S3.E1 Bugs and Drugs

From the University of Toronto's Leslie Danth Faculty of Pharmacy, this is the I'm Pharmacy podcast. I'm Minas Hadros. Turning on the news, it's hard not to be hit with a story about healthcare. Discussions about failing systems, misinformation, overcrowded hospitals, inequality in access, healthcare systems around the world appeared to have reached a crumbling point. This hits very close to us Canadians. When asked what Canadians are most proud of, for years running, healthcare came second. Second only to the flag. It beat out a lot. Get this, beat out democracy, the armed forces, multiculturalism, and yes, even hockey. That's why it's not surprising to understand why the current narrative around struggling healthcare systems hits so very close to the Canadian identity. Even just Canada, it's hard to understand how important healthcare is to humans. The WHO defines it as a basic human right. But listening to all this news, it's easy to conclude we are in crisis. How can this be possible? We're constantly hearing about incredible scientific discoveries. Just last season we went on a journey about the amazing science occurring in drug development. We didn't even tackle new surgical techniques with robots, novel diagnostics, digital health, gene therapy. How can we be discovering so much, yet healthcare is failing? For many of us lucky enough to live in high-income countries, it is not a lack of technology but rather the systems in which things are delivered that seems to be struggling. The complexity of health is matched by the complexity of these problems. More so, it's not just that the problems are complex, but they don't fit nicely into boxes of problems. Problems have themes and there's many different types of that. Some of them range from the lack of access to others being quite the opposite to much access. Others can be simply overuse of a part of a system while others could be underuse of the system. It's not simple stuff. And that's why this season we will explore just that. What are the big problems affecting healthcare? We will explore all these different problems and dive deep into the themes that link them all together. We've selected a number of problems that we want to explore this season. On a side note, these weren't just picked by us. We were lucky enough to have many of you listeners give us ideas and suggestions that led to the selection of many of these problems we're going to tackle. More importantly, I promise I'm not going to just be a complainer this season. We're going to talk to amazing people, scientists, researchers, and clinicians from the University of Toronto and around Canada who are working to solve these problems. And that's why this season is titled "Big Problems, Bigger Solutions." Exciting, I know. But let's take a step back though. It's easy to forget and take for granted how far we've come as humans. For the last hundred years, we've experienced a rapid shift in the advancement and delivery in healthcare. For thousands of years, healthcare, although varied across the world and varied by tradition, was rather poor. And the proof of that you don't have to believe me, is simply life expectancy. For thousands of years, life expectancy, the average age that people die, was in our 30s. I, sitting in front of you here, would have been considered an elder, yet today many countries have life expectancies that are well into the 70s and some even crossing into 80. More amazing is the hawkistic jump that happened in life expectancy over the last hundred years. If you picture a graph that shows life expectancy by year, it sort of stays flat from the beginning of human history over time. We get a slight bump in the 1700s with the emergence of sanitation and vaccines, but somewhere in the 1920s, it jumps right up and it continues growing and growing. And many have pointed to the first major modern medical advancement, the discovery of penicillin, the first antibiotic. Now this is one of my favorite stories about drug discovery in its white famous. In 1928, Sir Alexander Fleming returned from a holiday to find mold, growing on a petri dish of bacteria. He noticed that the mold seemed to be preventing the bacteria from growing around it. He soon identified that the mold produced a self-defense chemical that could kill these bacteria. He named this substance penicillin. Classic good science, good observation and some good luck. By the 1940s, the drug was manufactured in available in many countries. This was a huge deal. Basically, before this, you got an infection and it was just over. You had no options. Can you imagine that any infection that you had, we had no options. Penicillin's discovery led to the development of more and more antibiotics, and then here we are. So why am I talking about this? How in the world could this be a problem? Well ever here of too much of a good thing, this is the classic problem we have now that is developed. It has led to something called antimicrobial resistance. Antimicrobial resistance or AMR for short occurs when infections, whatever they are, viral, bacterial, fungal, no longer respond to the medicines and it makes it harder and harder to treat and it increases the risk of disease spread. This is a growing concern and you don't have to take my word for it. This is such a big deal that the WHO has made this one of the top 10 global health concerns threatening humanity. So this seems like a perfect place for us to start this season. Today we're going to explore AMR, how does it happen, why is it such a big deal, and more importantly what can be done? To better understand the problem, I chatted with Dr. Mark McIntyre, who's a pharmacotherapy specialist at the University Health Network specializing in antimicrobial stewardship. He's also an assistant professor here at the Leslie Dan Faculty of Pharmacy. So this episode we're trying to dive into what the WHO calls one of the major public health threats to humanity, which is antimicrobial resistance. So maybe we can start off there. What is AMR, and how does it happen? AMR is the most ancient of life processes that happened when the first microorganisms existed in the oceans billions of years ago. This has started then. So we think of AMR as an antibiotic related problem or human related issue, and it's very little to do with us. It started out because you have organisms competing for scarce resources, and in order to protect those resources and promote their own growth, they need to fight other organisms. And AMR is really just a way to have different bugs fight each other for colonial expansion in a given area. And when it comes to fast forward, 2.5 billion years, we get into the current era where we have microbes in our body. They're everywhere in our body. You can see studies that say there's like a 10-to-1 ratio, a 1-to-1 ratio, a 1-to-3 ratio of human cells to bacterial cells in our body. And this is in our honor skin and our gut pretty much anywhere that is in a sterile site. We have bacteria. And as we expose ourselves to antimicrobials, which are almost always derived from sort of natural things that you're found in soils or found in water that are produced by other fungi, other bacteria, as you expose the bacteria in your body, either the good bacteria or the bad bacteria to these things, they will develop resistance. They develop their natural defense mechanisms turn on, and they'll be able to selectively avoids that most of them will die. Some of them won't. And those that don't die are the ones that are a little bit more tuned to preventing death because of those other factors involved. So what I'm trying to say is antimicrobial resistance, basically, is just a selection pressure thing that as humans, we're using antimicrobials, we get to see the end state of where when we use it to antimicrobials, we see more antimicrobial resistance and that can compromise therapeutic decision-making or the therapy that can compromise pharmacotherapy, it can compromise patient-well-being overall health. So is it a big problem or is it a problem that's going to happen in the future? It's a problem that is happening right now and it's going to get worse in the future for a couple of reasons. So right now, AMR, you know, in Canada, we're like one of the more cloistered countries when it comes to antimicrobial resistance impacting daily health, but that's changing. And things like methamethicillin resistance, staff worries, MRSA, resistant gram-negative infections, pseudomonal infections. These things happen on a daily basis here, and I just came from a meeting right before this, we were talking to a microbiologist and a couple other clinicians about a case where things went really badly because of a totally completely drug-resistant antimicrobial microorganism that we just couldn't treat. And so we had to do heroic measures to try to find something to do for this microorganism than it ultimately couldn't. And so it's a problem right now in Canada, and there was a publication a couple of years back that basically said that somewhere between 14 to 15,000 patients every year die of antimicrobial resistant infections in Canada. And that's like right now. So that's not something that's just 20 years in the future or 30 years in the future. That's like right now. And yeah, and there was another article that was just published in the Lancet earlier this year, looking at sort of global impact of antimicrobial resistance. 2019, there was about 1.7 million people who died directly as a result of antimicrobial resistance infections globally and about 5 million who were affected in some way that ultimately led to or was associated with their mortality, their death. So it's something that happens right now and it's something that will eventually get more common because we'll be used more antimicrobials, there'll be more people. And then the two of those things combined increased your risk of antimicrobial resistance. - Is it because of prescribing that we're here, like tell me a little bit about the causes of this. You talk a little bit about just natural selection, like this is gonna naturally happen with resistance. Are we making it worse or is this just an inevitable thing that's going to happen regardless? - Yeah, it is an inevitable trade, it's an intrinsic property event of microbes to become resistant to things they're exposed to. But the reason that we care about this and the reason that I have a job is that when we use antimicrobials, they promote resistance. There's a benefit to antimicrobials. And when we use antimicrobials beyond where there's benefit, that's the preventable harm of antimicrobials and antimicrobial resistance. So if we use antimicrobials more often than as necessary, then that pushes the rate of antimicrobial resistance up higher, it shifts the curve a little bit and you get more resistance for no benefit to society or the individual. - So, and you see this in the news, this talk about super bugs, that they're sort of like they feel like Thanos, like an evil Vino where they're collecting different resistance, right? So and once they have enough of them, they're unstoppable. How common are those types of bugs? And my other question is just, is this an uphill battle in the sense like, they're gonna just keep collecting them until they get more and more super? Or is it a cycle where they start to now suddenly be susceptible to things that we haven't used in a while? Like, is it more cyclical? Or is it more this sort of like arc where it's getting worse and worse? - There's a duality here. So when it comes to antimicrobial resistance, that will always continue to happen. And there are times where you see this sort of fluctuation around the mean where you use an antimicrobial and you see the more use of it, the more resistance there is. And at the same time, if you stop using an antimicrobial, there are times where your resistance rates fall back down. And so if you look at an individual patient, the risk for resistance is not static across time or across location. So the less antimicrobials you use, generally speaking, the less resistance you have. And that's really why we do the work we do because we need antimicrobials that are a necessary part of medical treatment and have to save millions of lives. But the question is, when we use more of them, there is no benefit and we can cause harm. So how do we get to the point where we know exactly in what patient to use an antimicrobial and what's one to use and for how long? And those are the questions we're really trying to answer. - After talking with Mark, we better understood why antimicrobial resistance was a problem. But I wanted to better understand how that resistance actually occurs. To do so, I talked to Dr. William Navar, an associate professor and vice chair in the Department of Molecular Genetics here at the University of Toronto. He's an expert in the biology of bacteria. - My life has primarily been interested in how microbes interact with one another to either affect the biology of their animal host that they live in. And I've been interested in how bacteria evolve to become more virulent or as relevant to this conversation, resistant antibiotics. Bacteria do a lot of what we call genetic exchange where they swap bits of DNA with one another. And we've been particularly interested in that process and in these pieces of DNA that we call plasmids that carry the genes that make bacteria resistant to antibiotics from one bacteria to another. So those have been the primary things that I've been studying in my laboratory over the past several years now. - So how do you actually ask those questions? - There's a lot of barriers to genetic transfer. One of the things is the bacteria also have to protect themselves against foreign DNA or DNA that comes in from other bacteria. So bacteria constantly playing this game of trying to protect themselves against things like viruses, which are also pieces of DNA or RNA that might try to invade them, while still maintaining the ability to evolve and rapidly take advantage of useful pieces of DNA that might come in from a foreign source. One experiment that we would typically do, we have a collection of these plasmids in bacteria that encode on them resistance to antibiotic, different antibiotics. Then we mix them with bacteria that are not resistant to antibiotics. And we actually can watch as the DNA is transferred from one cell to another from a variety of methods. But the most simple way is to simply watch how the new or the recipient bacteria now suddenly gains the ability to be resistant to an antibiotic. It was not previously resistant to, and we can look at the rates at which that happens. So we can see if we change some property of the recipient bacteria, do they pick up these antibiotic resistance genes more easily or are they more resistant to foreign DNA and picking them up? So we're very interested in the factors that dictate how easily a bacteria can become antibiotic resistant. - That's a perfect segue to my question, which is like how do they become resistant? I think so as a pharmacist, we always think about overuse of antibiotics and in a way it almost felt like a strange natural selection that the one that doesn't respond suddenly replicates more and then that's how it works. But maybe you can walk us through how actually does resistance occur within these bacteria and is it like a selection process or what happens in the wild? - Well, I think it's pretty clearly a selection process. I think definitely if you're in an environment, let's say where only 1% of the bacteria happen to have a penicillin resistance gene, they're not doing particularly well in the population overall. And then that population, let's say in the gutter wherever gets hit by penicillin, all of a sudden the dominant bacteria now is the penicillin resistant one. So it can grow to very high levels because it has no more competition in the gut. Now the ones that were not resistant to penicillin that managed to survive that first hit are just surrounded by a very large number of penicillin resistant bacteria. What's interesting about the penicillin resistance genes in this and many other drug resistance genes is that they're encoded on these plasmids that themselves have the ability to force themselves to jump from one bacteria to another. So these are what we call parasitic genomic elements and they make their own little pillars actually. So like a little fiber that sticks out and looks like a little flagella or something that sticks out of the bacterial cell can grab onto a neighboring bacterial cell, pull it closer and then through the center of that pillars shoot a piece of DNA, a copy of the plasmid into the new bacteria. So the plasmid itself is almost its own organism at that point. It's promoting its own spread. It's got all of the machinery, it encodes in its own genes, the machinery necessary to jump from bacteria to bacteria. So when we treat somebody with antibiotics, we lower the number of naive non-resistant bacteria. We get these big blooms of resistant bacteria. And so the number of chances for these plasmids to find targets and jump goes up quite a bit. And if you are not a resistant bacteria before, the chances of you becoming resistant go up astronomically. So what we're finding is that some of these plasmids will, as they travel from bacteria to bacteria, start to pick up more and more resistance genes and they'll do swaps of DNA with each other. And so we have plasmids out there that encode resistance to four or five or six antibiotics in a single plasmid, which means in a single gene transfer event, the bacteria can go from being completely sensitive to four or five or six antibiotics to being resistant in a matter of seconds. And so these jumping plasmids are really a huge problem in the clinic right now. - So how does your research try to tackle this, like as a solution side? So we've talked a little bit about here about the problem and how in a sense it spreads and how bacteria get that resistance. What are some potential ways that we. You know, we could be tackling this or at least curbing it. - Well, I think there's some stuff that was, whether some research that was done in the 1930s using bacteria phages. So these are the viruses that infect bacteria to cure infections with any number of bacteria. So almost every bacteria out there has, not just one, but many different viruses that can infect it and destroy it. Bacteria protect themselves against these viruses using things that we call restriction enzymes or CRISPR systems. Perhaps you've heard of CRISPR, this is the gene editing tool that is being used now to edit genes even in human cells. But this actually started out as a system in bacteria to destroy these viruses. So there's a huge, huge number of viruses out there and bacteria who got all sorts of different ways to resist phage attack. And so finding the right phage to kill the right bacteria is a bit of work. But in theory, if you have a phage that can kill a certain strain of bacteria, you could use that as an antibiotic itself. So there is a lot of interest right now in phage therapy. So this gets us away from classical pharmacology and more into using biological agents as methods of controlling infection. There's been some success with that. But the thing is just like with antibiotics is that bacteria also can evolve resistance to different phages. And so a phage that maybe worked against bacteria X a week ago may no longer work a week later because the bacteria picked up the ability or mutated in such a way that it's now resistant to the phage. So we've been interested in trying to make a whole panel of phages that or phage-like particles that could kill bacteria. That would be very difficult for bacteria to evolve resistance to. And if they evolve resistance to phage number one, we could just come back and hit them with phage number two because there is an almost endless variety of phages out there. - Novel therapeutics is one way to solve the problem. But there are other ways to curb it, including something called stewardship. Here's Mark to explain. - So in steps in some of your work, you mentioned stewardship. So what is stewardship? - Stewardship is basically using what we have in the most appropriate way possible. It's saying if we have an infectious disease, we want to use the rhinitis microbial for the right patient at the right time, at the right dose for the right duration. And it's an easy thing to say. It's a totally easy thing to comprehend. But we know that people don't walk in the door and we don't have a diagnosis. This is, I have a UTI. I need this number event of antimicrobial days. And so stewardship really is creating a program of strategic initiatives to make that best possible decision-making happen in all parts of the healthcare system. And so it's not just like do things well. Like everyone's to do things well. We all show up due to work to do things well. Stewardship is trying to make that a formalized system of interventions that work cohesively and collaboratively to make these behavior change strategies more impactful across time. So it's like, yes. We don't want to prescribe for bronchitis 'cause we know it's almost always viral. But the temptation is when you see something, he's got a really bad cough and they're really uncomfortable. You want to fix that. And so the knee-truck reaction is like, well, I've got two options here, three options. I'm gonna use one of them. Stewardship is trying to assess what the best strategy is for a given population for antimicrobial use and enact that in that population. - So what are the types of interventions you can do? Like what does that mean? How do you intervene aside from just stopping the prescription? Like is that, is that what you know? - Yeah, it's like a sentence reference. It's like antibiotics for everybody. Boo, antibiotics for nobody. Boo, all right, antibiotics for some. When we try to think about this, we're gonna be very, it's a very subtle art. I think of myself as an antimicrobial muse and not as an action pharmacist. - Yeah. - Like if I'm doing my job, I make other people think everything that I'm telling them to do was their idea and eventually I am redundant. And that is my entire goal for my entire job and career is to become redundant. - Right, because you haven't got there. - Haven't got a lot. So give me a couple months and hopefully I'll get there. But when it comes to how do we do that? How do we make ourselves redundant to stewards? Is it's to basically focus on the things that are easily to access and the things that are easy to accomplish and actually move the needle. And we look at things like antimicrobial use as these sort of benchmark across different settings to say this is what we're trying to impact. And to do that, we can do easy things. Like hey, you know what, things that are viral don't need antimicrobials. And that's like an educational intervention and it's an enolate strategy. And we try to reduce people's reliance on antimicrobials when they have something that's probably viral. The other things we can try to do were empower clinicians to say, I want to treat people with antimicrobials if they do have an infection for the shortest duration within their spectrum therapy that's effective. And so when we do that, we really try to empower people to say, you know, if you're I'm gonna treat a year uncomplicated as a site, this is a great example. So if we have somebody who's got a UTI, we know that five days of entry for Antoin or three days of SEPTRA, totally fine. We don't need to go five days or seven days. So it's saying if you have a likely infection, use an air spectrum therapy for the shortest duration possible. And we think those three options are really how we're gonna move the needle in the community setting and hospital setting, long-term care, trying to reduce the overall exposure of antimicrobials. - So the last question I wanna ask you is something as I was preparing for this episode, I was reading up a lot on AMR and things are happening. It seems like within the literature, there's just, I don't know if it's a good characterization, but there's a kingdom divided. In the sense that some people strongly believe that we should just learn to use better what we have. And then others are doubling down on the need to find new things. So as a, if you convince a policy maker or government that this is an important issue and they're gonna invest, where do they, what do they do? Which camp do they invest in? Is it one, two, both, where do you think that as we think about the future and solutions, where should we be investing or putting our resources? - So we had a big nuclear fusion breakthrough this past week, like the idea that we can actually make infinite wasteless energy is very compelling. And it's the panacea. It is a possibility, but your return on investment is gonna be over generations, not just years. And when you think about antimicrobial development and the idea of R&D, can we technologically advance our way out of this? Or do we have to kind of make the best of it and do what we can in the short term? You can't have either. You have to have both. Because as we, as we use more amoxic cell and like, we're good, we've had 50, 60, 70 years of penicillin therapy, and strep pneumo, it's pretty still effective. Beta lactose are still effective in strep pneumo. But there might be a tipping point and it's not always predictable. And so we both need to use what we have in the best way we can, because it's pretty cheap, pretty accessible and pretty low risk for patients. And at the same time, we do need to have something in the background working to find the next strategy, the next thing. Because for most people, they're not gonna need it. But more and more often, when we have advances in medical technology that affect people's immune systems, that don't allow them to fight off infections, when they're gonna get multiple recurrent infections, we're gonna need that. And we're gonna need that more and more. And so that long-term investment, even if it's a small investment over time, it has to be done in a way that it's coordinated, that has to be done in a way that is multinational, ideally, because this is in a single nation issue. It has to be something that is gonna work towards a goal. And I don't think it can be done in a sort of an economic way that is similar to other type of drug discovery, 'cause it's not gonna pay for itself, it never will. But it's for the benefit of humanity. In total, as we get more and more persistent pathogens that come up, so I wish I could say, you should do this direction or that direction, but I think your apportioning of resources has to be done logically. And I think the things that we can do right now, even if they're complicated or still fairly low-hanging fruit, and we can shift the curve by 5, 10, 15, 20%, depending on the organism and the sender that you're looking at. But I think we still have to keep the eye on the eventuality that what we have now won't always work. And there is a declining return. So we do need to think about the next decade, two decades. And not just here, not just in Canada, around the world. Or like as hard as it is sometimes in healthcare and as bad as these people have resistant infections, we have it really good. And the thing about people is that they're basically mobile sentient pyre reactors for antimicrobial resistance and they can move it around. So what we see right now isn't always going to be how it is in Canada, but what we see right now in Canada isn't how it is in the rest of the world. And so I think we need to be cognizant of that and not just focus on like, oh, we're doing great here. We need to think about how do we multinational and internationally develop a consortium to facilitate better antimicrobial discoveries for the next 15, 20, 30, 40 years to make sure that the things that are out there are treatable and that the mortality that we have is it is preventable as we go forward. I asked William the same question. Do we do we use what we have better or do we develop better things? And it sounds like you're landing on, we got to do both and so how would you, you know, maybe walk me through that because that's something that I've been wrestling with as I've been thinking about this episode is do we need new drugs and we keep developing new drugs and new therapies or are we just not using what we have optimally? I think it's definitely both. If I could wave a magic wand, I would immediately get antibiotics out of the agricultural space completely and out of the consumer market like triclosan and soaps and things like that out immediately. The antibiotic in agriculture, it turns out if you feed animals, antibiotics, it doesn't keep them healthy against infections. In fact, if anything, the infections can be worse, but it does help the animals gain weight. So it's actually a growth promotion factor for a lot of them. It changes their microbiota and for a variety of reasons, animals seem to gain weight much faster when they're on antibiotics. So the agricultural industry has been very slow to ditch the use of antibiotics. So there's that usage angle, so what we currently have, do we just use it better? I'm pretty pessimistic about finding new pharmacological agents, well, certainly in the current regulatory framework, that the bacteria won't just evolve resistance to anything new that we develop within a matter of a couple of years. So I think we're going to be on a treadmill there where you discover something new and you think you're getting ahead and then you're behind again. And I've just seen year after year for 30 years now, paper is about, oh, this new compound can kill this bacteria and then you follow it out and nothing happens. And so I really also think the toolkit needs to be completely reinvented and reimagined. The regulatory framework needs to be modified to allow that to happen. The money needs to be there and given the great risk and the very low potential for big reward, I think government's going to have to step in and actually fund the actual take on the cost of the risk and not just, it's a lot different than, let's say, how we deal with Viagra or something like that, where we try to give that to as many people as possible and the company is trying to make as much money as possible as quickly as possible. This is going to be a public good and I think we have to treat it as a public good and it's a different relationship that we would have to set up with industry because the bottom line is academic researchers like me can only get a drug so far before it needs the expertise and the production and the marketing of industry to make these things carry them across the finish line. But industry looks at the numbers and I don't blame them and says this is a lot of risk for very little chance and for award financially. I don't see the limitations necessarily being the science per se, I think the primary headwinds are everything downstream of the science. We need to unleash the science. That's a great way of it, you know, and we need to get smart about when one economic model is great for Viagra but it's not great for the next penicillin. Hey Amar is a problem, a major problem. A problem we aren't going to prescribe our way out of or drug discover our way out of, we have the science to improve it but what we need is a unified global strategy and more importantly a political will, a political will to improve our stewardship, the way we use antibiotics and the way that we bring new discoveries to market. The science is exciting and we just need to unleash the science. This episode of the I'm Pharmacy Podcast was produced by Steve Southon, Kate Richards and me, Minotadros. Musical accompaniment was from Steve Southon and Diego Martinez. This episode was edited by Steve Southon. Special thanks to Dr. Mark McIntyre and Dr. William Navarra. We'll be dropping new episodes every single month so make sure to subscribe wherever you listen to your podcasts. Stay safe and keep asking questions, catch you at the next episode.