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U.S. Department of Health and Human Services

Animal & Veterinary

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Ceftiofur Resistance in Salmonella enterica Serovar Heidelberg From Chicken Meat and Humans by Lucie Dutil, D.V.M., MSc

DR. DUTIL: Good morning everyone. Thanks to those who woke up early and got here. I would like to thank also the organizing committee for giving us the chance to present this information. This is not new information for many of you I am sure. It has been published recently in pier review journal and had several reports before that, but I did include some of the newest information that was just recently released from the 2004 --- report in there as well.

(Slide)

So ceftiofur in Canada is, like anywhere else in the world, a third-generation cephalosporin, but it is labeled in Canada in numerous species including in the poultry sector, in turkey in day-old chicks. In broiler chicken, it is not labeled for use in broiler chicken, however, in Canada extra label use is legal under current provincial regulations. The extra-label use we have in chicken is in-ovo injection in eggs. It is mainly to control E. coli omphalitis.

(Slide)

Salmonella Heidelberg in Canada is an important serovar. It is among the top three in humans since 1995 and probably even before, top two in broiler chickens. In humans it can cause severe illnesses including septicemia, extraintestinal infection, myocarditis, death. In our CIPARS collection, 9 percent of the isolates come from blood samples.

Now that we have hade this recent change in clinical resistance breakpoint, to be precise we now know and we can now say that ceftiofur resistance in our data at least almost always equals into ceftriaxone resistance. This is a problem because it can limit treatment options in some subpopulations like pregnant women and young infants. In our data, again, what we see is that the half of the blood isolates come from children under the age of 12.

(Slide)

So the data I am presenting comes from CIPARS. You know all about CIPARS if you were here yesterday because Richard did a very good job of presenting the program.

I am going to jump straight to the first graph that kind of got the ball started with this Heidelberg ceftiofur issue. This graph was presented in 2003 in the report in our first report where we were able to integrate data from the human and retail side.

This is a very busy slide, so we are just going to focus on the top of that graph that was showing resistance to all the 15 antimicrobials that were tested at the time and focus on the ceftiofur resistance. Here as you see, this is the old slide so ceftriaxone resistance is not high there because that was the old breakpoint.

What this graph is showing in essence is that when we were looking at the resistance of Salmonella Heidelberg from retail chickens in Ontario and Quebec and also in human clinical isolates from those two province, what we were observing was that there was significantly more resistance in the retail chicken from Quebec than from Ontario and as well in the Salmonella Heidelberg that were from the clinical samples from Quebec than from Ontario.

The other interesting finding was that resistance in Quebec was higher in the healthy retail chicken than in the sick people from Quebec.

In 2003, and I don’t think that Richard mentioned yesterday that when we started retail surveillance in 2003 we started in the summer. So those results came from a healthier surveillance which was not ideal. Frankly, we did not expect to see any significant difference in the first year of surveillance.

So as we were preparing the 2003 report, some data from 2004 were trickling in and were confirming that what we were observing in 2003 was not just, you know, something that was there just randomly, found because of a sampling scheme or something like that. But it was confirmed in 2004. We were getting exactly the same figures in Quebec as we had in 2003. In fact, in Ontario the resistance has emerged and had come to a point were it was in Quebec, you know, very similar to in Quebec in both chicken and humans.

(Slide)

So at the time we did not have and we still do not have any current state information on the drug use side in broiler chickens. However, coincidentally at the same time the University of Montreal conducted a survey in broiler chicken in the Province of Quebec at the abattoir level.

They randomly sampled lots from the abattoir and they collected fecal samples. They looked at the resistance profile in various enteric bacteria and also in parallel they administered a questionnaire. Part of that questionnaire was about drug use at the flock level, in the growing phase and also at the hatchery level.

The nice thing about this survey was that very few people declined participating. Out of 118 flocks that were initially selected, only eight declined participation. The other losses were due to snowstorms which happen once in a while in Quebec and also inability to contact people before the slaughter.

The other nice thing was that they validated most of the information. 87 percent of the questionnaires were validated by the veterinarians in charge of the flock or the hatchery. You have to know that in Quebec under provincial regulation, every single drug has to be prescribed by a veterinarian, including the growth promotants. So that was another giving strength to the results.

From the results of that survey, what we learned was that at least 74 percent of the lots had received ceftiofur during that period of time. That was before ceftiofur became an issue, so people would not have been biased on the way they answered because that was a nonissue at the time. People just did not know about that in 2003 – 2004.

(Slide)
So our 2003 report got released in early February 2005. You know, it takes usually a year to get the full report out. When the data became public, within two weeks the hatchery voluntarily withdrew the use of ceftiofur.

It was not politically imposed. It was not a regulation. The hatchery voluntarily did that based on the concern they had for public health. From the anecdotal information we have, it was very strictly followed, at least in 2005 and in the beginning of 2006. Then towards the end of 2006, we were hearing that people were starting to think of going back to ceftiofur use because they had problems controlling the E. coli infection.

Officially in 2007, the vets from the hatchery announced that they were going back to ceftiofur use but on a rotational basis, alternating with either no use or use of Linco-spectin or gentamicin or other drugs and for no more than six months in a row.

(Slide)

So when we look at the impact it had in terms of resistance on our data, you have -- I don’t know if you can see it very well -- the colors are a bit off, but here in green is the withdrawal period. So this is pre-withdrawal and post-withdrawal.

Pre-withdrawal we had a high level of use and also a high level of resistance in Salmonella Heidelberg from retail chicken, in Salmonella Heidelberg from human and in E. coli from retail chicken.

When we had the withdrawal, we had this steady decline in all three datasets. Then here when we started to have the reintroduction on a partial basis, we also saw a reemergence of resistance, but not to the level that we observed before the withdrawal.

I have to say that those are rolling averages. This is cordial (sic) the information that each point represents the average of this trimester and the two previous trimesters. The reason why we do that is our sampling team is made to provide reliable estimates on an annual basis. But we wanted to look at it on a more frequent timescale, like in a smaller timescale. To smooth out the noise created by the fact that you have a small sample size at a trimester level, we are using rolling averages.

Nevertheless, there is still a little bit of noise here. This is not necessarily because they are rotating, but I think much of that is because the numbers are not that big when you look at it at the quarterly level.

(Slide)

So this is looking at the data, the same data here from Quebec but on an annual basis like it is meant to be in CIPARS. What I am showing here, the purpose -- I am not going to discuss it in detail, but the purpose of showing it is that now we have in 2008 and 2009 significantly more resistance than we had at the end of the withdrawal in 2006, but still lower than what we had previous to the withdrawal.

In other provinces, like Ontario, we do have resistance as well to levels that are similar to those that we are observing now in Quebec. In Saskatchewan where we had almost no resistance at the beginning of our surveillance, we are seeing now resistance emerging, and it is now significantly higher than at the beginning of our surveillance.

In British Columbia, we have a high level of resistance, higher than in any other provinces. We do not have any coincidental data for all of those provinces. We know it is being used anecdotally, we know it is being used probably frequently in British Columbia, but this is a limitation. We do not have all the information on that but that indicates that there is likely use across Canada.

We have similar pictures for Salmonella which I am not going to show in the interest of time, but it follows pretty well.

(Slide)

For the previous slide that I presented, I was showing the proportion of those isolates that were resistant to ceftiofur. This slide is showing -- the vertical bars are showing the proportion of chicken samples where we found either ceftiofur-resistant E. coli in white or ceftiofur-resistant Salmonella Heidelberg.

In a nutshell what that graph is showing is that when you increase exposure -- and this is retail raw meat, so meat that is intended to be cooked, but nevertheless, when you see an increase in exposure, you see an increase in incidence which is the red bar here. The red is incidence of ceftiofur resistant Salmonella Heidelberg human cases. When exposure is high, incidence is high, and when exposure declines, incidence declines.

You see that across the provinces. We don’t have all the data for 2009 for the human side, so we are still missing some information there, but it still holds when you look at it across time.

The other thing to notice is that there is much more exposure to ceftiofur-resistant E. coli than there is to ceftiofur-resistant Salmonella Heidelberg.

(Slide)

Those are most -- generic E. coli most of them are probably commensal and not harmful to humans. However, some of them can be pathogenic.

Also what we know is that the plasmid that is carrying the resistance can go freely from Salmonella to E. coli or from E. coli to Salmonella and this is what this complex figure is showing.

You have the dendogram that has been generated through typing with RFLP and what this column indicates in purple, the E. coli strains and in blue the Salmonella strains. So there is a lot of variety in the types and the profiles, but you will find it in E. coli and Salmonella and you also find it in various feces.

We find that -- the colors are really odd-- but we find it more in chicken because we have more resistance in chicken, but we also find it in bovine and in porcine. It is mostly in bovine in clinical isolates, but also in E. coli isolates and in porcine as well, but in very low frequency.

(Slide)

This graph that is probably –- maybe you can’t read at the back there but this is only keeping the ceftiofur resistant-Salmonella strain from abattoir. Those are national data. The reason why I kept abattoir is that, you know, I wanted to show at the national level and surveillance has not changed over time since 2002 while in retail we have added new provinces and we know we have differences across provinces.

What it is showing is at the beginning of our surveillance at abattoir, most of the ceftiofur-resistant strains were carrying this profile with Amp C type profile, you know, with the resistance through all the beta-lactams.

More and more as we go now towards the years where rotational use has been established, what we see is that we have a decrease in proportion of those strains that were carrying only that profile and now we see emerging strains that are carrying also streptomycin, tetracycline, and some other strains here that are carrying also nalidixic acid-resistance, but without cefoxitin resistance.

So the nice thing is that for those Salmonellas most of the MDR comes from Salmonella Kentucky which are not causing problems in humans. So this is a good story, but we do see that in Salmonella Heidelberg as well.

(Slide)

So additional work currently we are discussing with the industry to establish drug use monitoring and this is working fairly well. On the Heidelberg side we are comparing through PFGE and soon -– I don’t think it has started yet –- MLVA. We want to compare the profile of the chicken and human isolates on the Salmonella Heidelberg side.

I just documented the case a little bit more. We would like to acquire information on burden of illness specific to Salmonella Heidelberg. We know in S. Typhimurium that you tend to have more, you know, worse infection with multidrug resistant strains. So we would like to see if this is the case also in Salmonella Heidelberg.

We also have collaborated with Dr. Amy Manges from University of McGill where she was looking for a collection of isolates and approached us to test our E. coli isolates. The publication that came out in January in EID was indicating that chicken was probably a possible reservoir for E. coli UTI infection in humans. Dr. Manges was looking for funding right now to make a bigger study to either confirm or, you know, find maybe other avenues to this hypothesis. She would like to confirm that on a bigger set of data and not just from data from Quebec.

(Slide)

So in conclusion, the reemergence of ceftiofur resistance in Salmonella and E. coli for us is a concern. In Canada, unfortunately, the control of extra-label use currently depends on voluntary initiatives which can turn out to be very effective and very rapid, but not long-lasting.

Or provincial willingness to modify regulations, but we have ten provinces that would have to move together and that may not happen.

(Slide)

And I would like to leave you with acknowledgement. There are several people working in CIPARS. This is not my data, but really the data of a big, big crew of people working really hard, including people from the industry who are voluntarily doing a very good job at the abattoir level. Without them, we would not be able to get the abattoir data.

So I thank you for your attention. I will be available for questions later.

(Applause)

DR. ZHAO: Thank you Lucie. Okay, our next speaker is Dr. Heather Green. Heather is a NARMS coordinator and before she took this position, she was selected as the FDA Commissioner’s Fellow which is a very prestigious fellowship program. We are so fortunate to have her to work with us over the last two years, working on using our PFGE database to look at the source attribution of salmonellosis. Her study will focus on the NARMS retail meat and CDC PulseNet human database. Okay. Heather?