Defeating Superbugs 🦠 An Evolutionary Battle (Part 2)

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Hello, everyone. Welcome back to the TechLink Health Podcast. I'm Rob McBride, and I'll be co-hosting this episode with Dr. Sarah Samaan. As many reflect on the past couple of years of the pandemic and start to think about emerging threats of the future, it's important to bring awareness to that very topic, the future, and what's on the horizon in public health. Today's episode is part 2. Of a series that focuses on the emerging threat of antimicrobial resistance, which has been deemed by the World Health Organization as one of the top 10 global public health threats facing humanity. The episode digs deeper into the innovations happening within healthcare to defeat superbugs, as shared from the perspective of this episode's guest, Dr. Stephanie Strathy, who is an epidemiologist, a distinguished professor, a global health solutions seeker, a TEDx speaker, and the author of The Perfect Predator, a memoir of her effort to save husband's life and the discovery of a forgotten cure that has the potential to save millions more. Stephanie also serves as the co-director of the Center for Innovative Phage Applications and Therapeutics at the University of California San Diego School of Medicine, as well as the associate dean of global health sciences. It goes without saying that Stephanie has played an instrumental role in the advancement of solutions focused on the emerging threat of antimicrobial resistance. superbugs, and we look forward to getting her perspectives today. So without further delay, we are excited to welcome Dr. Stephanie Strathy to the podcast. Stephanie, thanks a lot for joining us today.

Oh, it's a deep pleasure. Thanks so much, Rob and Sarah.

To start off with, we were hoping you could give our listeners some background. Can you take a moment to introduce yourself in a bit more detail and give us a quick snapshot of your career, your journey, and ultimately your work with stage applications and therapeutics?

Sure. So I'm actually a Canadian scientist raised in Toronto, where I did my undergraduate degree in the 1980s in microbiology. And I never dreamed that a lecture that I took in virology would be something that I would remember and would play an important role in saving my husband's life some 35 years later. So always pay attention in class, students. So I was recruited first to Johns Hopkins after I did my PhD, and then to the University of California, San Diego. where I have been a professor since 2004. And I joined my husband, Tom Patterson, who is an experimental psychologist and an evolutionary sociobiologist. And we have done a number of research studies together focused on HIV prevention among marginalized populations. So I never set out being a virologist or a phage researcher. I just remembered what they were. And my husband actually ended up acquiring a superbug infection in 2015 when we were on holiday in Thanks for that background.

Much appreciated. So, you know, I obviously, and many others know you from the authorship of the book, The Perfect Predator. And I was hoping we could get into that. If you could tell us more about the journey, which ultimately led to the creation of the book.

Absolutely. So as mentioned, my husband and I were on vacation in Egypt in 2015, Thanksgiving holiday in the US. So November, we were having a great time. He seemed to be in perfect health. He is 6'5. He carried his weight well, but he was overweight. He was pushing about 300 pounds at the time. And we were the only people on this cruise ship that we had booked. Everybody else had canceled because there had been a terrorist attack in Sharm el-Sheikh a couple of weeks prior. And I was a bit nervous about going on the trip. And Tom said, it's the perfect time to go. We are not canceling. I've always wanted to take this trip. It's a dream of a lifetime. And there'll be nobody at these ruins but us. So it's like, It's going to be wonderful. So nobody ever dreamed that the terror that we would experience would come from within because it turned out that Tom was actually harboring a giant abscess in his abdomen that had been caused by a gallstone. And he had periodic episodes of what appeared to be, you know, food poisoning, or he has an allergy to canola oil. So whenever he'd gotten sick, we just assumed that he just had canola. And it turns out. He actually had gotten very sick after this meal we had on top of the cruise ship. It was our last night. We were supposed to see the Valley of the Kings the next day. And when he started vomiting uncontrollably later that night, you know, I was a bit annoyed. I have to say I was not the perfect wife at the time. I, uh, I, you know, said, oh, I can't sleep. And, you know, he was just retching and he was, I told him, oh, you're praying to the porcelain god, you know? And I said, well, maybe you're going to just see King Tut's tomb feet first in your own tomb. And, you know, and of course, uh, we don't laugh about it as much anymore because like, uh, it ended up being pretty close to the truth. He got more violently ill. We had to call a doctor to the ship. The doctor said, well, he's, uh, probably got food poisoning. I'll give him some intravenous gentamicin and some fluids and he'll be right as rain in a couple hours. He'll be up for dinner. And he wasn't, he was actually worse. His abdomen kept getting more and more distended. He was in pain. And then he started complaining of back pain. Well, up until this point, I'd been calculating the incubation periods for different microorganisms that I thought may have led to what I, I, I thought was food poisoning. But when he started complaining of back pain, I realized, wow, maybe I've been all wet. Like, this is probably something totally different. So before I called the doctor back, I, I made a phone call to our colleague, Dr. Chip Schooley, who was then the head of infectious diseases at the University of California, San Diego. Where my husband and I both work, and he gave me some advice. He said no, he really does need medical attention. He could have pancreatitis or twisted bowel. Get him to the closest hospital. And of course, there was no hospital in Luxor. This is a you know a small village that exists primarily for tourism. But the doctor got us to the closest clinic and called several doctors up in the middle of the night to care for Tom, and they diagnosed pancreatitis within an hour. And I thought okay, great. That's an inflammation of the pancreas. I know what that is. But I just assumed that now that we had a diagnosis, that there would be a cure, and that cure would miraculously appear. Well, medicine doesn't always work that way, and they did the best they could with the limited resources they had. They did give him a CT, so he was able to get a scan the next day of his abdomen, and whatever they saw on that scan, they did not like the looks of. And after that, they started to help us get. Organized for medevac. Luckily, we had travel insurance that kicked in and he was first sent to Germany because he was too weak to be sent back home. And there in Germany, they repeated the CT scan and did an endoscopy and they found that this gallstone had blocked his bile duct and caused this abscess to form. The doctor appeared to me and showed me the fluid that had been in his abdomen and they took a sample of it in this A flask, and it was putrid. It was like brown, murky. And he said, "Look, if this abscess had just formed, this fluid would be clear. But the fact that it's brown and murky like this means not only that it's been there for a while, but there's something growing in it. So we're going to culture this, and we're going to put him on some antibiotics and hope that you know it's a garden variety microorganism because you're coming from Egypt, and there's a lot of multi-drug resistant organisms in the Middle East. That's why you're in not just the ICU, but in." Isolation, and so I still thought you know modern medicine was going to come to the rescue. It couldn't be that an organism that you pick up on vacation in Egypt, you know, is going to kill you, right? But I was wrong. Turns out this culture came back a couple days later, and it was Acinetobacter baumannii, which I remembered vaguely from my microbiology classes. But back then, it was like a wimpy organism that we used to plate on our petri dishes, and all we needed was like a lab coat and gloves and. I was like a freshman and, and like, how could this turn out to be something that is now so scary? Well, that's when I realized that my husband was this poster child for this post-antibiotic era that we're now entering. So that, that's how this whole episode started. And, and the rest is now medical history.

Stephanie, that is an extraordinary and harrowing story. And I can't even imagine how that must've felt to be so far from home with your husband so sick. In the book, it's well noted that you engaged with phage researchers all over the world to address this very complicated infection that your husband had. And so we'll talk about that and what that entails and why you chose to go in that direction. But I understand that you found allies at the FDA and researchers from Texas A&M and even a clandestine Navy biomedical center, and all in collaboration, you were able to able to resurrect the forgotten cure of phage therapy. So, I'm just really curious to know more about that. So, tell us more about that experience and what some of the best practices and advice that you have learned and have discovered for emerging innovators that will eventually need to orchestrate these types of efforts in the future development of new technologies.

Well, you know, I didn't start out thinking, well, my husband has a superbug. Wow. Let's try phage therapy. It ended up being quite a circuitous path. So first, in Germany, they stabilized him. He was medevaced back home to San Diego. And there it was actually my doctor friends that were now caring for Tom, including Dr. Schooley, who I had reached out to when we were in Egypt. And they repeated the antibiogram that had been done in Germany. And that basically is an antibiotic susceptibility profile that tells doctors what best antibiotics to use for an organism. It's not something that's often done unless there is resistance, and they knew that this organism was going to have resistance. And so initially it was partially sensitive to 3 antibiotics, but they were all what I call the gorilla-cillins. They're the kind of antibiotics that have to be infused into a patient and have very heavy side effects. So then once they realized that, okay, this is going to be a scary organism, but let's repeat the antibiogram in San Diego, and to their dismay, Now it was resistant to all known antibiotics, even colistin, which is the last resort antibiotic that had been developed in World War II. And at that point they said, well, we were going to operate, but now that would be a bad idea because if this organism gets into his bloodstream, he'll go into septic shock. We have nothing to cover it. So we're gonna put catheters in his abdomen and try to siphon out all the infected fluid and hope that the abscess shrinks. Well, that process was very prolonged. And so he was now in the hospital. This is like, say February, he'd been in the hospital for a couple of months. And one of those drains slipped and it poured all that infected fluid into his abdomen, into his bloodstream. And he immediately went into septic shock in front of my eyes. So just for anybody listening, everybody should know that sepsis is a major killer in hospitals and Basically, it's the body's overreaction to an invader that hits the bloodstream. So your immune system goes like, red alert, red alert, and it goes into overdrive. And so immediately the person usually starts sweating, um, and, you know, might, um, urinate. In this, his case, all this fluid started pouring into these ostomy bags. He lost 3 liters of fluid within the span of an hour. And then he started to shake. And those are the rigors. And he shook so badly that the bed frame hit the wall and they rushed him back into the ICU. They put him in a medically induced coma. And luckily he did come out of that coma on his own several days later. But, um, but at that point it was almost game over because now this organism was everywhere, right? It was like in his sputum, in his blood, everywhere. So that's when it was clear that he was dying a little bit each day. And he dropped over 100 pounds. So now he was like, I think he went down to 172 pounds and that might have included the bed frame. And this is like a guy who, you know, was 6 foot 5. So he looked like a concentration camp victim. And when the doctor said there's nothing else that they can do, do you want to start dialysis for his kidneys? I knew that what they were really getting at was, do you want to prolong his life? He's on life support as it is. He was on 3 different pressors or medications to keep his heart pumping. He was on a ventilator. They finally put in a trach vent. So people are familiar with the ventilator from the COVID pandemic. So, you know, he, he just looked horrible. And so when they asked me if I wanted to extend his life with dialysis, I was really in a quandary because we, like many couples, have talked about, you know, advanced directives if somebody, you know, is, you know, not You know, gonna live. And he said, "If I'm brain dead, please, please pull the plug. I wouldn't want to live like that." But his brain was alive; it's his body that was dying. So I didn't know what he wanted to do. And I had a conversation with him where I asked him if he wanted to live, and I said, "Squeeze my hand if you want me to kind of turn to alternatives." And when he squeezed my hand, I was elated, but I was also terrified because I realized that I was not a medical doctor, and my colleagues who were some of the best infectious disease physicians in the world. Had run out of options. So I did what anybody would do. I hit the internet. I used PubMed, and that's P-U-B-M-E-D, which is the National Library of Medicine's search engine. It's better than Google Scholar because it doesn't have a lot of misinformation and disinformation in there. Those are medical journal articles. And I put in the keywords multidrug resistance, the name of his superbug, and up popped a paper that mentioned phage therapy. And that's when that bell rang from my, my virology class from 1986 that I'd taken at the University of Toronto, where I was introduced to the concept of phages, which are viruses that have naturally evolved to attack bacteria. So I thought, wow, why couldn't we use this to treat Tom? So that's how it started.

Thanks so much for that story. If you had to summarize, what are the core takeaways of the book and more broadly, how the book has been instrumental in helping to address the challenges of antimicrobial resistance? Which according to the World Health Organization could kill over 10 million people by the year 2050.

Well, I think there's a number of takeaways from our story. You know, anyone who has lived through COVID and watched someone be hospitalized or die knows that how important advocacy is and to be able to come up with the idea of an outside-the-box, you know, type of experimental treatment that's considered fringe. It takes guts, but, but it also takes physicians that are willing to listen. And I think through this story that we've seen that when people come together to try to save someone's life, it's, it's, it's worth it. Never ever give up on a patient is what Dr. Schooley has always said. And in this case, it involved researchers from Texas A&M who were total strangers who offered phage, and they actually went on a phage hunt around the world asking fellow researchers if they had phage active against Acinetobacter baumannii, could they send it to Texas A&M? They turned their lab into a command center. So the power of collaboration is another aspect of this. The phage community is tremendous. Everybody helps each other. There's more patients than we can ever keep up with. So we've all banded together, and my husband lived and made a miraculous recovery. And that really has been described by many as Phage therapy 2.0. Phage therapy 1.0 was when Félix d'Hérelle, who was the discoverer of phage, used phage therapy for the first time on people in 1919. So back then, we didn't know a lot about the science behind phages, and it's caught up tremendously since then. But one of the important lessons from my husband's case is that you can inject phage into somebody's bloodstream, and the phage will get where they need to go. We don't actually understand all of the ways that they can maneuver around to find their targets, which are the bacteria that have receptors that they match to. But they can pass through tissues, they can cross the blood-brain barrier, they can get into people's lungs or their bladders. And, um, so if someone has a systemic infection like Tom, injecting phage, a billion phage per dose was injected into Tom every 2 hours. And essentially let nature run its course because the bacteria and the phage have been duking it out at an invisible level for almost 4 billion years. And we just need to make sure that we find the right phage, the perfect predator, if you will, to kill the bacteria that's causing the problem.

Stephanie, your story makes clear that this is a global issue with broad implications, especially in these days of antibiotic resistance. From a global perspective, there's several initiatives focused on phage applications and therapeutics. And from your perspective, what are the most promising applications, particularly as it relates to consumer health, and how will phage therapies enter our day-to-day lives? And also along these lines, one of the hot topics across industries is ChatGPT and the powers of AI technology. And I'm curious, can you tell us more about how these technologies can potentially work alongside the phage Or more broadly, other technologies or devices that can coexist alongside the phage therapies?

Well, right now, phage therapy is still considered experimental in most Western countries, including the US and Canada, and many parts of Western Europe. It's actually standard of care in Eastern Europe, like in the Republic of Georgia and Poland, where it's been used for generations. So it needs to undergo clinical trials in order to be licensed. Alongside antibiotics, up until then, it will be offered on a case-by-case basis in the U.S. and other countries with their own regulatory bodies overseeing it. But the FDA has never turned us down for a case where someone's critically ill. So certainly, that's the number one you know application right now is someone with a you know an infection that is not responding to antibiotics. But there are other applications as well. So, for example, if we had an outbreak of cholera, that's a very infectious bacterial pathogen. And usually if someone in the household gets cholera, everybody in the household gets it right away. So phage could actually be used prophylactically in settings like that to prevent people from getting cholera if they have a household member who's been exposed. So that's another application. There are applications in veterinary medicine, and there's companies that are starting to get interested in this because, of course, we live with our pets and We share our microbiomes with our cats and our dogs. But then also there's applications in livestock, uh, animal husbandry, and in agriculture and even aquaculture. Turns out that, and this is something that I didn't know prior to my husband's case, is that about 70% of antibiotics used in the US and over 80% in Canada are actually used in agriculture. And this is, say, in citrus, and also in animals to make animals grow fatter faster. So even though some countries have in place restrictions to try to prevent them being used as growth promoters, they're often used off-label in that way. So imagine phage replacing, or at least being allowed to reduce, the amount of antibiotics that are used in the environment. That would actually greatly curtail the antimicrobial resistance crisis that we're facing. And we've been talking mostly about natural phage up until now, but genetically modifying phage to make them better bacterial killers is something that is being hotly pursued by a number of biotechs and even pharmaceuticals. And that's also because they're easier to patent. There's also teams working on synthetic phages that could receive the bacterial DNA, the sequence, and that phage to that so that you wouldn't have to get the patient's bacterial isolate shipped in order to match phage to it. So there's lots of potential applications, but there's even applications in wellness. So these days, the microbiome and making sure that we have healthy microbiomes is on everybody's minds, but they're usually just thinking of the bacteria. The forgotten element of this is the bacterial killers, the phages that keep the bacterial numbers in check inside our microbiomes, and not just in our gut. but on our skin and in other parts of our bodies. So phages could be included in probiotics and in other different supplements or beverages, et cetera, to promote wellness. At this point, we don't know enough about microbial ecology to be able to match which phage would be best for a certain person, but personalized medicine is occurring, and so it's envisioned that this will be part of the repertoire that phage could contribute to in the future. And when it comes to AI, you know, certainly there's a number of machine learning applications that could make phage therapy better. The first one is that right now, when we try to source phage from the environment, we're doing it rather opportunistically. We're going to a duck pond or a sewage treatment facility, believe it or not. Wherever you find a lot of bacteria, you find a lot of phage that feed on those bacteria. So those are great places to go. But we don't really know if, for example, you have a staph infection, where would be the best place to identify phage that will kill that particular staph? So machine learning algorithms could be used to help us find better places in the environment to be able to source phage. They could also be used to decide which phages go best together in a cocktail, because it's seldom do we use a single phage. To attack a bacteria, we often put bacteria and phage together that attack different, that have different receptors, that they attach to different receptors of the bacteria. So being able to decide, if you have a whole bunch of phage to choose from, which ones would be best to go together that wouldn't compete, that would be synergistic, and also which phage are synergistic with which antibiotics, AI could play a role in all of those applications.

So continuing on that sort of thinking about the future and discussing the future, if you think about the next 10 years, what do you think is in store for the future of phage therapies, and how will related technologies continue to evolve in this space? And then tacking onto the end of that, are there any particular technologies that immediately come to mind in that regard?

Well, I think over the next 10 years, we're going to see a number of clinical trials being undertaken. Right now, They're translational in nature and usually quite small, but we will need to have efficacy trials to determine whether phage therapy works for different kinds of medical conditions. So, for example, if you're having a phage therapy trial for people with recurrent urinary tract infections, and it's successful, that doesn't necessarily translate to a phage therapy trial for people with cystic fibrosis, who tend to have lung infections. So we'll need to have different kinds of trials, different parts of the world, different kinds of organisms, different types of phage cocktails. Some of these phage cocktails could be fixed. That means off the shelf. There are organisms like Pseudomonas and Staph that some experts feel that a fixed cocktail could cover the majority of those circulating isolates, whereas others, like the infection that my husband had, Acinetobacter baumannii, the phage for that organism has a very narrow host tropism. By that, I mean that they're really picky phages. So you have to match the phage to not just the genus and the species of that bacteria, but to the specific isolate in that person. So in those cases, you're going to need to have a much bigger number of phage to choose from, or you get the genetically modified, you know, genetic engineering approaches, like using CRISPR-Cas gene editing to optimize the tropism of the phage so that it's broader, so that a fewer number of phage can hit a greater number of bacterial targets. So I think that those kinds of studies are going to be done. I think we're going to see, probably this year even, the first tech phage being used in a person as a case study. And of course, in those cases, it's going to need to be somebody who's critically ill, for whom there are no antibiotic options left. But if these trials are done and they're found efficacious, then the FDA and other licensing bodies around the world can approve them and make them available. And then you're going to see health insurers and consumers come to the table. Right now, we actually have so many requests for phage therapy, even among people who don't have a multidrug-resistant bacterial infection. They would just rather take what they seem to see as nature's green alternative to antibiotics. You know, they would rather take phage than antibiotics. So I think there's going to be a huge consumer demand for These types of treatments, and we're going to see them being used in probiotics. I'm certain that that's coming. I also see a potential for phage in nanomedicine. Phage, right now, we've been talking about their application as doing what they do best, killing bacteria. But if you see them as little nanovehicules, they can be reprogrammed to carry whatever payload we want to use. And so we know from Tom's case that you can actually inject a billion phages into somebody every 2 hours. and they don't die of septic shock. Well, it's no wonder because our microbiomes are awash with phage. It's estimated that 30 billion phages move in and out of our tissues every single day. So they're already part of our bodies. So that means that we can harness the shell of the phage to carry payloads. So in that case, I mean, like cancer treatments or even vaccines. So I think that is a tremendous potential for the future that takes us way beyond AMR.

That's fascinating. And that kind of feeds into the next question, from a global health perspective, outside of antimicrobial resistance, what do you see as some of the other threats that we should be thinking about, and perhaps the top 3 from your point of view, and how some of these technologies might interact?

Well, I think that the most important aspect to consider here is that climate change and antimicrobial resistance are 2 of the most important global health And they actually are making each other worse. So there was actually a recent report that came out that pointed to this, but you know, we talk about climate change and global warming as the planet warms and as the waters warm and as the temperatures increase around the world, that's fertile ground for bacteria. Bacteria grow faster and multiply faster when there's a warm environment. And when people have less access to water and sanitation, that means that if they're not bathing as frequently or don't have access to water, then that gives more opportunity for bacteria to grow. And in a globalized world that we're in right now, that means that an antimicrobial resistance gene that appears in one country is not just going to stay in that one country. It's going to be spread around the world very quickly. And just as an example, the MCR-1 gene that confers resistance to colistin, That last resort antibiotic that I mentioned, that my husband actually had that MCR-1 gene. It had just been discovered in China and published in a paper in The Lancet, the top medical journal in the world, in November of 2015, the same month that he fell ill. The doctors nearly fell off their chair when they realized that his bacterial isolate contained that gene, but it shouldn't have surprised them because it was already in 30 countries. It's just, we haven't done global surveillance. So what we need to do is bring together experts that are dealing with climate change and AMR together. We need to see this as not just the US problem or point to other countries and say it's their problem. They're still using antibiotics in pigs or whatever. We have created this problem together and we have to get out of it together. And so I think that both activists in these respects need to get together and researchers to combine their forces.

Those are great points, and indeed there's a great opportunity for more collaborative efforts in tackling some of these issues. Well, Stephanie, this has been a great conversation. Thank you for the many insights. In closing, any final advice for those who would want to learn more about your book or the Center for Phage Applications and Therapeutics that you founded at UC San Diego? What is the best way to stay connected to your work? Also, outside of your book and looking at the Center for Phage Applications and Therapeutics, Any other useful content that you would point listeners of this podcast to?

Sure. Well, thanks very much. I mean, we wrote our book because we realized that we were privileged, that without the resources that we have and a global village that stepped up to the plate to save my husband's life, that he wouldn't be with us now. And sharing that story, but also the science behind it in a way that was readable and that was enjoyable even for some. It's a scary story, but you know, the New York Times bestsellers called it like a memoir that reads like a thriller. So we even have some Hollywood interest. So if that happens, I guess you're going to be seeing a lot more of me, whether you like it or not. But up until then, you know, our center is a nonprofit. It's based at UC San Diego, the Center for Innovative Phage Applications and Therapeutics. The website is ipath.ucsd.edu. And anybody can contact us for a consult, or their provider. And we also have a quarterly newsletter. We're fundraising for a phage library because that's one of the biggest obstacles to being able to save lives right now is you have to find the right phage to kill the bacteria that's causing the problem. And if you have to go back to sewage every single time, that's just not scalable. So what we want is a giant phage library that maps onto a sewage treatment plant. Superbug Library. And so we're working hard. One of my favorite things to talk about is a program called the C. phages Program. Any of your younger listeners, or if you have kids, the C. phages is a program that was developed at the University of Pittsburgh by my colleague, Dr. Graham Hatfull. It was developed to teach students about microbiology and virology. So they go and they collect a sewage sample, and they put it on a Petri dish, and look to see whether or not it's got phage that will kill the bacteria that they've streaked on the plate. And if they find a new phage, they get to name it, they get to sequence it, the higher-level students annotate it, and they get to do some bioinformatics, and it's really fun. Well, it turns out that the phage library that's been created from C. phages has actually saved lives. And the first genetically modified phage cocktail to ever be successfully used in a human came from phages that were sourced by the Sea Phages Program. So that program exists in about 200 different universities around the world, but mostly upper-income countries. My dream is to actually take sea phages to lower- and middle-income countries because there we can teach people to collect samples from their own environment that are rich in superbugs and give them the capacity to be able to treat their patients with phages that are from their own backyard. So imagine how great that would be.

That'd be great indeed. Well, Stephanie, this has been an insightful conversation. Thank you so much for taking the time to be on the podcast. You have been a huge inspiration for me personally. I know that your book is a wonderful way to introduce people to the challenges of antimicrobial resistance and the power and the potential of phage therapy. So I definitely encourage people who haven't read it to find a copy, give it a read alongside some of the other recommendations you've made. I'm personally a fan of C. phages too, and some of the work that Dr. Graham Hatfield has done. It's very inspiring. So thanks for the time today. We really appreciate it.

Thanks to you and Sarah. Thank you.

Thanks for listening to this episode. TechLink Health is a healthcare advisory platform for consumers and organizations to stay informed with the latest insights while connecting with healthcare experts for telehealth, e-consults, and consulting services. For more details, For more details, visit www.techlink.health.