition in a safe manner, in
my opinion, and then throw up a road block. It really throws a big kink
in the R&D I see in the veterinary profession. And I believe the concern
was voiced before that we don't have the economics of third-party pay
that they do in the human medical community. And I really think this is
a little bit of a use of a medium risk, and questions about safety when
there are definite systems in place to protect the human health.

I probably would have to go on record and say myself, and a significant
part of the veterinary profession, thinks that Document #152 is very,
very, if not very conservative. And provides a great benefit of safety
because of its conservatism. And I think a medium risk there means we
really are at a medium to very low risk.

When we look at how we might \-- were these products to be approved,
look at use patterns. I think when we look at the fluoroquinolones as a
model, where extra-label use was prohibited, as that was explained to
me, one, and in my early years dealing with antimicrobial
susceptibility, I wanted to blame the human medical community for a lot
of the susceptibility. And it was explained to me that there was some
invasive Salmonella that this was a critical drug that they really,
really needed.

And then it was further explained to me that the thought processes
behind the approval for quinolones for animals were the initial poultry,
where there would be a very limited use opportunity, and fairly tight
control of going to other food animals with a prohibition on extra-label
use with, were things to work out such that microbial susceptibility
problems did not raise their head, then the extra-label use ban would be
lifted.

Were we to consider an extra-label use ban if this product were to be
approved, I really would like some point A, B, and C as to how that
would be lifted. I, myself, again, going back to the experiment in
Europe \-- which, I think, is pretty darn good information on use
patterns that are much broader than what we are seeing proposed today
\-- with what we do know about how the antibiotic acts and is
inactivated in the gut, knowing about the use patterns we would expect
based upon economics of this product, I really, really think that even
though the public safety has to be a very serious concern, with the
NARMS program in place, and with us having very good baseline
information for where we stand right now as far as susceptibility, I
have to reiterate, my answer to Number 1 is yes, and my answer to Number
2 would be no.

DR. CRAIGMILL: Thank you. Dr. Groseclose.

DR. GROSECLOSE: Well, I have limited experience with Guidance #152, but
followed that risk assessment model, in reading it, and then reading the
response from the sponsor. And I do think the extra-label use
prohibition would be something to consider because of the possibility of
wide-spread use that might lead to antibiotic resistance that would
impact public health.

And other than that, I don't have any other issues that I think would be
relevant.

DR. CRAIGMILL: Thank you. Dr. Brown.

DR. BROWN: Yes. I believe that limiting extra-label use would be
appropriate.

DR. CRAIGMILL: She didn't give me time to write the answer. Greg Jaffe.

MR. JAFFE: I guess I would agree with many of the other members of the
Committee here. I also don't see a need for \-- I do see the value of
having a prohibition on extra-label use of this drug, especially, given
the potential risk that happens that we have all agreed on for the
transfer of antimicrobial resistance. And I think that \-- I mean, the
sponsor is even saying that they only want to use it in this group of
animals for this specific thing.

It is clear that it is used in Europe for swine, now horses, lactating
dairy cows, and other things. So, it seems to me that if you didn't have
a prohibition extra-label use, there are clearly a number of other
animals and situations where it would be used. And since the sponsor
isn't asking for those here, there is this risk. If the drug is going to
be approved, I think it has to have that prohibition on extra-label use.
And I think that is the most important.

DR. CRAIGMILL: Thank you. Dr. Leggett.

DR. LEGGETT: Let me repeat that I am certainly not an expert on species,
the routes of administration in cattle. Other indications, today was the
first time I ever heard of metaphylaxis, for instance.

But I can't think of, in terms of Number 2, to me, it's not really a yes
or a no, it is sort of like are there other things to consider. And I
couldn't think of any other relevant issues since we were told that this
was only going to be the one species, it is only going to be the one
route of administration, and it is going to be the one indication.

I mean, if that is true, that is all well and good. Maybe I can give you
an anecdote from a recent CDER meeting in which we were told that one
particular new drug was only going to be used in the hospital for this
very, very resistant bug. And about two months later, I got a call from
my orthopaedic surgeon colleague saying, there is somebody here who
wants me to use this new drug for total hip arthroplasty prophylaxis.
So, I will leave my comments at that.

DR. CRAIGMILL: Dr. Sams.

DR. SAMS: What we heard this morning from the sponsor was a risk
assessment based on the industry Guidance #152 that was limited to the
specific application that they proposed. And, therefore, it seems to me
that any other use, either requires another risk assessment, based on
that use, or alternatively, a prohibition against extra-label use.

DR. CRAIGMILL: So I will take that as a no extra-label use.

DR. SAMS: That would be correct.

DR. CRAIGMILL: Thank you. And let's see, who did I forget here. Dr.
McGlone.

DR. MCGLONE: Well, what an interesting situation. I was disappointed
with some of the comments from the first question.

(Whereupon, a brief recess was taken due to hotel emergency alarm)

MS. SINDELAR: Do we have everyone here?

DR. CRAIGMILL: Just for the record, Dr. Papich has departed, but he is
not casting a vote. He is a non-voting member today, so his input is not
needed. I believe we are missing Dr. Reller. So we will wait one moment.

(Pause)

DR. CRAIGMILL: \-\-- Dr. McGlone and I to make our statements on Number
2.

MS. SINDELAR: Since we are just voting at this time, yes.

DR. CRAIGMILL: Dr. McGlone, if you would please.

MS. SINDELAR: Yes. I will go look for Dr. Reller.

DR. MCGLONE: Welcome back everybody. Question Number 2. First, I want to
comment on question Number 1. The basis of our decision, I thought, was
supposed to be based on science, and the science that we have available.
Some of the people last time said, for question Number 1, said there is
no evidence, it is unsafe, but they voted no; which doesn't seem logical
to me given what we do know.

So, I voted yes for Number 1. Number 2 though, I can't recall being
presented any data on different species; although, there was a mouse
paper in there I think. Or, other routes of administration, or other
indications, for example, for digestive diseases; which would be the
most common one we talked about.

So, without that information, likewise, you can't make a decision based
on science. I will say though \-- so I don't really have an answer for
sub-parts A, B, and C \-- but for D, other relevant issues, I think
there was an important point made a couple of times. And that is that
\-- that I agree with \-- that management practices contribute to the
incidence of BRD. And I would encourage the groups that made that point,
and the people that made that point, which included the industry and
some other groups, NGOs, that they work towards solving those problems.
It would be probably a much more effective way to reduce antibiotic use
by improving management and, thereby, eliminating the need for
antibiotics in some circumstances than it would to work on campaigning
against resistance and, thereby, increasing animal suffering by taking
away some tools.

So, I think the management issue is something that I hope that companies
that sell antibiotics, and people that produce cattle, and people who
have a concern for the industry would help educate and do research to
improve that situation. So that is the only other issue I have. Thank
you.

DR. CRAIGMILL: Thank you. I will go ahead again with the last statement
with respect to question Number 2. As one of the other things that I do
in my job is I head up the NRSP7 Minor Use Animal Drug Program for the
Western Region. And the use of antibiotics and other drugs in minor
species, the non-major species, things like sheep, goats, rabbits, other
little furry and eatable things, are a major concern for me. And one of
the biggest problems we have is the lack of availability of drugs for
these animals.

I would, personally, not like to see an extra-label use restriction on
this particular drug coming down because, frankly, one of the ways we
will get the data that will help us to get these drugs approved for
these other species is to be able to have them used extra-labeling and
collect that information.

So, I am opposed to extra-label use. Other routes of administration, I
really don't know. I can almost guarantee that if the drug is available,
somebody will plug it into an animal anyway it can be put in. And we
will probably get called at the Food Animal Residue Avoidance Databank,
FARAD, to help get a withdrawal time. Which is another reason why I like
to have extra-label use information.

I am not going to speak to indications. Other relevant issues. I think
maybe one of the major relevant issues, and at some point, might ask Dr.
Sundlof to comment on this, is that we were asked in the first question
to comment on the safety of cefquinome. And I guess one of the questions
that really comes up is whether or not \--

(Whereupon, a hotel emergency announcement was made)

DR. CRAIGMILL: Well, I guess we can keep going on that. The question I
think we also \-- and I think many of us eluded to \-- was the question
of whether or not the sponsor satisfied the criteria in order to get the
chemical approved. And that might have been one of the questions that
should have been here for that.

I don't know if Dr. Sundlof wants to comment on that. There was also a
question about whether there is a need, a current need, for a chemical
and whether that comes into the process of approval for a drug. In other
words, if there is not a need, is that a reason to not have another
drug?

Could I ask you briefly, Steven, at this point just to make a short
statement with respect to that?

DR. SUNDLOF: Yes. Thank you, Mr. Chairman. Let me just say, first of
all, that I do appreciate the comments and the sentiments around that
issue that we shouldn't be approving drugs that may not be as necessary
by virtue of the fact that there are other drugs currently available.

FDA cannot use that as a criteria for approving a drug. It is unlike the
traditional risk benefit to the patient that we do take into account. We
don't take into account whether or not a drug provides a highly useful
benefit to society or not. And so while I do appreciate the comments and
the sentiments, it is not something that could be used as a basis for
our decision.

In other words, if the drug were more necessary for treating diseases in
animals, we could make a different decision. That is just not the
dynamic that comes into play.

And back to your first statement that really, one of the things that we
have done \-- and I agree that the first question could have probably
been worded a little bit differently \-- but I think we all agreed as
the part of the VMAC process that Guidance for Industry #152 would be
the criteria against which we would base or decisions on safety. And so
from the FDA standpoint, what we did was we said to the company after
vetting it through the VMAC, that you will be judged \-- the microbial
safety of your product will be judged based on your ability to satisfy
the requirements of Guidance for Industry #152.

And so just listening to the conversation, we may be presented with the
dilemma that the companies did what they were asked to do, but the
decision was still that it wasn't safe. And then we were going to have
to come back and say what is it that we can do in addition to
demonstrate safety. And so, I think this is, although it has been a
very, again, enlightening conversation, there is going to be some
difficult decisions, I think, that may result as a result of that. So
that is in response to your first question.

DR. CRAIGMILL: Thank you, Dr. Sundlof.

***[Question Number 3]{.underline}***

DR. CRAIGMILL: So in the interest of expediting before we have another
fire-alarm, I would just go around the table in order and ask Dr. Brown
if she would like to comment about additional risk management
recommendations?

DR. BROWN: No, I think the question I had about will this be looked at
through NARMS was satisfied adequately, with the exception that the CDC
did not seem to be included in that due to resources. But, I suspect
that will be rectified with time.

MR. JAFFE: This is Greg Jaffe. I think that the risk management
recommendations that are identified by the sponsor aren't appropriate,
and should be modified. If this drug is to be approved, I think you have
to have a prohibition on extra-label use. I think you would want to
ensure that it is only used in individual treatments for individual
animals for therapeutic format. So, not for herds or groups.

And that seems to be what the sponsor has been saying, but I don't see
that in the document as written down as what it is going to actually be
used by. So I think those need to be specified legally as requirements.

DR. GLISSON: John Glisson. I don't have any other recommendations, other
than the ones we have already discussed several times.

DR. GROSECLOSE: Sam Groseclose. I would just state that to ensure that
NARMS is fully functionally labeled to look at fourth-generation
cephalosporins in human animal. All three arms of its activity.

And then just encourage FDA, I think, for interpretation of these data
to get a routine access to drug utilization information would really
provide you some context to interpret the data. And I have nothing else.

DR. LEGGETT: And speaking of another aspect of risk management, because
again, as infectious disease doctor, I know nothing about risk
management for animals. I think science was mentioned by my colleague
here, and I think that the way the Guidance is currently formulated is
not scientific. It appears that the critical drug mostly is different
from the highly important, if it has got a specific FDA indication for
an enteric pathogen.

Well, cefquinome is not that different from ceftiofur. And in human
medicine, their equivalents are used for those processes. So, even
though it doesn't get the C, the fourth-generation cephalosporins should
have a C. And if we are going to use the Guidance going forward, that
needs to be recognized. Because we use fourth-generation cephalosporins
just like we use third-generation cephalosporins.

DR. MCGLONE: I believe that the sponsor and the FDA did what they were
supposed to, according to the Guidance. But I think it is not so much
the risk management that we have to decide whether it is appropriate, it
is really the risk benefit that we have to decide if it is appropriate.
And that is what is in my mind missing from the equation.

If one were to see an animal with BRD on video, or whatever, and then to
see that it gets better with this drug, that would be a benefit that
would mitigate what I think is small risk associated with food safety.
But it wasn't presented like that.

The other aspect that I think would be important is whether this drug
has any benefit to the animal relative to the other drugs that are
available. And my interpretation from the data presented, by number of
organizations, is that there is a chance that this drug may provide
benefit in some cases where it would not be of benefit. In other words,
a third-generation drug that the animal might be resistant to. The
fourth-generation drug may work in this case.

And so without the benefit being laid on the table, and presented before
us, it is very difficult to assess the risk. And we want to weigh it, we
know there is a risk, it is not zero. We want to weigh that relative
risk with the benefits.

So, I think that the risk management recommendations are not complete.
It is not so much that they are not appropriate, but they are not
complete. Of course, I recognize that the epidemiology data that will be
collected will be important, and I, of course, would like to see that
information.

The other thing that is really important is that for drug, you are
starting from a basis where there is, or was, no large amount of
resistance out in the field. So, if you begin to see it in animal
populations, you would know then that it has developed. So, until that
happens, you really can't weigh the risk either. You don't know what,
you are going from zero to \-- maybe it will stay zero. And zero times
zero is no risk at all, of course.

So, I don't think we can answer that question the way we would like to;
particularly, on the side of the benefit. Thank you.

DR. RIDDELL: To reiterate some of the editorializing that I had in my
last response, I think, based upon Dr. Sundlof's comments, and something
that Dr. McGlone mentioned, we might have missed the point.

We have a document, #152, that I think is extremely conservative, and
extremely safe in how it sets things out. And from my aspect of the
profession, the bovine practitioner, it set the bar very high. We
thought too high, but we have accepted that. We have a system in place
to measure antimicrobial susceptibility in NARMS, which also seems to
set the bar very high, and the interpretation of that data seems to come
under extremely close scrutiny.

I think the systems are there. I guess I am \-- unfortunately, some of
my thoughts have come intuitively to me because I have worked in the
profession. I know that these cattle that Dr. McGlone talked about, and
it is easy to say you need to manage better, but you can't take a
well-managed set of cattle and put them on a truck and have a snow storm
intervene and say that that was a management breakdown. That kind of
stuff just happens.

And we have to have tools to be able to handle things like that. Yes,
management can always be better. Most of these diseases can be
prevented, but the variabilities we encounter with Mother Nature and
other situations are something you can't plan for, so you have to have
the tools to deal with them.

And I think this is another effective tool, and it doesn't need to be
the last effective tool. Nor does the last antibiotic need to be the
last effective tool.

One other things is I may be, in addition to some of the members of VMAC
not quite understanding how the cattle industries work, and how we work
very hard to provide a safe, well-managed, and well taken care of
product, that there are things such as AMDUCA, and extra-label usage.
Obviously, we don't quite understand how that works either, so I do
think that the risk management recommendations are very good and very up
to par, and we do a really good job and should not be modified.

DR. SAMS: I agree that the risk management recommendations are
appropriate, given the comments of the other speakers.

DR. CRAIGMILL: Well, we came around, and we still might get out at 5:00.
I was going to ask each whether or not the cattle have to put up with
the stress of fire alarms going off occasionally?

(Laughter)

***[Concluding Remarks and Next Steps]{.underline}***

***by Arthur L. Craigmill, Ph.D., Chairperson***

DR. CRAIGMILL: Once again, I would like to say that I think that these
management recommendations are appropriate. I, again, would not like to
see extra-label use prohibitions, unless they were extremely specific.
Again, because that would hinder the ability to treat other animals that
are also of vital importance, and have healthcare needs, and animal
welfare needs.

I think what we have been looking at is not so much a risk assessment,
as a hazard assessment under a lot of different conditions. And as Dr.
McGlone said, we have a lot of ways to look at this, and maybe now is
the time to see what happens when it is put out there.

And if there is any indication, and I believe that CVM, hopefully, has
mechanisms to implement immediate changes if there are indications that
this has gotten out of hand and that resistance is becoming a problem,
that they can nip it in the bud. But I would like to see it go as
planned.

At this point, I think we are just about done. I will turn it back over.
I would like to thank everybody who stayed the duration and came back
after the fire alarm.

MS. SINDELAR: And it needs to be reflected in the record, I know we said
this, that Dr. Papich has left. He was recused from voting.

And Dr. Reller left during the voting of the second question and did not
place a vote on the third, which under the customs or policies of the
agency that voting, you must be present through the voting procedures
for your vote to count. So, may the record reflect that Dr. Reller left
during the voting of the second question.

At this time, for Dr. Gilbert, Dr. Sundlof, any closing remarks here?

DR. SUNDLOF: No. Just again, to thank all of the members of the VMAC and
all of the people in the audience who took the time to come and take
part in this discussion.

We will certainly consider all of the comments that we have heard today.
There will be a transcript available at some time, Aleta, is that
correct?

MS. SINDELAR: Yes. In between two and three weeks, there will be a
transcript available. And we will be posting the PowerPoints within the
next couple of days. Could I please make sure that everyone who has
presented has their current PowerPoint presentation on this computer at
the podium. Thank you.

DR. SUNDLOF: Okay, and with that, I think we stand adjourned. Thank you
everyone.

(Whereupon, at 4:59 p.m., the meeting was concluded)