GAS, Streptococcus pyogenes: Call It What You Want, It’s Got a Big Reputation

[MUSIC] Hello and welcome to Breakpoints, the Society of Infectious Diseases Pharmacist Podcast. My name is Erin McCreary and I'm a clinical assistant professor at the University of Pittsburgh School of Medicine, and the Senior Director of Infectious Diseases Strategy at UPMC. We are back at Breakpoints with a really exciting episode today. Everything we want to know about group A strep or strep pyogenes because it is an awesome pathogen. So awesome in fact that the first panelist I'm going to introduce is actually currently wearing a Ares Tora-themed t-shirt about streptococcal vaccine development, which features the photo of one of our other panelists. I kid you not, I wish you guys could see this. So this is truly incredible, this group is super fun, and this is going to be an amazing episode. So Josh is a pediatric infectious diseases physician and an associate professor, recent promotion Josh, congratulations, who leads the vaccine challenges team in the Tropical Diseases group at Murdoch Children's Research Institute in Melbourne, Australia. Dr. Alzawiki's research focuses on strep pyogenes and human challenge research, which serves as an innovative platform for accelerating the development of vaccines and other interventions targeting high priority pathogens. He is also a lead investigator for the streptococcal adaptive platform trial or strep, which might sound somewhat familiar because it is the sister trial to the staff orius adaptive platform trial that we've talked quite a bit about on this podcast. I've had the honor of spending time with Josh when I was in Australia and can confirm he's as nerdy and awesome as he seems from that bio. So Josh, welcome to Breakpoints. Thank you Aaron, it's a real like a real high-rise for me to be on Breakpoint. It's a certain best of the infectious diseases podcast. I've been called a nerd by you Aaron is another career highlight really. So Breakpoint we probably don't know that when you were in Australia, the only person who's had a bigger, you know, more applause in Australia, more sands in Australia than Taylor Swift, his three concerts in Australia, with the biggest author and entire tour was Aaron McQuirey. Josh Davis brought an auto like an autograph book to meet Aaron and she signed every page of his autograph book. That is not even true, but thank you. You're very kind. It was a super joy to be with you guys in Melbourne. Okay, next is Dr. Shirani Shraskandan, who is a clinical professor of infectious diseases at the Imperial College in the United Kingdom and the head of the section of adult infectious diseases based at Hammersmith Hospital. She is also co-director of Imperial Center for Bacterial Resistance Biology. She leads research on strap pyogenes leading work on identifying novel potential vaccine targets and identification of new sub-linearages of serotypes M89 and M1 strap pyogenes where an expansion of these linearages has accounted for increasing proportions of invasive infections worldwide. Shirani is a fellow of the Royal College of Physicians and a fellow of the Academy of Medical Sciences. Shirani, it is such an honor to meet you. I'm so excited. Welcome to Breakpoints. Thank you. It's delighted to join you on the SIDP. So it's very exciting for me to be here. Yeah, you know, I knew Josh and I knew how much he loves strap. And when we talked about this episode, he was like, "You have to meet Shirani and you have to meet our third guest." So it's an honor to have you both. And so last but certainly not least, Tom Parks is a clinical associate professor in infectious diseases at Imperial College London, focusing on the genetics susceptibility to group A-strippedococcal disease, particularly rheumatic heart disease. His research involves understanding how complex genetic regions influence the acquisition of antibody-mediated immunity to various pathogens, including strap pyogenes. Tom is also the president of the Lansfield Society, which is an international association that promotes scientific collaboration and research in the field of strap-to-cocca and strap-to-coccal disease. Tom, welcome to Breakpoints. Thanks. It's a pleasure to be here. I think it's going to be a great conversation. And let's throw in some debates and discussion. And one of the things we like to do and be nerdy about is what are the origins of some of these things we talk about. I think that's often the case in our field that if we unpack these statements, dogmas, etc. we find this so much more interesting science to learn. So I think it's going to be a great conversation. Thanks for having me. Oh, I love that. Let's start at the beginning as much as we can, right? As much as we can reliably unpack the history. I think it's always good to level set for our listeners what we're going to be discussing today. So Tom, when it come back to you, serving as the president of the Lansfield Society is a big deal and very cool. The Lansfield Society for our listeners who may not be familiar is an international association that brings together professionals in the field of Streptococcal diseases to raise awareness and promote scientific collaboration aptly named for the Lansfield classification system. So I'm partial this because it was created by Rebecca Lansfield, a microbiologist from New York. We love strong women creating things left and right in the infectious diseases space. But Tom, can you describe for us what is the Lansfield classification system and do we still use it today? Yeah, for sure. Thank you for telling people about the society as well. So we think about Streptococcal in many different ways and when we talk about them in clinical practice, that actually can be quite confusing because we use what are essentially outdated terms that aren't there in the scientific literature or if they are there in the scientific literature, they can be used. They're a big microbiological groupings and the first thing that people really do is they think about hemolysis on the plate. So when we do that, you have different groups of hemolysis and really the way to think about that simply is the beta hemolytic groups and then the other groups. So if anyone studying for exams, there's a great way of remembering what beta means and that's better hemolysis, a bigger zone of hemolysis. And so you never need to remember again which way rounded is and then there's alpha hemolysis, which is basically a bit less hemolysis often with some discoloration and then it gets complicated. But basically there was a group that used to be called gamma and really now means no hemolysis. But what we're talking about today is what's in the beta hemolysis group and that's where you then hear this classification that Rebecca Lanzfield has self developed where we have these clinical terms group A, group B and C and G and so on. Now there are actually many of these groups which are based on serotyping but most of those we don't really use any more as terminology because the serotyping doesn't actually correspond exactly with the species. So the groups that people will be familiar with are group A, focus of today, also group B of a clearly important pathogen by human and animals but particularly in neonatal infections and then groups C and G as a cause of skin and sort of tissue infections. Then you have all the other groups of streptococcus which crucial include pneumococcus which is within that what used to be term viridens group and is of course itself a major major cause of infectious deaths globally and then many other very interesting streptococcus including causes of endocarditis and a whole series of fascinating and unusual infections. But if we bring it back to a group A what we are focusing on today it's that the Lanzfield carbohydrate that Rebecca Lanzfield described and demonstrated and showed that you can distinguish this and the reason that that term strep A or group A strep has stuck is because actually almost all of the time if you find the group A strep carbohydrate present then you're dealing with a streptococcus pyogenes that species and that's then a useful distinction in clavus. And this is a useful distinction in clinical practice which is going to determine much of what we're going to talk about going forward today. Thank you that was fantastic it also makes a nice acronym right we love an acronym medical vernacular we can't get away from them. And so yes as you said today we're going to focus only on group day streptococcus for the rest of the conversation or strep pyogenes. This is a bacterium that causes tonsillitis scarlet fever invasive infections such as necrotizing fasciitis maternal sepsis and toxic shock. It's always so funny to me because this bug it's susceptible to penicillin right and so it seemingly so would be but it's actually can be so deadly. Globally the post infectious strep pyogenes syndrome acute rheumatic fever leading to chronic rheumatic heart disease is the most common cause of acquired heart disease in young people. And yet despite this burden of illness there is no vaccine still and so Josh can you tell us more about this why is this wimpy but not wimpy bug so deadly and so invasive and if you're a listener who's even had something as simple as strep throat. What would surprise you most about how complex group a strap actually is as a pathogen sure so I was going to ask you know hey you know so are you calling a wimp because because really the thing about this pathogen is it gives the lie to the super bug term because streptopopus pygies doesn't need you know the strange environment of an antibody infested hospital to thrive that doesn't need and especially compromised host you know is a human pathogen. A human pathogen kind of power excellence and if a real super bug you know like sour and it's susceptible to the one ring to rule them all the beta lapidamry that continues to cause death and destruction anyway so for me that's a super bug a shirani is a streptopopal research royalty and Tom is the president I'm the core gester I'll start with some of the clinical spectrophilife and I'll hand over to them to cover some of their areas of expertise so. As you mentioned this pathogen has a diverse clinical spectrum and it's actually a clinical spectrum that was roughly guys centuries prior to identification of the pathogen itself and so you have these records of. the pockities and others clearly describing streptocopal syndromes typically, yet describing them as scarlet fever, and then patients who are very sick and died of that condition, who were said to have malignant scarlet fever or malignant scarletina. It's a diverse clinical spectrum that in different ways affects humans of every age and in every place on our planet from very common milder infections like in Batago and strepth throat or pharyngitis through to scarlet fever and what used to be called like I said, malignant scarlet fever. I think a better term for that now is severe acute invasive infection, including toxic shock syndrome, streptocopal toxic shock syndrome and necrotizing soft tissue infections. And those conditions are deeply even in the best equipped ICU's on the planet. And then despite a health frightening, some of those syndromes are, in fact, the greatest burden of disease globally, the greatest cause of death due to group-airstriptocopas, streptopopas, purgion is chronic disease and that's rheumatic heart disease caused following the immune mediated post-infecture syndrome of acute rheumatic fever. And a cause of heart failure in the first seconds, third defaits of life, requiring open heart surgery, valve replacements, putting patients at risk of stroke and ocarditis and heart failure. Death due to rheumatic heart disease always recorded as due to streptococcus because of chronic disease effects. And so right now, 55 million or so people are living with rheumatic heart disease, at least heart and million invasive cases a year around the world, more than 600,000 die, for most again, due to rheumatic heart disease, but also invasive disease. And hundreds of millions of empathigo and pharyngeitis cases every year. And so when you think about the burden of disease, we're talking about deaths, about disability, about chronic disease, about those absental child's hair, school work, health care usage, and even microbial resistance, and not because so much penicillin is prescribed, but because children adults presenting with sore throat, cellulitis, school sores, really common infections, often art prescribed penicillin, that prescribed all sorts of different antibiotics. So everyone knows that patient who, with cellulitis in your emergency department, who is prescribed, keep your cell on tazabaktam and vankemousen, despite the fact that everyone knows what absurd in the textbook, that this is almost certainly a beta hemolidic streptococcal injection. That's where its impact on AMR comes from. So I might pass to Tom maybe, to think a little bit about the host and kind of vulnerability. I think it's really always struck me that unlike some other pathogens, there's no classic person who, everyone thinks of, that's definitely group-ass strep, because that person has immunodeficiency A or comorbidity B, this is something that strikes healthy people as much as it's toxic. It's really, really important we think about why the host is vulnerable, and how it is that you get such diverse forms of disease in different individuals. And that's something that we're still are trying to puzzle. The bacteria itself is really, really crucial and we can come to that in a second, but thinking about the host, often it's going to be about barriers and people being vulnerable to the infection that can get through, establish itself, the innate system not being able to clear the infection, often because of virulent factors the pathogen itself is producing. But in the scenario severe disease, actually the immune system is actually overactivated, and there's a lot of collateral damage from that overactivation. And then in this scenario of post-infective disease, we think that recurrent infection is probably absolutely crucial, and then in some individuals you're getting infection after infection, and a breakdown in the systems that mean that those infections are contained, and that leads to this process of cross-reactivity. We've got a lot to try and unpick about that, but almost certainly because the ability to distinguish host from self is broken, and then you get damage to these key tissues like heart valve, or also in the context of gnarin and arthritis, which is even more neglected than rheumatic fever barely gets mentioned, the kidneys as well. And both of these are really contributing very substantially to the global burden of disease. - Yeah, and even thinking back in pharmacy school when we're doing bugs and drugs and trying to take in all infectious diseases as a base learner, you learn these bugs, you go strapped to caucas, strapped biogenies, penicillin, drug of choice, move on. And so it does, I said, when I say Wimpy, it seemed so simple, and I think because there are very active in vitro antibiotics, people don't give it the respect that it deserves 'cause this is truly quite a terrible disease. Josh, I did wanna ask you about one of your recent publications titled "Chains of Misery, Surging Invasive Group A Streptococcal Disease." Listeners, if you pubmed Josh, all of his paper sound like 80s rock bands, and there's many to choose from with very creative titles, but Josh, can you explain to us why this is true? I think anecdotally, those of us in practice feel like we have seen more patients with invasive group A Strepto-Zes, what happened? Did it just decide to manifest or what's going on here? - Well, yes, they chaise at misery, of course, as an Iron Maiden song. It was a follow-up paper to one called "Malasing Chains" with US Streptococcal Legend, Dicton Nizé. But very clearly, there was a surge in many countries. I think there are, so in relatively higher income countries, like the UK, US, and Australia, we saw the effects of pandemic interventions to restrict human contact to movement through the community results in a dissruption to what is generally a seasonal kind of sore tooth pattern for invasive group A Streptococcal Disease, as well as the Fahrenheit. So there's sore tooth that's stocked for a couple of years and then surged back as a pandemic. Tom Asher, I need a dozen beautiful words, look at the immunological basis for that. But for mentioning that, what I thought is really important to say is that that sore tooth pattern and that pandemic level isn't seen in every country, so it's seasonal. And so some countries that don't have clear seasons and we don't see it, that of sore tooth pattern, we just see an extremely high rate of invasive disease that happens all year round, often in the realm of somewhere between double to 10 times what we see in our countries. And that many of those countries saw no dip in disease through 2020 and 2021. And even the surge that we saw in many of our countries in 2022 and 2023 didn't exceed the right scene in some of those poorer countries mostly. Shiraani? - The really fascinating thing about that post pandemic upsurge, I mean, it was really bad, right? And was only seen in the countries that, as you say, have this seasonal upsurge. And so for many of us, it happened in the wrong season, right? So that was really kind of valuable in some respects, in that it taught us that actually, 'cause for years we'd been kind of wondering, why was it always a springtime? Was there some strange springtime event that was kind of bringing it on, like the tree pollen or pollution from Europe? Technically that's not the point, because it happened in November. But the other interesting thing, and I think underlying the pandemic interventions that kind of led to reduction in population immunity was the fact that countries like Japan had a really similar upsurge, but a whole year later, because they dropped their precautions much, much later than the rest of the world. I mean, it was so bad in Japan, I mean, I think even resulted in the cancellation of a World Cup qualifying match with North Korea. I mean, I think you were involved in some of the press about this, Josh, 'cause the people were saying, is it safe to go to Japan? And it was even reported in the UK press, which of course, had completely forgotten that we had added much word, worse upsurge a whole year earlier. So it just goes to show the public's memory, it's pretty short. Except when you cancel football, that's tragic. That's when people take it seriously. That's when they know it's real. The pandemic in 2020 didn't feel real until they canceled the rest of the NBA season in the United States and the NHL hockey season, and then people took it seriously. - I was gonna add that one of the things to put into the interesting context of that is that actually rates of particularly invasive infection seem to have been rising, particularly in countries like the UK for much longer than that. So although that post-pandemic upsurge is really key and has caused a lot of mobility and mortality and has taught us a lot about the disease process, got a bear in mind that actually since the 1980s, or possibly even longer, I'm not sure. People have been saying, well, there's more invasive group-raised strap, there's more invasive group-raised strap. And I think there are things going on in the general population that perhaps we've not been paying attention to that could be driving that. And some of that starts to relate to some of the issues around post-infective disease as well, because the extent to which things like overcrowding, living conditions haven't gone away, poverty, these are all diseases of underserved population. And that's a real tragedy and a shame on the societies we live in that actually we're allowing these diseases to persist and continue to increase. And so it's this really striking change that there was that lockdown and then you got these big increases, but on a background of actually and neglect of this problem for decades before that. I'd also add, Erin, that in the US there was one group where there was no real dip in 2020 and 2021. And that was in young adults who, unlike the UK and Australia, have really taken off as a second to much older adults, as a suffering group-raised strap-de-coccal disease, and almost certainly attributed to people who inject drugs. And the nature of the US opioid epidemic is quite different from what has been seen in other countries. And we did see a dick in children in the US, in the CDC, ABCs, and that just wasn't seen in young adults at all. And also interestingly in terms of the distribution of drugs. of strain types in young adults, what you saw in that group, strains kind of classically associated with skin disease and typically a distribution of looks like a low-income country, as opposed to the fairly classic distribution of invasive strains, commonly associated with tarantitis as well in higher income countries. I would just echo that because we saw the same thing in the UK. During that period of time, only group as strapped, you saw really, with kind of these skin type strains, not all in injecting drug users, also homeless people, and actually some people didn't do any of those things as far as we know. So we lost all of the typical sort of farangitis strains, which unfortunately also tend to be the ones which are associated with the higher mortality when they cause invasive disease. What then happened was after the pandemic, those were the ones that came and hit us really badly, and that's why the mortality was so high. And perhaps if we explore, because if listeners are less familiar with this issue of actually the age group affected and what we think was happening with immunity, we looked at this particularly in the under five group, and it's really interesting that it's the group after the pandemic who are aged about three to five years, and that's exactly the group where there was the biggest upsurge for highest mortality. And so we think those children were about a year behind in acquiring immunity to group history. So these were children who were essentially born around or just before the time of the pandemic, and they're growing up in that early year, those early years when they're learning to encounter these pathogens, they're probably encountering them regularly, and this issue actually would be really interesting to hear Josh and Shira and he's thoughts on this, but this, we've probably learned a lot about how immunity needs to be maintained and wasn't maintained during those populations. So that period where these children should have been acquiring immunity just flattened out, and so they had immunity equivalent to children a year younger than them, which made them so vulnerable to these life-wrecking infections. I think it's, this is so fantastic. Thank you guys for all of this. I think it's so fascinating, the societal, cultural, and structural underlay of infectious diseases. And we see this all around the world and other diseases. We could talk for hours about tuberculosis and about other infections like this. So I think that's so interesting, and I think we'll see the collateral of the pandemic for quite some time, and I think it'll be really fascinating to watch every age group from what you were from 2020 to 2023 out that then segues over time because I think impacts are going to be longstanding and pretty much every aspect. It's a nice segway in terms of immunity, so Shira and we're coming to you next because prevention is always the goal, right? For any infectious diseases, we just hope you don't get it to begin with. And Shira and we have had effective vaccines for pneumococcus for decades. But can you describe for us the incredible work you and others are doing in vaccine development for this pathogen? Where have we come? Where are we going? And what has made group-a-stripe so challenging and so hard to develop a vaccine? And then, you know, do you think we're finally turning a corner? Is there hope? I'm going to have to kind of answer the later of those questions first because it's easy for me to go chronologically and so why we've been so rubbish at doing this, right? So it's not like pneumococcus. So pneumococcus has got this polysaccharide capsule. And although there are lots of different types, if you inject that polysaccharide alone, you make an immune response against it. But the problem with group-a-stripe, it doesn't have a polysaccharide capsule. It's got a capsule that's made of high-alurona, which is basically what we're made of. It's that same stuff that's in cosmetics that should make me younger. And so we can't make an immune response against it. There is a kind of similar story with Nicerium enanjititus, right? Because we've got kind of capsule polysaccharide vaccines against that. But we never had one against syrograp B because syrograp B, the capsule there, looks a bit like something else in our body. So you couldn't make an immune response against it. And then the other issue about group-a-stripe is it's basically it's a card-carrying pathogen. It's much better in terms of a bug than pneumococcus, right? Because for a start it doesn't just die when you try and grow it. And secondly, it makes a ton of stuff that that just nukes our immune response, it nukes our innate immune response, and all of the antibodies that we make, it's got loads of enzymes that chop antibodies up. And it also makes these things called superantogens that Numa doesn't do, which confuses the immune response and means that we actually switch off our B cells. So basically number one, we can't vaccinate against the capsule and number two, it's a beast. So and then it comes to well, what can we do? Clearly we do become immune to it, as Tom's alluded to, as we grow up, right? So there is hope. I kind of think there's more hope almost than Staphores because there's a very clear age demographic. I don't go around getting strep sore throat and I don't think Tom and Josh do either, but their kids will do and even my kids who are kind of in their 20s and 30s might do. So we remove our ability to get a group-a-stripe sore throat, we must acquire immune to it. The question is we have no idea what the app is. And then then Josh is trying to work that out through his human challenge model work, but the question is, which bit of the bug could we vaccinate against? So there's kind of other things on the surface, there's the M-protein. So we talked about M-types earlier. Rebecca Lancefield described the polysaccharide antigen, but she also kind of identified that there was this sticky out protein on the surface of it, which is called M-proteins. The different types of these were worked out by lots of people. For some of the strains, if you vaccinate against just the M-protein, you get an immune response that will actually kill those strains. So that sounds like a really good idea, but it doesn't work for all the M-types. And then the other problem is that there's a whole bunch of these M-types. I mean, well over 100, so it's not a great idea because clearly if you vaccinate against one, you're going to have the other ones coming up. And then the other problem is, well, the other possibilities that you vaccinate against all the other proteins, which are much more common on the surface. So that's the strategy that's being used now. And that was the strategy that's worked for my seri-manageritist. Back to me, I really complicated. They're much more complicated than COVID. Or any of these viruses. Viruses got tiny genomes. Really, it's not that difficult to vaccinate against them, but back to the real-life group-based trip have got very, very huge genomes compared with the virus. Lots of different virulence factors and different surface things that you might design a vaccine against. It's not going to be one of them that's going to be enough, right? And so we've got to probably vaccinate against a number of different things. The question is, what's the most parsimonious combination of things we can stick into a vaccine that would be good enough? So that's what people are working on now. And then there's also the carbohydrate that Tom alluded to, the LeBeck-Alancefields group A-carbohydrate, which is potentially another target. So we still don't know what's the right thing to do, but there is a whole other problem about this, which is that kind of just because group A-strip also can cause auto-immunity, there's been this concern for like 50 years that if you vaccinate again with a bit of group A-strip, that you could trigger auto-immunity. So we've also been kind of self-flagulating over that for decades. I think finally we're over that. I'm not going to be through the history of it because it's actually, I mean, I kind of find it now quite boring. The other was a trial in the 60s and it was JAMA, I think, and three kids got rheumatic fever. But those kids actually had group A-strip infections during the vaccine trial. And we've never done, I mean, it was with a really dirty vaccine as well. So it's such a bad example of why we need to worry about this, that it's not worth talking about. The only thing that's ever actually caused dramatic fever is group A-stripped-to-coccal infection, and that's what I keep telling myself and everybody else. So that should not worry us about developing a vaccine. So we are, where we are, there are vaccines against M-protein that have actually gone through a phase one trial, and some of them are in phase two trials. There are vaccines against the other proteins of group A-strip that I mentioned before, some of which haven't got the carbohydrate, which are in phase one. So that's super exciting. I mean, we are in a place where we weren't even 10 years ago. Yeah. So that's quite exciting. What we don't know is whether they can or were. Now target, the target really is to prevent a group A-stripped sore throat. Ultimately, the rationale for that is because the burden of disease that we're trying to prevent is rheumatic heart disease. There's a sort of pressure to show that not only are you preventing strep throat, also you're going to be preventing rheumatic heart disease, and that's that's quite a long term thing to prevent, right? Well, that really puts vaccine companies off. Basically, the child gets lots of strep infections when they're 5, 6, 7, but doesn't get the rheumatic heart disease till they're 12. That's a very long clinical trial, and you'd need tens of thousands of people. No, it's going to say it's not going to happen. It's not going to happen. Very big and very expensive. So that's really the borers seemingly way too high. So we need we need a different outcome. We need a different benchmark to prove efficacy. Josh, yeah. Yes. So one of the challenges in a way is that what Shurani is describing is a 21st pathogen that requires a 21st century vaccine, but a vaccine that requires like development, according to kind of the way that we did it in the 40s, 50s and 60s, which was just going out there, vaccinating tens of thousands of people, sorry, all the syndrome's in there, calling it all, you know, group-based tropical injection and seeing what happened. We don't really develop vaccines like that anymore, but you know, when you look at most of the vaccines that are currently in the schedule, for instance, the eight or so that Mori's still in and developed that are still in the schedule. Most of them were pretty much tested in that kind of way in institutional outbreaks or just in mass-daxing campaigns where they vaccinated a lot of people and saw what happened. And things are, you know, for very good reasons, slower, more deliberate these days, but it also raises the hurdle, you know, big weight. And I think that's where where things are at now. We've got a pathogen, and a spectra of disease that everyone can agree makes a great case for a vaccine from a health point of view. I think there are several companies who think this is now a just a wonderful product that if they could show that it works, they need to show that it works, they need to show that it's safe and they need to get it through that kind of phase one, two, three pathway to have a license product. And that's a harder task than it sounds. He's a good idea for a vaccine, doesn't give you a good vaccine and a good vaccine doesn't give you a good vaccination. And that's where we're at the week group as chapter couple back there. There are lots of great people on the case. There's this wonderful group called the strip, a vaccine, global consortium or save apps that's apparently led by Jerome Kim. It's the infertile by Thene Institute of Seoul. Melissa might like to hear that Jerome was the first author of a very famous article in history infectious diseases called spiraling impuricism or something about a laws and temptations or something. And I'm wrote that as an ID resident, is now their leading save app and he co leads it with Professor Andrew Steeh, who's my boss in Melbourne. We are also connected. It is a very small world. SIDP actually has a list of must read infectious diseases papers when you start in the space and that paper is indeed included. Josh, you've done work in the vaccine space too. Your group has looked at human infection models, even some PKPD around penicillin dose finding. Has it related to vaccines? Can you just describe that work for us? Like describe your life's work in like three minutes, but give it a go. No problem. But basically Andrew Steeh gave me the keys to a Ferrari and that Ferrari was this wonderful idea that he had with T.S. Meisters, a great Belgian pediatric ID physician to reinvigorate or suscitrate, revive this project of human challenge models for group-based chapter copies. So way back in the 1920s, there was a great work by pioneering US scientists, Gladys and George Dick, who basically proved that group-based chapter was the cause of scarlet fever by culturing it from scarlet fever patients and painting it on the roads of healthy adult volunteers and giving them scarlet fever. So they proved that it was the cause. Something that wasn't really known definitively prior to them doing that work in the 1970s. We have this wonderful work again in the US showing that a prototype M1 vaccine prevented serengydus caused by homologous M1 strains in a human challenge bottle and there's a study for a peripheral vaccine, about 90% of the vaccine has been in that study and then a study for a mucosal vaccine. So again, there's sure I need to say the problem with that approach is that you can't create a 250-valent vaccine. That as a prototype of vaccine for one strain, they showed that actually protecting a human from group-based chapter copy of it actually is possible. So that was 1975 or so and then 40 years or so later Andrew and Pierre and others gave me the keys to the Ferrari of this idea and I get to drive it forwards for my PhD to develop a new human challenge model using the kind of approaches that we take to ethics to strain manufacturing to clinical trials that are appropriate in our era. And so we take healthy adults, we do a netocardial gram to prove that they haven't got baseline rheumatic heart disease and we have an M75 strain initially and more recently an M1 U.K. strain. We paint it on our volunteers' tonsils with a swab from these single dose vials that we manufacture as if they were a drug to kind of to similar quality levels and they develop the kind of, you know, the streptopoeid that you all know and within a tap rate of something like 70 to 80% to depend on a few, they're kind of baseline immunity. And that baseline immunity question is locked around, it was getting up before which is that you can actually look at that baseline immunity so they're pre-challenged immunity and look at that in as many different ways as you'd like. I'm an antibody point of view, cellular point of view, mecosal, whatever you'd like. Then actually look at how that influences their journey through challenge, looking at their clinical microbiological and immunological trajectory and then seeing what their immunity looks like afterwards and that model sets up, you know, all sorts of possibilities we can re-challenge someone. So to another challenge, we could challenge with the other strain and see if you get heterologous protection. But the really exciting thing and the whole reason that we did it is that one day we'd like to actually test it vaccines, if new vaccines can protect against a paragitis and possibly skin disease in the future if we develop a skin model. And why bother doing this one? Just go phase one, two, three, like every other, you know, every other vaccine people know it because of what Shorani said before, which is that a phase three vaccine is a huge undertaking, it's an expensive undertaking. It's not something that any company is launching into in a hurry. So how do you know, it's a little bit of reassurance that the product that you have actually has some useful assumption, takes you a long way towards taking that leap. I was thinking when the monoclonal antibodies for COVID-19 started came out, they used immunobridging endpoints and you know, some people were like, what is that? That's not a clinical outcome, whatever. And then many of us were like, you need to do something. We can't hold things accountable to certain standards or we're never going to be able to develop in a new world. So I love it. That's really, really fascinating. That example is actually wonderful because we're considering Australia that we work with by the Miles Dabriport, by the way, we work with David Kuri on if he's team and David and Miles did this wonderful work. Look at neutralizing antibody levels associated with the monoclonals for COVID and looking at the neutralizing antibody from exposure to an infection and vaccines are essentially really nicely showing neutralizing antibody as a correlate of protection. So I think this basic idea of of trained, elating all correlates of protection and thinking about immunobridging for that thin development because ultimately we're going to be doing phase ones and the first phase two is any healthy adults that are actually about the entire group initially is young children. So we've got to get to young children somehow and immunobridging is going to be one way that we do that. Sure, any anything to add? I mean, just on the subjects of young children, one of the other approaches to vaccine discovery has actually been to look at children who have had one of these infections, whether it's group A-strek or NUMO or something. And remember, the first week of recovering from this, the children are making plasma blasts, making B-cells and antibodies. And if you can capture what they're doing and they're getting better, then you might just be able to capture the B-cells making the right antibody. And obviously with all the right ethics in place and so on, this is reverse fax analogy 2.0, you could discover what those antibodies are through cloning the B-cells, eventually making monoclonal. And provided you have some idea about how those monoclonal's might be working against group A-strek. But remember, we didn't really know. You might be able to then come up with an antibody and then you'd be able to find out what it was against because you could then kind of mix it up with some group A-strek kind of soup and use clover mass spec and work out which protein, for example, it was attaching to. I mean, this is a sort of real thing. This is actually being done. But whether it will find something new, who knows. But it is possible, right? That when we observe antibodies that are being made by people, again, after an infection, we're just looking at bystander antibodies. And they're not actually protective. We have no real idea whether what we're measuring because we're measuring antibodies against our favourite proteins and so on. We know they're actually protective, but we need to find out what it is that children make that ends up protecting them from sore throats in the future. That's what we need to find out. One approach to thinking about what children make is to go and dig out a lymph node from a child. And that sounds horribly invasive, but in fact, it's a very common operation called a "tect electomy." And tensils from children are a really valuable resource, a really interesting resource. So they're not perfect because there's a reason they come out, usually because they're not very healthy. That's nonetheless, you can actually reach into that taste like find germinal centers. The place where immune memory is made. And you can find germinal centers that are specific for group-based drug antigens. So you can actually find that the earliest kind of development of the immune memory. You know, it's not perfect immune memory because children go on to develop more streptococcal infections. And potentially the reason they had their tonsils out is because they have lots of streptococcal infections. But nonetheless, it's a pretty unique opportunity to get inside of an lymph node. There's some wonderful work that Danica Hylp has recently published looking at lymph nodes from kids, bleans from adults that have removed for a range of different reasons, mostly trauma. And some of our challenge samples and trying to again, try and calculate on what might be a protective signal. Mostly what we're finding without actually intervening with something like the vaccine, what you're looking for is a correlative risk. Unfortunately, curled severe risk might just be related to repeated exposure and not actually be at the mechanism of protection. It's fascinating. Thank you. Okay. That was an amazing overview of vaccine development and prevention. But if we cannot prevent disease, which we currently cannot, then you get disease, unfortunately. And so a very popular pro-con debate was featured at the Mano-Amano session at ID Week. And I've seen it in several other forums, pediatric conferences. I really actually very much. I don't know. I assume you guys have a strap congress of meeting of sorts and I want to come because you guys are awesome. This is the best conversation. But this comes up all the time as derasions of antibiotic therapy for group-by-strap fair and gaites, in particular, will focus on, you know, real pediatric patients for the most part. And the history here is that we have to give at least 10 days or longer derasions of therapy because if you don't, you are condemning your patient to developing rheumatic fever and heart disease because that's going to develop if you don't give a long enough duration. And there's a significant school of thought of all those data. Our garbage and they were misinterpreted and they were in military men. And it's actually really quite fascinating when you dig into this history and try to uncover this myth and do we actually. actually even know how long we need to do anything or how we treat anything. So Tom, coming back to you, can you tell us about this terrible complication, a bit of your research and why not all strap or create it equal? Sure, sure. So first of all, do you come to our conference? The Landsfield Society runs a meeting called the Landsfield Symposium that runs every three, probably it's going to be every two years. So listeners look out for that, it's going to be some exciting announcements very soon, we'd love you to join us. Romantic fear is this fascinating disease that we don't really fully understand yet, but I think I'm pretty confident that we're making great progress now and maybe some answers are coming not so far away. Actually, it's interesting you pose your question as not all strap or create it equal because I think what you're driving at there is the idea that's out there and sort of really widely accepted is that, well, romantic fear is just as the consequence of some straps and this idea that romantic genic straps drive this problem is still very prevalent, but actually I would argue something quite different that straps are much more equal than we think. And I think the field has a pretty clear consensus on that, we've maybe just not quite communicated it, that this idea that only some strains of strap will cause romantic fever is probably something we should discard now. And that matters because it leads to myths that persist in clinical practice, which we hear all the time. So, for example, we don't have romantic fever here in the UK because the strains aren't present anymore. And that's just not true, but the teaching on this can be quite outdated or it's just actually not taught and it leads to all sorts of misconceptions. There are strains that probably are better able to do this, the classic one being MA team which cause these outbreaks in the US. And there are probably some strains that don't do this, but they're pretty unusual, but basically most straps deliberately to use that phrase will do something that induces auto immunity. And basically if a susceptible individual gets enough strap infections, they'll flip over into this scenario where they get mostly antibodies damaging tissue. Now, the tissues that are affected are particularly the joints, that's what gives us this phrase romantic fever and children get this very characteristic oligor arthritis often migratory. But actually, of course, the time you see a child, it may just be one joint that's affected. And in modern healthcare countries, in modern healthcare settings in many countries, what you'll find is that the kid will come in with knee pain, having been to the emergency department in a different setting several weeks ago with elbow pain and no one will necessarily join those two things up. And people weren't necessarily take the history or examine the patient to actually work out. This is something that's been grumbling for a few weeks. There's been a bit of fever. Perhaps someone doesn't think to listen to the heart or doesn't have the skills to do that. Also, of course, caritis can be subclinical as well. So really, what we need is to increase availability and access to ultrasound because the key pathology is the valve, the valve of the disease. And it's a fascinating thing that we need to understand is it's really the left-sided valve, particularly the mitral valve, and then to some extent the eortic valve actually far less the right side of the valves that are affected by this disease. And what happens is cumulative infections cause more and more pathology in the mitral valve. Amazingly, all the other tissues get completely better and go back to normal, no residual disease in joints or anywhere else. But the mitral valve scars and over time, that leads to basically the valve of the heart disease, which will affect adolescents and young adults often leading to premature death. Thank you. Yes, it's my job to ask the provocative question. So thank you for mythbusting that. Vramatic heart disease, we alluded on this earlier in the episode, but I want to unpack it a bit more. It does disproportionately affect children, adults, and low-middle-income countries. So as you think about your work and vaccine developers, think about equity, how are we addressing this in both design of vaccine or treatment trials and just access in general? Yeah, exactly. And I think there's a little bit of a myth that it doesn't exist globally, actually. I think it can still happen at lower levels almost everywhere and perhaps to some extent clinicians have just forgotten the disease. But the real burden is obviously in underserved populations, in countries where there's a huge amount of strength infection. And this has been best studied in settings where there's been some seminal work, including our mentors that we've mentioned already in Fiji and also in settings like Uganda and several other countries. And really what happens if you go and look in children in primary school and do ultrasound of the heart, you find that about 1 to 2% of children in many of these settings will already have established romantic heart disease. So that's a huge burden. What no one has really studied except for in a couple of settings and our working Fiji is one of the few examples of that is what happens to those children. Not just what happens to them in terms of how do their valves look in a couple of years of time. Like actually how many of these children die. And so I'm going to tell a little story to sort of provide some context of that. I actually went to Fiji originally to look at issues that we've been talking about in genetic susceptibility and mechanism. And we sat down on our first afternoon of trying to do this with our research nurse with this list of patients we'd call out and get a blood sample. And we call the first I can't remember three or four patients and they will die. And I mean, making that up that's really what happens. So people get this disease when they're adolescents. And five years later, 10 years later they're dead without intervention because the vast majority of the countries where this disease happens. No, there's no intervention. There's very little surgery or other things you can do. And at the time Fiji has done this amazing work to increase access to insulin prophylaxis, which is the key intervention, but at the time there was very little of that available. So what you've actually then got to do is understand what this disease is doing in young adults or adolescents and young adults. And colleagues have sort of tried to measure this using things like reporting and ICT 10 codes, which things like the Global Burn of Disease Project. But if you actually unpack that, most of the deaths are in the elderly and there are very few deaths reported in young adults in those settings because the regions of the world where rheumatic heart disease happens just don't actually have the resources to do robust reporting on causes of hospitalization causes of death. So when we measured this, essentially trying to measure the excess number of deaths and hospitalizations due to rheumatic heart disease, we find that the similar number of deaths to things like drowning, road traffic accidents, suicides, the big killers of young people have a similar number of deaths to rheumatic heart disease. So this is really a leading cause of death in children and young adults globally. And you talk to any general physician in settings, some of the settings we've been talking about, they'll tell you that. You go into a general medical ward, as I've had the privilege to do in places like Uganda, go around and do a ward round and you'll have two or three young adults on the ward with torrential mitral regurgitation who very sadly have probably got a very limited prognosis. And yet that's just not on the radar of sort of many people thinking about global health or what are the major global health priorities. Because what happens to those people sadly is they die of usually heart failure or a stroke and the classification of those deaths. Although it sounds like a terribly dry or technical thing and really we're talking about someone's life rather than just like a number or a statistic. But they get labeled as like eschemic heart disease or pneumonia or sepsis or all those sort of things as we sort of alluded to earlier in the recording. It's not actually labeled that this is rheumatic mitral regurgitation that was caused by group haystrap. And that is very hard to do and we really haven't done that enough yet I would argue in countries where this happens. And so while we can throw these big numbers around like 55 million, they're really important that Josh mentions because we have to have numbers that we can tell governments industry and so on that this is a global health priority. My view is actually we need to do far more of that because if you're going to introduce interventions that might change the public health situation like better access to antibiotics, like better access to health care, like eventually vaccines, you've got to really know and understand the baseline. Yeah, absolutely. Letting data drive what you do in that space. Josh, I'm coming to you. So go ahead. Yeah. Erry, what I was going to say is that question you asked at the beginning around these manoeum antibiotics around duration of treatment for pharyngeitis. As you said, does this fascinating history of where that number came from and some dodgy preparations, a benzoyl penis and G at tiny doses and things like that. But it's just ton of point about the rheumatic heart disease burden, which is, you know, chubromatic fever is at least in the conception of the US researchers, the reason for for prescribing antibiotics for kids with streptococcal tons of pharyngeitis. But the one thing that Tom didn't mention is actually really important is that most children who turn up with rheumatic heart disease, whether or not someone finds that by ephorcardiography with no symptoms or if they just present with heart failure, most children, most young adults don't provide a story that fits at all with the classical story of rheumatic fever. They may tell you that they had a fibral episode, or, you know, having a fever in childhood is not very unusual. But certainly they don't tell you anything like what those US soldiers had in the 40s and 50s, you know, where this clear picture of sore throat followed by acute rheumatic fever followed by chronic heart disease. And so there might be lots of different reasons for treating sore throat, lots of reasons for treating sore throat. but I don't think that treating sore throat antibiotics for one, five or ten days is the difference between having a rheumatic heart disease as a global problem and eliminating it. I think that's going to take a vaccine. So the deconme is going to point out that the part of the reason for this difference between different countries is it goes back to the whole thing about sore throat being seasonal. I mean those of us who are living in the US and the UK and in fact most of Europe and much of Northern Asia, group-aestrap is an epidemic disease. It comes in seasonal epidemics where it's in the tropical regions, it's endemic. There's a very high level of disease and I think that well I mean just from my reading it seems to me that it's almost like a acute rheumatic fever, it's almost like a different disease in these different regions. Because in these Northern hemisphere regions and probably some Southern hemisphere regions as well which are temperate, we recognize this very acute phenomenon of rheumatic fever with joint pains, kind of rashes and so on. And that's either because we're looking out for it but it also used to be associated with outbreaks of group-aestrap, right? In boarding schools, even before all of all these soldiers were getting it in the US, there were boarding school outbreaks in the UK of scarlet fever and very clearly some of those but not all of those were associated with outbreaks of rheumatic fever. And so that's where also this concept of rheumatic strains came in, right? Rheumatician strains. But you don't get that in the tropics where the biggest burden of diseases because you've got this group-aestrap going around all the time and probably there are recurrent infections all of the time boosting this group-aestrap to coccul harmful auto-immunity. But in the US and the UK we've got rid of this terrible burden of seasonal epidemics that used to wipe children out with scarlet fever because we've got antibiotics now and we recognize as a season we treat it. Yeah, I mean I agree with a lot of that shronny except that I think that one of the things around rheumatic fever in many regions of the world is this people simply haven't looked, they haven't looked or ever not as rheumatic fever. And actually when you go and look as we did in three-jewy years ago and as with colleagues we've done and many fantastic people have done in Uganda and now in several other countries through the rheumatic fever, ARC diagnostic network, we find rheumatic fever. It's exactly the same disease, it looks exactly the same as the classical descriptions. It's just no one looked before and the clinicians in their settings were aware. It was there. Josh's point is actually fundamental that actually it's a rheumatic fever is a rare manifestation of this whole thing and in fact Floyd rheumatic fever is very rare. So the things that are in the sort of classical descriptions were the extreme cases and I think often those are really extreme where there's probably even a sort of mycolitis sometimes that leads to death and that's why someone ends up sadly in an autopsy study because they're sort of some sort of an outlier basically. But when we look for a rheumatic fever in the countries where we're studying it we find absolutely classical migratory large joint arthritis with sub-utaneous nodules with torrential mitral valve disease. It's the same process. It's just that what you've got is this big disconnect between those cases in the hospital and of course there are the minority who actually make it to the hospital and then this big burden of early disease in the community that is there and is not going to cause problems for another 10-15 years. So first of all I think vaccines are absolutely key because we're not going to get I agree we're not going to get to that bigger burden in the community just by treating the streps or throats. The second thing is times of how you intervene and this problem as it exists right now you've got to get to that large pool in the community with early disease and work out how you can intervene there not just focusing on the extreme cases in the hospital. I know as doctors we tend to focus on that sort of extreme group but it's the bigger group out there who actually we need to work with communities and work out how we access them. So to get back to neuro-inoriginal question which was 10 days of penicillin agree disagree. Actually the problem Aaron is that all of these things were empiric right back in the day. It was like someone was doing a randomized controlled trial of penicillin 10 days versus five days or something like that. It was either penicillin or no penicillin and it happened to be that they chose 10 days and now the funder trial to compare the two you're not going to be able to do that to prevent rheumatic fever for the same reason you can't do a vaccine trial so you'd have to do it to cure group-based streps or throats but it's very difficult to get funding for that. In fact what you get is funds to kind of compare some new kephosporin that no one's heard of with a moxacillin or something like that. I guess in that respect you know the NIHR in the UK would probably fund that sort of slightly boring trial, boring but important not. The difficulty is that we'll hit in the UK. Streatings group-based streps or throatist thought to be an extravagance and it's probably not necessary. Group-based streps is thought to be self-curing and therefore most cases you don't need to treat. That's is the view of all nice guidelines but they didn't take into account all of the complications of group-based streps like outbreaks. They took into account the rheumatic fever how there ever happens. Thank you guys so much. This is so good. Let's segue into treatment though. Penicillin has been first-line treatment for group-based streps for over 70 years with essentially no resistance so Josh I loved in the beginning of the episode how you alluded to the fact that it's kind of a misnomer of a super bug because we always think of AMR truly means antibiotic resistance and these big bad bugs that we have no active drugs to treat. This is a bug where we have many many many active drugs to treat. In fact one of the first antibiotics ever developed is effective in vitro yet can be quite deadly right. It can be quite a terrible pathogen. So do you think not a lot of resistance and streptococcal disease is a success story or do you think that's made us somewhat complacent? It's a bacteria certainly highly successful isn't it? Yeah. Despite that penicillin. Group-based streps kick in our butts. Yeah. So I think there is that element of complacency that I think you mentioned in your teaching that you came through as an infectious disease pharmacist and what you knew about group-based streptococcus was that it was susceptible to penicillin. And that there isn't a what else is there when it comes to just thinking about esses and eyes whatever eye stands for in your country, the SI and R. But there is more to this spectra-red disease as we've discussed than susceptible or resistant. And so I think it's first of all a really interesting microbiological question that's been the subject of whole symposia about why group-based streptococcus was susceptible to penicillin. Beyond that I think what we need to think about is that invasive group-based streptococcal disease is kind of like a car crash. Patients arrive in hospital injured and when you start antibiotic treatment they've been in that crash and we need to kill the bug and help them recover and heal. And rheumatic heart disease is kind of like a slow motion train wreck. Again, you know, we can kind of slow it down with the prophylactic antibiotics if we make a diagnosis early enough. But antibiotics D answer to the global problem even is there an answer to an individual's very big problem in front of you. People remember back to the heyday of ID twitter one of the hottest topics was it was around treatment of invasive group-based streptococcal disease and particularly thinking about adjunctiv antibiotics and intravenous amino globulon therapy is a great common true piece by Nicko Cortes-Tenfield and Jonathan Wright who both been on the show before I think. I'm discussing frozen con for a couple of different adjunctiv antibiotics, clindamycin which the science behind using clindamycin was essentially established in the late 40s by Harry Eagle in some of seminal mouse studies and then kind of intravenous amino globulon which kind of harcens back to the work of georgian gladistic and others in the 20s that really showed that you could do things like inject convalescent serum into the skin of someone with scarlet fever and show that it neutralized the rash. And then you could even use some of that antibody as a or equine versions that antibody as treatment as serotherapy. And you could even turn it into a vaccine by giving these kind of very small doses of supernations from bacterial cultures collected from patients with scarlet fever. So they're pretty compelling idea that antibody has something to do with this and maybe helpful for patients with scarlet fever or invasive disease. And so not to discussion here, not a lot of evidence, some interesting animal works and interesting in the true I say is a whole lot of retrospective studies, like most retrospective studies, kind of hinting at a positive effect but with all the biases that come with with observational research, everyone ending every single one of those papers on adjunctive antibiotics and IVIG when there is single center, multi center or systematic reviews saying the same thing, you know, we need to actually find some real evidence here and you know, after a prospective clinical trial. So these are the big questions. Can we do better than penicillin? For those patients who come in very sick with invasive disease, they're really hot question. There are some people who point to the experience with staph orias where combination treatment just consistently seems to not look particularly beneficial across the board, others when you talk to them about IVIG. So there's a group who are completely committed, it obviously works and there's another group that is seen that are starred by the activated protein C stories, Igris and sheal that this is, you know, we're really we're doing this again, we're injecting a blood product, the juice of 3 to 10,000 people, you know, that's that's what we're doing again without an RCT. Yeah. And you know, so I think that's that's the discussion that the Nico and Jonathan's piece can think about, "Clyndomycin versus Wenezlet," I think was really inspired by this observation. that something like 25% or more invasive tropical cases in the US are caused by clean, domestic resistance strains causing many to question whether or not music bath drug as adjunctive treatment is still held for. Serenity and mother UK researcher Michael Marx nicely, he thought of this great editorial where they essentially liken the use of clean, domestic and IVIG of adjunct antibiotic and IVIG to kind of putting a blanket on a fire. Because that's what explosive and basic cases are like, they seem to be running away from you like a wildfire. And the hope is that these adjunctive interventions put out the fire. They help. Yeah, so there's a lot to unpack there, Josh. That was exceptional. Thank you. I think first and foremost, I have to comment. The first paper I ever published was about the Eagle Effect and I went to Auburn University in the States in Alabama and I feel like past someone on the street who has an Auburn shirt on. You say War Eagle. It's kind of our like battle cry, so to speak, or exchange of pleasantries. And so this whole Eagle concept I did at FNaFs and Pharmacy School at Auburn. And it's always been very near and dear to my heart. And then I'll say my career kind of went, I practiced and transplant ideas. I really focused on fungal viral and gram negative resistance for quite a bit. And I found myself like falling back into this gram positive space. And it's so, so interesting. I mean, we could talk for hours about your comment about combo therapy for stuff. Or is I don't actually think the nail is in that cough. I think adjunctive clindamysin we saw at Eskmit Global 2026, the results of the adjunctive domain were presented where it was futile. There was no no difference in adjunctive mice in for invasive staff of caucal disease. But I think combinations like empiric daptoseph terreline. We had an RCT and no one died in the combination arm. They stopped the trial because the mortality gap was so significant and then people didn't want to believe the results. They're like, it's too good to be true. It's still not something we should do. And I think except you know, like a 10 to 25% mortality rate for gram positive bacteria amazes. And I just really think we can do better. So, and I think Josh, you think that too. And Sean and Tom as well. So, that's a really nice segue. Josh, you started to allute to some of the therapies we need to definitively understand in a randomized clinical trial. Are they beneficial or not? And so hence the strap idea came about the Streptococcal adactive platform trial. Can you tell us a little bit more about I think we know why this came about as we all a lot of the data we have for treatment right now is observational. We don't have strong evidence for most of these things. But can you walk through what the domains and treatment questions of the strap trial will be and what we're hoping to unpack here? So, so it's a strap I think as you said, you described that I think as a sister of staff, I think probably daughter of staff is more accurate in that I think snap has you know has paved the way for us exciting kind of adaptive platform trials for hard questions like this. So, strap is a definitive treatment trial. I wanted to highlight that Shirani and Tom are also part of the strap team. They've expanded to team that the standards for the UK and New Zealand and several other countries. This isn't an impure treatment trial. It's for patients who survive to the point that we know that they have invasive group gastroeptococcal disease and I think that's a really important point because one of the things about invasive group gastroeptococcal disease isn't really nicely highlighted by Shirani and others in the UK surge in recent years is just how many patients don't get to that point of a definitive diagnosis before they die. And so we're making post-mortem diagnosis and so this isn't that trial. It's not a trial of super early incorrect therapies. It's a trial of definitive therapies and there are three domains and one is a backbone domain looking at benzal penicillin so just you know four to six hourly benzal penicillin versus keftriax a daily in most settings and they'll really will look at non-in theory already if keftriax and so that domain and for all the sort of the entire platform the primary outcome can buy the mortality and they is alive today 30. So in that first domain is non-in theory already of keftriax so. And so that was one that I think didn't particularly excite everyone except to the people running outpatient antibiotic programs that were very exciting for the people with any kind of interest in hospital administration and resource allocation that was a hot topic. I mean one dose of keftriax so per day if you think of the nursing time associated with delivering that compared to up to six doses of benzal penicillin and g. I mean that's a huge huge difference and so if we were able to show that in fact these patients are doing as well in terms of mortality and days alive and time to discharge and the like but also in terms of secondary outcomes related to antibiotic resistance and the like then you know then that's a really important finding. The other thing I'll just point out because it's so gross and so I hope people who generically manufacture some of these drugs in the United States at least are listening you know penicillin sodium is actually quite expensive in the United States and so we have like a therapeutic interchange in my institution where we're will put patients on penicillin potassium based salt unless they can't tolerate it unless they're potassium side they've been failure whatever but it's wild that these drugs have such a cost to them it's penicillin so sometimes it's after accident is just a cost effective easier option but of course it's so much broader and we care about the microbiome and we care about all these things so I think that'll be super interesting and important to answer. And as a side note there was a period of time in Japan where you forget an oral carbopenum but not benzopenicillin. So domain 2 is around adjunct antibiotics and so there are three arms no adjunct antibiotics, a clindamysin and linesolate and this is you know essentially considering the superiority of those adjunct antibiotics versus placebo. And then the third domain and this is for patients with severe disease, severe invasive group based trap to cockle disease is idig versus no IVIG. Now the whole platform will be up and running initially in Australia and the UK and we're hoping for other countries to be involved and Australia at least is beginning with the within basic group based trap to cockle disease as well as trap to cockles, discolactyose subspecies episimilus and group GMC's trap to cockle which are now setting at least and in adults is even more common than invasive group based trap to cockle disease. Those are the three domains and there are what the interesting inclusion and exclusion criteria as you'd expect. It's a pragmatic trial so there are some really interesting points like how you dose clindamysin, the UK is well known for using a dose of clindamysin that far exceeds what almost any other country on the planet uses and they still will in the struck trucks and IVIG. Many countries we use two ways to kill those are symbol dose, other countries will spread it out as either two doses of 1 gram or even even smaller dose of 400 billion nanospiculograms over five days. As a pragmatic trial we're not going to change everyone's mind about every element of what they're providing but we really hope that people, hospitals and doctors get on board answering these really important questions because this is one of those trials that everyone wants everyone wants these answers and in surveys when you ask them if they want these answers they say absolutely and then you ask them you know will you randomise your patients and they say maybe I'm uncomfortable yeah I will tell you I will tell you every pharmacist reading these are going to want the doses but it makes good sense that it just doesn't make sense to try to standardise the doses in this regard you have to let people just dispense from routine care and treat per what they would do is just give the drug or not. I do want to talk about the adjunctive domain a bit more because I think it's probably the thing that's sexiest to listeners right now especially the slinese lid versus clindamysin which I am of course quite partial to so I think there's a couple things I'm specifically about so sure any first I want to ask you about the dosing because you did light up even flexing a little bit our listeners can't see her but when Josh talked about the clindadocing in the UK and this microbiological kind of mismatch of if clindamysin is in vitro resistant would it still have a toxin suppression effect because I think that's quite a debate as well and you know some people say absolutely like the in vitro resistance doesn't matter when you're adding in as adjunctive toxin suppression is still going to get that effect other people are like it's resistant how is it finding to the protein how is it exerting its anti bacterial activity and so what are your thoughts on that? So so I can't really come say anything sensible other than flexing my muscles over the clindamysin dosing it's just that's what we do right this is what we've always done but you're giving 1200 milligrams right just so I think I don't think we have to press it so you guys are giving 1200 milligrams that's a lot of drug we do 900 some people do 600 to be honest we don't always do that and quite often we've we start off on half of that and then and it's often because the patients are progressing they've got progressive invasive disease to say to be fair we don't say all this patient has got invasive group of streptop disease let's give them Ben Penn and Clendar we don't do that we often have them on a beta laksam and it could be ketroaxen or Ben Penn or even the ibimoxicillin but we add in clindamysin when the patient is going downhill and I suppose it is just anecdote that when we have used the half dose that you guys might be more familiar with and they've carried on progressing our pharmacist says it was well you can go higher so we do and then they get better so it's entirely anecdotal we have no I have no good evidence for it but the patients do seem to tolerate it and it's short term and we very rarely leave the one clindamysin for more than three or four days right just get them over this hump and that and these are in very many patients who who have survived to sort of day two yeah and they are remember that I mean as as you alluded to most deaths happen in the first 24 hours correct right so actually in this trial what we're going to be trying to prevent mortality wise is the tail end of mortality which might be as low as you know 4% and it's mostly then in the elderly almost all deaths happen after day two or three will be in the elderly and and they've got comorbidities it probably what the dying of is their comorbidities not a lack of clindamysin a mice in oral lack of IVIG. And I'm being blunt here, that's what I think. And so I'm slightly worried about the trial in that I worry that what we're going to find is a negative effect of these agents. And people will then infer that they are never going to be a benefit. Yeah. And what-- I was going to say that. So Josh, I think that's probably the most important point because quite frankly, when we think about adjunct of therapy, we think about it at ground zero. So we think about it as you're coming in the emergency department, you're sick as hell, you're getting started on pressors, and that's our trigger. So with our Necrotizing Feshitis Order Set, at least, which is also our invasive Streptococcal disease pathway, if you are closer to death than life on presentation in quite ill, we start adjunctive therapy, and we stop it when you're off pressors or after last return to OR. So we really think of it as like very beginning stage, and then we stop as soon as possible. In it's so hard to enroll in empiric trials, and we've talked about this a lot, is with ESBL therapy. And these are all really therapy trials. So what is the inclusion criteria for the adjunctive domain? How soon do patients need to be able to enroll in the adjunctive to qualify? And are you concerned that if they don't start till 72 hours, we've kind of missed the vote, adjunctive therapy? So first of all, maybe. But second of all, you and I are post-Authers Aaron on a paper a few years ago in CMI, essentially, talking about which trial we need, arguing that eventually we're doing a waiver of consent trial for empiric therapies in the sickest patients with suspected toxic shocks syndrome and suspected necrotizing soft tissue infection. I think we're in a distance away from getting that trial done. I think it's a hard trial because of just how sick that group of patients are, and I think strap is an important step to thinking about a trial like that. So I think there is your prior on whether or not extra antibiotic, so it's two or three days into a patient's journey for those who survive. And it may be quite low in terms of adding extra benefit. I think we are all going into that with our eyes open and very aware that from the beginning, this is not an empiric treatment trial. This is a definitive treatment trial. So we're expecting you, most patients, have a diagnosis of group-aestropoccal infection between something like 24 hours and 72 hours, depending on your center, and depending on the diagnostics, your microbiology lab used, and will need to be, and really, patients as soon as possible, once that diagnosis is made. And within the latest, I think, the number is 72 hours from definitive diagnosis. Go for it, Tom. Yeah, I was just going to add that time to diagnosis is really critical. And one of the things I'm passionate about is the whole issue around recognition and measuring the extent of this problem. And that's partly because when we talk to our patient groups, that's what they actually say they want people to be diagnosed and found earlier. So the trial, the group of mescans, and the trial we need to be able to do is think about how we can push our institutions to get that diagnosis as early as possible. And maybe, to some extent, we're just going to find we can't do this, but if that, we can't get it much earlier. But actually, the trial then sets up the conversation about what really would be needed to deliver an empiric therapy earlier, or deliver rapid diagnostics in a way that would mean we could treat more patients with a targeted therapy much earlier in their journey. And I think just while we're thinking about sort of what we want to say about these conditions outside of the context of the trial, all the general messaging about diagnosis remains really important. So we mentioned an activity fashion, to for example, there are so many slip-up points that people continue to fall into, like for example, waiting for imaging. These really sort of concerning fundamental things where actually you need to be pushing to make this diagnosis. And we as a strict community need to be really reminding people that this is not just, I would argue, the sort of generic stepsist that is so often feared in a hospital, this is a really distinct and virulent condition with extremely high mortality. That doesn't mean that at the front door, particularly at adults, you can call one thing or the other. Actually, most of the time we come, I think maybe Josh might want to comment, perhaps in children it's a bit different, but it's not me comment this thing, which is, but actually you've got a sort of sick adult of any age, particularly if there's very severe skin and sobs, tissue infection. We've got as healthcare professionals, we act extremely fast to get those diagnostics off, really get high quality diagnostics off, and get a patient to theatre, for example, rapidly and talking to the right people, your intensive care colleagues, and so on, to get the finitive therapy. And of course, what a trial does is it really sets up various conversations in each of the institutions where the trial is happening. And I think we could do a lot to improve delivery of care for these patients just from the fact the trial is happening. - Yes, the US-based listeners told us not suggesting taking the patients to go see a play. He's suggesting that it's the operating room as soon as possible. - That's so funny, because I was just about to come in and make a comment about surgery without directly calling him out on the use of the word theatre. So thank you for that, Josh. - Can I do a The Clean Demiasing question about the dose? - So just quickly, so you asked the question about susceptibility and resistance. And I think, as has been shown really nicely on break points and a whole series on break points, the way that we think about susceptibility testing, it's a model. And it's a model that considers antibiotic dosing, bacterial anoculum, and it's unsurprising to me that if the issue of resistance is that the antibiotic has a lower affinity for the target, if you double the dose, there's every chance that in fact you achieve an effect that you weren't achieving at half the dose. And so that makes some sense. But what I would say is that we've done some very cool in vitro that hasn't been published where we've compared like strains. So an M1 strain with and without antibiotic resistance determinants for clean demise and virtually identical in every other way. And when you expose a strain, it's strange like that to clean demise and then you look at their production of superantogens and other relevant kind of toxins. It's pretty clear that clean demise and having much less of an effect on the resistance strain than it is on the susceptible strain. That I think that-- - There's some nice published work now in vivo also showing that for cleanser mice and resistance strains, there's no rationale for using cleanser mice. - Correct. - And I think in medical legally, it would be hard to justify that. - And I think the resistance amongst strep species to cleanser mice and is underappreciated quite frankly, that it's actually quite common. And then when you add the staff resistance, using clinders and empiric drug becomes quite silly-- - It way around. - Depends where you are, you're under here. - Yeah, we just don't see that. And the other thing to say about clinders resistance in group-based strep is entirely cladependent, right? So it's not something that's organically gradually getting worse. It's not like there's a gene that they've all got. It's simply a transferable element and it's in certain clones. So because the US has got these weed clones that have come in, I think during the pandemic, you've got a high rate of clindermycin resistance. We just don't see that. Except that we did get an M49 strain, I think probably from you guys. And now we've got it too, but it's nowhere near 30%. - We spread bad things. - So I guess, sorry about that, yeah. - It's a China. - Oh, it's a China. - It's a well-wed. - Yeah, I have no idea. - Yeah, the number in China where the M-type distribution is different again and looks like almost all M1 and M12. You know, you're seeing kind of 80% plus clindermycin resistance. That's so high that you think clindermycin empirically makes it not very serious. - And we don't have the same problems you guys do with MRSA. So we don't have USA 300. - So we generally don't need to worry about needing lines led for staff. So when you've got this, is it staff, is it group-a-strat? We don't automatically reach for lines leds. - 'Cause most likely not MRSA, yeah. So as with all things, and infectious diseases, you know, knowing your local epidemiology, from our lens in the States, I'll just say this 'cause I think I caused the problem here. And I had a wonderful resident named Josh. Most of you guys named Josh, that are great at this work. So because of the resistance, because of absolutely being the most C-diff propensity causing antibiotic kind of when crusade in my health system several years ago to say, I'm gonna eliminate clindermycin from every order set. It was a lofty goal. And we essentially achieved it. I'm proud to say, exercising fasciitis were the ones at first that people were like, we can never get rid of it, we have to keep it. And the more experience we got with lines led in the United States, Necrotizing fasciitis backbone therapy had to include anti-MRSA therapy. And so folks were getting pepper cell and taisal backtam, vancomycin, junked protein synthesis inhibitor. If you had a pen allergy, you were getting cephapeme, metronite is all vancomycin and a protein inhibitor. It was a mess. And so I thought, you know, can we streamline this to pepper cell and taisal backtam and lines led. And then lines led serves as both your anti-MRSA and your toxin inhibitor in that setting. And honestly, we just changed our order sets and got buy-in from providers. It wasn't a randomized study. It wasn't anything that because we couldn't do that. We just simply said, we're going to change our treatment paradigm because we think there's equipoids to do so. And then we did a prepose. So the data are observational in nature. And I'm so happy Josh, you're doing the randomized trial because it's so very important. But at least what we saw, and we had very few actual group-assetrapped patient study, but you know, at least what we saw is there was really no difference. And in fact, all these collateral benefits because the IV to PO switch became much easier for folks and then in the weirdest twist of fate in our ICUs, because patients were on lines led, they got more nervous about serotonergic agents. And so they stopped using continuous sedation and they started using more just intermittent sedation, which is better for patients all around. And we found after we changed our algorithm, but finding that surprised me the most that was the most beneficial to patients probably was that we stopped using continuous fentanyl infusions. And I was like, who would have thought that that was the actual, maybe that's why patients did better. But I think it's so fascinating. I'm super excited for your trial, Josh, and we'll see what happens. All right. Well guys, this has been such an amazing discussion. I can't thank you enough for your expertise. But the time has come. Breakpoints faithful for I feel nerdy. I feel nerdy is meant to be a safe place and a closing segment for our panelists to nerd out over their favorite ID quirks, topics and fun facts. So for today's I feel nerdy, please tell me your favorite random fact or historical tidbit about Streptococcus. I feel like you guys are just a wealth of information. So Shorani, do you want to go first? Yeah, okay. So I grew up in the 90s in research and I was constantly challenged us to what why was I working on group-based Strept? It wasn't important. So like all good kind of family history people I then went back and researched the history of my bug because I was determined to prove it was more important than staff and C-Def which was what I was or in fact HIV which I was told I should be working on. And so what I found was that it was actually the basis for a whole load of vaccine discovery back in the day as Josh will tell you but also antibiotic discovery. And of course the very first antibacterial that was used in trials was the sulfonamide not penicillin and it was used against group-based Strept by Leonard Colbrook and in fact the very first molecular epidemiology study of outbreaks was done by his sister Dora Colbrook and our hospital, Queen Charlotte's Hospital which is kind of stuck onto the Hammersmith Hospital right now. So that's my Gigi fact that group-based Strept we would not I don't think anyone would have bothered developing penicillin. If they hadn't seen the dramatic fall in mortality from sepsis after sulfonamide and that was in 1936 and in fact it's 90 years since that Lancetrile was published. That's my Gigi I love it that's amazing Tom. Yeah we mentioned Rebecca Lantfield already and her wonderful work. I actually want to highlight a British pediatric rheumatologist called Barbara Ansel who basically founded the field of pediatric rheumatology off the back of work on rheumatic fever and she's little known she's far less known than Rebecca Lantfield and it happens at the hospital you'd think this was all at a sort of fancy teaching hospital but actually it was a little tiny hospital that's not far from where I live outside London in a place called Taplow the Canadian Red Cross Memorial Hospital set up after the Second World War and basically this little site which became the MRC Center for Accommoderates the exact term pediatric rheumatology and the whole specialty comes out of this because they had all these children with inflammatory joint disease and at that time they just thought they all had rheumatic fever and actually really really careful clinical documentation really really thorough thinking about cases and descriptive epidemiology and then they started to break this down and say well actually these are the ones that have rheumatic fever and then they're all these different pediatric conditions that start to emerge so just this sort of wonderful example of how someone who's sort of so committed and so passionate and I mean I imagine the barriers to her doing this work even the sort of her obituary described by one of the posts she applied for she wasn't allowed to do because she was a woman and so on it's just amazing and yet basically the specialty exists because of her it's amazing. That's incredible thank you for sharing that story Josh. So I think my nerdy fact combines the two of the previous so Wyland was a group-based streptococcus as a kind of the inspiration for innovation and the other one was powerful women in the history of streptococcal research. I wanted to highlight Nanyolsthar Pentiay and Jenessa Dudner who reached deep into group-based streptococcus and they ripped something out and what they ripped out was CRISPR. CRISPR Cas9 the people now know is this revolutionary gene editing technology for which they won the Nobel Prize you know given how much we've highlighted today that we don't know about this pathogen isn't it remarkable that you know that it is responsible for bringing us CRISPR and you know one of the nerdiest things about being a streptococcal research is spending time the lance field that symposium with all those people and it's a terrific terrific meeting I think whiskey is more our drink rather than beer. If I succumb to the next lance field symposium and you're all welcome at the George and Glater Stick after hours whiskey appreciation society. That's incredible let me know what it is I'll do my best to attend you guys are so fun and with that thank you for listening to break points the society of infectious diseases pharmacist podcast this episode was hosted by Aaron McCruery featuring guest sharani shraskandan tom parks and josh azoickey break points was created by julie and josto Aaron McCruery in jason poke this episode was produced by lacy warden and making clat it was edited by making clat and it was peer reviewed by lacy warden the executive producer of break points is lisa dumb cow our theme song was recorded by s_i_d_p_ members dr steve smoke and you can subscribe to break points on apple podcast spotify or wherever you get your podcasts thanks for listening and helping s_i_d_p_ achieve our vision of safe and effective antimicrobials for now and the future