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U.S. Department of Health and Human Services

Animal & Veterinary

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The Cattle Industry by Michael Apley, DVM, Ph.D., Kansas State University

DR. APLEY: -- thank you for that introduction Dr. Cray. Good afternoon. I am Mike Apley and I am asked to be here by the cattle industry to present some views on this. I have really enjoyed the meeting and sitting through and listening to the various ways we are evaluating this.

(Slide)

I don’t consider myself an official representative of the cattle industry. I am probably an unknown commodity to a lot of you. I would like to give you just a little bit about the background I come from.

I am a recovering feedlot consultant and I am a member and Past President of the Academy of Veterinarian Consultants which represent the vast majority of the fed cattle in the U.S. 

I also served on the Pharmaceutical and Biologic Issue Committee of the American Association of Bovine Practitioners. I recently served on the Antimicrobial Use Taskforce to the AVMA as an AVMA member. Also I am Past President of the American College of Veterinarian Clinical Pharmacology. 

So I kind of come at this looking as clinical pharmacologist’s view of someone actually involved in the industry.

I want to assure you I take the antibiotic resistance issue very, very seriously. I have listened with great interest to the meeting so far. I can assure you that producers and food animal veterinarians also take this very seriously.

(Slide)

So there are some things that when we start talking about monitoring that always hit me. One of the things I take great interest in is how many of us here can really define resistance. I have heard that said before when we start talking about enteric isolates and food animals and we stick a ceftiofur respiratory disease resistance criteria against it, yeah, it is crashing at breakpoint. That is where the MIC is. What is the implication for that organism? Those are things that don’t often get considered.

The other thing as we start talking about further sampling, I don’t think it is appropriate to determine the metrics after we collect the data. I think we have to think very carefully about how we are going to do that. 

One of the things I listened to with great interest earlier today was the concept of which population we compare between retail meat isolates with foodborne disease. Yes, meat is distributed around the U.S., but there are regional distributions, there are changes. Different meats from different animals will have different distribution patterns that may be local or not. 

I realize the magic happens here in Atlanta, but the industry happens out around the world. So I would invite everyone to come out who is responsible for those data and talk to some people who understand how meat is actually distributed before we go start comparing populations.

Another thing I listened with great interest on and the debate is how, you know, growth promotion uses which are actually labeled for increase in rate of gain or feed efficiency, and then control or prevention claims, and then therapeutic uses, almost as if there is a line. A line where they are clearly different applications, different uses, etcetera.

(Slide)

So I put together this little chart, went through chlortetracycline, tetracycline, and oxytetracycline approvals in cattle. The blue bar represents those that are classified for growth promotion. They would be classified only for improvement in rate of gain or feed efficiency. So we are down there around -- the lowest one is 0.1/mg per head/day in calves up to 250 pounds. That is the very smallest one.

Then we go up some more. Then the green bar represents where we also have clearances for control or prevention of a disease. This may be for enteric disease, respiratory disease, or it may be for anaplasmosis for which the tetracyclines are only labeled preventative products.

Then the yellow is where we actually have a treatment claim. So I think while people that may not look at these have a clear idea of the defined difference between the different uses, I as a clinical pharmacologist am somewhat confused.

The doses range from again, 0.1 mg/head per day in those very small calves up to 10 mg/pound/day for more brief periods. It is up there at the very top of the chart.

So it is a continuum and some of our other drugs have continuums like this. Some are at the low end, some are at the high end. 

But to me as we start talking about specific uses as one being worse than the other, etcetera, there is the dogma out there that certain concentrations for certain periods of times are the leaders for antibiotic resistance. 

Again, as one of my grad students found out when he made that comment during his prelims, I am confused on that. At the end of about 45 minutes, he recognized that he was confused too. It is exactly where selection pressure starts or ends. So just a little point where I am very open to be edified.

(Slide)

So as we move sampling back towards the animal, how do we view that? So there are some questions that we have on those. One of the first ones is, is presence of a resistant isolate on a production site an indication that selection pressures on the site are responsible for the presence? We will come back to that.

If a resistant isolate is detected, what is the probability that this isolate would be present in a week, a month, or six months? That is basically the question we are all interested in. How long does the effect of a selection pressure last? I think if we knew that they would be greatly advanced.

There is some stuff out there that gives us some indications and I have got some references that we won’t go into detail, but you should make sure in your bibliography of things you reviewed as we look at this.

How does the presence of a resistant isolate at a production site relate to the presence of a foodborne hazard? I guess if we actually knew that, that is what we are after, right? That is the question. So that is one of the things we need to agree how we are going to evaluate before we move in that direction.

Is there a threshold for concern? If we were to move back further towards the animal, do we have a place where we say, “That is enough that that causes us concern.” There are many in this room I recognize from the threshold meetings of 1998 or 1999. We struggled with thresholds there and I imagine we would struggle with them again. But those are things that we have to think of in forward, ahead of time.

(Slide)

Here is one of my favorite quotes from one of my favorite epidemiologists, Dale Hancock. I will let you read that. Only Dale would bring Joseph Priestly into it. It is a comment on discovering where something is and where it started. 

I want to mention an article, not to criticize the authors but to bring up challenges in interpretation. The Faye article on the ceftriaxone-resistant Salmonella in Nebraska is often cited. I think it was from like 2002. In some testimonies I have seen, it is brought up as proof, one of the proofs that antibiotic use in food animals leads to resistant disease in humans. 

I am not standing up here to say that antimicrobial pressure does not select for resistant isolates, don’t interpret that way. But, one of the things that happened with this article is they did not go to the field. If they would have gone to the field, they would have found that the calving grounds required you to trip over geese as you walked through those calving grounds in the spring while the calves were hitting the ground. That is Kansas for being born.

If they would have checked up in a year, they would have found that the ceftriaxone resistant isolates in those four herds were gone. They showed up, they briefly flourished, they did not have a selection pressure resulting in the added benefit to stay, and they were gone.

So when we cite some of these articles, looking back at what happened later and whether or not they actually tell us it is a selection pressure that resulted in them being there or it is a clonal spread that we happened to catch at a brief period of time.

(Slide)

So simply put, I think we will always find effects in some of the compartments we look at. If the compartment is the animal, the compartment is the production site, the compartment is the processing facility, the compartment is the food counter at the grocery store.

The challenge is to take those compartments and agree on how we are going to apply them to the production system and then also, thinking about how we might evaluate the consequences to the whole system when we find something in a compartment. Which again, if we truly understood all that, we would have a lot of answers here today. But that is one of the things we are thinking about to do it.

Then, also, causality. When can you and can’t you show causality?

(Slide)

So here is something that our friends from the FDA will have heard many times before and we have struggled with, but something that strikes us as a very serious issue in the cattle side of things. We evaluate risk but we evaluate risk in the absence of the benefit these compounds can have. 

I think there is a benefit they can have, not only to animal welfare and animal health, but to human health. I think the healthy animals produce healthy food. Yes. Is there definitive proof that these antibiotics decrease foodborne illness? It is weighted against the proof they don’t, I guess.

But to me we have to come up with ways of evaluating the benefits. I would ask you to consider your lifestyle if you only dealt on risks, none of us would be here today obviously. But I think that is something that has to be included into the formula.

(Slide)

So here are just some that will be in the presentation that is put up on the web for you to look at. Some of these involve therapeutic use. Some of them involve some very, very long uses for which some remnant effects were detected at harvest. Some of them showed some uses from higher shorter term which the effect on E. coli rapidly left afterwards.

Which brings up a point that we will cover in our last slide. 

(Slide)

So here are those references for you.

(Slide)

One of the last points I want to talk about are diagnostic laboratory isolates. I was fortunate enough to be one of the workers on the Veterinary Antimicrobial Decision Support System and we used diagnostic laboratory data to try to get a grasp of what was happening with some different populations. It very rapidly brought up the question of how biased are diagnostic laboratory isolates.

This summer we are in the process of getting the questionnaire, which we probably deliver in person, approved by our institutional review board to take some respiratory isolates from cattle from this year and follow up on ones that are multidrug resistant and ones that are pansusceptible, go out to the field, and we have identified a long list of clinical criteria, such as where did they come from, were they comingled, were they treated for control of respiratory disease, how many were treated in the pen before this one was selected, had this one been treated, what with, what was the morbidity rate in the pen, all these types of things and try to look for characteristics of multidrug resistant and pansusceptible isolates.

We hope to use that as seed date to go for even a larger study where we can then apply that to give us an idea of what is going on with the diagnostic lab data and try to delve into that question of biases that could be causing us to see something that is a false indication of what is actually happening in the population. Or is it a true indication of changes that are happening out there in pretreated animals? 

So that is one of the things that we are doing that is pretty exciting.

(Slide)

So I would propose that we are pretty good at coming up with numerators, but denominators challenge us. I think going back to some of the things I have already talked about show that. But as an industry we are very concerned that when we come up with numbers, when we come up for applications, when we come up for this many “R”s that we put it against the correct denominator and to help us look at those.

One of the biggest things about that is looking at percent resistance. This can lead us to some interesting conclusions when in fact what we might be seeing is we might be seeing a higher percent resistant, but an overall great decrease in the total pathogen load of that organism. One example is pathogenic E. coli, or just E. coli

Which gets us back to the diagnostic lab issue. Many of these E. coli isolates might just be gut E. coli we are isolating and not associated with disease in any way. That is one of the first things that laboratory diagnosticians tell me when I want to see their generic E. coli data, we are not sure how these are associated with disease. So one of the questions.

(Slide)

There are a couple of other things that I look at that I will finish with that are huge things to move us forward from a clinical pharmacologists point of view. I see routinely in tox that we are to give the drugs for the total period of therapy so that the survivors can’t survive to create a resistant population. Let’s think about that. 

We are supposed to expose the patient to the drug longer in order to suppress resistance development? That is just another thing I am simple enough not to have figured out yet, I guess.

The other thing we are working on very heavily in veterinary medicine is the accuracy of dosing, especially in food animals. In the feedlots, we are moving to more and more along with our individual animal records, to computerized dose calculation that we have scaled into the shoot so if that animal weighs 750 pounds, it is dosed exactly for 750 pounds. 

In closing, I was very, very thrilled to see in Lancet an article where the human medical profession was thinking of exploring per kilogram dosing of adult patients. Welcome to the century. 

I would offer that if this causes a problem, just stroll down to your local vet clinic and we will help you with the math. Thank you.

(Applause)

DR. FEDORKA-CRAY: Thank you Michael. It is always a pleasure. Break now? Okay break now.

So we are going to have a break now and questions and the poultry presentations and the last of the industry presentations and the other presentations then. 15 minutes. Let’s be back at 2:10.

(Whereupon, a brief recess was taken.)

DR. FRYE: So here were are, the final leg of our journey. We will continue. What we will do is we will do the chicken and turkey and then we will take some questions after that, after all the industry groups have presented. Then we will continue on with the other talk.

So let me bring up -- he is already up here -- Tim Cummings to tell us a little bit about the poultry.