114. The Yeasts: Cryptococcus part 2, management

Alyssa and Callum continue to speak to Jeremy Day about Cryptococcus, focusing on the evidence base for management. 

To further encapsulate your learning, be sure to listen to part 1 last week!

Show notes for this episode here: https://idiots.notion.site/113-114-Yeasts-Cryptococcus-14fd0e7ed6a2478cb5734f1e21f49029?source=copy_link

Chapters

• 0:00 Cryptococcus part 2
• 27:20 Edited to here

Transcript

0:00

Hi everyone. Welcome to the Idiots Podcast. That's infectious disease insights of these specialists. I'm Callum, and that's Alyssa. And we're going to tell you everything you need to know about fungal infection. Soon, may the editing come to discontinue the Tazo sun one day when the S piece done, we'll take our leave and go.

Callum: 0:22

Hello, Alyssa and

Jeremy: 0:24

Hi.

Alyssa: 0:25

Hi Callum and Jeremy

Callum: 0:28

We're privileged to be joined by, Jeremy Day, who, if you want to hear more about, you really should go back and listen to the last episode. very much. which was our introduction to Cryptococcus. If you haven't listened to that, what are you doing? Go back and listen to it now.

Jeremy: 0:42

It's great to be here. Thanks for having me.

Callum: 0:46

Alyssa, have you got any puns? We used all our puns at the end of last episode.

Alyssa: 0:50

you actually absolutely rinsed all the buttons.

Callum: 0:56

excited.

Alyssa: 0:59

So today we're going to be focusing on management of cryptococcal disease. And I guess just to flag up some of the sort of key guidelines that this information is coming from which are included in the show notes. So we've got the British HIV Association guidelines of Management of opportunistic infections in HIV, which cover crypto disease, but these are really quite outdated now. So these are 2011 guidelines. So the WHO 2022 guidelines, which cover HIV associated, crypto cases. management and then some more recent guidelines by ECMM and IDSA 2024 guidelines which cover cryptococcal disease in both HIV and non HIV populations.

Callum: 1:54

Yeah, just to touch on the BIVA guidelines. So I know that the overarching guidelines are quite old and I think their approach now has seemed to split that into different, organ systems and conditions. So there was guidance published in 2024 about, pulmonary infection, which very briefly touches on cryptococcus. I don't think there's CNS guidance, but they may well be published. Soon is that, do you have any more information about that,

Jeremy: 2:17

I'm not involved with the BIBA guidelines, but the WHO and the ECMM guidelines I'm an author on. I think the ECMM guidelines are the gold standard, really.

Alyssa: 2:27

Yeah.

Jeremy: 2:27

I say ECMM, it's a collaboration with ECMM and IDSA. And many of us who are also involved with WHO guidelines are involved with these guidelines. So I think they're the kind of state of the art. So I I think it's great to say, guidelines have evolved from, the IDSA, 2020 10 and WHO guidelines, and most recently ECMM and IDSA combined to reduce a guideline, which was published in February of this year. And,

Alyssa: 2:54

Yeah. And I think the main thing with those guidelines is that it's, they've talked about the non HIV population as well, which is an important group.

Callum: 3:04

You think that is useful knowledge just to know which guidelines to go to.'cause I think, often when I talk to trainees who are advising for their exams, they're confused because it's not always clear unless you're an expert in the field, which ones you should be going to. So I guess if we, moving forward, just focusing on those ones you mentioned there,

Alyssa: 3:18

I think one, one thing I wanted to talk about, is the role of screening for cryptococcal disease, before we go into diving into, the management of cryptococcal disease.

Jeremy: 3:29

Yeah.

Alyssa: 3:29

talk about screening for cryptococcal disease and when, patients might be commenced on, preventative therapy.

Jeremy: 3:38

Yeah. I think the challenge of crypto is that at least in terms of HIV, most HIV disease occurs, there's a lot of cryptosis disease. So screening of patients who are immunosuppressed, CD4 counts less than 200, in sub Saharan Africa reveals antigen positivity in patients of in the order of 5 to 10%, and the challenge is that if you start antiretrovirals in patients who are, who have cryptic ophthalmeningitis or early stage disease, you can make them sicker. And so the purpose of screening really it's twofold, it's to identify patients who've got active disease. So if someone has a symptom suggestive of cryptococcal disease or they have a blood antigen test that's positive, then they need a lumbar puncture, And if they've got any CSF abnormalities, then they should be treated as though they've got cryptococcal meningitis. And we're going to come on to that later. If they are truly asymptomatic, no headache, no nothing, they're absolutely well, but they've just got a positive antigen test, then the guidelines suggest that you can treat those patients with high dose azole drugs for a prolonged period. And then when you've treated got them established on antifungal therapy, you could then start their antiretroviral treatment. But this really comes from a study of David Mayer and David Bulwer and colleagues done in Uganda, published, about 2015, where they showed that early antiretroviral treatment started within, the first 10 days of treatment of cryptococcal meningitis, early institution of antiretroviral treatment was associated with worse outcomes, than starting five weeks later. after the point of diagnosis. There'll be some other work done, looking at, the use of azoles. So I think David LaLue's group did a study looking at, treatment with azoles in HIV patients who are asymptomatic and had negative antigen tests. And show, I think, a benefit of ASOLs in those. But ultimately the guidelines recommend screening. Patients with CD4 cancer less than 200 with antigen tests to see if they're positive with sensitive antigen tests, like the IMI test. If they're positive, thorough evaluation for cryptococcal meningitis, including lumbar puncture. If they're truly asymptomatic, and no evidence of meningitis, then you treat with azoles. If they've got any evidence of meningitis, then you treat as if they've got meningitis and this stops people dying.

Alyssa: 6:11

And I think thinking about patients without HIV, there isn't really any evidence for CRAG screening in these patients. So that's currently not recommended for those other immunocompromised individuals.

Jeremy: 6:24

Yeah, so there isn't any sort of parallel with, quantifier on testing in patients starting with biologics or patients are going to be, suppressed fatigue.

Callum: 6:33

Thanks. So I guess it makes sense, doesn't it? People are at risk, we do an antigen test if they're HIV positive, and we treat them with preventative therapy.

Jeremy: 6:44

Yeah. So what happens is that if you start antiretrovirals in the absence of antifungal treatment, you lead to what we call an un unmasking,, immune reconstitution, inflammatory syndrome. So the immune system wakes up and it wakes up prior to us really having much in the way of measurable changes in CD four counts in blood, it starts fighting the crypto. And then that leads to, florid cryptococcal meningitis with the concomitant risks of blindness and death, in the order of 30 to 40%.

Callum: 7:14

God, yeah. Okay. As you mentioned in the last episode,, the similarities of TB continue, because there's not many things now that we talk about. Delaying treatment or so on, HIV because of all the evidence now that early starting is by the right thing to do. You spend a lot of time thinking about when to start HIV therapy and now it's just get on and do it. But there are some exceptions to that rule, aren't there? So maybe if we move on now and so say that the clinical scenario, we've talked last time about diagnostics. So we've got someone, we've diagnosed them with cryptococcal meningitis. What's the approach to treatment? What treatment options do we have? What does the literature say?

Jeremy: 7:54

the great thing is that we do have a body of literature that helps us make good choices now about, about treatment that the challenge as with most fungal diseases is that we don't actually have many very good drugs for treating fungal diseases. But the mainstay of treatment is Amphotericin B in some form and what Joe Jarvis and colleagues have shown recently is that, a single dose of liposomal Amphotericin B at a high dose, 10 milligrams a kilogram, in resource limited settings, is equivalent to a prolonged course of amphotericin therapy. So to take a step back for a moment, the key drugs that we use to treat cryptococcal meningitis are amphotericin B, flucytosine, and Fluconazole. And the first large study that looked at the combination of Amphotericin and Fluconazole was done by Charles Van der Horst and published in the late 90s. It was in HIV patients in America. It was about 400 patients. And what they found was that if you gave Amphotericin B combined with Flucitazine, that was probably a better combination of sterilizing CSF than amphotericin monotherapy. Why do I say probably? Because the p value was 0. 06. Okay, they had a very low death rate in that study. It's actually quite hard to work out the death rate because there's a subsequent randomization stage to fluconazole or itraconazole for the consolidation phase of therapy. So, second point is that we treat cryptoin phases. And we have what we call an induction phase of treatment where we start with a combination of drugs. The challenge with antifungal drugs is that they're generally a bit toxic. So we give an induction phase of treatment where we try and hit the fungus hard and then we simplify once the infection is, we hope, somewhat under control to an azole drug, which can be taken orally and has,, better tolerability and we usually treat for a further eight to ten weeks after the two week induction period and following that we would then go on to a long term lower dose of azole drug that we hope just keeps any residual infection, away. or stops any recrudescence of disease and we keep that induction treatment going until we've had immune reconstitution in our patients. Immune reconstitution of course being dependent upon receiving antiretroviral treatment. So induction, consolidation, long term suppression. Those are the three phases. So it looked like this Amphotericin and Flucitazine treatment was a good treatment, better rates of sterilization, but we didn't know if it would stop you dying. And that was the first trial we did in Vietnam, was a study powered to mortality, to look at that combination of Amphotericin with Flucitazine versus Amphotericin alone. And we also had a third arm in our study, which was Amphotericin combined with, Fluconazole 800mg a day, so that was a high dose of Fluconazole. And what we found in that study was that the patients who received Amphotericin and Flucytosine had better survival than the patients who received the other two combinations. The standard of care at that time in Vietnam was Amphotericin for 4 weeks, so that was our best. comparator arm, and then we compared our amphotericin with flu cytosine, which was given for two weeks, which was the IDSA guideline at the time, and then our novel combination, which was amphotericin with fluconazole. Not only did the patients who received amphotericin and flu cytosine survive better, they also cleared the yeast from their CSF more rapidly. Biological plausibility that this wasn't some chance finding at getting rid of the yeast more rapidly, which is the thing that's causing the disease and the surviving. So it was great to show that combination did result in improved survival and then subsequently studies done by Tom Harrison's group and Joe Jarvis and their colleagues, David Mayer and many, many, hardworking HIV doctors in South Africa and, and Uganda, David Mayer and colleagues, doing other trials, looking at different combinations of amphotericin B and flucytosine, different durations of induction therapy, to find out what is the best, and most tolerable. And really, the most recent of those studies has shown that A single dose of lipothermal amphotericin, given it 10 milligrams a kilogram, so a big dose, and then followed by a combination of flucitazine and fluconazole for the induction period, and then fluconazole after that for the consolidation period is, non inferior to two weeks of amphotericin and flucitazine treatment. And not only is it non inferior in terms of survival, it You know, it was actually favor the liposomal amphotericin in terms of survival, but it wasn't superior, but there were fewer adverse events. So the challenge with amphotericin is, certainly what we used to worry about when I worked in the UK was renal impairment. And you see these rises in creatinine that are largely reversible and seem to be a bit dependent upon the total dose of amphotericin given, but they're largely reversible. And hypokalemia, actually. We've been looking at lots of patients and working in low income settings. The challenge is marrow suppression. And they need profound anaemia, thrombocytopenia, neutropenia. And that's bad for patients. And the liposomal amphotericin as used in this single dose. Has lower, significantly lower rates of those adverse events. So, really great news. Of course, the other, the other benefit there is you're giving a single dose of an injectable. Everything else can be taken oral, so less risk from having lines and such. You don't need a line in for two weeks. And also, you don't actually have to be in hospital for two weeks necessarily. So that's the current guideline. It's very eloquently described in the ECMM IDSA guidelines as we've mentioned. So please use that as your reference. In terms of non HIV disease, we really lack data from RCTs. And there is a move to start including non HIV patients in clinical trials. And, we certainly did that with our last trial in Vietnam, which was looking at, using tamoxifen to treat cryptococcal meningitis and, tamoxifen has an anti yeast effect in vitro and it synergistic with amphotericin in vitro, it doesn't work. Made absolutely no difference in our patients, small study. But, generally we're extrapolating from, trials in HIV patients or from case series and so on to try and define the best treatment for non HIV infected patients. Which is suboptimal, but, it's a rare disease outside of HIV patients. And so that's where we are. There is a, it is a collaborative research environment and I think things will get better as time goes on.

Alyssa: 14:45

Can I just ask, so obviously there, there are two sort of main preparations of amphotericin B, so you've got your amphotericin B deoxycholate, which my understanding is that's the one that's predominantly associated with toxicity, particularly renal impairment. Whereas the liposome amphotericin B, is much more costly and perhaps, less readily available in, low, middle income, settings, is associated with lower risk of nephrotoxicity. So in, low income settings, the single dose liposomal, high dose liposomal amphotericin B followed by the combination of flucytosine and fluconazole is going to be the go to. regimen, but in, a, higher income settings, such UK, which would we still be going for the 14 days of, like, teratinib and flucitacin before switching to, the consolidation phase?

Jeremy: 15:45

Yeah. Yeah. So that's what's in, that's, what's in the guidelines. So what's behind that just to go back, take a step back just for a second in terms of renal impairment. Liposomal amphotericin B, if you look at studies in crypto is not associated with lower rates of severe grade three or four renal impairment than, patient presenting, amphotericin deoxycholate, it is with lower rates of grade one and two, renal impairment, but I think the main, the difference that's more striking is the effect on marrow suppression.

Alyssa: 16:17

Okay. So liposomal formulation is less, um,

Jeremy: 16:22

It's less toxic. Yeah, but the severe renal impairment isn't, there isn't a difference really, at least in the crypto studies. Yeah, we then talked about in better resource settings, the guidelines do recommend two weeks of treatment with the standard doses of liposomal amphotericin, three to five. I think, I think, the feeling behind this is that. That's what they do in wealthy settings and the death rates overall from crypto are lower, in the order of around about 10 percent in HIV patients and patients with other reasons for getting crypto, which compares with the death rates in low income settings of around 20 percent to 30 percent. So I think the feeling is, we're doing something all right at the moment. My experience has been largely with crypto and low income settings. So every patients. So I think, the challenges, as we've said before, that there are not so many RCT based high quality data to help us guide the information, high income settings and in, and then HIV and infected patients and, hard to ignore, better death rates. So I think they went, they decided to go for that. status quo to some extent.

Callum: 17:47

Just looking at the guidelines that I've never read these before. But, I really like the way that the data that there's obviously a lot of nuance to these things. So the figures in particular

Jeremy: 17:57

quite useful, aren't they?

Callum: 17:59

Really useful, particularly, as you're talking about there, the availability of these drugs. Jamie and I talked before about where all the new antibiotics going episodes and we were talking about availability of things that are on the hue essential medicines list as well as it says, what, where liposomal and amputation is available isn't universal. And so this figure free in the, in those guidelines actually talks about the. Dantefungal availability, and I think that would be a really useful place to go and, reckon. There's no point in having a guideline that people can't follow because they don't have access to the drugs. So, the treatment differs by where in the world you are and availability of the drugs, but is in general going to be an induction phase involving like amphotericin, and then, if you a little middle income country, you may be using, a single dose of amphotericin, liposomal, and then the two weeks of the conazole for cytosine. And then we're going to consolidation and what differentiates consolidation and then the maintenance or long term suppression phases?

Jeremy: 19:07

of,, fluconazole is reduced in the consolidation phase to round about 200 milligrams a day. Whereas in the consolidation phase, It's, treatment dose. Mean, just to go back to that single dose lipo,, I think that's a trial that should be done in high income settings because it may be that it is much better tolerated. There are fewer side effects even in, in high income settings. So it's worth doing in that, that lower death rate is for likely for multiple. Reasons in terms of better nutrition of patients and who knows what? Yeah, earlier presentation to care doesn't mean that there isn't necessarily an advantage from giving a single dose of liposomal amphotericin. Yeah.

Callum: 19:50

that makes complete sense. So the induction phase is some, is usually about two weeks, so there might be longer if it's, so it's GATTI, it's longer if it's cryptococcoma, it's longer if it's disseminated non CNS cryptococcus, it's longer.

Jeremy: 20:08

I think you can see from this chart, from the guidelines that, that some of these recommendations are based on careful thinking about things. And some of them are based upon having good quality evidence.

Callum: 20:20

Yeah, like the color coding for the strength of recommendation is quite, there's a tendency towards the longer recommendations being less, strongly recommended. And then once you move out to that, your consolidation is eight weeks and then maintenance is about 12 months. Is that, is there any parameter, is it always 12 months or do you, do we monitor, we talked about CRAG, is that something that's useful to monitor and what else should monitoring on therapy

Jeremy: 20:46

so I think as with much of microbiology, we're not quite sure how long we should be giving our antimicrobials for. And there's a variability in the rates of immuno constitution. And if you have a patient who rapidly reconstitutes their immune system and has a CD4 count of, more than 200, sustained control, undetectable viral load. Seven months after the starting treatment for their crypto, I'm sure you could stop your flu, your fluconazole maintenance therapy. Some patients take longer to, for their CD4 counts to recover. Ideally, we're waiting for CD4 counts to be sustained above a hundred before we would want to stop, or maybe higher before we'd want to stop our axons. Maintenance.

Callum: 21:33

Have we mentioned already the monitoring of opening pressure,

Jeremy: 21:37

Oh, yeah, no, we didn't talk about that in treatment, did we, but yeah, really important. So, as we said before, about two thirds of patients will have raised, CSF opening pressure at the point of diagnosis. And then as you treat, and you kill the organism and the immune system of your body wakes up a bit, then you can actually get a more inflammation in the CSF. As time goes on in your HIV patients and that can lead to further rises in, CSF pressure. And, managing that, CSF pressure is thought to be really important in getting the best outcomes that meningitis. So in our practice in Vietnam, we would do, at least two lumbar punctures a week for the first two weeks of treatment. And then we would do them depending on the symptoms of the patient. And what their previous opening pressures have been. So if you did a CSF, you did a opening pressure on a patient, a lumbar puncture on a patient, the opening pressure is 30, we would drain CSF to about half that opening value, or within the normal range, whichever came first. A normal range of pressure is, 5 to 20 centimetres of CSF. And that could mean that you take 20, 20, 25, 30 mils of CSF from a patient. The normal rate of CSF production, in an adult human is about 30 to 60 mils an hour. And the volume of CSF is about 180 mils. So the CSF is generally, replenished three or four times a day in an adult, human. And I think I'm just saying this because I think as doctors we're a bit, we're a bit anxious about taking CSF and we take half a mil and think we've done a good job. And in in so many, our techniques and microbiology their sensitivity is so dependent on having a good sample, isn't it? So for TBM, we know that you get a much better, you're much more likely to make the diagnosis if you take a larger volume of CSF for TB. So we want between five to 10 mils of CSF just for the micro tests. And we spin it, similarly, and it doesn't hurt the patient, okay, it gets replaced. And, and in crypto, we're taking, we were taking these large volumes and it's making patients better., The pathophysiology is different, obviously, if you think your patient is at risk of coning, that's a worry. Patients cone. When they have critical meningitis, coning, of course, we mean when the brain gets pushed through the frame and magnum and it's catastrophic. It's not clear how lumbar puncture alters that risk. If the brain looks normal on a CT scan, then it's very hard to predict which of those patients will cone or not. It's hard to tell whether that's anything to do with having a lumbar puncture or not. It happens in the absence of lumbar punctures. I think the other thing just to say about raised intracranial pressure is that patients will tell you when they need a lung puncture. So our patients, we did frequent lumbar punctures because we were particularly interested in looking at rates of clearance of use from CSF, but also to measure the pressure and see how that altered as we treated patients. Because they feel relief from their headaches after they've had, their pressures released, they would actually ask us for lumbar punctures. And so we would do lumbar just throughout, throughout this duration to stay in hospital. Sometimes they would come back to hospital and have another lumbar puncture if needed. One of the things we worry about with raised intracranial pressure is that it's going to result. is that it's associated with visual loss, loss of sight. And that's, one particular reason for doing that. Ultimately, I think there's lots of reasons for visual loss in crypto, but raising the impression maybe one is optic nervous ischemia, direct invasion of the optic nerve by yeast, lots of different reasons. End up thalmitis due to the yeast. But just to say, because we're a bit nervous about doing lumbar punctures as doctors often, because it feels a bit brutal, actually patients would ask us for lumbar punctures because it made them feel better.

Callum: 25:39

I think there's a lot to talk about with lumbar puncture for infection specialists and, I spoke to Fiona McGill about it briefly, but I think after that decided that, need to go away and do a separate episode, particularly about lumbar puncture and talking about some of these issues about CSF and so on.

Jeremy: 25:53

Good idea.

Callum: 25:56

So what have we not talked about that we need to talk about? We've not really talked about steroids.

Alyssa: 26:01

so that's an interesting one, isn't it? Because we start steroids in, bacterial meningitis.

Jeremy: 26:07

Yeah, happy to talk about steroids.

Callum: 26:08

There was an increased risk of adverse events and cryptococcal meningitis and in clinical

Jeremy: 26:13

Yeah. So we did that trial, in Vietnam and in Southeast Asia and Africa. So work from Andrew Seaton and Dave Lalue when they were in Papua New Guinea in the 90s in Gati. They found doing a retrospective study that patients who happen to receive steroids. That they were probably being given because of reactions to amphotericin had lower rates of blindness in patients who didn't receive steroids. And we know from other illnesses that are not dissimilar pathophysiologically to crypto TB meningitis, for example, that steroids reduce the risk of death. So the trial that was done in Vietnam by Guy Thwaites and colleagues of steroids in TB meningitis showed that, 20 percent of those patients had HIV showed a reduced risk of death if you gave. steroids. So with that info, with that, and we know, in, acute bacterial meningitis in Vietnam and in Europe that you reduce the risk of death or complications if you give steroids. And then we had lab data suggesting that steroids didn't interfere with antifungal effect in vitro and, and their prolonged survival in the absence of antifungals in the animal model of crypto. So with all this evidence, all these data, we did an RCT of steroids given at the point of diagnosis in cryptococcal meningitis. And we found that We stopped the study afterward and enrolled 450 patients. This was in Uganda, Malawi, Vietnam, Laos, Thailand, India, Indonesia. And, the study was stopped early by the safety committee because there were increased risk of adverse events occurring in patients receiving steroids. And, the survival curves actually cross. So initially the survival curve for patients receiving steroids, this was placebo controlled, this study, was better than for patients receiving, standard of care, placebo, although not statistically significant. And then after about six or seven weeks, those lines crossed. and the survival curve for patients receiving steroids was below the survival curve for patients on placebo. And, if we'd carried on and enrolled a full 800 patients, then, who knows, we might've shown a statistically significant difference. I'm glad we stopped the study. We didn't want to show that steroids were harmful. Just wanted to see if they did any good. I think it's just the reason I mentioned that story about the survival lines to crossing is because I think it's underlines the importance of doing rigorous studies to understand where the treatments work. Because you could imagine if you looked at that anecdotally, your patient comes into the hospital, you give them some steroids, a headache's gone away. If they feel a bit better, we think the steroids are doing these people good. You send them home after four weeks and then they know you don't see them again, you never know what happened to them because that's what happens. And like I'm setting, she might be thinking, Oh yeah, these steroids seem like a good thing. They seem to make patients better in the first instance. Actually, in the long run, they weren't making people better. They were having more adverse events and potentially we didn't show an effect on survival, but it might be have we carried on that, steroids would have been overall really quite bad for you. So, yeah, there is no role for steroids at the point of diagnosis in cryptococcal meningitis. In the guidelines, there is talk about potentially using them in the context of immune reconstitution and so on, or where there's cryptococcal meningitis with mass effect and so on. So it's all a little bit, crafty medicine, but, that, that may well be right, but definitely not a good treatment like they use in acute bacterial meningitis or TB meningitis. Thanks.

Callum: 29:55

I've linked to that paper. It's always great when you say there's a trial, but this and then you're like, the other person says, I'm the offer. So, yeah, just honored that you're here. Yeah. So I've linked to that in the show notes and put in the graph that you're mentioning, which is figure two into the notes. So you should be able to find that there. And then I guess some other things, maybe just worth mentioning, in the treatment. So we've talked about the antifungals, LPs, we've talked about steroids. I guess you mentioned earlier on that toxicity is a major concern. So for amphotericin, We're looking for nephrotoxicity, the low potassium electrolyte derangement, and myelosuppression, and then flu cytosine. We're really monitoring again for myelosuppression, raised LFTs, nephrotoxicity, and then azole drugs. I guess we're wondering about, hepatotoxicity, And

Jeremy: 30:48

mean, Azoles, there's a theoretical risk of QT prolongation, which vanishingly rarely causes any, meaningful problem. The big challenge with Azoles is teratogenicity, I think, and, if your patient's pregnant, you can't give an Azole and then you're in a hard place really. Yeah.

Alyssa: 31:04

Is it first trimester that it's absolutely contraindicated? Yeah.

Jeremy: 31:09

Yeah. I think they're, To be avoided. Obviously, you're balancing some very difficult risks, but, yeah, you would probably stick to the AMP,

Alyssa: 31:16

Yeah. I think the guidelines, have the treatment of pregnant women with cryptococcal disease.

Callum: 31:25

Yeah, that's Treating anybody that's pregnant always, becomes very complicated, and I find that one of the most the scary thing, There's so many more risks and complexities around it, but this seems a fungal disease in particular. Yeah, Anything else that we should, we need to talk about meningoencephalitis? Jeremy or I think just looking at our notes to see what else that we've put in there is obviously a really complicated subject and I think again, we're just, point people towards the guidelines. This is a sort of brief introduction. But if you're got an actual case, then you'll be, speaking to experts and looking at guidelines,

Jeremy: 31:58

yeah, yeah, yeah. I think the key is to really keep an eye on what's going on in the CSF and what's going on with the pressures, make sure you're treating according to the guidelines and we all love to talk about things that we've worked on and feel comfortable talking about. And so, don't be afraid to talk to someone you think might have more expertise if you want to. I certainly do about lots of things.

Alyssa: 32:25

And I guess one of one of the major issues with cryptococcal meningoencephalitis. It's sometimes I feel like in, in studies we focus on those mortality benefits, but it's the long term morbidity that the patients can get from, they can get long lasting visual defects or headaches and things from having had cryptococcal meningitis. And would you say that the aggressive management of their raised intracranial pressure is? is really important in reducing that longer term morbidity.

Jeremy: 33:02

That's certainly the consensus is that managing rate of cranial pressure is important in terms of both survival and those risks of visual loss, particularly.

Callum: 33:15

then in terms of sort of other syndromes, briefly, because, I guess the meningoencephalitis is the most common. The most severe, I guess would be fair to say. So, pulmonary, so just reading from the guidelines, and please correct me if I'm wrong, it's the same, it depends, whether it's gatae or neophormans, if it's mild Then you might give fluconazole for six to 12 months if it's severe. So multiple large lesions, cavitation, multi lobar hypoxemia. Then you give lipo liposomal amin b titis for two weeks longer if it's a crypto coma fall by consolidation of maintenance phase. So your treatment's more in line with the meningoencephalitis. Treatment.

Jeremy: 34:03

I think we're lacking good data from RCTs and how to manage these so yeah,

Callum: 34:10

about what we know from the other disease and then cutaneous. We're talking about three to six months of the colonosal or until healed, which I think is a good caveat and then disseminated. You treat it as per, meningoencephalitis or severe pulmonary cryptococcus again. Data lacking.

Jeremy: 34:27

yeah I mean as I mentioned before Most cryptococcal patients is A manifestation of disseminated disease, or they're at least, they're at least fungemic, and often they have some skin lesions as well. It's probably in the brain, but they've got the bug in their blood. But yeah, I think it may be that it recrudesces in the brain and that it's lurked in the brain. It lurks in lots of different places in the body. One, one place it's postulated to lurking is the prostate actually. I think the consensus is it recrudesces within the brain and maybe it's spreading into the blood, but I don't know for sure.

Alyssa: 35:04

So I think, as we've said, A, we have, we've previously discussed this, that we have limited number of classes of antifungal drugs compared to, antibacterial agents, for example. And then with Cryptococcus, we are really limited to these, three main drugs, the azoles, flucitazine, and the polyene. So cryptococcus, lacks beta D glucan in the fungal cell wall, so it has an intrinsic resistance to the kinocandins. That's just not a useful class of drugs at all. And then I guess one of the major worries, about treating cryptococcus is that there is, resistance recognized within these three major classes of drug that you use to treat it.

Jeremy: 35:50

Yeah,

Alyssa: 35:51

My understanding is that flucytosine already has a very low barrier of resistance to resistance, so that's why it's only used in combination with amphotericin D or fluconazole to help prevent resistance. But can you talk to us a bit about the issue of, azole resistance of Cryptococcus nearformans? Because we use those a lot on their own, like either, prophylaxis or preventative, therapy, and then in the consolidation and maintenance phase. So that does seem pretty concerning if there's, rising resistance to azoles.

Jeremy: 36:27

That's a funny thing, isn't it? You've listed the mechanisms there, the, but to go back to my earlier comment, we don't really understand the clinical implication of this. This resistance, we know our treatments aren't very good and we have high death rates, you know, 20 to 10 to 20 to 30 percent, depending on where you are in the world, but I'm not sure that is determined by resistance, at least as measured within the laboratory. The organism isn't spread from person to person, so it's unlikely that how we're treating patients. It's going to have an effect on how we manage to treat patients in the other patients in the future.

Alyssa: 37:07

Okay.

Jeremy: 37:08

Having said that, there is massive use of azole and polyene type drugs within the environment as pesticides. So, on the rice in Vietnam and elsewhere around the world. And you can, we see that with aspergillus.

Alyssa: 37:24

Yeah. Yeah.

Jeremy: 37:28

compounds that are medic, not medical, not human medical compounds, but are medically important because of shared methods of resistance. So I think, the lessons probably are the lessons that we learned. Again, in, in Europe. infectious diseases that generally combinations are important. And we know that with flu cytosine, can't give it on its own or it stops working. But when we give it with amphotericin B, it has a sort of synergistic effect and there's much, so combination treatment, certainly for the induction phase is important. And then giving drugs in sufficient dose. I think that's the other thing. So There's a study published recently by Bob Larson and colleagues from UCLA which was a global study, looking at bigger doses of azoles and finding them fairly tolerated and wasn't a massive study, but probably some sort of plateauing of effect after about 1600 milligrams per person. But maybe we need to be thinking about weight based dosing for azole drugs, because I think we've published them with, William Hope from Liverpool data showing that there's actually very wide variability in the pharmacokinetics of azole drugs with between patients and certainly many are not hitting what we would think the M. I. C. to be from our lab testing, though, as I've said before, not quite sure what that means. So,, I think, yeah, We need more drugs, don't we? We need better, we need less toxic drugs, we need more potent drugs, and we need to keep having people working in the field and how to use them best together.

Alyssa: 38:55

Yeah. But potentially the use of, azole and polyene related agents in,, agriculture could expose these environmental pathogens to, these drugs and that could have potential implications for developing resistance. Yeah. I

Jeremy: 39:14

yeah, in theory, yeah. But yeah, I'm not sure we're seeing that yet with crypto, although I know it's worried about this. Yeah.

Callum: 39:24

So I guess drawing things to, to a close there. And the second part of our, two-parter on, on Crypto Occus. We've talked through the management focusing on the E-C-M-M-I-D-S-A guidelines, which we've linked to in the show notes and hardly recommend you go, look at, we flew through the site. It seems flew through Flucytosine. So talking about the management of Meningeal encephalitis, predominantly and some key points I've taken away there, is about the in induction consolidation and. and maintenance phases, the drug choices and how that differs. And the duration of those differs depends on the clinical syndrome you're treating, of those drugs and how that impacts your treatment and the importance of aggressive management of intracranial pressure. Regular LPs and patients may even, be the ones, suggesting when you need to do the LP, which is helpful, that steroids aren't, recommended, monitoring for drugs or toxicity. The need for delayed initiation of antiretroviral therapy in patients with HIV is key, and then we briefly went through some other, clinical syndromes and how to treat them, but really have focused on the meningeal metropholitis. So, I guess two things what to finish with one huge thanks to Alyssa for prepping the notes as always, because I would recommend you go look at them on notion, the links in the podcast description there. They're fantastic. Lots and lots of links. And secondly, thanks to Jeremy for giving up, your time to, to come and talk to us. And also just, I guess the huge amount of work that you and colleagues have done and researching this important disease, because often on the podcast, we're talking about stuff. We're saying there's no clinical data. We don't have trials, we just don't know. And it's only by, the hardworking clinicians and the patients that are consenting to be in it, that we actually have. stuff to say that we can recommend.

Jeremy: 41:16

Many thanks. It's been a real pleasure to meet you and to participate in this. Thanks.

41:22

This Mycology series of episodes is sponsored by the British Society for Medical Mycology. The 59th BSMM annual conference is due to take place in Norwich from the seventh to the 9th of September, and aims to bring together clinicians and researchers in the field of medical mycology. Registration is only two 40 for trainees and includes accommodation and meals. Abstract submission is now open and we welcome abstracts on research, clinical cases and auditing QI projects in medical. Now that the episode's done, we hope you learn, had lots of fun. So go forth and treat people with some of what you now know.