130. Azole Antifungals

Flustered by fluconazole? 

An ignoramus on itraconazole and isavuconazole?

Puzzled by Posa? VEXED BY VORI? 

Never fear: You can be amazed at the Azoles, just learn how to use 'em right! That's what this episode's all about! Alyssa and Jame UNITE in the first of our episodes on antifungal drugs! 

Transcript

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

alyssa, how are you doing?

Alyssa: 0:12

Hi, Jane. I'm good, thank you. How are you?

Jame: 0:14

I'm fine. I'm just waiting for the pun to come.

Alyssa: 0:17

I played golf yesterday for the first time

Jame: 0:20

Okay. That seems unlikely, but I'm going with it. Go ahead.

Alyssa: 0:24

and I got I got hole in one.

Jame: 0:26

Oh, that's very good.

Alyssa: 0:27

Yeah. It was a real fluke. It was a fluke on a hole.

Jame: 0:37

Oh, you told me that was gonna be bad. That's really good. That's one of the best ones we've had in a while. Callum, if you're listening, that's how you do it. Okay. Frankly, you'll be lucky if you gets invited back. And what a coincidence that is, Alyssa. Because what are we discussing today?

Alyssa: 0:55

Today we are gonna discuss the azos, the class of antifungal drugs called the

Jame: 1:00

Indeed our first solo recording together. I feel like I should have made a plaque or something like that instead of this calf here of coffee to help us get through this. Yes, that's right. So the Azo class, we may release this first actually, even though we've recorded another episode, beforehand. But we did that with a guest, an honored guest, uh, just in case that honored guest is listening. Probably not. But easels are the. Main class of antifungals, I guess I would say certainly in terms of scope of use. And so they are the drugs that general practice will use and most non ID specialists will use as their first line. So let's let's dive into it. They're actually two separate but very closely related drug classes, the Oles and the Tri AOLs. Most of this episode's gonna be on the Triazoles'cause those are the ones that are systemic. So you could equally divide these into systemic and topical Azos. So, we'll talk about them first. Sls talk about the Oles. A little bit about the structure first. So all of these are drugs that have a five member drink with at least two nitrogen atoms. That's what makes it an aol. And this is a class of chemicals. And the midsoles have two nitrogen atoms in the ring. And the ones that are available in the UK include clotrimazole. Wait. Alyssa, me and Callum have this thing where we do an alternating reading out of the drugs. And I would like to bring this tradition on with with you. So, allow me clotrimazole, which I've never heard of ketoconazole

Alyssa: 2:34

my conazole.

Jame: 2:35

and Tioconazole. And then the Tri aals have three nitrogen atoms in the ring. And these are the ones that are used systemically and they are fluconazole.

Alyssa: 2:45

Eyes of Econazole

Jame: 2:46

Itraconazole

Alyssa: 2:48

Posaconazole.

Jame: 2:48

and Voriconazole, and there's another one called Pel Conazole, which we may cover in a future episode, but it is not in market yet. Is that right, Alyssa? Yeah.

Alyssa: 2:57

Yeah, that's right. So that's still in clinical development. So it's an inhaled tri aal. And I think there, there has been some experience with its use around the country in individual patients for compassionate use.

Jame: 3:10

code for, you've used it. I

Alyssa: 3:13

I haven't, no, I haven't. But I've heard case presentations and things at conferences. Yes. So,

Jame: 3:20

And it's only going to be inhaled. It's not going to be IV or oral or anything like that. So it's.

Alyssa: 3:24

yeah. No, it's in inhaled preparation.

Jame: 3:26

Interesting. So I guess it must be used or the plan is to use it for lung fungal disease, like aspergillus and related things like that. Okay.

Alyssa: 3:36

Yeah, I think so. Yeah.

Jame: 3:37

How do the AOL antifungals work? Alyssa?

Alyssa: 3:40

So they kind of have two steps in the mechanism of action, I suppose. So essentially they inhibit a GOs synthesis, and a goss is a really key component of the fungal cell membrane. So they disrupt the fungal cell membrane.

Jame: 3:54

so as cholesterol in our cell membrane, so two for Argos, The fungal cell membrane. This is the main, if you looked at us on a cellular level compared to the fungi, that's the main way that you would tell between us. Okay. When you say two steps, what do you mean?

Alyssa: 4:07

So they essentially inhibit a fungal enzyme called LAN Nostril 14 Alpha Demethylase, also known as er, ER 11. So it's encoded by the ER 11 gene, and this enzyme converts sterol to. So inhibition of that enzyme results in depletion of ergosterol, so it disrupts the fungal cell membrane, resulting in increased membrane permeability and arrest of fungal growth. And then the second mechanism. Is that the Len Nostril builds up and then this is metabolized by a different enzyme called sterile C five Desaturate encoded by the IRC three gene. And this results in conversion of Len Nostril to a toxic sterile, which is toxic to the fungus and that accumulates when, is inhibited by Azos. So it's a twofold mechanism there. The depletion of ole and the buildup of this toxic, sterile metabolites.

Jame: 5:12

But Alyssa I don't understand when you say a toxic, sterile can, you name said toxic, sterile. You seem to have jumped over it in the preparatory notes here.

Alyssa: 5:21

That's really unfair. So it's called 14 Alpha methyl Augusta, 8 24 Diane, three six dial

Jame: 5:32

Thank you, Alyssa. Yeah. And is this fungus static or fungal?

Alyssa: 5:39

So AOL's, a fungo static against candida, but fungicide or against aspergillus and molds.

Jame: 5:45

And the significance of that will be expanded upon in our dens episode by somebody who is much more qualified to do so, than us. We'll be, go into indications.

Alyssa: 5:56

Yeah. Sounds good.

Jame: 5:57

So I pulled this from the BNF because I have to admit, apart from clotrimazole, my experience with every other, ole antifungal is fairly limited. But most of them, they're used to treat surface infections. That will be skin infections, like tinia of various areas of your body, hair, fungal disease, and vulva and auto mucosal fungal disease vary. Occasionally I've put a heat map in the prep notes. Maybe we'll just point to, clotrimazole for example. And then ask everybody else to have a look at the the pre notes if they want the detail. But clotrimazole can be used for skin vulva and otitis, erna fungal disease. And then there's other IOLs which are indicated for nail here or mucosal. Is there anything to add there?

Alyssa: 6:48

I don't think so. I guess I always think of ketoconazole, it comes as a shampoo, doesn't it? So I always think of that for hair and

Jame: 6:55

Yeah, well actually I suppose it's the only one that's indicated for, has an indication for hair, doesn't mean it can't be used. And similarly, my conazole is the only one that's indicated for auto mucosal, which I suppose is, it's an issue actually with we have somebody who's. Th this will become a more of a problem, I think as time goes on. It's somebody who's on a biologic and they are being troubled by recurrent or mucosal esophageal candidia isis and what to do because your only alternative really is to use one of the tri aals. Well, one of the things that you can try is you can use Chlorhexidine mouthwash as more of an antiseptic not necessarily an antimicrobial. And my conazole gel to try and coat the esophagus to make the environment less favorable to candidate overgrowth. So that's one of the things that we are trying with these patients locally. As for the systemic ones, we've got the big five fluconazole and then the. Three others, and then a svic conazole, the very new one. And their indications are quite varied. Suffice it to say the fluconazole is indicated for every yeast infection possible and coio mycosis. What I've done is I've arranged this table by yeasts, then molds, then D morphs and then ole. Surprisingly only has a couple of license indications. One, aspergillus and two is mucormycosis. I mean, I know that when you have your back to a wall, you can use this more widely. Alyssa, any comments to make on this?

Alyssa: 8:24

I don't think so. So I think, yeah, the main take home message from that table is that Fluconazol always. Indicated for all of the yeasts but doesn't have any mold activity, whereas all of the other azoles have some mold activity in a indicated for different mold infections.

Jame: 8:42

when people say mold active aals, what they really mean is everything that isn't fluconazole.

Alyssa: 8:47

And I guess it's important to note that for all of them have activity against aspergillus, but for Muco Mycosis which is the second most common mold infection in the uk only is Avu Conazole and pos econazole have activity against Muco. Myas.

Jame: 9:03

Is that true? Micro myosis is the second most prevalent. Wow, I didn't know that. Okay. Yeah. And then there's we've put sort of heat maps for other stuff like fu uh. only OSA and Vori have indications for that por only vori, and then Blas Mycosis only posaconazole. So everybody's got their special interest there. And then for histoplasma, the treatment of choice, et cetera. And for Coad Mycosis, it's Fluconazole or Posaconazole. But if you go and look at the relevant guidelines, you'll see that. The other ones have been used individually. It's just that there's less potent evidence behind them.

Alyssa: 9:41

Yeah, in the BNF it doesn't list muco mycosis as an indication of pos econazole, but actually pos econazole is used to treat Muco mycosis either as a salvage therapy or as a step down for therapy following their initial treatment with liposome b.

Jame: 10:00

Okay. So we are going to talk about the the tris for the remainder of this talk. I feel that's mostly what ID and microbiology specialists are using, particularly in secondary care. Let's talk about Fluconazole. First in terms of spectrum. So you've mentioned it's treating candida all candida, Alyssa.

Alyssa: 10:23

So. Fluconazole doesn't have any activity against Candida rei, so that's important to remember. Candida REI are intrinsically resistant to fluconazole the majority of Candida ris, so by 90% of Fluconazole resistant. So again, it's not gonna be your go-to for our risk. And. Candida Glabrata has elevated mics to Fluconazole. So if you were to use Fluconazole you'd need to use high dose, but it's generally not recommended due to hetero resistance. So if you want to hear more about that, going back to our Candida episodes we discuss that in more detail.

Jame: 11:02

Yeah. And then so the candidates where you have break points against them. And Fluconazole would be okay to use are albicans, Dublin, ANSYS, parapsilosis, and Tropicalis. And there's a a slightly elevated break point for Gil Moni as well. So that's the other candida fuz that you would be able to use. And then all the other aol. Will also treat most candidates as well. And there will be variable susceptibility to those problematic ones that you just mentioned. Iris and cruise eye. So if you test it and it is susceptible, by all means use it. But if not, then you'll have to use an alternative drug class. What about the molds at your aspergillus, your fusarium, et cetera?

Alyssa: 11:49

So Fluconazole doesn't have any reliable activity against these, so not used to cover a mold infection.

Jame: 11:57

But the remainder do so aspergillus all of them will be active agents with fusarium. Voriconazole is favored, but the others can be used a second or third line for. Uc, it's Posaconazole and Svic. Conazole. The evidence base with a svic Conazole, I take it, isn't as sturdy as with osa. Would OSA be your first line in a Les case?

Alyssa: 12:24

So it wouldn't be first line, so it would be liposome one, amphotericin

Jame: 12:27

Oh, no, but I stepped down afterwards in the sort of

Alyssa: 12:30

as a step line. I'm not sure actually what, yeah. What the benefits are of PAs over Econazole.

Jame: 12:37

Cost or something. But yeah. And then for ski uh, voriconazole is number one there and the others would be second line. What about your dimorphic?

Alyssa: 12:46

yes. So generally Fluconazole has some activity against, most Dimorphic fungi. But it's only really recommended for cocci Mycosis. And I think the go-to for treatment for your other dimorphic fungal pathogens is itraconazole.

Jame: 13:04

so the easy way to remember is econazole is indicated for all dimorphic fungi, and the others have variable recommendations. Although, if you go and look at the guidelines that we use for developing this are the ECMM, guidelines for dealing with dimorphic fungi. And then the other one to would be the IDSA guidance for the individual fungi. But anyway, these indications are taken from ECMM but for his osteoblast. On Coio, you could use Fluconazole, but I think etra would still be first line. And then for Parais. Voriconazole would be another option for Talaromyces. It's just IRA with ZA and VRI as second line options. And for Emeris, again, etra with is Savu, za and VRI as second line options. And lastly, for Spiro, if you're going to use an nasal antifungal etra as the only recommended choice. So yeah. It only gets complex if you can't use Itraconazole for whatever reason, which would probably be a side effect profile. Let's talk about the pharmacology. So all of these are available both IV and oral. And in terms of PD target attainment, it's a UC over an MIC is the PD target as it is for most other antimicrobials these days. So, we've got a table here on what the standard and the high dose is, and it's also got some monitoring targets for you. I think we may let the loyal listener have a look at that in the prep notes and not go over it in detail in terms of who you would do monitoring for. It's fairly routinely recommended if somebody is going on long term. Mold, activ, aal. So Raza and Voriconazole, it's not routinely recommended for Fluconazole and Isoconazole, but may have a role in complex cases or renal impairment what about the side effects Alyssa?

Alyssa: 14:48

aals have quite a considerable side effect profile, I guess, I think they're generally safe and well tolerated. Common side effects of all AALS include GI upset, headache and skin rash. Is one to think about. So that's been described for all aals, but is particularly common with Itraconazole. So that can be. Problematic for itraconazole. similarly QT prolongation and have been reported with all systemic azos. But is generally rare though this risk may be increased by co-administration with other drugs that. It can also prolong your qt, so we'll come onto that a bit more in the adverse drug reactions. That's another thing to think about. And then other notable side effects for individual agents. So fluconazole. Can cause alopecia. But that's mainly with reported with long courses over say three months. And I think voriconazole is the one associated with most side effects. So that can cause one of the most common side effects is visual disturbance where patients might report blurred vision. And this tends to be transient and reversible when treatment stopped. They can also get a photo sensitive rash and they can also develop encephalopathy. But that's particularly with very high levels if your levels are over 5.5. Milligrams per liter.

Jame: 16:18

Okay. What about drug interactions?

Alyssa: 16:23

So drug interactions are a big problem with Tri aals, and it's something that, if you're starting a patient on Tri aals, you really need to be thinking about what other drugs they're on and potential interactions. So Tri aals are associated with the highest number of drug interactions of all. Antifungal classes. And there was a review article in JAC in 2024 that really goes into this in some detail. And we've put a link to that in the show notes. And they start with this quote that nearly 600 severe drug interactions and over 1,100 moderate interactions requiring dose modifications are described or anticipated with systemic antifungal agents. So lots of things are gonna interact with your tri azos and we're never gonna be able to remember all of those drugs. So we need to be using drug interaction checkers. And the reason for this is mainly that azos are both inhibitors and substrates for cytokine P four 50 enzymes to varying degrees. So for Econazole, itraconazole and Isoconazole are both substrates and inhibitors of these enzymes. Fluconazole and I econazole are less potent inhibitors than the other azoles. And Fluconazole and Posaconazole are not really substrates, so they're not significantly metabolized by these enzymes. and then with regard to severe drug interactions, these most common with voriconazole, followed by Itraconazole, posaconazole, fluconazole, and then least common with I Avu Conazole.

Jame: 18:09

Is that because it's not used very much or just'cause it has less. In fact, it shortens the QT slightly. It's just not doing the stuff that the other people are doing.

Alyssa: 18:17

Yeah, exactly. It's just, it's not as patent. An inhibitor, I think is one of the reasons it doesn't affect the P 50 enzymes to the same degree. So in this paper that I've talked about they've got a really nice table that summarizes a number of drugs that cannot be safely used with Azos. So I think that's, group of drugs that it's worth being aware of. And it's quite lengthy. I dunno if you want to go run through that or we just point people towards that table.

Jame: 18:49

I think Jane and Alyssa alternately read the names of the drugs is appropriate here. Ivabradine

Alyssa: 18:55

Ine

Jame: 18:55

Plein, known

Alyssa: 18:57

fentanyl, quetiapine, rifampicin, sirolimus, and carmazapine.

Jame: 19:07

So what anti-epileptics, which are also enzyme inducers. I mean, a lot of this are in the PC brass mnemonics. So your rifampin, pheto and carbamazepine, they're all there. Barbiturates aren't but presumed because they're not used very much these days. And then you've got stuff that you might see in cardiac patients like Ava Ivabradine and aone. So it's worth knowing about. And the table has has statements saying which AOLs you need to worry about. And the reason to avoid that combination. So, for example Feni Toin. It can't be given with any tril because it accelerates the metabolism that azel because it's an enzyme inducer. So, fairly easy there. And it is not the case that you can give an enzyme inhibitor, an enzyme inducer, and hope that they just balance each other out. It doesn't work that way. The enzyme inducers will usually overcome the inhibitor, a shame. But there we go. Alyssa, let's now have a comparison off. We've listed all these drugs, but which one is the best? There's only one way to find out. Let's have a big AOL fight. So which one is superior? The one aol, to rule them all.

Alyssa: 20:09

So I think, fluconazole has been the go-to azo for lots of treatment of aspergillosis and other mold infections. But over the last 10 years, there've been a number of RCTs comparing Fluconazole for to other azos. So there was one called the secure trial in 2015 comparing Isab Econazole. To voriconazole for treatment of invasive mold disease, including aspergillus one in 2021, comparing posaconazole to voriconazole for treatment of invasive aspergillosis. And then a more recent one last year called the Victor CPA trial, which compared oral itraconazole to oral voriconazole for treatment of chronic pulmonary aspergillosis. And the key findings for these were that eyes of econazole and posaconazole were found to be non-inferior to Boric conazole for the treatment of invasive mold infections or invasive aspergillosis respectively. And Boric Conazole was not superior to Itraconazole for the treatment of chronic pulmonary asper. But I think the key thing to take away that in all of these studies fewer treatment related adverse events were seen in the, is avu, conazole, pos, econazole, and itraconazole groups compared to the voriconazole groups. So I think that, voriconazole. It's gonna be increasingly less used and more replaced by some of these other agents because of its side effect and adverse reaction profile.

Jame: 21:44

Yeah, and that'll take a while to work its way out of the the guidance, but particularly as this new stuff comes off patent and becomes quite cheap, I think the. Argument for using a equally efficacious but more side effect laden drug becomes less and less fine. A little bit on the pharmacokinetics. Now, my chance to shine in this mold heavy episode Alyssa. So the good news about these drugs is that they are generally speaking quite highly bioavailable, which means that if you move from ORs to iv, you don't need to do any dose or many dose conversions. So Fluconazole is. Vori, they're all more than 90% bioavailable, so just as good orally as the RIV. So another opportunity to switch people if you are wanting to get a cannula out and get them home. Posaconazole has very variable bioavailability, and in fact, I difficulty getting numbers. Numbers of this. I had to dig deep. But it ranges between eight and 47%. Itraconazole is about 55%, so moderately bioavailable. Their protein binding varies. Markedly. So Fluconazole is very low, 11% and the others are very high at over 90% with the exception of Vori, which is about 58. And that affects their volume of distribution as well. The fluconazole volume distribution is moderate at about 40 liters, and everything else is several hundred. So the, these are very lipid soluble drugs and they leave the plasma very quickly. So you may want to factor that in if you're thinking about, treating plasma board infections like,

23:18

Fungemia.

Jame: 23:18

and things like that. If you're not using that kind canon, which easel antifungal do you want to use? I. Most of them are metabolized by sips as you say, but the metabolism is fairly minimal before they're excreted. And with the exception of the corzo, most of them are leaving in in feces. So some of them have a little bit of renal excretion, but not very much at all. And in terms of have lives, they're all long I would say so. Most of these are. Once or twice daily dosing, depending on if you're using the high dose or not. And that's'cause they're half-life range between about 11 to well, fluconazole is 30 hours. And I will just point out that Svac Conazole is about 120 hours. So these are. Incredibly long acting. You might think why can't we give a s conazole once weekly? I presume it's toxicity reasons that limits the the giving of that. Less frequently than once a day. Anything to add, Alyssa?

Alyssa: 24:19

So I think it's just important to note that the bioavailability, oral bioavailability of Pasal, Conazole and itraconazole varies depending on which preparation you use. So for Itraconazole it's lower with the capsules compared to with the oral solution. And with Posaconazole it's the other way round. So, the oral solution has more reliable PK than the capsules.

Jame: 24:44

Let's talk about penetrance. And I have taken this from a paper called Tissue Penetration of Antifungal Agents by Felt Etal. We've got a link to it in the show notes. I think this paper is brilliant and one of the things it's got is it's got a table with a heat map. And, I'm a sucker for a heat map. Alyssa, fluconazole osa. I think this paper predates Sconzo. So apologies there. And it's basically just going through the penetrance into various tissues. And I'm not going to go through this in excessive. Detail, but we'll say for fluconazole let's say so it's got a good penetration into skin and spleen and it's got average penetration into just about everywhere else and poorer penetration into bone tissue and prostate tissue as well. Probably not much of a surprise. Most stuff has difficulty getting into the prostate there. But for a more deep. Breakdown. I would strongly suggest going to the paper because it's very granular. For example, for bone. They've got different penetration rates for bone tissue, but synovial fluid, it's average to good. So yeah, please go and have a look at that.

Alyssa: 25:53

CSF, none of them looking great. Are they?

Jame: 25:56

No, not particularly. No. I think CSF is a bit of a problem. I we're gonna have a penetrance problems mini series on what gets into what. And we'll have to do a fungal sub series of that, which you will be welcome back to, but that's several years in the future. Need to finish all the gram negatives first. In terms of like UCAS break points, we've got them here. I've pulled them from uca 2026. I think that's UCA 16. But we may not comment on it. Particularly unless you've got something that you want to say about them and we've got them broken down for both yeasts and molds. There oh there is something to mention here for other fungi you cast have a separate. Paper. They didn't want to set break points, but they've basically said if the MSEs below this, you can consider using it with that sort of mealy mouthed might work, might not statement that they've also got for some of the bacterias like daptomycin, enterococcus, et cetera, et cetera. So do go and have a look at that. And we've linked to that on the prep notes as well. Let's talk about resistance. Let's talk about why it doesn't work sometimes. So we've broken this down into candida and aspergillus. Do you want to take candida?

Alyssa: 27:02

Yeah, I can take candida. So candida, mechanisms of AOL resistance. So we've already talked about how azos work. They inhibit AGAs synthesis. By inhibiting the ER 11 enzyme. So one of the mechanisms of resistance is mutations in ER 11 making the mutant enzyme less susceptible to AAL binding and also overexpression of ER 11 which is mainly seen in candida Aans. And then as we talked about the second mechanism of action a ails is this accumulation of toxic sterols. But mutations can also occur in the ER three gene, which converts Len nostril to the toxic sterile which can therefore reduce the efficacy of aals. And then other mechanisms include flx pumps. So there's a variety of different genes that encode FLX pumps that will pump the AALS outta the fungal cell. Then finally aneuploidy which is duplication of the genome. So for example, duplication of the ER 11 gene, which is the target for azos or duplication of some of these pumps

Jame: 28:23

Yeah. Well, it's a promoter. Tac one is the one that they mentioned, and that stands for transcriptional activator of CDR. So CDR is one of the FLX pumps that they they have, it's part of the A, B, C. FLX Pump Superfamily, which listeners to our pseudomonas episode will remember we did a little mini dive on Flx pumps. These are conserved between Procardia and Ucar, and so they are, seem to be important for candida. So yeah a lot there. A lot of opportunities I feel for Canada resistance And then for aspergillus there's three main mechanisms. One is modification of the CYP five one A enzyme, which reduces aol affinity. Two is overexpression of CYP 51 a which is a combination of a mutated promoter and then a snip L 98 8 for those of you who are paying attention. And then. The last one is overexpression of an flx pump which is CDR one B. So that's one of the a, b, c family flx pumps. And just for clarity, CYP five one E is what? This paper is calling er 11 in Aspergillus. And that's all we had to say, really. Anything else to say?

Alyssa: 29:40

No, I don't think so. I think one thing. That's that I found interesting. We certainly mentioned it in the aspergillus episodes, is that, we use azos as antifungals in agriculture. So they're not the same drugs that we use in humans, but they're the same class of drugs. And that's actually driving azo resistance in aspergillus environmentally. And then we are seeing these. Resistant isolates, but resistant to fluconazole and other azos in clinical settings. So, it's quite interesting that sort of one health aspect of mycology because a lot of fungi are environmental organisms.

Jame: 30:21

I feel that it's much of, more of an issue with antifungal resistance, not least because fungi are more burdensome to plant health and agriculture than bacteria. But also the stuff that we tend to get infected with. With the exception of candida tends not to be something that lives in us normally. It's an environmental thing. Aspergillus is an environmental thing, and so if you, the environmental gram negatives are the other big burden of antimicrobial resistance. But environmental fungi most fungi don't need to live in a human in a fact, they're opportunistic pathogens of humans. And really they want to be somewhere else. They want to be in a cold-blooded animal. They want to be in a plant, they want to be in the environment, et cetera, et cetera. They're just making a home for themselves. If they get the opportunity to, and then they've got all of these resistance mechanisms because they're being exposed to them through the agricultural industry or veterinary industry. I feel it's going to be much more of. A problem. In fact, I think we will dive into it in a bit more detail when we talk about the new agents for which there is already resistance emerging because of historical use of related antifungals, which weren't able to be used in humans because they were too toxic. But now we have something like a fil I'm thinking of in particular that can be used in humans. We've already got resistance because its cousin has been used as a fungicide for decades.

Alyssa: 31:43

Yeah.

Jame: 31:45

So I feel we couldn't finish the episode without mentioning the oncoming antimicrobial apocalypse, so there we are.

Alyssa: 31:51

Great.

Speaker: 31:52

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.