Antimicrobial resistance - how to stop a quiet pandemic

Robin Pomeroy: What is antimicrobial resistance or AMR?

Christopher Murray, Murray Director of the Institute for Health Metrics and Evaluation: Antimicrobial resistance is when a bacteria or a pathogen is able to avoid the effects of an antibiotic so they have a mutation and the drugs, the antibiotics, just don't work on a resistant pathogen. And it's important because if you get one of those infections and you're counting on an antibiotic saving your life, for example, and they don't work well, that that leads to much worse outcomes.

Robin Pomeroy: And this is what's sometimes known as a superbug. Is that right?

Christopher Murray: Well, yes. The term superbug is sometimes reserved for pathogens or bacteria that are resistant to pretty much everything that's out there. And so but it's of that idea, that our tools that we use clinically to manage infections are just not working.

Robin Pomeroy: Why is this a problem in the grand scheme of things? So if I get ill of something that I want to be cured, I [may be] unfortunate and the disease will kill me. But is it bigger than just a few individuals affected by that? Is this a threat to the whole of humanity in some way?

Christopher Murray: If you go back 70-80 years, we've seen real progress on managing the toll of infectious disease around the world because of the advent, the discovery, of antibiotics, going back to penicillin with Pasteur. And if those antibiotics that we count on to have brought down death rates from things like pneumonia, which still kills a lot of children but was a much bigger killer 50-60 years ago, if we lose the ability to treat those infections, then it's a real threat to the progress we've made in these last 70 years.

Robin Pomeroy: So how do bugs become resistant to antibiotics?

Christopher Murray: Bugs become resistant by getting a bit of DNA that allows them to avoid the mechanism of action for the antibiotic. And the only way they're going to get that bit of DNA is if there is antibiotics in some way out there selecting for mutations. And so that resistance pattern spreads. So you get it by using antibiotics - that's the paradox here: the more you use antibiotics, the more likely we are to see mutations that will be resistant to those antibiotics.

Robin Pomeroy: Let's look at this on a global scale, as exactly you did for this work in The Lancet. Could you tell us what you were trying to do in that report?

Christopher Murray: The basic idea of the report goes back five years ago when this effort started, which was to build into that annual effort, the Global Burden of Disease Study, the assessment of how many people die, how many people get sick from antimicrobial resistance.

We started by trying to find all the data that's out there from labs, from hospitals, from clinics, from death certificates, that would give us some insight into how many people are dying from each bacteria and then how many of those deaths are related to drug resistance. And when we did all that, we found it's a really big problem. One and a quarter million people, their deaths are directly attributable to resistance, and nearly 5 million deaths are occurring from infections where the bacteria is resistant to an antibiotic.

Robin Pomeroy: So you've called this the first global estimate of the burden of bacterial AMR. This is the first time the world's had some idea of the size of this problem all around the world is that right?

Christopher Murray: Yes, there's been lots of very good detailed studies in a particular hospital or a particular place. There was even a sort of comprehensive look at bacterial and drug resistance in Europe. But this is the first ever effort to try to look at the totality in every country of the world of deaths and disease attributable to antimicrobial resistance.

The number of 1.25 million deaths is when we look at how many people have resistant pathogens and then how much more likely are you to die if the bacteria that you're infected with is resistant versus if it's not? So that's the 1.25 million deaths.

You can also just count the number of times people die, and the bacteria that they're infected with is drug resistant, and that's the bigger number: 5 million. And the difference between them is whether or not you think if ... let's say, the pneumonia was a drug-resistant bacteria, you would have had no pneumonia at all or would you have been infected with a drug-sensitive one? And that's the difference between the 1.25 and the 5 million. The truth, or the full burden, is somewhere between those two numbers. So in any way you count, this is a very big global problem.

Robin Pomeroy: Was there anything in this study that surprised you?

Christopher Murray: You know, there were lots of things that surprised me. I think the biggest surprise is that lots of people thought that AMR was really a problem only in rich countries. But what we found is that it's a global problem.

It's not only present in low-income and middle-income countries, but actually, the death rate from antimicrobial resistance is highest in the low-income world and it's actually lowest in the high-income world.

There's two things going on there. One is the fraction of infections that are resistant, and then the total number of infections. While the fraction of infections in, let's say West Africa, that is resistant is lower than in Europe, the actual number of pneumonias, of urinary tract infections, of bloodstream infections, is so much higher, that the death toll from AMR is actually highest in West Africa.

Robin Pomeroy: So not a 'first world problem', as some people may have thought. Places with great healthcare and lots of money being spent on pharmaceuticals and maybe an overuse of antibiotics, which is one of the major problems here. Is it going to get worse?

Christopher Murray: We think that it will get worse. In fact, we're trying to do that more formally and give a sense of how much worse and over what timeframe. But that's work in progress. But all the the direction of use of antibiotics is towards more use, not less. And the more we use, the more we'll see resistance, the more we should expect to see the burden of AMR go up in the future, not go down.

Robin Pomeroy: OK, so what? What should we do about it? I noticed there's a list of strategies, things that we do need to be aware of.

Christopher Murray: There's lots of ways to think about this package of strategies to try to manage this problem. But I tend to put it together as a set of things we should do globally, and then what you should do at the national level, and then what we can do as individuals.

At the global level there's really two things. One is monitor - have better surveillance on antimicrobial resistance. This was a first-ever, almost herculean, task of trying to pull together all these disparate data sources. But we should, on a routine basis, be tracking this. It's a true health problem. We should we should track it at the global level.

Secondly, and perhaps more importantly, we need to have a robust pipeline of discovery of new antibiotics. It's like an arms race - if the bugs figure out how to evade our current antibiotics we need to be continuing to invest in the R&D to come up with new antibiotics, both by pharmaceutical companies and the research councils that are out there.

Robin Pomeroy: Is that happening already or not enough?

Christopher Murray: I think we're starting to see more. But the rate of discovery of new antibiotics has been much lower in recent years than in past decades. And to some extent, I think it's because people, including the pharmaceutical industry, have not recognised how quickly antibiotics are becoming ineffective and so that it is going to be an important area for discovery and for for sales in the future.

That's the global story. At the national level, governments can do lots of things and clinical societies can do lots of things to try to encourage the appropriate use of antibiotics. Somebody who needs an antibiotic needs to get it, otherwise they'll get sick and die. On the other hand, there's lots of people who don't need antibiotics where we use them and that encourages the development of resistance. Some people call this antibiotic stewardship, but it's really about using antibiotics appropriately when they're needed and not when they're not needed.

Robin Pomeroy: There's also talk about antibiotics used in farming in livestock.

Christopher Murray: There's two other strategies to deal with the burden of antimicrobial resistance. One is, although the evidence is not included in our study, there are suggestions, and it makes sense, that widespread use of antibiotics in animals is also selecting for resistant antibiotics. And so that's an area that could well yield benefits by reducing just the amount of antibiotic that's out there in the food supply.

There's another strategy as well, which is where we have tools to reduce the number of infections - let's say pneumococcal vaccine for pneumonia - we should use those to the greatest extent possible because one sure way to avoid getting a drug resistant pneumonia is just not to get pneumonia in the first place. So intervening through vaccines and reducing other risk factors that increase infections is also part of the sort of the overall strategy here.

Robin Pomeroy: Maybe we've all got better at health prevention during COVID?

Christopher Murray: Well, we've seen a very dramatic effect of mask wearing and social distancing on things like flu and respiratory syncytial virus and possibly some bacterial pneumonias. It's quite dramatic actually in the numbers, the side benefit of those behaviours. Will those be sustained? I doubt it. We might see seasonal mask use as is common in East Asia becoming part of our culture in which case we might see a reduction in some of those conditions.

Robin Pomeroy: You set it out at a global level, national level, personal level. So let's look at the personal level. If I get sick, then should I not be asking the doctor to give me an antibiotic? Should I kind of just tough it out? It's a tough decision to make, isn't it?

Christopher Murray: Well, if you get sick, you should not badger your health care provider to give you antibiotics when they're not saying you need them. A lot of healthcare providers, physicians and others, often feel pressure from patients to give them something. And when they say, 'Look, you have a viral infection and there's nothing much I can offer you at this point,' there is often pushback to get antibiotics. There's also availability of quite sophisticated antibiotics over the counter in some countries where individuals just go and self-prescribe and buy antibiotics. And that's also not helpful.

Robin Pomeroy: And on a global level, is there some kind of global policy that could help?

Christopher Murray: There isn't a governing body that has any authority over all the healthcare providers in the world. WHO has got a programme on antibiotic resistance. They've upgraded their presence on it. There's now an assistant director general for antimicrobial resistance, which is a really good thing. It's signalling that they see it as important. And they can provide general guidelines and encouragement towards coming up with national action plans. But it's not really WHO's role to set out clinical guidelines and best practises.

One of the things that really was surprising to me and to the team: just how there's a set of bacteria that most people have never heard of that cause hundreds of thousands and in some cases millions of deaths each year in the world. There's a group of these large bacterial pathogens that just aren't on the radar, even of professionals in the global health field. And I think that's been a surprise that because they cause so many different clinical syndromes, they're buried in the details. And so when you put the numbers together, suddenly you realise that there's this set of pathogens that are as big as or in some cases bigger than HIV and tuberculosis and malaria. And yet there's no global programme on them. They're not even a recognised target, necessarily, for vaccine development. There's really, I think, some surprising insight into the world's leading pathogens that comes from this study as well.

Robin Pomeroy: And so it's surprised people at that level who are involved in it. Doesn't that show there's a real lack of understanding and a lack of appreciation of this problem and how big it is and how diverse it is?

Christopher Murray: Well, this goes back to the core reason we run this study that's now been going for 30 years. First step towards doing something about them is you have to recognise there is a problem. And so it reaffirms our general belief on the importance of getting the numbers right and telling people about it, whether they're in the general public or even the technical audience that also may lack insights into the totality of what's out there.

Robin Pomeroy: Have attitudes to AMR changed?

Sally Davies, UK Special Envoy on antimicrobial resistance: I am actually a doctor and [AMR] has always been a problem. It was predicted by Fleming when he won his Nobel prize that bugs would develop resistance to antibiotics and people would die as a result. It's natural selection.

And I still remember looking after patients through my career where the microbiologists would come and say, 'this patient has a bacterium that is resistant to the standard treatment - now you need to swap to a different treatment.'

That was fine. The problem that has arisen is that we are running out of antibiotics and the pipeline's rather empty. And just to give you an example of this, of the 26 antibiotics in the clinical pipeline active against priority pathogens at WHO, only seven fulfil at least one criteria of innovation. And not putting enough money into it. So just under 10 billion into cancer research and only 132 million into antibiotics research.

And what I found as Chief Medical Officer, and it first really hit me in 2013, was the technical people, our microbiologists, knew of this problem - antimicrobial resistance, AMR - and how it was rising, not just resistance in bacteria, but HIV, TB, malaria, all infections. And yet they weren't managing to get a policy focus and action on it.

I think we've steadily raised awareness, but not fast enough and not good enough.

In 2019 we had, as a result of a lot of activity and pushing at the UN from our government and many others, the Dutch, the Swedes, the Japanese, we had a high-level meeting and they set up the Inter-Agency Coordination Group in 2019. That group warned there was no time to wait.

In 2020, the World Health Organisation listed antimicrobial resistance as one of its top 10 threats facing humanity. In '21 we had a concrete analysis of the global pipeline of antimicrobials, and it's insufficient.

And now here we are in 2022. We've recently got the data from the GRAM [Global Research on AntiMicrobial resistance] study showing that deaths associated with antimicrobial resistance are the third leading cause of death globally.

So the problem is rising. People have been raising the flag of concern, yet not enough action. And I think that the COVID-19 pandemic has shown to the world what a pandemic of untreatable disease can do, not just to people but to economies. So we're going to have to do more about it.

And politicians are getting it. G7 finance ministers made commitments under our UK G7 presidency. The Germans in their G7 presidency have antimicrobial resistance as an issue. But there's a long way to go.

We need to start with preventing infections. That was shown to be important through COVID - infection prevention and control, good hygiene, clean water and sanitation, good vaccine programmes. But then we need to use antibiotics effectively and have a pipeline that's strong. This matters to everyone on the planet and everyone's got to play their role, whether it's the patients, the clinicians, the private sector, governments.

I'm at the moment arguing that we really need to have antimicrobial resistance in any pandemic treaty that comes out of the negotiations that have just started at the WHO. We've got to include AMR in the surveillance, in the risk assessments, and I would argue that we need to include AMR in ESG standards for investment.

We've really got to move forward and take this seriously at every level. But it'll be much easier than climate change. And if we don't sort it people will be dead before climate change kills them.

Robin Pomeroy: Wow. Well, that puts it into perspective. It's similar to climate change in that the experts who are up against it all the time are telling us about these risks. But until it becomes a massive, immediate crisis, as we had with COVID, which I know is a different issue, but a global health problem, suddenly the world engages. But this is one of these that's creeping up on us and has been for decades, just like climate change.

Sally Davies: Absolutely. And of course, the other thing there is the complexity. It's very difficult for policymakers and everyone to handle complexity. We need more drugs, we need better diagnostics, we need to prevent infections, we need to be looking after the drugs we've got - all of this complexity.

And it's not just human health. In animals - over 70% of antibiotics are used in the food chain and animal health. And of course, we want to treat sick animals, but we actually need to stop using antibiotics as cheaper than cleanliness, biosecurity, and as growth promoters, and a lot is.

So there's all these other ramifications. And a final one, let me just put on the table now, is environmental contamination. Animals pee and poo out over 70% of antibiotics, so they go into the water through the sewage. Meanwhile, a lot of antibiotic preparing factories are spewing out masses of antibiotics into water tables. So you can see how this complexity, just like climate change, makes it even more difficult to take forward action.

Robin Pomeroy: You were talking there about a global treaty. What were you referring to?

Sally Davies: Arising out of the pandemic at the World Health Organisation assembly early summer last year, there was an agreement that we needed to have an instrument across the world, a treaty of some form, that meant that we were better prepared and better able to respond. So with the member states, the WHO have started to negotiate a treaty and have agreed a negotiation group of countries and people who are working on this.

My argument is, you're now thinking about SARS and viruses. But it could be a flu pandemic, both viruses. But it could be Ebola that really gets out of its box. It can be bacteria. And antimicrobial resistance is a form of pandemic. It satisfies the definition - it's across multiple continents and it's untreatable and we haven't met it before as it goes up and up.

So I think that as most of the solutions that we need for pandemics, we need for AMR, we need to integrate the work. After all, you have to have surveillance, you need vaccines, you need infection prevention and control. Most of it is exactly the same need, so I would argue that we'd be very silly as a world to leave AMR out of any pandemic treaty. And I hope that everyone listening to your podcast will be asking their negotiators from their countries to make sure antimicrobial resistance is part of the treaty.

Robin Pomeroy: Very interesting. You mentioned a handful of important things that need to be done. Let's look at one of them: this pipeline of research into new treatments, into new antibiotics. I'll just quote you a line from an article published on the World Economic Forum's agenda by Jeremy Farrar, the director of the Wellcome Trust, and by Mads Krogsgaard Thomsen, Chief Executive Officer of the Novo Nordisk Foundation. They say in the article, which you can find on the World Economic Forum website:

"Over the last years, we have seen biotech companies going bankrupt and pharmaceutical companies withdrawing from investing in the development of new antibiotics. What is perhaps even worse, we see scientists – crucial to delivering the new innovation we need – abandoning the cause."

Has it become the case that there's just not enough research going on and not enough investment going on? And what can we do about it?

Sally Davies: Yes, I would absolutely agree with that article and what they say. We were seeing people leaving the field. Thanks to major investment by the US government, the Wellcome Trust and indeed we and the Germans are contributing to CARB-X. The beginning part of that, the early part, is now developing and people are coming back into it.

But I had a conversation only this morning with a company who have got a very interesting - funded by CARB-X and Innovate UK - an anti-Gram-negative antibiotic, and they're finding it difficult to get investment in this valley of death to take it forwards. And until we sort out the pull side of this economic problem, it's going to go on being difficult.

At the moment, we pay far too little for antibiotics compared to how much we pay for other life-changing and life-saving technologies, particularly cancer drugs, that are an obvious example. We pay peanuts and most are generic. And think about it: if you ran a company, would you want to invest in cancer treatments which make a lot of money or an antibiotic where you're not going to get a lot of money for it? Oh, and resistance will develop. You just hope it doesn't develop during your patent lifetime.

So we have to find different ways of pulling them through and getting people to take them seriously and invest. One way that we've been trying this out in England is to have a pilot of what we've nicknamed our Netflix subscription system, where we're trying to evaluate the value of a new antibiotic to our society at a broader level, and then pay a subscription. So we're paying for it to sit on the shelf and only be used when it's really needed. And that's working its way through our system at the moment.

Robin Pomeroy: Is a health service paying for the access to these drugs rather than paying each time they use the drug? What's the benefit of that?

Sally Davies: You're absolutely right. Normally, drug companies get funded or paid by 'pile them high and get a small profit on each one' or drugs for rare diseases so they have a massive profit each time.

And for antibiotics, what we want is to have them available, but only used when essential. So we want to value the advantage to an individual patient whose life is saved, the advantage to that ward and the hospital, that they can't pass on that bug because it's being treated, and therefore to society.

So if we make this part of our way of going forward, then we'll only take the ones and put them through the subscription system where we pay each year for that right, because they attack bugs that are really a problem for us, and they're innovative and we can't get it another way. But if enough countries move into this sort of payment, then actually that is a pull-incentive. And at the moment, America is having a look at the Pasteur Act, which is a bipartisan act looking to do exactly this sort of pull-incentive subscription mechanism. So our learning is really important for them, and we really hope that that will go through.

Robin Pomeroy: So obviously, all of this requires a big international effort. Do you see anything on the horizon that can move this forward?

Sally Davies: Well, I'm always hopeful. And under the UK G7 presidency, health ministers recognised the wider value of antimicrobials and agreed a way to procure, reimburse and pay for them, called G7 Shared Valuation Principles. Meanwhile, the finance ministers said that they thought implementing pull-incentives was very important and they agreed to pilot. So Germany is now picking up on the antimicrobial issue in their G7, and they've said it's a priority, and we've opened discussions with Japan to build on this - how do we get pull-incentives to happen. Different countries want to do it in different ways. But so that the sum of the parts is big enough to make it a market worthwhile that we will have the drugs to save lives and enough money in the system that biotechs making first class drugs don't go bust. The patient gets them at the end of the day.