Game of Spores: Blasto, Histo, Crypto, and Cocci

[ Music ] >> Hello and welcome to Breakpoints, the Society of Infectious Diseases Pharmacist Podcast. My name is Erin McCree 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 highly requested topic in one of my personal favorite topics, which is fungal infections. Today we'll focus on endemic fungi, histoplasma, blastomyces, coxidiodes, but we'll also review some current literature in cryptococcus. Let's get right into it and introduce our panelists. And you are in for a treat today, dear listeners, because we have two of the greats in our virtual room to teach us all things. So first, Dr. Greg Eschenhauer is a clinical professor in the Department of Clinical Pharmacy at the University of Michigan College of Pharmacy and a pharmacy specialist in infectious diseases at Michigan Medicine. Dr. Eschenhauer received his doctorate pharmacy from Butler University and completed his infectious diseases specialty residencies at the University of Michigan. After completing his residency, he then worked at New York Presbyterian Hospital and the University of Pittsburgh Medical Center prior to joining the University of Michigan. So Greg and I didn't overlap at Pitt, but I definitely spent my first few years being not Greg, which is in the best way, but very true. I actually got hired. I got hired to do anti-fungal stewardship at Pitt. That was like my specific goal in 2018 and I definitely spent many years Greg being not Greg. So it's an honor really to get to talk to you about fungus, Greg. Welcome to Breakpoint. Thanks so much for the introduction, Eric. And I'm sure you quickly made everyone forget about me at Pitt. It's a real honor to be invited to do this and despite me growing up outside Cleveland and thus hurting me to say all this, Pitt's an amazing city, amazing place, and so many great memories and everything. It's a fun town. The only good memory is not restricting subterranean zones. Which we don't do anymore. We did when Greg was there. And I spent a lot of time answering phone calls for subterranean accent and then I said, not today, not today. I'll hold back on comments on that one, but I have a lot to see about that. I know, I know, I know. I thought I'd be provocative to start us off here. Next, our next guest is Dr. George R. Thompson who goes by GR from here on out. He is a professor of medicine at the University of California Davis School of Medicine in Sacramento. And he has a joint appointment in the departments of medical microbiology and immunology and internal medicine, the Division of Infectious Diseases. Dr. Thompson specializes in the care of patients with invasive fungal infections and his research interests are in fungal epidemiology, pathophysiology, diagnostics, treatment, and outcomes. He has served as the co-chair of the National Academy of Sciences Symposium on Cox City and Micoses in the fall of 2022 and as an advisor to the World Health Organization for fungal priority pathogens and has served on multiple international guidelines. He's been the chair of the Micosi Study Group Education Committee and is responsible for the development of fungal educational content to practitioners globally. And he's currently the president-elect of the Micosi Study Group. GR, we are so lucky to have you with us today. Welcome to Breakpoints. Hey, thanks, Aaron, for that kind introduction. It's really a pleasure to be here. I've listened to SIDV podcasts for a number of years and learned a ton from you and all of your distinguished guests. So really happy to be part of this today. Thank you. I'm so excited to have you both. And honestly, the intros are the hardest part for me. Some always worried I'm going to mess them up, which I probably stumbled over a few of those words. You said my name correctly. That's like amazing. Half the battle, right? I mean, the more impressive you guys are, which is you're so impressive, the more like, divisions you're part of. And I'm like, how many words are there here? But okay. Well, let's start at the very beginning, which, you know, a very good place to start. Endemic fungi, endemic being defined as, quote, regularly occurring within an area or community. And, quote, so we're thinking these are things that are common occurrences in certain areas of countries. And, you know, I was taught over a decade ago that to think about these in kind of distinct buckets, where histoplasmosis is in Ohio, and Greg, we can insert many Ohio Pittsburgh jokes here. You beat me to it already. And the Mississippi River Valley. And then, Coxie, aka Valley Fever, would be in the Southwestern United States, kind of a classic board question, someone's traveling from Arizona, right? And then, blast to my co-sees, which is found in areas around the Great Lakes and the Mississippi River as well. So, Greg, why don't you start us off here? Is that true? Is it that simple or is this changing? Yeah. So, this is a complex question. I'll try, I'll try to keep it brief as possible. And please, of course, both of you, have been on any gaps or mistakes. So, endemic my co-sees are caused by thermally-dimorphic fungi. Generically, that means that they exist in the environment as molds and at body temperature as yeasts. The portal ventures usually inhalation of spores from the environment, which can cause acute infection, but can also reactivate years later. These molds, the different molds are not ubiquitous, but can, but rather thrive in different environments. In generic terms, coxuodies like arid environments, blast to my seas appears to like soil, near bodies of water, like river banks, just two years ago, we had a large outbreak out of paper mill along a river, and the upper peninsula here in Michigan, and over 100 folks that worked at that mill, developed in pectin blast to my seas. Histoplasmas classically associate with soil contaminated with bird or bat droppings, but not so strictly that is exclusively seen in people with overt exposures to chicken coops or caves, but rather general farming, remodeling, cleaning out an old barn are often what we can glean? In terms of the precise geographic areas where these molds are found, well, it's complicated. So the data that largely informs the classic maps that you just spoke of are skin testing studies from as far back as the 1940s. Those areas were and remain, you know, quote unquote, hot spots for those for these infections. However, those tests were imperfect, and of course, if a lot has changed since then, including a factor that would make sense to potentially impact the distribution of these environments sensitive fungi, that being climate change. We have some recent studies using Medicare data of patients and diagnosis of the endemic infections. And this data certainly suggests that there's been an expansion of endomicity, but it's limited to because where a patient resides may not indicate where they inhaled the spores. So just this month, we had a patient who lives in Michigan, traveled to Arizona, Texas, Mexico, and came back and was diagnosed here with Caxiotes, my co-sys. So they live here, are diagnosed here, but did not acquire it here. Of course, the seemingly most straightforward or logical approach would be to study where you can actually identify the fungi from the environment. But if you think about doing that in a way to map out endomicity, you can imagine that as much easier said than done, both practically in terms of expense and manpower. And even then, GR pulled study where the authors hypothesized that the cluster of cases in Washington could be due to soil contaminated by a burial site from humans or animals that had migrated from the San Joaquin Valley thousands of years ago. And so it's just really, really difficult to precisely identify and map out where these fungi are in the environment. So where does that leave us? To put it generically with uncertainty, but also expanded maps and new areas of endomicity. So for the United States, you can find updated maps on the CDC website. These include Caxiotes being found in soil all the way up to Washington State. Like I said, Tisto map now looks like the entire Midwest, but extends south through Texas and extends north. The blasto map now just looks like the entire eastern half of the United States. And of course, these fungi are not restricted to the United States. Histo is endemic to central and South America, areas of Africa and Australia. Blastoise is found in most of Africa. For that distribution, there's a paper by Asheroff and colleagues from 2020 that goes in depth on worldwide distribution. But at the end of the day, given how much people travel and given some of this uncertainty with kind of where these fungi live and true endomicity, everyone everywhere has to retain some index suspicion for all of these and be aware of them. Thanks, Greg. I think that's awesome to start us off. And that's why I wanted to start there. Because I want to talk next about when should we be thinking about these infections? And is it just, okay, I live in Mississippi or I live in Wisconsin or I live in Ohio and therefore, Histo's on my radio, Blastoise on my radar? Or is it all the time? Any patient can present with these kinds of infections and you need to be aware of them no matter where you live and the United States or even in the world. On the flip, though, it's definitely more common in certain areas. So I did my training in Wisconsin as most people know. And I remember so vividly, there's like things that stand out from your residency, like that you could recite forever and then things that you completely black out right, never want to remember. But something that I remember so vividly, I was rounding in the ICU and an intensivist, not an ID guy, an intensivist was like, if a young healthy person comes into the ICU with ARDS, whether you know the history or not, but usually the history is like, I was out hunting and doing these Wisconsin type things, then they started in pereclyposomal infotarison because that was Blasto-ARDS until proven otherwise. And that is just not something I think most people think of empirically, certainly not in an immunocompetent host. And so, GR, why don't you talk us through that? The clinical presentation of these infections, common hosts, if you're immunocompetent, what are your risks, and then certainly we find these in our immunocompromised, then walk through the different endemic infections. Yeah, that's a great question. And I hesitate to give a really long answer, which it certainly would be done here. Well, that's fine. You can talk forever. We'll have a few more questions. Well, first, yeah. Yeah, but I totally agree. It's really a product of, like Greg was saying, there's regions that these are hyperendemic. There's regions that they're hypodendemic. there's probably some areas that they're transiently endemic. So to use coxies as an example, it may sort of blow up to southwestern Colorado and then with the freeze killed off in the winter so it has a cycle and may come and go. And then these regions are definitely increasing and I'm not totally sure why. Lots of things have been proposed. People travel a lot now, so lots of these are going to be diagnosed when people return home from a vacation or a trip. The climate change, I'm not totally sure what to make of how much of this is just uncovering infection that's maybe already there like that coxie cases in Washington. They thought maybe it had been there for a thousand years of minimum amount of time based on the molecular clocks of the organisms, but maybe more like 10,000 years. You know, we actually, there was a bison jaw in a museum in Nebraska that was thought to have coxie in the bone and we actually called that guy up on the phone and was like, hey is this still on display? Can we sample that and see if we can sequence ancient coxie? We did and we didn't find any coxie. We found bison antiquitous DNA so we know that the DNA work, it was successful, but there's no coxie there unfortunately. And then histo, right, it's carried by bats and birds which have tremendous ranges. So it's kind of a global endemic. You know, it's definitely hyperendemic in some places and then blastos definitely increased as well. But the reason I give more of that is is our patients, we can't always get a history from. And if you're in Wisconsin and they have ARDS, that's a little different differential diagnosis than to say Alabama, Mississippi versus California, right? So there's going to be very different epidemiology of these diseases. But blastos, most of those patients are in it coming with some respiratory complaint. ARDS is definitely part of that. We have a vet school here. So we are very used to asking patients about their animals, the companion animals, and blasto, a lot of those patients, at least in the literature, have had a dog with blasto miceys even before they're diagnosed. And then the unique thing about blasto is even an immunocompanid people. Historically, the literature said 50% of them have evidence of dissemination. But those reports were really based on autopsy series and some things like that. So it's probably more like 20% of patients with chronic blasto. So skin lesions, those are super easy. Can be really helpful for diagnosis. You can just do a touch prep on a skin lesion see if you can find blasto in the microscope. Then you don't even have to wait for an antigen test to come back. And then it does have this unique pre-election for the GU tract, which is a little bit more like we think of with, you know, brucella or something. It's sort of one of the unique ID organisms that likes the GU tract. And then histo, what the medical school of Missouri saw, a lot of histo there. That was sort of the pre-TNF alpha blocker era. So now there's a ton. So definitely in our immunocompromised or relatively immunocompromised patients, that's really a big concern. And then sort of just personally to interject this for story time. We had a huge outbreak at histo when I was in college. And that's actually how to lymph node that was histo positive. And that's what actually got me interested in my colleges and undergrad student. So yeah, so that's sort of what the how everything began. Back to the patients, you know, the immunocompromised patients are the ones that are tough. They come and often even with sepsis bone marrow bopsies are pretty quick way to diagnose those patients. But they often do have GI lesions. If you really examine them carefully, particularly in the oral cavity. And that makes a little bit of sense, right? So they're carried by birds and bats that this GI pre-election for those patients might actually help with their ecological spread. If birds and bats can carry those in their GI tract, and then as they fly over areas to spread that from their GI tract, just as they, you know, defecate and fly to when they roost, et cetera. So that might be one of the reasons has such a big range. And then coxy, you know, I think a lot of people forget about coxy other than when they're cramming for boards. But if you're in the central valley of California or in the hyperdemic of phedics and Tucson, about 25% of all chameleonia is actually coxy. So it's so common in some of those places that they'll treat patients empirically with cat bacterial coverage, but add fluconazole for coxy while they're waiting for their serologies to come back. So that's kind of the big picture of the endimics of early presentation for most patients. Distiminated disease obviously is kind of a different ball game, but that's how most of patients initially come in. Awesome. Thank you for that overview. I know that's, it's so interesting. We have a Greg and I, you know, we have many conversations about like ampsel back to inversaceph traaxone for cap. And you guys are like, how about everyone gets fluconazole. It's just totally different game changer and it just underscores the importance of local epidemiology following your local guidance. Okay, let's move on to cryptococcal disease, which is like doesn't really like like fits and doesn't fit as a teaser. We're going to do a mold episode on breakpoint later this year as well. And when we were breaking these out, we were like, okay, we have histoblast of coxy and then our aspergillus and muqueous going to come later. And then we're like, all right, where do we fit crypto? We're going to fit it into this episode guys. We're going to do it all. So let's talk about cryptococcal disease. I actually just finished a stretch on our abdominal transplant ID service like last week. So just prior to recording this episode. And we had a solid organ transplant patient who presented with crypto meningitis kidney, not a liver. And after taking, you know, that incredibly thorough ID history, right? If you know, you know, ID providers, the team discovered that the patient had recently adopted this pet bird. And he was pretty far out from transplant. So I think they forget all the not fun things are allowed to do when they have a transplant. And so he has his bird. And we had I kid you not guys we sat in one of my attendings offices. We had like four of us, the pharmacist, the fellow, the ID fellow. And we had a legitimate conversation about whether or not we needed to quote, vilify this bird and quote, and it was, you know, funny, but not funny. But so where do we see crypto? We are very familiar with this as an opportunistic infection in HIV patients. But how else does crypto present Greg? Do you want to talk us through this? Yeah, yeah, sure. I can start. You made me think of there's a New England journal case just a couple of years ago where New England did vilify the, I think it was apparent in that case. So yeah, it's always a bird. Okay, first of all, birds are gross. Like I, I am not a bird fan in any which way. I hate when birds fly at you on the sidewalk. I don't want to see a bird. I'm, but it's always the bird. Don't get a pet bird. I mean, get a dog and get blasted. Oh, I'd rather have a dog and a blast. Cats and talk so yeah, so are you a dog? Are you a dog person, Greg? Before you talk about crypto, I know you're, I love dogs. Yeah, you know, I always say in my college house with my college buddies, we had what two mastiffs, a German short hair corner, but also two cats that actually ruled over those dogs. So yeah, I love cats do that. And we have one dog and four cats in three kids. So I think that puts us pretty close to DSM five criteria. Yeah, I don't know. I've almost got the, I don't know if it's the inverse of that, but four kids and two cats now currently. Yeah, you can't have more cats than family members. So we have a dog and a cat. And I swear the dog just like lives its life waiting for the cat to notice it. Like every now and then the cat will walk up to the dog and like try to play. And I swear it makes the dogs an entire day. But cats are the boss. All right, we die. We digress. Okay, crypto birds, crypto, yeah, so crypticuck is neoformans is a yeast that is everywhere is it has worldwide distribution. It causes pulmonary infection, but also has a predilection for causing CNS disease, which is the presentation that I see most commonly in practice. It's in fact most common cause of meningitis and sub-saharan Africa. It's found in soil, and like histoplasmas is classically associated with soil and decaying vegetation contaminated with pigeon or other bird droppings like we talked about. And now, even though you're right, you're absolutely right that ID positions like GR are absolutely the best at figuring out if you fed some pigeons in the central park that one day 15 years ago, even they often cannot identify any sort of intense pigeon exposure. It's more often some sort of nothing or maybe the pets or just something that you can't pin down. Infection by crypticuck is neoformans classically occurs in immunocompromised patients, especially classically in patients with advanced HIV infection, which as GR likely touch on is where the vast majority of randomized control trial data comes from. Then there's crypticuck is gadi, which is a distinct species that sometimes classify as as an endemic organism because traditionally infections were primarily seen in distinct geographical locations like Australia and tropical and sub-chropical areas. Unlike crypticuck is neoformans, the environmental link, as I understand it, was to trees in particular eucalyptus trees, both infections being noticed in the Pacific Northwest, starting to think in the early 2000s. Obviously, other trees in vegetation are likely involved as well. Pomania infections more common with gadi than with neoformans as are cryptic acomas. Another difference with gadi is that while infection can certainly be seen in the immunosuppressed population, infection and kind of classically immunocompetent individuals is not unusual. I put immunocompetent in ear quotes because although you can't see it because there's some work suggesting that there may be underlying immune defects predisposing to infection in some of these patients. The terms of when to think about crypticuck is so like a lot of the same as Dr. Thompson said with the endemics, so they can cause pneumonia, but like I said, definitely a concern in patients presenting the CNS infection, especially those with HIV or other sorts of community suppression. All right, great. I think, yeah, so we think crypto definitely CNS presentation. We see it in our immunocompromise host. We see it in patients with liver disease. As we start to think about treatment, you think about fluconazole as your mainstay for maintenance therapy. I don't know about you guys, but I've never done susceptibility testing ever. But when we were prepping for this episode, GRU actually brought up and asked, are you guys doing susceptibility testing? Cause maybe there's something here and maybe we see increasing resistance. So GRU, do you want to tell us a little bit about that? Yeah, sure. In Northern California, we still see a lot of cryptococ euphoria. Foreman's, but we do see some of these cryptogadiicases as well. And at least the clade 2Bs had noticed a much higher MIC to flu connozzol in the past. So we often definitely check and identify them to species level, which not everybody does. But then once we have an isolate, we do send it out for susceptibility testing because some of these really high flu MICs, we're going to pursue alternative treatment options. So I don't think it's well established outcomes as things like Canada that we're more used to doing that. But we do definitely check all of our patients. And then there's a single report that shows even in patients with sort of denovo, you know, first episode of me, a foreman's meningitis, somewhere between 7 and 10% of those are thought to have high flu connozzol MICs. We haven't seen rates quite that high here, but we definitely other sites around the country have. So we keep looking, you know, trying to improve outcomes just based on MIC data. Interesting. And where are you sending your susceptibility testing in the United States? Where are the options to send it? Well, I send everything to the fungus testing lab because I trained there with Nathan Weeter Hold who runs that lab. So he's a good guy. He's a friend of the pod. He's been on breakpoints before. Yep. All right. Greg, what about you guys? Are you doing any AST for any of these pathogens? So not really. There's not CLS site breakpoints for any of these. So we don't really know what, quote unquote, resistant is. We do send dimorphic fungi to our state lab. They confirm the ID, but they don't do susceptibility testing. I asked Virginia Pierce, our amazing microbiologist. She said we've only had one request for his door blasto susceptibility testing as long as they can remember. If we did do it, we'd of course send it to the fungus testing laboratory in the UT with the larger question with the dimorphics is of course where there's evidence of utility. But at least for his stone blasto, of course, I haven't seen it, which is why we don't do it. And then like GR said, crypto is a bit more interesting because, you know, if you look at flukonzo, my season, cryptococ, and mse distributions and cryptococcus, they do look a little more, I call it laboratory, and then albicans, you know, more than the 816 range, even for kind of denovolicilits, you can see that. And there are, as GR said, there are cases of even further MIC increases in patients who fail therapy. But there's not consistent data that MIC predicts response. And again, we're not using in a specific cryptococcal meningitis, we're not using flukonzo upfront, right? And it's a bit unclear in terms of what MIC should cause concern and what you should do about it, because that's a whole other question too, right? In Azoles, across resistance is usually the plan, right? And so just because you have lower MICs with other Azoles, they also achieve lower AUCs. And so you get into that whole kind of circular issue of what, well, what do I do now? And Michigan medicine, we have the ability to perform testing for cryptococcus species using the same panel that we use for Canada, at least generate MICs. And I can't say that it's ever really changed my treatment plan. Given that at least on an MIC basis, flukonzo is not a profoundly active drug, and trying not to preempt our treatment discussions too much, I've always taken the MICs, you know, sort of like I said, elevated MICs compared to profoundly active MICs to mean to not went out with flukonzo doses. We can talk about what that means. And maybe we, yeah, and I know when I say went out, it's probably not even to the level of what GR does with flukonzo on coxie, which I'm sure we'll get into. But I have always taken that to potentially mean that with your, to give more flukonzo up because these MICs aren't great. And then, you know, like I said, it also means that in induction therapy, you want to use, if you can, more active therapy and really severe disease, which will also get into. Yeah, guys, I was raised in the school of David Andes in Wisconsin. So I use a lot of flukonzo, very high doses. He was like, if you're not giving two grams a day, you're doing it wrong, not really. But he was like, never, never be afraid of flukonzo. But yeah, you will. So Greg, you beat me to it. As I was going to say, we're going to talk about treatment in a little bit. But, you know, maybe fluk is becoming upfront treatment for crypto meningitis in certain parts of the world as we're getting away from two to three weeks of amphoteric and, you know, less resource rich countries. But I'll say even in the United States, and certainly around the globe, but let's not forget in the United States that even Candida susceptibility testing is not common or routine, right? At most hospitals in the country. And so I'm sure we have listeners who are like, I don't even, I can't even get senses or species, perhaps, in my Candida, much less my crypto, my histone, my blasto, my coxie. And so if you're not doing susceptibility testing, don't feel bad. You're not behind necessarily. But I think the whole point of this podcast is to be provocative, to get us thinking, and maybe we need to, maybe we need to start looking into these things. And then what about coxie? So we don't do susceptibility testing and we think fluk, but we'll talk about treatment later. We see a lot of coxie that doesn't respond to fluk. So, are you guys doing AST or are you just going on clinical response if you change from fluk? Yeah, I mean, if they're failing therapy, we definitely try to get an isolate from them. And often unfortunately, that's, you know, rebiopsy or something like that because it's, you know, the vast majority of coxie patients are just diagnosed serologically. We never have a culture. But like our bad meningitis patients, bad chronic pneumonia, decimated, we're going to try to biopsy them, get an isolate and send it for susceptibility. And into quote, Greg, the MICs are definitely glibrata like at baseline. The MICs 50s are often 8 to 16. A third of the isolates are going to be over over that all the time. And the MICs for VORI pose a icer are typically like.03. And we know that they're, they definitely respond to a change in azol as a salvage setting. But we don't have any prospective studies really that show it's definitely better than flukonazole, the sort of classic ittra versus flu paper published in the annals. You know, did show that ittra was probably a little better in it. It's always listed as for bone disease. But we sort of in the coxie community interpret that paper more of the mold active agents are real coxie drugs and flukonazole is a amateur at the table. So we sort of really sort of prefer all, yeah, we really prefer all of the other drugs when patients have bad coxie. And this is a longer, you know, story that probably want to get into. But so we definitely prefer the mold active asals. You know that annals paper is interesting. We actually just obtained all of the patient level data from that. And there's actually a later time point that shows itra is definitely better across all groups. But it sounds like since that was sort of an afterthought in the analysis and not a pre specified primary secondary outcome. It wasn't allowed to the original publication. So a reanalysis of that paper is kind of ongoing. Wow. Fascinating. Okay. You guys are skipping to treatment a little bit, which is great. It's going to be the bulk of our discussion. But before we get into treatment, let's make sure we're diagnosing the infection rate, which you started to hint at. So what kind of serologies and are we getting culture or are these just kind of diagnostic tests? So do you are what is new in diagnostics? You know, urine antigens are those still tried and true? Is that still the only thing we're doing to diagnose or should we be viewing other things to find these diseases, especially as we start to think perhaps these diseases are seen in more patients around the country? What do you think? How do you diagnose these? Yeah, for sure. So blastomicis, again, if they've got a skin lesion, that's going to be pretty straightforward. You come back to that, hopefully do a touch prep, get a very quick diagnosis for those patients. Otherwise, you're going to have to pursue wherever the symptom is, right? pneumonia, you know, some of those patients in the ICU, bronchoscopies, going to be helpful. Or you're an antigen testing, but that's going to probably have at least a two-day turnaround time, which is a long time for some of these patients. But the less ill, that's probably fine. And then for histoplasma, pretty similar. Most of those patients are going to have an antigen test. It's also very useful to follow prognostically, would engage their response to therapy. Surrology with ID or CF for histose, not done very often. Some people do that for chronic pulmonary manifestations that are not antigen positive. And again, if they've got a skin lesion, a GI lesion, you're going to find that much more quickly. But a lot of histo is syndromic diagnosis and started on therapy based on epidemiologic factors. And they're immunocompromised state, et cetera. And then coxy, most of those patients are going to be diagnosed serologically with the EIA test to screen and then confirmed by ID or CF. Testing, there is a urine test for coxy. That's pretty much reserved only for really immunocompromised patients. So sort of very low T cell count with AIDS, transplant patients. And then some people use that in the spinal fluid as well. But we unfortunately haven't found utility in following that longitudinally in the spinal fluid. But that's kind of the high level diagnostics for the three endimics. For cryptococcus, though, I think that there's one thing to call out. A lot of these patients are going to be diagnosed by their meningitis and cephalitis panel if CSF is a concern. But every once in a while, the meningitis and cephalitis PCR panel is going to miss some of the cryptococcus cases. The sensitivity of that is just lower than doing cryptococcal antigen testing. So if you really think they have cryptococcus, don't realize solely on the ME panel of the CSF. And then do you do antigen testing on both serum and CSF? Or do you only send it on the CSF? For cryptococcus, we generally do send it for both CSF and from blood for several different reasons. They're not useful to follow longitudinally. That's been sort of a debate for a long time. And you'll still see people, you know, repeat cryptococcal antigens and then they say, oh, they're failing treatment, but that's not necessarily true. The kinetics of that are pretty long. So it's really not recommended to follow those, you know, just go by their clinical response and hopefully reverse their immunosuppression if you can. What about following antigen values in blast-on histo? Yeah. For histo, I think it's really well-established to follow their urine antigens. And there's even some data now out of sort of South America and Central America that they're they're looking at quantitative PCR testing, and that may be. pretty useful too and the nice part about that is if it's done as a kit it could be done in-house and delay, avoid some of the delays with turnaround time for those. For Blasto there's very limited data for following those longitudinally. We sort of summarized all of that a few years ago and it's the panel was a little bit equivocal on how they used that. Interesting and then I have to ask because we're talking about fungus and it's everything everyone's favorite thing to like hate or love or something in between I don't know help the people out. Is there any utility to fungital for any of these diseases? Oh we get so many consults from my job is ask the questions guys please don't judge me please don't judge me okay I have to be comprehensive all right. No we get yeah beta glue can testing we get a call almost daily about how do we interpret this positive beta glue can test in somebody with almost no pre-test probability right so. So we have looked at that in the past because we thought well what if we're way outside of the endemic region we can't get a coxy result for like a week but they've got a really positive beta glue can is that helpful for a coxy and it's positive right I mean coxy in the lab as far as two thirds dry weight beta glue can so they're floridly positive as a cause of beta glue can but they're just so non-specific there's so many causes of false positive beta glue cans antibiotics, gauze, IVIG, yeah gut leak concesses. you know, breathing, existing. Yeah it's so frustrating. Listening to Taylor Swift like literally anything I'll do it really anything. Yeah we actually so we actually removed the test like we don't have it we don't offer it. I hope. And it's a send out for like PJP cases or things where it's like maybe having one over 500 would like put the nail in the coffin here for this differential but we tried to just sway it by removing it but then people just excessively sent it out and that was that kind of backfire. I don't have a good answer really but yes beware of beta-dubly hand testing and it's not something any of us would recommend I think in your empiric workup here. All right anything to add to any of that before we get into the best part which is treatment. I think I just want thing to bring up about crypto with susceptibility testing is crypto and a little bit of Canada but mostly in crypto this has been worked out is under stress they develop anti-poity they start to just non-specifically replicate their chromosomes so they can end up with three or four multiple copies of either a target site Erg 11 or an efflux pump and that's the primary mechanism for resistance we put resistance in quotes. Ascences no CLS I break points for crypto caucus and you know just with drug pressure or free radical pressure etc. you know the ones that don't have these extra chromosomes are going to be picked off and die but they're not point mutations when you sequence these isolates with high MICs they look like wild type sequences. You'd have to do RNA-seq or something else to see the up regulation of all these different chromosomes genes it's been beautiful work that was done really at the NIH but just kind of a cool mechanism just thought I'd bring that up because it's not what we use or used to thinking about. That's so cool I did not know that I love learning thank you that was really neat. Greg do you have any final thoughts before we move into treatment you look like you really want to say something No I'm still pondering what you are said before and now with what he's saying now in terms of elevated fluke MICs but retained exceptionally low warrior MICs because like I said elsewhere that's usually not the case and and I'll have to stew on that a little bit more but that's that's that's all very interesting in terms of whether there's a relationship. Yeah so this? Yeah so some of the crypto isolates that if it's primarily efflux mediated their warrior MICs will increase it seems like pose to stay a little bit lower cure and marred it a lot of this work in the past which is really nice. So we it's anyway we end up checking not just one MIC but we end up checking kind of all the Hazels but again it's very data panic right there's not much literature to guide us we just try to choose one of the lower ones that makes sense with PKPD parameters and go from there and see how they do. Did you just call it data panic like data panic yeah low data oh I'm stealing that like not I think I stole that from Jim Lewis actually but that's insane I love it so much okay that was fantastic well all right all right guys I don't think this can get better but it's going to because we're about to dig into treatment I'm actually going to flip orders we had an outline but let's since we're on the crypto train let's talk about crypto so ambition trial 2022 single dose liposomal infotarisin for crypto-calculment and gytus resulted in an update to the WHO guidelines in 2022 but I will tell you locally this is not what we're doing should we be doing single dose infotarisin and high dose flu cytosine and fluconazole or GR what's the deal how do we treat crypto meningitis yeah this is this is a great question because it seems like something that we've just had this great paper about and we've just in the us ignored it just like well that's what we do so you know I was talking to the some of the crypto gurus the new England journal of medicine rc t ain't good enough that's not sufficient right yeah okay but I'm talking to the crypto group about hey you know what are your thoughts why do you think we're just not doing this and they all kind of shrug their soldiers but it sounds and not to scoop a different group but there's a paper it sounds like it's coming out in a high tier journal that's going to show one of the US centers that has switched to sort of an ambition more protocol so they have pre-ambition the old way of doing things but with lipid ampheterisin this is you know the ambition trial looked at deoxycolate and I think that's one of the reasons we've kind of ignored it but this US study pre-ambition right has lipid info plus flu cytosine for 14 days and post-ambition did exactly what they did in the study and shows better outcomes with the once a week dosing fewer side effects less time in the hospital so you know I do think that paper may be practice changing because it's going to show in the US these outcomes are also seen so time will tell if the paper says everything it's over over drinks is said to say but yeah I think that the time is coming that you know it's cheaper it gets petitions out of the hospital faster less toxicity we probably should be switching to this more ambition type model the thing that I always this caused me a little bit of fear and again that shouldn't override data is you know we just talked about flu cons on and perhaps you know a higher baseline on my season things like that and so traditionally I've always thought you know especially with CNS disease ampho until they're better right and when you give it to a one-time dose they're not going to be better right even if it's 10 makes per kick right off the bat and say you know the period of time where you there they're still going to be sick and now you've started kind of the second phase of treatment and that's probably just something like you said that we just have to get over in terms of you know they've got now a depot of liposomal ampheteris and be in and that that kind of standard practice of amphol tour they're better in this study wasn't proven to be better well and Greg I think to that point like Jared said like you know I I still have colleagues that trend crypto antigens we still have they'll have high opening pressures yeah exactly and it's like what you can do keep them the hospital forever I mean I don't know and but to that point and just to remind our listeners are I got excited and and all of our listeners not may may not be as overly familiar with the ambition trial so just a level set this looked at a single high dose of liposomal amphotaricin which was 10 makes per kick on day one and then 14 days of flu cytosine and fluconazole which they gave it 12 hundred milligrams a day a real a real dose for two weeks but the comparator I think what GR was getting at and Greg what you're referring to was was ampob deoxy colate which was the WHO standard and so I think in the United States really well our standard is liposomal amphotaricin for two three weeks and so you know that is it better than that regimen and people didn't quite know but I'm super excited to see those data you talk about because that would be a game changer right if we can move to a single dose of amphotaricin that's good for patients guys yeah and in terms of data we also have to be honest with ourselves that those of us who are saying well deoxy colate's not our standard well if you look at the rcts there's not liposomal it is actually yeah you know it what we're saying is our standard is not data is data panic right of course because Greg we just like to squint and make ourselves feel better I know so but the big thing I think that people keep on coming back to it I'm really curious on both of your opinion on this is you know that this was conducted in patients with HIV and if you're looking like the past crypto guidelines they differentiate patients with HIV versus patient salad organ transplant versus those who did not and in some hair in Africa so I'm just wondering does that influence you know does that influence your confidence in extrapolating this to salad organ transplant patients or non HIV patients not in in in the United States no it's a super good point because that yeah ambition was HIV positive individuals and so with or without art and so obviously you have a means to an end with HIV positive individuals wherein they can become immunocompetent and actually quite healthy and the amazingness that is art and like that salad organ transplant patients are always going to be immunosuppressed to a certain degree and so can we extrapolate these data which we do all the time right but they're different hosts and the host matters when you're talking about opportunistic infections so um okay crypto to round out Greg I'm gonna put you on the spot you ready are you excited for crypto all right because the people want to know yeah okay it's about dosing it's pharmacy stuff sorry GR okay ready so Greg if you dose lymphosomal ampheterisin makes per cake right what body weight do you use oh yeah I also have the luxury of having um it pie here at our college who's like the world expert in dosing in obesity but he he makes things pretty simple for us in the hospital to it in general for make per cake drugs even those with good bombies distribution once you get into kind of especially the morbidly obese area of things we're using some quote unquote adjusted weight whether that's a cyclavier or burliposomal ampheterisin - Okay, I'm gonna adjust it gal too. Just wanted to confirm. Total or adjusted, total or adjusted. And then flu side is seen. What weight do you use? - Again the same. I don't think we really know how to dose a side to scene actually. The original, you know the. - You dose it until they're cell counts. - Well, I don't think we have to. - Decrease. - And then you decrease the interval. - We used to dose the original RCTs. I think dose it more aggressively. Like more of like 150 makes per kick per day. And then we dropped down to more amp foe, but less flu side is seen. And at this high kind of 100 make per, you know, this 25 make per kick Q6 and pristine renal function. I don't really see toxicity with it. And so, you know, I've never felt compelled to really be a super aggressive with flu side is seen. I just haven't seen the data to support that. And so, no, I'm the same thing. I'm total unless, the significant obesity and then I'm transitioning to adjusted, but that's completely. - Really? - I'm not sure what I'm saying is any deviation from that is absolutely acceptable. It does have a huge rise distribution, right? And so, you could certainly justify always actual. - Yeah, yeah. And then, yes, okay. Yeah. And then just rounding, it only comes as a 250 and a 500 milligram. - Yeah. - So of course, so just kind of round. So I feel like I just give everyone 1,500 Q6 or 2006. Like I just feel like I only have 2 doses. - Yep. - Okay. All right, GR, you can chime in now for the fluconazole piece 'cause no one knows the answer. So consolidation maintenance fluconazole. What do you do? Do you do a mixed per kig sitch? Do you do 400 or 800? Do you do 1200? - That's a great question 'cause flu sounds benign, right? In the literature, but patients tend to hate it as soon as they start feeling better from their infection. So we definitely go by the renal function and give them at least 600. And I'm always struck by a paper that's, it's all animal model data, but it basically should, no matter how much fluconazole you give them for cryptococcus, it's not enough. I always remember this, right? 'Cause it's so frustrating that we're giving them something that makes their hair fall out and they get key lightest and zerosis from and it may not be that effective for them long term, but as long as we can, I mean reconstitute them, that's just what we do. - Okay. And you said that quickly, but that's an important point. I mean, I call out for our listeners. So long term, high dose fluconazole. This is one of my favorite things to teach my residents. You get a lot of dryness, dry skin, dry mouth, dry eyes, your hair falls out, you get really tired. And that's when you can start to see hormone-related side effects, which we've seen interestingly in earlier shorter courses with Posa, Vory, Itra, as all the data on pseudo-hybridal dosterinism, which was out of your center, came out. And like we understand, I remember when I was a resident, I was just thought like, oh, if you put a patient on Posa, like replaced their potassium, but the why was missing, right? And so now we're understanding, it makes sense with how azels work and why they're contraindicated in pregnancy and all of these things. So, but that's important in patients do hate that. I agree. And after they don't want to take 800 a day forever. So we're kind of in the same boat. We usually do 800 for like a week and then step them down. But Greg, does that kind of follow your pattern? Like you said, more fluconazole. Yeah. Yeah. Give me, give me more. Give me more. OK, and then tell the-- And the long term toxicies, it's really unfortunate because otherwise fluconazole is the easy-ease-all, right? In terms of relatively benign in the short term, general, significantly less need for therapy, drug monitoring, drug interactions are generally a little more mild, et cetera. But with long term, as with most things, you can run into issues, especially with the-- and I'm sure the way we-- like you said, the way we-- you'll compel to dose it doesn't help. Yeah. OK. And then last but certainly not least, I want to talk about this here because I think it fits best here with this disease. It was studied in this disease. But where are we at with oral amphotairs in? Because I think we're all quite excited. GR, do you have any health issues? Don't shake your head. Please. Yeah, that actually made me really sad. I didn't expect you to shake your head. And no one can see you shaking your head, so we're going to verbalize that. But that was a sad response. I think we were all pretty excited about the possibility of oral ampho. From what I understand is the company that made that is having a rough time just financially right now. So I think that it's sort of stuck in development at this time. So I'm afraid I don't have great news there from what I know. I mean, there's another company that's making the new polyene. And it looks like it might be just once a week with a lot lower nephrotoxicity. So maybe that'll save a lot of these issues that come up. But that's in sort of the preclinical setting. So I don't think we have a great option still. One of our ID positions here, Marissa Misselli, gets us access to all these in development agents. And she published some of our experience with oral ampho. And man, we had a-- I mean, we had a disseminated histo in a kidney transplant patient who, of course, couldn't tolerate amphoteric and bee. And oral ampho just was life saving. I mean, the science of it is so cool. I have talked about this on other breakpoints episode, so you can go back and listen. I won't. But the science of that molecule is fascinating. And it's so interesting and how it enhances efficacy against the pathogen, but limits toxicity. And that's a bummer. We hope it sees the light of day one day. But in the meantime, let's move on to histo, plasmosis. Greg, how do you treat histo? Yes. So there are ongoing-- GR, are you on them? I DSA histo plasmosis guideline updates. You're on like 80% of everything I read on the endemic. So I just-- Just assume. Yeah. But you know, with the point I wanted to clean is the updates have been released so far focus on some populations that you may not need to treat. So you don't necessarily need to treat all histo. Patient with self-limited mild to moderate histo. They're immunocompetent. You may not need to treat. So definitely check out those updates. For those that do warrant treatment, initial amphotericins recommend for severe and/or disseminated disease or in patients who are significantly immunocompromised, generally until they're stable and improved. And there is some of that ambition data we can get into with histo. And then for step down therapy or initial therapy in more modern, in fact, mild, modern infections, itchocanosol is preferred. So the itchopiece is based on a couple prospective non-reinemized trials in the '90s. We're a successful one like 85% of patients in cases. In the '90s, we also had some data with fluconazole where it didn't achieve the same high rates of successes at your connozol. And relapse was actually white common, like up to 50% of patients on fluconazol relapse. So this suggests that we should be cautious with using alternatives and that itchocanosol has the best data and should be preferred. There's also some data from St. Louis that found a higher mortality rate in patients who received BORI versus itchora, which absolutely may be true, given what we know about fluconazole. To be fair, this was a retrospective study and I think only, I forget, 19 patients or something, 90% of patients received itchora, and 10% received BORI, so there could be some selection, you know, differential bias there. Dr. G.R., I know you compiled some experience with isabi connozol in upwards of, I think, seven to 10 patients in which it seemed to perform reasonably well. In terms of alternatives, so not flu and not BORI, I think of azoles in terms of kind of two families. And if you look at their structures, we kind of got into this a little bit before. And if you look at their structures, you can see this clearly. There's fluconazol in his babies, BORI and isabi, there's Tito and its babies, itcher and poza. And these descendencies do not predict everything, but there's several examples in the fungal world where they do like cross resistance and like we talked about canopropylosis or aspergillus, or some toxicity like, like we talked about hypertension and hypochalemia with itcher and poza. But so given those concerns with fluconbori, I like poza, as my next go to after itcher, but of course, it depends on why you need to switch. If it's because of hypertension, hypochalemia, you're not going to switch to poza, right? Which is actually, I think, a more potent inhibitor of that problematic enzyme than itcher. If it's because the original capsules, we'll talk about I'm sure all this mess, but if they need their PPI and insurance, as a problem with the suba itcher or something, then poza is fine. If it's like a patient we just had this week, or two weeks ago, renal transplant patient with histo who's on river oxaban, then poza is not going to solve that either, right? And then maybe you look at GRs data to suggest something I sav you. But going back to this susceptibility thing, I'm also now going to bring up something that'll probably be confusing to me, but also contradict some of that descendancy story that I just said. So that 1990 study where like 50% of patients relapse on fluconisol, there have been some studies, I think Joe Wheat and Nandra Speck have done some studies where they have those isolates frozen, and they've run those denovo isolates and the relapse isolates to fluconisol, other azols. And as you may expect, there is a significant increase in fluconisol, MIC from the denovo isolates to the relapse isolates. And as you would expect again, VORA MICs also increased in those same isolates that's all increased MICs. But what was it did not, you would expect that, itcher did not. But really surprisingly, I savvue connoisseur MICs also did not increase between the denovo isolates, denovo in the relapse isolates. So I don't know how to explain that mechanistically, but perhaps it's another feather in the cap for I savvue. And then in terms of treatment, the other thing I guess to briefly mention is we do have a mini ambition for histo. And so it's a phase two study, RCT, this one is done in Brazil. Again, patients with H.I.C., with disseminated histo and they had three arms with interest starting right after the ampoh induction. So single dose 10 make for giga of flippers and amputaries. Like you said, and then the third arm, which is kind of classic control, which is three makes for giga flippers on more per two weeks. Day 14 clinical response was similarly effective and so a survival up to a year out. And so again, another interesting post ambition or ambition correlate. Gior, I don't know if there's if you know if there's a larger study in the works for histo to to explore this regimen further, but another one that's really provocative. Yeah, I was I was told they're gearing up to do a phase three study. I don't know if it started or not. I'm not I'm not sure who's funding or that's all been squared away. Yeah, thank you, great. That was awesome. That is a very interesting study. I want to unpack our consolidation maintenance therapy, which is which A's old we choose. And you mentioned this briefly, the St. Louis group, which is the Hendrix at all study from CID in 2021 that looked at Vory versus Itra for initial and step down of histo and they found that Vory was associated with higher mortality, but you're right. Only 19 patients are 10% of the total study population received. Vory con is all in that study. So some people say it's kind of just a numbers game. G.R. What's your take on that publication? Is Itra your first choice for histo or do you think they're kind of a toss up of the Azels or do you just go straight to I Savio? No, I think Itra is really the first line agent for histo plasma. If they fail, I tend to go to Posa. It's very different. We use almost no Vory con is all. There's too much sunshine in California to get people Vory out here. They come in, you know, red from head to toe and just that case of fluorosis last week. I know I'm like as I I'm sorry. I know it's like 20 degrees. I was like, yeah, I have to interject. So I've lived in like the Northeast and Wisconsin most of my life and except for my time in Auburn. And I went to my first PCP appointment ever like a month ago because like who has time to take care of themselves. And my vitamin D was undetectable you guys. Undetectable. I was like, what on this? I'm on the 50,000 supplement weekly right now. Oh my gosh. Like I'm an 84 year old. I am like, anyway. Just not. No vitamin D at all. No vitamin D. None. None. It is great. Every day in Pittsburgh. Yes. Okay. We carry on. Okay. So yeah. So it's your escape. Okay. So let's get into the itter nuances then and then we'll move on to other fungus. So itra is one of my favorite antibiotics actually because of the pharmacological nuances between the different products. So Greg, you started to allude to this. But let's talk to them. So we have the original capsule, the solution and then a new capsule, which is the suba itra capsule, doesn't come IV, which is unique amongst the azels. So what's the deal? What's the differences between the original capsule and the solution to start? Yeah. So we still caught suba. They should have called it that, but they call it Tulsa, right? It was developed it. That's the brand. Well, that's the brand. Yeah. Yeah. So suba is so suba stands for super bi-available, which I thought was cool. So yeah. So the original capsule, like you said, absorption optimized when you gave with food and without acid suppression. So if you think of like that original Posa liquid that no one ever uses anymore, you have to give like four times a day and you have to tell poor cancer patients to have no acid suppressives and to take a big fat meal every time four times a day and it wasn't possible, etc. That's itra original capsule, right? And then the then there, like you said, there was a solution that was developed using this cyclic dextrined vehicle to be able to dissolve it into lick into solution. And that generally achieves better exposures than the capsule. This one's op and it's not dependent on gastric acidity. It's opposite of the capsule in that you want to give it without food to maximize exposure. The bad thing about it is that this cyclic dextrined vehicle enables the solution but also causes a lot of GI upset. And so that's really the limiting factor in terms of in terms of the solution, which is a significant problem with a fair amount of patients. And then like you said, the newest hit on the block is suba itra, which is less dependent upon being in the fasting or fed state or gastric acidity. It's recommend to take with food just to improve tolerability but in terms of levels you don't really need to. And the suba part of it comes into play in that. You give 65, you know, 135 milligrams a day instead of 200 milligrams a day and you achieve roughly the same exposures. GRI, I know you did the MSG study of suba itra in endemic infections. So really just to hear your experience with it too. Yeah, there's still some questions from that study that I really don't understand the answer to. Yeah, I don't know. So that's my answer to all the questions. But the toxicity for suba seemed lower despite kind of more favorable pk. I think that's a little bit tough to wrap my head around. But that was GI stuff, right? Mostly with the capsule, which was a little unusual too. Yeah, and I think you've even had less edema. I'd have to pull the paper up, I've read it for a while. But yeah, we've had a hard time getting stupid for our patients that need it. And I know that's not really answering your question. So I'm just changing the subject. But so we just give patients a pose. And that's the most important point though. And I mean, I used to 10 years ago I had a preformed prior off for solution. That was like here's all the pk studies here's why the capsules are trash. They're not going to drink cans of coke when they take each capsule. They come in with undetectable concentrations like they need the solution. Now, most people I think can get the solution, but sometimes they can't tolerate it. You're right. And then we do end up usually switching them to Posa in that setting, which brings me to my last question. And then we'll move on is TDM. So are you guys, if you're treating histoplasmosis, are you guys routinely performing therapeutic drug monitoring of it your connoissell? Now, didn't you write these guidelines? I sure did. That's why I can't answer the question. Don't hate me. We love TDM. That was awkward. Yeah, I did. So you should, so obviously I'm a big fan of Azul TDM, but what's your take? You can disagree with me. There can be thoughtful dialogue. GR, you want to go first? Yeah, I mean, generally for Istra, I think everybody needs TDM. But one of the questions that comes up is, you know, that like if the old literature was bioassay based TDM and the new literature, depending on where you get the drug level, it's going to have an Istra connoissell blood level and then some labs are going to give you an Istra and a hydroxy-itra level. So how do you interpret those is probably the most common question we get asked. So we tried to pool all the literature to figure this out came up with if your Istra level is above one, that's fine, or you can add them together and try to get it above two. And that sort of fit with the clinical experience that had been published. And so we published that and so now it's dogma in my own mind. You all can disagree. That's totally fine. That was, I'm so glad you brought that up because that was hands down the most controversial thing when that panel was writing those guidance. We were like, what the heck do we do with Istra and hydroxy-itra and it's funny because it was one of those things that I think people just do what they've always been taught and had never really questioned and I was guilty of that. So I was taught at Wisconsin, Adam together and as long as and that's Adam together and you want that to be over one actually. Like we said, the active metabolite counts and the goal from the literature is one and so that's good. And I just repeated that forever and never took the time to dig into the literature. And when we did it was actually our, we'll mention again our good friend Nate Wederhold. He was like, you know, but if we really dig into it, all the data with the greater than one is on the parent drug. And so like that's what the target is with the parent drug. And then if you want to add the metabolite, cool, have fun, but it is active, but we have no idea what that means. And then yes, your group kind of came up with the two thresholds. And that's why in that document we say it really is just a parent drug. But that was the thing I got the most emails about too because people were like really had big fields if they'd been taught to add them together. But I was taught to add them together. And I was like, I was taught a lot of things and the data saved this. And I'm so so so so so sorry. We actually, and I will say like, and I'll say at pay, and I'm not saying this is even necessarily wrong, you know, some centers because reporting both is really confusing. Some centers just like report one value. So we do that at pay. Like we've in house, asal TDI at our main hospital are very fortunate. And but itchra we we run both and we report one number. We add them together for the clinician and only report the added it. Which maybe that's maybe that's a disservice we're doing because people are too confused by the OH and whatever. And so yeah, I don't think there is a good answer. But but the the be all end all in what the old data say is that it's the parent drug only. But yeah, okay. Blasto Greg, this can be shortened sweet. How is it similar different from histo? What are the cliff notes on Blasto in relation to his? Yes, Blasto I will make or try to make a little more brief. So one difference is that the guidelines do recommend treating all patients with Blasto my co-exist to prevent progression of disease unlike like I talked about some patients not being able to not having to treat who have histo. But otherwise there's generally lots of similarities in initial info for severe disseminated disease transition to itchoconazole or it in the issue of itchoconazole and more moderate infections is preferred. Itchur generally for six to 12 months depending upon if the patient's immunocompromised and if that remains. So with itchra in Blasto that's based on an early 90s open label study in which success was seen in over 90% of patients. There were then two subsequent studies randomized studies evaluating fluconazole. One was I think in the kind of 200 to 400 milligram range and the second one was in the 600 to 800 milligram range. The first one saw success in like 60 to 70% of patients which is why they did the second study with the higher doses and their success approached 90% but still yet wasn't kind of the greater than 90% that was seen with Etra. So it's a story in supreme, I believe, at least here. But unlike HISTO where you definitely don't want to use flukonzo, the higher dose of flukon zo in Blasto may be an option. There's very limited data with worry, poser ice savvy, but I'm inclined to think that likely also probably work reasonably well. I guess the other scenario that I sort of forgot to mention is this maintenance therapy because post-anfeterisant step down in CNS infection and that's pretty controversial as well in terms of what you used. You prefer something like worry given that it's CNS penetration but in HISTO, I don't know because you're worried about flukon worry, right? And so there's kind of opinion all over the place in Blasto. I think the expert opinion is aligned with worry in that scenario. But you'll see data for Etra or ice even ice savvy or a poser in terms of CNS infection step down from Ampho. But in general, it's Etra but probably a little bit more confidence in flukonzo on alternatives in Blasto than in HISTO. Yeah, especially for mild skin disease, I think high dose fluk is maybe okay sometimes. But I sav you for CNS is super interesting. And we'll talk about that as we end with Coxie here. But it's something that we've studied, we've looked at. And so ice savvy is definitely getting to the CNS and Poseid does and I don't know, there's just less clinical data. The problem is we have this paradigm of measuring CNS penetration of CSF, right? Oh yeah, don't even get me started. Or only measure. The substance in your body that is literally designed to never have anything in it and to declare itself at all times. Or we could biopsies of sites and then mush them all together so we can't discriminate basculature from tissue, from necrotic, etc. And so we're just, yeah, I think, like you said, the literature suggests that for a special prankable disease, we shouldn't be basing it purely on our CSF paradigm. Yeah, absolutely. I could talk for another hour about this. But when you sample, because when you sample CSF, and it also depends on where you sample CSF flows to gravity, right? So if you're sampling F and EVD versus a lumbar spine, like you're going to get totally different things. And it's designed to be clear. Your body is always working to not have anything in your CSF. And this is beyond the scope of today. But this data is fascinating in the kind of candens. Because in animal models, the kind of candens are in brain tissue and very high concentrations. It's just they're not in the CSF because they're not supposed to be. But yeah, we digress. But I think that was a great overview. I think something we haven't explicitly said that I just want to say for our listeners is it was really tough. There's a ton of drug-drug interactions. We call it affectionately the dirtiest of the azules in terms of its drug interactions. It causes heart failure with long term use. I mean, there's a lot of issues with with it. We talked about the issues with Vory, the photosensitivity, long term, neuropathes, LFT abnormalities, anecdotally seem to be very pronounced with Vory and maybe less so with other azules. So moving on to those options is reasonable in those settings. Okay. And then last but certainly not least, GR, we're coming to you because you are the coxy king. How do you treat? Oh, man, I wanted to be king of something better than coxy. How do you treat? I'm just kidding. I don't want to be king of anything. Well, I mean, you're like really good at this. So it's, you know, of what you're doing. We see so much coxy. It's just unbelievable. It's awesome. Yeah. It kind of is back to the climate change that we mentioned at the beginning of this. We are seeing so many more cases and so many more severe cases. And not totally sure why. Like climate is probably a part of that. Like, you know, I think that there's some sociologic aspects that are wrapped up in that that have been overlooked. And so what I mean by that is like housing prices in the big go way up. So people move inland. So they're not immune because they didn't grow up in the Central Valley of California. Kids do better with all infections. You got coxy as a kid. Even your immune is an adult. So this is the flip side of that. Moving there later. So these are all just theories we talk about on rounds and have no answers for. But we're definitely seeing so much more coxy in some really severe cases. So, you know, if they come in with pneumonia, just the classic valley fever where a cough, I have some fever, weight loss. And my joints hurt, you know, flukon is all as fine for the vast majority of those people. It's our least favorite coxy drug, but it does work for most of those patients and they're going to be on it for somewhere between three and six months. The bad part though is after we stop. And what dose? Oh, yeah, sorry. What dose of flukon is old? So a regular 70 kilo person with normal renal function, we're going to give 600 milligrams of flu. The bigger they are, the more flu they're getting adjusted for renal function. The bad part though is even after they are doing great, we've stopped their drug, they often still have symptoms for particularly fatigue for months and months and months. And we worked on that in the lab and it looks like just like an EBV, coxy causes mitochondrial dysfunction that just has to abate over time. Like just we just tell people, hey, I'm sorry, you're going to get better, you know, we're going to have to start doing physical therapy, et cetera. So that's even in the simplest of cases. The more complicated ones, the disseminated cases, chronic pulmonary, they end up on sort of multiple different azoils over time. One of our fellows used to call it, they're like trying on shoes to see which one fits. I don't know if I totally was on board with that analogy, but I got what they were saying. So they all start with flu because it's cheap and then insurance will pay for it. And then once they start having side effects or lack of efficacy, they end up usually on itcher, opposed the next. And we just kind of see how things go from there. But lots of things go into that drug interactions, which Greg you mentioned, PKPD, we do talk a lot about CSF versus CNS, which doesn't matter even. They all tend to work. But that's generally our sort of big picture approach. Is there any role when you talk about CNS disease? Is there any role for intracurricular infotariousin? Do you ever do that? Oh goodness, yes. That's like the last resort. Like the papers you read it, you're like, oh, this sounds great. It's just, you know, just squirt a little amputariousin in there. I think that's because of our experience when we have like bad gram negatives in the CNS. Like, you know, someone gives a little bit of genomice in for a few days or something and it tends to go well. But introthetical ampho, just like infusions with ampho or inflammatory, same thing in the CSF space. So they can get headaches. They can have nausea and vomiting. And then they can develop a raccoiditis from just the drug itself. So it can be very problematic to manage. There are also long courses of introthetical therapy. They're not getting it for just a few days. They get it for months. And then how everybody tapers off of that is different, different sensors do different things. But it's not for the faint of heart. It's logistically challenging. Patient tolerability is a big issue. But when we get patients with coxymeninjitis just off the bat, we do scan their whole spine as well because some of them, either from ampho, IT or just the infection with a raccoid itis, some of them will even start to compartmentalize their CSF. So they'll have sort of two different CSF's faces. And then how do you give introthetical therapy that's going to sort of get to all those areas? So we do talk through a lot of these different issues. So we consider a drug problem. And then we call this the plumbing problem. Like, can ampho even circulate everywhere it needs to go? Yeah, and that's a fascinating point too about that system. You have to get your friendly neighborhood neurosurgeon involved. And then, which is something we so rarely say in infectious diseases. And then, okay, and you said this at the beginning of the episode and I let it slide. I let you just grace on through it because I wanted to bring it back to this specific point right now. This whole concept of itchra for the bone. We've heard it. Some of us may have heard it. I have. Where'd that come from? What is that? Why? Why is that a thing? Yeah, so that really came from that annuals paper when the patient's with coxy. And in that paper, the annals, it's flu versus itchra. It's kind of all comers with different forms of coxy. And the patient specifically with bone infection did better than patients with really any other form of coxy in the itchra group. So that's really the background of where that comes from. And again, we tend to interpret that a little differently. It's just real mold active azoils or better coxy drugs in general. But that was also the theme of all of the endemics. We mentioned the flu failures with some of the other endemics and sporethrics were not used in flu, we didn't talk about sporethrics today, but we tend to use itchra for that one too. So it is a little bit hard to say, well, for this other endemic, just give way more flu connozzol. And we've picked some fights with the coxy study group. And the group is now kind of split with that, but you know, like to use a poor and terrible example, like if you have staff back to remia, we tend to not give you just more back to them, we give you a better drug. And so we use that analogy with some of these bad cases of coxy, they don't need more flu connozzol, there's just more toxicity, give them a more efficacious drug. Yeah. So that will stir up some controversy. I get it. That's fine. Oh, I'm here for it. I like it. But we definitely like the mold drugs. We are here for the conversation. So another controversy that I want to end with is potentially that of prophylaxis. You mentioned earlier in the episode, you know, it's something 20% upwards of cap in your area of the country might be due to coxy. And so I've been hearing that systems, colleagues and friends out in Utah, Colorado, California, now, they are giving flu connozzol prophylaxis for he, men, solid organ transplant patients outside of their other fungal prophylaxis. But it just things going into this. So is that something you do? Like are we prophylaxing coxy in certain settings? We definitely do. And it is very controversial, depending on what century you talk to and what type of solid organ. Okay. So the coxy group, the Mayo group has sort of led this effort. They've kind of put all the transplant centers from California, Arizona, Utah, Nevada, and then some nonendemic areas, you know, like Boston, et cetera, just to get an outside view. Because they certainly see coxy in their transplant patients too. And there's been no consensus reached. So some groups put people on prophylaxis for life, some do it for like a year, some just monitor frequently. And we've not really reached a conclusion for what to do. I mean, we know if someone, they're going to be able to do that. if the organ donor had active coxie, don't take the organ. If they had recent coxie, most places would agree the recipient's going to need prophylaxis most likely for life. But some places do it for just a year and then monitor them closely. Some places leave them on 400 of flu, some on 100 of flu, which is really sub-MIC. So I don't have a great answer other than that we'll continue to watch people stir the pot and argue with each other and hopefully come to a nice, tidy resolution. But I'm not, we're not quite there yet. Yeah, it's a super interesting space to watch evolve. Because this comes up a lot here, Greg, I don't know if this happens in Michigan too. I am often at a loss of when, you know, certain organs get broad spectrum antifungal prophylaxis after transplant across the board, lungs, livers, it's like, oh, we're all into risk factors. They have a re-exploration and up on ECMO postop, what have you, and then maybe they get mold coverage till they leave a hospital or whatever. But then when patients come back and they're getting multiple rounds of rejection treatments, they've gotten a gram on methyl pred once a month for six, seven, eight months. It's like, do we restart them on fungal prophylaxis? I don't, we have these conversations all the time about who really needs it. And so then thinking about the endomics too, it's really fascinating to me and I appreciate the dialogue. Yeah, I mean, that balance, the considerations always whether you're doing more good than harm, right? Because forever, foray is not great either, right? It's not for a reasonable concern for invasive fungal infection. And so finding out where that benefit's greater than the risk is really hard. And like you said, a lot of those risk factors and a lot of that data is old at this point too. Right. So it's, it's, I agree with you. It's really, really challenging. Yeah, I know because yeah, you're like, I don't want to expose you to this drug forever, but I also don't want you to get an invasive fungal infection. Okay. All right, guys, before we get, go to our closing segment. I have one final question that it didn't really fit. I guess we could have talked about it when we talked about infoterosin, but I forgot to ask. You can now completely out of place, but you are. You recently published a very cool study on amphoterosin infusion reactions. And we talked a lot about asal long-term side effects and drug interactions with asals. And we unpacked that. We didn't really unpack amphoterosin toxicity. So I want to circle back on it. So as we know, when we give our patients amphoterosin, definitely deoxycolic, but even with the liposolmal amphoterosin, some can have pretty terrible infusion reactions. And this can manifest a hypertension fever, sometimes pain. Our group did a lot of work on that, and please tell our audience what you found, because it's very interesting. Yeah, so we were sort of intrigued by this, and this came up in the old, well now kind of old, aspergillous guidelines, is that it's proposed that the lipid, specifically liposomal amphoterosin B, cause complement activation related pseudoallergy. So it's not IgA mediated, but why would that happen? So it's thought that this complement activation related pseudoallergy is really kind of a primitive immune response, like you would need if you got bit by a mosquito or something, right? You don't have time to make an antibody. You need like an immediate reaction, and that's why you get infusion reactions with this. And it's really fascinating. If you look at liposomal amphoterosin B under like an electron microscope, structurally, they're very similar to like bacterial organelles. So if you had like a lice bacteria, your body would need to clean that up, or an envelope double strain to DNA virus. So that's, we think why you manifest these very rapid reactions during amphoterosin impusion. And so it's mediated though by C3, through C5, and then also sort of to look at that terminal complement with C9 as well. So when we did the study, we recruited patients who were going to receive liposomal amphoterosin B. This is part of the usual care. And we did a blood draw immediately before infusion, five minutes into infusion, and then an hour after it stopped and looked at sort of their complement levels and change. And we saw exactly what you would think with this hypothesis that this is carpa driven, this complement pseudogy, where their complement levels start to go up. But we noticed a few interesting things, not other than just explaining the mechanism. If you premedicated them with either a acetaminophen or anihistamines, it actually reduced their complement levels and did correlate with less symptoms in those patients getting lipid impoterosin. And also, if you were able to kind of just keep going, to keep telling patient, you know, this reaction is likely to go away. By day seven, their complement levels with infusion went way down. And anecdotally, that is what we've seen, that these reactions sort of extinguish over time. So we thought that was sort of helpful. Premedication is probably good. I don't give patients my parodine afterwards. We just, I don't know, I think that creates more problems. But we do premedicated with Tylenol anihistamines now and tell them, just keep going. We can turn the rate down, whatever you need. But you will get over this in the vast majority of patients. Awesome. That's so interesting. And the fact that you also showed the tapering of responses, like you said, is perfectly correlates with what we see clinically. Before this, did you do routine premed? We did. We left the premedication for this study up. We probably should have randomized them. But we just left it up to the treating position's discretion, because there's sometimes very dogmatic opinions about things in the hospital, which I'm sure is a big surprise to everyone. So we got fortunate that we saw that effect. It wasn't part of the design really, but it is something we wanted to look at. Cool. Awesome. And then last thing, what they've got to say is acute kidney injury. So that's something we see quite commonly. I was taught you have to give fluids pre and post the dose in order to help mitigate some of this A.K.I. And that it had to be normal sailing because it's actually the sodium load and not the fluid that helps. Is that true? So I think a lot of this mechanistic work could benefit from the development that you are just interested for the infusionary reactions, because I don't think we completely understand some of the Nefertile toxicity components of Ampeteris and B. You know, the theory is that there's a tubular gomereller feedback process that Ampeteris and B. Activates their results in A.K.I. and arterial are very basic. Construction with results in ischemia, salt depletion exacerbates its salt repulsion or loading reduces it, right? And so the early literature showed that you could just give supplement oral salt to emeliorate or even reverse renaum parent, right? And then there's even data. And again, this was an RCT. This is kind of just anecdotal experience. Some of it even looked at like Nefertile toxicity as a function of the amount of salt that they were getting in other drugs. Like one study showed that patients who were getting tycarcylin, which we all know of salt load and some of our penicillins, that that was protective, right? But IV phosphamide ischemia. Exactly. No one is A.K.I. And those studies seriously, everyone does great in on the IV phospho studies and you're like, okay, what? But most studies, I think you utilize intravenous saline solutions. And there's one RCT in patient with leshmonisis that compared D5W to normal saline that found a benefit. And so I think I don't know the answer to your question. I really don't. It's probably the salt. But yeah. Well, and then how much fluid do you guys give? Because sometimes I feel like we give a liter of prepost and then that lasts all of one day and then they can't breathe. So then, you know, so I think at this point, we, I honestly, if patients, I think they have A.K.I. baseline or our frail, we do 250 preposts and then if they're younger and healthier or 500, but I made that up. Do you guys have a fluid strategy? Yeah, we ballpark it like you just said. Most people will get 500 if they, if they're a little frail or have some reduced ejection fractions. Sometimes they get almost nothing or just 250. But Aaron, I think that's really important is to try not to do harm with, he is saying everyone has to get a liter or something like that. That's not, that's not, you know, that's going to result in more harm than benefit in good degree of patients in the hospital. So yeah, just whatever, whatever is right for the patient. I try really hard not to hurt my patients. That's great. That is the goal. But when you can talk about these things, you can, right? In terms of everyone, we've got to do this. And I think that's where knowing that the data is not super robust, that there's not RCTs that you need a liter, you need this exact amount given that uncertainty, then I think that gives you the flexibility to balance that better. You mean not everyone needs 30 mils per kilo of fluids? I don't understand, Greg. That can't be true. Okay. Well, guys, this has been the most fun. I think I speak for myself and hopefully all of our listeners, when I thoroughly enjoy this, I've learned a ton from you both. I appreciate you so much. And with that, the time has come. The break points faithful for I feel nerdy. I feel nerdy is meant to be a safe place and closing segment for our panelists to nerd out over their favorite ID topics, quirks and fun facts. And for today's I feel nerdy. I mean, we had to stay in the antifungal theme. I want you guys to tell me about your favorite drug and it can be something commercially available or something in the pipeline. Okay. And it doesn't necessarily have to be one we talked about today. So Greg, why don't you go first? What is your favorite antifungal? Well, G are just ruined. Ruin this, what? A little while ago. You know, I was tempted to see. Oh no. Was it going to be oral? I was tempted to see the azols or as I call them, why God created pharmacists, although the timeline doesn't match up. Yeah. The TDM mechanism of action that just happens to be a major endocrine pathway for human's, mccay, you know, all the things that you talk about. But then I was thinking of, you know, normally we think of ancient anti-infectives. We think of bad stuff like cliston, which was abandoned for good reason. And we never really should ever bring it back. And so amphitheater, but then there's amphitheaterism. Right, which is an ancient drug and, you know, but is still the drug you want if you have a really severe pongo infection while at the same time you're. It's absolutely not the drug you want because of how toxic it is. And so yeah, I was going to say, or if it here isn't be, because what could be better in terms of the drug I trust the most, but can't use these at toxicity, but now I can. And it still penetrates the CNS and still retains its activity and efficacy. So yeah, please, please keep that one moving forward. It's okay to believe, Greg. Yeah. What could happen with septiviral? You know, like it's okay. It's okay. GR, what about you? Oh, this is tough one. We've gotten a lot of experience with both the Laura Femian, FOSMENAGEPICS. And I am a fan of both. Like they have gotten us out of some patients who we had nothing else to offer. And several of those patients are now off all agents and back doing life as they want to be doing it. I mean, it's just amazing. Some of the successes we've seen with the drugs that are coming out. I will put a plug in here for our CDC colleagues. So FOSMENAGEPICS has this unique mechanism. So it is a Laura Femian, but very similar compounds were approved for use in the environment. So we were concerned, oh my gosh, we're going to lose these drugs before they're even on the market with development of resistance. And CDC has gotten this big group together to try to tackle this so that things are no longer approved kind of in silos, you know, veterinary versus agriculture versus human health. So they'll all sort of sit at the table together and hopefully solve this problem. So I guess maybe that's a pass. I chose two drugs and neither on the market yet. So sorry, but we love both of them and they're coming hopefully soon. Yeah, that's okay. I think they're both amazing drugs. And it's a great actually end and segue into listeners will be having a mold episode coming out later this year. I would co-sign that what we've seen with our compassionate use FOSMENAGEPICS and a Laura Femian patients is incredible. Truly life saving. People that are able to get transplanted that would never have been able to be transplanted before and had a patient on service last week. That was an allore Fem bridge to transplant. And it's just it's incredible science. So really, really cool. With that, thank you both so much. Again, this has been incredible and thank you for listening to break points. The Society of Infectious Diseases Pharmacist podcast. This episode was hosted by Aaron McCree and featured guests Greg Eschenhauer and GR Thompson. Breakpoints was created by Julianne Justo, Aaron McCreeery and Jason Poke. This episode was produced by Lacey Warden and Megan Klaat. It was edited by J.D. Bushard and peer reviewed by Ryan Munster and Carly Berry. The executive producer of Breakpoints is Lisa Dumcow. Our theme song was recorded by SIDP member Steve Smoke and you can subscribe to Breakpoints on Apple Podcasts, Spotify or wherever you get your podcasts. Thank you for listening and helping SIDP achieve our vision of safe and effective antimicrobials for now and the future. [Music]