132. Echinocandins Part 1: the old stuff

Alyssa and Jame are joined by Tihana Bicanic, to discuss the second great antifungal drug class, Echinocandins. 

Part 1 of 2! (this episode we discuss the old stuff, next episode we discuss Rezafungin in more detail). 

Show note for this episode found here: https://idiots.notion.site/132-133-Echinocandins-2d76a1ea09d8811f800ad3a446c6726e

(Note if you have any echo on the audio for this episode, try re-downloading the episode)

Transcript

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Speaker 2 0:00

Soon May the editing, editing come to discontinue Caspo fun gun. One day when the BDG is done, we'll take our leave and go.

Jame 0:10

callum, you. Oh, you look different. Have you, um, had a haircut or something?

Alyssa 0:14

I've gray my hair. Jane.

Jame 0:15

Upgrade my head. Oh, Alyssa, what are you doing? I thought we weren't allowed to be on the same show. I thought Callum was constantly keeping us separate like two cats that don't get on.

Alyssa 0:27

Hi. How are you?

Jame 0:27

Hi James. How are you? I am fine. I had a little bit of trepidation of course, about setting up this podcast recording with the great Tihanna benik. And I thought I was gonna maybe email her and tell her candidly that I was a little bit nervous, but then I realized that I'm so extroverted, I said to myself, Eck, I know candid. And that reminds me Alyssa, what are we discussing today?

Alyssa 0:51

Oh, today we are discussing the.

Jame 0:53

discussing Thedid. What a coincidence. And our guest today, is this your first returning guest?

Tihana 1:12

This is

Jame 1:12

I guess she was on multiple candidate episodes, but I don't think that counts actually, because that's still one super episode just divided into three. 'cause there was so much to talk about. So I don't think that counts. So actually this is our first returning guest on the antifungal CDs, of course. Replacing Callum. Let's not say that. Let's let's just welcome you to the show.

Tihana 1:31

Thank you very much

Jame 1:32

Alyssa, why don't you tell us about a can of canons. What are they, where do they come from, and what do they

Alyssa 1:37

Yes, sure. So kinins are a class of antifungal drugs that inhibit fungal cell wall synthesis. So all of them have been derived from different fungal fermentation products, which I find quite interesting.

Jame 1:52

Interesting. Give me an example,

Alyssa 1:54

So an example is a ni of fungi is derived from aspergillus midlands.

Jame 2:01

And is that true of all the others? I

Alyssa 2:03

I think the others are, then they're like semisynthetic. Derivatives, but yeah, all from different fungal fermentation products.

Jame 2:11

Okay.

Alyssa 2:11

and they're really useful passive antifungals because they've got fairly broad activity. They've got really good side effect profile. They've got good biofilm activity. But I guess one of the major downsides is that they can only be given iv, which, makes their use a little bit limited.

Jame 2:30

yeah. I think quite a lot of people who've started ID training at least will be familiar with the drugs in this class because there's not that many of them. But there's not that many in any antifungal drug class. But for the record, they are Casper fun, micafungin and ni fun, and Regan the new kid on the block, and they have a cousin called i Brex of fungi, which rather annoyingly is not in the same drug class, but does almost exactly the same thing in as a pill. But we'll talk about that in a future episode. Alyssa, how do they work?

Alyssa 3:02

Majority of fungi have a major cell wall component called B 2D Glucan and they inhibit the synthesis of B 2D glucan by inhibiting the enzyme one three B 2D Glucan synthase.

Jame 3:19

And this is the same BDG that gets released into the plasma and gets detected by the BDG assays when you're looking for like invasive candid asis and all that sort of

Alyssa 3:27

Yeah.

Jame 3:28

Yeah, and so these are fungal as opposed to, certainly against candida as opposed to the easel antifungals, which are fungo static. I don't know. I'm actually gonna leap off the script at the moment and now go over to our resident expert Tiana. I, when I talk about static and cydal in bacteria. We've had a whole episode on this. We say that it is a microbiological phenomenon only and it's completely nonsense. And when you're selecting your drugs, the least important thing is whether or not the drug is static cidal. 'Cause there are multiple trials showing that static ones are just as good or in the case of sli better than their cidal equivalents. Is that true of fungus stasis and fungus ality?

Tihana 4:11

I would say Although it's, it hasn't been conclusively. Proven in clinical trials in terms of comparisons of mortality, say in Candidemia, for example, at in Candidemia you've got fungus static, which is the azoles, usually fluconazole, and then akin canons of fungi fungal. And actually that is the reason that they are chosen as the drug of choice for treating invasive candidiasis. It's mainly really related to the time taken to clear the blood culture so they clear the, in some of the clinical trials. I think the anular, funkin and fluconazole head-to-head study, I think the median time to culture conversion for nula was two days against five days for fluconazole. So I think it is important To clear the bloodstream compartment quickly. Yes. In the head-to-head trials. Essentially there was superiority actually for anular fungi over fluconazole, particularly in albicans, interestingly, and also in terms of the side effect profile. So overall ality is important. It's also important in cryptococcal meningitis, a separate infection. But certainly for invasive candidiasis, rapid killing is important. Partly, potentially because patients are sometimes immunocompromised and therefore drugged, which kills quickly is

Jame 5:47

Do you think that is the main component, which is the patient population that you're using are much more likely to die because they're immunocompromised? Or do you think it's just that, that time to clearance of three days difference between a nasal and an neck and a hand. Like when I'm thinking about bacterial time to clearance, because quite a lot of the time it's a secondary outcome. It'll be like 12 hours versus eight. And then there'll be no mortality difference. And I look at that and I think I'm going to ignore that. 'cause I think

Tihana 6:13

exactly. It's whether

Jame 6:15

phenomenon. But three days is different. Yeah.

Tihana 6:17

Yeah, that is a significant difference. Where it matters, as one of the things when we investigate patients in candidemia is for breakthrough or even relapsed infection. and Where you have a slower time to culture conversion, there's much more chance of metastatic complications that's already been shown, for example. eye involvement or endocarditis. So you do want to clear the bloodstream compartment quickly. Certainly for candidemia, and as you've said the akina canons, again, the reason they are salvage or second line for aspergillosis. Are because, so it's flipped over in Aspergillosis. So for Candida, akin Canin, societal and aals, a static. Whereas for invasive aspergillosis, voriconazole is Sal and is first line Akin Canin, which are fungus. Static are second or third line, usually salvage therapy or used in combination. with azoles

Jame 7:20

Ah, Yes.

Tihana 7:20

first line therapy.

Jame 7:22

Okay. That's interesting. Thank you. Thank you. And just to finish off this part here in mechanism of action, we do have some activity against PCP as well. And in fact I've seen case reports who've been used as an adjunct in people in whom primary therapy has failed, or, you can imagine a patient the loyal listener can imagine a patient in their head, somebody who's got poor renal function. You can't use cold trim, they're intolerant of other therapies, et cetera, et cetera. Casper Fungin has been used as a salvage therapy because it is active against pCP has BDG in its cell wall. That's why you, it's involved in some diagnostic assays looking at BDG levels alongside with P-C-P-P-C-R of bowel, but also the BDG is found in the cystic form. But you've put here, Alyssa, not the trophic form. You're gonna have to remind me about the PCP lifecycle here a little bit.

Alyssa 8:12

So the cystic form my understanding is that's the one that responsible for transmission between individuals. But then in the hosts, it exists in both the cystic form and the trophic form. The raffic form doesn't have BG in the cell wall. So the kind ofs might play a role as an adjunct but wouldn't be able to.

Jame 8:39

Yeah. That's such a weird fungus. No wonder we thought it was a protest for about, 50 years or something like that. Alyssa, let's chat about what, these drugs are indicated for in the BNF and talk about how we don't pay attention to this whatsoever in, in clinical practice, but go ahead.

Alyssa 8:53

So when you look through, yeah, these four different agents in the bnf, the main indications are, so all four of them are indicated as first line therapy in Candidemia, in invasive candid. And that's also reiterated in the recent ECMM 2025 guidelines for diagnosis and management of Candidiasis. Other uses as Tehani is alluded to say catheter fungi is indicated for invasive aspergillosis, but I don't think any of us would use that as a first line treatment. It's more used as salvage therapy. Or as an adjunct particularly in AAL resistant as aspergillus infections. Casper Fung is listed as indicated as empiric treatment of systemic fungal infection in patients with neutropenia. And micafungin is listed as an agent that can be used for phylaxis of candidiasis in patients undergoing bone marrow transplant, who expected to be neutropenic for over 10 days.

Jame 9:57

Tiana, should I pay any attention to what these individual drugs are indicated for, or should I do what I'm doing already and basically use them interchangeably because my trust only has access to one at the time? Usually the cheapest one they can get their hands on.

Tihana 10:14

You are absolutely right. That's what we've done. In fact over the last

Jame 10:18

Oh, thank God for that

Tihana 10:19

cycled through them and we're on anular fungi at the moment. The only time you should pay attention is in patients with liver disease because ISSA will be coming to anular. Fungi is the only one that's not hepatic, metabolized, and therefore, in patients with liver cirrhosis, liver failure where aals, as we know are contraindicated, that's the kinin I would go for. The hematologists tend to prefer, certainly in my hospital, Casper Fungi, that's the one they know. The pediatricians tend to prefer micafungin, but often that's just to do with what populations the licensing trials. and which drug. But Personally, I use them interchangeably.

Alyssa 11:07

Yeah, just mentioned in the show notes some key guidelines that feature a, I probably haven't included all of them but I think the top one if listeners haven't read already to read, is the ECMM 2025 Global Guidelines for Diagnosis and Management of candidiasis.

Jame 11:24

Alyssa, is this the one that was presented at fis?

Alyssa 11:26

was, yeah, it was presented by Rena Richardson.

Jame 11:29

So they're now recommending can canons, including ung you've said here as first line for candidemia and all forms of invasive candidiasis except CNS Inocular. And I presume that is a penetrance issue.

Alyssa 11:41

Yeah. That's with the penetrance. Yeah,

Jame 11:43

So if you want it in the eye, can an ophthalmologist inject it directly into the eye are we still stuck with voriconazole? As far as that's concerned?

Alyssa 11:53

yeah. So then other guidelines of notes. So the esid ECMM 2017 are guidelines for diagnosis and management of aspergillus diseases. So the use of acquired canines is generally second or third line for treatment of aspergillosis. That's with voriconazole or posar being the first line agent, or in combination with voriconazole in the context of azo resistance. And then finally thinking about prophylaxis for the EYL 2025 primary antifungal prophylaxis and hematological malignancies guidelines. MICAFUNGIN is recommended for prevention of invasive fungal disease in A-M-L-M-D-S and allogeneic hemato stem cell transplant recipients.

Jame 12:41

My fun only I take it. We will look at that and replace it with any in can and again, and of our choice, unless E CLL have some secret reason to prefer myung in their patient population.

Tihana 12:52

Is there any reason to prefer it? No. We use Casper fun in our hematologic oncology, but I don't think there's any reason to prefer it. Are you aware of any reasons, Alyssa,

Alyssa 13:02

No, I'm not.

Tihana 13:03

Across?

Alyssa 13:05

and I think this was, reflects what's said in the BBN.

Tihana 13:08

It's to do with licensing. My understanding is from the manufacturers, they can't recommend if you've not done a clinical trial for a certain indication in a certain population, you don't get a license in that.

Jame 13:22

Yeah. Although the more and more I'm working as a as a consultant, the more and more I find that when you are recommending things in empirical guidance, people will sometimes say, oh, this doesn't have a license indication for it. Cotrimoxazole in pyelonephritis UTI, would be an example, but. To that I say you can say it's not got a license until you're blue in the face. It's got the most evidence behind it, for for that indication. And what you are arguing doesn't make any pharmaco logical sense. All the kinna canons there essentially interchangeable with a couple of exceptions. So that's how I'm going to behave with them. I guess you're right, Alyssa, you the micro fung indication of prophylaxis of candida in patients undergoing B mg, et cetera, et cetera. Maybe that's the underlying reason for eil. 'cause there must be a trial underpinning that, but I don't think that means that you must be weighed to MICA for the rest of your life. I'm sure the drug companies would love that because that would lock you in to it. But like when you buy a machine that needs special kind of batteries that only they can provide. Let's talk a little bit about dosing. So the, you've got the doses in a table. Then we've got in fun, the one that started all. So usually there's a stat dose and then a maintenance dose. The loading dose is 200 milligram stat and then a hundred milligrams daily. Casper Fung is 70 milligram stat and then 50 milligrams daily, unless you are over 81 kilograms, in which case you use 70 milligrams as a maintenance dose. Why it's not over 80? I will never know. Micafungin, there is no loading dose, which is a bit annoying. Maybe that's why pediatricians prefer it. I dunno. But then it's a hundred milligrams once daily if your weight is over 40 kilos and then two mgs per kg if your weight's under. So that would max out it at 80 kilograms for a 40 kilogram patient. And then a raise of fungin, which we will talk about shortly, is a 400 milligram loading dose. But then a week later you start 200 milligrams weekly. Tiana, is there any asterisk that you want to put against any of that

Tihana 15:22

No. I think when we come to talking about the head-to-head with resin, I think this idea of a larger loading dose in resin could have enacted the kind of differences, you talk about differences in time to culture conversion. In the trials they, with sung it was 27 versus 24 hours. So really, I think the loading dose, clearly if you're comparing a bigger loading dose of something, then the early pharmacokinetics. May differ, but it's again, what sort of difference in time to clearance is actually significant, clinically significant, and if it's several hours, does that really matter?

Jame 16:08

And

Tihana 16:08

into the chat just to say, I mean, I don't know, as an aside, two references. The re trial that I talked about, the fungi versus Fluconazole, and then the one where they did a sub-analysis looking at time to clearance, just for your reference. Can you see that?

Jame 16:26

you see that? Yes. And I've got them up and I'll include them as links in the

Tihana 16:29

Yeah. Yeah. Because it just shows you that although they were non-inferior, because that's how the trial was designed. When you look at it in more detail, there is faster clearance, particularly for albicans. And if You like the p value, for the difference in mortality is 0.13. So although it's non-inferior, actually a kind of dens have been not just in this updated, guideline, but cornelle, but even the previous. IDSA guideline for candidiasis, which was our reference until recently the 2016 also recommended, a kind of dens first line.

Jame 17:05

I have to say, up in Scotland until recently, a few years ago, I'm talking about, we were using Fluconazole as our first line agent because two reasons really. One, we don't have a lot of issues with fluconazole resistance in Canada, or at least we didn't back then. And two, we didn't want to get it. So applying from our antimicrobial surgery in the bacteria world we said, why not use an nasal if an nasal will do well? I think the answer is that maybe an nasal won't do, and maybe it isn't as, as effective as the ecs based on the stuff that you were saying. We're now using e EC as our first line

Tihana 17:39

When I was a registrar in the two thousands, when just to go back to the antifungal timeline, just to add to your thing that, that the kinins are the last. Developed, I mean, there are other new antifungal classes now in the drug development pipeline, but the first Casper Fungin was licensed in 2001. So in the early days here at St. George's where I work, we used to use a kind of canons only for ICU patients for first line, and we used to use Fluconazole for everyone else. and then gradually the guideline changed over time as more data came out to make them first line for everything. So yes, you're absolutely right that in the past, fluconazole was first line, particularly when there was less resistance and for the less sick patients. But now across the board, the for more fungicide kinins are first line,

Jame 18:36

Turning to the pk for a minute. In terms of absorption, there isn't any, their IV only they distribute well into most tissues, but they do not penetrate C-N-S-C-S-F. I prostate or urine particularly. So the urine penance of Casper Fungin is something in the order of two to 4%. So you get very little penance into urine. Renal parenchyma is a different story but they don't get out that way. And so they're not very useful as UTI agents. That's something to bear in mind. Fungal UTIs are pretty difficult to deal with in terms of metabolism. They don't really get metabolized particularly. They undergo hepatic metabolism. Casper fun and mica. But dulo fun is not, and degrades slowly and naturally. And then in terms of excretion, cast fungi and micro fung are excreted in both urine and feces, but again, only tiny amounts in urine. Andal fungi is only excreted into feces. In terms of the pharmacodynamics, they they have concentration dependent killing, which promotes a once a day high dose approach, similar to the aminoglycosides, similar to daptomycin. And you've mentioned here that there is an eagle effect with these agents. Alyssa, do you want to tell us briefly seeing as you have a microbiology qualification and I do not about the eagle effect, something that I have ignored up until now.

Alyssa 19:58

yeah, a paradoxical effect that's observed in the lab in VI training is the eagle effect. And it's just been noted that the fungal effect of thes, particularly fun against candida albicans and candida deline disappears at at higher concentrations. So that's something that's observed in the laboratory. I don't know the clinical significance of that. I don't know if that's been correlated to clinical outcomes. But it's something that is seen with higher concentrations of these agents.

Jame 20:32

Whenever I see something like this, I think, how high could I get this in a human without killing the human first? I know kinins are very indolent and they've not got a terrible side effect profile, certainly compared to the oxide. But I, whenever I see the eagle effect in something I think is this, would I have to get the beta-lactam level so high that the patient would be in status epilepticus before I got to this? Effect do. Do you know what I mean?

Tihana 20:56

Yeah, I think you can just probably ignore it. It's certainly noted, but laboratories just ignore it. And it may be in effect called tolerance, which we may have discussed in the antifungal resistance episode. But There are mechanisms of adaptation to the drug that in the cell wall that are different to resistance. but from a non-research from a clinical perspective, I think it's a phenomenon that's more common with Casper fungi, which is when it comes to, MIC testing usually. The labs do use other kinins, such as I think Bristol uses a Ular Funkin as its reference antifungal for MIC testing because of this effect. And it does make it more challenging for interpreting Casper fungi mics.

Alyssa 21:50

So I, I think with regard to Casper, it's interesting, isn't it? Because cas don't give any break points for Casper fungi. And maybe that's why, because of these challenges. So you have to infer from yeah, fun and micro fun. Yeah. For the susceptibilities,

Jame 22:05

alyssa, tell me about the resistance ana canons that we can encounter either intrinsic or acquired.

Alyssa 22:12

So I'll talk about the intrinsic and then I might pass over to Tahan to talk about. So I think it's just important to note that whilst the kind of canons have fairly broad spectrum of activity, we've talked about their activity against candida species, some activity against fungo, static activity against aspergillus, some activity about pneumocystis that they don't have any activity against cryptococcus. And that's because cryptococcus lacks BC Glucan in the cell wall.

Tihana 22:44

It actually has beta one six. DEG Glucan as opposed to Beta one three, is the one that we measure in the assay and the one that kinins target,

Alyssa 22:56

Okay, so it does have a be a beed e glucan, but not the

Tihana 22:59

not that one.

Alyssa 23:00

not that one. And similarly s lack one three BBC Glucan in their cell walls. They, no activity against s no activity against non aspergillus mold, such as fusarium and no activity against the Dimorphic Fungi.

Jame 23:17

And what about acquired resistance,

Tihana 23:18

so the enzyme beta one three glucan synthase that the kinins target, it's synthesized by a gene called FKS. And most candida have either or both of fk S one and two. Fortunately, unlike Azo resistance, akin canine resistance is Generally more straightforward in that it's caused by mutations in this FKS genes. So in general, although there are some newer mutations being added, most clinically described acquired resistance is due to, FKS mutations. And the kind of patients it occurs. in certainly, that's been described in the literature, are patients on many weeks of akin kind of therapy. Usually either in a focus such as urine that we. talked about where akin of canons don't penetrate well, or more commonly a deep intrabdominal focus, which is another area where akin of canons have. Reduced penetration. And in fact, all antimicrobials is often into pass and intraabdominal collections. So in those kind of patient theories Say on treatment for six weeks or more for intraabdominal candidiasis FKS mutations have been described and that's the most common mechanism of acquired resistance. Of all the candida orus and candida glabrata seem to have the greatest. propensity to develop this,

Jame 24:52

calling it Candida gta, are we?

Tihana 24:55

or we can call it NCAs ISIS glottis. But frankly, I find that a bit of a mi mouthful.

Jame 25:01

You know who you should have told that to the bloody world Mycology Association or whoever it was when they changed all these bloody

Tihana 25:07

I know. What about candida, Aris?

Jame 25:11

I know. What about Zi or whatever you want to say. God, make it easy on us guys. But

Alyssa 25:16

And is that seen also occasionally for albicans?

Tihana 25:20

It is seen occasionally for albicans, but it is described, but it's just less common.

Alyssa 25:27

Okay.

Tihana 25:28

If you think about it, with albicans, we're much more likely 'cause the guidelines tell us, don't they, that after three to five days when you have the susceptibility tests and when the patients are stabilized, if you know that it's an albicans and it's AOL susceptible, which still fortunately in this country albicans is largely fluconazole susceptible, then you tend to deescalate. So these are not the patients who mute, maintain on long-term kinins, whereas. Orus, which is always, or in 90% of cases, fluconazole resistant and glabrata, which has this inducible resistance mediated via influx pumps so that it's always either intermediate resistant fluconazole. We tend to always treat for longer, periods with the kind of canons. So this could be another reason. why it's more likely. And then just to add, actually, for candida parasitosis, 'cause let's remember that in the UK, the top three species, causing candidemia albicans, glabrata and parasitosis and candida parasitosis it's mics, two akin canons are higher than the other species, I think around about four-ish, as opposed to N point naught. Three and below for the other species. And that is because they have a natural occurring variant in, FKS. It is not because they're actually resistant, but they do have higher mics. But to date, there's not clinical evidence that makes them more likely to develop resistance.

Jame 27:12

So would you still use kin canons with parasitosis?

Tihana 27:17

would, yeah.

Jame 27:18

Okay fine. So the main resistance mechanism is FKS gene modification and gene product. It remind me, it, it makes b, d, G, is that right?

Tihana 27:27

Beta Glucan syntase. The enzyme that catalyzes the synthesis of be one three glucans, which are a key component of the Candida and other fungal cell walls, the polysaccharides that crosslink the cell walls,

Jame 27:44

Fine. Alyssa, tell me all about the myriad side effects of the ethnic and drug class.

Alyssa 27:50

One of the reasons that kinins a great and are u recommended first line for invasive CAN in Candidemia is that they are generally really well tolerated. So side effects are quite few. These include things like flushing, PRUs, rash, urticaria. They not being renal exquisite, they have very few problems with nephrotoxicity. There are minimal drug interactions. So I think the only thing that that I'm aware of. Is that the dose of Casper fungi if the patient isn't already on 70 milligrams once a day. So if they're that below 80 kilos the dose should be increased to 70 milligrams once a day if the patient is already on an enzyme inducer. Carmazapine, dexamethasone phenytoin or Rifampin. We talked briefly about the possible risk of

Jame 28:46

Risk

Alyssa 28:48

hepatotoxicity. That's mainly seen with Casper, fun and myung. But according to the BNF can also occur with Aung. And then numerous other drugs may further increase this risk of toxicity. So when you look in the interactions on the bmf BNF, lots of them say, potential increased risk of hepa toxicity. Soof fungi doesn't require any dose adjustment in hepatic toxicity. Whereas dose adjustment of Casper fungi is recommended in moderate hepatic toxicity from 70 milligrams once a day to 35 milligrams once a day. Myung should be avoided in severe hepatic impairment and monitoring of LFTs is recommended in the BNF for Myung. But would you say that Casper Fung and Myung are a similar risk of hepatic toxicity and therefore we should do LFT monitoring when using either or?

Tihana 29:44

I personally don't have clinical experience of using myung, but I've not found LFT abnormalities to be a common side effect. In fact, in my clinical experience now for the last 20 years of using kinins is that the side effects are incredibly rare. Both let's say, let's call them broadly infusion reactions that you described allergy type things or electrolyte abnormalities, which are described, for example, in the recent resin trials there. Hyperkalemia and also diarrhea as two commonly listed adverse effects. That's not been my clinical experience with, any Akin Canin, so I would follow the guidance. around monitoring LFTs. But as we've mentioned already, just use anular fungi if there's severe liver impairment. And otherwise these drugs are usually used in inpatients in whom we will be doing this routine monitoring.

Jame 30:43

Yeah. I have to say I have been told when moving to different trusts that we're using different kin accountants, that the reason for using this was because of fewer side effects. Trying to avoid mic fungi moving to du blah, blah blah, but it's a different kinna can in every trust and it's a different kinna can in the same trust at different time points. It just seems to be that cost acquisition is the dominant feature and like you say, the side effect profile is so minimal that it doesn't factor into your choice of which one to use

Tihana 31:12

I think clinically also, this is what makes Akin Canin a very attractive drug for use in empiric prescribing, in my clinical experience where akin of canons are used the most are actually not for targeted prescribing, which is what we've been talking about. empiric prescribing, particularly on the ICU, I don't know about your trusts, so

Jame 31:36

No. Echo Canon number one. Yeah. 'cause they've got a central line in anyway, so it's just another port and it's only once a day.

Tihana 31:43

Yeah. So essentially we've found in previous antifungal stewardship audits we've done at Ireland Trust and two others that. The predominant mode of prescribing of akin canid is empiric. And as we know. on the ICU that's predominantly targeted at suspected invasive candidiasis. So sometimes if you've got Beto D Glucan on site, these would be the patients who are septic with evidence of organ impair impairment and one or more candida risk factors such as recent abdominal surgery or TPN or being immuno immunosuppressed or diabetic. And then candida colonization. And these are the kind of patients Who who have this high candida risk score and are not responding to broad spectrum antibiotics that we tend to start. Akin of canines and that act as a trigger for sending off the BE 2D glucan.

Jame 32:40

Do you do that on everyone who's on neck and account in I-T-U-A-B-D-G goes off by default,

Tihana 32:45

we have a candida risk score that we set up years ago as an amalgamation of the published Candida risk scores. And in fact, we've just had a poster at FIS presented on auditing How our candida risk score performs with and without B. 2D glucan. So essentially both the candida risk score that I just talked about and we have a score of a maximum of four that for us is acts as a trigger to both consider starting an empirica kin canin and sending a beta d glucan. So that's the way that we have implemented it. When the beta D glucan comes back, if it's negative. that's then a stewardship trigger for stopping. However, the challenges of both of those tests is that their negative predictive value is much better than their positive predictive value. but in our practice, and we intend to. publish it, the positive predictive value, if you use the two together, does improve it to around 70% from around 30 to 40%. Again, it's not brilliant. Some trusts who have Candida PCR available use that, but in our trust, rather than just giving, empiric Akin Canin to anyone who's been on antibiotics for 48 to seven two hours, this is a way of formalizing the decision of who is at greater, risk of invasive, candid, narrowing down the prescription of akin Canin to that group. And then once you have the beta D glucan result, you come in with your antifungal stewardship team and you stop it if it's negative, if it's positive, of course, you then have to repeat it. Review the patient in light of all available information. The other group, we do not use it in that setting, but many trusts use Akin ofAnd also for febrile neutropenia, empiric prescribing, including the Marsden in London is my understanding why. Again, because they're very safe, tolerated drugs so like we mentioned earlier, that kinins have cover against candida not as good, but cover against aspergillus and possibly some against. pneumocystis. So the argument is that AmBisome or liposomal amphotericin B, the other alternative for this population is much more toxic. So hematologists often prefer akin of canids, and indeed the guidelines suggest that. However, I have always preferred using liposomal amphotericin B in this population, the Hemat oncology bone marrow transplant. Why? because the spectrum of activity of AmBisome is much broader and includes mucor, which kind of canons don't cover at all, at which these patients are at risk of, and Aspergillus amphotericin B is much more effective. and is a side drug against aspergillus as opposed to akin of cans which are static. So again, it depends what your index of suspicion. You can either use a drug that's less toxic but doesn't have as good cover in those patients who might end up developing a fungal infection versus using a bit of A, more toxic drug but having a better spectrum.

Alyssa 36:17

And I think, certainly for, For ICU it's gonna be invasive panis that you're mainly concerned about, and then you've got a bit of extra cover, just in case. But in your hematology patients they're susceptible to such a wide range of fungal infections.

Jame 36:34

Infections

Alyssa 36:35

Casper fun would probably cover, the majority of faces, but not gonna serious cover against serious mold infections.

Tihana 36:45

And The other reason why, as you mentioned, alluded to earlier but the intensivist lover canons 'cause they don't need dose adjustment in, Continuous renal replacement therapy. renal impairment mostly unless it's severe liver impairment. These are attractive drugs to use, particularly in this population, and in fact are where they are most widely used in clinical practice.

Jame 37:10

Fine. Let's turn now to the new kid on the block. Raise fungi. Actually, let's note, this episode's getting a little bit long, so we've divided it into two, part two. Concentrating on raise Fungi will be next week.

37:25

Okay.

Speaker 37:26

This Psychology episode was produced with support from the British Society for Medical Psychology. The BSMM brings together clinicians and academics in the study of fungal disease. For more information on the benefits of membership and details of their annual conference, visit bsm.org.