This Podcast Will Kill You - Ep 51 The Path of Most (Antibiotic) Resistance

Episode Date: May 26, 2020

No story of antibiotics would be complete without the rise of resistance. As promised in our last episode, this week we dive into what the WHO calls ‘one of the biggest threats to global health, food security, and development today’ - antibiotic resistance. In the decades since their development, misuse and overuse of antibiotics has led to many becoming all but useless, and our world seems on the verge of plunging into a post-antibiotic era. How does resistance work? Where did it come from? Why did it spread so far so rapidly? Is there any hope? In this episode, we answer all these questions and more. First, we explore the many ways bacteria evade the weaponry of antibiotic compounds. Then we trace the global spread of these resistant bugs by examining the major contributors to their misuse and overuse. And finally we assess the current global status of antibiotic resistant infections (spoiler: it’s very bad) and search for any good news (spoiler: there’s a lot!). To chat about one super cool and innovative alternative to antibiotics, we are joined by the amazing Dr. Steffanie Strathdee (Twitter: @chngin_the_wrld), Associate Dean of Global Health Sciences, Harold Simon Professor at the University of California San Diego School of Medicine and Co-Director at the Center for Innovative Phage Applications and Therapeutics. Dr. Strathdee provides a firsthand account of helping her husband, Dr. Tom Patterson, fight off a deadly superbug infection by calling on a long-forgotten method of treating bacterial infections: phage therapy. To read more about phage therapy and Dr. Strathdee’s incredible experiences, check out The Perfect Predator: A Scientist's Race to Save Her Husband from a Deadly Superbug: A Memoir.  See omnystudio.com/listener for privacy information.

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Terms and conditions apply. Visit blueapron.com slash terms for more information. I'm Amanda Knox, and in the new podcast, Doubt, the case of Lucy Letby, we unpack the story of an unimaginable tragedy that gripped the UK in 2023. But what if we didn't get the whole story? Evidence has been made to fit. The moment you look at the whole picture, the case collapsed. What if the truth was disguised by a story we chose to book?

Oh, my God, I think she might be innocent. Listen to Doubt, the case of Lucy Lettby on the IHeartRadio app, Apple Podcasts, or wherever you get your podcasts. I'm Clayton Eckerd in 2022. I was the lead of ABC's The Bachelor. But here's the thing. Bachelor fans hated him. If I could press a button and rewind it all I would. That's when his life took a disturbing turn.

A one-night stand would end in a courtroom. The media is here. this case has gone viral. The dating contract. Agree to date me, but I'm also suing you. This is unlike anything I've ever seen before. I'm Stephanie Young. Listen to Love Trapped on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts.

Hi, I'm Stephanie Strattie. People call me Steph. I'm the Associate Dean of Global Health Sciences at the University of California, San Diego. And I now co-direct the new Center for Innovative Fage Applications and Therapeutics, known as IPAP. That's the first phage therapy center in North America. But that's the end of the story. You want to hear how I got there, right? Well, it's a crazy story.

People often don't even believe that it was true. But it really is. My husband and I went on vacation in Egypt in the fall of 2015, and we're scientists. We travel together, and we always do off the beaten path kinds of things. We had a dream of going to see King. Tutt's tomb and we floated down the Nile River in a wonderful ship. So everything went great

until the night before we were supposed to see King Tutt's tomb. And Tom and I had this wonderful meal on top of a cruise ship and he got violently ill afterwards. I mean, he was throwing up all over the place. And, you know, I just thought he had a bad muscle or something like that. But actually he got very sick. We had to call a doctor to the ship. The doctor said he's going into shock. There was no hospital in Luxor where the ship was docked. So we ended up having to go to a community clinic. There they diagnosed him with pancreatitis, which is essentially an inflammation of the pancreas.

But when I called back home to our colleagues who are leading the Department of Infectious Diseases at UC San Diego, they said, hey, that's just a symptom of something else because you're the wine drinker in the family. Tom doesn't drink nearly as much as you. and that's usually one of the causes of pancreatitis. They said something else is going on.

And luckily, we had travel insurance, so we were able to get him medevac to Frankfurt, Germany, because he was too sick to be medevac home. And there they did a CT scan and saw that he had a giant abscess in his abdomen, the size of a football. And the doctors came to me and said, you know, there's something lurking inside this abscess, and they showed me this putrid flask of fluid that they'd taken from this abscess.

And they said, something's growing in there and we have had to culture it. It's going to take a couple of days. But let's hope it's a garden variety microorganism because there's a lot of multi-drug-resistant bacteria in Egypt. Well, I was getting a little bit worried. But, you know, I thought, hey, we have antibiotics, anything, you know, that's growing in there, we can handle it. Well, the doctors came back in a couple days and they showed me that,

This name of this organism was osomidobacter bomaniae. And it's something that I used to plate on my petri dishes back in the 1980s when I was taking a rusty old degree in microbiology at the University of Toronto. And again, I really wasn't that worried, but they said, look, this is actually the worst bacteria on the planet. I thought, you know, what? How can this be the worst bacteria in the planet? Because like, you know, 20 years ago, we just had to use, like, goggles and lab code.

And that was it. it was not worrisome at all. Well, it turns out that the antimicrobial resistance crisis had crept up on us. And Tom was essentially the poster child for this post-antibiotic era that we've entered now. And so the doctors did what's called an antibiogram to find out the antibiotics that could be used to hopefully treat this thing. And they came back and they were even more alarmed because there was only a couple of antibiotics that it was partially sensitive to. and it was resistant to 15 right off the top. Well, I started to get worried now.

And this is right before Christmas of 2015. Luckily, they stabilized him, got him sent back to San Diego where my colleagues in the Department of Medicine were looking after him. And I thought, okay, we're fine. We're home now, right? Everything's going to be fine. We'll find some antibiotics to, you know,

to cocktail together to cure this thing. And they repeated the culture, and they found out that now, and even though only a few weeks had passed, this organism was resistant to all antibiotics. I mean, even the last resort antibiotic colistin that was developed in World War II. Well, they said, you know, he's too weak for surgery. We have no choice but to use interventional radiology to essentially stick, you know, holes in his abdomen and put these catheters in there to try to drain out this infected fluid out of the abscess

and hopefully it would shrink and then he'd be better, right? well not so fast because even though he had started to improve one day he sat up in bed and this tube inside his abdomen slipped and it just dumped all that infected fluid into his abdomen into his bloodstream and immediately he went into septic shock right in front of my eyes and I'm telling me it was one of the scariest moments of my life we were actually supposed to get discharged to an acute care facility the next day but that wasn't happening any time fast. In fact, he was rushed back to the ICU in the same hospital and put into an induced coma for a couple days to give his body to rest. And he did wake up from that. But now, this organism

is now in his whole body. He was like fully like systemically infected. And from that moment on, he was dying a little bit more each day. And it was just horrible to watch. He lost 100 pounds off of his frame. He was in and out of a real coma that he wasn't waking up from. And one day I heard some colleagues on a conference call when I was trying to, you know, keep one tethered back to the real world. And they said, does anybody realize that, you know, there's anybody told step that her husband is going to die? And I thought, oh my God, like nobody has. And I cradled the phone in my arms like a baby. And I thought, they just didn't want to tell me. And I'm going to lose them unless I do something.

So I had this conversation with Tom and asked him if he wanted to live. And I didn't know if he could even hear me, but I said, if you want to live, please squeeze my hand and I'll leave no stone unturned. And he squeezed my hand. Now, I mean, I was thrilled, but I thought, you know, what am I going to do? Like, I'm not a medical doctor. I don't know how to cure this thing. But I did what anybody would do in my shoes because I'm a scientist.

I went home and I hit PubMed, you know, the Google Scholar for scientists at the National Library of Medicine has developed, and I found this ancient 100-year-old therapy called phage therapy, which are essentially these bacteriophages are viruses that have naturally evolved to attack bacteria. And I'd heard about them in my microbiology classes way back in the 1980s, but I never knew that they'd been used to treat bacterial infections. Well, it turned out that they had that they were considered experimental treatment in the West, and they're only being used in the former Soviet Union and in parts of Eastern Europe. So I asked the colleagues that were treating Tom, I said, you know, could we use phage therapy to treat Tom?

And that lead infectious disease doctor, Dr. Chip Scooley, who's a close colleague of mine, he said, what an interesting and intriguing idea. You know, if you can find phages that match to Tom's bacterial isolate, I'll call the FDA and request compassionate use permission for us to use phage therapy to, cure them, but I've never done this before, and I don't know anybody who has, so, you know, it's a long shot. Anyway, long story short, a global village of researchers from all over the world stepped up, including researchers from Texas A&M University, San Diego State University, and even the U.S. Navy chipped in, and we found phages in the nick of time to match Tom's bacteria, and we injected them into his body a billion phages per dose.

every two hours. We didn't know if we were going to kill him or cure him. But three days later, he lifted his head off the pillow and kissed his daughter's hand. And I'm telling you, it was the happiest day of my life. So that's our crazy story. I left a lot of it out, but it's in our book, The Perfect Predator, if you want to hear more details. You want to say hi, Tom? Hi, Tom. How are you feeling these days? I'm feeling great. Can't complain. Well, I could, but nobody's going to listen after I got. saved like this. Well, it's better than the alternative, right? You're damn right.

That was amazing. Thank you so much, Stephanie. We really appreciate you taking the time to come on the podcast and share your story with us. We really, really do. It's, oh, man. What a bonkers story. I really, really, and we'll mention this again, but I really, really encourage everyone to go out there and read the perfect predator, which is the book that she wrote about this experience, it was unput downable, if that's a word. I could not put it down. How about that? I really hope that that's a word.

Yeah. I don't think it is. Hi, I'm Erin Welsh. And I'm Aaron Olman Updike. And this is, this podcast will kill you. So today we're talking about antibiotic resistance. Yes. You thought you heard all that you wanted to know about.

antibiotics in the last episode? No way. Nope. Wrong. Not so fast. There is so much more in the world of antibiotics to learn about, to read about, to hear about, and that's what we're doing this episode. We promise it's not all depressing.

Like, it's mostly depressing, but. Yeah, we're going to end it on a hope for the future. Nope. Absolutely. Yeah. A couple of things. We completely forgot. Aaron and our excitement to do the episode last week to talk about why we were so excited beyond just the fact that it was antibiotics.

It was our 50th regular season episode. I totally forgot about that. Oh my gosh. I can't believe we've made that many episodes. I really can't. I remember going back to one of the earlier ones. And I remember how we used to be like, oh my gosh, episode seven, can you believe we've made it this far? To be fair, I was shocked that we made it to seven episodes.

That's fair. It was a true sentiment at the time. The other thing is that I completely forgot to mention where the first-hand account came from in the antibiotics episode. And that was, I mean, it's like we're amateurs at this. On our 50th episode, we failed to do the most important things. Sometimes. The days just keep. to you. So that, so the firsthand account from our last episode on antibiotics came from a book called

The Youngest Science by Lewis Thomas. Okay. So, Aaron, to accompany our quarantini for the antibiotics episode, which was penicillin, the classic cocktail, what are we drinking this week? This week we're drinking the plasmid. Oh, if that's not funny to you now, it will be funny. as soon as I explain the biology of antibiotic resistance. Exactly, exactly. You're like, why are they laughing so hard? Erin, what's into plasmid? Great question.

It is mescal, like a honey mint simple syrup, and lime juice. It's kind of like a penicillin, but it's a take on a penicillin. It's a plasmid of a penicillin. Exactly. That's not right. It's a plasmid containing resistance to penicillin. We will post the recipe for the alcoholic quarantini and the non-alcoholic placebo ita on our website.

This podcast will kill you.com as well as all of our social media channels. Any other business? I don't think so. Let's get right to it. I can't wait. We'll take one quick break first. Dinner shows up every night, whether you're prepared for it or not. And with Blue Apron, you won't need to panic order takeout again.

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Listen to the Sixth Bureau on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. Antibiotic resistance. Okay. It's a big topic, so we're going to break it down. Here's how. First of all, hopefully everyone's listened to the antibiotics episode, so you have a framework for how antibiotics work. As a very brief overview, antibiotics are designed to either kill or halt the growth of bacteria,

and they do so by targeting various elements of bacterial cell walls, protein synthesis, DNA replication or metabolism. That's our whole episode in 10 seconds. Well, that's a lot shorter than what the episode actually turned out to be, Erin. Okay, so the question first on a basic level is, what are the mechanisms of antibiotic resistance? Like, how do bacteria actually resist these antibiotics? Just sheer force of will. That's the answer. Episode over.

Once we understand that, then we can ask two bigger picture questions. What drives antibiotic resistance? And how does this resistance spread through populations? Okay. Are you excited? I'm super excited. All right. So what are the mechanisms of resistance?

First of all, you can have intrinsic resistance and you can have acquired resistance. if you are you being bacteria. Right. Okay. I'm a bacterial cell. You're a bacterial cell. So very broadly, intrinsic resistance makes a lot of sense in the context that a lot of antibiotics come from bacterial products, right?

So it makes sense that a streptomyces bacteria, for example, will be naturally resistant to streptomycin. That makes sense, yeah. So that is intrinsic resistance, which is neither the interesting. nor the concerning part of antibiotic resistance. So that's all we'll say about it. What is both interesting and concerning is acquired resistance. And there are a few big categories of mechanisms by which bacteria can evade the effects of antibiotics.

Let's go through them. Number one, bacteria can resist antibiotics by changing the target enzymes. So what does that mean? For drugs like quinolones that we talked about, fluroquinolones, or rithampin or the sulfonamides, these are drugs that bind directly to certain enzymes, DNA gyrase or RNA polymerase. So if bacteria modify these enzymes slightly,

change their structure just a little bit, then these antibiotic compounds are no longer able to bind to them. Boom, they don't work. Makes sense. And that seems like a relatively, easy or like a relatively simple mutation would be necessary. Like one little quirk. Exactly. One little quirk for sure. Another way that's actually very similar. In the case of the classes of antibiotics that work by binding to ribosomes instead of enzymes, if bacteria evolve mutations to their

ribosomes such that antibiotics can no longer bind, then again, boom, resistance. That's pretty straightforward, right? Yeah. Okay. So we can alter our enzymes that the antibiotics bind to, or we can alter the proteins such as ribosomes that antibiotics bind to. All right. Two other ways that are also related.

Remember that gram-negative bacteria especially have a second membrane that surrounds the outside of their cell wall. Right. And this membrane is less permeable than the cell wall is. So we know that gram-negative bacteria are already harder to target with antibiotics because of that. So for gram-negative bacteria, the way that antibiotics enter the cells is through pores, porins, little channels in the membrane. Well, if antibiotics can only enter certain porins and bacteria then evolve changes either to the type of porins or sometimes just to the number of pores on their surface, that can, make them more resistant to certain classes of antibiotics. Makes sense.

Makes sense, right? Basically just changing the way that antibiotics are able to get into the cell, making it harder for antibiotics to get in. Mm-hmm. Mm-hmm. Another similar mechanism is you could kick antibiotics out at a faster rate. So these are called e-flux pumps. Mm-hmm.

Yeah. Bacteria have e-flux pumps because especially when they have, especially gram-negative bacteria that have two layers of membrane plus a cell wall, they have to be able to get stuff in and out of their cells. So e-flux pumps are a way that they can shuttle molecules outside of their cells. And it turns out that the genes for these types of e-flux pumps aren't turned on all of the time because they can be quite costly. They can lead to bacteria exporting too much stuff, and that can change the membrane potential of their cells and ultimately lead to cell death. Okay. That's interesting. That makes sense, too.

I like that, though. Yeah. But in the face of antibiotics, if you can upregulate those e-flex pumps, then you can ship the antibiotic molecules out of the cell before they have time to kill you. Right. So it's worth it. Even though it's costly, it's worth it in the face of something that is actually going to kill you. That is like the, that's like antibiotic resistance in a nutshell. It's worth it if the antibiotic is going to kill you. Yeah. I mean, that's evolution in a nutshell. Yes, 100%. Okay, so those are the two other ways. You can change your e-flux pumps and you can change your pourins, right?

Make it harder for antibiotics to get in or export them out even faster. And then the last way that you can evade antibiotics is by changing the antibiotics themselves. This is my personal favorite mechanism. Ooh, right? So bacteria can evolve ways to alter the antibiotic compounds themselves and render them useless. So for this, I'm going to actually go through a couple of examples. There's a lot of different ways that bacteria can do this. So we'll go through two examples of it.

The first are amino glycosides, which you might remember from our last episode. These are streptomycin, tobermysin. These act on bacterial protein synthesis. They bind to ribosomes. Okay? Mm-hmm. So bacteria can produce enzymes, naturally produce enzymes that bind to these antibiotics and add stuff to them, whether it's a phosphate or just a little.

carbon group, and that changes the structure of the amino glycoside itself so that it no longer works. It basically inactivates it. That seems like much trickier to pull off. Maybe, but they do it really well. It's really cool. All right. The other most famous example of this are, of course, the beta lactamases. Have you heard of this? Yes, there are enzymes that actually break down the beta-lactam ring, right? Yes. And the beta-lactam ring is how beta-lactam antibiotics like penicillin and cephalosporin actually work. So many bacteria, especially gram-positives, produce these enzymes called beta-lactamases that bind to and inactivate that beta-lactam ring.

It is so common, like beta-lactamases are so common and ubiquitous that we actually have a whole other set of drugs that we call beta lactamase inhibitors. And these drugs inhibit or reduce the activity of those enzymes. So it's actually really common that when we give a beta lactam antibiotic like amoxicillin, we give it in combination with a beta lactamase inhibitor like clavulonic acid. That combination is called augmentin. It's sort of like the lactamase inhibitors hold back the little guards. And they're like, no, no, you can.

can invade the castle. Okay, so there's a dorkiest. There's a series of videos that most any med student listening is going to laugh really hard at that because we watch these videos called sketchy micro and they show like beta lactams are these rings.

And then the beta lactamases are these little like laser shooters that shoot away the beta lactambs. And then you have like the clavulonic acid that has like a armor that comes in. Anyway. I like it. It's really great. I mean, it's very easy to envision all these as like little cartoons for sure. Yes. Oh, and they help you learn it a lot, a lot easier. Yeah, so it's very cool. We already have, like, we've known that beta lactamases exist for so long that we already have drugs that specifically target those.

But what's scary is that now many bacteria are what we call extended spectrum beta lactamase. producers. So they're making even stronger beta lactamases that can break even more of our drugs, essentially. Yeah, I mean, that's sort of the theme. Like, this is the same story ever, like over and over again with just tiny variations. Exactly. So then that kind of gets to the next question, which is what actually drives this resistance? Why is it that we have resistance cropping up again and again. And we've kind of already touched on it, but the basic answer is mutation and selection. Right. It's a numbers game. Yeah. So for resistance to happen, first, a gene for that resistance, any one of those types of resistance that I already mentioned, a gene for that has to appear in the

population. And often this happens by random mutation, which seems like it should be very unlikely, right? Well, given the generation times and how many generations, like even within a year or something, a strain of ecoli will have, it's not. It becomes surprising that there's not resistance rather than surprising that there is. Would you like to put some hard numbers on that, Aaron? You know that I would, Aaron. So mutations like this that can provide resistance occur about once every 10 million cells. And because many bacterial species divide so frequently like once every half an hour, it would only take six hours to get to 10 million cells. And all it takes is one. All it takes is one. Okay. Okay, so that's the first step, right? Mutation. You have to mutate your DNA in such a way that you produce one of those changes. And then the second thing that has to happen is selection pressure, which essentially means

you have to wipe out most but not all of the bacteria in a population. So let's put some numbers on this again. Let's say you have like 10,000 bacteria living in a wound on your hand. If you killed 9,000 of those bacteria by any means, antibiotics or otherwise, you have selected 1,000 survivors. Those 1,000 survivors will go on to reproduce. And oftentimes those 1,000 survivors aren't representative of that whole 10,000. 1,000 group of bacteria, right? They all have their own little mutations that are slightly different. But those are the ones that are going to go on and reproduce. So if any of those 1,000 had the

ability to resist an antibiotic, those are going to be the ones that now grow and proliferate. Right. Okay. Because remember, like I mentioned, especially with e-flux pumps, but this is true for many of those other mechanisms of resistance, a lot of the genes that confer resistance to antibiotics are not useful and in some cases they're harmful in the absence of antibiotics. Right. So you could see over time if you don't put any selection pressure on, you know, a bacterial strain as they replicate and replicate and replicate, then the resistance genes might drop out because it's more costly to maintain. Exactly. Right. Okay. So then how does this gene that's present in, let's say, a couple of those 1,000 bacteria that are left,

how does it spread through a population? Because we see antibiotic resistance growing at very rapid rates, right? Right. So to understand this, we basically just have to know that bacteria don't just reproduce by fission, right? That's how they mainly reproduce, but they also can transfer genetic material between cells. Okay. So I'll just get so excited about this. I think we talked about this in E. E. coli, right, with Joshua Lederberg? I think so. Who discovered this? Yeah. So there are three ways that bacteria can introduce some variety into their genes besides just mutation. Conjugation, transformation and transduction. Conjugation is kind of like bacterial sex.

So basically two bacteria get together. They pull out their pylis, and then they attach their pylis to their partner's pylis, and then they can share plasmids. Plasmids are circles of DNA, just little round nuggets, pieces of DNA, and they can transfer them. So they can like hand a plasmid to their partner. and they can grab a plasmid from their partner. And sometimes, oftentimes,

those little plasmids have super useful things on them, like a better e-flux pump or a new type of beta lactamase, for example. Mm-hmm. Okay. That's conjugation. Transformation is when bacteria pick up DNA from the environment. So if their neighbor dies and explodes and leaves a bunch of DNA floating around, another bacterium can swim by and pick some of that up.

And finally, transduction is when viruses get involved. So bacteriophage, which are viruses that infect bacteria, okay, these are important. These bacteriophages have to use host cell machinery in order to reproduce. So what they do is they inject their DNA into a bacterium, and then some of that DNA can get incorporated, into the bacterial DNA. So then every time a virus picks up and infects a new bacterium,

they might transfer a little bit of that bacterial DNA to a neighboring cell. That is super cool. Also, we forgot to mention this early on, but you will hear a lot more about phages and their potential role as treatment for antibiotic-resistant infections. later on in the episode from Stephanie as well. Big time, big time. So, I mean, that's pretty much how resistance works.

Okay. So if we go back to that population of 10,000 bacteria that lives in your festering hand wound, okay, just to kind of sum all this up. Mm-hmm. Actually, let's call it 10 million bacteria. Okay. Now my hand wound is really, really just oozing. It's pussy.

It's pussy. Yep. Okay. So you cut yourself. Now you have 10 million bacteria in the cut on your hand. And one of them happens to be resistant to penicillin. And that's what you went to the doctor. And that's what they're going to use to treat your hand infection.

Okay. So you take the penicillin and it wipes out all but one of those bacteria, right? You have just one lone bacterium left. That's not a problem for your hand wound necessarily. But that single bacterium is going to continue to multiply and multiply. And now inevitably, your hand is exposed to tons of other bacteria all the time, right? Everything you touch is covered in bacteria. So eventually that one bacterium that was left and now reproducing, that colony that's growing,

is going to come into contact with some new bacteria. And he'll probably go, hey, just so you guys know if you're planning on making a home here, all my friends just got wiped out by penicillin recently. And I have this little plasmid. It seems really helpful like I survived. So do you want this? It's just a little beta lactamase. Do you want one?

And all of the new bacteria are going to be like, yeah, heck yeah, give me one of those. So they'll get together, conjugate, and share that plasmid with their friends. And voila. Antibiotic resistance. I feel like we have this idea of an antibiotic resistant bacteria to be completely like bulletproof, basically. But your body can still fight off that infection. Oh, for sure. Yeah, yeah. For sure, for sure. The other thing, too, though, is that many of these antibiotic resistance genes come from environmental bacteria. So they don't necessarily have to originate by mutation in that one bacterium that was left behind.

They could have been introduced from outside populations to begin with, and then they can spread because of selection pressures. Oh, yeah. And I'll talk about some of those sources of resistance. I can't wait. So, yeah, that was a lot, but that was antibiotic resistance in a nutshell. I loved it. I loved it. Oh, good. I'm so glad. So, Erin, how the heck did we get here? I can't wait to tell you. Should we take a quick break first?

Let's do that. Anyone who works long hours knows the routine. Wash, sanitize, repeat. By the end of the day, your hands feel like they've been through something. That's why O'Keefe's working hands hand cream is such a relief. It's a concentrated hand cream that is specifically designed to relieve extremely dry, cracked hands caused by constant hand washing and harsh conditions. Working hands creates a protective layer on the skin that locks in moisture.

It's non-greasy, unscented, and absorbs quickly. A little goes a long way. Moisturization that lasts up to 48 hours. It's made for people whose hands take a beating at work, from health care and food service to salon, lab, and caregiving environments. It's been relied on for decades by people who wash their hands constantly or work in harsh conditions because it actually works. O'Keefs is my hand cream of choice in these dry color.

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A verdict, a villain, a nurse named Lucy Letby. Lucy Letby has been found guilty. But what if we didn't get the whole story? The moment you look at the whole picture, the case collapses. I'm Amanda Knox, and in the new podcast, doubt the case of Lucy Letby, we follow the evidence and hear from the people that lived it, to ask what really happened when the world decided who Lucy Ledby. was. No voicing of any skepticism or doubt. It'll cause so much harm at every single level of the

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So, Aaron, you might think that this story, the story of antibiotic resistance, maybe it starts with the first sulfonamide or penicillin-resistant strains of bacteria that were found in hospitals in the 1940s? Are you going to tell me it's way further back than that? Oh, way, way, way further back. Like millennia, millions of years even?

Okay, okay. So even today, like you said, many of the antibiotics that we use are compounds produced by microbes, fungi or other bacterial species. And in the early years of antibiotics, they were all like that. Like synthetic antibiotics really only started to become developed in the past. few decades. And so I think it's easy to take it for granted sometimes that these antibiotic compounds are just produced by these soil microbes or fungi and not question why exactly they might have evolved to produce substances that can kill bacteria. Because like you said, when you're producing

something like that, it can be a costly thing. Like it can be a costly thing to kind of go above and beyond just simply replicating yourself and like getting food. I feel like we talk a lot about this in our plant crossover episodes with Matt. Like it takes a lot for plants to make these compounds that kill us. It takes a lot for bacteria to make these compounds that kill other bacteria. Yep. It was just like that with the botulism episode. Like why does this toxin exist? Yeah. So why do these compounds exist in nature? They didn't just arise in the 1940s with penicillin. Like they've been there for millions of years. Okay. So what do these compounds do in nature? Yeah. So let's just think about a little handful of soil.

Okay. Got side and you've grabbed some soil. In that soil, you have this beautiful, complex, rich world of microbes, even though it looks just like a handful of soil. It's really like teeming with microbial life. And each one of these microbes are all pushing and pulling and fighting for space and basically doing what it takes to continue on to the next generation. This is a battle that has been going on for millions of years. And over that, time, some microbes have evolved strategies to help them stay one step ahead of the race to gain just a little more ground. An antibiotic is one example of this type of strategy. In nature, these antimicrobial compounds actually help the bacteria or fungi that produce them in any

number of ways, like to make super durable biofilms or to more easily invade an animal cell, type 3 secretion system, or to clear the competition in a particular. particular area or to also better work alongside another group of bacteria. So they actually can help some groups of bacteria. And it's also important to remember that in nature, the amount of antibiotic compounds produced by some of these bacteria or fungi, especially those that make something like tetracycline, for example, is super small. Like nowhere near what a therapeutic dose would be for humans. That is really important to keep in mind. Yeah. Wow. Really important.

Yeah. And so when we make antibiotics in a lab or in an industry setting, you are like farming penicillin. Like you are like farming the fungi and the bacteria. You're making gobs and gobs and gobs of it, which wouldn't happen in nature. Yeah. Yeah. Or IRL. Okay.

So yeah, make a mental note of that. Okay. So even though we may tend to think. of these antibiotic compounds as these brute-forced drugs that punch holes in cell walls or tear apart ribosomes, their role in nature is much more nuanced and much more long-standing. So it makes sense, then, that if these microbes have evolved the ability to produce antibiotic compounds over thousands or millions of years, the bacteria that they are targeting with those antibiotics have also evolved a trick or two. Resistance genes.

Yeah. And this isn't a guess. This isn't just like the logical flow. Antibiotic resistance is ancient, which is actually the, you know, word for word title of a paper that I read. Peer-reviewed paper. And in this paper, they analyzed 30,000-year-old permafrost sediment to look for genetic traces of antibiotic resistance. And guess what they found? They found genes that gave resistance to beta lactams, tetracycline, glycopyptides, even vancomycin antibiotics.

Yeah, wow. So at least roughly 29,000 and 30 years before penicillin was discovered, these resistance genes existed. Just 29,000 years. No big deal. Well, I think that this at least helps to a small degree in understanding just how quickly some of these resistance genes have popped up. Because like you said, some have arisen just through mutations. So some you could take, you could start in the lab and start with like, or on a human body and start with, you know, a colony of a particular type of bacteria.

And then you could evolve resistance just by applying that selection pressure. But I think it's also important to remember that some of these mutations may be the ones that are a little bit more complex, some of the genes that provide resistance to more complex antibiotic structures, they might have roots already just in nature. Right. And many, many bacteria already have these genes. They might just not. be turned on until they face the selection pressure. So that's the other thing. It's like they might be there. They're just not using them yet. Right. Exactly. You know what's funny, Erin? You say exactly right. And I say right exactly. I've noticed this when I'm editing. It's very funny to me.

Okay. Now I'm going to be self-conscious about it. Okay. All right. So now we have a little bit better idea of the ancient roots of some of these resistance genes, but how do they spread so far and so wide so quickly? And you talked about the mechanisms of this. So like the transfer of genetic material through all these different strategies, but humans have been a huge helping hand in the geographic spread of this. Bacteria can only move so far, Aaron. It's true. It's very true. Okay, so, Erin, you asked how did we get here? Yeah. And like you always do.

I always do. And I think that's really the perfect question to ask about antibiotic resistance because only by understanding what has driven the rise of resistance, are we going to be able to have a chance of slowing it or stopping it? And you're going to talk a little bit about what here actually looks like in terms of how do we get here. Right. But, spoiler alert, it is absolutely terrifying.

Yeah, it's not great. That's an understatement. It's an understatement, yeah. So we see widespread, multi-drug-resistant bacterial species across the world. And for many microbes, our options have completely run out. Like we are back in the age of before antibiotics. So far, with maybe one or two exceptions, this seems to be a one-way street. So, like, resistance seems to be only increasing. And we've stopped asking the question, will antibiotic resistance

emerge against a particular antibiotic? And now it's just a matter of when will it emerge. And this state of things has been a long time coming. And this massive increase in antibiotic-resistant bacteria should not have come as a surprise to anyone. And for many people, it didn't. So in 1945, the same year that he was awarded the Nobel Prize for his discovery of penicillin, Alexander Fleming warned about how easy it was to make microbes resistant to penicillin. And I don't know if I quoted this directly in the Mercer episode. I think that you did, because we have definitely quoted this before. Okay. It's a great quote. Okay. I don't know if it's the same one because there were a few that I was choosing between. So we'll see if I was

consistent in my choices. Okay. So he said specifically about improper use, quote, the greatest possibility of evil and self-medication is the use of two small doses so that instead of clearing up infection, the microbes are educated to resist penicillin and a host of penicillin fast organisms is bred out, which can be passed to other individuals and from them to others until they reach someone who gets a septicemia or an ammonia, which penicillin cannot save. So, like, this was in 1945. This was a couple years after it was, after penicillin was introduced to soldiers, and like a year after, or the year, it was released to the public. So, you know, like we saw it coming. We saw it coming. Despite these warnings, penicillin was everywhere. It was available over the counter in the U.S. until the mid-1950s.

And like we said, is still available without a prescription in many places. it was put in cough drops, throat sprays, mouthwashes, soaps, you name it. Oh my gosh. At one point, Erin, it was even available as like a powdered daily dose human growth promoter. Stop it. Yep. Like a powdered penicillin. Emergency penicillin?

Emergency protein powder, just whatever. Oh, no. Just pop that into your antibiotic-laden milk. Oh dear. Yeah. And even though regulation slowly increased, it didn't do so uniformly, right? And even today, antimicrobials or antibiotics can still be found in products you never would have expected them to. And their use is still incredibly widespread and not as well monitored, especially in some places.

Yeah. Yeah. You know, and as we've said a thousand times on this podcast, pathogens don't respect political boundaries. So the rise of an antibiotic-resistant strain of bacteria somewhere is a rise everywhere. Right. The story of the rise of antibiotic resistance itself is pretty simple and pretty repetitive. You develop a new antibiotic, and then depending on how effective it is and how broad its targets are, it becomes the hot ticket item. is widely used. And then there's a ton of selection pressure. And so resistance develops. And then

resistance spreads quickly as well. And then that antibiotic is no longer the miracle drug that was promised and gets resigned to the back shelf. The microbes win. Another antibiotic comes along. Resistance develops. It gets shoved to the back shelf. Another antibiotic? More resistance. Rinse and repeat. This has been going on since the creation of penicillin. And since that time, there have been more than 150 antibiotics that have been developed, and resistance has been found for all or nearly all of them. I watched a documentary called resistance that I really enjoyed, and I'm going to borrow one of the graphics that they presented and put it in audio form as a way of illustrating the rise of resistance, because it's kind of amazing to see just how quickly it became

widespread. Yeah. So, okay. Sulfonamides introduced 1935. resistance detected 1940. Penicillin, 1942, introduced resistance 1945. Stereptomycin, introduced 1944, resistance 158. Tetracycline introduced 1948, resistance 1954. Chlorine phenocal, introduced 1949, resistance detected, 1956, and so on and so on. Like this goes, I could list this with like 10 more antibiotics that you would recognize by name. It's incredible. And so it became increasingly apparent, obviously, as we are aware today, that resistance is inevitable. It's just like Thanos. I'm just kidding.

Another reference. Another Marvel reference. But resistance is what we expect. And the discovery of plasmids and the ability of bacteria to transfer genes not just within species, but across them in the 1950s is when those things were kind of discovered or developed, that helped us a lot in terms of understanding the mechanism and how these bacteria were able to gain resistance so quickly and how it could spread so rapidly. But still, enthusiasm for these miracle drugs and maybe like our own hubris that we could, oh, we'll just keep going digging in the soil or we'll go here and there and we'll just

keep finding new soil bacteria to make new antibiotics, like that maybe also blinded us to the horrific implications that these discoveries carried, right? The development of antibiotics in the 20th century was arguably the most impactful, or at least one of the most impactful medical advancements that we have ever seen. Like, it must have been incredible. Yeah. But within a matter of decades, we seem to be witnesses. the rise and fall of these wonder drugs. So the big question is, where did we go wrong?

The short answer is through overuse or improper use in both medical and agricultural settings. Yeah. So let's dive a little bit deeper into each. As we are want to do. Let's start with the medical side of things. As I've mentioned before, once they came onto the seen, antibiotics were indiscriminately used for anything that might be, could be, possibly was a bacterial infection. And they were even used preventatively, right? And they still are used preventatively. That's true, actually.

We still. In surgery and stuff? Yeah. Yeah. It's like in surgery, though, it like really reduces mortality. Right, right, right. And so, yeah. And so I think one thing that I want to get across is that antibiotics still should be used.

Right. Like, they're not bad things. No. hugely important, but we need to really consider how we use them so that we save them for when we really need them. Right. So it's sort of proper use, right? Not saying it's reducing their overuse and turning improper use into proper use.

Right. Yeah, yeah. Totally. Because resistance will continue to happen, but at least we can slow it down a bit. Okay. So on the medical side of things, I see this falling into three different issues. So the first lies with improper prescription. And so particularly in the earlier days of antibiotics, this was a huge issue, but it also

has continued to be a huge issue because there sometimes might be a thought that like, okay, if there's a 95% chance that an infection is viral and a 5% chance that it's bacterial, you might just want to prescribe that antibiotic anyway because if it's bacterial, then you could wipe out that infection and reduce the suffering of your patient. And if it's not, well, what's the harm to that patient? It's thought on an individual patient level scale, right? And that makes sense. And jumping ahead a bit, a study showed that in 2010, 80% of primary care doctors and 70% of emergency room doctors were prescribing antibiotics for acute bronchitis, which is viral.

Almost always. Almost always. And so then that's what we get into the almost always issue. So it's sort of a matter of treating the individual versus considering. the group as a whole. It's a very tricky decision. It's a very tricky situation. A thing I think a lot about because my whole background is in public health and like thinking about these things on a population level. And now I'm going into medicine where you're like concerned about the patient in front of you. And there's often a conflict between what's best

for the individual patient and what is best for the public. And it is a tricky landmine. Mm-hmm. Mm-hmm. Yeah. Yeah, and I'm not going to talk about what we should do and the ways we should change it, but I think the consensus is that we do need to change sort of the directives of this. Yeah. We need to change how we use them. Like antibiotics are also not benign, right? Like we talked about this in the last episode.

They have side effects, right? They're wiping out your microbiome. They're going to cause side effects. So they're also not benign to give a patient, to give a person. and antibiotics if they don't really need them. Right. And this is something that we're becoming more and more aware of. Right.

As we talk about the microbiome and some antibiotics, like you said, are also toxic in themselves. Like they have, they damage certain organs. So it's, yeah. And then there's also just sanitation issues within hospitals. So, I mean, when you're in a hospital, the rate of people that have infections, it's high. Like, infections are very high there, very prevalent.

And this is talking about drug-resistant and antibiotics-s susceptible infections. And this makes transfer between patients really easy. And this just speaks to the nature also of how equipped these bacteria are to keeping their foothold in a place and surviving. Like some of these are really, really difficult to get rid of. Yeah. And so a hospital just provides tons of opportunities for bacteria to exchange info and to settle onto the skin or into the surgical incision site or into the intestine of someone who happens to be in the hospital.

Finally, there's the third issue, which is that people who are prescribed antibiotics might not take them properly. So they might not finish their course. By that, I mean, if you're prescribed 10 days of an antibiotic and you only take five because you start feeling better, all you've done is kind of train the bacteria in your body to become resistant. And so if that happens and you get severely sick and then you have to go to the hospital, hospital, and then you're bringing your drug-resistant bacteria into the hospital.

Yeah. Which is like, come on, which is not good. And then that same 2010 study that I mentioned just a little bit ago, they also showed that up to 40% of people fail to complete their full course of antibiotics. Oh, yeah. And so these three health care issues have been a part of what is driving antibiotic resistance in hospital and community settings. And for the most part, I have to say that it doesn't, like, we have to.

made some forward progress in terms of regulating them, but we still have a long way to go. Okay, that's just the medical side of things. We're only getting started. No, this is horrifying. Because even if tomorrow we enacted all of those changes, it might slow down the spread of resistance in healthcare settings, but it wouldn't stop the problem entirely. And a small part of that is due simply to the nature of resistance. It's due to this arms race of bacteria and antibiotic compounds, resistance will always evolve. But another huge part is improper antibiotic use in agriculture. And we talked a bit about this in the last episode, but I want to go more into the history of this, since it's such an integral part of the story of resistance.

So this history starts with yet another chance discovery when a researcher was looking for a natural source of B12 to supplement the food of chickens to help them grow better. Okay. So he learned that streptomyces areopacens produces vitamin B12 during the fermentation process for making streptomycin. So he was like, hey, can I have some of that waste from fermentation, just like the leftover gunk or whatever? I'm going to mix it into the chicken's food and just see what happens. Okay. And the results were remarkable. Like the chickens grew tremendously much faster than he expected due to just B12. And so did the piglets that he also tried it out on.

He was like, okay, is it actually the B12 that's in the fermentation waste or is it trace amounts of the antibiotic that's causing this growth? And maybe he was like, well, maybe it's suppressing gut, like harmful gut bacteria or something else. Like regardless of the reason, he couldn't deny that they were actually having an effect. So on average, livestock that were fed these growth promoters grew three to 11% faster than their non-anibiotic-ridden counterparts. But I've seen actually much higher rates quoted particularly early on in these experiments. Oh.

And this led to because you could make more meat faster, you could sell more meat. And so consumption overall really grew. And then it kind of in that way firmly established these. growth promoters, so-called growth promoters, as a necessary part of agriculture. And so I'm going to use the term growth promoters a lot. And that basically means these trace amounts. So like non-therapeutic doses of antibiotics that are included in food for animals, like agricultural animals, livestock. Okay. Okay. So these antibiotic laced foods plus preemptive treatment, so like not just as growth promoters, but actually like, oh, we're going to dose you.

that you don't get this or that ulcer or whatever. That led to some farmers just packing them all in, all these animals in as tightly as possible because they were secure in the knowledge that the crowd diseases that they had previously been worried about wouldn't be much of a concern with these antibiotics. And so it really led to the rise of like the industry, some of the more the nastier sides of the industry that we see. Wow. Yeah. Yeah. I did not know that part of it. But that makes so much sense. Mm-hmm. Mm-hmm. And the drug companies that were producing these antibiotics ate it up, or rather they were

enthusiastic about the livestock eating up their antibiotic fermentation waste products. Because this was all stuff that was like, they were just throwing it away anyway. So it's great for them. So sub-therapeutic doses of antibiotics were sold as growth promoters starting in the 1950s, and the huge threat of antibiotic resistance had been known and discussed for at least a decade before that. And this basically provided the perfect breeding ground for antibiotic resistance. Because if you think about, like think about an industrial farm full of pigs packed in, you know, all close to one another. And then they're all just with antibiotics. Like bacteria, they can move so easily that way. Resistance can move so easily that way.

Like, it's, and manure is one of the best sources for antibiotic resistance bacteria, apparently. Gosh. And then there's runoff. Okay. Anyway. And it wasn't just restricted to growth promoters and food. Farmers began toying with different ways to deliver the antibiotics to the animals. So they were like in the water before they were slaughtered.

Like, here's some water. Injected, injected into the areas for prime cuts. What? painting, painting raw steak with antibiotics, or mixing them in with ground beef. I'm sorry, why would you mix it in with the meat that you're selling to humans? What is the purpose of that? Well, because then it has a longer shelf life. Are you kidding me?

I'm not kidding you. Oh. Dude, spinach was even washed in streptomycin. I'm so serious I don't ever want to eat anything again chickens were literally sold in antibiotics because that would lengthen their shelf life

my face so like you could squeeze out like the chicken juices from a raw chicken at the grocery store back then and you could get like antibiotics in those juices The world got its first taste of how the use of antibiotics on farms bled into human life in the 1950s, around the same time when it was first started to ramp up. Around this time, penicillin had been made prescription only in the U.S. and in Britain,

partly because the rates of penicillin allergy were just like skyrocketing. And so with these increased regulations, physicians and epidemiologists expected to see fewer penicillin allergies crop up. Makes sense, right? No, that's not what they saw. Instead, they saw an increase. They saw surge. And it turns out that the source of the penicillin, this is done through like a lot of

detective work, the source of the penicillin was in the milk that people were drinking. Some milk contained so much penicillin that it could have been sold as a drug. Milk. It was therapeutic doses, yes. Grody. So this finding led the FDA, at least to rule that you could no longer treat meat with antibiotics prior to it being sold. Okay, so like my stakes are not washed in antibiotics anymore? No, no.

That's all done. Small blessings. Yeah, but yeah. This did nothing to stop the addition of antibiotics in feed for animals as a growth thing. promoter. And then there was a series of studies in 1960s that clearly demonstrated that growth promoters led to the rapid development of resistance in microbes, colonizing both the animals, as well as the people working with the animals.

So this was kind of a cut and dried, very eye-opening experiment. Fortunately, this was taken somewhat seriously by governments. So the UK took action early on in limiting antibiotic use and agriculture. culture. Starting in 1971, they banned antibiotics as growth promoters if those antibiotics were used to treat disease in animals and humans. Okay. So like you can no longer use tetracycines because we use those to treat disease. For example. Yeah. Okay. Got it. And you had to have a prescription for them if you wanted to use them therapeutically. Okay. And the U.S. was like this close to following suit. Oh dear. But, you know, we didn't.

A little bit after this decision in the UK, the FDA was like, I'm going to lay down the law, and we're going to limit the use of antibiotics purely to therapeutic purposes. But then the mighty dollar of the agricultural industry overruled. Representative Jamie Witten, who was like part of the spokesperson for this industry, basically, said that he would hold hostage the budget of the FDA if the regulations passed. And so because he has to be. Somehow he had that power, Aaron. I don't know. So the White House gave in, since the budget holdup would have also hurt many other important projects. And so Witten, this representative,

insisted that the data in support of banning the use of non-therapeutic antibiotics and agriculture was incomplete and biased against farmers. And so then they were like, okay, well, we want the farmers, we want the agricultural industry to design their own projects and do their own research to figure out what the truth is. Oh, there's no bias there at all. Right. I mean, the burden of proof has been on epidemiologists and researchers to find that antibiotic use in agricultural settings leads to antibiotic resistance that is clinically important in humans.

Yeah. Right. But this insistence that those studies were inaccurate or that the research was incomplete was just a flat-out lie. Because in the 1970s, a researcher named Dr. Stewart Levy wanted to see how rapidly resistance could develop or spread in livestock given these growth promoters. So he tested out some young chickens who were given tetracycline. Within 36 hours of first being given the feed laced with tetracycline, their gut E. coli was resistant. 36 hours. So that's scary enough. And tetracycline is like, was a broad spectrum, just like awesome, widely used drug.

Was. Was. And so that's scary enough on its own. But what made it even scarier is that over the next three months, the E. coli also added to its arsenal genes that made it resistant to ampicillin, streptomycin, and sulfonamides. And the chickens had never even received any of those drugs. Whoa. The tetracycline.

And it acted like a call to arms for these bacteria. Like we've faced and defeated one antibiotic, so we need to be prepared for any others that might come our way. Man, oh, man. And I bet you didn't think that the study could show even more concerning results, but it did. And you're not going to be surprised by them. But Levy found the same antibiotic resistance in the gut e coli of the farmers and the families of those farmers that had kept the chickens. None of them had received tetracycline. Right.

There have been literally dozens, dozens and dozens of peer-reviewed articles demonstrating clearly that antibiotic use in animals impacts humans. Two epidemiologists and physicians and microbiologists and biochemists, whether or not rampant use of sub-therapeutic levels of antibiotics was leading to a huge increase in resistance and resistant organisms, that wasn't a scientific question. Right. It was firmly established that it was. Instead, it was a political one.

Does it sound familiar? Sounds too familiar, Aaron. Yeah. And despite the strong evidence that growth promoters also promoted antibiotic resistance and all of the terrifying implications that came along with it, the U.S. declined to ban tetracycline as a growth promoter. It, along with many other antibiotics, continued to be used freely for decades in live. stock. You said for decades, are you going to tell me some happy news at the end of this,

like no longer or what? There are some bright moments. And there's some really cool little case studies that I won't go into, but I'll mention and I'll mention places to read further about them because Denmark and Netherlands, who, who, okay. And just because a country had stricter regulations doesn't mean that they weren't also contributing to the resistance problem. A lot of the time, there wasn't much regulatory oversight into just how much antibiotics were being sold to agriculture. And when there was sort of a retrospective look at the amount over time, like a number of tons or millions of pounds sold over time, there actually wasn't really a decrease after some of these bands were put into place,

because the labeling just changed for a lot of these things. Another issue was that these bands, like I mentioned, often limited use of antibiotics to those that weren't also used to treat animal or human infections. But this is also a problem. And that's because as resistance to the most common antibiotics grew, doctors had to reach increasingly to the back of that cabinet it for the third and fourth string antibiotics that had been deemed too toxic or too specific or too expensive to be used.

Vancomycin was one of these antibiotics. So it kind of came, it was one of the earlier ones that had been discovered and developed, but it was deemed to be too expensive and had some nasty side effects. So people were like, no, no, we'll just use metacillin instead. And so in the. 1980s, it was dusted off and increasingly used to treat stubborn resistant infections. And it seemed to be remarkably effective in that microbes weren't showing resistance towards it. So that was promising. And some researchers were like, okay, well, how exactly does it work?

And they were like, it's so complex that it would be nearly impossible for a bacterium to develop all of the genetic changes needed to overcome this mechanism. It's like an unsinkable ship. Like, why do we say these things? It's just tempting fate. In 1989, the first strains of vancomycin resistant enter a cocky, VRE, started popping up in hospitals in the U.S. And by 1993, it was close to being endemic in many hospitals. VRE, baby.

VRE, baby. It's really bad. Within five years of first showing up, VRE was widespread. spread in the U.S. Something that it took Mercer about metacillin-resistant staphoreas, about 15 years to do. So they were like, what the heck? This is super complex. So how could there have been enough time that has passed for these mutations to actually

emerge? Like, what is going on here? What happened? Turns out the answer is in agriculture. A vancomycin-like antibiotic had been used as a growth promoter in life. livestock for decades. Oh, gosh. And so when physicians started to reach into the back of that cabinet for vancomycin,

the resistance genes were already long present and quite prevalent. And then with that added selection pressure of being used in a clinical setting, it just spread like wildfire. And bad turned to worse when in 1996 the first vancomycin-resistant staff ORIUS VRSA infections, infections emerged in Japan. At this point in time, about 50% of all hospital staphoreas infections were methanol resistant, so treatable only by vancomycin. Within the next few years, Versa was basically everywhere.

And again, there was still lobbying for the continued use of vancomycin and other antibiotics as growth promoters in the U.S., and those lobbyists still refused to acknowledge how those practices could lead to resistance. So Robert Carnival, who is one of these lobbyists, is quoted as saying, I'm sure VRE can transfer from animals to people and it might be resistant, but is it of clinical importance? Yes. Yes, it is. Yes. Oh, gosh. And it wasn't just vancomycin resistance that agriculture was promoting. Calliston was another one of those antibiotics that had been put aside in favor of more sensitive drugs in the past. And it had also been used in agriculture. And so resistance was already super high there.

And it wasn't just resistance genes that spread from agricultural settings to hospitals or communities. People realized it was also the bugs themselves. Epidemics of expec, which I can't remember what that one is, but it's some sort of E. coli, toxic E. coli. Yeah. These UTIs caused by XPEX, they seem to be coming from food, specifically chicken. Oh, gosh. Quinelone-resistant salmone-resistatea-myrium strain DT-104. That's a bad one. That's spread through fresh dairy and can kill you. And that came directly from animals.

And quinolone-resistant campelobacter, that was found in grocery store chicken. Oh, gosh. So quinalone had been used in agriculture for years, but the sharp alarming rise of resistance to it prompted the FDA finally to propose a ban, propose a ban, for their use in animals. But a proposal was just a proposal. Some drug companies, including Bayer, declared that it would not comply voluntarily. So it would fight the proposal and ask for a hearing where it could show that quinolone use in animals was of no harm to humans. I'm just getting too depressed, Darren. I know. Okay.

But in the late 1990s, there's a little shining sun. The European Union moved to ban antibiotics as growth promoters, like all of them. Okay. But preventative use was still allowed, which still promoted resistance. Again, there didn't seem to be any decline in the amount of antibiotics sold for farm use. So from 1999 to 2006 and beyond, it stayed at 606 tons. per year. This is after the ban, right? However, some countries did actually do it on their own, and some countries, like in Denmark, the industry did it on their own themselves. They were like,

we're not going to, we're not going to list. Like they were just decided amongst the community and the farmers that they were going to do this because they were like, what's right for, you know? Social responsibility kind of a thing. Yeah. So the Netherlands, for example, really doubled down and started policing the use of antibiotics much more. And the result was that antibiotic use on farms actually declined dramatically, starting in 2013. And really cool, the occurrence of antibiotic-resistant bacteria found in meat also declined. And similar things happened in Denmark as well. And all of the horrible repercussions that had been promised, like a drop-off in the weight of livestock, sky high meat prices, more disease among livestock.

None of these things happened. The weight dropped a bit, a little bit, but it had been recognized for quite a while that growth promoters were no longer achieving the same dramatic gains that had been seen when they were first used. Oh, no, that's interesting. That is very interesting. So somewhere in the five or six decades, since antibiotics were first used in agriculture, they had lost their magical ability to promote growth.

So a couple of different things. It's probably likely that when they were first used, the antibiotics were compensating for some of the negative ways that the farms were run. So like as hygiene and monitoring and nutrition and breeding had changed, it had eliminated that gap that growth-promoting antibiotics had made up. And it's also possible that if it was affecting the negative, the harmful gut bacteria or whatever gut bacteria, that resistance had emerged. And so antibiotics were literally just doing nothing.

Doing less, yeah. Yeah. And by removing antibiotics from agriculture, places like Denmark and the Netherlands incorporated animal welfare into the business model. And with that, they improved quality, quality of life for the animals, quality of meat for consumption, quality of their investment, et cetera. But once again, the U.S. failed to make similar regulatory progress as Europe. In 2015, 34.3 million pounds of antibiotics were sold for use in animals compared to approximately 7.7 million pounds for humans. But even though

the U.S. government agencies were slow to stop the overuse and misuse of antibiotics, some companies actually voluntarily stopped using growth promoters because they realized that antibiotics for growth promotion may not be worth the cost for human health or the cost of the constant legal battles. This industry shift paralleled many others that were going on in food supply arenas. So it was one after another, both from the, you know, meat providing side of things. so these big name chicken farms to the food supply aspect, so like fast food restaurant, stuff like that, they were all starting to offer antibiotic-free meat options.

And so the market seemed to be responding positively to these changes. But that's all on the industry side. So even though starting in 2012, the U.S. has put in some regulations for monitoring the use of antibiotics and agriculture. for many years, the amount of antibiotics has actually increased rather than decreased. 2017 did see a decrease, but it doesn't seem 100% clear why that decrease happened. Maybe it's because of these bans, and that would be great. But antibiotic resistance and its association with agriculture is a perfect example again of why a one-health approach is essential.

humans and animals share one bacterial and viral world and fungal world and protozoal and parasitic, whatever. So the rise of antibiotic-resistant bacteria on farms means a rise of antibiotic-resistant bacteria everywhere. Just like with the medical side of things, there is such thing as proper use of antibiotics in agriculture. But there has been overuse in terms of growth promoters and in terms of pre-embrance. treatment, and it has remained a debate and a challenge to kind of see what the cost and benefits are. And I think we're only becoming more and more aware of the cost to humans. And it's also not going to just be antibiotic-resistant infections in humans. It's also going to be livestock as well. So it's an interesting thing to think about anyway. But it's not just the U.S. where overuse is an

issue. So in 2015, a group of researchers tried to predict how much antibiotics Brazil, Russia, India, and China could be predicted to use in the next 15 years as demand for meat continues to increase. If nothing changed, that estimate was 105,596 tons globally. Oh, dear. That's hard to wrap your brain around. the annual numbers of antibiotic resistant infections and deaths due to those infections are absolutely staggering. The history of resistance is like actively still being written and it's not looking good. I want to, I mean, there are some promising avenues of research ahead of us, but I want to end with a quote from the amazing book Big Chicken by Marin McKenna.

Antibiotic resistance is like climate change. It is an overwhelming threat created over decades by millions of individual decisions and reinforced by the actions of industries. It is also like climate change in that the industrialized West and the emerging economies of the global South are at odds. Well, with that, Erin, tell me where we stand with antibiotic resistance today. Are we basically on the brink of returning to a pre-eastern? antibiotic era? Is there any hope? I mean, let's find out. I need a short break. Yeah, same. Let's start with the depressing things and then we'll end on a at least hopeful note. How about that? Great. Okay. All right. So medically, in the U.S., at least, the CDC estimates that at least 40,

million antibiotic prescriptions in the U.S. each year currently are unnecessary. What? So we're doing great. Okay, what does unnecessary mean? Means, I don't know for sure because that was just a stat taking off their like antibiotic resistance general page. But in general, unnecessary means either not the right antibiotic for the infection or using an antibiotic to treat a non- on bacterial infection, right? You wouldn't expect ever to see zero, right?

Because if somebody comes in and they have, you know, some infection but you don't know what it is yet or you suspect it's a bacterial infection, you're going to try different antibiotics, right? And so that would be included in that. I'm just trying to wrap my brain around this 47 million number. Yeah, it's a good question. I don't know if that includes like every time that you give vancenzosen in the ER, which like everyone who comes into the ER gets those two antibiotics.

at first, right, when we don't know what they have yet. Right. So I don't know if that's included or if that's just prescriptions, like outpatient what you get, what you get sent home with. Either way, it's terrifying. I mean, 47 million. Oh, yeah. So that's in the U.S. Also in the U.S.

It's estimated that more than, and this is very recent data, so this is from a report that came out at the end of 2019. It's estimated that there are more than 2.8 million. antibiotic-resistant infections in the U.S. every year, that result in more than 35,000 deaths. Wow. So 35,000 people a year are dying in the U.S. because of antibiotic-resistant infections. Do you have global numbers? Great question. I tried really hard to get solid global numbers. It is very, very difficult. So the World Health Organization has set up in, I believe, 2015, they set up the global antimicrobial resistance surveillance system, which is basically every country setting up their own surveillance system. So I think now it's over 60 countries that are reporting their

antimicrobial resistance data to the World Health Organization. But they don't seem to aggregate that data and present it as overall numbers. Overall, World Health Organization estimates that in many parts of the world, over 40% of bacteria, infections are with bacteria that are resistant to antibiotics. But I don't have numbers on deaths. I do have numbers in the EU. In 2015, an estimate from the European Union was that 671,000 infections were likely antibiotic resistant, and that likely resulted in 33,000 deaths in 2015.

Oh, my gosh. So that's in the EU. But a lot of the increase in antibiotic use is in low and middle income countries. And we don't really have good data on the number of resistant infections worldwide. But it's bad. It's not good. It's a lot. So I have two questions.

Okay. The first question is about in the U.S., are antibiotic resistant infections reportable? Like, are you required to report them? That's a really good question. I don't fully know the answer to that. So there's the CDC, that report that came out in 2019 has a list of like the most concerning pathogens, right? And the World Health Organization also has a list of what their pathogens of greatest concern are. And those lists mostly overlap.

So I would think that most of those pathogens are going to be reportable in the U.S. Okay. But that doesn't mean like every time that, for example, someone comes in with a UTI. If you do a urine culture, you might send that culture off to see what the resistance profile is. And that bacteria might be resistant to a few antibiotics. So then we use that to choose what antibiotic we give to that person. But I don't think that we then report that necessarily to the CDC. It probably goes to the local public health district so that we can keep track of what the general antibiotic resistance looks like in our area.

Gotcha. So hospitals keep track of things like that. Okay. So I will say that a report that came out in 2014, which is earlier than most of the data I was hoping to find, estimated that currently worldwide, there are 700,000 deaths attributed to antimicrobial resistance worldwide. That is a lot. It's a lot. And they projected that out and estimated that by 2050, that number would go up to 10 million deaths. Oh, my God. If we do nothing.

Like if we just continue on the same pathway. Yeah. Oh, my gosh. Yeah. And then they also estimated what the overall cost, like the monetary cost of that would be, that it would cost the world up to $100 trillion. $1.microbial resistance. Yep. I can't. I can't comprehend that number.

Me neither. Wow. I was really hoping to find more recent, like, hard data on antimicrobial resistance. And I came across a paper that came out in 2016 that really highlighted some of the issues that we have and even trying to get a handle on this burden of antibiotic resistance. because that number, that estimated number of deaths, like it's such an estimate. We really don't have solid numbers on that. Well, and then I also, you know, my other question was about how do you attribute cause of death? Exactly. And so that's, yeah.

So like if you're in the hospital and you go in for like a routine surgery, like appendicitis, and you get MRSA and then you die, is that MRSA, is that. appendicitis. Right. Exactly. That's kind of exactly what they were highlighting in this paper. We can't calculate the number that we really need to calculate to know the number of deaths attributable to the failure of antibiotic therapy due to antibiotic resistance because we don't know enough about the rates of resistance or the rates of infection for so many different infections. You have so many things like diarrhea that can be caused by so many different pathogens. So, like, yeah, it's a really complicated big picture question.

But there is no question that it is leading to death and is horrible. Yeah, it really is. And it's a very multifactorial problem. Like you mentioned, Aaron, there's a number of different factors contributing to this, right? Inappropriate prescriptions. Misuse of taking those antibiotic prescriptions, agriculture, poor sanitation in hospitals. So I will say that all of the kind of action plans that CDC and WHO and all these different organizations, they're very holistic plans, right? They recognize that this is not going to be solved by just one change or even a few changes.

It's a whole bunch of different solutions that are going to be required for this problem. But one thing that it's definitely going to take are new methods of treatment. Because for many pathogens, resistance is all. already here. So we need new ways to target these pathogenic bacteria. And we do. And this is where we'll have some shining moments of hope, okay? Yay. The good news is there are so many people working on the issue of antibiotic resistance from a treatment standpoint. You heard in our last antibiotics episode about a group that's working on new methods of identifying antibiotic compounds using machine learning, which is so cool. I love it so much.

It's amazing. It's literally unbelievable. So cool. There are a number of other groups working on alternative therapy strategies as well. There's some really promising data on probiotic therapy, which I think is awesome. So basically boosting gut microbiomes to try and both treat and prevent toxic infections. Fecal transplants. Fecal transplants. So probiotic therapy is a very cool. I feel like we'll probably talk a lot more about that in a microbiome episode. But you should definitely Google fecal transplant. Oh, for sure. It's so cool. There's also a lot of work being done on combination therapy. So whether that's combinations of an antibiotic and another molecule that blocks a normal resistance mechanism to that antibiotic, like Augmentin. That was an example I gave early on. Or whether it's giving a number of different antibiotics in combination that have different mechanisms of action, which is how we are.

treat things like tuberculosis, for example. Right. Which, by the way, I know we touched on this in the tuberculosis episode, but like multi-drug or extremely drug resistant tuberculosis is terrifying. Erin, tuberculosis is so terrifying that it's not even included on the lists of the terrifying bacteria because it's like its whole own version. Like, we've known about resistance in TB for so long. Like, we don't even need to include it on our list. Oh, gosh. The escape list. Is that what you're talking about? Yeah, I didn't even mention the names of any of them, but I got ahead of myself. So some of those pathogens include enteroccus, feccium, staff orius, clobsiola, ascinetobacter balanii, pseudomonis, and enterobacter.

Those are the six that are really commonly, like, the big escape, I think just because they make a nice acronym. But there's really at least 12 that we need to be concerned about. But we don't care about the other six just because they don't make a good acronym. They don't make a good acronym. H. Pylori. M. Kampliobacter.

Gonorrhea, salmonella, strepnumo. You know, there's a lot. There aren't enough vowels in there. I know. That's why they're not included. We do care about all of those. Oh, especially gonorrhea, man. Oh, my gosh.

Yeah. So there's a lot. There's also a lot of work being done on antimicrobial peptides. There's work being done on stimulating the immune response and using our own immune system to better fight off infection. There's the use of things like iron scavenging molecules. One of the coolest areas and one that I've been most excited to talk about for a while now is phage therapy. Phage therapy. We briefly touched on it in the Mercer episode. Very briefly. Very briefly. Too briefly. Far too briefly. And so who better to tell you about the status of phage therapy research than the provider of our first-hand account who literally treated her own husband with phage therapy and also studies it?

Dr. Stephanie Strathie. Well, thank you so much for taking time out of your day to chat with us. We're really excited about this episode and thrilled to get the chance to talk to you. We'd love for you to kind of give us first, maybe a brief overview of what phage therapy is for our listeners and kind of how it works. Sure. Well, phages are viruses that have naturally evolved to attack bacteria. They're like the perfect predator for bacteria. They've actually co-evolved for four billion years. They're the oldest and most ubiquitous organism on the planet. And it's thought that there's about 10 million trillion trillion. That's 10 to the power of 31 for you numeric mathy people out there. And so they're everywhere. They're on our skin. They're in our guts.

We poop them out. They're in water. A single drop of water can have trillions of phages in it. We just haven't been able to understand what they're like because they're so small. They're about 100 times smaller than bacteria. And they were discovered in 1917 by a French Canadian named Felix de Heral. And, you know, he deduced that these must be viruses that are parasites of bacteria, even though you couldn't see them until the electron microscope was developed in the early 1940s.

And people actually had a big debate as to whether or not these were proteins or whether they were viruses or whatever. And De Harel himself was quite a character. He was very egotistical. He wasn't formally trained. And he was really pushed to the margins of society and the medical field. And then when he helped the former Soviet Union develop the first phage therapy center in the world, it got the label as Soviet science. And this was around World War II.

And of course, that led to a big geopolitical bias of like Pinko-Kami science. plants and that put a cloud over phage therapy for decades. And so that's one of the reasons why the West really abandoned it. And of course, penicillin came on the scene in 1942, even though it was discovered in 1988. It had been, you know, it took some time to come to into the field. And that was because it was needed on the warfront. And so people thought antibiotics or wonder drugs.

And of course, they were for a while. but antimicrobial resistance has just continued to outpace us. And nobody's really been paying attention to that until, you know, we get these people who are having, you know, minor scrapes or surgeries. And we realize, oh, my gosh, they got a super bug and there's nothing left to kill it anymore. Could you talk us through what a typical course of phage therapy might look like? So how do you even go about finding the right phages and then administering them? Well, the thing about phages that's both a blessing and a curse is that they're really finicky.

They only match to specific bacteria. So for an organism like Staphylococcus, which, you know, one of the strains is Mercer, right? Methacillin-resistant Staphorius, that's the superbug that was discovered first. Maybe about 20 to 30 phages will cover the majority of circulating strains around the world. and that's pretty good because you don't need that many of them and maybe you could have like a cocktail of phages that would you know cover the majority of those infections but for superpugs like thoms acetatobacter bomaniae it's very very specific so the phage um not doesn't just have to match the genus in the species it has to match the isolate so tom's bacteria so that means you have to like essentially look for a needle in a haystack. But it's a little worse than that because when you think about where there's a lot of bacteria, that's where you're going to find a lot of phages. So if you need to go on a fage hunt, you have to go to some of the worst places around. And we're talking like sewage,

barnyard waste, scummy ponds, that kind of thing. So the phages that were actually used to treat Tom were from so I can say literally that my husband is full of I mean, who could get to say that to their husband. That's amazing. And then so then once you, if you go in and you, you dig through all that sewage and you get lucky enough and you find that needle in the massive, massive haystack, do you then take that to the lab, culture it? And then what's the next step after that?

How do you actually get it into that person? Well, the old-fashioned plaque assay, and it's actually, this is something that's high school and freshmen learn how to do. You have a petri dish, say, with your bacterial lawn or your bacteria streaked on it. And if you want to see that if you have phages that are matching to that bacteria, you put a drop of sewage on the petri dish and you incubate it for 24 to 48 hours. And if it comes back looking like a little like Swiss cheese because there's holes in the Petri dish, you get really excited because even though you can't see the phage because they're smaller than the naked eye and even smaller than the light microscope can detect, you know that they've

been at work because they've gobbled up a bacterial colony there. So then you can pluck it out and add it to more bacterial suspension and then you need to purify it. And that's the tricky part. There's different techniques to purify phage suspension. But if you're going to treat with phage intravenously, you want to get it as a very much. as pure as possible because if there's a lot of bacterial debris in the suspension, it could elicit septic shock in the patient and could kill them. And that's what we were worried about with Tom's situation. And nobody really knew what the threshold for safety was. So we were taking a big risk. Yeah. So you mentioned kind of how difficult it is to even be able to identify and

find these phages, especially when you're dealing with bacteria where you maybe only have, like, have to find a very specific phage. So could you talk maybe a little more broadly about some of the pros and cons of using phage therapy, maybe in like comparing and contrasting that to antibiotics that we have currently? Yeah, well, the good news about phages is that, again, there's 10 million trillion, trillion phages on the planet. So there's almost an exhaustible supply of them. It's just you need to find the right phages to match the bacteria that you want to kill. So if you have to go back to sewage or, you know, barnyard waste or whatever, every single time you need to treat somebody, that would be a real pain. And obviously, it's very labor intensive and you may not find phages in time.

And we've been in that situation with other patients. But if you have a phage library or a phage bank that's essentially like a walking in cooler where you have thousands of phages and they're already identified and characterized and sequenced, then you can just kind of go in there and, you know, see if the bacteria that you want to kill has phages in the library. So that's that problem about how do you find the phages to match the bacteria that you want to kill can be overcome. Gotcha. So one of the questions I had was about dose and sort of one of the negative consequences of or potential consequences of phages. So like how do you know how much, how many? phages to give. And also, when those phages break apart those bacterial cells, what are some of

the risks associated with that? Well, to be honest, nobody really knows the right dose for phages in most cases. And that's part of the translational basic science research that needs to go on so that we can, you know, get ready for clinical trials. In Tom's case, we just, you know, took an estimate based on his weight and the fact that he had a systemic infection where the bacteria were in every cavity in his body. And we knew that if you underdose, if you give too few phages, the body's own immune system can eliminate them. And the phages might not ever reach their target.

And we thought, well, is there a risk of overdosing him or whoever you're treating? And we talked to experts and they said, you know, we haven't actually, you know, seen any side effects of this, as long as the endotoxin, which is essentially the bacterial debris that is caused when you are growing up a lot of phage in the context of a lot of bacteria. That endotoxin, if there's a lot of endotoxin left, that could kill the person. So again, we haven't seen that, though. We've treated over a dozen patients at UC San Diego and dozens other internationally. Gotcha. Yeah. So you talked a little bit about some of these challenges moving forward with phage therapy,

but let's talk about the bright future. So since the publication of your book, there's been a lot of forward progress in phage therapy and in new initiatives. And so can you talk a little bit about what you see as the future for phage therapy? And also, are there going to be genetically engineered phages for specific infections? Well, yes. There's been a lot of really excited. development since then. The first is that the first genetically modified phage cocktail to be used successfully to treat a human bacterial infection was published in May of 2019, so a year ago from now. And it was an incredible case, just as fantastic as Tom's. This is a young girl, her name's Isabel. I happen to know her now through our connections in Facebook and social media.

She has cystic fibrosis, and she'd had a double lung transplant and had acquired this what's called mycobacterium obsessus. And people who are familiar with tuberculosis will know that mycobacterium tuberculosis, a cousin to this microvacterium obsesses, is the biggest bacterial killer in the world. It almost kills 2 million people per year. And so this is a very difficult to treat pathogen, and she was literally dying. She was in hospice and her mother heard about Tom's case, contacted her doctor.

The doctor contacted some of our colleagues. And we happened to know that there was a fellow named Graham Hatful at the University of Pittsburgh who runs this wonderful training program called C-fages that teaches students how to find fages. And essentially they're doing this fage hunt that I described earlier. And all of the fages that they find go into a giant fage bank. and they have about 15,000 mycobacterium phages. They'd never even dreamed

that they could be used therapeutically. And when asked, they said, wow, we'll certainly see if any of our phages will be a match for Isabella's bacteria. And three of them were, and one was perfect. Its name was muddy. It was found on a rotting eggplant from South Africa by a student there.

And all the students who find new phages get to name them, right? that's part of the bonus. And two of the other phages were the sleepy kind. In our book, I described them as, you know, hitting the snooze button. They actually don't kill the bacterial cell. But that's all they could find. So what they did was they genetically manipulated those two phages by clipping out the repressor gene

in a technique called recombineering, which is, you know, a prequel to a CRISPR gene editing. And it forced those sleepy phages to become the first. phage rage kind of phages that actually kill the bacterial cell. And then they had to convince the UK government where she was living in the UK that this was okay to use. And luckily they went along with it because they said, well, it's not a GMO because you took away a gene, you didn't add a gene. And Isabel received phage therapy intravenously because based on trauma's protocol,

we convinced them that it was safe. she left the hospital within a week. It was just stunning, and she's made a great recovery. She's, I believe she's still receiving phage therapy now, but she's, you know, working. She's finished her A-level exam. She's learned to drive a car. You know, she's dyed her hair purple.

You know, she's like, I believe she's 18 now, and she's doing great. So that case is a landmark because that's the first time that, genetically engineered phage has been used to treat a bacterial infection in a human being successfully. And also, it's the first time that a mycobacterium infection in a human has been successfully treated with phage therapy. And it lends hope that maybe someday we could treat tuberculosis with phage therapy. Wouldn't that be awesome?

That is so exciting. Wow. That is amazing. I mean, and it seems like it's coming at just like a highly, highly needed time. And we need to do something about this, you know, huge, huge and continuing to grow problem of antibiotic resistance. And so, you know, how, how have you felt the receptivity of phage therapy in, you know, academic circles, for instance? Do you feel like it's people are being fairly receptive or is there still some pushback? Well, initially when Tom's case was

started to become publicized. About a year after he was treated, it was presented at the 100th anniversary of the discovery of bacteriophages at the Pasteur Institute. And then the story went viral. I mean, literally, I was getting contacted by people from all over the world, wanting phage therapy. But it was mostly patients in their families. Doctors were very skeptical. And until Chip Schooley started making presentations to infectious disease physicians, that's when they started to realize, wow, this isn't just a one-of. There's several other cases, and it's looking really exciting. And they're very well documented, and Tom's case is published, and several other cases have

been published. Now, of course, the Georgians and the polls have been doing this phage therapy for years now, and there's also interest in their work, and they have extraordinary clinical experience. But it had been really kind of poo-poohed because it was thought of as a Soviet science. And so it's really been a watershed moment for reasons that, you know, I don't completely understand, but the story itself has kind of led to a lot more interest in phage therapy. Pharma's and biotechs have started to get into the space because they realized, too, that with genetically engineered or even synthetic phages, they'll be easier to patent. The NIH, which had traditionally not funded any phage therapy, they've funded now two clinical trials of, Phage therapy, the first is going to be undertaken by our center, IPath, in collaboration with

the antibiotic resistance leadership group, a network of research institutions around the U.S. that had predominantly focused on new antibiotics, but since there's no antibiotics in the pipeline to speak of, they've embraced phage therapy. So we're very excited by that, because that's what we need now. We need clinical trials to advance phage therapy and to first show efficacy. and then we can hope that the FDA will license it alongside antibiotics. We don't think that phage is ever going to replace antibiotics altogether, but it will be an important adjunct,

and it will allow us to reduce the amount of antibiotics that we're using. We've even seen that phage can be synergistic with antibiotics. We saw that in Tom's case and in several other cases, so if we can leverage the power of phage, we'll be using antibiotics more wisely. I'm just happy that our story can, can kind of take a rightful place in medical history. I mean, Tom and I are really privileged.

I mean, if we had been living anywhere else or if I didn't have the connections that I did and wonderful colleagues at our university hospital, you know, I'd be holding, you know, an urn with its ashes instead of his hands. So that was one of the reasons we decided to tell our story because we realized how privileged we are and that most people dying from superbugs

are in lower and middle income countries. and they don't have the resources we have. So my dream someday is to have an open source phage bank that can be accessible to anyone, anywhere. And I'm fundraising for that through IPath. That's our Center for Innovative Phage Applications and Therapeutics. And hopefully one of these days we'll be able to, you know, say goodbye to superbugs. That was amazing. We were so excited to speak with you.

Thank you so much for taking the time to chat phage. So cool, so cool, so cool. The coolest, the coolest. Aaron, do we have anything else or is it time for sources? This was such a fun episode. Let's cover sources. Let's do it. I think I might have mentioned a couple of times the book Big Chicken.

Just a few. Just a few by Marin McKenna. It's great. It's about the use of antibiotics in agriculture, particularly the chicken industry. And I also read a few papers that I will put on the website, but another book that I read is called The Killers Within, The Deadly Rise of Drug-Resistant B. B. Schneiersen and M.J. Plotkin. And finally, you guys should definitely check out Dr. Strathie's book called The Perfect Predator,

a scientist race to save her husband from a deadly super bug, a memoir. So good, you guys. So good. So good. I heavily used actually the same book that I used for the antibiotics. episode edited by Rosaline Anderson at all called antibacterial agents, chemistry, motive action mechanisms of resistance and clinical applications. And then there's another great paper from 2016 called Mechanisms of Antibiotic Resistance that I will link to, plus a whole bunch of papers on the kind of current status of antibiotic resistance. And we'll link to all of our

sources from this episode and every episode on our website. Yes. Thank you again so much to Dr. Strathie for coming on and chatting with us and telling her story. We really appreciate it. So, so much. Thank you so much for taking time to speak with us. And thank you to Bloodmobile for providing the music for this episode and all of our episodes. Yes. And thank you to you, listeners, for listening. We appreciate it. 51 episodes long. Now we can continue our excitement. Awesome. All right. Well, until next time, wash your hands. animals. I'm Amanda Knox, and in the new podcast, Doubt, the case of Lucy Lettby, we unpacked the story of an unimaginable tragedy that gripped the UK in 2023. But what if we didn't get the whole story?

I just been made to fit. The moment you look at the whole picture, the case collapsed. What if the truth was disguised by a story we chose to believe? Oh my God, I think she might be innocent. Listen to Doubt, the case of Lucy Letby on the Iheart Radio app, Apple Podcasts, or wherever you get your Podcasts. I'm Clayton Eckerd. In 2022, I was the lead of ABC's The Bachelor. But here's the thing. Bachelor fans hated him.

If I could press a button and rewind it all I would. That's when his life took a disturbing turn. A one-night stand would end in a courtroom. The media is here. This case has gone viral. The dating contract. Agree to date me, but I'm also suing you. This is unlike anything I've ever seen before.

I'm Stephanie Young. Listen to Love Trapped on the IHeart Radio app, Apple Podcasts, or wherever you get your podcasts. This is Special Agent Regal, Special Agent Bradley Hall. In 2018, the FBI took down a ring of spies working for China's Ministry of State Security, one of the most mysterious intelligence agencies in the world. The Sixth Bureau podcast is a story of the inner workings of the MSS and how one man's ambition and mistakes opened its fault of secrets. Listen to the Sixth Bureau on the IHeartRadio app, Apple Podcasts, or wherever you get your podcasts.