Speaker 1: Hi.
Speaker 2: I'm Stephanie Strappie. People call me Steph. I'm the Associate
Speaker 2: Dean of Global Health Sciences at the University of California,
Speaker 2: San Diego, and I now co direct the new Center
Speaker 2: for Innovative Page Applications in Therapeutics known as iPath. That's
Speaker 2: the first page therapy center in North America. But that's
Speaker 2: the end of the story. You want to hear how
Speaker 2: I got there, right, Well, it's a crazy story. People
Speaker 2: often don't even believe that it's true, but it really is.
Speaker 2: My husband and I went on vacasion in Egypt in
Speaker 2: the fall of twenty fifteen, and we're scientists. We travel
Speaker 2: together and we always do off the beaten path kinds
Speaker 2: of things. We had a dream of, you know, going
Speaker 2: to see King Tut's tomb, and we floated down the
Speaker 2: Nile River in a wonderful ship. So everything went great
Speaker 2: until the night before we were supposed to see King
Speaker 2: Tut's tomb, and Tom and I had this wonderful meal
Speaker 2: on top of a cruise ship and he got violently
Speaker 2: all afterwards. I mean he was throwing up all over
Speaker 2: the place, and you know, I just thought he had
Speaker 2: a bad muscle or something. Like that, but actually he
Speaker 2: got very sick. We had to call a doctor to
Speaker 2: the ship. The doctor said, he's going into shock. There
Speaker 2: was no hospital in Luxor, where the ship was docked,
Speaker 2: so we ended up having to go to a community
Speaker 2: clinic there. They diagnosed him with pancreatitis, which is essentially
Speaker 2: an inflammation of the pancreas. But when I called back
Speaker 2: home to our colleagues who are leading the Department of
Speaker 2: Infectious Diseases at UC San Diego, they said, hey, that's
Speaker 2: just a symptom of something else. Because you know you're
Speaker 2: the wine drinker in the family. Tom doesn't drink nearly
Speaker 2: as much as you, and that's usually one of the
Speaker 2: causes of pancreatitis. They said, something else is going on.
Speaker 2: And luckily we had travel insurance, so we were able
Speaker 2: to get him medevact to Frankfurt, Germany, because he was
Speaker 2: too sick to be metavact home. And there they did
Speaker 2: a sea tea scan and saw that he had a
Speaker 2: giant abscess in his abdomen, the size of a football.
Speaker 2: And the doctors came to me and said, you know,
Speaker 2: there's something lurking inside this abscess, and they showed me
Speaker 2: this putrid flask of fluid that they'd taken from this abscess,
Speaker 2: and they said, something's growing in there, and we have
Speaker 2: had to culture it. It's going to take a couple
Speaker 2: of days. But let's hope it's a garden variety of
Speaker 2: microorganism because there's a lot of multi drug resistant bacteria
Speaker 2: in Egypt. Well, I was getting a little bit worried,
Speaker 2: but you know, I thought, hey, we have antibiotics. Anything
Speaker 2: you know that's grown in there, we can handle it. Well,
Speaker 2: the doctors came back in a couple of days and
Speaker 2: they showed me that this name of this organism was
Speaker 2: ascimeo bactor bomanii, and it's something that I used to
Speaker 2: plate on my petri dishes back in the nineteen eighties
Speaker 2: when I was taking a rusty old degree in microbiology
Speaker 2: at the University of Toronto. And again I really wasn't
Speaker 2: that worried, but they said, look, this is actually the
Speaker 2: worst bacteria on the planet. I thought, you know what,
Speaker 2: how can this be the worst back here on the planet, because,
Speaker 2: like you know, twenty years ago, we just had to
Speaker 2: use like goggles in a lab code and that was it.
Speaker 2: It was not worrisome at all. Well, it turns out
Speaker 2: that the antime chrobia resistance crisis had crept up on us,
Speaker 2: and Tom was essentially the poster child for this post
Speaker 2: antibiotic era that we've entered now. And so the doctors
Speaker 2: did what's called an antibiogram to find out the antibiotics
Speaker 2: that could be used to hopefully treat this thing. And
Speaker 2: they came back and they were even more alarmed because
Speaker 2: there was only a couple of antibiotics that it was
Speaker 2: partially sensitive to, and it was resistant to fifteen right
Speaker 2: off the top. Well, I started to get worried now,
Speaker 2: and this is right before Christmas of twenty fifteen. Luckily,
Speaker 2: they stabilized him, got him sent back to San Diego,
Speaker 2: where my colleagues in the Department of Medicine were looking
Speaker 2: after him. And I thought, okay, we're fine, we're home now, right,
Speaker 2: everything's going to be fine. We'll find some antibiotics to,
Speaker 2: you know, to cock tol together to cure this thing.
Speaker 2: And they repeated the culture and they found out that now,
Speaker 2: and even though only a few weeks had passed, this
Speaker 2: organism was resistant to all antibiotics, I mean, even the
Speaker 2: last resor antibioticaliston that was developed in world War two. Well,
Speaker 2: they said, you know, he's too weak for surgery. We
Speaker 2: have no choice but to use interventional radiology to essentially
Speaker 2: stick the holes in his abdomen and put these catheters
Speaker 2: in there to try to drain out this infected fluid
Speaker 2: out of the abscess and hopefully it would shrink and
Speaker 2: then he'd be better. Right, Well, not so fast, because
Speaker 2: even though he had started to improve, one day, he
Speaker 2: sat up in bed and this tube inside his abdomen
Speaker 2: slipped and it just dumped all that infected fluid into
Speaker 2: his abdomen into his bloodstream, and immediately he went into
Speaker 2: septic shock right in front of my eyes. And I'm
Speaker 2: telling you, it was one of the scariest moments of
Speaker 2: my life. We were actually supposed to get discharged in
Speaker 2: a cute care facility the next day, but that wasn't
Speaker 2: happening anytime past. In fact, he was rushed back to
Speaker 2: the ICU in the same hospital and put it into
Speaker 2: an induced coma for a couple of days to give
Speaker 2: his body to rest. And he did wake up from that,
Speaker 2: but now this organism is now in his whole body.
Speaker 2: He was like fully, like systemically infected, and from that
Speaker 2: moment on. He was dying a little bit more each day,
Speaker 2: and it was just horrible to watch. He lost one
Speaker 2: hundred pounds off of his frame. He was in and
Speaker 2: out of a real coma that he wasn't waking up from.
Speaker 2: And one day I heard some colleagues on a conference
Speaker 2: call when I was trying to, you know, keep one
Speaker 2: tether back to the real world, and they said, does
Speaker 2: anybody realize that you know there's anything? Told step that
Speaker 2: her husband is going to die? And I thought, oh
Speaker 2: my god, like nobody has. And I cradled the phone
Speaker 2: in my arms like a baby, and I thought they
Speaker 2: just didn't want to tell me, and I'm going to
Speaker 2: lose them unless I do something. So I had this
Speaker 2: conversation with Tom and asked him if he wanted to live.
Speaker 2: And I didn't know if he could even hear me,
Speaker 2: but I said, if you want to live, please squeeze
Speaker 2: my hand and I'll leave no stone unturned. And he
Speaker 2: squeezed my hand. Now, I mean, I was thrilled, but
Speaker 2: I thought, you know what am I going to do?
Speaker 2: Like I'm not a medical doctor. I don't know how
Speaker 2: to cure this thing. But I did what anybody would
Speaker 2: do in my shoes. Because I'm a scientist. I went
Speaker 2: home and I hit PubMed, you know the Google scholar
Speaker 2: for scientists that the National Library of Medicine has developed,
Speaker 2: and I found this ancient, one hundred year old therapy
Speaker 2: called phage therapy, which are essentially these bacteria. Phages are
Speaker 2: viruses that have naturally evolved to attack bacteria. And I
Speaker 2: had heard about them in my microbiology classes way back
Speaker 2: in the nineteen eighties, but I never knew that they've
Speaker 2: been used to treat bacterial infections. Well turned out that
Speaker 2: they had, that they were considered experimental treatment in the West,
Speaker 2: and they're only being used in the former Soviet Union
Speaker 2: and in parts of Eastern Europe. So I asked the
Speaker 2: colleagues that were treating TOM. I said, you know, could
Speaker 2: we use phage therapy to treat tom and that lead
Speaker 2: infectious disease Doctor doctor Chip Schooley, who is a close
Speaker 2: colleague of mine, he said, what an interesting and intriguing idea.
Speaker 2: You know, if you could find phages that matched a
Speaker 2: Tom's bacterial isolate, I'll call the FDA and request compassionate
Speaker 2: use permission for us to use phage therapy to cure them.
Speaker 2: But I've never done this before, and I don't know
Speaker 2: anybody who has, so you know it's a long shot. Anyway,
Speaker 2: long story short, global village of researchers from all over
Speaker 2: the world stepped up, including researchers from Texas A and
Speaker 2: M University, San Diego State University, and even the US
Speaker 2: maybe chipped in, and we found phages in the nick
Speaker 2: of time to match Tom's bacteria, and we injected them
Speaker 2: into his body, a billion phages per dose every two hours.
Speaker 2: We didn't know if we were going to kill him
Speaker 2: or cure. But three days later he lifted his head
Speaker 2: off the pillow and kissed his daughter's hand, and I'm
Speaker 2: telling you, it was the happiest day of my life.
Speaker 2: So that's our crazy story. I left a lot of
Speaker 2: it out, but it's in our book, The Perfect Predator.
Speaker 2: If you want to hear more details, you want to say,
Speaker 2: Hi Tom, Hi Tom, how are you feeling these days?
Speaker 3: I'm feeling great.
Speaker 4: Can't complain.
Speaker 3: Well I could, but nobody's going to listen after it.
Speaker 3: I got saved like this, Well it's better than the alternative, right,
Speaker 3: You're damn right.
Speaker 4: That was amazing. Thank you so much, Stephanie. We really
Speaker 4: appreciate you taking the time to come on the podcast
Speaker 4: and share your story with us.
Speaker 3: We really really do. It's oh man, what a bonkers story.
Speaker 4: I really really and we'll mention this again, but I
Speaker 4: really really encourage everyone to go out there and read
Speaker 4: The Perfect Predator, which is the book that she wrote
Speaker 4: about this experience. It was on put downable. If that's
Speaker 4: a word, I could not put it down. How about that.
Speaker 3: I really hope that that's a word.
Speaker 4: Yeah, I don't think it is.
Speaker 2: Hi.
Speaker 3: I'm Aaron Welsh and I'm Aaron Oman Updyke.
Speaker 4: And this is the this podcast will kill you.
Speaker 3: So today we're talking about antibiotic resistance.
Speaker 4: Yes, you thought you heard all that you wanted to
Speaker 4: know about antibiotics in the last episode. No way, nopeng
Speaker 4: There's so much so fast. There is so much more
Speaker 4: in the world of antibiotics to learn about, to read about,
Speaker 4: to hear about. And that's what we're doing this episode.
Speaker 3: We promise it's not all depressing, like it's mostly depressing.
Speaker 4: But yeah, we're going to end it on a hope
Speaker 4: for the future. Nope, absolutely, I think.
Speaker 3: Yeah.
Speaker 4: A couple of things we completely forgot Aaron and our
Speaker 4: excitement to do the episode last week to talk about
Speaker 4: why we were so excited beyond just the fact that
Speaker 4: it was antibiotics. It was our fiftieth regular season episode.
Speaker 3: I totally forgot about that. Oh my gosh, I can't
Speaker 3: believe we've made that many episodes.
Speaker 4: I really can't. I remember, like going back to one
Speaker 4: of the earlier ones, and I remember how we used
Speaker 4: to be like, oh my gosh, episode seven, can you
Speaker 4: believe we've made it this far.
Speaker 3: To be fair, I was shocked that we made it
Speaker 3: to seven episodes. So that's fair, that's fair. It was
Speaker 3: a true sentiment at the time.
Speaker 4: The other thing is that I completely forgot to mention
Speaker 4: where the first hand account came from in the antibiotics episode,
Speaker 4: and that was I mean, it's like we're amateurs at
Speaker 4: this On our fiftieth episode, we failed to do the
Speaker 4: most important things.
Speaker 3: Sometimes the days just get to you.
Speaker 4: So that so the first hand account from our last
Speaker 4: episode on antibiotics came from a book called The Youngest
Speaker 4: Science by Lewis Thomas. Okay, so Aaron to a company
Speaker 4: our quarantine for the antibiotics episode, which was penicillin, the
Speaker 4: classic cocktail. What are we drinking this week.
Speaker 3: This week we're drinking the plasmid. Oh if that's not
Speaker 3: funny to you, now, it will be funny as soon
Speaker 3: as I explain the biology of antibiotic resistance exactly exactly.
Speaker 4: And you're like, why are they laughing so hard?
Speaker 3: And what's in the plasmid?
Speaker 4: Great question. It is mezcal, like a honey mint, simple
Speaker 4: syrup and lime juice. It's kind of like a penicillin,
Speaker 4: but it's a take on a penicillin.
Speaker 3: It's a plasmid of a penicillin exactly.
Speaker 4: It's a plasmid of It's a plasmid containing resistance to penicillin.
Speaker 4: We will post the recipe for the alcoholic quarantini and
Speaker 4: the non alcoholic place Berta on our website. This podcast
Speaker 4: will kill you dot com as well as all of
Speaker 4: our social media channels any other business I don't think,
Speaker 4: So let's get right to it.
Speaker 3: I can't wait. We'll take one quick break first, antibiotic resistance. Okay,
Speaker 3: it's a big topic, so we're going to break it down.
Speaker 3: Here's how. First of all, hopefully everyone's listened to the
Speaker 3: antibiotics episode, so you have a framework for how antibiotics work.
Speaker 3: As a very brief overview. Antibiotics are designed to either
Speaker 3: kill or halt the growth of bacteria, and they do
Speaker 3: so by targeting various elements of bacterial cell walls, protein synthesis,
Speaker 3: DNA replication, or metabolism. That's our whole episode in ten seconds.
Speaker 4: Well that's a lot shorter than what the episode actually
Speaker 4: turned out to be erin.
Speaker 3: Okay, So the question first on a basic level, is
Speaker 3: what are the mechanisms of antibiotic resistance? Like, how do
Speaker 3: bacteria actually resist these antibiotics?
Speaker 4: Just sheer force of will?
Speaker 3: That's that's the answer episode over. Once we understand that,
Speaker 3: then we can ask two bigger picture questions, what drives
Speaker 3: antibiotic resistance and how does this resistance spread through populations? Okay,
Speaker 3: are you excited?
Speaker 4: I'm super excited.
Speaker 3: All right, So what are the mechanisms of resistance? First
Speaker 3: of all, you can have intrinsic resistance and you can
Speaker 3: have acquired resistance.
Speaker 4: If you are you being bacteria right, all right, I'm
Speaker 4: a bacterial cell.
Speaker 3: You're a bacterial cell. So very broadly, intrinsic resistance makes
Speaker 3: a lot of sense in the context that a lot
Speaker 3: lot of our antibiotics come from bacterial products. Right, So
Speaker 3: it makes sense that a Streptomyces bacteria, for example, will
Speaker 3: be naturally resistant to streptomycin.
Speaker 4: That makes sense.
Speaker 3: Yeah, So that is intrinsic resistance, which is neither the
Speaker 3: interesting nor the concerning part of antibiotic resistance. So that's
Speaker 3: all we'll say about it. What is both interesting and
Speaker 3: concerning is acquired resistance. And there are a few big
Speaker 3: categories of mechanisms by which bacteria can evade the effects
Speaker 3: of antibiotics. Let's go through them. Number one, bacteria can
Speaker 3: resist antibiotics by changing the target enzymes. So what does
Speaker 3: that mean for drugs like quinolones that we talked about,
Speaker 3: fluoroquinolones or refampin or the sulfonamides. These are drugs that
Speaker 3: bind directly to certain enzymes DNA gyrase or RNA polymerase.
Speaker 3: So if if bacteria modify these enzymes slightly change their
Speaker 3: structure just a little bit, then these antibiotic compounds are
Speaker 3: no longer able to bind to them. Boom, they don't work.
Speaker 4: Makes sense, And that seems like a relatively easy or
Speaker 4: like a relatively simple mutation would be necessary. Like one little.
Speaker 3: Quirk exactly, one little quirk for sure. Another way. That's
Speaker 3: actually very similar in the case of the classes of
Speaker 3: antibiotics that work by binding too ribosomes instead of enzymes.
Speaker 3: If bacteria evolve mutations to their ribosomes such that antibiotics
Speaker 3: can no longer bind, then again, boom resistance. That's pretty straightforward, right, yeah, Okay,
Speaker 3: So we can alter our enzymes that the antibiotics bind to,
Speaker 3: or we can alter the proteins such as ribosomes that
Speaker 3: antibiotics bind to. All right, two other ways that are
Speaker 3: also related. Remember that gram negative bacteria especially have a
Speaker 3: second membrane that surrounds the outside of their cell wall, right,
Speaker 3: and this membrane is less permeable than the cell wall is.
Speaker 3: So we know that gram negative bacteria are already harder
Speaker 3: to target with antibiotics because of that. So for gram
Speaker 3: negative bacteria, the way that antibiotics enter the cells is
Speaker 3: through pores porins little channels in the membrane. Well, if
Speaker 3: antibiotics can only enter certain porins, and bacteria then evolve
Speaker 3: changes either to the type of porins or sometimes just
Speaker 3: to the number of pores on their surface that can
Speaker 3: make them more resistant to certain classes of antibiotics.
Speaker 4: Makes sense, makes sense?
Speaker 3: Right? Basically, just changing the way that antibiotics are able
Speaker 3: to get into the cell, making it harder for antibiotics
Speaker 3: to get in. Similar mechanism is you could kick antibiotics
Speaker 3: out at a faster rate. So these are called eflux pumps.
Speaker 1: Mmmm.
Speaker 3: Yeah, bacteria have e flux pumps because, especially when they have,
Speaker 3: especially gram negative bacteria that have two layers of membrane
Speaker 3: plus a cell wall, they have to be able to
Speaker 3: get stuff in and out of their cells. So eflux
Speaker 3: pumps are a way that they can shuttle molecules outside
Speaker 3: of their cells. And it turns out that the genes
Speaker 3: for these types of eflux pumps aren't turned on all
Speaker 3: of the time because they can be quite costly. They
Speaker 3: can lead to bacteria exporting too much stuff and that
Speaker 3: can change the membrane potential of their cells and ultimately
Speaker 3: lead to cell death.
Speaker 4: Okay, that's interesting, that makes sense too. I like that though.
Speaker 3: Yeah, but in the face of antibiotics, if you can
Speaker 3: upregulate those eflex pumps, then you can ship the antibiotic
Speaker 3: MOLUCU out of the cell before they have time to
Speaker 3: kill you.
Speaker 4: Right, So it's it's worth it. Even though it's costly,
Speaker 4: it's worth it. In the face of something that is
Speaker 4: actually going to kill you.
Speaker 3: That is like the that's like antibiotic resistance in a nutshell,
Speaker 3: it's worth it if the antibiotic is going to kill you.
Speaker 4: Yeah, I mean that's that's evolution in a nutshell.
Speaker 3: Yes, Okay, So those are the two other ways. You
Speaker 3: can change your eflux pumps, and you can change your
Speaker 3: porins right, make it harder for antibiotics to get in
Speaker 3: or export them out even faster. And then the last
Speaker 3: way that you can evade antibiotics is by changing the
Speaker 3: antibiotics themselves. This is my personal favorite mechanism.
Speaker 2: Oohoo.
Speaker 3: Right, So bacteria can evolve ways to alter the antibiotic
Speaker 3: compounds themselves and render them useless. So for this, I'm
Speaker 3: going to actually go through a couple of examples. There's
Speaker 3: a lot of different ways that bacteria can do this,
Speaker 3: so we'll go through two examples of it. The first
Speaker 3: are aminoglycosides, which you might remember from our last episode.
Speaker 3: These are streptomycin tobomycin. These act on bacterial protein synthesis.
Speaker 3: They bind to ribosomes. Okay, h So bacteria can produce
Speaker 3: enzymes naturally, produce enzymes that bind to these antibiotics and
Speaker 3: add stuff to them, whether it's a phosphate or just
Speaker 3: a little carbon group, and that changes the structure of
Speaker 3: the aminoglycoside itself so that it no longer works. It
Speaker 3: basically inactivates it.
Speaker 4: That seems like much trickier to pull off, maybe, but
Speaker 4: they do it really well. It's really cool, all right.
Speaker 3: The other most famous example of this are, of course,
Speaker 3: the beta lactine maces. Have you heard of this?
Speaker 4: Yes, there are enzymes that like actually break down the
Speaker 4: betaalactam ring, right.
Speaker 3: Yes, And the beta lactam ring is how betaalactam antibiotics
Speaker 3: like penicillin and cephalosporin actually work. So many bacteria, especially
Speaker 3: gram positives, produce these enzymes called betaalactamases that bind to
Speaker 3: and inactivate that betaalactam ring. It is so common, like
Speaker 3: betaalactamases are so common and ubiquitous that we actually have
Speaker 3: a whole nother set of drugs that we call betaalactamase inhibitors,
Speaker 3: and these drugs inhibit or reduce the activity of those enzymes.
Speaker 3: So it's actually really common that when we give a
Speaker 3: beta lactam antibiotic like amoxicillin, we give it in combination
Speaker 3: with a beta lactamase inhibitor like clavelanic acid. That combination
Speaker 3: is called augmentin mm hmm.
Speaker 4: It's sort of like the lactamase inhibitors hold back the
Speaker 4: little guards and they're like no, no, you can invade
Speaker 4: the castle. Okay.
Speaker 3: So there's a there's a series of videos that most
Speaker 3: Med students, any Med student listening is gonna laugh really
Speaker 3: hard at that, because we watch these videos called Sketchy
Speaker 3: Micro and they show like beta lactams are these rings,
Speaker 3: and then the beta lactamases are these little like laser
Speaker 3: shooters that shoot away the beta lactams, and then you
Speaker 3: have like the clabulonic acid that has like a armor
Speaker 3: that comes in anyway.
Speaker 4: I like it. It's really great. It's very easy to
Speaker 4: envision all these as like little cartoons for sure.
Speaker 3: Yes. Oh, and they help you learn it a lot,
Speaker 3: a lot easier. Yeah, So it's very cool. We already have,
Speaker 3: like we've known that beta lactamases exist for so long
Speaker 3: that we already have drugs that specifically target those. But
Speaker 3: what's scary is that now many bacteria are what they
Speaker 3: what we call extended spectrum beta lactamese producers, so they
Speaker 3: are making even stronger beta lactamases that can break even
Speaker 3: more of our drugs.
Speaker 4: Essentially, Yeah, I mean that's sort of the theme, Like
Speaker 4: this is the same story, like over and over again,
Speaker 4: with just tiny variations exactly.
Speaker 3: So then that kind of gets to the next question,
Speaker 3: which is what actually drives this resistance? Why is it
Speaker 3: that we have resistance cropping up again and again? And
Speaker 3: we've kind of already touched on it, but the basic
Speaker 3: answer is mutation and selection.
Speaker 4: Right, It's a numbers game.
Speaker 3: Yeah, So for resistance to happen, first a gene for
Speaker 3: that resistance, any one of those types of resistance that
Speaker 3: I already mentioned, a gene for that has to appear
Speaker 3: in the population. And often this happens by random mutation,
Speaker 3: which seems like it should be very unlikely, right.
Speaker 4: Well, given the generation time and how many generations, like
Speaker 4: even within a year or something, a strain of E.
Speaker 4: Cola will have it's not. It becomes surprising that there's
Speaker 4: not resistance rather than surprising that there is.
Speaker 3: Would you like to put some hard numbers on that, Eric,
Speaker 3: You know that I would erin so mutations like this
Speaker 3: that can provide resistance occur about once every ten million cells,
Speaker 3: and because many bacterial species divide so frequently, like once
Speaker 3: every half an hour, it would only take six hours
Speaker 3: to get to ten million cells.
Speaker 4: And all it takes is one.
Speaker 3: All it takes is one. Okay, okay. So that's the
Speaker 3: first step, right, mutation. You have to mutate your DNA
Speaker 3: in such a way that you produce one of those changes.
Speaker 3: And then the second thing that has to happen is
Speaker 3: selection pressure, which essentially means you have to wipe out most,
Speaker 3: but not all, of the bacteria in a population. So
Speaker 3: let's put some numbers on this again. Let's say you
Speaker 3: have like ten thousand bacteria living in a wound on
Speaker 3: your hand. If you killed nine thousand of those bacteria
Speaker 3: by any means, antibiotics or otherwise, you have selected one
Speaker 3: thousand survivors. H those one thousand survivors will go on
Speaker 3: to reproduce. And oftentimes those one thousand survivors aren't representative
Speaker 3: of that whole ten thousand group of bacteria, right, They
Speaker 3: all have their own little mutations that are slightly different,
Speaker 3: but those are the ones that are going to go
Speaker 3: on and reproduce. So if any of those one thousand
Speaker 3: had the ability to resist an antibiotic. Those are going
Speaker 3: to be the ones that now grow and proliferate, right, Okay,
Speaker 3: because remember, like I mentioned, especially with eflux pumps, but
Speaker 3: this is true for many of those other mechanisms of resistance.
Speaker 3: A lot of the genes that confer resistance to antibiotics
Speaker 3: are not useful, and in some cases they're harmful in
Speaker 3: the absence of antibiotics.
Speaker 4: Right. So you could see over time, if you don't
Speaker 4: put any selection pressure on, you know, a bacterial strain,
Speaker 4: as they replicate and replicate and replicate, then the resistance
Speaker 4: genes might drop out because it's more costly to maintain
Speaker 4: exactly right.
Speaker 3: Okay, So then how does this gene that's present in
Speaker 3: let's say a couple of those one thousand bacteria that
Speaker 3: are left, how does it spread through a population Because
Speaker 3: we see antibiotic resistance growing at very rapid rates, right right.
Speaker 3: So to understand this, we basically just have to know
Speaker 3: that bacteria don't just reproduce by fission, right They that's
Speaker 3: how they mainly reproduce, but they also can transfer genetic
Speaker 3: material between cells. Okay, so this gets a get so
Speaker 3: excited about this.
Speaker 4: I think we talked about this in Ecola right with
Speaker 4: Joshua Letterberg, I think, so who discovered this?
Speaker 3: Yeah, So there are three ways that bacteria can introduce
Speaker 3: some variety into their genes besides just mutation, conjugation, transformation,
Speaker 3: and transduction. Conjugation is kind of like bacterial sex. So
Speaker 3: basically two bacteria get together, they pull out their pillas,
Speaker 3: and then they attach their pillas to their partner's pillas,
Speaker 3: and then they can share plasmids. Plasmids are circles of DNA,
Speaker 3: just little round nuggets pieces of DNA, and they can
Speaker 3: transfer them. So they can like hand a plasmiad to
Speaker 3: their partner, and they can grab a plasmid from their partner,
Speaker 3: and sometimes oftentimes those little plasmids have super useful things
Speaker 3: on them, like a better eflux pun or a new
Speaker 3: type of betaactamase for example. Okay, that's conjugation. Transformation is
Speaker 3: when bacteria pick up DNA from the environment. So if
Speaker 3: their neighbor dies and explodes and leaves a bunch of
Speaker 3: DNA floating around, another bacterium can swim by and pick
Speaker 3: some of that up. And finally, transduction is when viruses
Speaker 3: get involved. So bacteria phase which are viruses that infect bacteria. Okay,
Speaker 3: these are important. These bacteria phasias have to use host
Speaker 3: cell machinery in order to reproduce. So what they do
Speaker 3: is they inject their DNA into a bacterium and then
Speaker 3: some of that DNA can get incorporated into the bacterial DNA.
Speaker 3: So then every time a virus picks up and infects
Speaker 3: a new bacterium, they might transfer a little bit of
Speaker 3: that bacterial DNA to a neighboring sell.
Speaker 4: That is super cool. Also, we forgot to mention this
Speaker 4: early on, but you will hear a lot more about
Speaker 4: phages and their potential role as treatment for antibiotic resistent
Speaker 4: infections later on in the episode from Time Stephanie as well,
Speaker 4: big time, big time.
Speaker 3: So I mean that's pretty much that's pretty much how
Speaker 3: resistance works. Okay, So if we go back to that
Speaker 3: population of ten thousand bacteria that lives in your festering
Speaker 3: hand wound, Okay, just to kind of sum all this up,
Speaker 3: mm hmm. Actually let's call it ten million bacteria.
Speaker 4: Okay, Now my hand wound is really really just it's
Speaker 4: cicy bacteria, yep.
Speaker 3: Okay, so you cut yourself, Now you have ten million
Speaker 3: bacteria in the cut on your hand, and one of
Speaker 3: them happens to be resistant to penicillin, and that's what
Speaker 3: you went to the doctor, and that's what going to
Speaker 3: use to treat your hand infection. Okay, so you take
Speaker 3: the penicillin and it wipes out all but one of
Speaker 3: those bacteria. Right, you have just one loan bacterium left.
Speaker 3: That's not a problem for your hand wound necessarily, but
Speaker 3: that single bacterium is going to continue to multiply and multiply,
Speaker 3: and now inevitably your hand is exposed to tons of
Speaker 3: other bacteria all the time. Right, everything you touch is
Speaker 3: covered in bacteria. So eventually that one bacterium that was
Speaker 3: left and now reproducing that colony that's growing, is going
Speaker 3: to come into contact with some new bacteria and he'll
Speaker 3: probably go, hey, just so you guys know, if you're
Speaker 3: planning on making a home here, all my friends just
Speaker 3: got wiped out by penicillin recently, and I have this
Speaker 3: little plasmid. It seems really helpful, like I survived. So
Speaker 3: do you want this? Just the little betaalactomies? Do you
Speaker 3: want one? And all of the new bacteria're gonna be
Speaker 3: like yeah, heck yeah, I gave me one of those,
Speaker 3: so they'll get together, conjugate and share that plasmid with
Speaker 3: their friends in la antibiotic resistance.
Speaker 4: I like, I feel like we have this this idea
Speaker 4: of an antibiotic resistant bacteria to be completely like bulletproof basically,
Speaker 4: but your body can still fight off that infection.
Speaker 3: Oh for sure, Yeah, yeah, for sure, for sure. The
Speaker 3: other thing too, though, is that many of these antibiotic
Speaker 3: resistance genes come from environmental bacteria, so they don't necessarily
Speaker 3: have to originate by mutation in that one bacterium that
Speaker 3: was left behind. They could have been introduced from outside
Speaker 3: populations to begin with, and then they can spread because
Speaker 3: of selection pressures.
Speaker 4: Oh yeah, and I'll talk about some of those sources resistance.
Speaker 3: I can't wait. So yeah, that was a lot, but
Speaker 3: that was antibiotic resistance in a nutshell.
Speaker 4: I loved it. I loved it.
Speaker 3: Oh good, I'm so glad. So Erin, how the heck
Speaker 3: did we get here?
Speaker 4: I can't wait to tell you?
Speaker 5: Should we take a quick break first, let's do that,
Speaker 5: so Erin.
Speaker 4: You might think that this story the story of antibiotic resistance.
Speaker 4: Maybe it starts with the first sulfonamide or penicil and
Speaker 4: resistant strains of bacteria that were found in hospitals in
Speaker 4: the nineteen forties.
Speaker 3: Are you going to tell me it's way further back
Speaker 3: than that.
Speaker 4: Oh, way, way way further back, like millennia, millions of
Speaker 4: years even, Okay, okay, so even today, like you said,
Speaker 4: many of the antibiotics that we use are compounds produced
Speaker 4: by microbes, fungi, or other bacterial species, And in the
Speaker 4: early years of antibiotics, they were all like that, Like
Speaker 4: synthetic antibiotics really only started to become developed in the
Speaker 4: past few decades. And so I think it's easy to
Speaker 4: take it for granted sometimes that these antibiotic compounds are
Speaker 4: just produced by these soil microbes or fungi and not
Speaker 4: question why exactly they might have evolved to produce substances
Speaker 4: that can kill bacteria, because, like you said, when you're
Speaker 4: producing something like that, it can be a costly thing,
Speaker 4: Like it can be a costly thing to kind of
Speaker 4: go above and beyond just simply replicating yourself and like
Speaker 4: getting food.
Speaker 3: I feel like we talk a lot about this in
Speaker 3: our Plant Crossover episodes with Matt, like it takes a
Speaker 3: lot for plants to make these compounds that kill us.
Speaker 3: It takes a lot for bacteria to make these compounds
Speaker 3: that kill other bacteria.
Speaker 4: Yep. It was just like that with the bachulism episode,
Speaker 4: Like why does this toxin exist?
Speaker 3: Yeah?
Speaker 4: So why do these compounds exist in nature? They didn't
Speaker 4: just arise in the nineteen forties with penicilin like, they've
Speaker 4: been there for millions of years. Okay, so what do
Speaker 4: these compounds do in nature?
Speaker 1: Yeah?
Speaker 4: So let's just think about a little handful of soil. Okay,
Speaker 4: God side, and you've grabbed some soil. In that soil,
Speaker 4: you have this beautiful, complex, rich world of microbes. Even
Speaker 4: though it looks just like a handful of soil, it's
Speaker 4: really like teeming with microbial life. And each one of
Speaker 4: these microbes are all pushing and pulling and fighting for
Speaker 4: space and basically doing what it takes to continue on
Speaker 4: to the next generation. This is a battle that has
Speaker 4: been going on for millions of years, and over that time,
Speaker 4: some microbes have evolved strategies to help them stay one
Speaker 4: step ahead of the race to gain just a little
Speaker 4: more ground, and antibiotic is one example of this type
Speaker 4: of strategy in nature. These antimicrobial compounds actually help the
Speaker 4: bacteria or fungi that produce them in any number of ways,
Speaker 4: like to make super durable biofilms, or to more easily
Speaker 4: invade an animal cell type three secretion system, or to
Speaker 4: clear the competition in a particular area, or to also
Speaker 4: better work alongside another group of bacteria. So they actually
Speaker 4: can help some groups of bacteria. And it's also important
Speaker 4: to remember that in nature, the amount of antibiotic compounds
Speaker 4: produced by some of these bacteria or fungi, especially those
Speaker 4: that make something like tetracycling, for example, is super small,
Speaker 4: like nowhere near what a therapeutic dose would be for humans.
Speaker 3: That is really important to keep in mind.
Speaker 4: Yeah, wow, really important. And so when we make antibiotics
Speaker 4: in a lab or in an industry setting, you are
Speaker 4: like farming penicillin, like you are like farming the fungi
Speaker 4: in the bacteria. You're making gobs and gobs and gobs
Speaker 4: of it, which wouldn't happen in nature. Yeah, yeah, or
Speaker 4: irl Okay, So yeah, make a mental note of that.
Speaker 3: Okay.
Speaker 4: So even though we may tend to think of these
Speaker 4: antibiotic compounds as these brute force drugs that punch holes
Speaker 4: and cell walls or tear apart ribosomes. Their role in
Speaker 4: nature is much more nuanced and much more long standing.
Speaker 4: So it makes sense then that if these microbes have
Speaker 4: evolved the ability to produce antibiotic compounds over thousands or
Speaker 4: millions of years, the bacteria that they are targeting with
Speaker 4: those antibiotics have also evolved a trick or two resistance genes. Yeah,
Speaker 4: and this isn't a guess, This isn't just like the
Speaker 4: logical flow. Antibiotic resistance is ancient, which is actually the
Speaker 4: word for word title of a paper that I read,
Speaker 4: peer reviewed paper. And in this paper, they analyzed thirty
Speaker 4: thousand year old permafrost sediment to look for genetic traces
Speaker 4: of antibiotic resistance. And guess what they found. They found genes.
Speaker 4: They gave resistance to beta lactyms, tetracycline, glycopeptides, even vancomyocin antibiotics.
Speaker 1: Yeah.
Speaker 4: Wow, so at least roughly twenty nine thousand and thirty
Speaker 4: years before penicillin was discovered, these resistance genes existed.
Speaker 3: Just twenty nine thousand years.
Speaker 4: No big deal. Well, I think I think that this
Speaker 4: at least helps to a small degree in understanding just
Speaker 4: how quickly. Some of these resistance genes have popped up because,
Speaker 4: like you said, some have arisen just through mutation. So
Speaker 4: some you could take you could start in the lab
Speaker 4: and start with like or on a human body and
Speaker 4: start with, you know, a colony of a particular type
Speaker 4: of bacteria, and then you could evolve resistance just by
Speaker 4: applying that selection pressure. But I think it's also important
Speaker 4: to remember that some of these mutations may be the
Speaker 4: ones that are a little bit more complex. Some of
Speaker 4: the genes that provide resistance to more complex antibiotic structures,
Speaker 4: they might have roots already just in nature.
Speaker 3: Right, and many many bacteria already have these genes. They
Speaker 3: might just not be turned on right until they face
Speaker 3: the selection pressure. So that's the other thing, is like
Speaker 3: they might be there, they're just not using them yet.
Speaker 4: Right exactly. You know, it's funny erin you say exactly right,
Speaker 4: and I say, right exactly. I've noticed this when I'm editing.
Speaker 4: It's very funny to me. Okay, now I'm gonna be
Speaker 4: self conscious about it. Okay, all right, So now we
Speaker 4: have a little bit better idea of the ancient roots
Speaker 4: of some of these resistance genes. But how do they
Speaker 4: spread so far and so wide so quickly, And you
Speaker 4: talked about the mechanisms of this, so like the transfer
Speaker 4: of genetic material through all these different strategies. But humans
Speaker 4: have been a huge helping hand, oh in the geographic
Speaker 4: spread of this.
Speaker 3: Bacteria can only move so far, Aaron.
Speaker 4: It's true, It's very true. Okay, So, Aarin, you asked,
Speaker 4: how did we get here?
Speaker 3: Yeah, And like you always do, I always do.
Speaker 4: And I think that's really the perfect question to ask
Speaker 4: about antibiotic resistance, because only by understanding what has driven
Speaker 4: the rise of resistance are we going to be able
Speaker 4: to have a chance of slowing it or stopping it.
Speaker 4: And you're going to talk a little bit about what
Speaker 4: here actually looks like in terms of how do we
Speaker 4: get here?
Speaker 3: Right?
Speaker 4: But spoiler alert, it is absolutely terrifi.
Speaker 3: Yeah, it's not great. That's an understatement.
Speaker 4: It's an understatement. Yeah. So, we see widespread multi drug
Speaker 4: resistant bacterial species across the world, and for many microbes,
Speaker 4: our options have completely run out, like we are back
Speaker 4: in the age of before antibiotics. So far, with maybe
Speaker 4: one or two exceptions, this seems to be a one
Speaker 4: way street. So like resistance seems to be only increasing,
Speaker 4: and we've stopped asking the question will antibiotic resistance emerge
Speaker 4: against a particular antibiotic, and now it's just a matter
Speaker 4: of when will it emerge. And the state of things
Speaker 4: has been a long time coming. And this massive increase
Speaker 4: in antibiotic resistant bacteria should not have come as a
Speaker 4: surprise to anyone, and for many people it didn't. So
Speaker 4: in nineteen forty five, the same year that he was
Speaker 4: awarded the Nobel Prize for his discovery of penicillin, Alexander
Speaker 4: Fleming warned about how easy it was to make microbes
Speaker 4: resistant to penicillin. And I don't know if I quoted
Speaker 4: this directly in the MRSA episode.
Speaker 3: I think that you did, because we have definitely quoted
Speaker 3: this before. Okay, it's a great quote.
Speaker 4: Okay, I don't know if it's the same one, because
Speaker 4: there were a few that I was choosing between. So
Speaker 4: we'll see if I if I was consistent in my choices. Okay,
Speaker 4: So he said specifically about improper use. Quote, the greatest
Speaker 4: possibility of evil and self medication is the use of
Speaker 4: two small doses, so that instead of clearing up infection,
Speaker 4: the microbes are educated to resist penicillin, and a host
Speaker 4: of penicillin fast organisms is bred out, which can be
Speaker 4: passed to other individuals and from them to others until
Speaker 4: they reached someone who gets a septicemia or an ammonia
Speaker 4: which penicillin cannot save. So like this was in nineteen
Speaker 4: forty five, This was a couple years after. It was
Speaker 4: after penicillin was introduced to to soldiers, and like a
Speaker 4: year after or the year it was released to the public.
Speaker 4: So you know, like we saw it coming, we saw
Speaker 4: it coming. Despite these warnings, penicillin was everywhere. It was
Speaker 4: available over the counter in the US until the mid
Speaker 4: nineteen fifties, and like we said, is still available without
Speaker 4: a prescription in many places. It was put in cough drops,
Speaker 4: throat sprays, mouthwashes, soaps, you name it.
Speaker 3: Oh my gosh.
Speaker 4: At one point, errand it was even available as like
Speaker 4: a powdered daily dose human growth promoter.
Speaker 3: Stop it, yep, Like goodbye, powdered peniculian to see penicillin.
Speaker 4: Emergency protein powder. Just whatever, Just not pop that into
Speaker 4: your antibiotic.
Speaker 3: Laden milk, oh dear.
Speaker 4: Yeah, And even though regulation slowly increased, it didn't do
Speaker 4: so uniformly, right, and even today, antimicrobials or antibiotics can
Speaker 4: still be found in products you never would have expected
Speaker 4: them to, and their use is still incredibly widespread and
Speaker 4: not as well monitored, especially in some places. Yeah, yeah,
Speaker 4: you know. And as we've said a thousand times on
Speaker 4: this podcast, pathogens don't respect political boundaries. So the rise
Speaker 4: of an antibiotic resistant strain of bacteria somewhere is a
Speaker 4: rise everywhere, right. The story of the rise of antibiotic
Speaker 4: resistance itself is pretty simple and pretty repetitive. You develop
Speaker 4: a new antibiotic, and then, depending on how effective it
Speaker 4: is and how broad its targets are, it becomes the
Speaker 4: hot ticket item and is widely used. And then there's
Speaker 4: a ton of selection pressure, and so resistance develops, and
Speaker 4: then resistance spreads quickly as well, and then that antibiotic
Speaker 4: is no longer the miracle drug that was promised and
Speaker 4: gets resigned to the backshelf the microbes win. Another antibiotic
Speaker 4: comes along, resistance develops, it gets shoved to the back shelf,
Speaker 4: another antibiotic, more resistance, rinse, and repeat like This has
Speaker 4: been going on since the creation of penicillin, and since
Speaker 4: that time there have been more than one hundred and
Speaker 4: fifty antibiotics that have been developed, and resistance has been
Speaker 4: found for all or nearly all of them. I watched
Speaker 4: a documentary called Resistance that I really enjoyed, and I'm
Speaker 4: going to borrow one of the graphics that they presented
Speaker 4: and put it in audio form as a way of
Speaker 4: illustrating the rise of resistance, because it's kind of amazing
Speaker 4: to see just how quickly it became like widespread, Yeah,
Speaker 4: so okay. Sulfonamides introduced nineteen thirty five, resistance detected nineteen forty.
Speaker 4: Penicillin nineteen forty two, introduced resistance nineteen forty five, Streptomycin
Speaker 4: introduced nineteen forty four, resistance nineteen fifty eight. Tetracycline introduced
Speaker 4: nineteen forty eight, resistance nineteen fifty four, chlorum phenacol introduced
Speaker 4: nineteen forty nine, resistance detected nineteen fifty six, and so
Speaker 4: on and so on, like this goes. I could list
Speaker 4: this with like ten more antibiotics that you would recognize
Speaker 4: by name. It's it's incredible, and so it became increasingly apparent, obviously,
Speaker 4: as we are aware today that resistance is inevitable. It's
Speaker 4: just like thanos just another reference, another marvel mar reference.
Speaker 4: But resistance is what we expect, and the discovery of
Speaker 4: plasmids and the ability of bacteria to transfer genes not
Speaker 4: just within species but across them in the nineteen fifties
Speaker 4: is when those things were kind of discovered or developed.
Speaker 4: That helped us a lot in terms of understanding the
Speaker 4: mechanism and how these bacteria were able to gain resistance
Speaker 4: so quickly and how it could spread so rapidly. But
Speaker 4: still enthusiasm for these miracle drugs, and maybe like our
Speaker 4: own hubris that we could, oh, we'll we'll just keep
Speaker 4: going digging in the soil, or we'll go here and
Speaker 4: there and we'll just keep finding new soil bacteria to
Speaker 4: make new antibiotics. Like that maybe also blinded us to
Speaker 4: the horrific implications that these discoveries carried.
Speaker 3: Right.
Speaker 4: The development of antibiotics in the twentieth century was arguably
Speaker 4: the most impactful, or at least one of the most
Speaker 4: impactful medical advancements that we have ever seen. Like it
Speaker 4: must have been incredible, yeah, but within a matter of
Speaker 4: decades we seem to be witnessing the rise and fall
Speaker 4: of these wonder drugs So the big question is where
Speaker 4: did we go wrong? The short answer is through overuse
Speaker 4: or improper use in both medical and agricultural settings. So
Speaker 4: let's dive a little bit deeper into.
Speaker 3: Each as we are wont to do.
Speaker 4: Let's start with medical side of things. As I've mentioned before,
Speaker 4: once they came onto the scene, antibiotics were indiscriminately used
Speaker 4: for anything that might be could be possibly was a
Speaker 4: bacterial infection. And they were even used preventatively, right, And
Speaker 4: they still are used preventatively.
Speaker 3: That's true. Actually, we still in surgery and stuff. Yeah, yeah,
Speaker 3: it's like in surgery though, it like really reduces mortality.
Speaker 4: Right right, right, and so yeah, and so I think
Speaker 4: one thing that I want to get across is that
Speaker 4: antibiotics still should be used. Like they're not bad things.
Speaker 4: They're still hugely important, but we need to really consider
Speaker 4: how we use them so that we save them for
Speaker 4: when we really need them need right. So it's sort
Speaker 4: of proper use, right, and not saying it's it's reducing
Speaker 4: their overuse and turning improper use into proper.
Speaker 3: Use, right yeah, yeah, yeah, totally.
Speaker 4: Because resistance will continue to happen, but at least we
Speaker 4: can slow it down a bit. Okay, So on the
Speaker 4: medical side of things, I see is falling into three
Speaker 4: different issues. So the first lies with improper prescription, and so,
Speaker 4: particularly in the earlier days of antibiotics, this was a
Speaker 4: huge issue, but it also has continued to be a
Speaker 4: huge issue because there sometimes might be a thought that like, okay,
Speaker 4: if there's a ninety five percent chance that an infection
Speaker 4: is viral and a five percent chance that it's bacterial,
Speaker 4: you might just want to prescribe an antibiotic anyway, because
Speaker 4: if it's bacterial, then you could wipe out that infection
Speaker 4: and reduce the suffering of your patient. And if it's not, well,
Speaker 4: what's the harm to that patient. It's thought on an
Speaker 4: individual patient level scale, right, and that makes sense, And
Speaker 4: jumping ahead a bit, a study showed that in twenty ten,
Speaker 4: eighty percent of primary care doctors and seventy percent of
Speaker 4: emergency room doctors were prescribing antibiotics for acute bronchitis, which
Speaker 4: is viral almost always, viral almost always, and so then
Speaker 4: that's how we get into the almost always issue. So
Speaker 4: it's sort of a matter of treating the individual versus
Speaker 4: considering the group as a whole. It's a very tricky decision.
Speaker 4: It's a very tricky situation.
Speaker 3: A thing I think a lot about because my whole
Speaker 3: background is in public health and like thinking about these
Speaker 3: things on a population level, and now I'm going into
Speaker 3: medicine where you're like concerned about the patient in front
Speaker 3: of you, and there's often a conflict between what's best
Speaker 3: for the individual patient and what is best for the public.
Speaker 3: And it is a tricky landmine.
Speaker 4: Mmmmmmm hmm.
Speaker 3: Yeah.
Speaker 4: Yeah, And I'm not going to talk about what we
Speaker 4: should do and the ways we should change it, but
Speaker 4: I think the consensus is is that we do need
Speaker 4: to change sort of the directives of this. Yeah, we
Speaker 4: change how we use them.
Speaker 3: Like, antibiotics are also not benign, right, Like we talked
Speaker 3: about this in the last episode. They have side effects, right,
Speaker 3: They're wiping out your microbiome. They're going to cause side effects,
Speaker 3: So they're also not benign to give a patient, to
Speaker 3: give a person antibiotics if they don't really need them.
Speaker 4: Right, And this is something that we're becoming more and
Speaker 4: more aware of as we talk about the microbiome. And
Speaker 4: some ambiotics, like you said, are also toxic in themselves,
Speaker 4: like they damage certain organs so it's yeah, and then
Speaker 4: there's also just sanitation issues within hospitals. So I mean,
Speaker 4: when you're in a hospital, the rate of people that
Speaker 4: have infections, it's high. Infections are very high, They're very prevalent.
Speaker 4: And this is talking about drug resistant and drugs and
Speaker 4: antibiotics susceptible infections, right, and this makes transfer between patients
Speaker 4: really easy. And this just speaks to the nature also
Speaker 4: of how equipped these bacteria are to keeping their foothold
Speaker 4: in a place and surviving, Like some of these are
Speaker 4: really really difficult to get rid of. Yeah, and so
Speaker 4: a hospital just provides tons of opportunities for bacteria to
Speaker 4: exchange info and to settle onto the skin or into
Speaker 4: the surgical incision site, or into the intestine of someone
Speaker 4: who happens to be in the hospital. Finally, there's the
Speaker 4: third issue, which is that people who are prescribed antibiotics
Speaker 4: might not take them properly, so they might not finish
Speaker 4: their course. By that, I mean, if you're prescribed ten
Speaker 4: days of in an antibiotic and you only take five
Speaker 4: because you start feeling better, all you've done is kind
Speaker 4: of train the bacteria in your body to become resistant.
Speaker 4: And so if that happens and you get severely sick,
Speaker 4: and then you have to go to the hospital, and
Speaker 4: then you're bringing your drug resistant bacteria into the hospital. Yeah,
Speaker 4: she's like, come on, which is not good. And then
Speaker 4: that same twenty ten study that I mentioned just a
Speaker 4: little bit ago, they also showed that up to forty
Speaker 4: percent of people fail to complete their full course of antibiotics.
Speaker 3: Oh yeah.
Speaker 4: And so these three healthcare issues have been a part
Speaker 4: of what is driving intibiotic resistance in hospital and community settings.
Speaker 4: And for the most part, I have to say that
Speaker 4: a dozen like, we have made some forward progress in
Speaker 4: terms of regulating them, but it's we still have a
Speaker 4: long way to go. Okay, but that's just the medical
Speaker 4: side of things. We're only getting started. No, this is
Speaker 4: horrifying because even if tomorrow we enacted all of those changes,
Speaker 4: it might slow down the spread of resistance in healthcare settings,
Speaker 4: but it wouldn't stop the problem entirely. And a small
Speaker 4: part of that is due simply to the nature of resistance.
Speaker 4: It's due to this arms race of bacteria and antibiotic compounds.
Speaker 4: Resistance will always evolve. But another huge part is improper
Speaker 4: antibiotic use in agriculture. And we talked a bit about
Speaker 4: this in the last episode, but I want to go
Speaker 4: more into the history of this since it's such an
Speaker 4: integral part of the story of resistance. So this history
Speaker 4: starts with yet another chance discovery when a researcher was
Speaker 4: looking for a natural source of B twelve to supplement
Speaker 4: the food of chickens to help them better. So he
Speaker 4: learned that streped to mices areo facins, produces vitamin B
Speaker 4: twelve during the fermentation process from making stripped micin. So
Speaker 4: he was like, Hey, can I have some of that
Speaker 4: waste from fermentation, just like the leftover gunk or whatever.
Speaker 4: I'm gonna mix it into the chickens food and just
Speaker 4: see what happens, okay, And the results were remarkable, like
Speaker 4: the chickens grew tremendously much faster than he expected due
Speaker 4: to just B twelve, and so did the piglets that
Speaker 4: he also tried it out on. He was like, Okay,
Speaker 4: is it actually the B twelve that's in the fermentation
Speaker 4: waste or is it trace amounts of the antibiotic that's
Speaker 4: causing this growth? And maybe he was like, well, maybe
Speaker 4: it's suppressing gut like harmful gut bacteria or something else, like,
Speaker 4: regardless of the reason, he couldn't deny that they were
Speaker 4: actually having an effect. So, on average, livestock that were
Speaker 4: fed these growth promoters grew three to eleven percent faster
Speaker 4: than their non antibiotic ridden counterparts. But I've seen actually
Speaker 4: much higher rates quoted, particularly early early on in these experiments.
Speaker 4: Oh and this led to because you could make more
Speaker 4: meat faster, you could sell more meat, and so consumption
Speaker 4: overall really grew. And then it kind of in that
Speaker 4: way firmly established these growth promoters, so called growth promoters,
Speaker 4: as a necessary part of agriculture. And so I'm going
Speaker 4: to use the term growth promoters a lot, and that
Speaker 4: basically means these trace amounts, so like non therapeutic doses
Speaker 4: of antibiotics that are included in food for animals like
Speaker 4: agricultural animals, livestock. Ok okay, so these antibiotic laced foods
Speaker 4: plus preemptive treatment, so like not just as growth promoters,
Speaker 4: but actually like, oh, we're going to dose you so
Speaker 4: that you don't get this or that ulcer or whatever.
Speaker 4: That led to some farmers just packing them all in
Speaker 4: all these animals in as tightly as possible because they
Speaker 4: were secure in the knowledge that the crowd diseases that
Speaker 4: they had previously been worried about wouldn't be much of
Speaker 4: a concern with these antibiotics. And so it really led
Speaker 4: to the rise of like the industry some of the
Speaker 4: more the nastier sides of the industry that we see.
Speaker 3: Wow, yeah, yeah, I did not know that part of it,
Speaker 3: but that makes so much sense. M M.
Speaker 4: And the drug companies that were producing these antibiotics ate
Speaker 4: it up, or rather they were enthusiastic about the livestock
Speaker 4: eating up their antibiotic fermentation waste products because this was
Speaker 4: all stuff that was like they were just throwing it
Speaker 4: away anyway, so it's great for them. So sub therapeutic
Speaker 4: doses of antibiotics were sold as growth promoters starting the
Speaker 4: nineteen fifties, and the huge threat of antibiotic resistance had
Speaker 4: been known and discussed for at least a decade before that,
Speaker 4: and this basically provided the perfect breeding ground for antibiotic
Speaker 4: resistance because if you think about like think about a
Speaker 4: industrial farm full of pigs packed in, you know, all
Speaker 4: close to one another, and then they're all just just
Speaker 4: with antibiotics, like the bacteria that they can move so
Speaker 4: easily that way. Resistance can move so easily that way,
Speaker 4: like it's and manure is one of the best sources
Speaker 4: for anbiotic resistance bacteria apparently, and then there's runoff. Okay anyway,
Speaker 4: and it wasn't just restricted to growth promoters and food
Speaker 4: farmers began toying with different ways to deliver the antibiotics
Speaker 4: to the animals, so they were like in the water
Speaker 4: before they were slaughtered. Like, here's some water injected injected
Speaker 4: into the areas for prime cuts. What painting painting raw
Speaker 4: steak with antibiotics or mixing them in with round beef.
Speaker 3: I'm sorry, why would you mix it in with the
Speaker 3: meat that you're selling to humans? What is the purpose
Speaker 3: of that?
Speaker 4: Well, because then you could it has a longer shelf life.
Speaker 3: Are you kidding me?
Speaker 4: I'm not kidding you. Oh dude. Spinach was even washed
Speaker 4: in streptomycin. I'm so serious.
Speaker 3: Don't chicken eat We're sold in.
Speaker 4: Chickens were literally sold soaking in antibiotics because that would
Speaker 4: lengthen their shelf life. My face, so like you could
Speaker 4: squeeze out like the chicken juices from a raw chicken
Speaker 4: at the grocery store back then, and you could get
Speaker 4: like antibiotics in those juices. The world got its first
Speaker 4: taste of how the use of antibiotics on farms bled
Speaker 4: into human life in the nineteen fifties. So around the
Speaker 4: same time when it was first started to ramp up.
Speaker 3: Oh my god.
Speaker 4: Around this time, penicillin had been made prescription only in
Speaker 4: the US and in Britain, partly because the rates of
Speaker 4: penicillin allergy were just like skyrocketing. And so with these
Speaker 4: increased regulations, physicians and epidemiologists expected to see fewer penicillin
Speaker 4: allergies crop up. Makes sense, right, No, that's not what
Speaker 4: they saw. Instead, they saw an increase, they saw surge.
Speaker 4: And it turns out that the source of the penicillin.
Speaker 4: This is done through like a lot of detective work.
Speaker 4: The source of the penicillin was in the milk that
Speaker 4: people were drinking. Some milk contained so much penicillin that
Speaker 4: it could have been sold as a drug, those therapeutic doses, yes, Groad.
Speaker 4: So this finding led the FDA at least to rule
Speaker 4: that you could no longer treat meat with antibiotics prior
Speaker 4: to it being sold.
Speaker 3: Okay, so, like my stakes are not washed in antibiotics anymore.
Speaker 4: No, No, that's all.
Speaker 3: Done, small blessings.
Speaker 4: Yeah, but yeah, this did nothing to stop the addition
Speaker 4: of antibiotics in feed for animals as a growth promoter.
Speaker 4: And then there was a series of studies in the
Speaker 4: nineteen sixties that clearly demonstrated that growth promoters led to
Speaker 4: the rapid development of resistance in microbes, colonizing both the
Speaker 4: animals as well as the people working with the animals.
Speaker 4: So like this was a kind of a cut and dried,
Speaker 4: very eye opening experiment. Fortunately, this was taken somewhat seriously
Speaker 4: by governments. So the UK took action early on in
Speaker 4: limiting antibiotic use and agriculture. Starting in nineteen seventy one,
Speaker 4: they banned antibiotics as growth promoters if those antibiotics were
Speaker 4: used to treat disease in animals and humans.
Speaker 3: Okay, so you can I no longer use tetracyclines because
Speaker 3: we use those to treat disease for example.
Speaker 4: Yeah, got it. And you had to have a prescription
Speaker 4: for them if you wanted to use them therapeutically.
Speaker 3: Okay.
Speaker 4: And the US was like this close to following suit,
Speaker 4: but you know, we didn't a little bit after this
Speaker 4: decision in the UK, the FDA was like, I'm going
Speaker 4: to lay down the law and we're going to limit
Speaker 4: the use of antibiotics purely to therapeutic purposes. But then
Speaker 4: the mighty dollar of the agricultural industry overruled. Representative Jamie Whitten,
Speaker 4: who was like part of the spokesperson for this industry,
Speaker 4: basically said that he would hold hostage the budget of
Speaker 4: the FDA if the regulations passed, and so because he
Speaker 4: had somehow he had that power aeron I don't know,
Speaker 4: So the White House gave in since the budget hold
Speaker 4: up would have also hurt many other important projects, and
Speaker 4: so Witten, the representative, insisted that the data in support
Speaker 4: of banning the use of non therapeutic antibiotics in agriculture
Speaker 4: was incomplete and biased against farmers. And so then they
Speaker 4: were like, okay, well, we want the farmers. We want
Speaker 4: the agricultural industry to design their own projects and do
Speaker 4: their own research to figure out what the truth is.
Speaker 3: Oh, there's no bias there at all, right.
Speaker 4: I mean, the burden of proof has been on epidemiologists
Speaker 4: and researchers to find that antibiotic use in agricultural settings
Speaker 4: leads to antibiotic resistance that is clinically important in humans.
Speaker 4: Yeah right, But this insistence that those studies were inaccurate
Speaker 4: or that the research was incomplete was just a flat
Speaker 4: out lie because in the nineteen seventies a researcher named
Speaker 4: doctor Stuart Levy wanted to see how rapidly resistance could
Speaker 4: develop or spread in livestock given these growth promoters, So
Speaker 4: he tested out some young chickens who are given tetracycline.
Speaker 4: Within thirty six hours of first being given the feed
Speaker 4: laced with tetracycline, their gut E. Coli was resistant thirty
Speaker 4: six hours. So that's scary enough. And tetracycline is like
Speaker 4: was a broad spectrum, just like awesome used drug was was.
Speaker 4: And so that's scary enough on its own. But what
Speaker 4: made it even scarier is that over the next three months,
Speaker 4: the E. Coli also added to its arsenal genes that
Speaker 4: made it resistant to ampicillin, stripped to miceine, and sulfonamides,
Speaker 4: and the chickens had never even received any of those drugs.
Speaker 4: Whoa the tetracycline had acted like a call to arms
Speaker 4: for these bacteria, like we've faced and defeated one antibiotic,
Speaker 4: so we need to be prepared for any others that
Speaker 4: might come our way, Man oh Man, And I bet
Speaker 4: you didn't think that the study could show even more
Speaker 4: concerning results, but it did, and you're not going to
Speaker 4: be surprised by them. But Levy found the same antibiotic
Speaker 4: resistance in the gutty coli of the farmers and the
Speaker 4: families of those farmers that had kept the chickens, none
Speaker 4: of them had received tetracycline. There have been literally dozens,
Speaker 4: dozens and dozens of peer reviewed articles demonstrating clearly that
Speaker 4: antibiotic use in animals impacts humans. To epidemiologists and physicians
Speaker 4: and microbiologists and biochemists, whether or not rampant use of
Speaker 4: sub therapeutic levels of antibiotics was leading to a huge
Speaker 4: increase in resistance and resistant organisms, that wasn't a scientific question,
Speaker 4: It was firmly established that it was. Instead, it was
Speaker 4: a political one. Does it sound familiar?
Speaker 3: Sounds too familiar, Aaron?
Speaker 4: Yeah. And despite this strong evidence that growth promoters also
Speaker 4: promoted antibiotic resistance and all of the terrifying implications that
Speaker 4: came along with it, the US declined to ban tetracycling
Speaker 4: as a growth promoter, It, along with many other antibiotics,
Speaker 4: continued to be used freely for decades. In livestock, you.
Speaker 3: Said, for decades. Are you gonna tell me some happy
Speaker 3: news at the end of this, like no longer or what?
Speaker 4: There are some some bright moments and some really cool
Speaker 4: little case studies that I won't go into, but I'll mention,
Speaker 4: and I'll mention places to read further about them. Because
Speaker 4: Denmark and Netherlands, whoo whoo okay, And just because a
Speaker 4: country had stricter regulations doesn't mean that they weren't also
Speaker 4: contributing to the resistance problem. A lot of the time,
Speaker 4: there wasn't much regulatory oversight into just how much antibiotics
Speaker 4: were being sold to agriculture, and when there was sort
Speaker 4: of a retrospective look at the amount over time, like
Speaker 4: number of tons or millions of pounds sold over time,
Speaker 4: there actually wasn't really a decrease after some of these
Speaker 4: bands were put into place, because the labeling just changed
Speaker 4: for a lot of these things. Another issue was that
Speaker 4: these bands, like I mentioned, often limited use of antibiotics
Speaker 4: to those that weren't also used to treat animal or
Speaker 4: human infections. But this is also a problem, and that's
Speaker 4: because as resistance to the most common antibiotics grew, doctors
Speaker 4: had to reach increasingly to the back of that cabinet
Speaker 4: for the third and fourth string, antibiotics that had been
Speaker 4: deemed too toxic, or too specific, or too expensive to
Speaker 4: be used. Fankomycin was one of these antibiotics. It kind
Speaker 4: of came. It was one of the earlier ones that
Speaker 4: had been discovered and developed, but it was deemed to
Speaker 4: be too expensive and had some nasty side effects, so
Speaker 4: people were like, nana, we'll just use methicillin instead, and
Speaker 4: so in the nineteen eighties it was dusted off and
Speaker 4: increasingly used to treat stubborn resistant infections, and it seemed
Speaker 4: to be remarkably effective in that microbes weren't showing resistance
Speaker 4: towards it, so that was promising, and some researchers were like, Okay, well,
Speaker 4: how exactly does it work? And they were like, it's
Speaker 4: so complex that it would be nearly impossible for a
Speaker 4: bacterium to develop all of the genetic changes needed to
Speaker 4: overcome this mechanism. It's like an unsinkable ship. Like why
Speaker 4: do we say these things. It's just tempting fate. In
Speaker 4: nineteen eighty nine, the first strains of vancomized and resistant
Speaker 4: entercocci VRE started popping up in hospitals in the US,
Speaker 4: and by nineteen ninety three it was close to being
Speaker 4: endemic in many hospitals. VR baby, VR baby, It's really bad.
Speaker 4: Within five years for showing up, VRE was widespread in
Speaker 4: the US, something that it took MRSA about methicillin resistant
Speaker 4: staff oreas about fifteen years to do. So they were like,
Speaker 4: what the heck? This is super complex, So how could
Speaker 4: there have been enough time that has passed for these
Speaker 4: mutations to actually emerge? Like, what is going on here?
Speaker 4: What happened? Turns out the answer is an agriculture. A
Speaker 4: vancom ioson like antibiotic had been used as a growth
Speaker 4: promoter in livestock for decades. Oh gosh, And so when
Speaker 4: physicians started to reach into the back of that cabinet
Speaker 4: for vancom ioson, the resistance genes were already long present
Speaker 4: and quite prevalent, and then with that added selection pressure
Speaker 4: of being used in a clinical setting, it just spread
Speaker 4: like wildfire, and bad turned to worse when in nineteen
Speaker 4: ninety six, the first vancom iceon resistant staff OUREUSSA infections.
Speaker 4: VERSA infections emerged in Japan. At this point in time,
Speaker 4: about fifty percent of all hospital staff OREUS infections were
Speaker 4: methicone resistant, so treatable only by vancom iyosin. Within the
Speaker 4: next few years, versa was basically everywhere, And again there
Speaker 4: was still lobbying for the continued use of vancom iosin
Speaker 4: and other antibiotics as growth promoters in the US, and
Speaker 4: those lobbyists still refuse to acknowledge how those practices could
Speaker 4: lead to resistance. So Robert Carnival, who is one of
Speaker 4: these lobbyists, is quoted as saying, I'm sure vre can
Speaker 4: transfer from animals to people and it might be resistant,
Speaker 4: but is it of clinical importance?
Speaker 3: Yes, yes, yes it is, yes, oh gosh.
Speaker 4: And it wasn't just vanca icein resistance that agriculture was promoting.
Speaker 4: Calliston was another one of those antibiotics that had put
Speaker 4: aside in favor of more sensitive drugs in the past,
Speaker 4: and it had also been used in agriculture, and so
Speaker 4: resistance was already super high there. And it wasn't just
Speaker 4: resistance genes that spread from agricultural settings to hospitals or communities.
Speaker 4: People realized it was also the bugs themselves, epidemics of
Speaker 4: xpec which I can't remember what that one is, but
Speaker 4: it's some sort of ecoli, toxic ecoli. Yeah, these UTIs
Speaker 4: caused by xpecs. They seemed to be coming from food,
Speaker 4: specifically chicken. Oh gosh, quinnolone resistant Salmonella typhomerium strain DT
Speaker 4: one O four that's a bad one that spread through
Speaker 4: fresh dairy and can kill you, and that came directly
Speaker 4: from animals, and quinnolone resistant Campilo bacter those that was
Speaker 4: found in grocery store chicken.
Speaker 3: Oh gosh.
Speaker 4: So quinnilone had been used in agriculture for years, but
Speaker 4: the sharp, alarming rye of resistance to it prompted the
Speaker 4: FDA finally to propose a ban, propose a ban for
Speaker 4: their use in animals, but a proposal was just a proposal.
Speaker 4: Some drug companies, including Bayer, declared that it would not
Speaker 4: comply voluntarily, so it would fight the proposal and ask
Speaker 4: for a hearing where it could show that quinn alone
Speaker 4: use in animals was of no harm to humans.
Speaker 3: I'm just getting too depressed, Darren.
Speaker 4: I know, okay, but In the late nineteen nineties, it
Speaker 4: is a little shining sun. The European Union moved to
Speaker 4: ban antibiotics as growth promoters like all of them, but
Speaker 4: preventive use was still allowed, which still promoted resistance. Again,
Speaker 4: there didn't seem to be any decline in the amount
Speaker 4: of antibiotics sold for farm use, so from nineteen ninety
Speaker 4: nine to two thousand and six and beyond it stayed
Speaker 4: at six hundred and six tons per year. This is
Speaker 4: after the ban, right However, However, some countries did actually
Speaker 4: do it on their own, and some countries, like in Denmark,
Speaker 4: the industry did it on their own themselves. They were like,
Speaker 4: we're not gonna We're not gonna listen, like they were
Speaker 4: just decided amongst the community and the farmers that they
Speaker 4: were going to do this because they were like what's.
Speaker 3: Right for you know, everyone kind of thing.
Speaker 4: Yeah, So the Netherlands, for example, they really doubled down
Speaker 4: and started policing the use of antibiotics much more, and
Speaker 4: the result was that antibiotic use on farms actually declined
Speaker 4: dramatically starting in twenty thirteen and really cool. The occurrence
Speaker 4: of antibiotic resistant bacteria found in meat also declined, and
Speaker 4: similar things happened in Denmark as well, And all of
Speaker 4: the horrible repercussions that had been promised, like a drop
Speaker 4: off and the weight of livestock sky high meat prices,
Speaker 4: more disease among livestock, none of these things happened. H
Speaker 4: The weight dropped a bit, a little bit, but it
Speaker 4: had been recognized for quite a while that growth promoters
Speaker 4: were no longer achieving the same dramatic gains that had
Speaker 4: been seen when they were first used. Oh no, So
Speaker 4: somewhere inesting that is very interesting. So somewhere in the
Speaker 4: five or six decades since antibiotics were first used in agriculture,
Speaker 4: they had lost their magical ability to promote growth. So
Speaker 4: a couple of different things. It's probably likely that when
Speaker 4: they were first used, the antibiotics were compensating for some
Speaker 4: of the negative ways that the farms were run, so
Speaker 4: like as hygiene and monitoring and nutrition and breeding had changed,
Speaker 4: it had eliminated that gap that growth promoting antibiotics had
Speaker 4: made up. And it's also possible that if it was
Speaker 4: affecting the negative, the harmful gut bacteria or whatever gut bacteria,
Speaker 4: that resistance had emerged and so antibiotics were literally just
Speaker 4: doing nothing.
Speaker 3: Doing less.
Speaker 4: Yeah yeah. And by removing antibiotics from agriculture, places like
Speaker 4: Denmark and the Netherlands incorporated animal welfare into the business model,
Speaker 4: and with that they improved quality, quality of life for
Speaker 4: the animals, quality of meat for consumption, quality of their investment,
Speaker 4: et cetera. But once again, the US failed to make
Speaker 4: similar regulatory progress as Europe. In twenty fifteen, thirty four
Speaker 4: point three million pounds of antibiotics were sold for use
Speaker 4: in animals, compared to approximately seven point seven million pounds
Speaker 4: for humans. But even though the US government agencies were
Speaker 4: slow to stop the over use and misuse of antibiotics,
Speaker 4: some companies actually voluntarily stopped using growth promoters because they
Speaker 4: realized that antibiotics for growth promotion may not be worth
Speaker 4: the cost for human health or the cost of the
Speaker 4: constant legal battles. This industry shift paralleled many others that
Speaker 4: were going on in food supply arenas, so it was
Speaker 4: one after another, both from the meat providing side of things,
Speaker 4: so these big name chicken farms to the food supply aspect,
Speaker 4: so like fast food restaurants, stuff like that, they were
Speaker 4: all starting to offer antibiotic free meat options, and so
Speaker 4: the market seemed to be responding positively to these changes,
Speaker 4: but that's all on the industry side. So even though
Speaker 4: starting in twenty twelve, the US has put in some
Speaker 4: regulations for monitoring the use of antibiotics and agriculture, for
Speaker 4: many years, the amount of antibiotics has actually increased rather
Speaker 4: than decreased. Twenty seventeen did see a decrease, but it
Speaker 4: doesn't seem one hundred percent clear why that decrease happened.
Speaker 4: Maybe it's because of these bands, and that would be great,
Speaker 4: But antibiotic resistance and its association with agriculture is a
Speaker 4: perfect example again of why a one health approach is essential.
Speaker 4: And animals share one bacterial and viral world, and fungal
Speaker 4: world and protozol and parasitic whatever. So the rise of
Speaker 4: antibiotic resist in't bacteria on farms means a rise of
Speaker 4: antibiotic resistant bacteria everywhere. Just like with the medical side
Speaker 4: of things, there is such thing as proper use of
Speaker 4: antibiotics in agriculture, but there has been overuse in terms
Speaker 4: of growth promoters and in terms of preemptive treatment, and
Speaker 4: it has remained a debate and a challenge to kind
Speaker 4: of see what the cost and benefits are. And I
Speaker 4: think we're only becoming more and more aware of the
Speaker 4: cost to humans. And it's also not going to just
Speaker 4: be antibiotic resistant infections in humans. It's also going to
Speaker 4: be livestock as well. So it's an interesting thing to
Speaker 4: think about anyway. But it's not just the US where
Speaker 4: overuse is an issue. Twenty fifteen, a group of researchers
Speaker 4: tried to predict how much antibiotics Brazil, Russia, India, and
Speaker 4: China could be predicted to use in the next fifteen
Speaker 4: years as demand for meat continues to increase. If nothing changed,
Speaker 4: that estimate was one hundred and five thousand, five hundred
Speaker 4: and ninety six tons globally. Oh dear, that's hard to
Speaker 4: wrap your brain around. The annual numbers of antibiotic resistant
Speaker 4: infections and deaths due to those infections are absolutely staggering.
Speaker 4: The history of resistance is like actively still being written,
Speaker 4: and it's not looking good. I want to I mean,
Speaker 4: there are some promising avenues of research ahead of us,
Speaker 4: but I want to end with a quote from the
Speaker 4: amazing book Big Chicken by Maren McKenna. Antibiotic resistance is
Speaker 4: like climate change. It is an overwhelming threat created over
Speaker 4: decades by millions of individual decisions and reinforced by the
Speaker 4: actions of industries. It is also like climate change in
Speaker 4: that the industrialized West and the emerging economies of the
Speaker 4: global South are at odds well with that. Erin, tell
Speaker 4: me where we stand with antibiotic resistance today. Are we
Speaker 4: basically on the brink of returning to a pre antibiotic era?
Speaker 4: Is there any hope?
Speaker 3: I mean, let's find out I need a short break. Yeah. Same, Well,
Speaker 3: let's start with the depressing things and then we'll end
Speaker 3: on a at least hopeful note. How about that? Great? Okay? Ah,
Speaker 3: all right? So medically in the US, at least, the
Speaker 3: CDC estimates that at least forty seven million antibiotic prescriptions
Speaker 3: in the US each year currently are unnecessary. What so
Speaker 3: we're doing great?
Speaker 4: Okay? What does unnecessary mean means?
Speaker 3: I don't know for sure, because that was just a
Speaker 3: stat taking off their like Antibiotic resistance general page, But
Speaker 3: in general, unnecessary means either not the right antibiotic for
Speaker 3: the infection, or using an antibiotic to treat a non
Speaker 3: bacterial infection.
Speaker 4: Right, you wouldn't expect ever to see zero, right, because
Speaker 4: if somebody comes in and they have, you know, some
Speaker 4: infection but you don't know what it is yet, or
Speaker 4: you suspect it's a bacterial infection, you're going to try
Speaker 4: different antibiotics, right, and so that would be included in that.
Speaker 4: I'm just trying to wrap my brain around this. Forty
Speaker 4: seven million.
Speaker 3: Yeah, it's a good question. I don't know if that
Speaker 3: includes like every time that you give vanken zosin in
Speaker 3: the er, which like everyone who comes into the ear
Speaker 3: gets those two antibiotics at first, right when we don't
Speaker 3: know what they have yet, right, So I don't know
Speaker 3: if that's included or if that's just prescriptions like outpatient
Speaker 3: what you get sent home with. Either way, it's terrifying.
Speaker 3: I mean forty seven million.
Speaker 4: Oh yeah, so that's in the US.
Speaker 3: Also in the US, it's estimated that more than and
Speaker 3: this is very recent data, so this is from a
Speaker 3: report that came out at the end of twenty nineteen.
Speaker 3: It's estimated that there are more than two point eight
Speaker 3: million antibiotic resistant infections in the US year that result
Speaker 3: in more than thirty five thousand deaths. Wow, so thirty
Speaker 3: five thousand people a year are dying in the US
Speaker 3: because of antibiotic resistant infections.
Speaker 4: Do you have global numbers?
Speaker 3: Great question. I tried really hard to get solid global numbers.
Speaker 3: It is very, very difficult. So the World Health Organization
Speaker 3: has set up in I believe twenty fifteen, they set
Speaker 3: up the Global Antimicrobial Resistance Surveillance System, which is basically
Speaker 3: every country setting up their own surveillance system. So I
Speaker 3: think now it's over sixty countries that are reporting their
Speaker 3: antimicrobial resistance data to the World Health Organization, but they
Speaker 3: don't seem to aggregate that data and present it as
Speaker 3: overall numbers. Overall, World Health Organization estimates that in many
Speaker 3: parts of the world over forty percent of bacterial infections
Speaker 3: or with bacteria that are resistant to antibiotics. But I
Speaker 3: don't have numbers on deaths. I do have numbers. In
Speaker 3: the EU. In twenty fifteen, an estimate from the European
Speaker 3: Union was that six hundred and seventy one thousand infections
Speaker 3: were likely antibiotic resistant and that likely resulted in thirty
Speaker 3: three thousand deaths in twenty fifteen.
Speaker 4: Oh my gosh.
Speaker 3: So that's in the EU, but a lot of the
Speaker 3: increase in antibiotic use is in low and middle income countries,
Speaker 3: And we don't really have good data on the number
Speaker 3: of resistant infections worldwide. But it's bad, it's not good.
Speaker 3: It's a lot.
Speaker 4: So I have two questions.
Speaker 3: Okay.
Speaker 4: The first question is about in the US, are antibiotic
Speaker 4: resistant infections reportable? Like are you required to report them?
Speaker 3: Well, that's a really good question. I don't fully know
Speaker 3: the answer to that. So there's this that report that
Speaker 3: came out in twenty nineteen has a list of like
Speaker 3: the most concerning pathogens, right, and the World Health Organization
Speaker 3: also has a list of what their pathogens of greatest
Speaker 3: concern are and those lists mostly overlap, So I would
Speaker 3: think that most of those pathogens are going to be
Speaker 3: reportable in the US. Okay, But that doesn't mean like
Speaker 3: every time that, for example, someone comes in with a UTI,
Speaker 3: if you do a urine culture, you might send that
Speaker 3: culture off to see what the resistance profile is, and
Speaker 3: that bacteria might be resistant to a few antibiotics, So
Speaker 3: then we use that to choose what antibiotic we give
Speaker 3: to that person. But I don't think that we then
Speaker 3: report that necessarily to the CDC. It probably goes to
Speaker 3: the local public health district so that we can keep
Speaker 3: track of what the general antibiotic resistance looks like in
Speaker 3: our area. Gotcha, So hospitals keep track of things like that.
Speaker 4: Okay.
Speaker 3: So I will say that a report that came out
Speaker 3: in twenty fourteen, which is earlier than most of the
Speaker 3: data I was hoping to find, estimated that currently worldwide,
Speaker 3: there are seven hundred thousand deaths attributed to antimicrobial resistance worldwide.
Speaker 4: That is a lot.
Speaker 3: It's a lot. And they projected that out and estimated
Speaker 3: that by twenty fifty that number would go up to
Speaker 3: ten million.
Speaker 4: Oh my god, if we do nothing, like if we
Speaker 4: just continue on the same pathway.
Speaker 3: Yeah, Oh my gosh. Yeah. And then they also estimated
Speaker 3: what the overall cost, like the monetary cost of that
Speaker 3: would be, that it would cost the world up to
Speaker 3: one hundred trillion dollars antimicrobial resistance.
Speaker 2: Yep.
Speaker 4: I can't. I can't comprehend that number. Wow.
Speaker 3: I was really hoping to find more recent, like hard
Speaker 3: data on anti microbial resistance, and I came across a
Speaker 3: paper that came out in twenty sixteen that really highlighted
Speaker 3: some of the issues that we have in even trying
Speaker 3: to get a handle on this burden of antibiotic resistance
Speaker 3: because that number, that estimated number of deaths, like it's
Speaker 3: such an estimate. We really don't have solid numbers on that. Well.
Speaker 4: And then I also, you know, my other question was
Speaker 4: was about how do you attribute cause of death exactly?
Speaker 4: And so that's yeah, so like if you're in the
Speaker 4: hospital and you go in for like a routine surgery
Speaker 4: like appendicitis, and you get MRSA and then you die,
Speaker 4: is that MRSA is that appendicitis?
Speaker 3: Right? Exactly? That's kind of exactly what they were highlighting
Speaker 3: in this paper. We can't calculate the number that we
Speaker 3: really need to calculate to know the number of deaths
Speaker 3: attributable to the fail year of antibiotic therapy due to
Speaker 3: antibiotic resistance because we don't know enough about the rates
Speaker 3: of resistance or the rates of infection for so many
Speaker 3: different infections. You have so many things like diarrhea that
Speaker 3: can be caused by so many different pathogens. So like, yeah, right,
Speaker 3: it's a really complicated, big picture.
Speaker 4: Question, but there is no question that it is leading
Speaker 4: to death. And it's horrible.
Speaker 3: Yeah, it really is, and it's a very multifactorial problem.
Speaker 3: Like you mentioned, Aaron, there's a number of different factors
Speaker 3: contributing to this, right, inappropriate prescriptions, misuse of taking those
Speaker 3: antibiotic prescriptions, agriculture, poor sanitation in hospitals. So I will
Speaker 3: say that all of the kind of action plans that
Speaker 3: CDC and WHO and all these different organizations, they're very
Speaker 3: holistic plans, right. They recognize that this is not going
Speaker 3: to be solved by just one change or even a
Speaker 3: few changes. It's a whole bunch of different solutions that
Speaker 3: are going to be required for this problem. But one
Speaker 3: thing that it's definitely going to take are new methods
Speaker 3: of treatment because for many pathogens, resistance is already here.
Speaker 3: So we need new ways to target these pathogenic bacteria.
Speaker 3: We do, and this is where we'll have some shining
Speaker 3: moments of hope. Okay, yay. The good news is there
Speaker 3: are so many people working on the issue of antibiotic
Speaker 3: resistance from a treatment standpoint. You heard in our last
Speaker 3: Antibiotics episode about a group that's working on new methods
Speaker 3: of identifying antibiotic compounds using machine learning, which is so cool.
Speaker 3: I love it so much.
Speaker 4: It's amazing. It's literally unbelievable, so cool.
Speaker 3: There are a number of other groups working on alternative
Speaker 3: therapy strategies as well. There's some really promising data on
Speaker 3: probiotic therapy, which I think is awesome. So basically boosting
Speaker 3: gut microbiomes to try and both treat and prevent toxic infections.
Speaker 4: Fecal transplants, fical transplants.
Speaker 3: So probiotic therapy is a very cool I feel like
Speaker 3: we'll probably talk a lot more about that in a
Speaker 3: Microbiome episode.
Speaker 4: But you should definitely google fecal transplant.
Speaker 3: Oh for sure, it's so cool. There's also a lot
Speaker 3: of work being done on combination therapy, so whether that's
Speaker 3: combinations of an antibiotic and another molecule that blocks a
Speaker 3: normal resistance mechanism to that antibiotic, like augmentin that was
Speaker 3: an example I gave early on, or whether it's giving
Speaker 3: a number of different antibiotics in combination that have different
Speaker 3: mechanisms of action, which is how we already treat things
Speaker 3: like tuberculosis for example.
Speaker 4: Right which by the way, I know we touched on
Speaker 4: this in the tuberculosis episode, but like multi drug or
Speaker 4: extremely druggers is in tuberculosis is terrifying aarin tubercula.
Speaker 3: Yes, this is so terrifying that it's not even included
Speaker 3: on the lists of the terrifying bacteria because it's like
Speaker 3: its whole own version. Like we've known about resistance in
Speaker 3: TV for so long, like we don't even need to
Speaker 3: include it on our list.
Speaker 4: Oh gosh, the escape list. Is that what you're talking about.
Speaker 3: Yeah, I didn't even mention the names of any of them,
Speaker 3: but I got ahead of myself. So some of those
Speaker 3: pathogens include Enterococcus, feceum, staph aureus, club Ciella, Assinitobacter balmani i, Pseudomonis,
Speaker 3: and Enterobacter. Those are the six that are really commonly
Speaker 3: like the big escape I think, just because they make
Speaker 3: a nice acronym. But there's really at least twelve that
Speaker 3: we need to be concerned about.
Speaker 4: But we don't. We don't care about the other six
Speaker 4: just because they don't make a good act.
Speaker 3: They don't make a good acronym. H. Pylori, lah, camplobacteror Gonorrhea, Salmonella, strep. New.
Speaker 4: You know, there aren't enough vowels in there.
Speaker 3: I know that's why they're not included.
Speaker 4: We do care about all of those.
Speaker 3: Oh it's especially gonorrhea, man, Oh my gosh. Yeah, So
Speaker 3: there's a lot. There's also a lot of work being
Speaker 3: done on antimicrobial peptides. There's work being done on stimulating
Speaker 3: the immune response and using our own immune system to
Speaker 3: better fight off infection. There's the use of things like
Speaker 3: iron scavenging molecules. One of the coolest areas and one
Speaker 3: that I've been most excited to talk about for a
Speaker 3: while now, is phage therapy.
Speaker 4: Phage therapy. We briefly touched on it in the MRSA episode,
Speaker 4: very briefly, very briefly, too briefly, far too briefly.
Speaker 3: And so who better to tell you about the status
Speaker 3: of phage therapy research than the provider of our first
Speaker 3: hand account who literally treated her own husband with phage
Speaker 3: therapy and also studies it, doctor Stephanie Strathty. Well, thank
Speaker 3: you so much for taking time out of your day
Speaker 3: to chat with us. We're really excited about this episode
Speaker 3: and thrilled to get the chance to talk to you.
Speaker 3: We'd love for you to kind of give us first
Speaker 3: maybe a brief overview of like what phage therapy is
Speaker 3: for our listeners and kind of how it works sure.
Speaker 2: Well. Phages are viruses that have naturally evolved to attack bacteria.
Speaker 2: They're like the perfect predator for bacteria. They've actually co
Speaker 2: evolved for four billion years. They're the oldest and most
Speaker 2: ubiquitous organism on the planet. And it's thought that there's
Speaker 2: about ten million trillion trillion. That's ten to the power
Speaker 2: of thirty one for you numeric matthew people out there.
Speaker 2: And so they're everywhere. They're on our skin, they're in
Speaker 2: our guts, we poop them out. They're in water. You know,
Speaker 2: a single drop of water can have trillions of phages
Speaker 2: in it. We just haven't been able to understand what
Speaker 2: they're like because they're so small. They're about one hundred
Speaker 2: times smaller than bacteria. And they were discovered in nineteen
Speaker 2: seventeen by a French Canadian named Felixe de Caral, and
Speaker 2: you know, he deduced that these must be viruses that
Speaker 2: are parasites of bacteria, even though you couldn't see them
Speaker 2: until the electron microscope was developed in the early nineteen forties,
Speaker 2: and people actually had a big debate as to whether
Speaker 2: or not these were proteins or whether they were viruses
Speaker 2: or whatever. And Deharel himself was quite a character. He
Speaker 2: was very egotistical, he wasn't formally trained, and he was
Speaker 2: really pushed to the margins of society and the medical field.
Speaker 2: And then when he helped the former Soviet Union developed
Speaker 2: the first page therapy center in the world, it got
Speaker 2: the label, as you know, Soviet science, and this was
Speaker 2: around World War Two, and of course that led to
Speaker 2: a big geopolitical bias of like pink O Komi science,
Speaker 2: and that put a cloud over phage therapy for decades,
Speaker 2: and so that's one of the reasons why the West
Speaker 2: really abandoned it. And of course penicillin came on the
Speaker 2: scene in nineteen forty two. Even though it was discovered
Speaker 2: in nineteen twenty eight, it had been you know, it
Speaker 2: took some time to come to end too the field,
Speaker 2: and that was because it was needed on the warfront.
Speaker 2: And so people thought antibiotics are wonder drugs, and of
Speaker 2: course they were for a while. But anti mycrobia resistance
Speaker 2: has just continued to outpace us, and nobody's really been
Speaker 2: paying attention to that until you know, we get these
Speaker 2: people who are having you know, minor scrapes or surgeries,
Speaker 2: and we realized, oh my gosh, they got a superbug
Speaker 2: and there's nothing left to kill it anymore.
Speaker 4: Could you talk us through what a typical course of
Speaker 4: phage therapy might look like. So how do you even
Speaker 4: go about finding the right phages and then administering them.
Speaker 2: Well, the thing about phages that's both a blessing and
Speaker 2: a curse is that they're really finicky. They only matched
Speaker 2: to specific bacteria. So for an organism like Staphylococcus, which
Speaker 2: you know, one of the strains is mursa right at
Speaker 2: the silin resistant staph wreas that's the superbug that was
Speaker 2: discovered first, maybe about twenty to thirty phages will cover
Speaker 2: the majority of circulating strains around the world, And that's
Speaker 2: pretty good because you don't need that many of them,
Speaker 2: and maybe you could have like a cocktail of phages
Speaker 2: that would you know, cover the majority of those infections.
Speaker 2: But for superbugs like Tom's asked me to back to Bomanii,
Speaker 2: it's very very specific. So the phage not doesn't just
Speaker 2: have to match the genus and the species, it has
Speaker 2: to match the isolate so Tom's bacteria. So that means
Speaker 2: you have to like essentially look for a needle in
Speaker 2: a haystack. But it's a little worse than that because
Speaker 2: when you think about where there's a lot of bacteria,
Speaker 2: that's where you're going to find a lot of phages.
Speaker 2: So if you need to go on a phage hunt,
Speaker 2: you have to go to some of the worst places around.
Speaker 2: And we're talking like sewage, barnyard, waist, scummy ponds, that
Speaker 2: kind of thing. So the phages that were actually used
Speaker 2: to treat tom we're from. So I can say literally
Speaker 2: that my husband is full of I mean, who can
Speaker 2: get to say that to their husband?
Speaker 4: That's amazing.
Speaker 1: And then so what then once you if you go
Speaker 1: in and you dig through all that sewage and you
Speaker 1: get lucky enough you find that needle in the massive,
Speaker 1: massive haystack, do you then take that to the lab
Speaker 1: culture it?
Speaker 4: And then what's the next step after that? How do
Speaker 4: you actually get it into that person?
Speaker 2: Well, the old fashioned plaque assay and it's actually this
Speaker 2: is something that's high school and freshmen learn how to
Speaker 2: do you have a Petrie dish, say with your bacterial
Speaker 2: lawn or your bacteria streaked on it, and if you
Speaker 2: want to see that if you have phages that are
Speaker 2: matching to that bacteria. You put a drop of sewage
Speaker 2: on the petrie dish and you incubate it for twenty
Speaker 2: four to forty eight hours, and if it comes back
Speaker 2: looking like a little like Swiss cheese because there's holes
Speaker 2: literally in the petrie dish, you get really excited because
Speaker 2: even though you can't see the phage, because they're smaller
Speaker 2: than the naked eye and even smaller than the light
Speaker 2: microscope can detect, you know that they've been at work
Speaker 2: because they've gobbled up a bacterial colony there. So then
Speaker 2: you can pluck it out and add it to more
Speaker 2: bacterial suspension, and then you need to purify it, and
Speaker 2: that's the tricky part. There's different techniques to purify phage suspension,
Speaker 2: but if you're going to treat it with phage intravenously,
Speaker 2: you want to get it as pure as possible because
Speaker 2: if there's a lot of bacteria debris and the suspension,
Speaker 2: it could elicit septic shock and the patient and could
Speaker 2: kill them. And that's what we're worried about with Tom's situation,
Speaker 2: and nobody really knew what the threshold for safety was,
Speaker 2: so we were taking a big risk.
Speaker 3: Yeah, so you mentioned kind of how difficult it is
Speaker 3: to even be able to identify and find these phases,
Speaker 3: especially when you're dealing with bacteria where you maybe only
Speaker 3: have like have to find a very specific phage. So
Speaker 3: could you talk maybe a little more broadly about some
Speaker 3: of the pros and cons of using phage therapy, maybe
Speaker 3: in like comparing and contrasting that to antibiotics that we
Speaker 3: have currently.
Speaker 2: Yeah, Well, the good news about phages is that again
Speaker 2: there's ten million, trillion trillion phages on the planet, so
Speaker 2: there's almost an exhaustible supply of them. It's just you
Speaker 2: need to find the right phages to match the bacteria
Speaker 2: that you want to kill. So if you have to
Speaker 2: go back to sewage or you know, barnyard waste or
Speaker 2: whatever every single time you need to treat somebody, that
Speaker 2: would be a real pain. And obviously it's very labor
Speaker 2: intensive and you may not find phages in time, and
Speaker 2: we've been in that situation with other patients. But if
Speaker 2: you have a phage library or a phage bank that's
Speaker 2: essentially like a walking and cooler, where you have thousands
Speaker 2: of phages and they're already identified and characterized and sequenced,
Speaker 2: then you could just kind of go in there and
Speaker 2: you know, see if the bacteria that you want to
Speaker 2: kill has phages in the library. So that's that problem
Speaker 2: about how do you find the phages to match the
Speaker 2: bacteria that you want to kill? Can be overcome, gotcha.
Speaker 4: So one of the questions I had was about dose
Speaker 4: and sort of one of the negative consequences of or
Speaker 4: potential consequences of phages, so like, how do you know
Speaker 4: how much how many phages to give? And also when
Speaker 4: those phages break apart those bacterial cells, what are some
Speaker 4: of the risks associated with that.
Speaker 2: Well, to be honest, nobody really knows the right dose
Speaker 2: for phages in most cases, and that's part of the
Speaker 2: translational basic science research that needs to go on so
Speaker 2: that we can, you know, get ready for clinical trials.
Speaker 2: In Tom's case, we just you know, took an estimate
Speaker 2: based on his weight and the fact that he had
Speaker 2: a systemic infection where you know, the bacteria were in
Speaker 2: every cavity in his body. And we knew that if
Speaker 2: you underdose, if you give too few phages, the body's
Speaker 2: own immune system can eliminate them and the phages might
Speaker 2: not ever reach their target. And we thought, well, is
Speaker 2: there a risk of overdosing him or whoever you're treating,
Speaker 2: And we talked to experts and they said, you know,
Speaker 2: we haven't actually, you know, seen any side effects of
Speaker 2: this as long as the endotoxin, which is essentially the
Speaker 2: bacterial debris that is caused when you are growing up
Speaker 2: a lot of phage. In the context of a lot
Speaker 2: of bacteria that endotoxin, there's a lot of antidoxin left
Speaker 2: that could kill the person. So again, we haven't seen
Speaker 2: that though we've treated over a dozen patients and you
Speaker 2: see San Diego and dozens other internationally.
Speaker 4: Gotcha. Yeah, So you talked a little bit about some
Speaker 4: of these challenges moving forward with phage therapy, but let's
Speaker 4: talk about the bright future. So since the publication of
Speaker 4: your book, there's been a lot of forward progress in
Speaker 4: phage therapy and in new initiatives, and so can you
Speaker 4: talk a little bit about what you see as the
Speaker 4: future for phage therapy and also are there going to
Speaker 4: be genetically engineered phages for specific infections.
Speaker 2: Well, yes, there's been a lot of really exciting developments
Speaker 2: since then. The first is that the first genetically modified
Speaker 2: phage cocktail to be used successfully to treat a human
Speaker 2: Bacterial Infection was published in May of twenty nineteen, so
Speaker 2: a year ago from now, and it was an incredible case,
Speaker 2: just as fantastic as Tom's. This is a young girl,
Speaker 2: her name's Isabelle. I happen to know her now through
Speaker 2: our connections and Facebook and social media. She had a
Speaker 2: hassistic fibrosis and she'd had a double lung transplant and
Speaker 2: had acquired this what's called Microbacterium obsessis. And people who
Speaker 2: are familiar with tuberculosis will know that michael Bacterium tuberculosis,
Speaker 2: a cousin to this Microbacterium obsessis, is the biggest bacterial
Speaker 2: killer in the world. It almost kills two million people
Speaker 2: per year. And so this is a very difficult to
Speaker 2: treat pathogen. And she was literally dying. She was in
Speaker 2: hospice and her mother heard about Tom's case contacted her doctor.
Speaker 2: The doctor contacted some of our colleagues, and we happened
Speaker 2: to know that there was a named Graham Hatful at
Speaker 2: the University of Pittsburgh who runs this wonderful training program
Speaker 2: called Sea Phages that teaches students how to find phages,
Speaker 2: and essentially they're doing this page hunt that I described earlier,
Speaker 2: and all of the phages that they find go into
Speaker 2: a giant phage bank, and they have about fifteen thousand
Speaker 2: Mycobacterium phages. They'd never even dreamed that they could be
Speaker 2: used therapeutically, and when asked, they said, wow, we'll certainly
Speaker 2: see if any of our phages will be a match
Speaker 2: for Isabella's bacteria. And three of them were, and one
Speaker 2: was perfect. Its name was Muddy. It was found on
Speaker 2: a rotting egg plant from South Africa by a student there.
Speaker 2: And all the students who find new phages get to
Speaker 2: name them, right, that's part of the bonus. And two
Speaker 2: of the other phages were the sleepy kind. In our book,
Speaker 2: I described them as hitting this snooze button. They actually
Speaker 2: don't kill the bacterial cell, but that's all they could find.
Speaker 2: What they did was they genetically manipulated those two phages
Speaker 2: by clipping out the repressor gene in a technique called
Speaker 2: we're commineering, which is, you know, a prequel to a
Speaker 2: crisper gene editing, and it forced those sleepy phages to
Speaker 2: become the phage rage kind of phages that actually kill
Speaker 2: the bacterial cell. And then they had to convince the
Speaker 2: UK government where she was living in the UK, that
Speaker 2: this was okay to use, and luckily they went along
Speaker 2: with it because they said, well, it's not a GMO
Speaker 2: because you took away a gene, you didn't add a gene.
Speaker 2: And Isabelle received phage therapy intravenously because based on Trum's protocol,
Speaker 2: we convinced them that it was safe. She left the
Speaker 2: hospital within a week. It was just stunning, and she's
Speaker 2: made a great recovery. She's I believe she's still receiving
Speaker 2: phage therapy now, but she's you know, working, She's finished
Speaker 2: her A level exam, she's learned to drive a car.
Speaker 2: You know, she's dyed her hair purple. You know, she's, like,
Speaker 2: I believe she's eighteen now and she's doing great. So
Speaker 2: that case is a landmark because that's the first time
Speaker 2: that genetically engineered phage has been used to treat a
Speaker 2: bacterial infection and a human being successfully. And also it's
Speaker 2: the first time that a Mycobacterium infection and a human
Speaker 2: has been successfully treated with PAGE therapy. And Len's hope
Speaker 2: that maybe someday we could treat tuberculosis with PAGE therapy.
Speaker 2: Wouldn't that be awesome.
Speaker 4: That is being so exciting. Wow, that is amazing, I mean,
Speaker 4: and it seems like it's coming at just like a
Speaker 4: highly highly needed time and we need to do something
Speaker 4: about this, you know, huge huge grin continuing to grow
Speaker 4: problem of antibiotic resistance. And so, you know, how how
Speaker 4: have you felt the receptivity of phage therapy in you know,
Speaker 4: academic circles for instance. Do you feel like it's people
Speaker 4: are being fairly receptive or is there still some pushback?
Speaker 2: Well, initially, when Tom's case was started to become publicized
Speaker 2: about a year after he was treated, it was presented
Speaker 2: at the one hundred anniversary of the discovery of bacteria
Speaker 2: phages at the past Or Institute, and then the story
Speaker 2: went viral. I mean literally, I was getting contacted by
Speaker 2: people from all over the world. I'm wanting page therapy,
Speaker 2: but it was mostly patients in their families. Doctors were
Speaker 2: very skeptical and until Chip school he started making presentations
Speaker 2: to infectious disease physicians, that's when they started to realize, wow,
Speaker 2: this isn't just a one of there's several other cases
Speaker 2: and it's looking really exciting and they're very well documented.
Speaker 2: And Tom's case is published, and several other cases have
Speaker 2: been published, and of course the Georgians and the Polls
Speaker 2: have been doing this page therapy for years now, and
Speaker 2: there's also interest in their work and they have extraordinary
Speaker 2: clinical experience. But it had been really kind of poo
Speaker 2: pooed because it was thought of as a Soviet science,
Speaker 2: and so it's really been a watershed moment for reasons
Speaker 2: that you know, I don't completely understand, but the story
Speaker 2: itself has kind of led to a lot more interested
Speaker 2: in phage therapy. Pharmas and biotechs have started to get
Speaker 2: into the space because they realized too that with genetically
Speaker 2: engineered or even synthetic phages, they'll be easier to patent.
Speaker 2: The ANIH, which had traditionally not funded any phage therapy,
Speaker 2: they've funded now two clinical trials of phage therapy. The
Speaker 2: first is going to be undertaken by our center iPath
Speaker 2: in collaboration with the Antibiotic Resistance Leadership Group, a network
Speaker 2: of research institutions around the US that had predominantly focused
Speaker 2: on new antibiotics, but since there's no antibiotics in the
Speaker 2: pipeline to speak of, they've embraced page therapy. So We're
Speaker 2: very excited by that because that's what we need now.
Speaker 2: We need clinical trials to advance page therapy and to
Speaker 2: first show efficacy, and then we can, you know, hope
Speaker 2: that the FDA will license it alongside antibiotics. We don't
Speaker 2: think that phage is ever going to replace antibiotics altogether,
Speaker 2: but it will be an important adjunct and it will
Speaker 2: allow us to reduce that amount of antibiotics that we're using.
Speaker 2: We've even seen that phage can be synergistic with antibiotics.
Speaker 2: We saw that in Tom's case and in several other cases.
Speaker 2: So if we can leverage the power of phage, we'll
Speaker 2: be using antibiotics more Wisely, I'm just happy that our
Speaker 2: story can kind of take a rightful place in medical history.
Speaker 2: I mean, Tom and I are really privileged. I mean
Speaker 2: we if we had been living anywhere else, or if
Speaker 2: I didn't have the connections that I did and wonderful
Speaker 2: colleagues at our university hospital, you know, I'd be holding
Speaker 2: you know, an earn with its ashes instead of his hands.
Speaker 2: So that was one of the reasons we decided to
Speaker 2: tell our story because we realized how privileged we are
Speaker 2: and that most people dying from superbugs are in lower
Speaker 2: and middle income countries and they don't have the resources
Speaker 2: we have. So my dream someday is to have an
Speaker 2: open source phage bank that can be accessible to anyone anywhere,
Speaker 2: and I'm fundraising for that through iPath. That's our Center
Speaker 2: for Innovated Phage Applications in Therapeutics and hopefully one of
Speaker 2: these days we'll be able to, you know, say goodbye
Speaker 2: to superbugs.
Speaker 4: That was amazing. We were so excited to speak with you.
Speaker 4: Thank you so much for taking the time to chat.
Speaker 4: So cool, so cool, the coolest to the coolest Aaron.
Speaker 4: Do we have anything else or is it time for sources?
Speaker 3: This was such a fun episode. Let's cover sources.
Speaker 4: Let's do it. I think I might have mentioned a
Speaker 4: couple of times the book Big Chicken, Just a Few,
Speaker 4: Just a Few by Maren McKenna. It's great. It's about
Speaker 4: the use of antibiotics in agriculture, particularly the chicken industry.
Speaker 4: And I also read a few papers that I will
Speaker 4: put on the website. But another book that I read
Speaker 4: is called The Killers Within the Deadly Rise of Drug
Speaker 4: Resistant Bacteria by MB Schneerson and MJ. Plotkin. And finally,
Speaker 4: you guys should definitely check out doctor Strathte's book called
Speaker 4: The Perfect Predator, A scientist race to save her husband
Speaker 4: from a deadly superbug. A memoir so good, you, guys,
Speaker 4: seriously so good.
Speaker 3: I heavily used actually the same book that I used
Speaker 3: for the antibiotic episode, edited by Roslen Anderson at All,
Speaker 3: called Antibacterial Agents, Chemistry, Motive Action, Mechanisms of Resistance, and
Speaker 3: Clinical Applications. And then there's another great paper from twenty
Speaker 3: sixteen called Mechanisms of Antibiotic Resistance that I will link to,
Speaker 3: plus a whole bunch of papers on the kind of
Speaker 3: current status of antibiotic resistance. And we'll link to all
Speaker 3: of our sources from this episode in every episode on
Speaker 3: our website.
Speaker 4: Yes, thank you again so much to doctor Strathte for
Speaker 4: coming on and chatting with us and telling her story.
Speaker 4: We really appreciate it so so much.
Speaker 3: Thank you so much for taking time to speak with us.
Speaker 3: And thank you to Bloodmobile for providing the music for
Speaker 3: this episode and all of our episodes.
Speaker 4: Yes, and thank you to you listeners for listening one
Speaker 4: episodes long fifty one episodes. Now we can continue our excitement. Awesome,
Speaker 4: all right, Well until next time wash your hands.
Speaker 3: You've filthy animals.
Speaker 6: Um um um u