WEBVTT - Ep 51 The Path of Most (Antibiotic) Resistance 0:00:01.240 --> 0:00:01.400 Hi. 0:00:01.480 --> 0:00:05.000 I'm Stephanie Strappie. People call me Steph. I'm the Associate 0:00:05.040 --> 0:00:07.680 Dean of Global Health Sciences at the University of California, 0:00:07.720 --> 0:00:10.680 San Diego, and I now co direct the new Center 0:00:10.720 --> 0:00:14.880 for Innovative Page Applications in Therapeutics known as iPath. That's 0:00:14.920 --> 0:00:18.479 the first page therapy center in North America. But that's 0:00:18.560 --> 0:00:20.480 the end of the story. You want to hear how 0:00:20.480 --> 0:00:23.800 I got there, right, Well, it's a crazy story. People 0:00:23.840 --> 0:00:28.520 often don't even believe that it's true, but it really is. 0:00:29.040 --> 0:00:32.120 My husband and I went on vacasion in Egypt in 0:00:32.159 --> 0:00:36.760 the fall of twenty fifteen, and we're scientists. We travel 0:00:36.800 --> 0:00:40.720 together and we always do off the beaten path kinds 0:00:40.760 --> 0:00:43.720 of things. We had a dream of, you know, going 0:00:43.760 --> 0:00:46.800 to see King Tut's tomb, and we floated down the 0:00:47.000 --> 0:00:51.320 Nile River in a wonderful ship. So everything went great 0:00:51.479 --> 0:00:53.920 until the night before we were supposed to see King 0:00:54.000 --> 0:00:57.520 Tut's tomb, and Tom and I had this wonderful meal 0:00:57.560 --> 0:01:00.720 on top of a cruise ship and he got violently 0:01:00.760 --> 0:01:03.600 all afterwards. I mean he was throwing up all over 0:01:03.640 --> 0:01:05.920 the place, and you know, I just thought he had 0:01:05.920 --> 0:01:08.360 a bad muscle or something. Like that, but actually he 0:01:08.400 --> 0:01:10.800 got very sick. We had to call a doctor to 0:01:10.880 --> 0:01:14.119 the ship. The doctor said, he's going into shock. There 0:01:14.240 --> 0:01:17.520 was no hospital in Luxor, where the ship was docked, 0:01:17.880 --> 0:01:20.160 so we ended up having to go to a community 0:01:20.160 --> 0:01:24.160 clinic there. They diagnosed him with pancreatitis, which is essentially 0:01:24.280 --> 0:01:27.039 an inflammation of the pancreas. But when I called back 0:01:27.080 --> 0:01:30.600 home to our colleagues who are leading the Department of 0:01:30.920 --> 0:01:34.200 Infectious Diseases at UC San Diego, they said, hey, that's 0:01:34.280 --> 0:01:37.200 just a symptom of something else. Because you know you're 0:01:37.640 --> 0:01:40.800 the wine drinker in the family. Tom doesn't drink nearly 0:01:40.840 --> 0:01:43.400 as much as you, and that's usually one of the 0:01:44.120 --> 0:01:46.800 causes of pancreatitis. They said, something else is going on. 0:01:47.680 --> 0:01:51.080 And luckily we had travel insurance, so we were able 0:01:51.120 --> 0:01:55.800 to get him medevact to Frankfurt, Germany, because he was 0:01:55.800 --> 0:01:59.640 too sick to be metavact home. And there they did 0:01:59.680 --> 0:02:01.600 a sea tea scan and saw that he had a 0:02:01.680 --> 0:02:04.560 giant abscess in his abdomen, the size of a football. 0:02:05.200 --> 0:02:07.720 And the doctors came to me and said, you know, 0:02:08.040 --> 0:02:11.000 there's something lurking inside this abscess, and they showed me 0:02:11.040 --> 0:02:16.120 this putrid flask of fluid that they'd taken from this abscess, 0:02:16.160 --> 0:02:18.800 and they said, something's growing in there, and we have 0:02:19.160 --> 0:02:21.080 had to culture it. It's going to take a couple 0:02:21.080 --> 0:02:23.600 of days. But let's hope it's a garden variety of 0:02:23.600 --> 0:02:27.120 microorganism because there's a lot of multi drug resistant bacteria 0:02:27.160 --> 0:02:29.880 in Egypt. Well, I was getting a little bit worried, 0:02:29.919 --> 0:02:32.400 but you know, I thought, hey, we have antibiotics. Anything 0:02:32.480 --> 0:02:35.520 you know that's grown in there, we can handle it. Well, 0:02:35.639 --> 0:02:37.800 the doctors came back in a couple of days and 0:02:37.880 --> 0:02:42.120 they showed me that this name of this organism was 0:02:42.200 --> 0:02:47.360 ascimeo bactor bomanii, and it's something that I used to 0:02:47.360 --> 0:02:49.880 plate on my petri dishes back in the nineteen eighties 0:02:49.919 --> 0:02:52.919 when I was taking a rusty old degree in microbiology 0:02:52.960 --> 0:02:55.840 at the University of Toronto. And again I really wasn't 0:02:55.840 --> 0:02:57.960 that worried, but they said, look, this is actually the 0:02:58.000 --> 0:03:01.079 worst bacteria on the planet. I thought, you know what, 0:03:01.120 --> 0:03:03.320 how can this be the worst back here on the planet, because, 0:03:03.360 --> 0:03:05.520 like you know, twenty years ago, we just had to 0:03:05.600 --> 0:03:09.040 use like goggles in a lab code and that was it. 0:03:09.120 --> 0:03:11.639 It was not worrisome at all. Well, it turns out 0:03:11.680 --> 0:03:14.839 that the antime chrobia resistance crisis had crept up on us, 0:03:15.120 --> 0:03:18.080 and Tom was essentially the poster child for this post 0:03:18.120 --> 0:03:22.600 antibiotic era that we've entered now. And so the doctors 0:03:22.600 --> 0:03:26.120 did what's called an antibiogram to find out the antibiotics 0:03:26.120 --> 0:03:28.920 that could be used to hopefully treat this thing. And 0:03:28.960 --> 0:03:31.400 they came back and they were even more alarmed because 0:03:31.400 --> 0:03:34.600 there was only a couple of antibiotics that it was 0:03:34.760 --> 0:03:38.200 partially sensitive to, and it was resistant to fifteen right 0:03:38.240 --> 0:03:41.600 off the top. Well, I started to get worried now, 0:03:41.840 --> 0:03:46.520 and this is right before Christmas of twenty fifteen. Luckily, 0:03:46.560 --> 0:03:49.600 they stabilized him, got him sent back to San Diego, 0:03:49.720 --> 0:03:53.200 where my colleagues in the Department of Medicine were looking 0:03:53.240 --> 0:03:56.119 after him. And I thought, okay, we're fine, we're home now, right, 0:03:56.200 --> 0:03:58.600 everything's going to be fine. We'll find some antibiotics to, 0:03:59.040 --> 0:04:01.480 you know, to cock tol together to cure this thing. 0:04:01.960 --> 0:04:05.440 And they repeated the culture and they found out that now, 0:04:05.840 --> 0:04:07.960 and even though only a few weeks had passed, this 0:04:08.120 --> 0:04:11.640 organism was resistant to all antibiotics, I mean, even the 0:04:11.720 --> 0:04:16.640 last resor antibioticaliston that was developed in world War two. Well, 0:04:17.120 --> 0:04:19.680 they said, you know, he's too weak for surgery. We 0:04:19.760 --> 0:04:24.680 have no choice but to use interventional radiology to essentially 0:04:24.800 --> 0:04:28.359 stick the holes in his abdomen and put these catheters 0:04:28.400 --> 0:04:30.719 in there to try to drain out this infected fluid 0:04:30.760 --> 0:04:33.000 out of the abscess and hopefully it would shrink and 0:04:33.040 --> 0:04:36.400 then he'd be better. Right, Well, not so fast, because 0:04:36.920 --> 0:04:39.920 even though he had started to improve, one day, he 0:04:39.960 --> 0:04:45.159 sat up in bed and this tube inside his abdomen 0:04:45.320 --> 0:04:49.000 slipped and it just dumped all that infected fluid into 0:04:49.000 --> 0:04:52.760 his abdomen into his bloodstream, and immediately he went into 0:04:52.760 --> 0:04:55.279 septic shock right in front of my eyes. And I'm 0:04:55.279 --> 0:04:57.080 telling you, it was one of the scariest moments of 0:04:57.080 --> 0:05:00.280 my life. We were actually supposed to get discharged in 0:05:00.360 --> 0:05:02.760 a cute care facility the next day, but that wasn't 0:05:02.960 --> 0:05:06.279 happening anytime past. In fact, he was rushed back to 0:05:06.320 --> 0:05:10.120 the ICU in the same hospital and put it into 0:05:10.160 --> 0:05:13.039 an induced coma for a couple of days to give 0:05:13.080 --> 0:05:16.320 his body to rest. And he did wake up from that, 0:05:16.520 --> 0:05:19.600 but now this organism is now in his whole body. 0:05:19.839 --> 0:05:25.359 He was like fully, like systemically infected, and from that 0:05:25.480 --> 0:05:28.400 moment on. He was dying a little bit more each day, 0:05:29.200 --> 0:05:31.360 and it was just horrible to watch. He lost one 0:05:31.400 --> 0:05:34.400 hundred pounds off of his frame. He was in and 0:05:34.400 --> 0:05:36.760 out of a real coma that he wasn't waking up from. 0:05:37.200 --> 0:05:39.960 And one day I heard some colleagues on a conference 0:05:39.960 --> 0:05:42.160 call when I was trying to, you know, keep one 0:05:42.240 --> 0:05:45.440 tether back to the real world, and they said, does 0:05:45.480 --> 0:05:49.039 anybody realize that you know there's anything? Told step that 0:05:49.080 --> 0:05:51.760 her husband is going to die? And I thought, oh 0:05:51.800 --> 0:05:55.120 my god, like nobody has. And I cradled the phone 0:05:55.560 --> 0:05:59.360 in my arms like a baby, and I thought they 0:05:59.440 --> 0:06:01.240 just didn't want to tell me, and I'm going to 0:06:01.279 --> 0:06:03.960 lose them unless I do something. So I had this 0:06:04.040 --> 0:06:06.920 conversation with Tom and asked him if he wanted to live. 0:06:07.600 --> 0:06:09.560 And I didn't know if he could even hear me, 0:06:09.640 --> 0:06:11.520 but I said, if you want to live, please squeeze 0:06:11.520 --> 0:06:14.599 my hand and I'll leave no stone unturned. And he 0:06:14.640 --> 0:06:18.520 squeezed my hand. Now, I mean, I was thrilled, but 0:06:18.800 --> 0:06:20.440 I thought, you know what am I going to do? 0:06:20.600 --> 0:06:23.040 Like I'm not a medical doctor. I don't know how 0:06:23.120 --> 0:06:25.920 to cure this thing. But I did what anybody would 0:06:25.920 --> 0:06:28.520 do in my shoes. Because I'm a scientist. I went 0:06:28.560 --> 0:06:31.440 home and I hit PubMed, you know the Google scholar 0:06:31.480 --> 0:06:34.160 for scientists that the National Library of Medicine has developed, 0:06:34.360 --> 0:06:36.719 and I found this ancient, one hundred year old therapy 0:06:36.760 --> 0:06:41.720 called phage therapy, which are essentially these bacteria. Phages are 0:06:41.960 --> 0:06:45.599 viruses that have naturally evolved to attack bacteria. And I 0:06:45.640 --> 0:06:48.080 had heard about them in my microbiology classes way back 0:06:48.120 --> 0:06:49.960 in the nineteen eighties, but I never knew that they've 0:06:49.960 --> 0:06:53.000 been used to treat bacterial infections. Well turned out that 0:06:53.040 --> 0:06:56.760 they had, that they were considered experimental treatment in the West, 0:06:57.080 --> 0:06:59.520 and they're only being used in the former Soviet Union 0:06:59.560 --> 0:07:03.520 and in parts of Eastern Europe. So I asked the 0:07:03.520 --> 0:07:05.920 colleagues that were treating TOM. I said, you know, could 0:07:05.960 --> 0:07:09.280 we use phage therapy to treat tom and that lead 0:07:09.680 --> 0:07:12.880 infectious disease Doctor doctor Chip Schooley, who is a close 0:07:12.880 --> 0:07:15.680 colleague of mine, he said, what an interesting and intriguing idea. 0:07:16.000 --> 0:07:18.640 You know, if you could find phages that matched a 0:07:18.760 --> 0:07:23.280 Tom's bacterial isolate, I'll call the FDA and request compassionate 0:07:23.400 --> 0:07:27.120 use permission for us to use phage therapy to cure them. 0:07:27.120 --> 0:07:29.400 But I've never done this before, and I don't know 0:07:29.440 --> 0:07:33.520 anybody who has, so you know it's a long shot. Anyway, 0:07:33.640 --> 0:07:37.400 long story short, global village of researchers from all over 0:07:37.400 --> 0:07:41.240 the world stepped up, including researchers from Texas A and 0:07:41.320 --> 0:07:45.600 M University, San Diego State University, and even the US 0:07:45.720 --> 0:07:49.200 maybe chipped in, and we found phages in the nick 0:07:49.240 --> 0:07:53.640 of time to match Tom's bacteria, and we injected them 0:07:53.720 --> 0:07:57.600 into his body, a billion phages per dose every two hours. 0:07:57.760 --> 0:07:59.360 We didn't know if we were going to kill him 0:07:59.560 --> 0:08:02.760 or cure. But three days later he lifted his head 0:08:02.800 --> 0:08:05.680 off the pillow and kissed his daughter's hand, and I'm 0:08:05.680 --> 0:08:07.840 telling you, it was the happiest day of my life. 0:08:08.560 --> 0:08:11.000 So that's our crazy story. I left a lot of 0:08:11.000 --> 0:08:13.400 it out, but it's in our book, The Perfect Predator. 0:08:13.400 --> 0:08:15.600 If you want to hear more details, you want to say, 0:08:15.680 --> 0:08:21.119 Hi Tom, Hi Tom, how are you feeling these days? 0:08:21.200 --> 0:08:22.080 I'm feeling great. 0:08:22.720 --> 0:08:23.560 Can't complain. 0:08:23.800 --> 0:08:26.200 Well I could, but nobody's going to listen after it. 0:08:26.520 --> 0:08:29.600 I got saved like this, Well it's better than the alternative, right, 0:08:29.760 --> 0:08:30.480 You're damn right. 0:09:16.760 --> 0:09:21.120 That was amazing. Thank you so much, Stephanie. We really 0:09:21.120 --> 0:09:24.400 appreciate you taking the time to come on the podcast 0:09:24.440 --> 0:09:25.880 and share your story with us. 0:09:26.040 --> 0:09:33.040 We really really do. It's oh man, what a bonkers story. 0:09:33.640 --> 0:09:36.800 I really really and we'll mention this again, but I 0:09:36.840 --> 0:09:39.680 really really encourage everyone to go out there and read 0:09:39.720 --> 0:09:42.520 The Perfect Predator, which is the book that she wrote 0:09:42.559 --> 0:09:47.000 about this experience. It was on put downable. If that's 0:09:47.040 --> 0:09:49.760 a word, I could not put it down. How about that. 0:09:51.679 --> 0:09:53.040 I really hope that that's a word. 0:09:53.640 --> 0:09:54.760 Yeah, I don't think it is. 0:09:55.360 --> 0:09:55.560 Hi. 0:09:56.200 --> 0:09:58.959 I'm Aaron Welsh and I'm Aaron Oman Updyke. 0:09:59.120 --> 0:10:01.200 And this is the this podcast will kill you. 0:10:01.720 --> 0:10:05.400 So today we're talking about antibiotic resistance. 0:10:06.080 --> 0:10:09.360 Yes, you thought you heard all that you wanted to 0:10:09.400 --> 0:10:13.559 know about antibiotics in the last episode. No way, nopeng 0:10:13.600 --> 0:10:17.199 There's so much so fast. There is so much more 0:10:17.679 --> 0:10:21.079 in the world of antibiotics to learn about, to read about, 0:10:21.160 --> 0:10:24.680 to hear about. And that's what we're doing this episode. 0:10:24.720 --> 0:10:29.560 We promise it's not all depressing, like it's mostly depressing. 0:10:29.080 --> 0:10:31.520 But yeah, we're going to end it on a hope 0:10:31.520 --> 0:10:33.400 for the future. Nope, absolutely, I think. 0:10:33.600 --> 0:10:35.600 Yeah. 0:10:35.679 --> 0:10:40.080 A couple of things we completely forgot Aaron and our 0:10:40.080 --> 0:10:43.640 excitement to do the episode last week to talk about 0:10:43.800 --> 0:10:46.120 why we were so excited beyond just the fact that 0:10:46.200 --> 0:10:51.400 it was antibiotics. It was our fiftieth regular season episode. 0:10:51.559 --> 0:10:54.840 I totally forgot about that. Oh my gosh, I can't 0:10:54.880 --> 0:10:56.720 believe we've made that many episodes. 0:10:57.400 --> 0:11:00.720 I really can't. I remember, like going back to one 0:11:00.800 --> 0:11:02.840 of the earlier ones, and I remember how we used 0:11:02.880 --> 0:11:06.120 to be like, oh my gosh, episode seven, can you 0:11:06.200 --> 0:11:07.560 believe we've made it this far. 0:11:09.200 --> 0:11:11.080 To be fair, I was shocked that we made it 0:11:11.120 --> 0:11:14.000 to seven episodes. So that's fair, that's fair. It was 0:11:14.040 --> 0:11:15.320 a true sentiment at the time. 0:11:18.000 --> 0:11:23.120 The other thing is that I completely forgot to mention 0:11:23.520 --> 0:11:27.080 where the first hand account came from in the antibiotics episode, 0:11:27.640 --> 0:11:30.840 and that was I mean, it's like we're amateurs at 0:11:30.840 --> 0:11:33.440 this On our fiftieth episode, we failed to do the 0:11:33.480 --> 0:11:34.480 most important things. 0:11:34.760 --> 0:11:37.960 Sometimes the days just get to you. 0:11:39.679 --> 0:11:43.040 So that so the first hand account from our last 0:11:43.080 --> 0:11:46.199 episode on antibiotics came from a book called The Youngest 0:11:46.240 --> 0:11:52.240 Science by Lewis Thomas. Okay, so Aaron to a company 0:11:52.880 --> 0:11:57.520 our quarantine for the antibiotics episode, which was penicillin, the 0:11:57.559 --> 0:12:00.360 classic cocktail. What are we drinking this week. 0:12:00.760 --> 0:12:05.560 This week we're drinking the plasmid. Oh if that's not 0:12:05.600 --> 0:12:08.079 funny to you, now, it will be funny as soon 0:12:08.120 --> 0:12:12.680 as I explain the biology of antibiotic resistance exactly exactly. 0:12:13.000 --> 0:12:14.920 And you're like, why are they laughing so hard? 0:12:15.480 --> 0:12:16.800 And what's in the plasmid? 0:12:17.440 --> 0:12:23.320 Great question. It is mezcal, like a honey mint, simple 0:12:23.360 --> 0:12:26.960 syrup and lime juice. It's kind of like a penicillin, 0:12:27.040 --> 0:12:28.679 but it's a take on a penicillin. 0:12:29.320 --> 0:12:32.960 It's a plasmid of a penicillin exactly. 0:12:33.280 --> 0:12:37.440 It's a plasmid of It's a plasmid containing resistance to penicillin. 0:12:39.320 --> 0:12:43.320 We will post the recipe for the alcoholic quarantini and 0:12:43.360 --> 0:12:46.240 the non alcoholic place Berta on our website. This podcast 0:12:46.240 --> 0:12:47.959 will kill you dot com as well as all of 0:12:47.960 --> 0:12:52.400 our social media channels any other business I don't think, 0:12:52.440 --> 0:12:54.320 So let's get right to it. 0:12:54.559 --> 0:13:23.640 I can't wait. We'll take one quick break first, antibiotic resistance. Okay, 0:13:23.840 --> 0:13:26.160 it's a big topic, so we're going to break it down. 0:13:26.480 --> 0:13:30.960 Here's how. First of all, hopefully everyone's listened to the 0:13:31.000 --> 0:13:34.800 antibiotics episode, so you have a framework for how antibiotics work. 0:13:35.280 --> 0:13:39.600 As a very brief overview. Antibiotics are designed to either 0:13:39.760 --> 0:13:44.160 kill or halt the growth of bacteria, and they do 0:13:44.320 --> 0:13:49.839 so by targeting various elements of bacterial cell walls, protein synthesis, 0:13:50.240 --> 0:13:55.960 DNA replication, or metabolism. That's our whole episode in ten seconds. 0:13:56.320 --> 0:13:58.720 Well that's a lot shorter than what the episode actually 0:13:58.720 --> 0:13:59.679 turned out to be erin. 0:14:01.559 --> 0:14:06.920 Okay, So the question first on a basic level, is 0:14:07.880 --> 0:14:12.280 what are the mechanisms of antibiotic resistance? Like, how do 0:14:12.400 --> 0:14:16.200 bacteria actually resist these antibiotics? 0:14:16.280 --> 0:14:17.920 Just sheer force of will? 0:14:18.080 --> 0:14:23.200 That's that's the answer episode over. Once we understand that, 0:14:23.480 --> 0:14:27.200 then we can ask two bigger picture questions, what drives 0:14:27.240 --> 0:14:33.440 antibiotic resistance and how does this resistance spread through populations? Okay, 0:14:33.960 --> 0:14:34.720 are you excited? 0:14:35.320 --> 0:14:36.360 I'm super excited. 0:14:36.400 --> 0:14:41.880 All right, So what are the mechanisms of resistance? First 0:14:41.920 --> 0:14:45.240 of all, you can have intrinsic resistance and you can 0:14:45.280 --> 0:14:47.320 have acquired resistance. 0:14:47.600 --> 0:14:51.320 If you are you being bacteria right, all right, I'm 0:14:51.360 --> 0:14:52.160 a bacterial cell. 0:14:52.200 --> 0:14:57.440 You're a bacterial cell. So very broadly, intrinsic resistance makes 0:14:57.560 --> 0:14:59.960 a lot of sense in the context that a lot 0:15:00.000 --> 0:15:04.600 lot of our antibiotics come from bacterial products. Right, So 0:15:04.680 --> 0:15:08.560 it makes sense that a Streptomyces bacteria, for example, will 0:15:08.600 --> 0:15:10.600 be naturally resistant to streptomycin. 0:15:10.920 --> 0:15:11.480 That makes sense. 0:15:11.560 --> 0:15:15.920 Yeah, So that is intrinsic resistance, which is neither the 0:15:16.000 --> 0:15:19.720 interesting nor the concerning part of antibiotic resistance. So that's 0:15:19.720 --> 0:15:22.560 all we'll say about it. What is both interesting and 0:15:22.680 --> 0:15:27.160 concerning is acquired resistance. And there are a few big 0:15:27.280 --> 0:15:32.560 categories of mechanisms by which bacteria can evade the effects 0:15:32.560 --> 0:15:37.680 of antibiotics. Let's go through them. Number one, bacteria can 0:15:37.760 --> 0:15:44.680 resist antibiotics by changing the target enzymes. So what does 0:15:44.720 --> 0:15:48.600 that mean for drugs like quinolones that we talked about, 0:15:48.600 --> 0:15:54.040 fluoroquinolones or refampin or the sulfonamides. These are drugs that 0:15:54.080 --> 0:15:58.760 bind directly to certain enzymes DNA gyrase or RNA polymerase. 0:15:59.440 --> 0:16:04.160 So if if bacteria modify these enzymes slightly change their 0:16:04.200 --> 0:16:07.560 structure just a little bit, then these antibiotic compounds are 0:16:07.600 --> 0:16:11.040 no longer able to bind to them. Boom, they don't work. 0:16:11.600 --> 0:16:18.200 Makes sense, And that seems like a relatively easy or 0:16:18.240 --> 0:16:22.080 like a relatively simple mutation would be necessary. Like one little. 0:16:21.840 --> 0:16:26.880 Quirk exactly, one little quirk for sure. Another way. That's 0:16:26.920 --> 0:16:31.640 actually very similar in the case of the classes of 0:16:31.640 --> 0:16:36.560 antibiotics that work by binding too ribosomes instead of enzymes. 0:16:37.040 --> 0:16:41.359 If bacteria evolve mutations to their ribosomes such that antibiotics 0:16:41.400 --> 0:16:48.400 can no longer bind, then again, boom resistance. That's pretty straightforward, right, yeah, Okay, 0:16:48.760 --> 0:16:52.360 So we can alter our enzymes that the antibiotics bind to, 0:16:52.720 --> 0:16:56.240 or we can alter the proteins such as ribosomes that 0:16:56.480 --> 0:17:00.920 antibiotics bind to. All right, two other ways that are 0:17:00.960 --> 0:17:07.919 also related. Remember that gram negative bacteria especially have a 0:17:07.960 --> 0:17:11.760 second membrane that surrounds the outside of their cell wall, right, 0:17:11.960 --> 0:17:14.919 and this membrane is less permeable than the cell wall is. 0:17:15.600 --> 0:17:18.919 So we know that gram negative bacteria are already harder 0:17:18.960 --> 0:17:22.800 to target with antibiotics because of that. So for gram 0:17:22.840 --> 0:17:26.720 negative bacteria, the way that antibiotics enter the cells is 0:17:26.840 --> 0:17:33.240 through pores porins little channels in the membrane. Well, if 0:17:33.280 --> 0:17:38.200 antibiotics can only enter certain porins, and bacteria then evolve 0:17:38.480 --> 0:17:41.960 changes either to the type of porins or sometimes just 0:17:42.040 --> 0:17:45.160 to the number of pores on their surface that can 0:17:45.160 --> 0:17:47.880 make them more resistant to certain classes of antibiotics. 0:17:48.840 --> 0:17:49.960 Makes sense, makes sense? 0:17:50.040 --> 0:17:54.359 Right? Basically, just changing the way that antibiotics are able 0:17:54.400 --> 0:17:57.080 to get into the cell, making it harder for antibiotics 0:17:57.119 --> 0:18:03.399 to get in. Similar mechanism is you could kick antibiotics 0:18:03.440 --> 0:18:08.360 out at a faster rate. So these are called eflux pumps. 0:18:09.119 --> 0:18:09.479 Mmmm. 0:18:10.040 --> 0:18:14.359 Yeah, bacteria have e flux pumps because, especially when they have, 0:18:14.720 --> 0:18:18.920 especially gram negative bacteria that have two layers of membrane 0:18:18.920 --> 0:18:20.960 plus a cell wall, they have to be able to 0:18:20.960 --> 0:18:23.840 get stuff in and out of their cells. So eflux 0:18:23.920 --> 0:18:28.000 pumps are a way that they can shuttle molecules outside 0:18:28.040 --> 0:18:32.120 of their cells. And it turns out that the genes 0:18:32.119 --> 0:18:35.640 for these types of eflux pumps aren't turned on all 0:18:35.680 --> 0:18:39.080 of the time because they can be quite costly. They 0:18:39.080 --> 0:18:43.160 can lead to bacteria exporting too much stuff and that 0:18:43.200 --> 0:18:47.679 can change the membrane potential of their cells and ultimately 0:18:48.160 --> 0:18:49.080 lead to cell death. 0:18:49.359 --> 0:18:52.120 Okay, that's interesting, that makes sense too. I like that though. 0:18:52.320 --> 0:18:55.120 Yeah, but in the face of antibiotics, if you can 0:18:55.280 --> 0:18:59.560 upregulate those eflex pumps, then you can ship the antibiotic 0:18:59.640 --> 0:19:02.800 MOLUCU out of the cell before they have time to 0:19:02.880 --> 0:19:03.199 kill you. 0:19:03.760 --> 0:19:06.120 Right, So it's it's worth it. Even though it's costly, 0:19:06.160 --> 0:19:08.200 it's worth it. In the face of something that is 0:19:08.240 --> 0:19:09.240 actually going to kill you. 0:19:09.760 --> 0:19:13.960 That is like the that's like antibiotic resistance in a nutshell, 0:19:14.040 --> 0:19:16.760 it's worth it if the antibiotic is going to kill you. 0:19:17.400 --> 0:19:19.760 Yeah, I mean that's that's evolution in a nutshell. 0:19:20.000 --> 0:19:25.240 Yes, Okay, So those are the two other ways. You 0:19:25.280 --> 0:19:28.360 can change your eflux pumps, and you can change your 0:19:28.600 --> 0:19:31.520 porins right, make it harder for antibiotics to get in 0:19:31.960 --> 0:19:37.000 or export them out even faster. And then the last 0:19:37.080 --> 0:19:43.359 way that you can evade antibiotics is by changing the 0:19:43.480 --> 0:19:47.679 antibiotics themselves. This is my personal favorite mechanism. 0:19:48.000 --> 0:19:48.400 Oohoo. 0:19:49.200 --> 0:19:53.440 Right, So bacteria can evolve ways to alter the antibiotic 0:19:53.480 --> 0:19:57.360 compounds themselves and render them useless. So for this, I'm 0:19:57.359 --> 0:20:00.680 going to actually go through a couple of examples. There's 0:20:00.720 --> 0:20:03.080 a lot of different ways that bacteria can do this, 0:20:03.240 --> 0:20:06.480 so we'll go through two examples of it. The first 0:20:06.760 --> 0:20:10.639 are aminoglycosides, which you might remember from our last episode. 0:20:10.720 --> 0:20:16.040 These are streptomycin tobomycin. These act on bacterial protein synthesis. 0:20:16.040 --> 0:20:21.200 They bind to ribosomes. Okay, h So bacteria can produce 0:20:21.400 --> 0:20:27.479 enzymes naturally, produce enzymes that bind to these antibiotics and 0:20:28.080 --> 0:20:32.879 add stuff to them, whether it's a phosphate or just 0:20:32.960 --> 0:20:37.960 a little carbon group, and that changes the structure of 0:20:38.000 --> 0:20:42.320 the aminoglycoside itself so that it no longer works. It 0:20:42.359 --> 0:20:43.920 basically inactivates it. 0:20:45.240 --> 0:20:50.359 That seems like much trickier to pull off, maybe, but 0:20:50.480 --> 0:20:54.360 they do it really well. It's really cool, all right. 0:20:55.280 --> 0:20:58.640 The other most famous example of this are, of course, 0:20:59.080 --> 0:21:02.120 the beta lactine maces. Have you heard of this? 0:21:03.040 --> 0:21:05.639 Yes, there are enzymes that like actually break down the 0:21:05.640 --> 0:21:06.960 betaalactam ring, right. 0:21:07.040 --> 0:21:12.120 Yes, And the beta lactam ring is how betaalactam antibiotics 0:21:12.119 --> 0:21:17.320 like penicillin and cephalosporin actually work. So many bacteria, especially 0:21:17.400 --> 0:21:22.280 gram positives, produce these enzymes called betaalactamases that bind to 0:21:22.600 --> 0:21:27.639 and inactivate that betaalactam ring. It is so common, like 0:21:27.680 --> 0:21:31.960 betaalactamases are so common and ubiquitous that we actually have 0:21:32.080 --> 0:21:36.680 a whole nother set of drugs that we call betaalactamase inhibitors, 0:21:37.720 --> 0:21:41.640 and these drugs inhibit or reduce the activity of those enzymes. 0:21:41.760 --> 0:21:44.280 So it's actually really common that when we give a 0:21:44.320 --> 0:21:48.760 beta lactam antibiotic like amoxicillin, we give it in combination 0:21:49.000 --> 0:21:53.840 with a beta lactamase inhibitor like clavelanic acid. That combination 0:21:54.040 --> 0:21:56.280 is called augmentin mm hmm. 0:21:56.880 --> 0:22:00.879 It's sort of like the lactamase inhibitors hold back the 0:22:00.920 --> 0:22:03.360 little guards and they're like no, no, you can invade 0:22:03.359 --> 0:22:04.359 the castle. Okay. 0:22:04.440 --> 0:22:10.280 So there's a there's a series of videos that most 0:22:10.359 --> 0:22:13.080 Med students, any Med student listening is gonna laugh really 0:22:13.080 --> 0:22:15.720 hard at that, because we watch these videos called Sketchy 0:22:15.760 --> 0:22:19.679 Micro and they show like beta lactams are these rings, 0:22:19.720 --> 0:22:23.040 and then the beta lactamases are these little like laser 0:22:23.160 --> 0:22:27.159 shooters that shoot away the beta lactams, and then you 0:22:27.240 --> 0:22:30.360 have like the clabulonic acid that has like a armor 0:22:30.359 --> 0:22:31.920 that comes in anyway. 0:22:34.359 --> 0:22:37.639 I like it. It's really great. It's very easy to 0:22:38.160 --> 0:22:40.400 envision all these as like little cartoons for sure. 0:22:40.640 --> 0:22:43.000 Yes. Oh, and they help you learn it a lot, 0:22:43.160 --> 0:22:48.199 a lot easier. Yeah, So it's very cool. We already have, 0:22:48.440 --> 0:22:52.080 like we've known that beta lactamases exist for so long 0:22:52.200 --> 0:22:56.239 that we already have drugs that specifically target those. But 0:22:56.320 --> 0:22:59.320 what's scary is that now many bacteria are what they 0:22:59.440 --> 0:23:05.080 what we call extended spectrum beta lactamese producers, so they 0:23:05.080 --> 0:23:09.280 are making even stronger beta lactamases that can break even 0:23:09.400 --> 0:23:10.840 more of our drugs. 0:23:10.920 --> 0:23:14.520 Essentially, Yeah, I mean that's sort of the theme, Like 0:23:14.600 --> 0:23:17.520 this is the same story, like over and over again, 0:23:17.560 --> 0:23:19.800 with just tiny variations exactly. 0:23:19.880 --> 0:23:22.639 So then that kind of gets to the next question, 0:23:22.680 --> 0:23:25.919 which is what actually drives this resistance? Why is it 0:23:26.000 --> 0:23:30.159 that we have resistance cropping up again and again? And 0:23:30.200 --> 0:23:32.199 we've kind of already touched on it, but the basic 0:23:32.280 --> 0:23:35.760 answer is mutation and selection. 0:23:36.040 --> 0:23:37.200 Right, It's a numbers game. 0:23:37.520 --> 0:23:41.840 Yeah, So for resistance to happen, first a gene for 0:23:41.920 --> 0:23:45.480 that resistance, any one of those types of resistance that 0:23:45.520 --> 0:23:48.320 I already mentioned, a gene for that has to appear 0:23:48.359 --> 0:23:52.640 in the population. And often this happens by random mutation, 0:23:52.840 --> 0:23:57.399 which seems like it should be very unlikely, right. 0:23:58.320 --> 0:24:02.159 Well, given the generation time and how many generations, like 0:24:02.320 --> 0:24:05.240 even within a year or something, a strain of E. 0:24:05.359 --> 0:24:08.640 Cola will have it's not. It becomes surprising that there's 0:24:08.680 --> 0:24:10.959 not resistance rather than surprising that there is. 0:24:11.080 --> 0:24:13.640 Would you like to put some hard numbers on that, Eric, 0:24:13.960 --> 0:24:16.880 You know that I would erin so mutations like this 0:24:17.440 --> 0:24:22.680 that can provide resistance occur about once every ten million cells, 0:24:23.600 --> 0:24:28.600 and because many bacterial species divide so frequently, like once 0:24:28.680 --> 0:24:32.120 every half an hour, it would only take six hours 0:24:32.160 --> 0:24:34.000 to get to ten million cells. 0:24:35.000 --> 0:24:36.080 And all it takes is one. 0:24:36.320 --> 0:24:39.800 All it takes is one. Okay, okay. So that's the 0:24:39.840 --> 0:24:42.800 first step, right, mutation. You have to mutate your DNA 0:24:43.080 --> 0:24:45.800 in such a way that you produce one of those changes. 0:24:46.280 --> 0:24:48.760 And then the second thing that has to happen is 0:24:49.000 --> 0:24:53.639 selection pressure, which essentially means you have to wipe out most, 0:24:53.920 --> 0:24:58.080 but not all, of the bacteria in a population. So 0:24:58.160 --> 0:25:01.240 let's put some numbers on this again. Let's say you 0:25:01.320 --> 0:25:05.239 have like ten thousand bacteria living in a wound on 0:25:05.280 --> 0:25:09.439 your hand. If you killed nine thousand of those bacteria 0:25:09.520 --> 0:25:14.240 by any means, antibiotics or otherwise, you have selected one 0:25:14.320 --> 0:25:18.639 thousand survivors. H those one thousand survivors will go on 0:25:18.880 --> 0:25:25.920 to reproduce. And oftentimes those one thousand survivors aren't representative 0:25:26.000 --> 0:25:28.959 of that whole ten thousand group of bacteria, right, They 0:25:29.080 --> 0:25:31.959 all have their own little mutations that are slightly different, 0:25:33.080 --> 0:25:34.919 but those are the ones that are going to go 0:25:35.080 --> 0:25:38.719 on and reproduce. So if any of those one thousand 0:25:39.080 --> 0:25:42.800 had the ability to resist an antibiotic. Those are going 0:25:42.840 --> 0:25:46.840 to be the ones that now grow and proliferate, right, Okay, 0:25:47.359 --> 0:25:50.879 because remember, like I mentioned, especially with eflux pumps, but 0:25:50.920 --> 0:25:54.399 this is true for many of those other mechanisms of resistance. 0:25:54.960 --> 0:25:58.520 A lot of the genes that confer resistance to antibiotics 0:25:58.800 --> 0:26:02.639 are not useful, and in some cases they're harmful in 0:26:02.720 --> 0:26:04.960 the absence of antibiotics. 0:26:05.200 --> 0:26:08.040 Right. So you could see over time, if you don't 0:26:08.440 --> 0:26:12.520 put any selection pressure on, you know, a bacterial strain, 0:26:12.600 --> 0:26:15.320 as they replicate and replicate and replicate, then the resistance 0:26:15.359 --> 0:26:18.360 genes might drop out because it's more costly to maintain 0:26:18.600 --> 0:26:19.720 exactly right. 0:26:20.840 --> 0:26:25.119 Okay, So then how does this gene that's present in 0:26:25.200 --> 0:26:29.159 let's say a couple of those one thousand bacteria that 0:26:29.200 --> 0:26:33.320 are left, how does it spread through a population Because 0:26:33.320 --> 0:26:38.639 we see antibiotic resistance growing at very rapid rates, right right. 0:26:39.080 --> 0:26:41.600 So to understand this, we basically just have to know 0:26:42.320 --> 0:26:48.080 that bacteria don't just reproduce by fission, right They that's 0:26:48.080 --> 0:26:53.080 how they mainly reproduce, but they also can transfer genetic 0:26:53.200 --> 0:27:00.679 material between cells. Okay, so this gets a get so 0:27:00.720 --> 0:27:01.520 excited about this. 0:27:02.280 --> 0:27:04.639 I think we talked about this in Ecola right with 0:27:04.840 --> 0:27:07.639 Joshua Letterberg, I think, so who discovered this? 0:27:07.880 --> 0:27:12.840 Yeah, So there are three ways that bacteria can introduce 0:27:12.920 --> 0:27:19.840 some variety into their genes besides just mutation, conjugation, transformation, 0:27:20.240 --> 0:27:26.600 and transduction. Conjugation is kind of like bacterial sex. So 0:27:26.720 --> 0:27:30.520 basically two bacteria get together, they pull out their pillas, 0:27:31.760 --> 0:27:35.280 and then they attach their pillas to their partner's pillas, 0:27:36.040 --> 0:27:40.200 and then they can share plasmids. Plasmids are circles of DNA, 0:27:41.600 --> 0:27:45.640 just little round nuggets pieces of DNA, and they can 0:27:45.720 --> 0:27:47.879 transfer them. So they can like hand a plasmiad to 0:27:47.920 --> 0:27:50.520 their partner, and they can grab a plasmid from their partner, 0:27:51.000 --> 0:27:56.280 and sometimes oftentimes those little plasmids have super useful things 0:27:56.320 --> 0:28:01.440 on them, like a better eflux pun or a new 0:28:01.680 --> 0:28:09.639 type of betaactamase for example. Okay, that's conjugation. Transformation is 0:28:09.680 --> 0:28:13.080 when bacteria pick up DNA from the environment. So if 0:28:13.119 --> 0:28:16.280 their neighbor dies and explodes and leaves a bunch of 0:28:16.359 --> 0:28:20.200 DNA floating around, another bacterium can swim by and pick 0:28:20.240 --> 0:28:24.960 some of that up. And finally, transduction is when viruses 0:28:25.119 --> 0:28:32.360 get involved. So bacteria phase which are viruses that infect bacteria. Okay, 0:28:32.520 --> 0:28:38.240 these are important. These bacteria phasias have to use host 0:28:38.280 --> 0:28:41.320 cell machinery in order to reproduce. So what they do 0:28:41.440 --> 0:28:45.160 is they inject their DNA into a bacterium and then 0:28:45.240 --> 0:28:49.600 some of that DNA can get incorporated into the bacterial DNA. 0:28:50.840 --> 0:28:54.800 So then every time a virus picks up and infects 0:28:54.880 --> 0:28:58.600 a new bacterium, they might transfer a little bit of 0:28:58.640 --> 0:29:03.160 that bacterial DNA to a neighboring sell. 0:29:03.200 --> 0:29:07.400 That is super cool. Also, we forgot to mention this 0:29:07.440 --> 0:29:10.920 early on, but you will hear a lot more about 0:29:10.920 --> 0:29:16.600 phages and their potential role as treatment for antibiotic resistent 0:29:16.680 --> 0:29:20.880 infections later on in the episode from Time Stephanie as well, 0:29:21.120 --> 0:29:21.960 big time, big time. 0:29:23.720 --> 0:29:26.680 So I mean that's pretty much that's pretty much how 0:29:26.920 --> 0:29:32.040 resistance works. Okay, So if we go back to that 0:29:32.160 --> 0:29:36.360 population of ten thousand bacteria that lives in your festering 0:29:36.400 --> 0:29:38.920 hand wound, Okay, just to kind of sum all this up, 0:29:39.560 --> 0:29:42.840 mm hmm. Actually let's call it ten million bacteria. 0:29:43.160 --> 0:29:46.680 Okay, Now my hand wound is really really just it's 0:29:46.880 --> 0:29:48.680 cicy bacteria, yep. 0:29:48.800 --> 0:29:51.719 Okay, so you cut yourself, Now you have ten million 0:29:51.760 --> 0:29:55.080 bacteria in the cut on your hand, and one of 0:29:55.080 --> 0:29:58.200 them happens to be resistant to penicillin, and that's what 0:29:58.280 --> 0:30:00.360 you went to the doctor, and that's what going to 0:30:00.440 --> 0:30:03.720 use to treat your hand infection. Okay, so you take 0:30:03.760 --> 0:30:07.440 the penicillin and it wipes out all but one of 0:30:07.520 --> 0:30:12.600 those bacteria. Right, you have just one loan bacterium left. 0:30:13.240 --> 0:30:16.720 That's not a problem for your hand wound necessarily, but 0:30:16.920 --> 0:30:22.000 that single bacterium is going to continue to multiply and multiply, 0:30:23.040 --> 0:30:27.760 and now inevitably your hand is exposed to tons of 0:30:27.840 --> 0:30:31.160 other bacteria all the time. Right, everything you touch is 0:30:31.240 --> 0:30:35.920 covered in bacteria. So eventually that one bacterium that was 0:30:36.000 --> 0:30:41.080 left and now reproducing that colony that's growing, is going 0:30:41.120 --> 0:30:45.280 to come into contact with some new bacteria and he'll 0:30:45.280 --> 0:30:48.160 probably go, hey, just so you guys know, if you're 0:30:48.200 --> 0:30:50.920 planning on making a home here, all my friends just 0:30:50.960 --> 0:30:54.440 got wiped out by penicillin recently, and I have this 0:30:54.480 --> 0:30:58.200 little plasmid. It seems really helpful, like I survived. So 0:30:58.520 --> 0:31:01.920 do you want this? Just the little betaalactomies? Do you 0:31:01.920 --> 0:31:05.080 want one? And all of the new bacteria're gonna be 0:31:05.120 --> 0:31:06.800 like yeah, heck yeah, I gave me one of those, 0:31:07.400 --> 0:31:12.440 so they'll get together, conjugate and share that plasmid with 0:31:12.520 --> 0:31:16.680 their friends in la antibiotic resistance. 0:31:18.120 --> 0:31:22.320 I like, I feel like we have this this idea 0:31:22.480 --> 0:31:28.960 of an antibiotic resistant bacteria to be completely like bulletproof basically, 0:31:29.600 --> 0:31:32.240 but your body can still fight off that infection. 0:31:32.440 --> 0:31:35.000 Oh for sure, Yeah, yeah, for sure, for sure. The 0:31:35.040 --> 0:31:38.640 other thing too, though, is that many of these antibiotic 0:31:38.680 --> 0:31:43.840 resistance genes come from environmental bacteria, so they don't necessarily 0:31:43.880 --> 0:31:47.959 have to originate by mutation in that one bacterium that 0:31:48.000 --> 0:31:51.480 was left behind. They could have been introduced from outside 0:31:51.480 --> 0:31:55.200 populations to begin with, and then they can spread because 0:31:55.200 --> 0:31:56.360 of selection pressures. 0:31:56.880 --> 0:32:01.480 Oh yeah, and I'll talk about some of those sources resistance. 0:32:01.600 --> 0:32:05.320 I can't wait. So yeah, that was a lot, but 0:32:05.320 --> 0:32:07.320 that was antibiotic resistance in a nutshell. 0:32:08.120 --> 0:32:10.560 I loved it. I loved it. 0:32:10.640 --> 0:32:14.400 Oh good, I'm so glad. So Erin, how the heck 0:32:14.480 --> 0:32:15.120 did we get here? 0:32:16.040 --> 0:32:17.640 I can't wait to tell you? 0:32:17.880 --> 0:32:20.560 Should we take a quick break first, let's do that, 0:32:50.880 --> 0:32:51.560 so Erin. 0:32:52.600 --> 0:32:56.360 You might think that this story the story of antibiotic resistance. 0:32:56.760 --> 0:33:00.160 Maybe it starts with the first sulfonamide or penicil and 0:33:00.160 --> 0:33:03.640 resistant strains of bacteria that were found in hospitals in 0:33:03.640 --> 0:33:04.600 the nineteen forties. 0:33:04.800 --> 0:33:06.600 Are you going to tell me it's way further back 0:33:06.600 --> 0:33:07.040 than that. 0:33:07.360 --> 0:33:12.240 Oh, way, way way further back, like millennia, millions of 0:33:12.360 --> 0:33:18.440 years even, Okay, okay, so even today, like you said, 0:33:18.480 --> 0:33:21.200 many of the antibiotics that we use are compounds produced 0:33:21.200 --> 0:33:25.600 by microbes, fungi, or other bacterial species, And in the 0:33:25.640 --> 0:33:28.680 early years of antibiotics, they were all like that, Like 0:33:28.760 --> 0:33:31.560 synthetic antibiotics really only started to become developed in the 0:33:31.600 --> 0:33:34.440 past few decades. And so I think it's easy to 0:33:34.480 --> 0:33:38.800 take it for granted sometimes that these antibiotic compounds are 0:33:39.000 --> 0:33:43.080 just produced by these soil microbes or fungi and not 0:33:43.280 --> 0:33:47.320 question why exactly they might have evolved to produce substances 0:33:47.360 --> 0:33:50.280 that can kill bacteria, because, like you said, when you're 0:33:50.360 --> 0:33:53.440 producing something like that, it can be a costly thing, 0:33:53.520 --> 0:33:55.240 Like it can be a costly thing to kind of 0:33:55.240 --> 0:33:58.720 go above and beyond just simply replicating yourself and like 0:33:58.760 --> 0:33:59.400 getting food. 0:33:59.600 --> 0:34:01.440 I feel like we talk a lot about this in 0:34:01.480 --> 0:34:04.560 our Plant Crossover episodes with Matt, like it takes a 0:34:04.600 --> 0:34:07.080 lot for plants to make these compounds that kill us. 0:34:07.080 --> 0:34:09.640 It takes a lot for bacteria to make these compounds 0:34:09.680 --> 0:34:11.120 that kill other bacteria. 0:34:11.680 --> 0:34:14.680 Yep. It was just like that with the bachulism episode, 0:34:14.719 --> 0:34:16.400 Like why does this toxin exist? 0:34:16.560 --> 0:34:16.840 Yeah? 0:34:16.880 --> 0:34:19.440 So why do these compounds exist in nature? They didn't 0:34:19.480 --> 0:34:23.520 just arise in the nineteen forties with penicilin like, they've 0:34:23.520 --> 0:34:26.279 been there for millions of years. Okay, so what do 0:34:26.320 --> 0:34:27.880 these compounds do in nature? 0:34:28.120 --> 0:34:28.600 Yeah? 0:34:28.680 --> 0:34:31.680 So let's just think about a little handful of soil. Okay, 0:34:32.080 --> 0:34:35.040 God side, and you've grabbed some soil. In that soil, 0:34:35.320 --> 0:34:40.239 you have this beautiful, complex, rich world of microbes. Even 0:34:40.280 --> 0:34:43.120 though it looks just like a handful of soil, it's 0:34:43.160 --> 0:34:46.520 really like teeming with microbial life. And each one of 0:34:46.560 --> 0:34:49.440 these microbes are all pushing and pulling and fighting for 0:34:49.560 --> 0:34:53.000 space and basically doing what it takes to continue on 0:34:53.040 --> 0:34:56.560 to the next generation. This is a battle that has 0:34:56.600 --> 0:35:01.360 been going on for millions of years, and over that time, 0:35:01.560 --> 0:35:05.200 some microbes have evolved strategies to help them stay one 0:35:05.280 --> 0:35:07.719 step ahead of the race to gain just a little 0:35:07.760 --> 0:35:12.399 more ground, and antibiotic is one example of this type 0:35:12.400 --> 0:35:16.640 of strategy in nature. These antimicrobial compounds actually help the 0:35:16.640 --> 0:35:20.120 bacteria or fungi that produce them in any number of ways, 0:35:20.880 --> 0:35:25.040 like to make super durable biofilms, or to more easily 0:35:25.080 --> 0:35:29.400 invade an animal cell type three secretion system, or to 0:35:29.600 --> 0:35:33.360 clear the competition in a particular area, or to also 0:35:33.480 --> 0:35:36.760 better work alongside another group of bacteria. So they actually 0:35:36.760 --> 0:35:40.440 can help some groups of bacteria. And it's also important 0:35:40.440 --> 0:35:43.759 to remember that in nature, the amount of antibiotic compounds 0:35:43.800 --> 0:35:48.360 produced by some of these bacteria or fungi, especially those 0:35:48.400 --> 0:35:53.280 that make something like tetracycling, for example, is super small, 0:35:53.800 --> 0:35:57.440 like nowhere near what a therapeutic dose would be for humans. 0:35:58.080 --> 0:35:59.680 That is really important to keep in mind. 0:35:59.760 --> 0:36:04.879 Yeah, wow, really important. And so when we make antibiotics 0:36:04.920 --> 0:36:07.680 in a lab or in an industry setting, you are 0:36:07.719 --> 0:36:11.800 like farming penicillin, like you are like farming the fungi 0:36:11.840 --> 0:36:14.240 in the bacteria. You're making gobs and gobs and gobs 0:36:14.239 --> 0:36:19.359 of it, which wouldn't happen in nature. Yeah, yeah, or 0:36:19.400 --> 0:36:26.560 irl Okay, So yeah, make a mental note of that. 0:36:26.920 --> 0:36:27.320 Okay. 0:36:28.200 --> 0:36:30.839 So even though we may tend to think of these 0:36:30.840 --> 0:36:34.800 antibiotic compounds as these brute force drugs that punch holes 0:36:34.840 --> 0:36:38.360 and cell walls or tear apart ribosomes. Their role in 0:36:38.480 --> 0:36:42.880 nature is much more nuanced and much more long standing. 0:36:43.320 --> 0:36:47.000 So it makes sense then that if these microbes have 0:36:47.120 --> 0:36:51.120 evolved the ability to produce antibiotic compounds over thousands or 0:36:51.160 --> 0:36:54.319 millions of years, the bacteria that they are targeting with 0:36:54.440 --> 0:37:00.520 those antibiotics have also evolved a trick or two resistance genes. Yeah, 0:37:00.560 --> 0:37:02.799 and this isn't a guess, This isn't just like the 0:37:02.880 --> 0:37:08.480 logical flow. Antibiotic resistance is ancient, which is actually the 0:37:09.400 --> 0:37:11.640 word for word title of a paper that I read, 0:37:12.520 --> 0:37:16.360 peer reviewed paper. And in this paper, they analyzed thirty 0:37:16.440 --> 0:37:19.760 thousand year old permafrost sediment to look for genetic traces 0:37:19.800 --> 0:37:23.920 of antibiotic resistance. And guess what they found. They found genes. 0:37:23.920 --> 0:37:30.560 They gave resistance to beta lactyms, tetracycline, glycopeptides, even vancomyocin antibiotics. 0:37:30.760 --> 0:37:30.960 Yeah. 0:37:31.040 --> 0:37:36.320 Wow, so at least roughly twenty nine thousand and thirty 0:37:36.440 --> 0:37:41.520 years before penicillin was discovered, these resistance genes existed. 0:37:41.280 --> 0:37:43.000 Just twenty nine thousand years. 0:37:43.000 --> 0:37:46.759 No big deal. Well, I think I think that this 0:37:47.040 --> 0:37:50.680 at least helps to a small degree in understanding just 0:37:50.760 --> 0:37:53.960 how quickly. Some of these resistance genes have popped up because, 0:37:54.000 --> 0:37:56.920 like you said, some have arisen just through mutation. So 0:37:56.960 --> 0:37:59.399 some you could take you could start in the lab 0:37:59.440 --> 0:38:02.239 and start with like or on a human body and 0:38:02.320 --> 0:38:05.040 start with, you know, a colony of a particular type 0:38:05.040 --> 0:38:08.759 of bacteria, and then you could evolve resistance just by 0:38:08.760 --> 0:38:12.480 applying that selection pressure. But I think it's also important 0:38:12.480 --> 0:38:15.239 to remember that some of these mutations may be the 0:38:15.239 --> 0:38:17.440 ones that are a little bit more complex. Some of 0:38:17.480 --> 0:38:21.880 the genes that provide resistance to more complex antibiotic structures, 0:38:22.520 --> 0:38:26.160 they might have roots already just in nature. 0:38:26.080 --> 0:38:29.920 Right, and many many bacteria already have these genes. They 0:38:30.000 --> 0:38:33.840 might just not be turned on right until they face 0:38:33.880 --> 0:38:36.000 the selection pressure. So that's the other thing, is like 0:38:36.040 --> 0:38:39.520 they might be there, they're just not using them yet. 0:38:39.800 --> 0:38:44.879 Right exactly. You know, it's funny erin you say exactly right, 0:38:44.960 --> 0:38:49.600 and I say, right exactly. I've noticed this when I'm editing. 0:38:50.840 --> 0:38:54.040 It's very funny to me. Okay, now I'm gonna be 0:38:54.080 --> 0:38:59.360 self conscious about it. Okay, all right, So now we 0:38:59.400 --> 0:39:02.480 have a little bit better idea of the ancient roots 0:39:02.560 --> 0:39:06.359 of some of these resistance genes. But how do they 0:39:06.400 --> 0:39:10.640 spread so far and so wide so quickly, And you 0:39:10.760 --> 0:39:14.080 talked about the mechanisms of this, so like the transfer 0:39:14.120 --> 0:39:18.320 of genetic material through all these different strategies. But humans 0:39:18.360 --> 0:39:22.279 have been a huge helping hand, oh in the geographic 0:39:22.320 --> 0:39:22.880 spread of this. 0:39:23.120 --> 0:39:26.319 Bacteria can only move so far, Aaron. 0:39:26.480 --> 0:39:30.640 It's true, It's very true. Okay, So, Aarin, you asked, 0:39:30.840 --> 0:39:31.759 how did we get here? 0:39:32.000 --> 0:39:34.520 Yeah, And like you always do, I always do. 0:39:35.120 --> 0:39:38.360 And I think that's really the perfect question to ask 0:39:38.440 --> 0:39:42.680 about antibiotic resistance, because only by understanding what has driven 0:39:42.760 --> 0:39:45.640 the rise of resistance are we going to be able 0:39:45.680 --> 0:39:49.040 to have a chance of slowing it or stopping it. 0:39:50.680 --> 0:39:52.640 And you're going to talk a little bit about what 0:39:52.840 --> 0:39:54.920 here actually looks like in terms of how do we 0:39:54.960 --> 0:39:55.359 get here? 0:39:55.680 --> 0:39:55.799 Right? 0:39:56.480 --> 0:39:59.960 But spoiler alert, it is absolutely terrifi. 0:40:00.520 --> 0:40:03.960 Yeah, it's not great. That's an understatement. 0:40:04.400 --> 0:40:10.680 It's an understatement. Yeah. So, we see widespread multi drug 0:40:10.760 --> 0:40:17.920 resistant bacterial species across the world, and for many microbes, 0:40:18.239 --> 0:40:22.720 our options have completely run out, like we are back 0:40:22.760 --> 0:40:28.040 in the age of before antibiotics. So far, with maybe 0:40:28.080 --> 0:40:30.480 one or two exceptions, this seems to be a one 0:40:30.480 --> 0:40:33.880 way street. So like resistance seems to be only increasing, 0:40:34.840 --> 0:40:38.640 and we've stopped asking the question will antibiotic resistance emerge 0:40:38.719 --> 0:40:41.479 against a particular antibiotic, and now it's just a matter 0:40:41.560 --> 0:40:45.000 of when will it emerge. And the state of things 0:40:45.040 --> 0:40:47.720 has been a long time coming. And this massive increase 0:40:47.760 --> 0:40:52.360 in antibiotic resistant bacteria should not have come as a 0:40:52.400 --> 0:40:56.400 surprise to anyone, and for many people it didn't. So 0:40:56.520 --> 0:40:58.759 in nineteen forty five, the same year that he was 0:40:58.800 --> 0:41:02.920 awarded the Nobel Prize for his discovery of penicillin, Alexander 0:41:02.960 --> 0:41:06.240 Fleming warned about how easy it was to make microbes 0:41:06.280 --> 0:41:09.960 resistant to penicillin. And I don't know if I quoted 0:41:09.960 --> 0:41:12.480 this directly in the MRSA episode. 0:41:12.640 --> 0:41:15.240 I think that you did, because we have definitely quoted 0:41:15.280 --> 0:41:17.600 this before. Okay, it's a great quote. 0:41:17.840 --> 0:41:19.560 Okay, I don't know if it's the same one, because 0:41:19.560 --> 0:41:21.239 there were a few that I was choosing between. So 0:41:21.680 --> 0:41:25.560 we'll see if I if I was consistent in my choices. Okay, 0:41:25.760 --> 0:41:30.600 So he said specifically about improper use. Quote, the greatest 0:41:30.600 --> 0:41:33.680 possibility of evil and self medication is the use of 0:41:33.719 --> 0:41:36.720 two small doses, so that instead of clearing up infection, 0:41:36.920 --> 0:41:40.040 the microbes are educated to resist penicillin, and a host 0:41:40.280 --> 0:41:43.279 of penicillin fast organisms is bred out, which can be 0:41:43.360 --> 0:41:46.520 passed to other individuals and from them to others until 0:41:46.520 --> 0:41:49.360 they reached someone who gets a septicemia or an ammonia 0:41:49.440 --> 0:41:54.000 which penicillin cannot save. So like this was in nineteen 0:41:54.040 --> 0:41:57.440 forty five, This was a couple years after. It was 0:41:57.920 --> 0:42:02.600 after penicillin was introduced to to soldiers, and like a 0:42:02.680 --> 0:42:05.480 year after or the year it was released to the public. 0:42:05.760 --> 0:42:08.399 So you know, like we saw it coming, we saw 0:42:08.440 --> 0:42:12.080 it coming. Despite these warnings, penicillin was everywhere. It was 0:42:12.120 --> 0:42:14.520 available over the counter in the US until the mid 0:42:14.560 --> 0:42:17.759 nineteen fifties, and like we said, is still available without 0:42:17.760 --> 0:42:21.400 a prescription in many places. It was put in cough drops, 0:42:21.440 --> 0:42:24.600 throat sprays, mouthwashes, soaps, you name it. 0:42:24.840 --> 0:42:25.920 Oh my gosh. 0:42:26.200 --> 0:42:30.000 At one point, errand it was even available as like 0:42:30.120 --> 0:42:33.800 a powdered daily dose human growth promoter. 0:42:34.280 --> 0:42:40.720 Stop it, yep, Like goodbye, powdered peniculian to see penicillin. 0:42:40.320 --> 0:42:44.960 Emergency protein powder. Just whatever, Just not pop that into 0:42:45.000 --> 0:42:46.920 your antibiotic. 0:42:46.400 --> 0:42:52.320 Laden milk, oh dear. 0:42:52.880 --> 0:42:57.600 Yeah, And even though regulation slowly increased, it didn't do 0:42:57.840 --> 0:43:03.040 so uniformly, right, and even today, antimicrobials or antibiotics can 0:43:03.080 --> 0:43:05.880 still be found in products you never would have expected 0:43:05.880 --> 0:43:10.520 them to, and their use is still incredibly widespread and 0:43:11.239 --> 0:43:16.560 not as well monitored, especially in some places. Yeah, yeah, 0:43:17.360 --> 0:43:20.279 you know. And as we've said a thousand times on 0:43:20.320 --> 0:43:26.280 this podcast, pathogens don't respect political boundaries. So the rise 0:43:26.360 --> 0:43:30.200 of an antibiotic resistant strain of bacteria somewhere is a 0:43:30.320 --> 0:43:34.160 rise everywhere, right. The story of the rise of antibiotic 0:43:34.200 --> 0:43:40.160 resistance itself is pretty simple and pretty repetitive. You develop 0:43:40.160 --> 0:43:42.759 a new antibiotic, and then, depending on how effective it 0:43:42.840 --> 0:43:45.400 is and how broad its targets are, it becomes the 0:43:45.440 --> 0:43:48.560 hot ticket item and is widely used. And then there's 0:43:48.600 --> 0:43:51.799 a ton of selection pressure, and so resistance develops, and 0:43:51.840 --> 0:43:56.040 then resistance spreads quickly as well, and then that antibiotic 0:43:56.120 --> 0:43:58.279 is no longer the miracle drug that was promised and 0:43:58.320 --> 0:44:03.160 gets resigned to the backshelf the microbes win. Another antibiotic 0:44:03.200 --> 0:44:07.320 comes along, resistance develops, it gets shoved to the back shelf, 0:44:07.520 --> 0:44:10.560 another antibiotic, more resistance, rinse, and repeat like This has 0:44:10.560 --> 0:44:15.680 been going on since the creation of penicillin, and since 0:44:15.719 --> 0:44:17.359 that time there have been more than one hundred and 0:44:17.360 --> 0:44:20.759 fifty antibiotics that have been developed, and resistance has been 0:44:20.760 --> 0:44:25.640 found for all or nearly all of them. I watched 0:44:25.640 --> 0:44:29.160 a documentary called Resistance that I really enjoyed, and I'm 0:44:29.160 --> 0:44:31.600 going to borrow one of the graphics that they presented 0:44:31.760 --> 0:44:33.560 and put it in audio form as a way of 0:44:33.600 --> 0:44:37.560 illustrating the rise of resistance, because it's kind of amazing 0:44:37.640 --> 0:44:42.760 to see just how quickly it became like widespread, Yeah, 0:44:42.920 --> 0:44:48.680 so okay. Sulfonamides introduced nineteen thirty five, resistance detected nineteen forty. 0:44:49.080 --> 0:44:54.440 Penicillin nineteen forty two, introduced resistance nineteen forty five, Streptomycin 0:44:54.520 --> 0:44:59.120 introduced nineteen forty four, resistance nineteen fifty eight. Tetracycline introduced 0:44:59.200 --> 0:45:03.360 nineteen forty eight, resistance nineteen fifty four, chlorum phenacol introduced 0:45:03.400 --> 0:45:06.640 nineteen forty nine, resistance detected nineteen fifty six, and so 0:45:06.680 --> 0:45:08.799 on and so on, like this goes. I could list 0:45:08.840 --> 0:45:13.640 this with like ten more antibiotics that you would recognize 0:45:13.640 --> 0:45:21.080 by name. It's it's incredible, and so it became increasingly apparent, obviously, 0:45:21.120 --> 0:45:25.520 as we are aware today that resistance is inevitable. It's 0:45:25.600 --> 0:45:31.680 just like thanos just another reference, another marvel mar reference. 0:45:33.560 --> 0:45:37.360 But resistance is what we expect, and the discovery of 0:45:37.400 --> 0:45:40.960 plasmids and the ability of bacteria to transfer genes not 0:45:41.239 --> 0:45:44.640 just within species but across them in the nineteen fifties 0:45:44.719 --> 0:45:47.240 is when those things were kind of discovered or developed. 0:45:47.280 --> 0:45:50.880 That helped us a lot in terms of understanding the 0:45:50.960 --> 0:45:55.000 mechanism and how these bacteria were able to gain resistance 0:45:55.000 --> 0:45:58.360 so quickly and how it could spread so rapidly. But 0:45:59.080 --> 0:46:04.080 still enthusiasm for these miracle drugs, and maybe like our 0:46:04.120 --> 0:46:06.839 own hubris that we could, oh, we'll we'll just keep 0:46:06.840 --> 0:46:09.040 going digging in the soil, or we'll go here and 0:46:09.080 --> 0:46:12.560 there and we'll just keep finding new soil bacteria to 0:46:12.640 --> 0:46:18.880 make new antibiotics. Like that maybe also blinded us to 0:46:19.120 --> 0:46:23.160 the horrific implications that these discoveries carried. 0:46:23.320 --> 0:46:23.520 Right. 0:46:24.760 --> 0:46:28.360 The development of antibiotics in the twentieth century was arguably 0:46:28.480 --> 0:46:30.879 the most impactful, or at least one of the most 0:46:30.920 --> 0:46:34.719 impactful medical advancements that we have ever seen. Like it 0:46:34.840 --> 0:46:37.799 must have been incredible, yeah, but within a matter of 0:46:37.840 --> 0:46:41.320 decades we seem to be witnessing the rise and fall 0:46:41.480 --> 0:46:45.000 of these wonder drugs So the big question is where 0:46:45.000 --> 0:46:48.600 did we go wrong? The short answer is through overuse 0:46:48.719 --> 0:46:53.719 or improper use in both medical and agricultural settings. So 0:46:53.800 --> 0:46:55.600 let's dive a little bit deeper into. 0:46:55.400 --> 0:46:57.440 Each as we are wont to do. 0:46:59.480 --> 0:47:02.920 Let's start with medical side of things. As I've mentioned before, 0:47:03.160 --> 0:47:06.520 once they came onto the scene, antibiotics were indiscriminately used 0:47:06.560 --> 0:47:10.920 for anything that might be could be possibly was a 0:47:10.960 --> 0:47:15.319 bacterial infection. And they were even used preventatively, right, And 0:47:15.360 --> 0:47:16.719 they still are used preventatively. 0:47:17.200 --> 0:47:20.600 That's true. Actually, we still in surgery and stuff. Yeah, yeah, 0:47:20.640 --> 0:47:24.920 it's like in surgery though, it like really reduces mortality. 0:47:24.960 --> 0:47:27.200 Right right, right, and so yeah, and so I think 0:47:27.320 --> 0:47:29.239 one thing that I want to get across is that 0:47:29.400 --> 0:47:32.759 antibiotics still should be used. Like they're not bad things. 0:47:32.840 --> 0:47:36.680 They're still hugely important, but we need to really consider 0:47:36.800 --> 0:47:39.840 how we use them so that we save them for 0:47:40.239 --> 0:47:43.399 when we really need them need right. So it's sort 0:47:43.400 --> 0:47:46.480 of proper use, right, and not saying it's it's reducing 0:47:46.520 --> 0:47:50.120 their overuse and turning improper use into proper. 0:47:49.880 --> 0:47:52.040 Use, right yeah, yeah, yeah, totally. 0:47:52.000 --> 0:47:54.520 Because resistance will continue to happen, but at least we 0:47:54.560 --> 0:47:58.719 can slow it down a bit. Okay, So on the 0:47:58.719 --> 0:48:00.960 medical side of things, I see is falling into three 0:48:01.040 --> 0:48:06.120 different issues. So the first lies with improper prescription, and so, 0:48:06.320 --> 0:48:09.000 particularly in the earlier days of antibiotics, this was a 0:48:09.120 --> 0:48:11.640 huge issue, but it also has continued to be a 0:48:11.719 --> 0:48:15.640 huge issue because there sometimes might be a thought that like, okay, 0:48:15.640 --> 0:48:18.000 if there's a ninety five percent chance that an infection 0:48:18.160 --> 0:48:21.000 is viral and a five percent chance that it's bacterial, 0:48:21.719 --> 0:48:24.600 you might just want to prescribe an antibiotic anyway, because 0:48:24.600 --> 0:48:27.200 if it's bacterial, then you could wipe out that infection 0:48:27.280 --> 0:48:30.120 and reduce the suffering of your patient. And if it's not, well, 0:48:30.200 --> 0:48:33.600 what's the harm to that patient. It's thought on an 0:48:33.680 --> 0:48:39.440 individual patient level scale, right, and that makes sense, And 0:48:39.640 --> 0:48:43.479 jumping ahead a bit, a study showed that in twenty ten, 0:48:43.920 --> 0:48:47.239 eighty percent of primary care doctors and seventy percent of 0:48:47.280 --> 0:48:52.799 emergency room doctors were prescribing antibiotics for acute bronchitis, which 0:48:52.840 --> 0:48:56.239 is viral almost always, viral almost always, and so then 0:48:56.280 --> 0:48:58.560 that's how we get into the almost always issue. So 0:48:58.600 --> 0:49:01.360 it's sort of a matter of treating the individual versus 0:49:01.400 --> 0:49:05.040 considering the group as a whole. It's a very tricky decision. 0:49:05.080 --> 0:49:06.760 It's a very tricky situation. 0:49:06.680 --> 0:49:10.200 A thing I think a lot about because my whole 0:49:10.239 --> 0:49:14.040 background is in public health and like thinking about these 0:49:14.040 --> 0:49:17.759 things on a population level, and now I'm going into 0:49:17.800 --> 0:49:20.399 medicine where you're like concerned about the patient in front 0:49:20.400 --> 0:49:23.040 of you, and there's often a conflict between what's best 0:49:23.040 --> 0:49:26.040 for the individual patient and what is best for the public. 0:49:26.120 --> 0:49:28.839 And it is a tricky landmine. 0:49:29.360 --> 0:49:30.600 Mmmmmmm hmm. 0:49:30.800 --> 0:49:32.520 Yeah. 0:49:32.719 --> 0:49:34.960 Yeah, And I'm not going to talk about what we 0:49:35.080 --> 0:49:37.880 should do and the ways we should change it, but 0:49:38.239 --> 0:49:41.680 I think the consensus is is that we do need 0:49:41.719 --> 0:49:45.160 to change sort of the directives of this. Yeah, we 0:49:45.480 --> 0:49:46.640 change how we use them. 0:49:46.800 --> 0:49:53.080 Like, antibiotics are also not benign, right, Like we talked 0:49:53.080 --> 0:49:55.440 about this in the last episode. They have side effects, right, 0:49:55.440 --> 0:49:58.200 They're wiping out your microbiome. They're going to cause side effects, 0:49:58.239 --> 0:50:01.239 So they're also not benign to give a patient, to 0:50:01.280 --> 0:50:05.280 give a person antibiotics if they don't really need them. 0:50:05.440 --> 0:50:07.880 Right, And this is something that we're becoming more and 0:50:08.040 --> 0:50:11.200 more aware of as we talk about the microbiome. And 0:50:11.239 --> 0:50:15.080 some ambiotics, like you said, are also toxic in themselves, 0:50:15.160 --> 0:50:19.680 like they damage certain organs so it's yeah, and then 0:50:19.719 --> 0:50:23.480 there's also just sanitation issues within hospitals. So I mean, 0:50:23.880 --> 0:50:26.560 when you're in a hospital, the rate of people that 0:50:26.640 --> 0:50:31.080 have infections, it's high. Infections are very high, They're very prevalent. 0:50:31.280 --> 0:50:34.799 And this is talking about drug resistant and drugs and 0:50:34.840 --> 0:50:40.680 antibiotics susceptible infections, right, and this makes transfer between patients 0:50:41.239 --> 0:50:44.600 really easy. And this just speaks to the nature also 0:50:44.680 --> 0:50:48.280 of how equipped these bacteria are to keeping their foothold 0:50:48.320 --> 0:50:50.799 in a place and surviving, Like some of these are 0:50:51.000 --> 0:50:54.719 really really difficult to get rid of. Yeah, and so 0:50:54.960 --> 0:50:58.920 a hospital just provides tons of opportunities for bacteria to 0:50:59.000 --> 0:51:01.960 exchange info and to settle onto the skin or into 0:51:01.960 --> 0:51:05.040 the surgical incision site, or into the intestine of someone 0:51:05.040 --> 0:51:09.120 who happens to be in the hospital. Finally, there's the 0:51:09.200 --> 0:51:12.560 third issue, which is that people who are prescribed antibiotics 0:51:12.640 --> 0:51:15.760 might not take them properly, so they might not finish 0:51:15.760 --> 0:51:18.120 their course. By that, I mean, if you're prescribed ten 0:51:18.200 --> 0:51:20.160 days of in an antibiotic and you only take five 0:51:20.239 --> 0:51:23.560 because you start feeling better, all you've done is kind 0:51:23.600 --> 0:51:26.360 of train the bacteria in your body to become resistant. 0:51:27.160 --> 0:51:29.760 And so if that happens and you get severely sick, 0:51:29.800 --> 0:51:31.640 and then you have to go to the hospital, and 0:51:31.680 --> 0:51:35.680 then you're bringing your drug resistant bacteria into the hospital. Yeah, 0:51:35.760 --> 0:51:40.640 she's like, come on, which is not good. And then 0:51:40.680 --> 0:51:43.040 that same twenty ten study that I mentioned just a 0:51:43.040 --> 0:51:45.880 little bit ago, they also showed that up to forty 0:51:45.920 --> 0:51:49.279 percent of people fail to complete their full course of antibiotics. 0:51:49.360 --> 0:51:50.319 Oh yeah. 0:51:50.360 --> 0:51:53.279 And so these three healthcare issues have been a part 0:51:53.280 --> 0:51:57.040 of what is driving intibiotic resistance in hospital and community settings. 0:51:57.680 --> 0:51:59.319 And for the most part, I have to say that 0:51:59.400 --> 0:52:02.719 a dozen like, we have made some forward progress in 0:52:02.800 --> 0:52:05.640 terms of regulating them, but it's we still have a 0:52:05.640 --> 0:52:09.640 long way to go. Okay, but that's just the medical 0:52:09.640 --> 0:52:13.320 side of things. We're only getting started. No, this is 0:52:13.360 --> 0:52:17.719 horrifying because even if tomorrow we enacted all of those changes, 0:52:18.120 --> 0:52:21.000 it might slow down the spread of resistance in healthcare settings, 0:52:21.280 --> 0:52:24.360 but it wouldn't stop the problem entirely. And a small 0:52:24.400 --> 0:52:27.680 part of that is due simply to the nature of resistance. 0:52:27.719 --> 0:52:31.080 It's due to this arms race of bacteria and antibiotic compounds. 0:52:31.600 --> 0:52:36.960 Resistance will always evolve. But another huge part is improper 0:52:37.000 --> 0:52:41.919 antibiotic use in agriculture. And we talked a bit about 0:52:41.960 --> 0:52:44.000 this in the last episode, but I want to go 0:52:44.120 --> 0:52:46.799 more into the history of this since it's such an 0:52:46.800 --> 0:52:50.680 integral part of the story of resistance. So this history 0:52:51.080 --> 0:52:55.600 starts with yet another chance discovery when a researcher was 0:52:55.680 --> 0:52:58.600 looking for a natural source of B twelve to supplement 0:52:58.640 --> 0:53:01.680 the food of chickens to help them better. So he 0:53:01.800 --> 0:53:06.160 learned that streped to mices areo facins, produces vitamin B 0:53:06.280 --> 0:53:10.359 twelve during the fermentation process from making stripped micin. So 0:53:10.680 --> 0:53:12.839 he was like, Hey, can I have some of that 0:53:12.960 --> 0:53:16.520 waste from fermentation, just like the leftover gunk or whatever. 0:53:16.840 --> 0:53:19.600 I'm gonna mix it into the chickens food and just 0:53:19.600 --> 0:53:24.400 see what happens, okay, And the results were remarkable, like 0:53:24.440 --> 0:53:28.799 the chickens grew tremendously much faster than he expected due 0:53:28.840 --> 0:53:31.799 to just B twelve, and so did the piglets that 0:53:31.840 --> 0:53:34.920 he also tried it out on. He was like, Okay, 0:53:35.440 --> 0:53:39.600 is it actually the B twelve that's in the fermentation 0:53:39.719 --> 0:53:43.200 waste or is it trace amounts of the antibiotic that's 0:53:43.280 --> 0:53:46.600 causing this growth? And maybe he was like, well, maybe 0:53:46.600 --> 0:53:51.560 it's suppressing gut like harmful gut bacteria or something else, like, 0:53:51.680 --> 0:53:54.279 regardless of the reason, he couldn't deny that they were 0:53:54.280 --> 0:53:57.839 actually having an effect. So, on average, livestock that were 0:53:57.880 --> 0:54:01.520 fed these growth promoters grew three to eleven percent faster 0:54:01.640 --> 0:54:04.640 than their non antibiotic ridden counterparts. But I've seen actually 0:54:04.719 --> 0:54:09.480 much higher rates quoted, particularly early early on in these experiments. 0:54:10.160 --> 0:54:14.279 Oh and this led to because you could make more 0:54:14.320 --> 0:54:18.520 meat faster, you could sell more meat, and so consumption 0:54:18.719 --> 0:54:22.799 overall really grew. And then it kind of in that 0:54:22.880 --> 0:54:27.320 way firmly established these growth promoters, so called growth promoters, 0:54:27.600 --> 0:54:30.799 as a necessary part of agriculture. And so I'm going 0:54:30.880 --> 0:54:33.359 to use the term growth promoters a lot, and that 0:54:33.440 --> 0:54:37.040 basically means these trace amounts, so like non therapeutic doses 0:54:37.080 --> 0:54:41.880 of antibiotics that are included in food for animals like 0:54:41.920 --> 0:54:48.400 agricultural animals, livestock. Ok okay, so these antibiotic laced foods 0:54:48.440 --> 0:54:52.640 plus preemptive treatment, so like not just as growth promoters, 0:54:52.640 --> 0:54:55.200 but actually like, oh, we're going to dose you so 0:54:55.239 --> 0:54:58.520 that you don't get this or that ulcer or whatever. 0:54:59.200 --> 0:55:03.359 That led to some farmers just packing them all in 0:55:03.440 --> 0:55:06.799 all these animals in as tightly as possible because they 0:55:06.800 --> 0:55:10.080 were secure in the knowledge that the crowd diseases that 0:55:10.120 --> 0:55:12.320 they had previously been worried about wouldn't be much of 0:55:12.360 --> 0:55:14.839 a concern with these antibiotics. And so it really led 0:55:14.920 --> 0:55:18.120 to the rise of like the industry some of the 0:55:18.560 --> 0:55:21.080 more the nastier sides of the industry that we see. 0:55:21.360 --> 0:55:25.440 Wow, yeah, yeah, I did not know that part of it, 0:55:25.920 --> 0:55:28.160 but that makes so much sense. M M. 0:55:30.480 --> 0:55:33.480 And the drug companies that were producing these antibiotics ate 0:55:33.560 --> 0:55:36.640 it up, or rather they were enthusiastic about the livestock 0:55:36.760 --> 0:55:40.719 eating up their antibiotic fermentation waste products because this was 0:55:40.760 --> 0:55:42.560 all stuff that was like they were just throwing it 0:55:42.600 --> 0:55:47.080 away anyway, so it's great for them. So sub therapeutic 0:55:47.120 --> 0:55:49.960 doses of antibiotics were sold as growth promoters starting the 0:55:50.040 --> 0:55:54.520 nineteen fifties, and the huge threat of antibiotic resistance had 0:55:54.520 --> 0:55:58.319 been known and discussed for at least a decade before that, 0:55:59.200 --> 0:56:04.080 and this basically provided the perfect breeding ground for antibiotic 0:56:04.120 --> 0:56:07.480 resistance because if you think about like think about a 0:56:08.320 --> 0:56:11.600 industrial farm full of pigs packed in, you know, all 0:56:11.640 --> 0:56:14.440 close to one another, and then they're all just just 0:56:14.520 --> 0:56:19.279 with antibiotics, like the bacteria that they can move so 0:56:19.480 --> 0:56:22.480 easily that way. Resistance can move so easily that way, 0:56:22.600 --> 0:56:25.840 like it's and manure is one of the best sources 0:56:25.880 --> 0:56:31.960 for anbiotic resistance bacteria apparently, and then there's runoff. Okay anyway, 0:56:33.000 --> 0:56:36.240 and it wasn't just restricted to growth promoters and food 0:56:36.880 --> 0:56:40.120 farmers began toying with different ways to deliver the antibiotics 0:56:40.160 --> 0:56:42.800 to the animals, so they were like in the water 0:56:43.080 --> 0:56:48.359 before they were slaughtered. Like, here's some water injected injected 0:56:48.640 --> 0:56:55.680 into the areas for prime cuts. What painting painting raw 0:56:55.719 --> 0:57:00.640 steak with antibiotics or mixing them in with round beef. 0:57:02.000 --> 0:57:05.080 I'm sorry, why would you mix it in with the 0:57:05.120 --> 0:57:08.800 meat that you're selling to humans? What is the purpose 0:57:08.840 --> 0:57:09.200 of that? 0:57:09.640 --> 0:57:12.840 Well, because then you could it has a longer shelf life. 0:57:13.000 --> 0:57:14.160 Are you kidding me? 0:57:14.760 --> 0:57:20.520 I'm not kidding you. Oh dude. Spinach was even washed 0:57:20.680 --> 0:57:24.560 in streptomycin. I'm so serious. 0:57:28.080 --> 0:57:30.160 Don't chicken eat We're sold in. 0:57:32.200 --> 0:57:38.200 Chickens were literally sold soaking in antibiotics because that would 0:57:38.240 --> 0:57:41.640 lengthen their shelf life. My face, so like you could 0:57:41.680 --> 0:57:44.439 squeeze out like the chicken juices from a raw chicken 0:57:44.480 --> 0:57:47.280 at the grocery store back then, and you could get 0:57:47.320 --> 0:57:54.160 like antibiotics in those juices. The world got its first 0:57:54.160 --> 0:57:57.520 taste of how the use of antibiotics on farms bled 0:57:57.560 --> 0:57:59.800 into human life in the nineteen fifties. So around the 0:57:59.840 --> 0:58:02.840 same time when it was first started to ramp up. 0:58:02.960 --> 0:58:03.720 Oh my god. 0:58:05.040 --> 0:58:08.640 Around this time, penicillin had been made prescription only in 0:58:08.680 --> 0:58:11.920 the US and in Britain, partly because the rates of 0:58:11.960 --> 0:58:16.560 penicillin allergy were just like skyrocketing. And so with these 0:58:16.720 --> 0:58:21.440 increased regulations, physicians and epidemiologists expected to see fewer penicillin 0:58:21.480 --> 0:58:25.760 allergies crop up. Makes sense, right, No, that's not what 0:58:25.800 --> 0:58:30.160 they saw. Instead, they saw an increase, they saw surge. 0:58:30.760 --> 0:58:33.280 And it turns out that the source of the penicillin. 0:58:33.320 --> 0:58:35.440 This is done through like a lot of detective work. 0:58:35.760 --> 0:58:39.320 The source of the penicillin was in the milk that 0:58:39.360 --> 0:58:44.240 people were drinking. Some milk contained so much penicillin that 0:58:44.320 --> 0:58:51.040 it could have been sold as a drug, those therapeutic doses, yes, Groad. 0:58:51.280 --> 0:58:54.640 So this finding led the FDA at least to rule 0:58:54.680 --> 0:58:57.640 that you could no longer treat meat with antibiotics prior 0:58:57.680 --> 0:58:58.560 to it being sold. 0:58:58.920 --> 0:59:03.200 Okay, so, like my stakes are not washed in antibiotics anymore. 0:59:03.600 --> 0:59:05.600 No, No, that's all. 0:59:05.600 --> 0:59:09.040 Done, small blessings. 0:59:10.080 --> 0:59:16.000 Yeah, but yeah, this did nothing to stop the addition 0:59:16.040 --> 0:59:19.480 of antibiotics in feed for animals as a growth promoter. 0:59:21.000 --> 0:59:23.160 And then there was a series of studies in the 0:59:23.240 --> 0:59:26.920 nineteen sixties that clearly demonstrated that growth promoters led to 0:59:27.000 --> 0:59:30.760 the rapid development of resistance in microbes, colonizing both the 0:59:30.840 --> 0:59:34.520 animals as well as the people working with the animals. 0:59:34.960 --> 0:59:36.800 So like this was a kind of a cut and dried, 0:59:37.320 --> 0:59:43.760 very eye opening experiment. Fortunately, this was taken somewhat seriously 0:59:43.840 --> 0:59:47.280 by governments. So the UK took action early on in 0:59:47.320 --> 0:59:51.560 limiting antibiotic use and agriculture. Starting in nineteen seventy one, 0:59:51.720 --> 0:59:55.480 they banned antibiotics as growth promoters if those antibiotics were 0:59:55.600 --> 0:59:58.640 used to treat disease in animals and humans. 0:59:58.880 --> 1:00:01.840 Okay, so you can I no longer use tetracyclines because 1:00:01.840 --> 1:00:05.440 we use those to treat disease for example. 1:00:05.560 --> 1:00:07.680 Yeah, got it. And you had to have a prescription 1:00:07.800 --> 1:00:10.040 for them if you wanted to use them therapeutically. 1:00:10.240 --> 1:00:10.560 Okay. 1:00:10.880 --> 1:00:14.600 And the US was like this close to following suit, 1:00:15.720 --> 1:00:20.080 but you know, we didn't a little bit after this 1:00:20.160 --> 1:00:23.840 decision in the UK, the FDA was like, I'm going 1:00:23.880 --> 1:00:25.600 to lay down the law and we're going to limit 1:00:25.640 --> 1:00:29.720 the use of antibiotics purely to therapeutic purposes. But then 1:00:29.880 --> 1:00:35.920 the mighty dollar of the agricultural industry overruled. Representative Jamie Whitten, 1:00:36.320 --> 1:00:40.120 who was like part of the spokesperson for this industry, 1:00:40.160 --> 1:00:44.080 basically said that he would hold hostage the budget of 1:00:44.120 --> 1:00:49.000 the FDA if the regulations passed, and so because he 1:00:49.040 --> 1:00:51.320 had somehow he had that power aeron I don't know, 1:00:52.440 --> 1:00:55.240 So the White House gave in since the budget hold 1:00:55.320 --> 1:00:58.960 up would have also hurt many other important projects, and 1:00:59.080 --> 1:01:02.920 so Witten, the representative, insisted that the data in support 1:01:02.960 --> 1:01:06.320 of banning the use of non therapeutic antibiotics in agriculture 1:01:06.440 --> 1:01:10.000 was incomplete and biased against farmers. And so then they 1:01:10.000 --> 1:01:13.240 were like, okay, well, we want the farmers. We want 1:01:13.280 --> 1:01:16.880 the agricultural industry to design their own projects and do 1:01:16.960 --> 1:01:20.080 their own research to figure out what the truth is. 1:01:20.520 --> 1:01:23.240 Oh, there's no bias there at all, right. 1:01:23.080 --> 1:01:27.320 I mean, the burden of proof has been on epidemiologists 1:01:27.320 --> 1:01:33.040 and researchers to find that antibiotic use in agricultural settings 1:01:33.200 --> 1:01:39.120 leads to antibiotic resistance that is clinically important in humans. 1:01:39.360 --> 1:01:42.920 Yeah right, But this insistence that those studies were inaccurate 1:01:43.040 --> 1:01:45.440 or that the research was incomplete was just a flat 1:01:45.480 --> 1:01:49.840 out lie because in the nineteen seventies a researcher named 1:01:49.840 --> 1:01:53.840 doctor Stuart Levy wanted to see how rapidly resistance could 1:01:53.880 --> 1:01:57.320 develop or spread in livestock given these growth promoters, So 1:01:57.920 --> 1:02:01.160 he tested out some young chickens who are given tetracycline. 1:02:01.840 --> 1:02:05.080 Within thirty six hours of first being given the feed 1:02:05.160 --> 1:02:10.160 laced with tetracycline, their gut E. Coli was resistant thirty 1:02:10.160 --> 1:02:13.640 six hours. So that's scary enough. And tetracycline is like 1:02:13.960 --> 1:02:21.280 was a broad spectrum, just like awesome used drug was was. 1:02:22.720 --> 1:02:25.200 And so that's scary enough on its own. But what 1:02:25.240 --> 1:02:27.920 made it even scarier is that over the next three months, 1:02:28.000 --> 1:02:31.520 the E. Coli also added to its arsenal genes that 1:02:31.560 --> 1:02:35.600 made it resistant to ampicillin, stripped to miceine, and sulfonamides, 1:02:36.000 --> 1:02:39.440 and the chickens had never even received any of those drugs. 1:02:39.800 --> 1:02:44.240 Whoa the tetracycline had acted like a call to arms 1:02:44.240 --> 1:02:47.840 for these bacteria, like we've faced and defeated one antibiotic, 1:02:48.000 --> 1:02:49.840 so we need to be prepared for any others that 1:02:49.920 --> 1:02:54.000 might come our way, Man oh Man, And I bet 1:02:54.040 --> 1:02:56.160 you didn't think that the study could show even more 1:02:56.200 --> 1:02:59.400 concerning results, but it did, and you're not going to 1:02:59.440 --> 1:03:03.600 be surprised by them. But Levy found the same antibiotic 1:03:03.640 --> 1:03:07.200 resistance in the gutty coli of the farmers and the 1:03:07.240 --> 1:03:11.280 families of those farmers that had kept the chickens, none 1:03:11.360 --> 1:03:17.840 of them had received tetracycline. There have been literally dozens, 1:03:18.640 --> 1:03:22.920 dozens and dozens of peer reviewed articles demonstrating clearly that 1:03:23.000 --> 1:03:28.520 antibiotic use in animals impacts humans. To epidemiologists and physicians 1:03:28.520 --> 1:03:32.960 and microbiologists and biochemists, whether or not rampant use of 1:03:33.040 --> 1:03:37.160 sub therapeutic levels of antibiotics was leading to a huge 1:03:37.200 --> 1:03:43.040 increase in resistance and resistant organisms, that wasn't a scientific question, 1:03:43.960 --> 1:03:47.600 It was firmly established that it was. Instead, it was 1:03:47.640 --> 1:03:50.520 a political one. Does it sound familiar? 1:03:50.920 --> 1:03:53.120 Sounds too familiar, Aaron? 1:03:53.800 --> 1:03:58.600 Yeah. And despite this strong evidence that growth promoters also 1:03:58.680 --> 1:04:03.040 promoted antibiotic resistance and all of the terrifying implications that 1:04:03.080 --> 1:04:06.280 came along with it, the US declined to ban tetracycling 1:04:06.320 --> 1:04:10.439 as a growth promoter, It, along with many other antibiotics, 1:04:10.440 --> 1:04:14.800 continued to be used freely for decades. In livestock, you. 1:04:14.720 --> 1:04:18.440 Said, for decades. Are you gonna tell me some happy 1:04:18.480 --> 1:04:20.880 news at the end of this, like no longer or what? 1:04:22.160 --> 1:04:27.720 There are some some bright moments and some really cool 1:04:27.720 --> 1:04:30.360 little case studies that I won't go into, but I'll mention, 1:04:30.600 --> 1:04:33.240 and I'll mention places to read further about them. Because 1:04:34.320 --> 1:04:40.680 Denmark and Netherlands, whoo whoo okay, And just because a 1:04:40.760 --> 1:04:45.280 country had stricter regulations doesn't mean that they weren't also 1:04:45.440 --> 1:04:48.840 contributing to the resistance problem. A lot of the time, 1:04:48.920 --> 1:04:53.440 there wasn't much regulatory oversight into just how much antibiotics 1:04:53.640 --> 1:04:58.120 were being sold to agriculture, and when there was sort 1:04:58.160 --> 1:05:02.320 of a retrospective look at the amount over time, like 1:05:02.640 --> 1:05:05.480 number of tons or millions of pounds sold over time, 1:05:05.920 --> 1:05:09.360 there actually wasn't really a decrease after some of these 1:05:09.400 --> 1:05:13.000 bands were put into place, because the labeling just changed 1:05:13.160 --> 1:05:16.520 for a lot of these things. Another issue was that 1:05:16.560 --> 1:05:21.120 these bands, like I mentioned, often limited use of antibiotics 1:05:21.120 --> 1:05:23.920 to those that weren't also used to treat animal or 1:05:23.960 --> 1:05:28.600 human infections. But this is also a problem, and that's 1:05:28.680 --> 1:05:33.000 because as resistance to the most common antibiotics grew, doctors 1:05:33.040 --> 1:05:36.400 had to reach increasingly to the back of that cabinet 1:05:36.520 --> 1:05:39.240 for the third and fourth string, antibiotics that had been 1:05:39.240 --> 1:05:42.480 deemed too toxic, or too specific, or too expensive to 1:05:42.520 --> 1:05:47.720 be used. Fankomycin was one of these antibiotics. It kind 1:05:47.760 --> 1:05:50.640 of came. It was one of the earlier ones that 1:05:50.760 --> 1:05:56.040 had been discovered and developed, but it was deemed to 1:05:56.080 --> 1:05:59.040 be too expensive and had some nasty side effects, so 1:05:59.560 --> 1:06:04.200 people were like, nana, we'll just use methicillin instead, and 1:06:04.280 --> 1:06:08.560 so in the nineteen eighties it was dusted off and 1:06:08.640 --> 1:06:12.960 increasingly used to treat stubborn resistant infections, and it seemed 1:06:13.000 --> 1:06:16.720 to be remarkably effective in that microbes weren't showing resistance 1:06:16.760 --> 1:06:21.880 towards it, so that was promising, and some researchers were like, Okay, well, 1:06:21.920 --> 1:06:24.760 how exactly does it work? And they were like, it's 1:06:24.760 --> 1:06:28.400 so complex that it would be nearly impossible for a 1:06:28.440 --> 1:06:31.480 bacterium to develop all of the genetic changes needed to 1:06:31.560 --> 1:06:36.600 overcome this mechanism. It's like an unsinkable ship. Like why 1:06:36.640 --> 1:06:40.520 do we say these things. It's just tempting fate. In 1:06:40.640 --> 1:06:44.400 nineteen eighty nine, the first strains of vancomized and resistant 1:06:44.560 --> 1:06:48.400 entercocci VRE started popping up in hospitals in the US, 1:06:48.720 --> 1:06:50.960 and by nineteen ninety three it was close to being 1:06:51.040 --> 1:06:58.240 endemic in many hospitals. VR baby, VR baby, It's really bad. 1:06:59.120 --> 1:07:03.280 Within five years for showing up, VRE was widespread in 1:07:03.280 --> 1:07:07.440 the US, something that it took MRSA about methicillin resistant 1:07:07.480 --> 1:07:13.520 staff oreas about fifteen years to do. So they were like, 1:07:13.640 --> 1:07:17.400 what the heck? This is super complex, So how could 1:07:17.400 --> 1:07:19.640 there have been enough time that has passed for these 1:07:19.720 --> 1:07:23.240 mutations to actually emerge? Like, what is going on here? 1:07:23.280 --> 1:07:28.680 What happened? Turns out the answer is an agriculture. A 1:07:28.760 --> 1:07:32.240 vancom ioson like antibiotic had been used as a growth 1:07:32.280 --> 1:07:36.280 promoter in livestock for decades. Oh gosh, And so when 1:07:36.320 --> 1:07:39.080 physicians started to reach into the back of that cabinet 1:07:39.280 --> 1:07:43.440 for vancom ioson, the resistance genes were already long present 1:07:43.760 --> 1:07:47.520 and quite prevalent, and then with that added selection pressure 1:07:47.680 --> 1:07:50.200 of being used in a clinical setting, it just spread 1:07:50.240 --> 1:07:56.160 like wildfire, and bad turned to worse when in nineteen 1:07:56.240 --> 1:08:02.160 ninety six, the first vancom iceon resistant staff OUREUSSA infections. 1:08:02.280 --> 1:08:07.160 VERSA infections emerged in Japan. At this point in time, 1:08:07.560 --> 1:08:11.280 about fifty percent of all hospital staff OREUS infections were 1:08:11.280 --> 1:08:16.360 methicone resistant, so treatable only by vancom iyosin. Within the 1:08:16.400 --> 1:08:23.200 next few years, versa was basically everywhere, And again there 1:08:23.280 --> 1:08:26.519 was still lobbying for the continued use of vancom iosin 1:08:26.600 --> 1:08:30.040 and other antibiotics as growth promoters in the US, and 1:08:30.080 --> 1:08:33.880 those lobbyists still refuse to acknowledge how those practices could 1:08:33.960 --> 1:08:37.880 lead to resistance. So Robert Carnival, who is one of 1:08:37.920 --> 1:08:42.040 these lobbyists, is quoted as saying, I'm sure vre can 1:08:42.080 --> 1:08:44.880 transfer from animals to people and it might be resistant, 1:08:45.080 --> 1:08:46.680 but is it of clinical importance? 1:08:49.040 --> 1:08:53.600 Yes, yes, yes it is, yes, oh gosh. 1:08:53.640 --> 1:08:57.080 And it wasn't just vanca icein resistance that agriculture was promoting. 1:08:57.560 --> 1:09:00.320 Calliston was another one of those antibiotics that had put 1:09:00.360 --> 1:09:03.080 aside in favor of more sensitive drugs in the past, 1:09:03.760 --> 1:09:06.680 and it had also been used in agriculture, and so 1:09:06.880 --> 1:09:11.240 resistance was already super high there. And it wasn't just 1:09:11.400 --> 1:09:15.920 resistance genes that spread from agricultural settings to hospitals or communities. 1:09:16.439 --> 1:09:20.479 People realized it was also the bugs themselves, epidemics of 1:09:21.400 --> 1:09:23.360 xpec which I can't remember what that one is, but 1:09:23.400 --> 1:09:29.920 it's some sort of ecoli, toxic ecoli. Yeah, these UTIs 1:09:29.960 --> 1:09:33.400 caused by xpecs. They seemed to be coming from food, 1:09:33.560 --> 1:09:39.599 specifically chicken. Oh gosh, quinnolone resistant Salmonella typhomerium strain DT 1:09:39.800 --> 1:09:43.080 one O four that's a bad one that spread through 1:09:43.120 --> 1:09:48.000 fresh dairy and can kill you, and that came directly 1:09:48.000 --> 1:09:52.240 from animals, and quinnolone resistant Campilo bacter those that was 1:09:52.240 --> 1:09:53.599 found in grocery store chicken. 1:09:54.280 --> 1:09:55.200 Oh gosh. 1:09:55.800 --> 1:09:58.519 So quinnilone had been used in agriculture for years, but 1:09:58.560 --> 1:10:02.519 the sharp, alarming rye of resistance to it prompted the 1:10:02.600 --> 1:10:07.920 FDA finally to propose a ban, propose a ban for 1:10:07.960 --> 1:10:11.640 their use in animals, but a proposal was just a proposal. 1:10:12.400 --> 1:10:15.840 Some drug companies, including Bayer, declared that it would not 1:10:15.920 --> 1:10:19.559 comply voluntarily, so it would fight the proposal and ask 1:10:19.640 --> 1:10:21.599 for a hearing where it could show that quinn alone 1:10:21.680 --> 1:10:23.839 use in animals was of no harm to humans. 1:10:24.120 --> 1:10:26.479 I'm just getting too depressed, Darren. 1:10:26.880 --> 1:10:30.479 I know, okay, but In the late nineteen nineties, it 1:10:30.520 --> 1:10:33.800 is a little shining sun. The European Union moved to 1:10:33.880 --> 1:10:38.240 ban antibiotics as growth promoters like all of them, but 1:10:38.360 --> 1:10:42.439 preventive use was still allowed, which still promoted resistance. Again, 1:10:42.680 --> 1:10:46.519 there didn't seem to be any decline in the amount 1:10:46.600 --> 1:10:49.840 of antibiotics sold for farm use, so from nineteen ninety 1:10:49.920 --> 1:10:52.559 nine to two thousand and six and beyond it stayed 1:10:52.560 --> 1:10:55.320 at six hundred and six tons per year. This is 1:10:55.520 --> 1:11:01.479 after the ban, right However, However, some countries did actually 1:11:01.479 --> 1:11:04.839 do it on their own, and some countries, like in Denmark, 1:11:05.280 --> 1:11:08.240 the industry did it on their own themselves. They were like, 1:11:08.320 --> 1:11:11.080 we're not gonna We're not gonna listen, like they were 1:11:11.160 --> 1:11:15.200 just decided amongst the community and the farmers that they 1:11:15.240 --> 1:11:17.080 were going to do this because they were like what's. 1:11:16.960 --> 1:11:20.519 Right for you know, everyone kind of thing. 1:11:21.040 --> 1:11:24.639 Yeah, So the Netherlands, for example, they really doubled down 1:11:24.640 --> 1:11:27.880 and started policing the use of antibiotics much more, and 1:11:28.000 --> 1:11:31.160 the result was that antibiotic use on farms actually declined 1:11:31.240 --> 1:11:36.440 dramatically starting in twenty thirteen and really cool. The occurrence 1:11:36.479 --> 1:11:41.400 of antibiotic resistant bacteria found in meat also declined, and 1:11:41.479 --> 1:11:44.920 similar things happened in Denmark as well, And all of 1:11:44.960 --> 1:11:48.200 the horrible repercussions that had been promised, like a drop 1:11:48.240 --> 1:11:51.520 off and the weight of livestock sky high meat prices, 1:11:51.840 --> 1:11:57.600 more disease among livestock, none of these things happened. H 1:11:58.200 --> 1:12:02.360 The weight dropped a bit, a little bit, but it 1:12:02.439 --> 1:12:05.400 had been recognized for quite a while that growth promoters 1:12:05.439 --> 1:12:08.679 were no longer achieving the same dramatic gains that had 1:12:08.720 --> 1:12:12.080 been seen when they were first used. Oh no, So 1:12:12.360 --> 1:12:17.680 somewhere inesting that is very interesting. So somewhere in the 1:12:17.680 --> 1:12:21.680 five or six decades since antibiotics were first used in agriculture, 1:12:22.240 --> 1:12:27.920 they had lost their magical ability to promote growth. So 1:12:28.160 --> 1:12:31.360 a couple of different things. It's probably likely that when 1:12:31.360 --> 1:12:34.080 they were first used, the antibiotics were compensating for some 1:12:34.120 --> 1:12:37.200 of the negative ways that the farms were run, so 1:12:37.520 --> 1:12:41.559 like as hygiene and monitoring and nutrition and breeding had changed, 1:12:41.640 --> 1:12:45.040 it had eliminated that gap that growth promoting antibiotics had 1:12:45.080 --> 1:12:48.120 made up. And it's also possible that if it was 1:12:48.840 --> 1:12:53.320 affecting the negative, the harmful gut bacteria or whatever gut bacteria, 1:12:53.800 --> 1:12:57.760 that resistance had emerged and so antibiotics were literally just 1:12:57.920 --> 1:12:59.200 doing nothing. 1:12:58.960 --> 1:12:59.519 Doing less. 1:12:59.640 --> 1:13:04.600 Yeah yeah. And by removing antibiotics from agriculture, places like 1:13:04.680 --> 1:13:09.080 Denmark and the Netherlands incorporated animal welfare into the business model, 1:13:09.600 --> 1:13:12.240 and with that they improved quality, quality of life for 1:13:12.280 --> 1:13:16.360 the animals, quality of meat for consumption, quality of their investment, 1:13:16.439 --> 1:13:19.720 et cetera. But once again, the US failed to make 1:13:19.920 --> 1:13:25.439 similar regulatory progress as Europe. In twenty fifteen, thirty four 1:13:25.479 --> 1:13:28.360 point three million pounds of antibiotics were sold for use 1:13:28.400 --> 1:13:32.240 in animals, compared to approximately seven point seven million pounds 1:13:32.240 --> 1:13:36.680 for humans. But even though the US government agencies were 1:13:36.720 --> 1:13:39.800 slow to stop the over use and misuse of antibiotics, 1:13:39.840 --> 1:13:45.080 some companies actually voluntarily stopped using growth promoters because they 1:13:45.120 --> 1:13:48.639 realized that antibiotics for growth promotion may not be worth 1:13:48.680 --> 1:13:51.920 the cost for human health or the cost of the 1:13:51.960 --> 1:13:56.840 constant legal battles. This industry shift paralleled many others that 1:13:56.880 --> 1:13:59.640 were going on in food supply arenas, so it was 1:13:59.800 --> 1:14:06.040 one after another, both from the meat providing side of things, 1:14:06.080 --> 1:14:12.759 so these big name chicken farms to the food supply aspect, 1:14:12.840 --> 1:14:15.439 so like fast food restaurants, stuff like that, they were 1:14:15.479 --> 1:14:18.880 all starting to offer antibiotic free meat options, and so 1:14:19.280 --> 1:14:22.760 the market seemed to be responding positively to these changes, 1:14:24.040 --> 1:14:27.800 but that's all on the industry side. So even though 1:14:27.840 --> 1:14:30.320 starting in twenty twelve, the US has put in some 1:14:30.479 --> 1:14:34.200 regulations for monitoring the use of antibiotics and agriculture, for 1:14:34.360 --> 1:14:39.040 many years, the amount of antibiotics has actually increased rather 1:14:39.080 --> 1:14:43.960 than decreased. Twenty seventeen did see a decrease, but it 1:14:44.000 --> 1:14:47.679 doesn't seem one hundred percent clear why that decrease happened. 1:14:47.920 --> 1:14:50.040 Maybe it's because of these bands, and that would be great, 1:14:50.680 --> 1:14:54.640 But antibiotic resistance and its association with agriculture is a 1:14:54.680 --> 1:14:58.879 perfect example again of why a one health approach is essential. 1:15:00.240 --> 1:15:03.880 And animals share one bacterial and viral world, and fungal 1:15:03.920 --> 1:15:08.200 world and protozol and parasitic whatever. So the rise of 1:15:08.280 --> 1:15:11.680 antibiotic resist in't bacteria on farms means a rise of 1:15:11.720 --> 1:15:17.320 antibiotic resistant bacteria everywhere. Just like with the medical side 1:15:17.360 --> 1:15:20.880 of things, there is such thing as proper use of 1:15:20.920 --> 1:15:26.519 antibiotics in agriculture, but there has been overuse in terms 1:15:26.560 --> 1:15:30.320 of growth promoters and in terms of preemptive treatment, and 1:15:30.880 --> 1:15:34.800 it has remained a debate and a challenge to kind 1:15:34.840 --> 1:15:38.760 of see what the cost and benefits are. And I 1:15:38.800 --> 1:15:43.080 think we're only becoming more and more aware of the 1:15:43.200 --> 1:15:46.040 cost to humans. And it's also not going to just 1:15:46.080 --> 1:15:49.280 be antibiotic resistant infections in humans. It's also going to 1:15:49.280 --> 1:15:53.760 be livestock as well. So it's an interesting thing to 1:15:53.800 --> 1:15:57.559 think about anyway. But it's not just the US where 1:15:57.600 --> 1:16:01.920 overuse is an issue. Twenty fifteen, a group of researchers 1:16:01.960 --> 1:16:05.720 tried to predict how much antibiotics Brazil, Russia, India, and 1:16:05.800 --> 1:16:08.639 China could be predicted to use in the next fifteen 1:16:08.720 --> 1:16:13.960 years as demand for meat continues to increase. If nothing changed, 1:16:14.000 --> 1:16:17.679 that estimate was one hundred and five thousand, five hundred 1:16:17.680 --> 1:16:25.040 and ninety six tons globally. Oh dear, that's hard to 1:16:25.080 --> 1:16:29.639 wrap your brain around. The annual numbers of antibiotic resistant 1:16:29.680 --> 1:16:34.160 infections and deaths due to those infections are absolutely staggering. 1:16:35.080 --> 1:16:39.280 The history of resistance is like actively still being written, 1:16:39.960 --> 1:16:45.000 and it's not looking good. I want to I mean, 1:16:45.000 --> 1:16:48.760 there are some promising avenues of research ahead of us, 1:16:49.240 --> 1:16:51.439 but I want to end with a quote from the 1:16:51.600 --> 1:16:57.080 amazing book Big Chicken by Maren McKenna. Antibiotic resistance is 1:16:57.160 --> 1:17:01.000 like climate change. It is an overwhelming threat created over 1:17:01.120 --> 1:17:04.960 decades by millions of individual decisions and reinforced by the 1:17:05.000 --> 1:17:09.400 actions of industries. It is also like climate change in 1:17:09.439 --> 1:17:12.640 that the industrialized West and the emerging economies of the 1:17:12.640 --> 1:17:17.920 global South are at odds well with that. Erin, tell 1:17:17.960 --> 1:17:21.559 me where we stand with antibiotic resistance today. Are we 1:17:21.680 --> 1:17:25.160 basically on the brink of returning to a pre antibiotic era? 1:17:25.520 --> 1:17:26.479 Is there any hope? 1:17:27.160 --> 1:18:05.559 I mean, let's find out I need a short break. Yeah. Same, Well, 1:18:06.200 --> 1:18:10.040 let's start with the depressing things and then we'll end 1:18:10.120 --> 1:18:17.679 on a at least hopeful note. How about that? Great? Okay? Ah, 1:18:18.080 --> 1:18:23.680 all right? So medically in the US, at least, the 1:18:23.720 --> 1:18:29.520 CDC estimates that at least forty seven million antibiotic prescriptions 1:18:30.040 --> 1:18:36.960 in the US each year currently are unnecessary. What so 1:18:37.040 --> 1:18:38.280 we're doing great? 1:18:38.880 --> 1:18:41.639 Okay? What does unnecessary mean means? 1:18:42.080 --> 1:18:44.240 I don't know for sure, because that was just a 1:18:44.280 --> 1:18:48.720 stat taking off their like Antibiotic resistance general page, But 1:18:48.840 --> 1:18:52.800 in general, unnecessary means either not the right antibiotic for 1:18:53.080 --> 1:18:56.200 the infection, or using an antibiotic to treat a non 1:18:56.600 --> 1:18:57.519 bacterial infection. 1:18:57.760 --> 1:19:02.160 Right, you wouldn't expect ever to see zero, right, because 1:19:02.200 --> 1:19:04.960 if somebody comes in and they have, you know, some 1:19:05.479 --> 1:19:08.080 infection but you don't know what it is yet, or 1:19:08.160 --> 1:19:10.599 you suspect it's a bacterial infection, you're going to try 1:19:10.600 --> 1:19:13.320 different antibiotics, right, and so that would be included in that. 1:19:13.360 --> 1:19:15.320 I'm just trying to wrap my brain around this. Forty 1:19:15.360 --> 1:19:15.840 seven million. 1:19:16.000 --> 1:19:17.760 Yeah, it's a good question. I don't know if that 1:19:17.840 --> 1:19:21.240 includes like every time that you give vanken zosin in 1:19:21.320 --> 1:19:24.840 the er, which like everyone who comes into the ear 1:19:25.000 --> 1:19:27.720 gets those two antibiotics at first, right when we don't 1:19:27.720 --> 1:19:30.880 know what they have yet, right, So I don't know 1:19:30.920 --> 1:19:33.840 if that's included or if that's just prescriptions like outpatient 1:19:33.880 --> 1:19:37.160 what you get sent home with. Either way, it's terrifying. 1:19:37.240 --> 1:19:38.840 I mean forty seven million. 1:19:38.880 --> 1:19:43.640 Oh yeah, so that's in the US. 1:19:44.160 --> 1:19:47.800 Also in the US, it's estimated that more than and 1:19:47.880 --> 1:19:49.880 this is very recent data, so this is from a 1:19:49.920 --> 1:19:51.920 report that came out at the end of twenty nineteen. 1:19:52.800 --> 1:19:55.599 It's estimated that there are more than two point eight 1:19:55.880 --> 1:20:01.959 million antibiotic resistant infections in the US year that result 1:20:02.640 --> 1:20:10.120 in more than thirty five thousand deaths. Wow, so thirty 1:20:10.120 --> 1:20:12.160 five thousand people a year are dying in the US 1:20:12.200 --> 1:20:14.240 because of antibiotic resistant infections. 1:20:14.800 --> 1:20:16.040 Do you have global numbers? 1:20:16.160 --> 1:20:19.559 Great question. I tried really hard to get solid global numbers. 1:20:19.600 --> 1:20:23.520 It is very, very difficult. So the World Health Organization 1:20:23.680 --> 1:20:26.479 has set up in I believe twenty fifteen, they set 1:20:26.560 --> 1:20:31.720 up the Global Antimicrobial Resistance Surveillance System, which is basically 1:20:32.000 --> 1:20:36.080 every country setting up their own surveillance system. So I 1:20:36.120 --> 1:20:39.040 think now it's over sixty countries that are reporting their 1:20:39.080 --> 1:20:44.360 antimicrobial resistance data to the World Health Organization, but they 1:20:44.439 --> 1:20:48.280 don't seem to aggregate that data and present it as 1:20:48.360 --> 1:20:53.760 overall numbers. Overall, World Health Organization estimates that in many 1:20:53.800 --> 1:20:57.760 parts of the world over forty percent of bacterial infections 1:20:58.040 --> 1:21:01.960 or with bacteria that are resistant to antibiotics. But I 1:21:02.000 --> 1:21:04.519 don't have numbers on deaths. I do have numbers. In 1:21:04.560 --> 1:21:10.599 the EU. In twenty fifteen, an estimate from the European 1:21:10.720 --> 1:21:16.920 Union was that six hundred and seventy one thousand infections 1:21:17.120 --> 1:21:22.280 were likely antibiotic resistant and that likely resulted in thirty 1:21:22.320 --> 1:21:24.519 three thousand deaths in twenty fifteen. 1:21:25.040 --> 1:21:26.000 Oh my gosh. 1:21:26.120 --> 1:21:30.080 So that's in the EU, but a lot of the 1:21:30.240 --> 1:21:34.600 increase in antibiotic use is in low and middle income countries, 1:21:34.800 --> 1:21:37.320 And we don't really have good data on the number 1:21:37.400 --> 1:21:42.719 of resistant infections worldwide. But it's bad, it's not good. 1:21:42.920 --> 1:21:43.519 It's a lot. 1:21:44.479 --> 1:21:45.800 So I have two questions. 1:21:45.840 --> 1:21:46.160 Okay. 1:21:46.760 --> 1:21:50.640 The first question is about in the US, are antibiotic 1:21:50.760 --> 1:21:55.480 resistant infections reportable? Like are you required to report them? 1:21:55.840 --> 1:21:57.920 Well, that's a really good question. I don't fully know 1:21:57.960 --> 1:22:01.320 the answer to that. So there's this that report that 1:22:01.360 --> 1:22:03.720 came out in twenty nineteen has a list of like 1:22:03.840 --> 1:22:07.480 the most concerning pathogens, right, and the World Health Organization 1:22:07.560 --> 1:22:11.280 also has a list of what their pathogens of greatest 1:22:11.280 --> 1:22:15.120 concern are and those lists mostly overlap, So I would 1:22:15.160 --> 1:22:18.000 think that most of those pathogens are going to be 1:22:18.080 --> 1:22:22.479 reportable in the US. Okay, But that doesn't mean like 1:22:22.560 --> 1:22:25.839 every time that, for example, someone comes in with a UTI, 1:22:26.479 --> 1:22:29.360 if you do a urine culture, you might send that 1:22:29.520 --> 1:22:34.479 culture off to see what the resistance profile is, and 1:22:35.000 --> 1:22:39.360 that bacteria might be resistant to a few antibiotics, So 1:22:39.439 --> 1:22:41.920 then we use that to choose what antibiotic we give 1:22:42.000 --> 1:22:44.200 to that person. But I don't think that we then 1:22:44.320 --> 1:22:47.920 report that necessarily to the CDC. It probably goes to 1:22:47.920 --> 1:22:50.120 the local public health district so that we can keep 1:22:50.160 --> 1:22:54.200 track of what the general antibiotic resistance looks like in 1:22:54.560 --> 1:22:58.320 our area. Gotcha, So hospitals keep track of things like that. 1:22:59.120 --> 1:22:59.479 Okay. 1:23:00.479 --> 1:23:02.960 So I will say that a report that came out 1:23:02.960 --> 1:23:06.160 in twenty fourteen, which is earlier than most of the 1:23:06.240 --> 1:23:11.520 data I was hoping to find, estimated that currently worldwide, 1:23:12.000 --> 1:23:18.680 there are seven hundred thousand deaths attributed to antimicrobial resistance worldwide. 1:23:19.400 --> 1:23:21.479 That is a lot. 1:23:21.800 --> 1:23:26.160 It's a lot. And they projected that out and estimated 1:23:26.160 --> 1:23:29.160 that by twenty fifty that number would go up to 1:23:29.360 --> 1:23:30.400 ten million. 1:23:30.960 --> 1:23:34.120 Oh my god, if we do nothing, like if we 1:23:34.280 --> 1:23:37.240 just continue on the same pathway. 1:23:37.040 --> 1:23:42.920 Yeah, Oh my gosh. Yeah. And then they also estimated 1:23:42.960 --> 1:23:45.760 what the overall cost, like the monetary cost of that 1:23:45.800 --> 1:23:49.120 would be, that it would cost the world up to 1:23:49.240 --> 1:23:53.240 one hundred trillion dollars antimicrobial resistance. 1:23:53.520 --> 1:23:53.760 Yep. 1:23:53.840 --> 1:23:57.320 I can't. I can't comprehend that number. Wow. 1:23:58.960 --> 1:24:02.800 I was really hoping to find more recent, like hard 1:24:02.920 --> 1:24:06.400 data on anti microbial resistance, and I came across a 1:24:06.439 --> 1:24:09.960 paper that came out in twenty sixteen that really highlighted 1:24:10.120 --> 1:24:12.719 some of the issues that we have in even trying 1:24:12.760 --> 1:24:16.360 to get a handle on this burden of antibiotic resistance 1:24:17.760 --> 1:24:22.439 because that number, that estimated number of deaths, like it's 1:24:22.600 --> 1:24:27.720 such an estimate. We really don't have solid numbers on that. Well. 1:24:27.800 --> 1:24:31.160 And then I also, you know, my other question was 1:24:31.160 --> 1:24:35.360 was about how do you attribute cause of death exactly? 1:24:35.400 --> 1:24:38.360 And so that's yeah, so like if you're in the 1:24:38.360 --> 1:24:40.759 hospital and you go in for like a routine surgery 1:24:40.920 --> 1:24:44.559 like appendicitis, and you get MRSA and then you die, 1:24:44.760 --> 1:24:47.439 is that MRSA is that appendicitis? 1:24:47.520 --> 1:24:51.120 Right? Exactly? That's kind of exactly what they were highlighting 1:24:51.200 --> 1:24:54.640 in this paper. We can't calculate the number that we 1:24:54.760 --> 1:24:58.320 really need to calculate to know the number of deaths 1:24:58.439 --> 1:25:02.439 attributable to the fail year of antibiotic therapy due to 1:25:02.479 --> 1:25:07.120 antibiotic resistance because we don't know enough about the rates 1:25:07.120 --> 1:25:10.080 of resistance or the rates of infection for so many 1:25:10.120 --> 1:25:14.040 different infections. You have so many things like diarrhea that 1:25:14.080 --> 1:25:18.519 can be caused by so many different pathogens. So like, yeah, right, 1:25:19.080 --> 1:25:22.320 it's a really complicated, big picture. 1:25:22.400 --> 1:25:26.719 Question, but there is no question that it is leading 1:25:26.760 --> 1:25:29.599 to death. And it's horrible. 1:25:29.800 --> 1:25:33.519 Yeah, it really is, and it's a very multifactorial problem. 1:25:33.920 --> 1:25:36.720 Like you mentioned, Aaron, there's a number of different factors 1:25:36.800 --> 1:25:42.160 contributing to this, right, inappropriate prescriptions, misuse of taking those 1:25:42.200 --> 1:25:47.280 antibiotic prescriptions, agriculture, poor sanitation in hospitals. So I will 1:25:47.320 --> 1:25:49.960 say that all of the kind of action plans that 1:25:50.200 --> 1:25:54.080 CDC and WHO and all these different organizations, they're very 1:25:54.080 --> 1:25:58.040 holistic plans, right. They recognize that this is not going 1:25:58.080 --> 1:26:01.320 to be solved by just one change or even a 1:26:01.320 --> 1:26:05.479 few changes. It's a whole bunch of different solutions that 1:26:05.520 --> 1:26:08.880 are going to be required for this problem. But one 1:26:08.880 --> 1:26:12.360 thing that it's definitely going to take are new methods 1:26:12.400 --> 1:26:17.200 of treatment because for many pathogens, resistance is already here. 1:26:17.280 --> 1:26:20.640 So we need new ways to target these pathogenic bacteria. 1:26:21.400 --> 1:26:24.280 We do, and this is where we'll have some shining 1:26:24.280 --> 1:26:28.479 moments of hope. Okay, yay. The good news is there 1:26:28.479 --> 1:26:32.240 are so many people working on the issue of antibiotic 1:26:32.280 --> 1:26:36.040 resistance from a treatment standpoint. You heard in our last 1:26:36.040 --> 1:26:39.400 Antibiotics episode about a group that's working on new methods 1:26:39.439 --> 1:26:44.400 of identifying antibiotic compounds using machine learning, which is so cool. 1:26:45.320 --> 1:26:46.280 I love it so much. 1:26:46.479 --> 1:26:50.160 It's amazing. It's literally unbelievable, so cool. 1:26:50.439 --> 1:26:53.880 There are a number of other groups working on alternative 1:26:53.920 --> 1:26:57.559 therapy strategies as well. There's some really promising data on 1:26:57.680 --> 1:27:02.479 probiotic therapy, which I think is awesome. So basically boosting 1:27:02.560 --> 1:27:07.439 gut microbiomes to try and both treat and prevent toxic infections. 1:27:07.160 --> 1:27:09.800 Fecal transplants, fical transplants. 1:27:09.920 --> 1:27:12.920 So probiotic therapy is a very cool I feel like 1:27:12.960 --> 1:27:14.960 we'll probably talk a lot more about that in a 1:27:15.000 --> 1:27:17.040 Microbiome episode. 1:27:16.800 --> 1:27:19.080 But you should definitely google fecal transplant. 1:27:19.240 --> 1:27:23.559 Oh for sure, it's so cool. There's also a lot 1:27:23.600 --> 1:27:27.240 of work being done on combination therapy, so whether that's 1:27:27.360 --> 1:27:32.200 combinations of an antibiotic and another molecule that blocks a 1:27:32.240 --> 1:27:37.040 normal resistance mechanism to that antibiotic, like augmentin that was 1:27:37.080 --> 1:27:40.639 an example I gave early on, or whether it's giving 1:27:40.720 --> 1:27:44.200 a number of different antibiotics in combination that have different 1:27:44.240 --> 1:27:47.200 mechanisms of action, which is how we already treat things 1:27:47.240 --> 1:27:49.440 like tuberculosis for example. 1:27:49.080 --> 1:27:52.000 Right which by the way, I know we touched on 1:27:52.040 --> 1:27:56.160 this in the tuberculosis episode, but like multi drug or 1:27:56.160 --> 1:27:59.920 extremely druggers is in tuberculosis is terrifying aarin tubercula. 1:28:00.040 --> 1:28:02.320 Yes, this is so terrifying that it's not even included 1:28:02.439 --> 1:28:05.400 on the lists of the terrifying bacteria because it's like 1:28:05.439 --> 1:28:09.120 its whole own version. Like we've known about resistance in 1:28:09.240 --> 1:28:11.240 TV for so long, like we don't even need to 1:28:11.240 --> 1:28:12.320 include it on our list. 1:28:12.720 --> 1:28:15.720 Oh gosh, the escape list. Is that what you're talking about. 1:28:15.800 --> 1:28:17.840 Yeah, I didn't even mention the names of any of them, 1:28:17.880 --> 1:28:23.840 but I got ahead of myself. So some of those 1:28:23.880 --> 1:28:33.720 pathogens include Enterococcus, feceum, staph aureus, club Ciella, Assinitobacter balmani i, Pseudomonis, 1:28:33.760 --> 1:28:38.640 and Enterobacter. Those are the six that are really commonly 1:28:39.040 --> 1:28:42.559 like the big escape I think, just because they make 1:28:42.600 --> 1:28:46.080 a nice acronym. But there's really at least twelve that 1:28:46.120 --> 1:28:47.720 we need to be concerned about. 1:28:49.080 --> 1:28:50.880 But we don't. We don't care about the other six 1:28:51.000 --> 1:28:52.400 just because they don't make a good act. 1:28:52.479 --> 1:28:59.960 They don't make a good acronym. H. Pylori, lah, camplobacteror Gonorrhea, Salmonella, strep. New. 1:29:00.560 --> 1:29:02.960 You know, there aren't enough vowels in there. 1:29:03.120 --> 1:29:04.880 I know that's why they're not included. 1:29:05.880 --> 1:29:07.800 We do care about all of those. 1:29:07.880 --> 1:29:13.040 Oh it's especially gonorrhea, man, Oh my gosh. Yeah, So 1:29:13.160 --> 1:29:16.599 there's a lot. There's also a lot of work being 1:29:16.680 --> 1:29:22.160 done on antimicrobial peptides. There's work being done on stimulating 1:29:22.400 --> 1:29:26.400 the immune response and using our own immune system to 1:29:26.479 --> 1:29:30.960 better fight off infection. There's the use of things like 1:29:31.120 --> 1:29:36.920 iron scavenging molecules. One of the coolest areas and one 1:29:36.960 --> 1:29:39.160 that I've been most excited to talk about for a 1:29:39.240 --> 1:29:41.759 while now, is phage therapy. 1:29:42.520 --> 1:29:47.679 Phage therapy. We briefly touched on it in the MRSA episode, 1:29:47.920 --> 1:29:51.639 very briefly, very briefly, too briefly, far too briefly. 1:29:51.880 --> 1:29:56.160 And so who better to tell you about the status 1:29:56.240 --> 1:30:00.320 of phage therapy research than the provider of our first 1:30:00.360 --> 1:30:03.639 hand account who literally treated her own husband with phage 1:30:03.720 --> 1:30:10.880 therapy and also studies it, doctor Stephanie Strathty. Well, thank 1:30:10.920 --> 1:30:12.639 you so much for taking time out of your day 1:30:12.680 --> 1:30:15.240 to chat with us. We're really excited about this episode 1:30:15.280 --> 1:30:17.200 and thrilled to get the chance to talk to you. 1:30:18.120 --> 1:30:20.320 We'd love for you to kind of give us first 1:30:20.520 --> 1:30:24.120 maybe a brief overview of like what phage therapy is 1:30:24.400 --> 1:30:27.479 for our listeners and kind of how it works sure. 1:30:27.560 --> 1:30:32.440 Well. Phages are viruses that have naturally evolved to attack bacteria. 1:30:32.720 --> 1:30:36.200 They're like the perfect predator for bacteria. They've actually co 1:30:36.439 --> 1:30:40.320 evolved for four billion years. They're the oldest and most 1:30:40.479 --> 1:30:43.479 ubiquitous organism on the planet. And it's thought that there's 1:30:43.479 --> 1:30:47.880 about ten million trillion trillion. That's ten to the power 1:30:47.960 --> 1:30:51.760 of thirty one for you numeric matthew people out there. 1:30:52.160 --> 1:30:55.680 And so they're everywhere. They're on our skin, they're in 1:30:55.800 --> 1:30:59.360 our guts, we poop them out. They're in water. You know, 1:30:59.720 --> 1:31:02.280 a single drop of water can have trillions of phages 1:31:02.320 --> 1:31:05.720 in it. We just haven't been able to understand what 1:31:05.840 --> 1:31:08.559 they're like because they're so small. They're about one hundred 1:31:08.600 --> 1:31:13.679 times smaller than bacteria. And they were discovered in nineteen 1:31:14.360 --> 1:31:19.640 seventeen by a French Canadian named Felixe de Caral, and 1:31:20.120 --> 1:31:23.320 you know, he deduced that these must be viruses that 1:31:23.400 --> 1:31:26.920 are parasites of bacteria, even though you couldn't see them 1:31:27.000 --> 1:31:30.960 until the electron microscope was developed in the early nineteen forties, 1:31:31.479 --> 1:31:34.120 and people actually had a big debate as to whether 1:31:34.200 --> 1:31:36.959 or not these were proteins or whether they were viruses 1:31:37.120 --> 1:31:42.080 or whatever. And Deharel himself was quite a character. He 1:31:42.200 --> 1:31:45.360 was very egotistical, he wasn't formally trained, and he was 1:31:45.880 --> 1:31:50.120 really pushed to the margins of society and the medical field. 1:31:50.360 --> 1:31:55.799 And then when he helped the former Soviet Union developed 1:31:55.840 --> 1:31:58.559 the first page therapy center in the world, it got 1:31:58.600 --> 1:32:01.360 the label, as you know, Soviet science, and this was 1:32:01.400 --> 1:32:04.360 around World War Two, and of course that led to 1:32:04.439 --> 1:32:07.960 a big geopolitical bias of like pink O Komi science, 1:32:08.040 --> 1:32:12.400 and that put a cloud over phage therapy for decades, 1:32:12.479 --> 1:32:14.960 and so that's one of the reasons why the West 1:32:15.080 --> 1:32:17.760 really abandoned it. And of course penicillin came on the 1:32:17.800 --> 1:32:22.759 scene in nineteen forty two. Even though it was discovered 1:32:22.800 --> 1:32:25.120 in nineteen twenty eight, it had been you know, it 1:32:25.200 --> 1:32:27.840 took some time to come to end too the field, 1:32:28.040 --> 1:32:30.639 and that was because it was needed on the warfront. 1:32:31.120 --> 1:32:33.840 And so people thought antibiotics are wonder drugs, and of 1:32:33.920 --> 1:32:37.759 course they were for a while. But anti mycrobia resistance 1:32:37.800 --> 1:32:41.160 has just continued to outpace us, and nobody's really been 1:32:41.240 --> 1:32:44.800 paying attention to that until you know, we get these 1:32:44.880 --> 1:32:48.200 people who are having you know, minor scrapes or surgeries, 1:32:48.360 --> 1:32:51.200 and we realized, oh my gosh, they got a superbug 1:32:51.280 --> 1:32:53.320 and there's nothing left to kill it anymore. 1:32:54.200 --> 1:32:57.360 Could you talk us through what a typical course of 1:32:57.439 --> 1:32:59.760 phage therapy might look like. So how do you even 1:32:59.840 --> 1:33:03.840 go about finding the right phages and then administering them. 1:33:04.840 --> 1:33:07.519 Well, the thing about phages that's both a blessing and 1:33:07.560 --> 1:33:11.599 a curse is that they're really finicky. They only matched 1:33:11.680 --> 1:33:17.400 to specific bacteria. So for an organism like Staphylococcus, which 1:33:17.600 --> 1:33:20.960 you know, one of the strains is mursa right at 1:33:21.000 --> 1:33:23.840 the silin resistant staph wreas that's the superbug that was 1:33:24.240 --> 1:33:28.479 discovered first, maybe about twenty to thirty phages will cover 1:33:28.600 --> 1:33:33.360 the majority of circulating strains around the world, And that's 1:33:33.479 --> 1:33:35.680 pretty good because you don't need that many of them, 1:33:35.720 --> 1:33:38.120 and maybe you could have like a cocktail of phages 1:33:38.160 --> 1:33:41.120 that would you know, cover the majority of those infections. 1:33:41.520 --> 1:33:45.400 But for superbugs like Tom's asked me to back to Bomanii, 1:33:46.160 --> 1:33:51.479 it's very very specific. So the phage not doesn't just 1:33:51.960 --> 1:33:54.840 have to match the genus and the species, it has 1:33:54.920 --> 1:33:59.760 to match the isolate so Tom's bacteria. So that means 1:33:59.840 --> 1:34:02.320 you have to like essentially look for a needle in 1:34:02.360 --> 1:34:05.280 a haystack. But it's a little worse than that because 1:34:05.360 --> 1:34:08.240 when you think about where there's a lot of bacteria, 1:34:08.360 --> 1:34:10.040 that's where you're going to find a lot of phages. 1:34:10.560 --> 1:34:12.360 So if you need to go on a phage hunt, 1:34:13.080 --> 1:34:15.840 you have to go to some of the worst places around. 1:34:16.280 --> 1:34:22.000 And we're talking like sewage, barnyard, waist, scummy ponds, that 1:34:22.200 --> 1:34:25.400 kind of thing. So the phages that were actually used 1:34:25.520 --> 1:34:28.880 to treat tom we're from. So I can say literally 1:34:28.960 --> 1:34:31.559 that my husband is full of I mean, who can 1:34:31.640 --> 1:34:33.240 get to say that to their husband? 1:34:37.360 --> 1:34:38.040 That's amazing. 1:34:38.160 --> 1:34:40.800 And then so what then once you if you go 1:34:40.960 --> 1:34:43.400 in and you dig through all that sewage and you 1:34:43.520 --> 1:34:46.040 get lucky enough you find that needle in the massive, 1:34:46.120 --> 1:34:48.880 massive haystack, do you then take that to the lab 1:34:49.040 --> 1:34:49.519 culture it? 1:34:49.800 --> 1:34:51.920 And then what's the next step after that? How do 1:34:52.000 --> 1:34:53.479 you actually get it into that person? 1:34:54.680 --> 1:34:58.840 Well, the old fashioned plaque assay and it's actually this 1:34:59.000 --> 1:35:03.640 is something that's high school and freshmen learn how to 1:35:03.760 --> 1:35:07.600 do you have a Petrie dish, say with your bacterial 1:35:08.280 --> 1:35:11.720 lawn or your bacteria streaked on it, and if you 1:35:11.800 --> 1:35:14.040 want to see that if you have phages that are 1:35:14.120 --> 1:35:17.479 matching to that bacteria. You put a drop of sewage 1:35:17.520 --> 1:35:19.760 on the petrie dish and you incubate it for twenty 1:35:19.840 --> 1:35:22.360 four to forty eight hours, and if it comes back 1:35:22.479 --> 1:35:25.679 looking like a little like Swiss cheese because there's holes 1:35:26.080 --> 1:35:29.240 literally in the petrie dish, you get really excited because 1:35:29.400 --> 1:35:31.759 even though you can't see the phage, because they're smaller 1:35:31.840 --> 1:35:34.640 than the naked eye and even smaller than the light 1:35:34.760 --> 1:35:38.120 microscope can detect, you know that they've been at work 1:35:38.160 --> 1:35:41.400 because they've gobbled up a bacterial colony there. So then 1:35:41.439 --> 1:35:43.840 you can pluck it out and add it to more 1:35:43.960 --> 1:35:47.000 bacterial suspension, and then you need to purify it, and 1:35:47.160 --> 1:35:51.880 that's the tricky part. There's different techniques to purify phage suspension, 1:35:52.600 --> 1:35:55.840 but if you're going to treat it with phage intravenously, 1:35:56.000 --> 1:35:58.280 you want to get it as pure as possible because 1:35:58.320 --> 1:36:01.480 if there's a lot of bacteria debris and the suspension, 1:36:01.640 --> 1:36:04.400 it could elicit septic shock and the patient and could 1:36:04.479 --> 1:36:07.759 kill them. And that's what we're worried about with Tom's situation, 1:36:08.160 --> 1:36:11.160 and nobody really knew what the threshold for safety was, 1:36:11.280 --> 1:36:12.720 so we were taking a big risk. 1:36:14.360 --> 1:36:18.439 Yeah, so you mentioned kind of how difficult it is 1:36:18.560 --> 1:36:22.040 to even be able to identify and find these phases, 1:36:22.160 --> 1:36:25.400 especially when you're dealing with bacteria where you maybe only 1:36:25.520 --> 1:36:28.160 have like have to find a very specific phage. So 1:36:28.280 --> 1:36:30.320 could you talk maybe a little more broadly about some 1:36:30.479 --> 1:36:34.200 of the pros and cons of using phage therapy, maybe 1:36:34.320 --> 1:36:37.840 in like comparing and contrasting that to antibiotics that we 1:36:37.960 --> 1:36:38.559 have currently. 1:36:39.600 --> 1:36:42.840 Yeah, Well, the good news about phages is that again 1:36:42.880 --> 1:36:45.560 there's ten million, trillion trillion phages on the planet, so 1:36:45.640 --> 1:36:49.040 there's almost an exhaustible supply of them. It's just you 1:36:49.160 --> 1:36:52.200 need to find the right phages to match the bacteria 1:36:52.280 --> 1:36:54.519 that you want to kill. So if you have to 1:36:54.600 --> 1:36:57.800 go back to sewage or you know, barnyard waste or 1:36:57.840 --> 1:37:00.519 whatever every single time you need to treat somebody, that 1:37:00.560 --> 1:37:04.719 would be a real pain. And obviously it's very labor 1:37:04.760 --> 1:37:07.280 intensive and you may not find phages in time, and 1:37:07.360 --> 1:37:10.519 we've been in that situation with other patients. But if 1:37:10.560 --> 1:37:13.680 you have a phage library or a phage bank that's 1:37:13.800 --> 1:37:17.320 essentially like a walking and cooler, where you have thousands 1:37:17.360 --> 1:37:21.160 of phages and they're already identified and characterized and sequenced, 1:37:21.560 --> 1:37:23.600 then you could just kind of go in there and 1:37:24.640 --> 1:37:26.560 you know, see if the bacteria that you want to 1:37:26.640 --> 1:37:31.000 kill has phages in the library. So that's that problem 1:37:31.120 --> 1:37:34.000 about how do you find the phages to match the 1:37:34.040 --> 1:37:37.280 bacteria that you want to kill? Can be overcome, gotcha. 1:37:38.360 --> 1:37:41.360 So one of the questions I had was about dose 1:37:41.760 --> 1:37:45.160 and sort of one of the negative consequences of or 1:37:45.240 --> 1:37:49.000 potential consequences of phages, so like, how do you know 1:37:49.439 --> 1:37:54.400 how much how many phages to give? And also when 1:37:54.640 --> 1:37:57.960 those phages break apart those bacterial cells, what are some 1:37:58.040 --> 1:37:59.680 of the risks associated with that. 1:38:01.280 --> 1:38:04.559 Well, to be honest, nobody really knows the right dose 1:38:04.760 --> 1:38:09.640 for phages in most cases, and that's part of the 1:38:09.720 --> 1:38:13.640 translational basic science research that needs to go on so 1:38:13.760 --> 1:38:16.599 that we can, you know, get ready for clinical trials. 1:38:17.120 --> 1:38:21.160 In Tom's case, we just you know, took an estimate 1:38:21.240 --> 1:38:23.559 based on his weight and the fact that he had 1:38:23.560 --> 1:38:27.000 a systemic infection where you know, the bacteria were in 1:38:27.240 --> 1:38:30.439 every cavity in his body. And we knew that if 1:38:30.479 --> 1:38:34.320 you underdose, if you give too few phages, the body's 1:38:34.360 --> 1:38:37.680 own immune system can eliminate them and the phages might 1:38:37.760 --> 1:38:41.080 not ever reach their target. And we thought, well, is 1:38:41.160 --> 1:38:44.599 there a risk of overdosing him or whoever you're treating, 1:38:45.040 --> 1:38:47.400 And we talked to experts and they said, you know, 1:38:47.760 --> 1:38:51.160 we haven't actually, you know, seen any side effects of 1:38:51.520 --> 1:38:54.800 this as long as the endotoxin, which is essentially the 1:38:54.880 --> 1:38:58.880 bacterial debris that is caused when you are growing up 1:38:58.920 --> 1:39:01.320 a lot of phage. In the context of a lot 1:39:01.320 --> 1:39:04.599 of bacteria that endotoxin, there's a lot of antidoxin left 1:39:05.080 --> 1:39:09.320 that could kill the person. So again, we haven't seen 1:39:09.400 --> 1:39:14.360 that though we've treated over a dozen patients and you 1:39:14.479 --> 1:39:17.120 see San Diego and dozens other internationally. 1:39:17.880 --> 1:39:21.280 Gotcha. Yeah, So you talked a little bit about some 1:39:21.360 --> 1:39:25.040 of these challenges moving forward with phage therapy, but let's 1:39:25.040 --> 1:39:28.280 talk about the bright future. So since the publication of 1:39:28.360 --> 1:39:31.479 your book, there's been a lot of forward progress in 1:39:31.600 --> 1:39:34.600 phage therapy and in new initiatives, and so can you 1:39:34.680 --> 1:39:36.600 talk a little bit about what you see as the 1:39:36.720 --> 1:39:40.840 future for phage therapy and also are there going to 1:39:40.880 --> 1:39:45.320 be genetically engineered phages for specific infections. 1:39:46.439 --> 1:39:49.560 Well, yes, there's been a lot of really exciting developments 1:39:49.640 --> 1:39:54.439 since then. The first is that the first genetically modified 1:39:54.479 --> 1:39:58.479 phage cocktail to be used successfully to treat a human 1:39:58.880 --> 1:40:03.840 Bacterial Infection was published in May of twenty nineteen, so 1:40:04.320 --> 1:40:08.000 a year ago from now, and it was an incredible case, 1:40:08.280 --> 1:40:11.599 just as fantastic as Tom's. This is a young girl, 1:40:11.840 --> 1:40:14.960 her name's Isabelle. I happen to know her now through 1:40:15.280 --> 1:40:19.600 our connections and Facebook and social media. She had a 1:40:19.720 --> 1:40:23.560 hassistic fibrosis and she'd had a double lung transplant and 1:40:24.760 --> 1:40:28.880 had acquired this what's called Microbacterium obsessis. And people who 1:40:28.920 --> 1:40:33.560 are familiar with tuberculosis will know that michael Bacterium tuberculosis, 1:40:34.040 --> 1:40:38.160 a cousin to this Microbacterium obsessis, is the biggest bacterial 1:40:38.240 --> 1:40:41.000 killer in the world. It almost kills two million people 1:40:41.040 --> 1:40:45.519 per year. And so this is a very difficult to 1:40:45.640 --> 1:40:49.160 treat pathogen. And she was literally dying. She was in 1:40:49.320 --> 1:40:53.360 hospice and her mother heard about Tom's case contacted her doctor. 1:40:53.479 --> 1:40:58.679 The doctor contacted some of our colleagues, and we happened 1:40:58.720 --> 1:41:02.320 to know that there was a named Graham Hatful at 1:41:02.360 --> 1:41:05.439 the University of Pittsburgh who runs this wonderful training program 1:41:05.640 --> 1:41:09.799 called Sea Phages that teaches students how to find phages, 1:41:09.840 --> 1:41:13.759 and essentially they're doing this page hunt that I described earlier, 1:41:14.680 --> 1:41:16.599 and all of the phages that they find go into 1:41:16.640 --> 1:41:20.240 a giant phage bank, and they have about fifteen thousand 1:41:20.320 --> 1:41:23.320 Mycobacterium phages. They'd never even dreamed that they could be 1:41:23.439 --> 1:41:28.679 used therapeutically, and when asked, they said, wow, we'll certainly 1:41:28.720 --> 1:41:30.719 see if any of our phages will be a match 1:41:30.800 --> 1:41:35.080 for Isabella's bacteria. And three of them were, and one 1:41:35.240 --> 1:41:38.800 was perfect. Its name was Muddy. It was found on 1:41:38.920 --> 1:41:42.639 a rotting egg plant from South Africa by a student there. 1:41:43.360 --> 1:41:46.680 And all the students who find new phages get to 1:41:46.800 --> 1:41:50.120 name them, right, that's part of the bonus. And two 1:41:50.200 --> 1:41:52.880 of the other phages were the sleepy kind. In our book, 1:41:52.920 --> 1:41:56.320 I described them as hitting this snooze button. They actually 1:41:56.360 --> 1:41:59.559 don't kill the bacterial cell, but that's all they could find. 1:42:00.000 --> 1:42:03.799 What they did was they genetically manipulated those two phages 1:42:03.880 --> 1:42:07.400 by clipping out the repressor gene in a technique called 1:42:07.479 --> 1:42:11.840 we're commineering, which is, you know, a prequel to a 1:42:11.960 --> 1:42:16.760 crisper gene editing, and it forced those sleepy phages to 1:42:16.840 --> 1:42:19.760 become the phage rage kind of phages that actually kill 1:42:19.840 --> 1:42:22.760 the bacterial cell. And then they had to convince the 1:42:22.920 --> 1:42:26.600 UK government where she was living in the UK, that 1:42:27.000 --> 1:42:30.080 this was okay to use, and luckily they went along 1:42:30.120 --> 1:42:32.360 with it because they said, well, it's not a GMO 1:42:32.560 --> 1:42:35.439 because you took away a gene, you didn't add a gene. 1:42:36.240 --> 1:42:43.240 And Isabelle received phage therapy intravenously because based on Trum's protocol, 1:42:43.560 --> 1:42:46.360 we convinced them that it was safe. She left the 1:42:46.439 --> 1:42:50.479 hospital within a week. It was just stunning, and she's 1:42:50.680 --> 1:42:55.080 made a great recovery. She's I believe she's still receiving 1:42:55.160 --> 1:42:59.360 phage therapy now, but she's you know, working, She's finished 1:42:59.400 --> 1:43:01.479 her A level exam, she's learned to drive a car. 1:43:02.479 --> 1:43:05.280 You know, she's dyed her hair purple. You know, she's, like, 1:43:06.080 --> 1:43:08.960 I believe she's eighteen now and she's doing great. So 1:43:09.560 --> 1:43:12.800 that case is a landmark because that's the first time 1:43:13.320 --> 1:43:18.000 that genetically engineered phage has been used to treat a 1:43:18.080 --> 1:43:22.120 bacterial infection and a human being successfully. And also it's 1:43:22.160 --> 1:43:25.519 the first time that a Mycobacterium infection and a human 1:43:26.000 --> 1:43:29.559 has been successfully treated with PAGE therapy. And Len's hope 1:43:29.600 --> 1:43:33.719 that maybe someday we could treat tuberculosis with PAGE therapy. 1:43:33.760 --> 1:43:34.799 Wouldn't that be awesome. 1:43:35.400 --> 1:43:39.599 That is being so exciting. Wow, that is amazing, I mean, 1:43:39.720 --> 1:43:42.880 and it seems like it's coming at just like a 1:43:43.120 --> 1:43:46.000 highly highly needed time and we need to do something 1:43:46.040 --> 1:43:48.840 about this, you know, huge huge grin continuing to grow 1:43:48.960 --> 1:43:53.200 problem of antibiotic resistance. And so, you know, how how 1:43:53.280 --> 1:43:58.360 have you felt the receptivity of phage therapy in you know, 1:43:58.479 --> 1:44:01.040 academic circles for instance. Do you feel like it's people 1:44:01.040 --> 1:44:04.160 are being fairly receptive or is there still some pushback? 1:44:05.680 --> 1:44:09.480 Well, initially, when Tom's case was started to become publicized 1:44:09.520 --> 1:44:14.000 about a year after he was treated, it was presented 1:44:14.040 --> 1:44:17.360 at the one hundred anniversary of the discovery of bacteria 1:44:17.400 --> 1:44:21.080 phages at the past Or Institute, and then the story 1:44:21.160 --> 1:44:23.720 went viral. I mean literally, I was getting contacted by 1:44:23.800 --> 1:44:26.439 people from all over the world. I'm wanting page therapy, 1:44:27.680 --> 1:44:30.400 but it was mostly patients in their families. Doctors were 1:44:30.520 --> 1:44:35.600 very skeptical and until Chip school he started making presentations 1:44:35.680 --> 1:44:39.840 to infectious disease physicians, that's when they started to realize, wow, 1:44:40.360 --> 1:44:43.280 this isn't just a one of there's several other cases 1:44:43.479 --> 1:44:47.440 and it's looking really exciting and they're very well documented. 1:44:47.560 --> 1:44:50.080 And Tom's case is published, and several other cases have 1:44:50.160 --> 1:44:52.920 been published, and of course the Georgians and the Polls 1:44:53.000 --> 1:44:56.640 have been doing this page therapy for years now, and 1:44:57.400 --> 1:45:01.320 there's also interest in their work and they have extraordinary 1:45:01.439 --> 1:45:04.439 clinical experience. But it had been really kind of poo 1:45:04.479 --> 1:45:07.360 pooed because it was thought of as a Soviet science, 1:45:07.880 --> 1:45:12.679 and so it's really been a watershed moment for reasons 1:45:12.720 --> 1:45:16.040 that you know, I don't completely understand, but the story 1:45:16.120 --> 1:45:19.080 itself has kind of led to a lot more interested 1:45:19.080 --> 1:45:22.800 in phage therapy. Pharmas and biotechs have started to get 1:45:22.840 --> 1:45:26.280 into the space because they realized too that with genetically 1:45:26.360 --> 1:45:29.920 engineered or even synthetic phages, they'll be easier to patent. 1:45:30.600 --> 1:45:34.240 The ANIH, which had traditionally not funded any phage therapy, 1:45:34.840 --> 1:45:38.200 they've funded now two clinical trials of phage therapy. The 1:45:38.280 --> 1:45:41.959 first is going to be undertaken by our center iPath 1:45:42.840 --> 1:45:46.799 in collaboration with the Antibiotic Resistance Leadership Group, a network 1:45:46.840 --> 1:45:50.400 of research institutions around the US that had predominantly focused 1:45:50.439 --> 1:45:53.360 on new antibiotics, but since there's no antibiotics in the 1:45:53.400 --> 1:45:56.599 pipeline to speak of, they've embraced page therapy. So We're 1:45:56.720 --> 1:45:59.400 very excited by that because that's what we need now. 1:45:59.479 --> 1:46:03.560 We need clinical trials to advance page therapy and to 1:46:04.160 --> 1:46:08.479 first show efficacy, and then we can, you know, hope 1:46:08.479 --> 1:46:12.080 that the FDA will license it alongside antibiotics. We don't 1:46:12.120 --> 1:46:14.959 think that phage is ever going to replace antibiotics altogether, 1:46:15.360 --> 1:46:17.559 but it will be an important adjunct and it will 1:46:17.560 --> 1:46:21.519 allow us to reduce that amount of antibiotics that we're using. 1:46:21.960 --> 1:46:25.520 We've even seen that phage can be synergistic with antibiotics. 1:46:25.600 --> 1:46:28.160 We saw that in Tom's case and in several other cases. 1:46:28.640 --> 1:46:31.679 So if we can leverage the power of phage, we'll 1:46:31.720 --> 1:46:35.479 be using antibiotics more Wisely, I'm just happy that our 1:46:35.640 --> 1:46:39.320 story can kind of take a rightful place in medical history. 1:46:39.360 --> 1:46:41.720 I mean, Tom and I are really privileged. I mean 1:46:42.000 --> 1:46:45.519 we if we had been living anywhere else, or if 1:46:45.560 --> 1:46:49.160 I didn't have the connections that I did and wonderful 1:46:49.400 --> 1:46:53.439 colleagues at our university hospital, you know, I'd be holding 1:46:53.680 --> 1:46:56.439 you know, an earn with its ashes instead of his hands. 1:46:56.840 --> 1:46:58.720 So that was one of the reasons we decided to 1:46:58.760 --> 1:47:01.720 tell our story because we realized how privileged we are 1:47:02.160 --> 1:47:05.000 and that most people dying from superbugs are in lower 1:47:05.040 --> 1:47:07.480 and middle income countries and they don't have the resources 1:47:07.520 --> 1:47:10.599 we have. So my dream someday is to have an 1:47:10.680 --> 1:47:15.519 open source phage bank that can be accessible to anyone anywhere, 1:47:16.160 --> 1:47:19.679 and I'm fundraising for that through iPath. That's our Center 1:47:19.720 --> 1:47:23.840 for Innovated Phage Applications in Therapeutics and hopefully one of 1:47:23.880 --> 1:47:26.880 these days we'll be able to, you know, say goodbye 1:47:26.920 --> 1:47:27.640 to superbugs. 1:47:52.680 --> 1:47:56.880 That was amazing. We were so excited to speak with you. 1:47:57.000 --> 1:47:59.639 Thank you so much for taking the time to chat. 1:48:00.640 --> 1:48:04.360 So cool, so cool, the coolest to the coolest Aaron. 1:48:04.400 --> 1:48:07.360 Do we have anything else or is it time for sources? 1:48:07.560 --> 1:48:10.879 This was such a fun episode. Let's cover sources. 1:48:11.640 --> 1:48:14.400 Let's do it. I think I might have mentioned a 1:48:14.479 --> 1:48:17.439 couple of times the book Big Chicken, Just a Few, 1:48:18.280 --> 1:48:20.960 Just a Few by Maren McKenna. It's great. It's about 1:48:20.960 --> 1:48:25.000 the use of antibiotics in agriculture, particularly the chicken industry. 1:48:25.840 --> 1:48:29.160 And I also read a few papers that I will 1:48:29.160 --> 1:48:31.200 put on the website. But another book that I read 1:48:31.439 --> 1:48:34.240 is called The Killers Within the Deadly Rise of Drug 1:48:34.320 --> 1:48:39.639 Resistant Bacteria by MB Schneerson and MJ. Plotkin. And finally, 1:48:40.400 --> 1:48:44.759 you guys should definitely check out doctor Strathte's book called 1:48:45.000 --> 1:48:47.960 The Perfect Predator, A scientist race to save her husband 1:48:48.040 --> 1:48:51.679 from a deadly superbug. A memoir so good, you, guys, 1:48:52.280 --> 1:48:53.639 seriously so good. 1:48:55.160 --> 1:48:58.799 I heavily used actually the same book that I used 1:48:59.160 --> 1:49:03.200 for the antibiotic episode, edited by Roslen Anderson at All, 1:49:03.360 --> 1:49:07.360 called Antibacterial Agents, Chemistry, Motive Action, Mechanisms of Resistance, and 1:49:07.400 --> 1:49:10.880 Clinical Applications. And then there's another great paper from twenty 1:49:10.960 --> 1:49:14.320 sixteen called Mechanisms of Antibiotic Resistance that I will link to, 1:49:14.960 --> 1:49:18.320 plus a whole bunch of papers on the kind of 1:49:18.439 --> 1:49:22.599 current status of antibiotic resistance. And we'll link to all 1:49:22.640 --> 1:49:25.000 of our sources from this episode in every episode on 1:49:25.080 --> 1:49:25.639 our website. 1:49:26.960 --> 1:49:30.960 Yes, thank you again so much to doctor Strathte for 1:49:31.120 --> 1:49:33.719 coming on and chatting with us and telling her story. 1:49:33.800 --> 1:49:36.040 We really appreciate it so so much. 1:49:36.120 --> 1:49:38.120 Thank you so much for taking time to speak with us. 1:49:38.880 --> 1:49:41.360 And thank you to Bloodmobile for providing the music for 1:49:41.439 --> 1:49:43.320 this episode and all of our episodes. 1:49:43.920 --> 1:49:48.800 Yes, and thank you to you listeners for listening one 1:49:48.960 --> 1:49:56.080 episodes long fifty one episodes. Now we can continue our excitement. Awesome, 1:49:56.360 --> 1:49:59.600 all right, Well until next time wash your hands. 1:49:59.360 --> 1:50:00.439 You've filthy animals. 1:50:01.479 --> 1:50:20.000 Um um um u