Antimicrobial resistance - the path to sustainability

Ramanan Laxminarayan is the founder and president of the One Health Trust, Director of the WHO Collaborating Center on Antimicrobial Resistance in New Delhi, India, and an Affiliate Professor at the University of Washington, Seattle, WA. He is the lead author of The Lancet’s May 2024 series on Sustainable Access to Antibiotics. He joins Gavin and Jessamy to discuss how big of a problem AMR currently is and will be, what is being done, and what needs to be done.

Read the Series here:
https://www.thelancet.com/series/antibiotic-resistance?dgcid=buzzsprout_tlv_podcast_generic_lancet

Read all of our content at https://www.thelancet.com/?dgcid=buzzsprout_tlv_podcast_generic_lancet

Check out all the podcasts from The Lancet Group:
https://www.thelancet.com/multimedia/podcasts?dgcid=buzzsprout_tlv_podcast_generic_lancet

Continue this conversation on social!
Follow us today at...
https://twitter.com/thelancet
https://instagram.com/thelancetgroup
https://facebook.com/thelancetmedicaljournal
https://linkedIn.com/company/the-lancet
https://youtube.com/thelancettv

Transcript

This transcript was automatically generated using speech recognition technology and may differ from the original audio. In citing or otherwise referring to the contents of this podcast, please ensure that you are quoting the recorded audio rather than this transcript.

Gavin: Hello, welcome to The Lancet Voice. It's September 2024. I'm Gavin Cleaver, and I'm joined as ever by my co host, Jessamy Bagnell. Today, we have an episode focusing on a critical issue affecting health systems worldwide, Antimicrobial Resistance, or AMR. Our guest is Ramanan Laxminarayan. Founder and President of the One Health Trust, Director of the WHO Collaborating Center on Antimicrobial Resistance in New Delhi, and Affiliate Professor at the University of Washington, and he's also one of the authors on the Lancet's May 2024 series on sustainable access to antibiotics.

In this conversation, we talk about why access to effective antibiotics is crucial for modern medicine, but is increasingly threatened by AMR. We talk about highlighting the disproportionate impact on the very young, the very old, and the severely ill, And talk about how improved vaccination, water and sanitation can prevent deaths and reduce antibiotic use in low and middle income countries.

Ramanan Lajmunarian, thank you so much for joining us on the podcast. Thank you for giving us the time. You're one of the authors on the Lancet's May 2024 series on sustainable access to antibiotics. We're here today to talk about antimicrobial resistance. Perhaps we could start off by just talking about what's the burden of AMR?

How serious a problem is it right now? 

Ramanan: Antibiotics have only been around for about 85 years, and prior to that, if someone had a bacterial infection, they either got better because their body's immunity thwarted off or or they didn't get better and very frequently, they died. And the advent of antibiotics, starting with penicillin first patient treated late 1941, changed that entire picture.

You basically could cure someone of a bacterial infection, something that was not possible before. And over the years, we've seen the frequency of resistance, the frequency with which patients don't respond to antibiotics increase quite steadily. And since the 2000s, it has really gotten quite bad, both in rich and poor countries.

There are now an estimated 1. 3 million people who die every year because of antibiotic resistance indirectly attributable to and another close to 5 million people who die. of something else, but they also had a drug resistant infection at the same time, which possibly made it worse. If you see things in context, this is probably more than HIV, TB, and malaria deaths put together.

It's really quite a serious problem. Unlike malaria, unlike TB, and unlike, for the most part, HIV, antibiotic resistance burden is in both rich and poor countries. It affects both. Really the whole world. There's no country without antibiotic resistance. And and I should add that it's a problem not just for humans.

It's also a problem in animals. Animals need antibiotics just like we do. And when the drugs fail, then animals suffer and die. It's really a multisectoral problem with many affected people and animals. 

Gavin: On a very basic level, how does antimicrobial resistance develop over time? It's a worsening problem.

But what are some of the factors making that issue worse? 

Ramanan: So everyone has probably seen weeds on a lawn. And you know that if you keep applying herbicide, then the weeds become resistant. So in other words you have more and more of your garden be covered by those weeds that no longer respond to the herbicide.

And the same thing happens in nature in many instances, which is every application of control basically. Selects for the ability of what you're trying to control to be resistant and that happens with bacteria as well Initially, there is a small proportion of bacteria that are naturally resistant to antibiotics There might be the order of 1 in 10 million 1 in 100 billion But as we selectively kill off the ones that are sensitive we give a comparative advantage selective advantage This is directly, Darwinian selection where we're selecting for these bacteria that are able to survive, and they do really quite well in an environment where there's a lot of antibiotics around.

And today that proportion of resistant organisms is not 1 in 10 million or 1 in 100 million. In some instances, in many countries and hospitals, that frequency is 1 in 3 or 1 in 2, which means that there's a nearly 50 percent chance that an infection will not be treatable with the antibiotics that are available.

Gavin: So who is most at risk from antimicrobial resistance? 

Ramanan: Bacterial infections tend to be more successful at attacking, people with weakened immunity. Either they are newborns, Or they're the elderly population or other populations that lack immunity. Either they are immunocompromised or they are on the immunosuppression, the undergoing cancer chemotherapy.

So it's generally that population that is most at risk, but that's not necessarily the case. In the last two decades, we've seen resistant infections take down. People in their prime, people in their 20s and their 30s who it's hard to see why they would have, fallen to a bacterial infection, but but it happens.

And really in that sense, everyone is at risk, but the biggest age groups at risk are the young and the elderly. Yeah, 

Jessamy: and ask a question, Ramana, because many of us will have come into contact with AMR in some form, will have heard of it. People know perhaps that it's a slightly amorphous problem out there somewhere, not necessarily affecting them.

And we've all got quite I think strong stories in our head about what causes AMR. I wonder, whether that's going to the GP, the GPs are prescribing, the primary care practitioners are prescribing antibiotics or they're prescribing too much. These are the types of myths that we have, but when you actually drill down, what are the major problems in AMR?

What's driving AMR? And why do we have these other narratives going around? 

Ramanan: Those narratives are not wrong. We do have a lot of overprescribing of antibiotics in places where a prescription is being written. We have a lot of overuse of antibiotics, even in places where there are no prescriptions because people would just go to a pharmacy and be able to buy an antibiotic over the counter.

Now, the example I gave you of the herbicide, which is that every time you apply this control that you're going to select for resistance. Applies in the case of antibiotics as well. So every use of antibiotics, whether appropriate or inappropriate, the bugs really don't care whether it's appropriate or inappropriate but every application means that you are selecting for resistance.

And of course you are more likely to take those antibiotics if you had an infection in the first place. And ways of preventing infections through better water and sanitation, better hygiene, better, vaccination, better infection prevention, all reduces the risk of infection, which then produces the, the need to take an antibiotic in the first place.

So yes, ultimately it comes down to selection pressure, but it's also the transmission of resistant pathogens. In other words if I have a resistant bug, and because of, my not washing my hands or not, my not being careful, I'm passing that same bug on to someone else, that person now has an infection that is not treatable with antibiotics.

It has nothing with them nothing to do with them having taken antibiotics. They just happen to be handed antibiotics. A bug that was resistant when it arrived and this happens with HIV, this happens with TB as well. People get an infection from someone else, somebody else may have generated that resistance, but we're all at risk.

What are the 

Jessamy: things that you would like to tell people about what the main drivers are? When we're looking at a global scale, what are the main drivers of AMR? 

Ramanan: It's primarily, it has to do with with transmission of resistant pathogens, which I just mentioned. It also has to do with with selection, which means that every time we use antibiotics we're helping select for resistance and create new strains.

That said I think there's been a bit of a false narrative that either antibiotic resistance is not important or that there is nothing we can do about it. Thank you very much. And neither of these is true. It is extremely important, kills a lot of people, and chances are that if you're listening to this podcast, you probably know someone who has either undergone a transplant invasive surgery cancer chemotherapy, even a c section, and all of them have depended on effective antibiotics to have those procedures.

So if you do not have access to effective antibiotics. Automatically, those procedures become unviable because you're at high risk for infection, which then can't be treated. So we all depend on antibiotics, and therefore it's terribly important. The second part, is there something we can do about it, or is it one of these things that, it's out there, other people are messing it up, and there's nothing that we can do about it.

Not true. I think it's a very solvable problem. I think we can all do our bit, which is in our own spheres. The thing that people don't realize is that the more each of us uses antibiotics, we put ourselves individually at greater risk for a resistant infection. Now that's very different from climate change, right?

Climate change. You drive your SUV out there, you put out the carbon, that doesn't particularly affect you in a direct way. That's just getting out there and it's affecting every country around the world. But with antibiotics, people who take antibiotics frequently are far more likely to get a resistant infection themselves.

You can protect yourself and you should take it seriously. 

Gavin: Talk in the series published in The Lancet about sustainability as a concept within within antibiotic prescription. Perhaps you could tell us a little bit about what you mean by sustainability in, in this field. 

Ramanan: Sustainability simply means that you get to do it for a very long time and we would not be so concerned about sustainability if we thought there was an alternative to antibiotics that was arriving.

At some time in the future, now to the best of our knowledge, we have no alternative to antibiotics. We're going to be using them at least for the foreseeable future. And we just want to make sure that the power of antibiotics survives into the future so that our children, our grandchildren, our great grandchildren will all be able to use antibiotics.

So the idea of sustainability is simply that we use antibiotics appropriately and are mindful of how we use them. We're taking care of the power of these drugs so that their power is available for future generations. And right now, we're doing a pretty bad job at it. The Lancet series, by the way, is called Sustainable Access to Effective Antibiotics.

Now, antibiotics, that's obvious. Sustainability, I just explained. The other two words are also important. Access. More people die because of lack of access to antibiotics than because of resistance. Thank you. There's a lot of people who are dying in Africa, in Asia, not because they have a more resistant infection than what you would get in the UK or in Europe.

It's because people in the UK or in Europe or the United States or, in the wealthier countries would then have the option of taking an alternative antibiotic that works, which is an option which for various reasons is not available to the folks who are dying of this in resource poor countries.

Access is very important. It isn't just sufficient to have antibiotics at work unless you're able to get it into people. And the other last word is effective antibiotics. Now that is multiple things. One is, there is still a lot of fake, counterfeit, substandard antibiotics around. Remember, antibiotics are the most widely prescribed drugs on the planet.

The most widely prescribed drugs on the planet. There's a huge incentive to make. Fake antibiotics, counterfeit antibiotics. The drugs need to be effective. And the other sense in which we mean effective is, that they actually work. In other words, that they are not antibiotics that, to which resistance is already developed to a great extent.

All these four words are important. Sustainable access to effective antibiotics. And we chose those very clearly. Carefully, and the UN declaration that's about to be, agreed upon, hopefully in a week from today will actually cover all aspects of this need for patients.

Gavin: Interventions that are happening right now to make sure that antibiotics are still effective. How well are those interventions going and what needs to change? 

Ramanan: The interventions today are either in the form of preventing infections, vaccination, water and sanitation, infection prevention. We know how to make these work, but we haven't yet figured out how to make them work in every setting in every country.

So that's one. Second, interventions to figure out and treat patients with the right antibiotics. Diagnostics are missing in many parts of the world. Less than half of the planet even has access to any, diagnostics, even the most basic diagnostics. In a recent study that we conducted in Africa, we found that only 1.

3%. So only 1. 3 percent of labs in Africa are capable of even identifying the bacteria involved in a particular sample. And a subset of those are able to tell you whether the antibiotic is going to work or not. Diagnostics are very important to treat with the right drugs, so the access becomes very important.

So it's about prevention, it's about effective access and treatment, and then the third leg of this is about coming up with new antibiotics, because as I mentioned, even if you use antibiotics appropriately resistance is bound to arise, and so we constantly have to keep filling this pipeline with drugs.

And we have not done that very well in the recent past. And, consequently, we're playing catch up to come up with newer antibiotics. Obviously, that's more difficult, more expensive than what it might have cost, 20, 30, 40 years ago. But really, we have no choice because It's hard to imagine a world without antibiotics.

Gavin: You hear in the news quite often, of AI, especially recently discovering new antibiotics, so to speak, happening on particular new new formulations. What does the pipeline look like for new antibiotics? 

Ramanan: So the pipeline has improved in the last five or six years, but it's still a long way from where it needs to be.

And a large part of this is economic. It's very difficult for a company to make drugs, new antibiotics, and be profitable. I'm not talking about super profitable, just enough to even survive, simply because the cost of making drugs has been going up, and new antibiotics still have to compete against a lot of existing antibiotics that, May work or at least something works And so it's a hard business to survive in and so very few companies actually make it 80 percent of the companies with new drug development are small and medium sized enterprises very small companies you know literally teetering on the edge of survival.

So we have a challenge with the pipeline We are figuring out that this is not something that Entirely private companies with risk capital will be able to solve. So there are new models coming in with public private partnerships that are solving this problem and public private partnerships simply mean that you're able to take public funds and work with private companies to come up with drugs, but have them be sold in a way that's responsible, making sure that they're not oversold.

And making sure that they reach the patients who actually need the drug rather than just a lot of people who don't need the drug but are willing to pay for the drug. Now, the role of AI is interesting. What AI seems to be useful at doing is at closing out a lot of development pathways where the drug might be toxic, neuro or nephrotoxic, it's just bad for you.

And the AI is possibly able to do it because it's recognizing these patterns in previous drugs. Which resulted in the drug not, making it all the way through because there was something wrong with it. Now, we might have difficulty just figuring that out ex ante, but the AI is able to use pattern recognition from lots of other examples to say, listen, if there are some, 20 pathways to go down here maybe these 18 pathways should be pruned because they're not going to get somewhere good.

And maybe we focus on the two. So by increasing the odds that we will get to a successful drug, AI can be quite useful. I don't think we're yet at the stage where, you press a button and then AI spits out a new antibiotic, a new molecular structure. That's not what's going to happen. I think what AI is going to do is be like a guidance system.

It's going to tell you, don't go here. This is not a good thing to do. So think of it as I don't know, you're driving a car or, and you go above the speed limit and it starts beeping for you, or if there's a car that's too close to you, then it starts beeping or. You're able to see the back through a rear camera.

All these are just innovations that are not driving the car for you, but make your driving experience a lot safer. 

Gavin: It seems odd, given what's at stake, with increased antimicrobial resistance, that it is actually so difficult to bring new antibiotics to market in the way you describe. 

Ramanan: It is difficult for a number of reasons.

One reason is simply that, keep in mind that the bugs have already discovered a lot of. mechanisms by which they can be resistant. So think of these as keys that they can, unlock the locks that we put on them. And so we're going to we're not dealing with a naive population.

We're dealing with, not in a brain sense, but from a mechanism standpoint, a very smart population of bugs, that's number one. Number two there has just been a secular trend. increase in the cost of new drug development because the cost of trials expensive the compliance with, human subjects protection, all these protocols expensive.

So not just for antibiotics to develop any new drug today is an expensive proposition. That's just because society today demands much higher safety standards on everything 20 years ago or 40 years ago. The third reason is simply that, the success rate is. Is low because you're trying to do something which is really quite interesting.

So what you're saying is, I want to create this, the small molecule, which is going to pass through my body, which is filled with cells, not touch any of those cells, but then go and go attack specifically these bacterial cells in one part of my body. So it takes a very specific kind of a drug to identify only those cells that will go after and really attack rather than everything else.

And because, it's not going after, just any cell, just very specifically the bacterial cells. And that's a very specific a skill, so to speak, and consequently really quite difficult. It's not trying to create a statin to be able to prevent that particular part of your body from making cholesterol.

Yeah. That's not really dealing with attacking specific kinds of cells here. It's a very specific process, which is why, you really think about it. If the most effective chemical that we know that works against bacteria is alcohol, but consuming alcohol in large quantities is not going to get your infection, to be cured because alcohol doesn't work in that way but antibiotics have to work in that way that they are able to pass through a digestive system.

They'll be processed by the liver and still make it to places where they will go ahead and kill the bacteria. And that turns out to be a pretty hard thing to do. We're lucky we have antibiotics at all, to be honest. 

Jessamy: I find it very interesting, this discussion about How much it costs to make a drug and the involvement of big pharma companies, isn't it?

Because we had these discussions a lot at the beginning of the pandemic, didn't we? Where, many people were saying actually, yes, it is expensive to make a drug. But the reality is that Big pharma's expectations of the amount of money that they're going to bring back for their shareholders is also far too large.

So it's not really, there's not a sort of direct correlation between how much it costs to make a drug and ultimately how much it sells. And also these are corporations that, as you say, follow financial profits. And so there are lots of other factors in there as well, it seems to me. That, that are at play.

Ramanan: I think it's different from the pandemic. With the pandemic, you had a large ready market, right? So there was no question that there was a market that was willing to pay for a vaccine or a drug. And so that risk wasn't there that you showed up with a drug or a vaccine and then there was nobody standing at the other end.

Here you have a huge risk there. You can come up with a new antibiotic. And there's still not enough people willing to buy it. And particularly not at the prices that would cost you to develop that new drug. Many drug companies that have gone bankrupt in this space have done so after developing and having registered a drug.

It all has to do with risk and reward. It's a more complex picture than just saying, bad farmer one too much profits Therefore, this is not of interest, all companies are profit making they need to you know, return money to their shareholders but if there is money to be made here, they will make that money They're not going to say i'm not making an excessive amount of profit whatever that means, but here the risks truly are high and the risks are not just in the drug development process You The drugs are also in the regulatory process, and we didn't get into a lot of details in terms of what makes the regulatory process difficult for antibiotics.

And then you end up with the drug, and you're still not out of trouble because where are the patients? Turns out a lot of the patients who need the antibiotics happen to be sitting in poor countries where they just don't have the ability to pay. So one of the things that, I've written about and proposed is If there were a global facility or a fund that would pay for drugs, new antibiotics for people in poor countries, that would help the patients in need.

It would also help the pharmaceutical companies because they then are able to sell the drugs to a patient population that actually needs them. So it's a win situation in that sense, keeps the companies alive, and therefore brings new drugs to market. But This is still under discussion. 

Jessamy: I think that's very good.

But I also don't want our listeners to get the wrong impression because we've gone down a slight rabbit hole of antibiotics, but actually, as your series, and as you pointed out earlier on in this conversation, there's a lot of preventative stuff and a lot of things outside of just therapeutics and antibiotics that we can be doing.

We that's what we actually really need to focus on. 

Ramanan: Yes, absolutely. I think prevention is the first thing we should focus on. And that's what I want to get back to the point about. This being a very solvable problem, we know how to do vaccination, we know how to do hand washing, we know how to do, sanitation, hygiene, why don't we do those?

And, for a fairly modest investment the Lancet series reports that you can save about 750, 000 deaths just from that. You see a lot of Lancet numbers on, oh, so many people die of X. But here is an actual number of how many people are saved by X, and here is a very large number. That would not die because of these very simple interventions and I really think that a huge amount of the focus needs to be in prevention is just not it's not sexy, it doesn't get a lot of attention and therefore it it doesn't get much play.

Jessamy: I know we've fallen prey to that trap in this very podcast. Yes. But we can end on a strong note of prevention. 

Ramanan: Absolutely. Absolutely. If anyone is interested in more details, they should read the Lancet series, both the ones that we put out now, and they should also see the one that we did in 2016 prior to the previous UN declaration and it really details what we can do in this 

Gavin: space.

Well, Ramanan, thank you so much for joining us. We really appreciate your time. Thanks

so much for listening to this episode of the Lancet voice. Remember, you can subscribe to the Lancet voice where you usually get your podcasts, And if you'd like to see the other podcasts put out by the Lancet group, you can visit thelancet. com slash multimedia. Thanks and see you again next time.