Superbugs: Resistance rising, part 1

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1:15Roland Pease:Blue plaques on buildings in the UK mark places where important people lived or important things happened. The one on the red brick wall just behind me celebrates the birth of the age of antibiotics. I'm not outside St Mary's Hospital in London, where Alexander Fleming famously observed the lethal effects of penicillium mould on cultures of bacteria almost 100 years ago. Rather, I'm outside the Dunn School of Pathology in Oxford, where a decade later, Ernst Chain, Howard Florey and colleagues less famously turned that observation into a lifesaver for medicine. Or, as it says on the plaque, in this building, Howard Florey, Ernst Chain, Norman Heakley and colleagues first isolated and purified penicillin for the treatment of bacterial infection, 1938 to 1941.

2:14Roland Pease:Antibiotics have saved countless millions of lives since, but bacterial infections are constantly fighting back. I'm Roland Pease and in the next three episodes of Discovery from the BBC World Service I'll be hearing why health professionals worldwide are alarmed at the waning power of existing antibiotics and the struggle to find new compounds to stock the pharmacy shelves. But first, let's go inside the Dunn School and hear what happened here in 1940 and why the lessons from then still live on. Want to come in? Please, yeah. I'm Roland Pease, and I last looked into this vexed question of waning antibiotics on Discovery just over a decade ago.

3:01Roland Pease:Since then, much has changed, yet the picture looks depressingly similar. Maybe the roots of the problem might be glimpsed here at the birthplace of the age of antibiotics. Hi, Roland Pease from the BBC. Hi, please meet you. Christophe Tang, I work here at the Dunn School of Pathology. And this is where, for me, the age of antibiotics really started. Yeah, this is the actual building. It's remarkable to be in such a historic location. Out of interest, do you know which rooms they did the experiments in? I do, actually. The rooms are upstairs where some of the experiments took place and downstairs in the basement as well.

3:39You've got to take me to one of those at some point.

3:41Roland Pease:If you like it, I'd be lighted. If you can. I met Christophe Tang by a display on the ground floor of the Dunn School with old equipment and mementos from the dark World War II days when Ernst Chain and Howard Florey's team first manufactured penicillin. There were items I recognised from their pioneering papers of the time. This bottle in the middle looks like a sort of clay hot water bottle. This is the thing I've really been looking forward to. Right, well, it's actually a ceramic bed pan. It is a ceramic bed pan? It is a ceramic bed pan, and it was designed as the most efficient way to grow the mould penicillin, to generate as much penicillin into the liquid on top of which the fungus grew.

4:24Roland Pease:So what, they put some kind of broth in there? Yes, so just a spout into which the broth would be pussed. The fungus was seeded onto the top of that broth, and then it grew as a solid mat across the top, and produced penicillin into the liquid. and when the time came they're able then simply to tip that bed pan up and the liquid containing the penicillin would just fall out of the nozzle and then they would replenish it i mean it sounds so crude but in a sense this is this gets to the heart i think of the whole problem of antibiotics it's not just having some magic compound you've got to make and understand what you've got absolutely right and then the other challenge the team faced here at the time was obviously it was in the heart of the Second World War.

5:10So there wasn't the resources, or they couldn't get by equipment easily from suppliers of scientific instruments. So they had to come up with their own solutions, these things which looked like scientific equipment, but actually a lot of this was homemade and home-designed. So those porcelain small cylinders, those were used to test the potency of penicillin.

5:31Roland Pease:I mean, the famous part of the penicillin story is Alexander Fleming noticing that some bacteria in a culture had been killed off by this penicillium mould. Yes. That's sort of 19... Yeah, 1928. The paper was published in 1928. For me, what's really interesting is that that observation on its own is not the route to medicine. It's the work that was done here that turned this into something that has actually been a lifesaver ever since. And it's hard work. Yeah, it was absolutely hard work. It was three years' dedicated work before this could be tried in patients from when the team here found the original paper that was published by Fleming, to getting to a position where they had enough material, they had it pure enough so that it wouldn't cause side effects, that it could be given to a patient and tested in reality, basically.

6:21Roland Pease:And tested in quite a number of patients in the end. When they started the experiments, you must remember, they had no idea how effective it would be, how often they would have to give it, what the dose would be. So it was all trial and error. and the first patient, Albert Alexander, responded extremely well initially to penicillin but they just didn't have enough material to treat him completely so he cured. So unfortunately after about five days worth of therapy there was no more penicillin left despite all their best efforts and he subsequently died a few weeks later on. Though since then, Christophe told me, one estimate suggests 500 million lives have been saved by penicillin alone not to mention those saved by other antibiotics discovered in the following decades.

7:06Roland Pease:But this series is not only about the life-saving power of antibiotics, the ability of bacteria to fight back and invade the chemical assault is the bigger theme. And in my reading ahead of this visit, I saw the Oxford team's insight into that as well. There's one other paper which I picked up when I was doing this that was published at the end of 1940 in Nature from then. They've done very well to pick that paper up. And they say it's called an enzyme from bacteria able to destroy penicillin. So even as they were working on this, they understood that bacteria had the means by which they could actually fight back against antibiotics.

7:51Yeah, I think that's an absolute landmark paper. This is a paper by Abraham and Shane, who describe, as you say, this enzyme which could actually destroy penicillin being produced by bacteria. So basically, the cultures of penicillin that they were growing, of the mould, were contaminated by bacteria. And when they had contamination by the bacteria, they had no penicillin.

8:12Roland Pease:So this was the reverse of the Fleming experiment in a way. Exactly, exactly right. But it's so interesting because a major part of this series is about the fact that bacteria have always had mechanisms by which they can fight back against these antibiotics that we use. And, in fact, that's sort of why there's been this perpetual struggle to come up with new antibiotics, new ways of treating infections. Yeah, and I think it points to one problem of the approach that was used in the Dunn School, which is if you look for natural products which are produced in the natural world, bacteria will have encountered them before.

8:52If that's the case, bacteria will almost certainly evolve mechanisms to get rid of that antibiotic or that threat that they face.

9:01Roland Pease:What the Oxford researchers had already witnessed in 1940, when they'd only just started treating patients, has since been repeated countless times, not just reducing the effect of penicillin, but of every other antibiotic too. At a recent conference on reinvigorating the development of replacement antibiotics, Kevin Outterson, director of CARB-X, which funds current efforts, underlined the unusual nature in medicine of this loss of power. The first big antibiotic was penicillin, and it started being available for civilians in 1944 and 1945. Any other drug that was invented in 1945 still works as good today as it ever did.

9:43You know, if you took an aspirin from more than 100 years ago or any drug, they work forever, except for anything in which evolution causes the foe to change. So anything that's antimicrobial, going against parasites, viruses, and especially bacteria. And so penicillin is an amazing drug. We would love to have another penicillin, but time erodes its effectiveness because the bacteria evolve in response to it. So every other type of drugs, they work forever. these drugs, we need to reinvent them for every generation. Imagine if every cancer drug or every pain drug or every heart disease drug stopped working after 20, 30, or 40 years.

10:33Those doctors would be pulling their hair out, right? And that's the world the infectious disease doctors live in. The tools that they have today, the tools that they trained on in med school, work less effectively every year. So we always need to be innovating. We need to run faster just to avoid falling behind. But we haven't kept up. Excellencies, ladies and gentlemen, I welcome you all to this important high-level meeting as we address one of the most urgent global health threats and development challenges of our time,

11:11Roland Pease:antimicrobial resistance, AMR. The rising tide of antibiotic resistant bacteria has long been recognised, but the pressures have grown so intense that in 2024, the United Nations held its second special session on tackling the crisis. It is of concern. AMR is already linked to nearly 5 million deaths globally each year, and by 2050 it is projected to cause up to 10 million deaths annually. The inappropriate use of antimicrobial medicines has led to resistant microorganisms undermining our ability to control infections. As an infectious disease expert with wide experience across Southeast Asia, David Patterson sees the effect of this rising tide of resistant bacteria and contrast it with the potentially miraculous recovery brought about when antibiotics do work.

12:09It is the most satisfying thing in the world to have someone so, so sick and to be able to give them an effective antibiotic, knowing that in all Earth's history, up until the mid-1940s, those people would have died from that infection. You know, it is just so profound that we have a serious bacterial infection. We now have a therapy that can cure it. We obviously have to have a lot of supportive care, intensive care therapy, etc. But it's primarily the work of the antibiotic that is leading to the cure of the patient. So that is just absolutely a miracle of medicine. But when I go to hospitals where they have no antibiotics left that are active against these bacterial infections and the patient dies.

13:05You know, I'll give you an example. I was recently called about a lady in her 40s riding on her motor scooter. It was a wet day. She fell off, donged her head badly, needed to go to the intensive care unit, was on a mechanical ventilator. Actually the head injury was improving But on the fifth day of being in the intensive care She got a pneumonia The pneumonia was with a germ Resistant to almost all available antibiotics The only one that was left An antibiotic called colistin Was actually approved in 1959 We rarely use it in high income settings Because it's so toxic It causes kidney failure She got that, unfortunately, on the day when the neurosurgeon said her brain was recovering Her lungs went into failure and she died from this infection And this is not someone who's, you know, 80, had two liver transplants, has got leukaemia This is an otherwise healthy 42-year-old woman just skidded on the wet road and ended up with an infection in the hospital that killed her.

14:22And that, to me, is an absolute tragedy.

14:24Roland Pease:The problem in parts of the world is the large number of bacteria that are resistant to antibiotics and the number of antibiotic compounds that are being resisted, including many staples of hospital care. The go-to antibiotic is a breed, a class called carbapenems. They're pretty inexpensive now. Some parts of Africa, they're still too expensive to be widely available. But if we look across 2.5 billion people in Asia, they are accessible. The trouble is some of these bacteria have become resistant to this antibiotic. In fact, when we look at hospital-acquired infections across Asia generally, about 20-25 % are resistant to these carbapenems.

15:11Roland Pease:They're picking up these bacteria while they're in hospital because they accumulate there. That's right. These carbapenem-resistant organisms are on the bed rails, they're on the machines that ventilate patients, they're on the computers that the nurses access. Now, not everyone gets sick from them, but 50 % of the patients who get a serious infection with these germs will be dead in a month. I can't think of a leukemia or a cancer, the single disease, a single thing that happens in medicine where the outcome is as grim as a serious infection with one of these resistant bacteria. I think the general public doesn't know that.

15:58You know, they hear, oh, my cousin was admitted into the intensive care unit and they died. They don't know that the actual cause of death was not the head injury. it was the pneumonia that was with a resistant organism.

16:13Roland Pease:A reminder this is Discovery from the BBC with me Roland Pease looking at the antibiotics crisis. So far in the program I've talked about the power of antibiotics to cure infections and the ability of bacteria to resist antibiotics curative potential but there's a reason that resistance is spreading so fast. Bacteria don't have to invent resistance mechanisms each time. They're challenged by antibiotics. They keep their resistance genes once they've got them and, more importantly, they can borrow them. Bacteria take up DNA from the environment or from other bacteria and that DNA will contain genes that encode enzymes that can break down antibiotics.

16:57And this is the main reason why antibiotic resistance is spreading quickly, is via this process called horizontal gene transfer. For example, in our intestinal tract, there are billions and billions of bacteria. They're closely packed onto each other. So it's very easy for one bacterium to move a piece of DNA to another bacterium.

17:19Roland Pease:At Birmingham University, Willem van Zrijke is an expert on the way bacteria share resistance. Sometimes on cassettes of genes called plasmids, there are a process called conjugation. Conjugation is a process where there's certain mobile genetic elements, sorry for all the jargon again, called plasmids, they basically start moving around from one bacterium to another. It's a kind of bacterial sex, is it? It is. I mean, is it a particular issue with things like resistance? Yes. I mean, in a sense, it's a survival technique that bacteria have. Yeah, so this process, some bacteria have been called drug resistance traffickers because they move on all these genes that cause antibiotic resistance to other bacteria.

18:01So then you start with a plasmid, for example, being present at a very low level in a population. But then it starts to spread out to many other bacteria in a population. And then all these bacteria become resistant to antibiotics.

18:16Roland Pease:So if I've, and I have, I've taken all kinds of antibiotics over my life. So I'm getting those into my stomach. Do those antibiotics affect the microbes in my gut? And does it affect this resistance process? Depends a little bit on the type of antibiotic that you take, but many antibiotics end up in the intestinal tract, and then the bacteria that are there are exposed to the antibiotic. The ones that are susceptible, well, they will die, but the ones that are resistant, they survive, and they might be resistant because they have these plasmids or other mobile genetic elements that encode antibiotic resistance genes.

18:56So what's the clinical concern here? The clinical concern is that this is the major pathway towards resistance that is keeping microbiologists awake at night. Because it's such an effective process of sharing DNA, and there's very little that we can do about it, because bacteria like to have sex, they like to share their DNA around. And because these little pieces of DNA that move around have often multiple antibiotic resistance genes on them, it becomes increasingly difficult to treat infections.

19:31Roland Pease:You're saying that they can actually have not just one but several of these resistance genes. Yeah. I mean, what, they're all in a package? Yeah, so essentially what you often have is that these genes are often placed on these mobile genetic elements like a little train with different carriages and every carriage gives resistance to one antibiotic or one class of antibiotics. And so if you have multiple carriages on one of these mobile genetic elements, you get multi-drug resistance, so resistance to multiple antibiotics. Thanks to these mobile cassettes of resistance genes, resistant bacteria are so omnipresent that even those who can't conceivably have been exposed to antibiotics can nevertheless be infected.

20:18OK, so this is one of our surveillance laboratories.

20:21Roland Pease:Back at the Dunn School in Oxford where penicillin was invented, Kirsty Sands worked with hospitals in West Africa to track the problem. In some of our research we've found that within the first day of life, babies in their developing gut bacteria are carrying bacteria that have particular resistance markers. This was in babies in one day old, so the question is where are they getting this from? Is this an exposure at birth representing that environment within the hospital? Is it coming from the mum? It's really, really hard. We don't know the answer to that. but it's happening immediately at birth.

20:55Roland Pease:And so they are picking up not just bacteria, but bacteria that are resistant to antibiotics. They've never had antibiotics, that's the point. Exactly, absolutely. Yeah, within the first day or two of life, bacteria with often resistance markers to those reserve antibiotics as well. So not even the commonly used antibiotics. And that's telling you that there are bacteria in their environment, probably carrying those things, maybe just dormant, but sitting on a surface or something like that. Yes, absolutely. And in some parts of the world, these particular types of bacteria or resistant bacteria are very common.

21:28Roland Pease:And how big an issue is this in terms of the health of newborns? It's an absolutely huge issue because if babies are born carrying these types of bacteria or are exposed to it within that first day of life, they go on to get an infection, treating that with antibiotics that will be effective in a timely manner is really, really tough. A lot of these hospitals do not have the infrastructure to support diagnostics, so they're not able to test the blood. So the provision of antibiotics is empirical. There's the World Health Organization's recommended treatment options, but we know from our previous work that at least 75 % of bacteria are unlikely to respond to those.

22:07So a lot of hospitals will be using antibiotics that they've seen clinically have a better outcome.

22:13Roland Pease:I mean, this is deadly. Absolutely, yeah. Unfortunately, this is extremely life-burning. And, you know, those decisions within that day or two are really, really important. By decisions, Kirsty Sands means choosing antibiotics that are effective against the strain infecting a vulnerable newborn. By pioneering cost-effective diagnostics in pilot African hospitals, her project has more than halved mortality from sepsis among newborns from over 33 % to just 15%. A small dent in the huge number of infant deaths worldwide that make up the major burden of antibiotic resistance. But by a small river in central England, I learned that hospitals aren't the only place where resistance genes get spread around.

22:59Roland Pease:That's where a few years ago I joined microbiologists Liz Wellington and Greg Amos hunting for resistant bacteria. You want to get the exact same spot so we can repeat the word. Close to their base, Warwick University, this was an ideal location to sample antibiotic-resistant strains of bacteria washed out from sewage treatment works handling wastewater from local hospitals and from towns and villages. And a stick. These are just big glass beakers like you might see in any chemistry lab. Yes, we normally dredge the bottom to get the sediment and then we'll cut the water off so we just left the sediment.

23:40Roland Pease:So at the moment, slightly muddy water from a very typical English river. And it's not the water, but the mud at the bottom, the sediment at the bottom. It's the sediment which we focus on. And what you're looking for in here are not just any old bacteria. Resistant bacteria. So we're looking for resistance to antibiotics which are normally used in the clinic. So Kefetaxime, Keftazidine, and Amipenem, which are beta-lactam antibiotics used to treat E. coli and Klebsiella infections. Now Liz, for me these are resistance properties I'd expect to find in a clinic but this is a river miles from the nearest town.