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U.S. Department of Health and Human Services

Animal & Veterinary

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Session VIII Second Question and Answers Session

DR. FRYE: We can take some time for questions or comments from our last two presentations.

DR. VAUGHN: My name is Michael Vaughn. I am a food animal veterinarian from the private sector. I would like to make a comment to Dr. McDermott that this meeting was excellent. It was long overdue. I know you had concerns that you put too much in to two days, but I would not change the format. 

I just hope that we can do this again soon and do it on a more regular basis. I think the dialogue has been excellent. You know there are always people on different sides of the fence but we need this kind of a dialogue to bring everybody together. So I would like to thank you.

DR. CARNEVALE: My name is Dr. Richard Carnevale. I am with the Animal Health Institute and Dr. Lynfield, I would like to address this comment to you. I appreciate your talk, but I must comment on one of the slides that you showed because it is data that we actually collect. 

The slide that you showed, I know you did not generate that slide yourself; you got it from two gentleman in Denmark, Drs. Aarestrup and Wegener. But the slide is simply wrong because what they have included for U.S. data, for both the Union of Concerned Scientists and Animal Health Institute numbers are at least 45 to 50 percent of ionophore use. 

So if you take that 45 to 50 percent ionophore use out of that column on the last, it brings the U.S. levels down to comparable levels for many of the other countries listed. They did not include ionophore use for those other countries, so this slide is simply false. We have already told them about it and it is unfortunate that it is still floating around. 

I would also comment that the 70 percent number that we constantly hear quoted by everybody in the media and everyone else is simply wrong too because that number also includes the ionophore total. If you take that ionophore total out of that “70 percent” number, you are down to 37 percent of the drugs used in animals that are comparable to those used in humans.  So I wish people would stop using that 70 percent number because it is simply inaccurate.

DR. LYNFIELD: I didn’t ---

DR. CARNEVALE: I know you didn’t but it was in Steve’s slides which he didn’t show. But I just want to comment that that is a number that has driven us crazy for years.

DR. LYNFIELD: Is there a more accurate graph of the antimicrobial use in the animals per kilo comparing the countries that is published that can be used?

DR. CARNEVALE: I don’t have data on the other countries, but I have data on our own country.

DR. LYNFIELD: Is it published?

DR. CARNEVALE: Yes. Our data is published. Go to the Animal Health Institute website and you will see all the data and it will list exactly what compounds are included in that.

DR. APLEY: Mike Apley, Kansas State. Steve, I had a couple of questions for you on yours. You threw out quite a little bit of data. On the Alexander article, in your opinion, how does that relate to how that drug is used in production?

MR. ROACH: All I looked at was you do have use of, I think it was chlortetracycline and sulfamethazine in the feedlot. It was associated with E. coli resistance.

DR. APLEY: Well in the actual paper if you read it you would see that they started at 17 days on feed, fed it for 61 days, switched from silage ration, and I have this because it is one I use in my talks too. Then went 42 days later in the feeding period, much up closer to the end than would normally be done. This product is labeled for control or maintenance of weight gain in cattle experiencing respiratory disease. I am sorry that is approximated.

So the use in this study, while interesting as an over-the-top exposure is way far away from what actually would be done in production. As a matter of fact, they are very interested in getting those out of there because it is not cleared to --- currently with the other things we want to clear. 

So I think it is important when I see data like that thrown up as an example of what something does, I really think it is important to say if it actually is representative of what goes on in the industry.

One of the other important things about that is during the silage phase, percent resistant went up but the total number of E. coli went drastically down. So again, we are struggling for denominators.

The second point I found of interest in your presentation as a clinical pharmacologist was that feed grade tetracyclines in swine don’t reach a level that is effective. So from your opinion, what are effective levels and what are the plasma concentrations in swine?

MR. ROACH: Again, I was summarizing data from basically 1985 up to about 2009. They consistently said at least you aren’t getting anywhere near what your clinical breakpoint in the swine in the blood plasma. What they were suggesting was you wouldn’t find it in the lung tissue as well.

DR. APLEY: What are the validated clinical breakpoints in swine for tetracycline?

MR. ROACH: I don’t know them off the top of my head. You can look --

DR. APLEY: The answer is none. So what we are left with is evaluating the concentrations from CTC of around 0.25 to 0.5 microgram/ml and then we are looking at populations that may be relatively close to that and then relatively high. So the next question, since you are going to throw out PKPD data in your talk is what is the relationship between MIC and disease suppression for tetracycline?

MR. ROACH: Again, I don’t --

DR. APLEY: Again, you don’t know Steve, and that is my point. There are several things up there where you either just read the abstract or you are throwing something out that fits your agenda and that brings up a point that impacts our entire debate. 

When we start throwing around data in support of things that I agree is a real issue. You and I have agreed before that there is an issue and we need to address it. But when we are going to throw things out in front of groups like this and claim that tetracyclines don’t reach an appropriate concentration, or that the Alexander article shows that the industry uses of a tetracycline/sulfamethazine product drive this change in resistance, I think that we, both you and I engaged in this have an obligation to investigate whether or not those are accurate or whether they represent practices common in the industry.

MR. ROACH: I would like to respond to the second one on the tetracycline used orally. Again, I did not just read the abstract and pull that out. I was told by a swine veterinarian specifically that in their practice they don’t see efficacy of using the treatment and then they directed me to the research articles that supported that.

So it is not like I am just scanning through the articles and trying to find it. And the same thing with the Alexander article. I was looking at examples basically trying to find examples of where you have on farm use and in different food animal commodity groups where you can actually show use selects for resistance. Because there are some people that would deny that that actually happened.

So in the first case, with the chlortetracycline, no it was not something I just saw scanning the abstract. I actually was directed to look at that by a swine veterinarian who said okay this is an issue and here are the articles you should look at that suggest that there is unnecessary use on farms.

DR. APLEY: Well, I would advocate that those articles should not be all inclusive for all applications, so enough said I guess. Thank you.

Pat, I wanted to follow up with a comment on the cattle industry in support or not of sampling. I don’t want to leave this group with an impression that the cattle industry is opposed to NARMS. We support -- the people I have talked to, again I am not the official representative -- but we support monitoring programs. We support finding out what is happening because the cattle industry and cattle veterinarians are committed to, if we are confident that there is a problem being caused, we don’t want to be doing that.

The point I had hoped to drive home in my presentation and probably didn’t do a good enough job of bringing the latter part in, is that before we come on farm, before we would institute increases in monitoring, that we would want to be very sure how these data would be used, and that we have worked towards a metric or a way that we are going evaluate them, and that we are going to have a fair and objective evaluation of those data, and that there is the option in that sampling system that we would show that hey, these things are helping.

I personally and I know lots of others in the industry would be very happy to be involved in the process of moving forward in how your sampling might be altered. Thank you.

DR. McDERMOTT: Thank you for the clarification Mike and I appreciate the comments on it and we need your creativity and your knowledge that you have in practices or help to understand the best place to gather the samples because that is the first question in my mind. There are so many options and a lot of times I get the impression -- I am not saying you meant to create it -- that it is so complicated let’s all go home. 

You know, obviously we have got to think farther than that to what is practical, what is valuable, what is affordable. We have to balance all these things to get samples that give us the sort of data we need to make good sound decisions. So thank you for the clarification.

DR. WAGSTROM: Liz Wagstrom, University of Minnesota. This is for Ruth Lynfield. If you look at the WHO Global Principles for the Containment of Antimicrobial Resistance, the principle that says cessation of growth promotion is tied very closely to in the absence of risk assessment. So WHO talks about doing risk assessment to determine that growth promotion should probably be stopped unless you can show a risk assessment that can look at if there is a true adverse public health impact to those uses of growth promotion. Can you help me out from IDSA, tell me what kind of evidence you would like to see gathered and what IDSA feels on quantitative risk assessments for antimicrobial use and growth promotion?

DR. LYNFIELD: Liz, I can’t speak for IDSA on what IDSA would be looking for, but the point is well taken and I think that it has been brought up by folks from the poultry industry that a risk assessment needs to be done. 

What I can tell you is our approach is looking at those parts of the world that are no longer using growth promoters and the drop in resistance. And having our lens on human health, we are using that to say, you know, we think there is some evidence that one can certainly in some parts of the world get away without using the growth promoters and any use of antibiotics is going to increase selective pressure for resistance.

So I would welcome those folks from the agriculture world to come up with a risk assessment. It is always nice to have something solid to look at. That is another reason why I feel very strongly that we need to have accurate antibiotic use data and antibiotic resistance data to look at the impact of withdrawing growth promoters.

DR. WAGSTROM: Along those lines, IDSA -- we tend to be lumpers and splitters and often we lump all growth promotion together and if you are lumping and calling non-therapeutic, you are lumping even some of what is considered therapeutic by FDA. 

But to go back and look at it on a drug/bug or at least a specific drug basis, is that something that would be a consideration in the dialogue?

DR. LYNFIELD: I didn’t lump --

DR. WAGSTROM: No, I wasn’t -- I looked at Steve when I said non-therapeutic.

DR. LYNFIELD: Okay.

DR. WAGSTROM: I mean as far as lumping all growth promotion together. Can we talk drug by drug as the dialogue goes forward or is that an issue?

DR. AIDARA-KANE: Just a clarification. I am Awa Aidara-Kane from WHO. So just a clarification to say that in the WHO Global Principles, it is said the other way around, meaning that use of antibiotics as growth promoters should be stopped or phased out until you show that there is no adverse public health effect. So it is the other way around. The burden of the proof is on the users of antimicrobials as growth promoters.

DR. M’Ikanatha: I am Nkuchia M’ikanatha from Pennsylvania. I want to make a comment actually about the sampling because I have done a study that was a pilot study to validate NARMS data from a different site that was not involved in NARMS. We have actually published those data in peer-reviewed literature and we found no difference between the NARMS data and our data. 

We could not do that now because Pennsylvania is part of NARMS. However, I want to mention one thing. When we look at these data we want to understand what the real value is. This is a microbiological surveillance and it is being done over time. If you look at what is its purpose in the design of it, and look at it from a surveillance standpoint, only one disease has been eradicated. The person who explained that role, he told me that the concept is so simple you want to count and you want to know what you are counting. 

So before we say that there is something wrong with the design, we better look at what has happened, the success and the benefits we have gotten from the program. There are working groups of people who actually conduct the NARMS work and I am a member of that working group. So each time they are looking at ways to improve, not necessarily at a very high level, but at the low level people on the ground. Thank you.

DR. HUSA: Jeff Husa, Boehringer Ingleheim. I think I am the vaccine guy in the room, but I am a swine veterinarian. I wanted to make a couple of points on Mr. Roach’s presentation if I may. You point out it is a challenge to reduce feed antibiotic use in nursery phase. From the vaccine side of the house, our ideal would be a product which would generate absolute protection, compete against or overcome maternal antibody, and kick in fast with adaptive immunity. It is not always possible. 

So when we wean a pig, often times, and what you pulled out of Dr. Dritz’ information, is accurate. We need a bridge in many cases to try to help bring that animal into life on its own and oftentimes medications are that. 

I think we all watch the other veterinarian in the room try to utilize antimicrobials judiciously. There are cases where we need them in the finishing phase, but I hope that helps clarify why the nursery is a very delicate point of life for that newly weaned pig.

MR. ROACH: Yes. I mean you can definitely see the benefits in the literature. I think one of the things the Europeans did is they wean much later. But that is a rather costly proposition as well. I acknowledge there is a challenge there. It is pretty clear.

DR. HUSA: And as the manufacturer of the effective Lawsonia intracellularis vaccine, I thought I needed to point that out.

DR. CERVANTES: I would just like to point out for your benefit, the last two speakers, I probably have attended -- I come from the Poultry Science Annual Meeting in Denver and I probably have been through 50 symposiums on alternatives to growth promoting antibiotics. So believe me, it is not like the scientists are not listening. There is not one as of today that is as reliable and as effective as the so-called growth promoters. So I mean the people are listening. They are not just waiting for the sky to fall as we say.

The other comment that I wanted to make is in regard to the virginiamycin risk assessments. Virginiamycin risk assessments have been done. The first one was done by FDA. They did that one before -- no they did enrofloxacin before virginiamycin. You saw the outcome of that one. So they did virginiamycin and you have seen the outcome still on the market. It is open ended, meaning any new solid scientific data would be used to take action. 

I have not seen any new data. In fact, I have seen more data that supports that there is no detectable transmission of all the E. faecium that is definitely in the chicken carcasses, there is no doubt about it. The key question is, is it impacting human health to where we could even measure it? So far, it does not appear to be the case. 

There have been two more studies, one independently by Dr. Tony Cox that showed that showed again, negligible rates and one more where he looked at the benefit versus discontinuing the use and apparently is was more beneficial. The risk was greater of discontinuing virginiamycin so there are three risk assessments that I know of. There may be others. 

The final thing I wanted to say about the first speaker insofar as the U.S. using so much antibiotics. I travel extensively. I have been to every country in Latin America doing consulting or service for poultry companies. They use a pile more of antibiotics therapeutically, prophylactically. The use two growth promoters at a time, one for Gram-negatives, one for Gram-positives. They have no withdrawal; they have no monitoring of residuals. 

I mean, we have so many safeguards in this country that it kind of appalls me that we are focusing this on the first world countries rather than the third world countries where -- I am from Mexico, I can buy just about anything I want over the counter without a prescription. And I do when I go. Yes. I do. Because I am a veterinarian. My doctor here knows I suffer from chronic sinusitis. He knows that the issue is not that I am going to take it, just that it is easy to get. If these people moved up here and the genes started, you know, this exchange of genes and so forth, well then are we really going to accomplish much by not addressing the whole world? 

I know you mentioned it is a global issue, but we need to do a lot -- and I am trying my part as far as educating our people there on talks and say look I think this is a serious issue. We need to take it more seriously as professionals and respect withdrawals, therapeutic levels, you know.

DR. McDERMOTT: Pardon me for interrupting. I am sorry. I don’t mean to cut you off. Maybe you guys can take it to the hall and finish but we really have to -- if Christine can make it really quick, we have to get on to the last section. I apologize for interrupting.

DR. HOANG: Christine Hoang, American Veterinary Medical Association. For the record, I just wanted to say that the American Veterinary Medical Association is very supportive of NARMS. 

A couple of things to note is we are concerned that, similar to Dr. Apley’s concern of how the data collected from NARMS will be used. We would hope that future evaluation and interpretation of NARMS data would be done collaboratively and also transparently with all stakeholders involved.

We would also hope that if that NARMS data is used to trigger any sort of regulatory action, that again, the stakeholders are involved in sort of identifying those trigger points or at least being notified of what those trigger points are for further regulatory action. Thank you.

DR. McDERMOTT: Thank you Christine and thank you everyone for your candid comments. We are going to move on to the very last section of the meeting which is the public comment period and those of you who read the Federal Register Notice, this typically comes at the end of meetings like this and it gives people the opportunity to submit written comments to the docket or to sign up and get on the list to speak publically and express their views. Some of you have done that already in the questions and answers sessions.

For this meeting we only had one individual register to speak at this time, Jeremy Mathers from Alpharma and Dr. Mathers if you are here, the microphone is yours.