AMR unleashed: the silent pandemic
Thanks to UCL and Vaishnavi Sundaresan for their help in creating this programme, which has been supported by the EPSRC Digital Health Hub for Antimicrobial Resistance.
In this edition of The Naked Scientists, Antimicrobial Resistance, or AMR, is going under our microscope. What is it, how does it happen, what’s the scale of the threat, and how can we fight back?
In this episode
00:51 - The rise of superbugs: what is antimicrobial resistance?
The rise of superbugs: what is antimicrobial resistance?
Laura Shallcross, UCL
Today, we’re tackling a silent pandemic: it’s Antimicrobial Resistance, or AMR. Every year, millions of infections become harder to treat as microorganisms evolve to resist the medicines we normally use to fight them. I’ve still got the guidelines issued to me as a junior doctor, explaining what antibiotic to give for what infection. But when I looked at it again the other day, two decades after I last used it, I made the shocking realisation that many of the drugs on that list would not work reliably these days for the infections we were writing them up for back then. The bugs are all becoming resistant. And that’s just over the last 20 years. Moreover, there are almost no new antibiotics entering the market to replace those agents we’ve lost. As a result, many clinicians are extremely worried that we’re sleepwalking into a silent pandemic of epic proportions where even mundane infections can become lethal again like they were 100 years ago. So what can we do to stay one step ahead? I’ve been down to University College London to meet members of their new Digital Health Hub for Antimicrobial Resistance, which is seeking to tackle the problem. Laura Shallcross is the director of UCL’s Institute of Health Informatics…
Laura - AMR stands for antimicrobial resistance. Microbial is just a complicated way of saying different kinds of bugs, viruses, bacteria, parasites. And what the resistance bit means is we've got drugs that are used to treat those bugs, to treat those kinds of infections, but they aren't working as well. And so resistance is when an antibiotic that you rely on to treat bacteria doesn't do its job anymore.
Chris - Is this a recent phenomenon?
Laura - It really isn't a recent phenomenon. So we know way back when antibiotics were discovered by Fleming, he at the time said, we need to be really careful here because there's a massive risk if we use these drugs in the wrong way, we're going to end up developing lots of resistance. And that is exactly what has happened. But the new part now is that we used to be in a lucky position where every time we got resistance to a bug, we were able to find a new antibiotic. But for some time now, that pipeline of new antibiotics has really dried up. And so it means that we're running out of effective medicines. And that's a problem for all of us in lots of different ways.
Chris - Is it drying up because pharmaceutical companies have run out of ideas? Or is it drying up because they don't make as much money doing that? So they've turned their attention to look at other things?
Laura - That's a good question. So there's definitely something around the cost of developing new drugs, and about the incentives to invest in developing antibiotics. And what people often talk about is that if we get a new antibiotic, people want to put it in a cupboard, lock it away, don't let anyone use it. So why, as a pharmaceutical company, would you spend all that money inventing a new one? And so there are all sorts of perverse incentives that make it difficult to get new drugs to market. And it's difficult. I think we've been through the ones that were easier to discover, and now it's definitely harder.
Chris - Where does the whole resistance stem from in the first place?
Laura - So lots of people think that it's our bodies that get resistant, and it isn't. It's the bugs. So they evolve, and they evolve, and this is just something that they do. And as they evolve, they mutate, and they can learn how to become resistant to different kinds of antibiotics or antimicrobials. So the challenge is we can't really stop that process from happening. We have to respond to it, and that's why we need lots of different strategies to tackle AMR.
Chris - And can, if one group of microbes develop resistance, can they share the knowledge? So one bacterium has it, but can it give it to its mate that is a totally different kind of bacterium?
Laura - Yeah, absolutely. So these things work differently for different kinds of bacteria, but yes, absolutely, they're able to share genetic material between bacteria, and so to transfer those different ways of evading antibiotics, and so those traits spread.
Chris - What's our best strategy then for fending off the problem?
Laura - So there are lots of different things that are being tried, and the strength of evidence to support different approaches is variable. What everybody agrees on is that being more careful about how we use antibiotics is really important, because we know from how those bacteria evolve, if we use lots of antibiotics, it promotes the emergence of antimicrobial resistance. So if we use antibiotics more sparingly, that is a way of trying to preserve the ones that we've already got.
Chris - But if you've got an infection, you've got an infection.
Laura - And that's true. But sometimes people have viral infections that don't respond to antibiotics, and they get antibiotics anyway. And there's also a lot of ongoing uncertainty about the best way to use those antibiotics. So it used to be that we would use antibiotics for long courses, so maybe you treat somebody for seven days, and now there's much better evidence that actually you can treat say for three days. So we're really trying to learn about how we can maximise the use of these valuable drugs, but also minimise those harms and potential side effects.
Chris - Are there any hot spots where this is particularly a problem? Is it just a problem for hospitals? Is it a problem in the community? Are there some countries where this is a major problem, and those are the ones to watch?
Laura - So there are definitely areas of the world where we see higher rates of drug resistant infection for sure. Countries in Southeast Asia, for example. But it all partly depends on how much surveillance, how much testing and sampling you're doing, which makes it hard to get a very accurate sense of the prevalence of drug resistance across different countries. What is probably fair to say is that you see the impact of this at the severe end of the spectrum. So for example, if you're somebody who's had an organ transplant, you desperately need antibiotics to be able to survive that process. If you don't have access to those antibiotics, you could die, you could very easily die. So I think that many of us may be using antibiotics inappropriately, so we're all part of it, but actually the impact of it is seen in those most vulnerable groups.
Chris - If we carry on the way we're going, what does the future look like?
Laura - So I remember when Dame Sally Davis started really raising this as an issue going back over 10 years now.
Chris - Yes, she was our Chief Medical Officer. She made this very much her mission, didn't she? She famously said the threat is bigger than the threat from terrorism.
Laura - Yeah, and got it included on the risk register and so forth. So yeah, absolutely. And I think that the problem we've got is antibiotics underpin so much of care. So we have the example we're all familiar with. You go to the GP, you get an antibiotic, fine. But as I said about the transplant example, or if you're going in to have surgery in hospital, caesarean sections, or you get bitten by, let's say you get an insect bite and it becomes a skin, a deep skin infection, you need antibiotics. None of these things sound serious or scary until you think, well, what would happen if actually I couldn't get treatment for that and it got worse and it turned into a bloodstream infection? And if you sort of follow that thought process, you get to a place where medical procedures, the way that we have medicine now, doesn't work anymore. And it's a bit like going back in time where you get an infection, or maybe you die, or maybe you end up losing a limb, or that might sound a bit dramatic.
Chris - Is this a realistic prospect, Laura? Or is that sort of catastrophising and saying, this is the worst that could happen, but actually it probably won't?
Laura - I think that the risk here is that we sleepwalk into a situation like that because we keep thinking, oh, well, our antibiotics work. It's definitely a possible outcome. Yeah. I mean, we, you know, there are certain patients where if they don't have access to antibiotics, the outcome will be absolutely catastrophic. You may be fine with your cold in primary care, but if you have sepsis in hospital and you actually need antibiotics and the right antibiotics, that's not a good outcome. That's not where you want to be.
08:59 - The antibiotic crisis: why we're running out of cures
The antibiotic crisis: why we're running out of cures
Mark Sutton, UKHSA
Why haven’t we got a drug pipeline bursting with promising new antibiotics? Well, as we’ll hear from our next guest, Mark Sutton, who’s a scientific leader at UKHSA Porton Down and professor of Antimicrobial therapy at King’s College London, since the “golden era” for antibiotic discovery in the 50s and 60s, very few new compounds have come along, because to discover drugs with novel mechanisms of action involves risk and investment. And the industry doesn’t have the appetite to invest in a high-risk sector that might result in the development of a drug that either is used only as an agent of last resort, or rapidly drives resistance and falls off the formulary. So how are we going to solve this?…
Mark - This is not necessarily a science or microbiology issue. This is actually an economic issue. So we estimate it costs about a billion dollars to identify and take a new antibiotic through to the clinic. So you can understand why drug companies are a little bit risk averse. It's a billion dollar price tag to develop that new molecule. And then it may be obsolete within the matter of, in some cases, even two to three years, because bacteria evolve to overcome that drug and to become resistant to that drug.
Chris - Is it not also even more insidious than that? Because a microbiologist like me, if handed a golden drug on a plate, my reaction would be not to use it, which is not what the pharmaceutical company wants to hear, because they want to sell drugs to recoup their billion or more that they've spent. Whereas I'm saying I won't use this because it's the only thing I've got that works in extreme cases.
Mark - You're right. Those precious billion dollar price tag antibiotics will be stored or have been stored until recently to use in those very rare cases where the other antibiotics don't work.
Chris - So it breaks the business model for the pharma company?
Mark - It does.
Chris - How do we then re-incentivise them? Because we've got to de-risk that for them. Otherwise, they're going to carry on the way we are saying, well, we're much better off making a heart drug or an anti-cancer drug or a diabetes drug, because we know that people are going to take those for years and we'll make our money back.
Mark - I think this is an area where the UK has really been world leaders. So we launched a subscription scheme a few years ago. And the aim of the subscription scheme is to uncouple the financial returns to the company from the volume of drug use. So this issue around sitting antibiotics on the shelf and it is only being used in very, very rare cases. In the subscription scheme model, the income still accrues to the company and they can hopefully reinvest that in discovering new modules going forward.
Chris - The acid test, of course, will be whether that is genuinely replenishing our antibiotic pipeline that's currently pretty empty, isn't it? So are we beginning to see green shoots emerging as this is taking hold or is it too early to tell?
Mark - I think we've started to see two things happening. One is we've started to see a lot of funders that really focus on that development pathway piece, recognising the need to almost de-risk the development of some of those antibiotics. And then the second thing which I'm really excited about is I think we've seen an enormous range of innovation in smaller companies and biotech companies that have really explored lots of different ways of doing this. So rather than just this very narrow range of chemical entities, we're starting to see a large range of different therapeutic entities being explored by different companies. But then I think we've got the prospect of being able to pull some of those molecules through from that early stage phase and discover where they are now, and bring those through into the market. So I think we're seeing early green shoots. It's by no means an entirely straightforward pathway yet, but I think we've seen some very positive signs.
Chris - Talk me through in a bit more detail about how this subscription model will actually work and therefore how clonable it is internationally so that we can hopefully build this sort of momentum.
Mark - The model is that you have an application process and the criteria layout the sort of molecules that we think we need in terms of being able to refill that medicine cabinet. And there's an evaluation process that looks at the data and the robustness, and scores your antibiotic against that set of criteria. We see similar ranges of problem pathogens or priority pathogens in different parts of the world. So the things that largely affect clinical outcomes in the UK are very much the same as we'd see in other parts of the Western world and into lower and middle income countries as well. The WHO has published some really interesting work on this, which is trying to focus attention around a series of pathogens where we really need to develop new drugs. And then I think the subscription scheme model works well as a financial incentive in different settings.
Chris - And the hope is that with more money flowing through the system, lower risk and therefore higher reward, that will drive more innovation. And perhaps rather than that narrow spectrum of drugs we inherited from the 1970s, hopefully we will have a wider repertoire of things going forwards because we can afford to take a few more risks to develop new things.
Mark - That's right. And I think we understand so much more about the basis of antibiotic resistance, the sort of genomic revolutions coming over the last 20 to 30 years. It's much easier to be able to look at genome sequences of bacteria and say, well, you know, these are areas of concern. These are things that are likely to be able to drive resistance. And therefore, to some extent, you can modify your drug discovery and drug development process to be able to look at those issues and try and find a way past it.
14:34 - Cracking superbug codes: can a global genetic map save us?
Cracking superbug codes: can a global genetic map save us?
Andrew Singer, UK Centre for Ecology & Hydrology
One of the people trying to find a way past AMR is Andrew Singer, principal scientist at the UK Centre for Ecology & Hydrology. He takes the view that, to tackle a global problem, which this very much is, you need a global solution. And it turns out that, all around the world, a great number of disease outbreaks caused by antibiotic resistant microbes are being genetically sequenced to find out what the organisms are, and where they came from. But these data are only very rarely shared, meaning we struggle to see the big - joined up - picture of how antimicrobial resistance is operating and shifting on worldwide scales. And, as Andrew argues, prevention is much better than cure, and if we better understand the source of things like drug resistant E.coli infections, we’re better placed to stop it…
Andrew - What we can do is we can have all of these people across the world submit sequences of E. coli to a database and that database will accumulate all of these sequences. And as their sequence is being submitted to this database, it asks the database, where did this come from? Now, you know where your sample came from because it came from a human or came from the environment, but you don't know where that E. coli came from. And that's the critical bit, because if you know where it came from, you could do something about it. So was the bathing water polluted with sewage or was it polluted by a dog that pooed before you showed up or was it contaminated by a bird that just happened to really time itself really well? All of that matters because if you're the environment agency in this case, you have to solve that problem. And you can't solve it if you don't know where it came from. And if it's a natural thing, then you might say to people, don't feed the birds or don't walk your dogs on the beach. If it comes from sewage, you have another problem that needs solving. Or if it comes from farms and you know that it rained a lot and that the water rushed off the farm and it came into the river and the river contaminated your beach, you can then pinpoint, OK, there's something that needs to be done here.
Chris - So the genetic codes of these microbes is sufficiently different across those different situations, a source from an animal, a source from Thailand versus London. They're sufficiently different that we will be able to tell the difference if we've got those sequences. And we can almost plot a map of the world and the different example cases of what microbe goes with what. And that will give us that giant dictionary almost of what infections probably originate from what sources.
Andrew - Exactly. So at the moment, we don't have this, what we call a trusted research environment, which is what we're building. And it's a basically a playground for data. And the data sets that we currently have are really quite limited in numbers. They're in the thousands. What we need are millions of sequences, all E. coli from all over the world, from all of these different sources, from birds to dogs, to humans, to cows, to pigs, from everything, from every human that we can get a sample from. And you'd be surprised how many sequences are being generated a year just in the UK. It's hundreds of thousands. And so if we have a database where all of this goes and it's annotated who it came from, and then we train the algorithms to understand what a sequence looks like when it comes from a human, the likelihood of it then finding a new sequence or being asked, why did this new sequence come from? It's a very high likelihood that it's going to pinpoint where it came from and where it's not sure where it came from. If it came from a farm and it came from a farm worker, you are then asking the question, well, this is a really risky farm because it has E. coli that is able to transfer from a cow to a human or a human to a cow. And you don't really want that happening because that's how pandemics start. So you want to nip that one in the bud.
If it's something that's always human or always cow, then you feel a bit safer and you think, well, someone just did something a bit silly.
Chris - How does this solve the problem of antimicrobial resistance? If we've got that map and we can say, very well, I know where this thing came from. That doesn't help the fact that I'm still dying of infection I can't treat.
Andrew - Essentially, if you can problem solve, so if you know where the infections are coming from, the best way to combat AMR is to prevent people from getting infected in the first place.
Chris - So this is prevention.
Andrew - Yeah. So I've been led to believe that prevention is not the sexiest thing on the block. However, it is probably where we should be spending our time. This is a global resource. So once we all join this, we all benefit by having more and more data.
Chris - Presumably, then, if we know where something came from and it also happens to be an antimicrobial resistant form, then that gives us enormous information about sources of infection and spread of infections that are more likely to be troublesome.
Andrew - Yes, it's a canary in the coal mine kind of approach of trying to do prevention where you find the infectious organism as quickly as you possibly can. And once you've found it, you then interrogate its genome, looking for the resistance traits. And then depending on where in the world that had come from, you then have an added bit of information to then tackle the problem of AMR in the sense that if it came from another country, then you have maybe a higher priority of where investment needs to go.
Chris - But how far down the path have you got so far? And have you got buy-in from the international community? Is everyone willing to sign up and do this? Because I mean, it sounds very laudable, but it's going to be expensive, because this is not cheap doing this. And you need good technology to do it, which might limit the places on earth that will buy into the project. And it's going to take time. When do you think that you'll be able to walk into a room like this one where you and me are chatting, and show me this effective giant radar screen for the spread and origin of bacterial infection, plus or minus whether or not they're resistant to infections from the entire world?
Andrew - The proof of principle will be probably demonstrated in a number of use cases in the next couple of years. At any point during that next couple of year journey, the funding then needs to show up to then support this trusted research environment, which would then be a global resource. I'm always very optimistic, which puts me in around three to five years. It's too obvious of a solution for us to pass up. It's so good. And we're also in the driver's seat, we have all of the resources we need to do this in this country, and then be the leader. And I think we should just take it because I don't think it's that expensive.
21:43 - One Health, one fight: a global war on AMR
One Health, one fight: a global war on AMR
Colin Brown, UKHSA
The concept of “One Health” is gaining traction around the world: we’re increasingly realising that what affects nature also affects us - we’re in a dynamic equilibrium with the animal world, although nearly two thirds of the big animals on Earth are farm animals! We also share the planet with getting on for 9 billion people, meaning the other third are nearly all humans! And what happens on one side of the world doesn’t stay confined to that geography for long, as Covid showed us. So we need much more “joined up” thinking, that integrates a range of priorities and safeguards but is internationally implemented. Colin Brown is an infectious diseases clinician and public health microbiologist at UKHSA. This is his forte…
Colin - So One Health means the intersection between different environments. So how do we relate to each other? Is there linkages between our health, the health of animals, and the health in the environment, the antibiotics that we're given, the bacteria that might transfer between us? How interconnected are they? And how does affecting one element interface with all the others?
Chris - And how connected are they?
Colin - So I think the answer is we're still discovering that there are lots of potential connections. The antibiotics we give, for example, to animals, very similar in nature to the antibiotics we give to humans. Indeed, the antibiotics and antifungals we give to plants to help them grow are very similar to those that we give in humans as well. In terms of how the resistances flow, we're just learning a bit more about that. There are some obvious examples like Campylobacter, which is a bacteria that causes food poisoning that we pretty much get exclusively from animals by eating them, that are very, very related. So we see a direct correlation between what the animals have and what we have. And what we need to understand is particularly what are the levers we can do to affect change. So what we want to ultimately do is reduce antibiotic resistance and antifungal resistance within animals, humans, and the environment. And we need to know, is it turning off the tap of antibiotics in animals that might affect the resistance in humans? Is it an intervention to stop spread between the environment and humans, for example, in seawater and swimming and bathing? So it is very much like a spider's web. And what we're not quite sure of yet is the best bits of the web to cut that will stop the transmission to humans. But that's clearly where we want to be.
Chris - If there is a link, and the threat is very real, what's the solution? What do we have to do to mitigate that?
Colin - So I think that is the big question. And where we are in our current national action plan, so we launched a five-year plan in May of last year that is trying to address the questions of how widespread is the problem? And particularly, what can we do to stop it? What are the interventions that will work? I think those are where the key challenges are defining the best interventions that work. We know that reducing the widespread use of those broad-spectrum antimicrobials is a good thing in all types of animals, humans, and the environment. Targeted approaches, increasingly knowing everything about that person, their reasons that they may or may not have one antibiotic over another, and the right one for the right infection at the right dose, that's going to be the key to ensuring that we have those interventions across all of the domains.
Chris - A lot of the things you've been mentioning occur because there is very poor policy and stewardship in many countries. I've visited some of them, and I could walk into a shop, buy anything I wanted, take what I wanted for as long as I wanted, and not know anything about how antibiotics work. So a global problem like this needs a global joined-up solution. Are we possibly in a position to deliver something like that?
Colin - So there is increasing political will across the globe. I think it's absolutely right. We have very good regulations in the United Kingdom. So we have just, on the back of the United Nations meeting that was held in September of last year, put up a large amount of money, millions and millions of pounds, into a number of initiatives. One is helping a steering group decide on where the priority areas of research are. We, through the Fleming Fund, have provided hundreds of millions in upskilling local laboratories in different countries. And that is good, not just globally, but also for us in the UK, because it is a global problem. As you said, everything is interconnected. We see that when resistance develops in one part of the world, it rapidly spreads around.
Chris - Yeah, I mean, we're a highly mobile population. I think I asked Rolls-Royce, who reckon they're supporting about a third of the world's flyers in the air at any one time, how many people they think they're holding up there. They told me about one and a half million people are airborne around the planet at any one moment in time. So that means you've got no city more than 24 hours from any other. So if you've got a dread disease in one part of the world, very quickly it can be on the other side of the world, and where people go, their infections go with them.
Colin - Absolutely. And I think that's also because we are closer to animals than we used to be. Humans, moreover, are encroaching on the animal environment. And we saw, for example, with Covid and other viral infections that have spread from animals to people because of market interactions, everything is much more interconnected than it was in terms of the likelihood of transmitting between the different animal, human, and environment sectors. And then, as you say, rightly, can spread easily around the globe within a matter of hours. We are helping both steer the international narrative and upskill countries, particularly those where we have a lot of interaction and likely travel between us. For example, we have a big program of work in Nigeria to help countries deal with things at source to mean that they can diagnose and get on top of problems before they end up on our shores.
Chris - Are they dealing with it fast enough? Because we're approaching a situation, other speakers have been saying on this program, we're approaching a situation where things that we previously regarded as trivial may become untreatable. And if we don't have solutions to this soon enough, then we may end up in a very nasty position.
Colin - So Dame Sally Davies used to say it was a silent pandemic, but no longer calls it that because it's not so silent anymore. In fact, from my own clinical practice, I had an email this morning from a kidney doctor saying, where is the oral antibiotic? Because he expected there to be an antibiotic that he could give in tablet form for his patient. And the only options available are those that he needed to get for his patient as an intravenous course in a hospital.
Chris - Because what? All the oral options are now off the table because there's resistance.
Colin - Absolutely. Because every oral option had been resistant. So that it is absolutely coming that we are in a position, fortunately in the UK not at tipping point yet, but you go to other countries, even those in Europe, like Greece or Italy, where there's much higher resistance rates, and it is imperative for us globally to take action. Is every country doing as much as they can? I think it is difficult when countries have a lot of competing challenges.
Chris - We've also got wars going on, haven't we? I mean, the planet couldn't really be in a worse position geopolitically, with all the conflicts, with other crises, to try and deal with a problem like this that needs everyone to buy in and get behind it.
Colin - Very difficult, as you say, because there are multiple competing areas. What we are trying to do is to highlight within each of these, the imperative need to think of antimicrobial resistance as part of our pandemic preparedness, as part of our climate change action, as part of our response to times of conflict.
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