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Transcript - 2006 VMAC

Official Meeting of the
Veterinary Medicine Advisory Committee
New Drug Microbial Safety Review Under Guidance #152

September 25, 2006

Members Present:

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:

James E. Leggett, Jr., M.D.
L. Barth Reller, M.D., D.T.M.&H.


Opening Remarks
  by Steven F. Sundlof, D.V.M., Ph.D.     

Welcome and Introductions
   by Steven F. Sundlof, D.V.M., Ph.D.     

Background of Today’s Discussion
   by Steven D. Vaughn, D.V.M.      

Use and Importance of Cephalosporins in Human Medicine
   by John H. Powers, M.D.       

Importance of Cephalosporins in Veterinary Medicine with a Focus on Cattle Production Systems
   by Kelly Lechtenberg, D.V.M., Ph.D.

Introduction to Cefquinome and Overview of the Microbial Safety Assessment
   by Carl Johnson, D.V.M.       

Fourth-Generation Cephalosporin Use:  Experience in Europe
   by Andre Bryskier, M.D.       

CVM Response
      by Jeffrey M. Gilbert, Ph.D.      
      by David White, Ph.D.        

Public Comment Session
   by Patricia Griffen, M.D.        
   by Dr. Edward Belongia       
   by Dr. Richard Carnevale         
   by Steven Road          
   by Susan Prolman          

Questions of Public Comment Session Speakers
Questions Presented to VMAC
   by Jeffrey M. Gilbert, Ph.D.     

VMAC Deliberations
   by Arthur L. Craigmill, Ph.D., Chairperson  

   Question Number 1          
   Question Number 2           
   Question Number 3

Concluding Remarks and Next Steps
   by Arthur L. Craigmill, Ph.D., Chairman 

Keynote:  “---“ indicates inaudible in the transcript.
Keynote:  “(*)” indicates phonetic spelling in the transcript.

M O R N I N G  S E S S I O N

Opening Remarks
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.

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
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.

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.

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.

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.

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.

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.

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.

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.

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.

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
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...

...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.

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.

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
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.

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.

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 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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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.

Importance of Cephalosporins in Veterinary
Medicine with a Focus on Cattle Production Systems
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.

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.

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.

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.

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.

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.
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.
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.
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.
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.  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.
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.
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.
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.
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.
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.
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.
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?
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
There is a new label claim, crystalline-free acid, a tradename of Excede.  Again, a BRD claim, with a slightly longer withdrawal.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
Cefquinome will not be developed for applications via the feed or water.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.

Fourth-Generation Cephalosporin Use:  Experience in Europe
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.
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.
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.
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.
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.
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.
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.
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.
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.
I don’t know what has happened.
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.

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.
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.
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.
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.
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.
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.
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.
  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.
DR. BRYSKIER:  Thank you.  Sorry for these moments, but it is good we had a relax two minutes.
So, if we look at the charts, we see that resistant to cefepime is not so high.
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.
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.
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.
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.
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.
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.
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 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.
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.

CVM Response
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.
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.
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.

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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 F T E R N O O N  S E S S I O N

(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.
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

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.
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.

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.
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)
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 20th 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.
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.

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

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.

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.

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.

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.
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.

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

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.

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. 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?
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.
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.
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 25th, 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. 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. 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:  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. 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.
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.
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
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
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.

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

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. 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.
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

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 15th 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. 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.
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

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?

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)