Proceedings of the Standing Senate Committee on
Social Affairs, Science and Technology
Issue 6 - Evidence - February 12, 2014
OTTAWA, Wednesday, February 12, 2014
The Standing Senate Committee on Social Affairs, Science and Technology met this day at 4:16 p.m. to continue its study on prescription pharmaceuticals in Canada.
Senator Kelvin Kenneth Ogilvie (Chair) in the chair.
[Translation]
The Chair: I would like to welcome you to the Standing Senate Committee on Social Affairs, Science and Technology.
[English]
My name is Kelvin Ogilvie. I am a senator from Nova Scotia and chairman of the committee. I will ask my colleagues to introduce themselves.
Senator Eggleton: Art Eggleton, a senator from Toronto and deputy chair of the committee.
Senator Enverga: Tobias Enverga from Ontario.
Senator Seth: Asha Seth from Toronto, Ontario.
Senator Seidman: Judith Seidman from Montreal, Quebec.
The Chair: I want to remind us that we are here today dealing with the study on prescription pharmaceuticals and with unintended consequences, their nature and other aspects. The topic of our discussion today is the issue of antibiotic resistance.
We have two specialists in the area, and I'm going to introduce them as I invite them to speak. In the first instance, I'm will introduce Dr. Philippe Lagacé-Wiens, who is a medical microbiologist with the Department of Medical Microbiology and Infectious Diseases at the University of Manitoba, and he's with the Canadian Antimicrobial Resistance Alliance. Dr. Lagacé-Wiens, please.
Dr. Philippe Lagacé-Wiens, Medical Microbiologist, Department of Medical Microbiology and Infectious Diseases, University of Manitoba, Canadian Antimicrobial Resistance Alliance: Thank you very much. As was indicated, I'm here speaking primarily on behalf of the Canadian Antimicrobial Resistance Alliance. For those of you who are not aware, it is an alliance of scientists and physicians across Canada that is studying antimicrobial resistance in human pathogens across the country. We do a number of studies, the largest of which is the CAN-WARD study that studies antibiotic resistance in 13 Canadian hospitals across the country.
Through these studies, we actually try to ascertain trends in antibiotic resistance over time. It is a longitudinal study. We also try to evaluate the effectiveness of investigational antimicrobials.
I want to speak today and address a few points in my introduction. One is to try to address why it is that we see antimicrobial resistance emerge in human pathogens. One thing that people often don't realize is that resistance is out there whether we like it or not. Whether we use antibiotics or don't use them, it's out there.
Antibiotics or antimicrobials are simply exerting a selective pressure or basically driving evolution in these bacteria to survive. Darwinian laws apply. One of the major unintended consequences of antibiotic use is that we put selective pressure on bacteria, which are only trying to adapt to their environment. Bacteria are bombarded by a number of different stimuli to trigger a response and a desire to survive, and antibiotics are but one of them. A number of other factors are involved in the selection of antimicrobial resistance during the selection of any given pathogen that's going to emerge.
Knowing that resistance is out there, regardless of whether or not we use antibiotics, is important in our understanding of how resistance emerges. It does not matter when we start using an antibiotic, what antibiotics we discover in the future, what antibiotics we use as an alternative to another antibiotic; resistance will ultimately emerge. It is just a matter of fact, and it's very difficult to predict how fast it's going to happen and what the real consequences on human and animal health are going to be.
That brings me to how we predict whether or not antimicrobial resistance will emerge and how fast. We know it will. The biggest challenges are trying to predict whether or not these will emerge and whether or not it is associated with antibiotic overuse. Unfortunately, the answer is not clear.
We know that antibiotic use is a prerequisite for the selection of these resistant pathogens, but we will never know how fast it will happen because there are too many factors involved in that selection process. We only have control over one of these factors as humans, and that's the antimicrobial pressure we put on that evolutionary system. Basically, that's where we have to act. The other factors we can't really control.
My observation in the past six or seven years with the Canadian Antimicrobial Resistance Alliance has been that we will see resistance emerge, and it is just a matter of time.
Now, one thing that I did have in my brief that I circulated, and I hope everybody received it, is another factor in terms of antibacterial resistance emergence that I want people to focus on. It is not just about the use of antimicrobials in Canada but the use of antimicrobials in the whole world. That is migration. Human migration is a key component to the arrival of antibiotic resistance in Canada, and we have to stop thinking of ourselves as sort of protected because all the migration that humans do will bring resistance to Canada. It is not just our antibiotic use that's the problem. It is places in South Asia, for example, where most of the threats have come out recently, and migration and medical tourism is a huge problem. They bring back antibiotic resistance. It is not just about us anymore.
As a third point, I want to address a couple of the trends that we have observed in our studies in the past seven years. The most frightening trend that we have observed in Canada, and indeed worldwide, is the emergence of multi-drug resistance in gram-negative pathogens, primarily very common bacteria like E. coli, which you may have heard about, or Escherichia coli. This is an extremely common bacteria. It is in all of our intestines. It causes a number of different diseases in pretty well every body system. Over the past seven years that we have been longitudinally studying this among other pathogens, it has been the one that has shown us the most change in terms of drug resistance.
Fluoroquinolone resistance, which are drugs that are widely used in both animal and human health, has gone from about 1 per cent in 2000 to 23 or 24 per cent in 2014. That's just in my hospital. The trend has been the same across Canada. Even over the past seven years or so we have seen nearly a doubling of pathogen resistance to that drug.
Another scary one is the presence or evolution of what we call extended spectrum beta-lactamase producing E. coli, which has nearly doubled in prevalence just in the past seven years since we have been studying it in our CAN-WARD study. E. coli and all of its relatives represent a major challenge to antimicrobial use in Canada and will continue to do so.
To compound this problem, the number of new drugs that we have for treating infections caused by gram-negative organisms is extremely limited. A lot of drugs have been produced to fight gram-positive bacteria, like staphylococcus aureus and resistant strains thereof. There have been four or five new drugs in the past 10 years. When I say "new drugs," I mean new targets, totally novel drugs, not just changes on old drugs. In the past 10 years, there have been no developments on new gram-negative rod agents.
We're leading into a perfect the storm here. We're leading into a situation in Canada, and the world, in fact, where we have this pathogen that is well recognized as a problem pathogen and that is becoming very resistant and for which we have very few drugs to combat.
The last bastion of gram-negative pathogens has been what we call carbapenem-resistant enterobacteria. It was neat, because I finally saw the media catching on to this a few weeks ago. I had known about it for a long time. Nevertheless, we don't see very many in Canada yet, but we have heard reports of them, and they do spread quite rapidly. If the European experience tells us anything, we will be seeing it and it will be emerging.
To show how it is not just about antibiotic use, because the bacteria don't care and it could be just about any stimulus that drives it to evolve, we have seen over the past seven years a decline in methicillin-resistant staphylococcus aureus, which used to be a real problem pathogen. We are hearing a little bit less about it now, which is good news, but we don't understand why fully. It is not that we're using antibiotics better in Canada in any case, because we aren't. We're using them about the same amount as we have for the past 10 years. It is probably that some sort of other evolutionary pressure is moving resistant strains out of the way. I don't know what that is. I wish I did. I would probably get a good prize for that. But it is probably some sort of strain replacement.
In summary, the biggest threat in terms of antibiotic resistance as far as I'm concerned in Canada, and indeed worldwide right now, is these gram-negative pathogens like E. coli that are becoming resistant, that are becoming more virulent in some instances, and for which we have very few new drugs to treat them. The solution for these particular pathogens, obviously, at this point is to develop new drugs. But to prevent new pathogens that are even more resistant, we have to control the one thing we can control, and that's antibiotic overuse. The rest of the stimulus that makes these bacteria become resistant, we really can't control, but we can control one.
That's the gist of it. If you have any questions, please go ahead.
The Chair: We will get both the presentations out first. Thank you very much.
I'm going to move now to Dr. Scott McEwen, who is with the Department of Population Medicine at the University of Guelph, and he's with the Alliance for the Prudent Use of Antibiotics.
Dr. Scott McEwen, Professor, Department of Population Medicine, University of Guelph, Alliance for the Prudent Use of Antibiotics: Thank you very much, Mr. Chairman and ladies and gentlemen. I appreciate the opportunity to come to speak to you. I will be using some slides. I hope you have those in front of you. I will just say "next slide" when I get to them.
What I thought I would do today in the time available is to introduce you to some general principles about how antibiotics are used in animals and how that contributes to antibiotic resistance and what impacts we think that has on animal health and human health, and also some of the opportunities or methods available to try to control resistance development.
In general, the same classes of antibiotics used in humans are also used in animals. There are exceptions. As far as we know, for example, we're not using carbapenems, as Philippe has mentioned, but most of the other classes are used in one form or another.
We have poor information on the quantities of antibiotics used in animal agriculture and in pet animals in Canada. A lot of attention has been paid to that internationally to compare the relative quantities that are used.
In general, in Canada and the United States and similar developed countries, a greater quantity on a kilogram-active ingredient basis is used in animals, but it is very hard to compare that because there are marked differences in potency and other things.
We are lacking very detailed information in terms of what drugs are used for what purposes and what animals, and that's available in some countries, but not in Canada.
Before I forget to mention it, in addition to the specific uses, which I will talk about, there are hot-button issues in Canada around antibiotic use in animals. Two particular issues that keep popping up are what we call loopholes. One is use of antibiotics in farm animals that are brought into the country under the so-called own-use provision. That's been quite an issue for a number of years.
Also, there is the importation of active pharmaceutical ingredients. You may have heard about this in other contexts, but there is concern in some sectors that that's a way of bringing in drugs on a more or less uncontrolled basis that may be fed to animals and contribute to resistance problems.
In general, on the first slide, antibiotics are used for therapy. That may be in individual animals, pet animals or farm animals. Most of the drugs are on a prescription basis for therapeutic use, but we do have some over-the-counter medications in most provinces, with the exception of the province of Quebec, where prescriptions are required.
With animals, unlike people, they also used a lot of antibiotics in a group forum. I'm on the next slide. Because of the way we raise many production animals, like pigs and poultry and cattle, we raise them in large groups. It is not practical to treat them on an individual basis, so drugs are delivered to the entire group when they're needed. This may be for therapeutic purposes; if you have sick animals in the group, you treat the whole group. It may be for disease prophylaxis, which is prevention of disease at high-risk periods. And it may be for growth promotion. This is the most controversial type of antibiotic use in agriculture. Drugs are administered to animals with the anticipation that they will grow faster and use feed more efficiently. These drugs that we use for group treatment can be available over the counter in some cases, like the growth promoters, or they may be available with prescription only.
With regard to the next slide, another important issue for antibiotic resistance is extra-label drug use in veterinary medicine. It is a common practice, and there are many reasons for this. One of them is that because some of the types of food animals and pets that are raised are small market. There often isn't an incentive for drug companies to get label claims for different species, and that leads to a small number of licenced drugs in some cases. There are other reasons why extra-label use is widespread.
Unfortunately, most of the human safety focus around extra-label use is on preventing residues of drugs in foods from animals like milk, meat and so on. Little attention has been paid to the implications around resistance. I will give you an example in a few minutes of a major problem we've had because of extra-label drug use in veterinary medicine.
On the next slide, we believe that the major impact in terms of human health is mediated by selection of resistance of enteric pathogens of humans in animal populations. Some bacteria like salmonella, campylobacter and some E. coli are normal, commensal bacteria in animals. They often don't cause disease, but they can acquire resistance and contaminate food supplies or the environment and find their way into humans and cause illness. Some of the examples I have included on this slide are transmitted from animals to people in that way.
We have had problems with multiple drug resistance, MDR, in salmonella. We've had problems with fluoroquinolone-resistant campylobacter in the United States and European countries especially, not so much Canada.
VRE has been an important infection in humans. Vancomycin-resistant enterococci were a big issue in Europe because of growth promoter use. It was not an issue in Canada, but it raised the profile of antibiotic resistance in animals back in the 1990s.
There are other examples we can go into. Some of these are the same ones Philippe mentioned a few minutes ago.
On the next slide, this is a complicated picture that shows the ecology of antibiotic resistance. Again, it echoes what Philippe was saying, that bacteria and resistance determinants know no bounds. We're part of a global ecosystem. Bacteria resistance determinants and sometimes even antibiotics flow through various niches in the environment and spread resistance.
I point out to you that as far as we know, the major pathway from animals to humans is through the food supply, which goes across this figure. I also point out that it is a complicated pathway from the farm through to slaughter, food processing, food distribution and sometimes through a global economy. We have a ready flow of bacteria and determinants. It is very hard to measure. Even harder to measure is the flow through the environmental sector.
On the next slide, we are fortunate in Canada to have a very high-quality antibiotic resistance surveillance system called CIPARS, or the Canadian Integrated Program for Antimicrobial Resistance Surveillance. It's run by the Public Health Agency of Canada. It is a very useful resource. It monitors resistance enteric bacteria of different species in animals and human clinical cases, as well as meat, abattoirs and retail meat.
On the next slide, I want to show you this somewhat complicated chart that demonstrates an important principle about extra-label drug use, selection of resistant strains in animals and people and transmission to humans. This slide shows data concerning Salmonella Heidelberg, an important food-borne pathogen of people, and resistance to a drug called ceftiofur, which is used in animals but is in the same class as an important set of drugs in humans, third generation cephalosporins.
This graph has two sets of lines on it. One is data from Quebec and the other is data from Ontario. They're pretty much the same, as you can see. I'm going to concentrate on the data from Quebec because it is higher quality in one respect. What this graph shows on the left, or the Y axis, is the percentage of Salmonella Heidelberg isolates resistant to ceftiofur. On the X axis is time in years and months.
If you have a coloured version, the blue line with round dots is the prevalence of resistance to ceftiofur, this third generation cephalosporin, and Salmonella Heidelberg from people, human clinical cases. The black line at the top shows the prevalence of resistance in Salmonella Heidelberg from chicken. You can see that they're fairly high, from 30 to 70 per cent.
This alarmed public health officials. Investigations were made and it was determined that in the province of Quebec, and probably elsewhere in Canada, ceftiofur was being used extra-label to inject chicks or eggs at hatcheries. It was used routinely on a mass medication basis as a prophylactic drug to prevent E. coli infections and other infections in new chicks.
Microbiologists and public health officials drew this to the attention of the veterinarians in the hatchery industry. They stopped doing it, at least for a while, and that black vertical line is the voluntary withdrawal of this practice in the province of Quebec. As you can see, this was followed by a plummeting prevalence of resistance of Salmonella Heidelberg in humans and chickens and also in E. coli, which is gathered as an indicator species. The high correlation between the cessation of use and the drop in resistance tells us that this extra-label practice was exerting a highly selective effect on this important pathogen, Salmonella Heidelberg, in people. This data has received worldwide attention in the World Health Organization and other organizations.
On the next slide I show the major categories of interventions that have been used and are talked about in many countries of the world. This topic has been the subject of numerous national and international panels globally, and many people suggest that regulatory measures are required, such as improved drug regulation, improved rules around proper use of antimicrobials, proper manufacture, proper distribution and so on.
Some countries and groups advocate bans on certain types of use, most importantly growth motor use but also other types. Some people propose restrictions on certain types of uses as a measure of trying to reduce the public health impact of resistance.
Other interventions include better surveillance monitoring. A variety of voluntary measures is also proposed and promoted, such as prudent programs, antibiotic stewardship programs and the like. Unfortunately, in veterinary medicine we don't have very good data on the effectiveness of many interventions, especially those voluntary interventions. We really don't know if they work or not. We have some data from Europe on the effectiveness of some of the regulatory interventions, and we can talk about that in a few minutes.
On the next slide I would like to point out that in Canada a lot of effort has gone into this area of antibiotic use in humans and impact on resistance in people. There is a very detailed report available on the Veterinary Drugs Directorate website of Health Canada. It was published in 2002. I chaired it and it made something like 38 recommendations. The essence of the report is sound today, as it was in 2002. Some of the names of the important organisms have evolved, but otherwise the principles are the same. The group that did this was composed of stakeholders from all of the affected industries, medical officials, public health officials, veterinary officials. I thought it was well done, but I'm biased.
In summary, Mr. Chair, antibiotics are important for animal health and welfare. We need them to enable animal production, to feed society, to ensure that sick animals are treated. But we have to use them better. Antibiotic use contributes to resistance problems in animals and people, but we don't know how big an impact it's making. It's very hard for us to estimate the actual risk to humans. There have been numerous attempts to do that and we can go into that if you like.
I think that because of the urgency and the scale of resistance problems, more effort is needed to reduce this problem.
The Chair: Thank you very much.
Dr. McEwen, the committee just completed a study on off-label drug use. Can you confirm that you're using the term "extra label" in the same manner as off-label?
Dr. McEwen: That's correct.
The Chair: Thank you. I'm now opening up the floor to questions from my colleagues.
Senator Eggleton: Thank you for being here. This subject is one that seems to be alarming some major organizations. For example, the World Health Organization has called antibiotic resistance a global crisis that threatens to turn many common infections like strep throat into life-threatening ones.
Dr. Thomas Frieden, Director of the U.S. Centers for Disease Control, said:
If we're not careful, we will soon be in a post-antibiotic era — . . . for some patients and some microbes, we are already there.
We are dealing with a very serious business. I'm noticing that the United States has decided to clamp down on the use of antibiotics in terms of promoting livestock growth. You've talked about the use in animals with respect to individual animals and problems where antibiotics are prescribed. That's fine. But what we're finding is that there is a substantial amount of them used in growth, to the point where in the United States they're saying 80 per cent of antibiotics are used in animals or agriculture and aquaculture, fish as well. That's pretty alarming, 80 per cent, yet you don't seem to know what the equivalent would be here in Canada. Do we have any reason to believe that it would be any different in this country than in the United States?
Dr. McEwen: Thank you, senator. You're correct. It's reasonable to assume, I think, that the use patterns in Canada are similar to those in the United States. We have a similar spectrum of antimicrobials that are available for use in animals as they do in the United States, and our industries are quite similar.
I would like to acknowledge, as you've mentioned, that the Center for Veterinary Medicine, Food and Drug Administration in the U.S. recently announced that they are asking pharmaceutical companies to voluntarily withdraw the claims of growth promotion feed efficiency, improved feed efficiency, in the United States.
I don't know, but I believe they went to a voluntary request because they have found in the past that forcing companies to stop the practice or requiring them to stop a claim is a very long and onerous procedure. I don't know exactly, but it took them between two and four years, for example, to remove the claim for fluoroquinolone use in poultry, which was important in selecting for resistance in campylobacter as I mentioned. We, in a broader scientific field, hope that the companies comply with that and withdraw the claims.
One unknown is the extent to which that will result in a reduction in antibiotic use and in selection pressure, because evidence from other studies in Europe, for example, has shown that the major role that growth promoters probably play in animal production today is on disease prophylaxis. For example, when growth promoters were banned in Denmark, it was noticed that there was an increase in diarrhea in post-weaning pigs. So what I think might happen is when the growth promotion feed efficiency availability diminishes or stops, we'll see a concomitant increase in the use of many of these same drugs as disease prophylaxis agents in agriculture. I hope that doesn't happen, but it could.
Senator Eggleton: A lot of people seem to be saying that misuse of these medications, whether they're in human medicine or in agriculture, are to blame for this problem we're into.
Now, you've pointed out that the CIPARS group that comes under the jurisdiction of Public Health Agency of Canada is doing a good job in surveillance. What is the surveillance leading to? What should we be doing in this country in terms of this issue? Should we be following the pattern of the United States or maybe even Europe, because the European Union apparently imposed a user fee on non-human use of antibiotics?
But that, and the issue of getting the information here in Canada, concerns me. An article published last November states:
Infectious disease experts say Ottawa is treating national microbial surveillance reports like "sensitive government documents." And the doctors are so frustrated, they are releasing the data they can obtain on their own website.
"Otherwise, it's years before we see it on the federal website," says Dr. Mark Joffe, president of the Association of Medical Microbiology and Infectious Disease Canada (AMMI), which represents physicians, clinical microbiologists and researchers.
They go on to say: "I can get better access to data from tiny European countries like Estonia than I can from the Public Health Agency of Canada. . . ."
Here we have an inability to get a lot of information. The federal government health agency is hobbling efforts to control this stuff, while the potential for killing people here is enormous. Yet we see U.S. and Europe marching on with plans to do something about it and we don't seem to be doing anything about it.
The Chair: Would you like to comment?
Dr. McEwen: I have a comment to make. You make an excellent point about surveillance, detecting trends in resistance. The example I showed indicated that a reasonable measure would be to take action on the extra-label use of ceftiofur routinely in hatcheries. This illustrates one of the issues that exists in Canada in our federal structure; at the federal level, drugs like ceftiofur are approved for sale. The use is extra label, which is normally supposed to be under veterinary prescription, and is regulated at the provincial level, we're told. Our federal authorities at Health Canada indicated that they didn't have the legal authority to ban a use, that type of use. In contrast, the American officials at Food and Drug Administration, seeing the Canadian data, took the step to ban the extra-label use of ceftiofur in food animals.
We've seen time and again the difference we have in this sort of federal-provincial split. I'm sure you've heard this in other contexts as well.
Dr. Lagacé-Wiens: I have a few comments. The issue with CIPARS and surveillance data being accessible, I do echo that problem. I myself have had difficulties in accessing relevant and up-to-date data from the Public Health Agency in terms of antimicrobial resistance, to the point where I really don't use it at all. We use "own data," which is national data, which follows seven provinces across Canada, and does quite a lot of surveillance studies over the course of time, which is up-to-date. I could give you 2013 data today.
I do echo that problem. I'm not sure what to do about it. I suppose that has something to do with the government structure in terms of being able to release that data. I don't know enough about the structure to be able to comment on that, but I do agree that that's a problem.
As far as what Canada is doing in terms of addressing the problem of antimicrobial resistance, it has to be a global approach, as I have mentioned before. This is not just about Canada or the U.S. or Europe because people go to India, drink the water, pick up multi drug-resistant organisms and then come back to Canada. It's fine for anybody to put their head in the sand, but in the end we're all in it together, so I think we should be doing more. We should be following suit and hopefully that will drive more countries around the world to follow suit.
In many countries, it's not just about animal feed and use in animals. In many countries in the world there is a free-for-all on antibiotics. They're dirt cheap. They're easily available. They're end up in the water. Bear in mind a country like India, where there is over a billion people, taking antibiotics left, right and center, excreting them into the environment where they end up in the Ganges, which is a cesspool of bacteria, and where does resistance emerge? In these highly populous areas where there is a lot of resistance, bacteria and antibiotic misuse.
It has to be a global approach, I agree. We all have to follow suit and Canada is just one player in the game.
Senator Eaton: Thank you, doctors.
Should we restrict antibiotics the way we restrict narcotics?
Dr. Lagacé-Wiens: I guess that one is for me.
Senator Eaton: I think it was Dr. McEwen who brought up restrictions in his presentation. When you go to the pharmacy, if you're given a narcotic — he phones you up; he checks your identification; you get a prescription for antibiotic; you go to the pharmacy.
Dr. Lagacé-Wiens: From the medical perspective, as a medical doctor — and I'm trying to think of my colleagues who are general practitioners more than specialists — I think that's going a bit too far. Maybe that's swinging the pendulum too far. I do believe that a little bit more regulation in human use in any case would be warranted. Perhaps there should be a clear indication written on a prescription for an antibiotic use, but having to sign a prescription, get the triplicates done, get all of the approvals through your college, your physicians and surgeons in your province to be able to prescribe an antibiotic, I think some physicians would reduce the prescribing habits to the point where people would suffer who could benefit from antibiotics.
Senator Eaton: Could both of you perhaps think of recommendations you might consider as to how we could restrict the use of antibiotics in a reasonable way? You could send them to the clerk.
The Chair: You can take that away with you. That's something we can't get into in detail. We want to hear your overall answers with regard to the overall aspects. The restriction is a very significant, complicated issue. You can respond to the clerk after you leave.
Senator Eaton: You can perhaps think about it.
Dr. McEwen, I was with the Senate Agriculture Committee in Guelph last week and we went to Agri-Food Canada. They're doing some very interesting research on parasites in animals so that they don't have to use antibiotics. Is there any research being done in humans or have you heard of any interesting research being done to change how we use antibiotics?
Dr. McEwen: I'll address the issue with respect to animals, and maybe Philippe can touch on humans.
There is quite a lot of interest in alternate strategies to antibiotic use. That can involve alternative animal management strategies to reduce the need for antibiotics. That's improved vaccination programs, for example, to control infectious disease. It's improved what we call in the veterinary world biosecurity, which means improved infection control at the herd level and between groups of animals to try to slow down the transmission of infectious disease; measures to try to reduce stress in animals. There is a variety of non-therapeutic, not drug-related practices.
Senator Eaton: Antibiotic?
Dr. McEwen: A lot of research has gone into developing non-antibiotic growth promoters. These are various types of feed additives, probiotics, which are biological adjuncts. There is a variety of things.
Unfortunately, none have yet been shown to be as effective, possibly because they tend not to have the disease prophylaxis capabilities, and also they tend to, so far at least, have been more expensive because many of the feed grade antibiotics are quite cheap.
There is a fair bit of work going on globally to make these more available. On the plane here this morning I was going through my slides and the fellow in the seat beside me across the aisle said, "I couldn't help but see your slides." He works in the animal feeds area, trying to develop these types of things, so we got into a conversation about that.
I guess that's a long way of saying yes, there are some alternatives, but nothing yet that can quite take the place in terms of, especially, disease prophylaxis.
Dr. Lagacé-Wiens: The short answer is yes, a lot of different approaches are being studied in terms of alternatives to antibiotic therapy in humans and many of them are similar: immunotherapy, looking at vaccines to try to prevent common bacterial diseases. One that has successfully reduced the use of antibiotics for an indication would be the pneumococcal vaccine.
There is a lot of research in probiotics, for example, to prevent certain types of disease, alternatives to antimicrobial therapy for certain diseases like Clostridium difficile-associated diarrhea.
I would add to that, though, that there are some severe regulatory challenges to developing these strategies towards treating humans, the first of which is regulatory bodies like the FDA, in the United States, and Health Canada, which often follows the same regulations as the FDA. There's a dearth of companies there interested in developing these things as well, because there is no profit in it.
Senator Eaton: Well, there might be profit, depending on our trade with Europe or with TPP. If they disallow animals that have growth hormones or antibiotics, there might be a huge payoff.
Dr. Lagacé-Wiens: If it became as effective as antibiotics, yes, I agree; and in animals, yes, that's true.
In humans, though, when we're dealing with alternatives to antibiotics or antibiotics that are somehow better or do not trigger resistance to the same extent, these are treatments that are usually given for a week, or two weeks at best. Drug companies are not interested in this. They're interested in controlling your cholesterol for the rest of your life, which is much more profitable.
You were asking about ways to restrict antibiotic misuse. One of the things that causes global misuse is how cheap antibiotics are. It is so easy to dump an antibiotic on it. Why is it that we, as a society, believe that a life-saving drug should cost 10 cents a pill, whereas a life-extending, lifestyle fixing drug like cholesterol treatment costs $5 or $10 a pill. We could save children or we could make a 65-year-old have normal cholesterol.
So there seems to be a disconnect between the value of antibiotics to society and the value we actually attribute to them. That is driving a lot of these problems. You can easily throw antibiotics around, and there's no interest in developing new ones.
Senator Seidman: There's no question that the noise about the urgency of these issues is getting louder and louder and the language is getting ever more serious. In 2013, the U.S. Centers for Disease Control and Prevention released a landmark report — the report that Senator Eggleton referred to — entitled Antibiotic resistance threats in the United States, 2013 that called for urgent measures.
Less than a month ago, the Canadian Medical Association Journal published an article. They couched it in developing new antibiotics, but the issue very much referred to the European experience and the urgency in dealing with antibiotic control of some sort or another.
You have mentioned surveillance and regulation, but I also think of education for the public and for providers to try to understand the issues. So I would like to focus in on surveillance and education, if I might.
The education question is quite general in the sense that there are lots of public education programs for very serious public health problems over time. Perhaps the use of cigarettes has been the best-known one, where we have educated the public and the use of cigarettes has declined dramatically. The question is, what have we learned from that, and can we apply that to the serious situation we have with antibiotic use?
My other question is about whether the surveillance data from CIPARS has been used to inform policy development at all, and if there are any changes that can be implemented in order to make that data more effective.
Dr. Lagacé-Wiens: I am probably best positioned to discuss the question about education. Yes, absolutely, education primarily to providers of antibiotics in the human health environment — and I can't comment as much on the animal health — but on the human health side, and as Dr. McEwen kind of hinted at before, much of this falls on provincial public health authorities.
From my own experience in Manitoba, I have to say they have been doing a good job of trying to educate both providers and clients — or patients, however you want to call them — on the use of antimicrobials to the point we're actually starting to see some impact in Manitoba. I expect it is probably the same across Canada; I just can't speak specifically to those.
Patients understand now they don't need an antibiotic every time they go see their doctor. Doctors understand it is not the solution to everything. There has been a distinct change in terms of the prescribing behaviours of general practitioners regarding antibiotic use, and misuse, in fact.
There is still room for improvement there. There is still room for educating pharmacists and educating physicians and educating general practitioners who are major users of antimicrobials, but we are making huge steps in the right direction.
Yes, I think it should be encouraged is sort of the answer to the education question. I think provincial public health authorities should be empowered and even encouraged to do so, through posters, through advertising, et cetera. They have been very successful to some extent.
Now, as far as the CIPARS question, I'm not in a very good position to be able to comment on it, being quite displaced from the Public Health Agency myself. It is clear to me that they have a lot of data. It is clear to me that perhaps it hasn't been used to its utmost abilities, simply because I haven't seen much come out of it, personally.
I know some of the people that work with CIPARS at the Public Health Agency, at the National Microbiology Lab in Winnipeg, who have high-quality data, but I have not yet seen major products from that data. I really can't comment much more than that.
The Chair: Dr. McEwen, can you add to this?
Dr. McEwen: Yes, I can.
On education I agree completely. It is always good to have all the people involved be better informed of the problems and where they come from.
I'm not an expert in health promotion; I'm not an expert in behaviour modification. I think that's an important area to get into.
I would point out, though, that I think there's often a lack of motivation to address the problem. Several senators have raised the issue of the importance of resistance, and there is indeed a sense of crisis about resistance in the human health sector.
I have to say that on the animal health side of things, there is not the same sense of crisis. For whatever reason, we have not had the same problem with serious infections becoming resistant to just about everything.
I can point to some animal infections where there are resistance problems, but it has not reached the level of discourse that we have had in the medical field.
I think that's important in terms of trying to explain some of the lack of motivation, the lack of drive, in the animal sector, whether it is veterinarians or animal producers, to do something about resistance.
The main reason it is on the radar to the extent that it is, if you will, is because of the spillover of the problems in human medicine and the pressure that is felt in the veterinary sector to do something.
Sometimes the response is noble, and it says, "Well, we need to do something to enhance public health." Sometimes the response is more defensive, and that is, "We're not the problem; you guys are the problem and you take care of it." So there is an element, I think, of denial. That's where education can help to show that there are contributions from animal use to human impact.
As I said before, it is hard for us to measure the impact, and so then it is hard to convince people who are reluctant to accept the facts that there is a problem.
I think education is good, but in the main, we have to find ways to motivate people to want to change their behaviour.
With respect to CIPARS, I'm a strong advocate of CIPARS. It is the one opportunity we have to shed light on the resistance picture across the country, as it relates to enteric bacteria in animals and people. It has been enormously useful in the veterinary world to drawing attention to CIPARS. It has been very useful in a global sense where we're on a par with the United States, with European countries, in terms of having a competent surveillance system of resistance in animals and people and food. I think that's essential to have. If we don't have that window, then we're even more in the dark than we have been up until now, so it is essential.
The one thing I would say that is missing from CIPARS and would really be helpful is to have a better component on monitoring use; that is, what drugs are used, used in what animals, in what concentrations and for how long. That's a very difficult thing to do in our drug distribution system.
We don't have an infrastructure which is available to make that easy, like it is in some European countries which have primarily a pharmacy-based system of distribution and an electronic pharmacy system already there. I don't minimize the technical difficulties in doing that. I'm just saying it would be very helpful to have good use information to couple with resistance.
Senator Enverga: Thank you for the presentations.
From what I heard, according to what Senator Eggleton said, it is alarming. What I heard is the question is not "if" but "when." When are we going to have the highly resistant microbes? The concern here is the relationship between animals and human consumption.
As a regular person, what do you think we can do about this? Will cooking help a lot, cooking this food more, or do we have to eat organic foods? What can simple people like me do about this?
Dr. Lagacé-Wiens: Well, at an individual level, the answer is there's really not a whole heck of a lot you can do.
I will draw your attention to the lovely diagram that Dr. McEwen had in his slides that showed the environment and the movement of resistance between organisms and bacteria in humans and animals. That's just touching the tip of the iceberg.
There is complexity in the way bacteria mobilize and their genes mobilize in the environment and they, themselves, survive on surfaces. It is not just about meat; it is about everything around it. It's about all the things we touch. The microbiome, which is a term I like to use about the population of the bacteria in the world, is ubiquitous. It is everywhere, and there's very little the individual can do not to become exposed.
There are some things you can do to reduce your exposure such as wash your hands. Making sure you cook your food is one of them at least, especially for pathogens. Avoid travel to countries where there are a lot of these resistant organisms and you might not acquire them.
I think you would be fighting a losing battle at an individual level. I think it really has to be more at a higher level than that, because it is almost impossible not to be exposed to these organisms.
Dr. McEwen: I agree with Philippe. We are fortunate to live in a well-developed country. We have good infrastructure in terms of sanitation. We have excellent overall water quality. We have excellent sewage handling and treatment. Those are basic public health contributions that have done an enormous amount to reduce the impact of infectious disease. So equally, food safety control contributes to exposure of people to pathogens, resistant and susceptible.
I agree with Philippe that there are a lot of different ways that resistance is transmitted and flows. There's no magic bullet, I guess, no one thing that will take care of it.
Senator Enverga: Basically, controlling antibiotics will not make it any faster, but it will happen anyway way, right? Is that what you are saying right now? It will happen anyway, but we're just delaying it.
Dr. Lagacé-Wiens: The presence of the antibiotic in any environment, whether it is animals or humans, will eventually trigger selection of a pathogen, or an organism — it doesn't have to be a pathogen — that is resistant to that antibiotic. So the short answer is if there are antibiotics around, there will be resistance around.
The proper use of them does tend to extend the life of any given antibiotic simply because there's less exposure to the antibiotic in the whole environment, in the whole system.
Typically, it does emerge. Prudent use only delays the eventual emergence of resistance.
Senator Enverga: Do you have any suggestions, such as don't use antibiotics anymore? Can we do that?
Dr. Lagacé-Wiens: Well, let's be frank here. Antimicrobials have saved countless lives. In our current society, we live to 83 or 84 years of age on average partly because of antimicrobials and partly because of all these other interventions that Dr. McEwen indicated.
I don't believe by any stretch we should stop using antimicrobials, but it is really the misuse that is a problem. If you stopped using them, we would return back to a pre-antibiotic era, and people would die of pneumonia in their thirties.
Senator Seth: You have discussed that a lot of intervention has been done with the health professionals writing fewer prescriptions for antibiotics. That's a very difficult topic that we keep on discussing, but it will keep on moving — well, hopefully we can achieve that.
The Public Health Agency of Canada recently published an antimicrobial-resistant organisms surveillance report that intends to provide data on the rate of infection of antibiotic-resistant bacteria in different regions in Canada.
Can you summarize for the committee what region of the country has been mostly affected by this antibiotic-resistant bacteria and the cause of that? Do you have statistics on the number of people who die per year due to antibiotic-resistant disease in Canada?
Dr. Lagacé-Wiens: In answer to your first question about regions where it is more problematic versus less problematic, the prevalence of antimicrobial resistance is more or less equal across the country. There are a few exceptions. Highly populous areas like southern Ontario tend to have slightly higher rates of, let's say, overall resistance to antibiotics; likewise for Vancouver and highly populous areas.
Quebec, for whatever reason, seems to have lower rates of resistance than most of the rest of the country overall, but identifying differences between the provinces or differences between regions of the country is difficult to interpret. If I had to pinpoint specific observations, populous areas tend to have higher resistance rates. That's probably due to one of the things I already pointed out, high levels of migration more than misuse in those areas.
The second part of your question, could you repeat it again, please?
Senator Seth: Statistical data that has been provided showing how many people die per year.
Dr. Lagacé-Wiens: I wish we could get that data. If you want to talk about holes in the available data, the Canadian Antimicrobial Resistance Alliance doesn't actually collect case-specific data. We only collect isolates. We look at the proportion of resistant isolates based on very basic demographics of age, gender, where they were in the hospital and the type of infection they had. I cannot look at our data and say such-and-such individuals died.
That would be an important piece of data for provincial health authorities to be collecting, but large and wide, these organisms are not reportable to public health. In some provinces, methicillin-resistant staphylococcus aureus infections and vancomycin-resistant enterococcus infections are reported, but the ones that I'm most concerned about, those gram negatives, are typically not. I'm not aware in any provinces that they are, but I might be wrong on that.
Senator Seth: I understand why you use antibiotics for agricultural purposes, in animals, to encourage the growth in food, of course, producing animals and plants. Many argue this could be also contributing to the rise in antibiotic resistance. Could it not? Where do the antibiotics usually come from? Are they manufactured in Canada, or are they labelled here and come from different countries? What amount comes from different countries?
Dr. McEwen: I will try to answer your questions.
Certainly antibiotics are used extensively for growth promotion purposes and enhanced feed efficiency in Canada, and, yes, it does select for resistance to a variety of drugs. Many of the drugs used for growth promotion are members of the same classes that are used in human medicine, for example tetracyclines and sulphonamides. Many of them are older classes but, nevertheless, they may have important implications to human health.
As I indicated, we don't have a very good antibiotic use monitoring system. At the national level, CIPARS is able to get some aggregate data from the Canadian Pharmaceutical Animal Health Institute, which represents pharmaceutical companies in Canada. We have that sort of high level of data, and large quantities are used.
I think you asked whether it was manufactured in Canada or imported. I don't know the answer to that question. I believe that a lot of it is manufactured here, but there may be some imported drugs too.
Senator Seth: If an antibiotic is used in an animal and we eat the animal, is there an effect on the human being? Is there any research on that? Are we doing any data on that?
Dr. McEwen: The main human safety concerns from antibiotic use in animals are twofold. One is the safety around the presence of the residue of the drug in milk, meat and eggs that people eat. We have known about that for decades. We have a very good, internationally consistent approach to addressing that. It involves proper withdrawal times for drugs to make sure that we stop treating before the animal goes to slaughter in order to keep the residues below a level that we think is important to human health. That issue is well recognized. We have testing strategies to verify it and so on. I would say it is controlled quite well.
The other issue is about antibiotic resistance, which we have been talking about here today, and because of the biology of resistance in a large sense, as Philippe has mentioned, it is a much tougher thing to control. We have talked about some of the approaches being used in various countries to address the issue, and I can expand on any of those, if you would like.
The Chair: Dr. Lagacé-Wiens, you are agreeing?
Dr. Lagacé-Wiens: Basically I'm agreeing. I was going to mention that the issue of residue is the one that is best regulated and really not a problem as far as animals are concerned. It has already been mentioned.
[Translation]
Senator Chaput: My question is a follow-up to that of my colleague, because my concern is the link with human meat consumption, when we know that the animals are fed growth-promoting antibiotics.
I am told that in Canada, usually, these antibiotics are approved by Health Canada, but I have also read that producers can import antibiotics that are not approved in Canada and regulation differs depending on whether the medication is mixed in with feed or water.
Are there regulations in place for these antibiotics that are not approved for use in Canada and that producers can import for their own use?
[English]
Dr. McEwen: I'll try to answer that to the best of my knowledge. It is a difficult issue.
In the early part of my presentation, I touched on what I call two hot-button issues. One is own-use importation, and that I think addresses partly what you are speaking of. The other one was the so-called API, or active pharmaceutical ingredient importation. There are two aspects to that. The own-use provision, as I understand it, enables a farmer, for example, to legally purchase antibiotics in another country and bring them in for use in their own herd. The Canadian drug companies are very concerned about these two loopholes because it cuts in on their domestic market.
Anecdotally, I have heard that sometimes large quantities of drugs that are not approved for use in animals in Canada are imported in this way, either over the Internet or through bringing it across the border. It is only anecdotal information. I don't have firsthand data, and we don't have good aggregate data. Nobody collects this information at the border, so we don't know exactly what is coming in, but it is reported to occur. That's of concern.
If someone is bringing in large barrelfuls, for example, of poor quality fluoroquinolone from another country and mass medicating livestock, then that would be a serious problem. I don't know that that happens, but it is hypothetically possible, so a lot of people have been pushing to have that loophole closed.
I know the government is well aware of this. There has been a lot of lobbying over the years to have it closed, but I understand that they have met with resistance among various stakeholders in the country, and the same thing may apply to the active pharmaceutical ingredient thing.
I think a lot of people would be happy if those loopholes were closed. In the 2002 report to Health Canada, we recommended that that happen, and it's still available.
Senator Chaput: Would you know if it's the same antibiotics that are being put into the water versus the food for animals? Is the quantity the same, or can they do what they want?
Dr. McEwen: The mode of delivery, the mode of administration, varies, depending. Some drugs are water soluble and some are not. Fluoroquinolones, for example, can be administered in the water, and penicillin. A lot of drugs can't be. There is really not a big difference in terms of resistance selection whether it is administered in the water or the feed. The important thing is it is taken orally and has an opportunity to exert selective pressure on bacteria.
Senator Chaput: It could be the same drugs that we are taking as human beings, too, right? Antibiotics, I mean. It could be?
Dr. McEwen: It could be the same drugs or of the same class. For example, for the penicillin class, it doesn't matter if it's the same one we use in humans or animals. It selects resistance in the same way.
Senator Cordy: Thank you, doctors, for being here today.
Dr. McEwen, you spoke about the interventions, the regulatory changes, the monitoring and the voluntary measures, and you said that we don't know whether or not these interventions are actually working. I'm curious to know why we don't know they're working.
Second, you did say that we have data. You did say that there's data in Europe. I wonder if you could give us some information on the data in Europe.
Why don't we have that data in Canada?
Dr. McEwen: I was fortunate enough to be involved in a World Health Organization evaluation of the termination of growth promoters in Denmark. Denmark is very good at surveillance. They collected data on antibiotic use. They collected data on resistance in people, in animals and in food. They collected information on what we call zoonotic infections in animals, so how common salmonella and campylobacter were in poultry and livestock, for example. They collected this data over several years before growth promoters were banned and for several years after. Also, I should mention that they collected very detailed data on animal production, so the efficiency of animal production and the numbers of animals produced.
Briefly, the data showed that the ban on antimicrobial growth promoters resulted, as you would expect, in a marked reduction in the consumption of those drugs in animals because they stopped using those classes of drugs for growth promotion. They also saw a decline shortly after in resistance to many of those drugs in indicator bacteria, mainly gram positive for a variety of drugs. Those were both expected as a result.
What wasn't expected was an increase in diarrhea in piglets, primarily. This indicated that those growth promoters were having a disease prophylactic effect in pig populations. They saw a small increase in disease in broiler chicken production, but it was quite small.
From a public health standpoint there was some concern because in order to deal with this problem of piglet diarrhea, veterinarians prescribed drugs to prevent and treat that diarrhea. So there was a bit of a trade-off between reduction in growth promoter use and increase in therapeutic drug use. There is an offset. Some of the drugs that were used to treat the pigs were more closely related to human drugs than the growth promoters were.
The other important finding is that there was a minor blip in the productivity of pig production in Denmark. Denmark is one of the world's top pig producers and they have a very efficient industry. There was a blip, if you want to call it that, in terms of pig mortality and morbidity, but then they quickly compensated and continued to increase. The overall effects on production, if you will, were quite minor. There was some effect on disease in pigs, but they were able to address it.
That's the best quality data available because of Denmark's investment in monitoring. The reason why we don't have much data on the effectiveness of some of the other interventions is that intervention studies are quite expensive to do. I think there's also a motivational issue; we should be out there evaluating effectiveness of stewardship programs in veterinary medicine, but to my knowledge it hasn't happened yet. It's difficult and expensive to do. That may be part of it.
Senator Cordy: I certainly understand it would be expensive, but both said it's a global problem. Are we not pooling our resources to do some of the collection of data?
What is CIPARS?
Dr. McEwen: Certainly if we had mounted a national program for antibiotic stewardship, then CIPARS or similar national surveillance programs would be very useful in measuring that, but we haven't implemented any broad national strategies for better stewardship in animals.
Senator Cordy: Is CIPARS working with other countries or just within Canada?
Dr. McEwen: Yes. There are regular conferences and teleconferences between CIPARS and its comparable agency in the United States, the National Antibiotic Resistance Monitoring System. Both organizations are part of WHO's AGISAR group, the Advisory Group on Integrated Surveillance of Antimicrobial Resistance, which is also interested in integrated surveillance.
Senator Cordy: Should we have a national strategy?
Dr. McEwen: Absolutely.
Dr. Lagacé-Wiens: I could add one thing about the challenges of looking at interventions of antimicrobial stewardship programs and at actual outcomes for these interventions.
I wasn't aware of the Danish study; I don't follow that literature. It's quite remarkable that they managed to achieve that because even in humans it's difficult to fund these studies that look at stewardship impacts in reduction of antimicrobial resistance infections. There have been a few, but they have been difficult. They have demonstrated savings overall because treatment of antimicrobial resistant infections is expensive, but I don't know if the same would happen in animals.
As was mentioned earlier, often these infections don't seem to be a problem as much in animals, partly because they get slaughtered before they get to an old age when infections become a problem and partly because there is very little interest in following those trends in animals because they're rare and would be even more costly to follow. There is going to be resistance to studying that type of thing in animals as there is in humans, let alone the link between the two, which I don't think was achieved in the Danish study. I don't know whether Dr. McEwen can comment on whether they looked at the humans afterwards and down the food chain.
Senator Cordy: The public seems to be concerned that if they get really sick, an antibiotic is not going to be helpful because of what's going on.
What are pharmaceutical companies doing? Dr. Lagacé-Wiens, you said that there was little interest in developing new antibiotics. I guess there's the question of whether you just keep inventing more and more antibiotics, but the public are concerned that if they become sick, the antibiotics will not be useful.
Dr. Lagacé-Wiens: For the vast majority of the public — and I mean generally over 99 per cent of the public who get sick with a bacterial infection — there are still available antimicrobials to treat serious infections. A small minority of people would have difficult-to-treat infections where you're looking at last-line antimicrobials.
I think the fear is well placed, but perhaps a bit exaggerated. However, it's a good thing to have a bit of fear because it compels you to work on finding a solution.
As far as the interest in manufacturing new drugs, that's a big problem. First, very few pharmaceutical companies out there have active R&D programs for antimicrobial agents. I think there are four large companies worldwide now. Many of them are pulling out for a few reasons and I've mentioned some of them. One is the exorbitant cost of phase III studies to look at equal effectiveness between a standard antibiotic and their new antibiotic. You're looking at hundreds if not thousands of patients who need to enrol. It costs upwards of billions of dollars to develop this new drug to the point where it can be released to the public.
I'm not saying that's necessarily wrong. You want to make sure a drug is safe and effective before it's released to the public. But on the other side of the equation, these pharmaceutical companies are looking at fairly abysmal returns, in a way, for some of the same reasons I've discussed already: short course therapies, emergence of resistance, which is relatively assured at some point in time so their drug will become ineffective at some point in time. The other thing is patent laws. The drug companies are saying, "It cost me $3 billion to develop this drug; I'll only have the patent on it for 10 years" — I don't follow patent laws and am not into pharmaceutical industry, but whatever number of years they are allowed to have it. They don't see the profits making up for the cost.
It goes back to saying there's an expectation in society that an antibiotic is a cheap fix for a serious life-threatening disease; I don't know how that emerged, but it has. It's okay for treatment for a cardiac arrest or high blood pressure to be expensive because it seems to affect perhaps the population that's more able to afford it. So there are social issues weighing against the development of antibiotics as well as microbial issues.
The Chair: Senator Enverga asked a question about concerns regarding microorganisms on food. I think one of the great misfortunes — "tragedy" would be too strong a term — is the fact that an absolutely certain way of treating meat products and ensuring the public gets them absolutely free of microorganisms is irradiation. Forty years ago, Canada was a world leader in the technology that would irradiate foods and prevent absolutely any transmission of microorganisms, but because of the perceived public fear of anything with the term "nuclear" in it, that never got off the ground. Yet, irradiation of foods would deal with that part of the issue, which is a very small part of the total issue, because food handling is highly controlled in general, although we do see some outbreaks. There is an answer to the specific issue that Senator Enverga raised, but it's not available in general.
I think I'll leave other things until my colleagues have finished.
Senator Eggleton: I want to pick up on what Senator Cordy was asking about regarding the pharmaceutical industry. Yes, I've heard many times before about the billions in costs and it takes years. If it's not going to have a long shelf life, there is all the more reason why they would not be interested.
How do we overcome that? I would think part of the problem is to continue to get new antibiotics into the market as new bacterial strains become an issue. Does that mean more government assistance on that kind of thing? Do universities need to be a part of that as well? What do you think the answer is?
Dr. Lagacé-Wiens: A lot of very knowledgeable scholars have debated this issue, and you've touched on some of them.
Government support or even government research in the development of new antimicrobials that is funded by government as opposed to the pharmaceutical industry would be a possibility. We have a vested interest as governments in terms of developing antimicrobials. Grants from governments and other bodies, university involvement, are solutions.
There is also the other side. How do we make it more attractive to those big pharmaceutical companies to continue that research? Showing them that their profits may eventually one day pay for the R&D that went into it would probably help; extending patent laws, allowing these companies to hold the patent longer than current patent laws allow; and controlling what I will call the illicit manufacturing of antimicrobials. Some of these companies have spent billions of dollars on antimicrobials, and very large, populous countries will take the chemical formula, manufacture the drug and start distributing it at their own profit, despite the fact that it's effectively intellectual property. Yet their own governments, I won't say protect, but turn a blind eye to these issues.
There have been issues like that. India in particular has been involved in the production of licensed antimicrobials that are patented by other licensing bodies ostensibly in an effort to provide needed antimicrobials to a population that's quite large and can't afford them otherwise, but that's in the absence of the controls required to make sure that those are not misused.
I think there will be a multi-pronged approach to improving the development of new antimicrobials. There will be funds from public sources. It is going to be changing the laws such that the regulation controls illicit production and give them longer patents.
Also, I think there are the requirements for demonstration of non-inferiority. Organizations like the FDA demand that manufacturers prove that their drug is not inferior to another drug, a standard drug; and they need to have large numbers of enrolled patients in studies to prove safety and things like that. There is probably some wiggle room for making those studies less costly.
Maybe it shouldn't be about non-inferiority anymore. To show that a drug is effective is one thing; to show that it's non-inferior to another drug is much harder. It takes a lot more enrollment to prove that, simply because to statistically prove — I'm not going to get into the details of the statistics — that something is not worse than another drug is much harder to prove than it's equal to another drug. That can be very challenging.
Senator Eaton: I would like to ask you about hospitals and their practices. You were talking about medical tourism and the mingling of bacterial flora. I sit on a board of a hospital in Toronto, St. Michael's. You go in and there is the micro —
Dr. Lagacé-Wiens: The hand sanitizer, yes.
Senator Eaton: It's everywhere, and there is antimicrobial soap. Are we using too many of those products? You see products for the kitchen that kill 100 per cent of microbes. Are we over-clean? Is that part of our non-resistance? And not clean enough in hospital rooms?
Dr. Lagacé-Wiens: It's a big debate. Part of the problem about those hand sanitizers, especially the ones that are widely distributed in the community, on sale at Superstore, et cetera, first of all, they have no evidence that they're better than regular hand soap or regular washing. That's one big problem. They haven't been demonstrated to be effective to reduce the transmission of just about anything compared to regular hand washing in the setting of the community.
There is a double effect, too, because a lot of products now contain antimicrobials that have a long residual effect, so they end up in the environment in large quantities sufficient to trigger resistance in the environment; and in some instances, those are antimicrobials that are either used or being studied for human use. Triclosan is a good example. It is a compound that's put into a lot of things, from toothpaste to soap, as an antibacterial. In fact, most antibacterials that you see in the stores have triclosan in them. Similar compounds are now being studied for treatment of human infections. We are already starting behind the eight ball in that case.
In general, in the community, those types of products are a bad idea. Whether or not they actually contribute to your own personal susceptibility to microbes I can't answer, but overall, it's not proven and it's potentially harmful.
Senator Eaton: What about practices in hospitals?
Dr. Lagacé-Wiens: In hospitals, you're primarily protecting a patient population that is highly susceptible, in many instances, to illness.
Senator Eaton: I think this is a trend, but should we go back to single rooms, as small as they are? Did you see that article that now to clean rooms, they're sending foam that can go everywhere, creep around like a fog and clean?
Dr. Lagacé-Wiens: Now you're talking about infection control measures to prevent infections in primarily patients. In a perfect world, yes, every patient would be in a single room, and perhaps more importantly, every patient would have their own bathroom. Let us not forget that we have a lot of bacteria in our gut and it ends up everywhere.
Single rooms would also indeed allow for these robots, effectively, that can spray sanitizing solutions into hospital rooms to reduce the risk of transmission to the next patient. I think those are part of the solution at the individual level, to prevent infections in the individuals that are going into the hospital.
As far as the public health in antimicrobial resistance, I don't know that those interventions inside the hospital are going to have much of an impact because the reservoirs —
Senator Eaton: You could always just not go to a hospital unless you can help it; you're going to come out sicker than when you went in. That's what made me raise the question.
Senator Seidman: I did want to ask you about the development of new antibiotics. Senator Eggleton has mostly covered that. Do you think that is part of the solution? Would it be helpful to develop new antibiotics? Where does Canada fit in comparison to other countries in the world in their free disposition to doing that?
Dr. Lagacé-Wiens: New antibiotics are part of a much larger solution, yes. I've already hinted at the fact that even with prudent use of antimicrobials, you eventually will start to see resistance. The rate of which depends on the drug, how likely it is to select for resistance and where it's used, but in the end it will happen. So having a steady flow of new agents is good. You can also reduce side effects with new agents and things like that. There are benefits to doing that, for sure, but it's only part of a much greater solution.
Where Canada is in terms of pharmaceutical development compared to other countries, I think in terms of small pharma — what I mean by "small pharma" is small start-ups and new compounds that are perhaps interesting for antimicrobial use. We're probably par for countries in our population range. We don't have any major pharma in our country. Most of these compounds, as I mentioned, are so costly to develop beyond your basic "yes, it works" and maybe "yes, it's safe in rats" that they get sold to big pharma. They get sold to Johnson & Johnson. They get sold to Pfizer — Pfizer is out of the market now — AstraZeneca. Then they continue to develop them. You either have to drop them because they don't work or bring them to fruition, which is only a small proportion of them.
Senator Seidman: Dr. McEwen, I would like to ask you a couple of very specific questions about animal feed. We know that antibiotics are included in animal feed to promote growth, and there is a very particular process that they use — low concentrations over extended times. Are these classes of antibiotics also used in humans and, if so, do you think that there should be or are there regulations that would limit the use of antibiotics in humans from use in animal feed?
Dr. McEwen: Yes, among the drugs that are used in feed for growth promotion or disease control, many of them are members of classes used in human medicine. The Veterinary Drugs Directorate has classified, for purposes of the exercise that we're talking about today, antibiotics as to their importance to human medicine. There are four categories. There is highly important, very important, important, and not important, and the growth motors tend to fall in the last two categories. They are the older drugs — the sulfonamides, tetracyclines, lincosamides and so on. Some of them are in a higher category. There is a drug called Tylosin, which is used quite a bit. It's a macrolide. It's the second highest category.
Other countries have different classification systems. For example, in the U.S. that drug is in the highest category, so there is some difference there. The one class or group of drugs that is responsible for the largest volume in growth promotion is called ionafores. They're not used in humans, I believe for toxicity reasons, but they're used widely in animal production, both for growth promotion but also for prevention of a parasitic infection called coccidiosis. That's one of the problems with comparing aggregate numbers. When you compare total antibiotic use in animals and humans, the animal use in countries that have growth promotion, a lot of that is due to ionofores, which aren't used in people. But even if you take out that class, there is still a lot used in animals.
The other part of your question was, should there be regulation? I try to make a point of not promoting policy because I don't see myself as a policy person. That's government's job, I guess, or people who are policy-makers. It's hard not to do because you see things going on and think this will be the right thing to do, but, as you well know, I'm sure, when you change something it can have knock-on effects, unanticipated. We're talking about unwanted side effects here with resistance. The same thing can happen with policy.
I don't advocate a policy, but I can say that a lot of very well-informed people and groups believe strongly that antibiotics should not be used in growth promotion, particularly those used in humans.
The Chair: Dr. McEwen, I think with that last comment you've certainly hit something on the head: the unintended consequences of policy development. In this arena probably is a lot of discussion could occur on that alone.
The issues are complicated. Dr. Lagacé-Wiens, you have been quite fair with regard to your comments on the pharmaceutical industry and the development of antibiotics. It is a complicated issue. The market forces are tremendously important. When you can get a prescription for a few dollars for an existing pharmaceutical, the idea of spending a lot of research on more complex ways of interacting with micro-organisms through biotechnological routes is going to be a loser from the beginning in that kind of market, as you have correctly implied. You didn't use those specific examples, but you implied the complication here. That is a very complicated aspect.
You both have given us a great deal of important information with regard to the development of antibiotic resistance. I think, Dr. Lagacé-Wiens, you made a point that scientists all know but rarely articulate the same way, and that is that resistance is inherent and things will become resistant to almost anything. Now, the degree to which it occurs and the ways in which you can mitigate a broad spectrum resistance in compounds that are essential to human life, that's really the focus of where we want to try to find some direction here.
Dr. McEwen, there are suggestions in the literature of antibiotic use in animals to enhance growth rate, poultry in particular, that studies done some 40 or 50 years ago perhaps wouldn't meet the test of modern approaches to studies that would lead the kind of conclusion that was inferred back then. Do you have any comment on those observations? Is that a reasonable observation?
Dr. McEwen: I think you've summed it up very well. When you go to the literature, you see estimates of 5 to 10, 20 per cent improvement in rate of growth or efficiency of feed conversion. There are many who are very skeptical that that is realized today. I think the Danish data demonstrated that there was only marginal improvement in productivity in poultry that was offset by the cost of the drug. I didn't mention that. So taking the growth motor away didn't cost the industry in terms of enhanced production.
We use a different set of growth motors here, so we can't extrapolate it directly, but I suspect it's probably a similar phenomenon.
Personally, based on the Danish findings, I suspect that a lot of the benefit accrued from growth promotion use is as a result of disease prophylaxis and that benefit probably varies a lot depending on the quality of the management of the animals and how healthy they are, how well they're looked after. You'll probably see a spectrum.
I suspect if we took away growth promoters and it wasn't immediately compensated by people calling it something else like disease control, we would see, based on the Danish experience, and the same thing in Sweden, probably greater problems with post-weaning diarrhea in pigs. We might see some necrotic enteritis problems in broilers.
The Chair: Those are important different aspects, aren't they? We don't throw antibiotics at humans to get them to grow faster. We throw them some other things, we know, but generally we don't think of using them in quite that way in human use.
I want to come to this. You made I thought a very important point that if you identified use of antibiotics in animals for clearly identified disease issues, that's one thing. With regard to the tremendous use of them in a general way with perhaps marginal or no benefit, I wanted to come to the regulation side of this. We know how difficult regulation is to enforce, but the farming industry is highly competitive and anything that removes a cost, however small, in terms of mass production, if there was any savings to farmers economically by not using antibiotics broadly, it might well be that as part of the so-called educational piece of benefit in the long run, there might be more positive impact in that route. If you combined the two possibilities, that is, holding antibiotic use purely for identified disease issue versus the holus bolus use for theoretical or inferred possible growth rates of marginal value, something in that area might be useful.
I want to come back to one of the questions that Senator Eaton raised. We asked you to think about what you have discussed with us today, away from this place, when you are on the plane and you say, "Gee whiz, if I just thought of that." Well, write those "gee whizzes" down and get them to our clerk, because we want to identify pragmatic issues that we can deal with as a committee and make recommendations that might actually have some benefit in this area.
This is a complex area we're dealing with. We're touching on one aspect here today, but do not hesitate to drop us a quick line through our clerk of any thoughts you have, as you leave here, either issues that we should have addressed or, more specifically, on thoughts you have with regard to specific recommendations that might, if implemented, make a difference down the road.
With that, once again, I want to thank my colleagues for their questions and both of you for very informative presentations and dialogue here with us today.
(The committee adjourned.)