Hi.
I'm Stephanie Strappie. 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 Page Applications in Therapeutics known as iPath. That's the first page 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's true, but it really is.
My husband and I went on vacasion in Egypt in the fall of twenty fifteen, and we're scientists. We travel together and we always do off the beaten path kinds of things. We had a dream of, you know, going to see King Tut'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 Tut's tomb, and Tom and I had this wonderful meal on top of a cruise ship and he got violently
all 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 know 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 medevact to Frankfurt, Germany, because he was too sick to be metavact home. And there they did a sea tea 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 of 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 grown in there, we can handle it. Well, the doctors came back in a couple of days and they showed me that this name of this organism was ascimeo bactor bomanii, and it's something that I used to plate on my petri dishes back in the nineteen eighties 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 back here on the planet, because, like you know, twenty years ago, we just had to use like goggles in a lab code and that was it. It was not worrisome at all. Well, it turns out that the antime chrobia 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 fifteen right off the top. Well, I started to get worried now, and this is right before Christmas of twenty fifteen. 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 cock tol 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 resor antibioticaliston that was developed in world War two. Well,
they said, you know, he's too weak for surgery. We have no choice but to use interventional radiology to essentially stick the 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 you, it was one of the scariest moments of my life. We were actually supposed to get discharged in a cute care facility the next day, but that wasn't
happening anytime past. In fact, he was rushed back to the ICU in the same hospital and put it into an induced coma for a couple of 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 one hundred 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 tether back to the real world, and they said, does anybody realize that you know there's anything? 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 that the National Library of Medicine has developed, and I found this ancient, one hundred year old therapy called phage therapy, which are essentially these bacteria. Phages are viruses that have naturally evolved to attack bacteria. And I had heard about them in my microbiology classes way back in the nineteen eighties, but I never knew that they've
been used to treat bacterial infections. Well 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 doctor Chip Schooley, who is a close colleague of mine, he said, what an interesting and intriguing idea.
You know, if you could find phages that matched a 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, global village of researchers from all over the world stepped up, including researchers from Texas A and M University, San Diego State University, and even the US maybe 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. 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 it. 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 on put 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 Aaron Welsh and I'm Aaron Oman Updyke.
And this is the 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, nopeng There's so much 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, I think.
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 fiftieth 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, like 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. So that's fair, 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 fiftieth episode, we failed to do the most important things.
Sometimes the days just get to you.
So that so the first hand account from our last episode on antibiotics came from a book called The Youngest Science by Lewis Thomas. Okay, so Aaron to a company our quarantine 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.
And you're like, why are they laughing so hard?
And what's in the plasmid?
Great question. It is mezcal, 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.
It's a plasmid of It's a plasmid containing resistance to penicillin. We will post the recipe for the alcoholic quarantini and the non alcoholic place Berta on our website. This podcast will kill you dot 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, 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 ten 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 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, all right, 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 lot of our 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,
fluoroquinolones or refampin or the sulfonamides. These are drugs that bind directly to certain enzymes DNA gyrase or RNA polymerase. So if 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 too 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. Similar mechanism is you could kick antibiotics out at a faster rate. So these are called eflux pumps.
Mmmm.
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 eflux pumps are a way that they can shuttle molecules outside of their cells. And it turns out that the genes for these types of eflux 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 eflex pumps, then you can ship the antibiotic MOLUCU out of the cell before they have time to kill you.
Right, So it's 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 that's evolution in a nutshell.
Yes, Okay, So those are the two other ways. You can change your eflux pumps, and you can change your porins 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.
Oohoo.
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 aminoglycosides, which you might remember from our last episode. These are streptomycin tobomycin. These act on bacterial protein synthesis.
They bind to ribosomes. Okay, h 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 aminoglycoside 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 lactine maces. Have you heard of this?
Yes, there are enzymes that like actually break down the betaalactam ring, right.
Yes, And the beta lactam ring is how betaalactam antibiotics like penicillin and cephalosporin actually work. So many bacteria, especially gram positives, produce these enzymes called betaalactamases that bind to and inactivate that betaalactam ring. It is so common, like betaalactamases are so common and ubiquitous that we actually have a whole nother set of drugs that we call betaalactamase 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 clavelanic acid. That combination is called augmentin mm hmm.
It's sort of like the lactamase inhibitors hold back the little guards and they're like no, no, you can invade the castle. Okay.
So there's a there's a series of videos that most Med students, any Med student listening is gonna 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 lactams, and then you have like the clabulonic acid that has like a armor that comes in anyway.
I like it. It's really great. 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 they what we call extended spectrum beta lactamese producers, so they are 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, 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 time and how many generations, like even within a year or something, a strain of E. Cola 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, Eric, You know that I would erin so mutations like this that can provide resistance occur about once every ten 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 ten 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 ten thousand bacteria living in a wound on
your hand. If you killed nine thousand of those bacteria by any means, antibiotics or otherwise, you have selected one thousand survivors. H those one thousand survivors will go on to reproduce. And oftentimes those one thousand survivors aren't representative of that whole ten thousand 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 one thousand
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 eflux 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 one thousand 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 They that's how they mainly reproduce, but they also can transfer genetic material between cells. Okay, so this gets a get so excited about this.
I think we talked about this in Ecola right with Joshua Letterberg, 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 pillas, and then they attach their pillas to their partner's pillas, 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 plasmiad 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 eflux pun or a new type of betaactamase for example. 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 bacteria phase which are viruses that infect bacteria. Okay, these are important. These bacteria phasias 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 sell.
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 resistent infections later on in the episode from Time Stephanie as well, big time, big time.
So I mean that's pretty much that's pretty much how resistance works. Okay, So if we go back to that population of ten thousand bacteria that lives in your festering hand wound, Okay, just to kind of sum all this up, mm hmm. Actually let's call it ten million bacteria.
Okay, Now my hand wound is really really just it's cicy bacteria, yep.
Okay, so you cut yourself, Now you have ten 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 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 loan 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? Just the little betaalactomies? Do you
want one? And all of the new bacteria're gonna be like yeah, heck yeah, I gave me one of those, so they'll get together, conjugate and share that plasmid with their friends in la antibiotic resistance.
I like, I feel like we have this 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 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, so Erin.
You might think that this story the story of antibiotic resistance. Maybe it starts with the first sulfonamide or penicil and resistant strains of bacteria that were found in hospitals in the nineteen forties.
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 bachulism episode, Like why does this toxin exist?
Yeah?
So why do these compounds exist in nature? They didn't just arise in the nineteen forties with penicilin 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, God 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, and 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 three secretion system, or to clear the competition in a 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 tetracycling, 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. 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 in 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 force drugs that punch holes and 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 word for word title of a paper that I read, peer reviewed paper. And in this paper, they analyzed thirty thousand year old permafrost sediment to look for genetic traces of antibiotic resistance. And guess what they found. They found genes.
They gave resistance to beta lactyms, tetracycline, glycopeptides, even vancomyocin antibiotics.
Yeah.
Wow, so at least roughly twenty nine thousand and thirty years before penicillin was discovered, these resistance genes existed.
Just twenty nine thousand years.
No big deal. Well, I think 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 mutation. 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 right until they face the selection pressure. So that's the other thing, is like they might be there, they're just not using them yet.
Right exactly. You know, it'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 gonna 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, oh in the geographic spread of this.
Bacteria can only move so far, Aaron.
It's true, It's very true. Okay, So, Aarin, 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 terrifi.
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 the 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 nineteen forty five, 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 MRSA 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 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 reached someone who gets a septicemia or an ammonia which penicillin cannot save. So like this was in nineteen
forty five, This was a couple years after. It was after penicillin was introduced to 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 US until the mid nineteen fifties, 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, errand it was even available as like a powdered daily dose human growth promoter.
Stop it, yep, Like goodbye, powdered peniculian to see penicillin.
Emergency protein powder. Just whatever, Just not 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 and 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 backshelf the microbes win. Another antibiotic comes along, resistance develops, it gets shoved to the back shelf, another antibiotic, more resistance, rinse, and repeat like This has been going on since the creation of penicillin, and since that time there have been more than one hundred and fifty 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 like widespread, Yeah, so okay. Sulfonamides introduced nineteen thirty five, resistance detected nineteen forty.
Penicillin nineteen forty two, introduced resistance nineteen forty five, Streptomycin introduced nineteen forty four, resistance nineteen fifty eight. Tetracycline introduced nineteen forty eight, resistance nineteen fifty four, chlorum phenacol introduced nineteen forty nine, resistance detected nineteen fifty six, and so on and so on, like this goes. I could list this with like ten more antibiotics that you would recognize
by name. It's it's incredible, and so it became increasingly apparent, obviously, as we are aware today that resistance is inevitable. It's just like thanos just another reference, another marvel mar 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 nineteen fifties 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 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 twentieth 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 witnessing 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. So let's dive a little bit deeper into.
Each as we are wont to do.
Let's start with medical side of things. As I've mentioned before, once they came onto the scene, 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. Like they're not bad things. They're still hugely important, but we need to really consider how we use them so that we save them for when we really need them need right. So it's sort of proper use, right, and not saying it's it's reducing their overuse and turning improper use into proper.
Use, right yeah, 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 is 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 ninety five percent chance that an infection is viral and a five percent chance that it's bacterial, you might just want to prescribe an 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 twenty ten, eighty percent of primary care doctors and seventy percent of emergency room doctors were prescribing antibiotics for acute bronchitis, which is viral almost always, viral almost always, and so then
that's how 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.
Mmmmmmm 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 is that we do need to change sort of the directives of this. Yeah, we 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 antibiotics if they don't really need them.
Right, And this is something that we're becoming more and more aware of as we talk about the microbiome. And some ambiotics, like you said, are also toxic in themselves, like 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. Infections are very high, They're very prevalent.
And this is talking about drug resistant and drugs and antibiotics susceptible infections, right, 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 ten days of in 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, and then you're bringing your drug resistant bacteria into the hospital. Yeah,
she's like, come on, which is not good. And then that same twenty ten study that I mentioned just a little bit ago, they also showed that up to forty percent of people fail to complete their full course of antibiotics.
Oh yeah.
And so these three healthcare issues have been a part of what is driving intibiotic resistance in hospital and community settings. And for the most part, I have to say that a dozen like, we have made some forward progress in terms of regulating them, but it's we still have a long way to go. Okay, but 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 B twelve to supplement the food of chickens to help them better. So he learned that streped to mices areo facins, produces vitamin B
twelve during the fermentation process from making stripped micin. So he was like, Hey, can I have some of that waste from fermentation, just like the leftover gunk or whatever. I'm gonna mix it into the chickens 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 B twelve, and so did the piglets that
he also tried it out on. He was like, Okay, is it actually the B twelve 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 eleven percent faster
than their non antibiotic ridden counterparts. But I've seen actually much higher rates quoted, particularly early 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. Ok 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 so 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. M M.
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 the nineteen fifties, 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 a industrial farm full of pigs packed in, you know, all close to one another, and then they're all just just
with antibiotics, like the bacteria that 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 anbiotic resistance bacteria apparently, 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 round 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 you could 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.
Don't chicken eat We're sold in.
Chickens were literally sold soaking 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 nineteen fifties. So around the same time when it was first started to ramp up.
Oh my god.
Around this time, penicillin had been made prescription only in the US 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, those therapeutic doses, yes, Groad. 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 promoter. And then there was a series of studies in the nineteen sixties 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 like this was a 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. Starting in nineteen seventy one, they banned antibiotics as growth promoters if those antibiotics were used to treat disease in animals and humans.
Okay, so you can I no longer use tetracyclines because we use those to treat disease for example.
Yeah, got it. And you had to have a prescription for them if you wanted to use them therapeutically.
Okay.
And the US was like this close to following suit, 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 Whitten, 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 had somehow he had that power aeron I don't know, So the White House gave in since the budget hold up would have also hurt many other important projects, and so Witten, the representative, insisted that the data in support
of banning the use of non therapeutic antibiotics in 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 nineteen seventies a researcher named doctor Stuart 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 are given tetracycline. Within thirty six hours of first being given the feed laced with tetracycline, their gut E. Coli was resistant thirty
six hours. So that's scary enough. And tetracycline is like was a broad spectrum, just like awesome 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, stripped to miceine, and sulfonamides, and the chickens had never even received any of those drugs.
Whoa the tetracycline had 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 gutty coli of the farmers and the families of those farmers that had kept the chickens, none
of them had received tetracycline. There have been literally dozens, dozens and dozens of peer reviewed articles demonstrating clearly that antibiotic use in animals impacts humans. To 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, It was firmly established that it was. Instead, it was
a political one. Does it sound familiar?
Sounds too familiar, Aaron?
Yeah. And despite this strong evidence that growth promoters also promoted antibiotic resistance and all of the terrifying implications that came along with it, the US declined to ban tetracycling as a growth promoter, It, along with many other antibiotics, continued to be used freely for decades. In livestock, you.
Said, for decades. Are you gonna tell me some happy news at the end of this, like no longer or what?
There are some some bright moments and 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, whoo whoo 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 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 for the third and fourth string, antibiotics that had been deemed too toxic, or too specific, or too expensive to
be used. Fankomycin was one of these antibiotics. 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, nana, we'll just use methicillin instead, and so in the nineteen eighties 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 nineteen eighty nine, the first strains of vancomized and resistant entercocci VRE started popping up in hospitals in the US, and by nineteen ninety three it was close to being
endemic in many hospitals. VR baby, VR baby, It's really bad. Within five years for showing up, VRE was widespread in the US, something that it took MRSA about methicillin resistant staff oreas about fifteen 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 an agriculture. A vancom ioson like antibiotic had been used as a growth
promoter in livestock for decades. Oh gosh, And so when physicians started to reach into the back of that cabinet for vancom ioson, 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 nineteen ninety six, the first vancom iceon resistant staff OUREUSSA infections.
VERSA infections emerged in Japan. At this point in time, about fifty percent of all hospital staff OREUS infections were methicone resistant, so treatable only by vancom iyosin. Within the next few years, versa was basically everywhere, And again there was still lobbying for the continued use of vancom iosin and other antibiotics as growth promoters in the US, and those lobbyists still refuse 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, yes it is, yes, oh gosh.
And it wasn't just vanca icein resistance that agriculture was promoting. Calliston was another one of those antibiotics that had 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 xpec which I can't remember what that one is, but
it's some sort of ecoli, toxic ecoli. Yeah, these UTIs caused by xpecs. They seemed to be coming from food, specifically chicken. Oh gosh, quinnolone resistant Salmonella typhomerium strain DT one O four that's a bad one that spread through fresh dairy and can kill you, and that came directly from animals, and quinnolone resistant Campilo bacter those that was found in grocery store chicken.
Oh gosh.
So quinnilone had been used in agriculture for years, but the sharp, alarming rye 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 quinn alone use in animals was of no harm to humans.
I'm just getting too depressed, Darren.
I know, okay, but In the late nineteen nineties, it is a little shining sun. The European Union moved to ban antibiotics as growth promoters like all of them, but preventive 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 nineteen ninety nine to two thousand and six and beyond it stayed
at six hundred and six tons per year. This is after the ban, right However, 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 gonna We're not gonna listen, 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, everyone kind of thing.
Yeah, So the Netherlands, for example, they 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 twenty thirteen 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 and the weight of livestock sky high meat prices,
more disease among livestock, none of these things happened. H 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, So somewhere inesting 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 US failed to make
similar regulatory progress as Europe. In twenty fifteen, thirty four point three million pounds of antibiotics were sold for use in animals, compared to approximately seven point seven million pounds
for humans. But even though the US government agencies were slow to stop the over use 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 meat providing side of things, so these big name chicken farms to the food supply aspect, so like fast food restaurants, 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 twenty twelve, the US 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. Twenty seventeen did see a decrease, but it doesn't seem one hundred percent clear why that decrease happened.
Maybe it's because of these bands, 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. And animals share one bacterial and viral world, and fungal world and protozol and parasitic whatever. So the rise of antibiotic resist in't 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 preemptive 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 US where overuse is an issue. Twenty fifteen, a group of researchers tried to predict how much antibiotics Brazil, Russia, India, and China could be predicted to use in the next fifteen years as demand for meat continues to increase. If nothing changed, that estimate was one hundred and five thousand, five hundred
and ninety six 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 Maren 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 antibiotic era? Is there any hope?
I mean, let's find out I need a short break. Yeah. Same, Well, let's start with the depressing things and then we'll end on a at least hopeful note. How about that? Great? Okay? Ah, all right? So medically in the US, at least, the CDC estimates that at least forty seven million antibiotic prescriptions in the US 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 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. Forty seven million.
Yeah, it's a good question. I don't know if that includes like every time that you give vanken zosin in the er, which like everyone who comes into the ear 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 sent home with. Either way, it's terrifying. I mean forty seven million.
Oh yeah, so that's in the US.
Also in the US, 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 twenty nineteen. It's estimated that there are more than two point eight million antibiotic resistant infections in the US year that result in more than thirty five thousand deaths. Wow, so thirty five thousand people a year are dying in the US 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 twenty fifteen, 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 sixty 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 forty percent of bacterial infections or with bacteria that are resistant to antibiotics. But I don't have numbers on deaths. I do have numbers. In the EU. In twenty fifteen, an estimate from the European Union was that six hundred and seventy one thousand infections were likely antibiotic resistant and that likely resulted in thirty three thousand deaths in twenty fifteen.
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 US, are antibiotic resistant infections reportable? Like are you required to report them?
Well, that's a really good question. I don't fully know the answer to that. So there's this that report that came out in twenty nineteen 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 US. 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 twenty fourteen, which is earlier than most of the data I was hoping to find, estimated that currently worldwide, there are seven hundred thousand deaths attributed to antimicrobial resistance worldwide.
That is a lot.
It's a lot. And they projected that out and estimated that by twenty fifty that number would go up to ten million.
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 one hundred trillion dollars antimicrobial resistance.
Yep.
I can't. I can't comprehend that number. Wow.
I was really hoping to find more recent, like hard data on anti microbial resistance, and I came across a paper that came out in twenty sixteen that really highlighted some of the issues that we have in 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 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 fail year 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, right, it's a really complicated, big picture.
Question, but there is no question that it is leading to death. And it's 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 already here. So we need new ways to target these pathogenic bacteria. 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, fical 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 already 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 druggers is in tuberculosis is terrifying aarin tubercula.
Yes, this 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 TV 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 Enterococcus, feceum, staph aureus, club Ciella, Assinitobacter balmani i, 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 twelve that we need to be concerned about.
But we don't. We don't care about the other six just because they don't make a good act.
They don't make a good acronym. H. Pylori, lah, camplobacteror Gonorrhea, Salmonella, strep. New.
You know, there aren't enough vowels in there.
I know that's why they're not included.
We do care about all of those.
Oh it's 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 MRSA 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, doctor Stephanie Strathty. 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 like 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 ten million trillion trillion. That's ten to the power of thirty one for you numeric matthew 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. You know, 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 one hundred
times smaller than bacteria. And they were discovered in nineteen seventeen by a French Canadian named Felixe de Caral, 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 nineteen forties, and people actually had a big debate as to whether or not these were proteins or whether they were viruses
or whatever. And Deharel 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 developed the first page therapy center in the world, it got the label, as you know, Soviet science, and this was around World War Two, and of course that led to a big geopolitical bias of like pink O Komi science, 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 nineteen forty two. Even though it was discovered in nineteen twenty eight, it had been you know, it took some time to come to end too the field, and that was because it was needed on the warfront. And so people thought antibiotics are wonder drugs, and of
course they were for a while. But anti mycrobia 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 realized, oh my gosh, they got a superbug 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 matched
to specific bacteria. So for an organism like Staphylococcus, which you know, one of the strains is mursa right at the silin resistant staph wreas that's the superbug that was discovered first, maybe about twenty to thirty 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 superbugs like Tom's asked me to back to Bomanii, it's very very specific. So the phage not doesn't just have to match the genus and 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 phage hunt, you have to go to some of the worst places around. And we're talking like sewage, barnyard, waist, scummy ponds, that kind of thing. So the phages that were actually used to treat tom we're from. So I can say literally that my husband is full of I mean, who can get to say that to their husband?
That's amazing.
And then so what then once you if you go in and you dig through all that sewage and you get lucky enough 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 Petrie 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 petrie dish and you incubate it for twenty four to forty eight hours, and if it comes back looking like a little like Swiss cheese because there's holes literally in the petrie 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 it with phage intravenously, you want to get it as pure as possible because if there's a lot of bacteria debris and the suspension, it could elicit septic shock and the patient and could
kill them. And that's what we're 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 phases, 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 ten 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 and cooler, where you have thousands of phages and they're already identified and characterized and sequenced, then you could 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 you know, 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, there's a lot of antidoxin left that could kill the person. So again, we haven't seen that though we've treated over a dozen patients and you see 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 exciting developments 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 twenty nineteen, 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 Isabelle. I happen to know her now through
our connections and Facebook and social media. She had a hassistic fibrosis and she'd had a double lung transplant and had acquired this what's called Microbacterium obsessis. And people who are familiar with tuberculosis will know that michael Bacterium tuberculosis, a cousin to this Microbacterium obsessis, is the biggest bacterial killer in the world. It almost kills two 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 named Graham Hatful at the University of Pittsburgh who runs this wonderful training program called Sea Phages that teaches students how to find phages, and essentially they're doing this page hunt that I described earlier, and all of the phages that they find go into a giant phage bank, and they have about fifteen thousand
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 egg plant 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 hitting this snooze button. They actually don't kill the bacterial cell, but that's all they could find. What they did was they genetically manipulated those two phages by clipping out the repressor gene in a technique called we're commineering, which is, you know, a prequel to a crisper gene editing, and it forced those sleepy phages to become the 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 Isabelle received phage therapy intravenously because based on Trum'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 eighteen 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 and a human being successfully. And also it's the first time that a Mycobacterium infection and a human has been successfully treated with PAGE therapy. And Len's hope that maybe someday we could treat tuberculosis with PAGE therapy. Wouldn't that be awesome.
That is being 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 grin 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 one hundred anniversary of the discovery of bacteria phages at the past Or Institute, and then the story went viral. I mean literally, I was getting contacted by people from all over the world. I'm wanting page therapy,
but it was mostly patients in their families. Doctors were very skeptical and until Chip school he 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, and of course the Georgians and the Polls have been doing this page 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 pooed 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 interested in phage therapy. Pharmas 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 ANIH, 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 US that had predominantly focused on new antibiotics, but since there's no antibiotics in the pipeline to speak of, they've embraced page therapy. So We're very excited by that because that's what we need now.
We need clinical trials to advance page therapy and to first show efficacy, and then we can, you know, 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 that 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 kind of take a rightful place in medical history. I mean, Tom and I are really privileged. I mean we 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 earn 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 Innovated Phage Applications in 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. So cool, so cool, the coolest to 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 Maren 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 Bacteria by MB Schneerson and MJ. Plotkin. And finally, you guys should definitely check out doctor Strathte's book called The Perfect Predator, A scientist race to save her husband from a deadly superbug. A memoir so good, you, guys, seriously so good.
I heavily used actually the same book that I used for the antibiotic episode, edited by Roslen Anderson at All, called Antibacterial Agents, Chemistry, Motive Action, Mechanisms of Resistance, and Clinical Applications. And then there's another great paper from twenty sixteen 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 in every episode on our website.
Yes, thank you again so much to doctor Strathte 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 one episodes long fifty one episodes. Now we can continue our excitement. Awesome, all right, Well until next time wash your hands.
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