139. Polyenes

Process your Polyene Prescribing Paralysis by partaking in this proliferous podcast pondering on the particulars of these P-harmacological agents.* 

*Alyssa had no part in the making of this podcast description. 

Transcript

Jame 0:00

Alyssa, how are you doing?

Alyssa Hudson 0:01

Thank you. How are you, Jane?

Jame 0:02

I'm fine.

Alyssa Hudson 0:03

That's great.

Jame 0:03

Oh, is that the end of it? No pun.

Alyssa Hudson 0:05

No pun. No pun here. Have

Jame 0:06

Okay. Well, no, no polienes are serious business so I I couldn't possibly. And what a coincidence that is, Alyssa, 'cause what are we talking today? I don't know if that makes any sense anymore.

Alyssa Hudson 0:16

So today we're gonna be talking about polyenes, which is the first ever class of antifungal drug discovered, and they're quite old.

Jame 0:25

Really? I didn't know that. I, I assumed that the azole antifungals were first.

Alyssa Hudson 0:30

No, so it was back in the late nystatin was discovered. And then it was in the 1950s that amphotericin B was discovered.

Jame 0:43

I see. Fine. So the polyene drug class. So you've mentioned a couple there. Do you want to mention the black sheep of the polyene family as well, that I basically knew nothing about before prepping these notes?

Alyssa Hudson 0:55

Yeah. So in the polyene drug class, we've got amphotericin B nystatin, and then natamycin.

Jame 1:02

Which I have never used. Have you ever used it?

Alyssa Hudson 1:04

I have used it before. Yeah, yeah, for

Jame 1:07

In...

Alyssa Hudson 1:07

topically for fungal keratitis.

Jame 1:09

Okay. Well, you can tell me all about it in a few minutes. So let's start with amphotericin B, which I think is the big daddy of the polyene family. So this is a naturally occurring antifungal agent produced by the bacterium Streptomyces Quite a lot of antifungals are produced by bacteria to kill their, rivals in the eukaryotic world. This is directly fungicidal, and it acts on the fungal cell membrane to increase cell permeability. And how does it do this? It binds to ergosterol, this cholesterol analog that only fungi have. It binds that, and then that forms a transmembrane channel, increasing the permeability, and there's then cell death due to leakage of essential cell contents into the extracellular space. Its affinity for ergosterol is much more than its affinity for cholesterol, but it does still bind to sterols in humans' cell membranes, which partially explains its toxicity. And you can reduce that toxicity by giving it a little lipid coat for it to wander about in, because then it's only released at the target site. Do you wanna talk a bit about the spectrum?

Alyssa Hudson 2:20

Yeah, sure. So it's very broad spectrum. So in vitro it's got activity against most yeasts and a lot of molds. so it's active against candida, cryptococcus. It's not active against pneumocystis jeroveci because this has a cholesterol cell membrane. It's active against aspergillus and mucorales variably active against fusarium. So you need susceptibility testing for fusarium. Notably aspergillus terreus has very high MICs to amphotericin B, so that's the exception within aspergillus. And a lot of the mycetoma causing molds it's, it's not active against. it has activity against the dimorphic fungi, so histoplasma, blastomyces uh, paracoccidioides but not against sporothrix. And it's also used in treatment leishmaniasis. So it has some protozoal activity against leash-leishmania.

Jame 3:22

Yeah, and can be used in, of short courses of, about six days for treatment of cutaneous and systemic leishmaniasis. Fine. And how is it used in clinical practice?

Alyssa Hudson 3:34

So it's, it's a treatment option for invasive aspergillosis as, as an alternative to voriconazole. It's also a treatment option for invasive candidiasis as an alternative to azoles. It's really the drug of choice for treating mucormycosis. Often used in combination with a second agent, but not always, such as azoles that have activity against mucorales, so posaconazole or isavuconazole. It's also used in treatment for cryptococcal meningitis along with flucytosine. and it can be used in induction treatment for endemic mycoses such as severe blastomycosis or disseminated histoplasmosis. So very broad range of uses. And because of its broad anti-mold activity it's often used empirically in context of neutropenic sepsis. And also it's used for prophylaxis of fungal infection in certain groups.

Jame 4:40

Yeah. We have some breakpoints here. They have full breakpoints against most Candida species and Cryptococcus neoformans and Aspergillus fumigatus and niger. But they don't have breakpoints against much else. Candida auris has one of those nought point nought nought one breakpoints, so you're always gonna be using the higher dose. And there are some other TCOFs and ECOFs in the table that I don't think we really need to discuss let's talk about the pharmacology, and then you can take the dosing Alyssa. So this does not get absorbed orally, so you have to give it IV. There is an intrathecal preparation available for CNS infection, which I have never used, and it is generally available in three formulations. Amphotericin deoxycholate or D-Amph. This is Fungizone is the trade name, and this is one of the few circumstances where your trust may request that you prescribe it by trade name so that you don't confuse it with the liposomal formulations 'cause the dosing is different. It's colloquially known as D-Amph and the D is for deoxycholate. So that's the naked amphotericin. Amphotericin B lipid complex or ABLC, I forget which company makes this. And then there is liposomal amphotericin or L-Amph, which is AmBisome or amphotericin B Tilamed liposomal. It is in the UK because Tilamed also have a formulation of this, which is considered bioequivalent to AmBisome itself. Okay

Alyssa Hudson 6:13

the lipid formulation, I've only ever used AmBisome. I don't know about you. I haven't used

Jame 6:18

yeah, I've-- we have used TILAMED. So we've, we've rolled TILAMED into our use in Nador's Royal Infirmary South. And we... I think we're doing it in Nador's Royal Infirmary North as well, but that requires a bit of crossover and a bit of due diligence before you do that. But yeah, it has been done in UK hospitals.

Alyssa Hudson 6:40

Okay, so moving on to dosing. So we'll, we'll talk a little bit more about toxicity later and, and limitations of these different preparations. But standard dosing, so for amphotericin deox- B-deoxycholate is usually one milligram per kilogram, per day. And the, is really limited to that because of issues with toxicity. The standard dose for liposomal amphotericin B is between three and five milligrams per kilogram. the higher dose is five to 10 milligrams per kilogram, and that's used for mucormycosis. And if you have CNS infection, then generally you'd use the higher end of the spectrum, so more the 10 milligram per kilogram for CNS mucormycosis.

Jame 7:37

Right. I'll take the pharmacokinetics. They vary quite widely depending on whether you're using liposomal or deoxycholate amphotericin. But they're all, given IV because they don't have any oral absorption. I think it's important for- people who are using this know what the differences are and why you would-- and, and how that varies, your use. So deoxycholate, for example, will penetrate the CNS, but very low concentrations will be found in the CSF. It concentrates quite well into the urine. So if you're using it to treat urine candidal infections, which I've had to do recently, you would want the deoxycholate version not the liposomal. Whereas liposomal will also penetrates CNS but also has low concentrations found in the CSF. Was not significantly concentrated into the urine and therefore is not suitable for treating UTIs. Concentrates quite well into renal parenchyma, so you can use it to cause pyelonephritis caused by Candida species. And I've got some actual PK data here. So the volume of distribution is between nine point eight and eighteen liters and that increases with increased dosing, so it is not flat. And protein binding is about ninety percent. Both of them are excreted unchanged in urine and bile. In terms of metabolism, both formulations are excreted unchanged. In terms of how they are excreted, about two to five percent of deoxycholate is excreted into the urine, and the rest is hepatic. And ambisome or liposomal amphotercin is excreted extremely slowly over several weeks in feces and urine. Both of them have a very long half-life of about a hundred and twenty-seven or a hundred and fifty-two hours. And the important thing about ambisome is that it's got nonlinear kinetics. Clearance will increase with increased dosing so that's something to watch out for.

Alyssa Hudson 9:25

And then regarding pharmacodynamics. So the PD target is Cmax over MIC. It has good penetration of lung, liver, spleen, bone marrow and kidneys but really relatively poor of the CNS, so low concentrations found in the CSF about 5% of, that found in plasma. And

Jame 9:47

Yeah. that's because some toxicity effects. So like we said, deoxycholic amphotericin is more likely to be associated with these side effects and liposomal amphotericin limits it considerably. But that doesn't mean that it's side effect free. So about eighty percent of patients will either have an infusion reaction or nephrotoxicity. That's less with the lipid formulations. The infusion reactions are, they, they kinda look like they're having a rigor really. They've got fevers, chills, and this is part of a, a pro-inflammatory cytokine response. They can get cardiotoxicity if you infuse it too rapidly. I think that's more with the deoxycholic formulation than liposomal. And hepatotoxicity is an issue as well, and those, metabolic changes that you're monitoring for with use knees and the magnesium are low potassium, low magnesium, and with long-term administration, you can get a anemia as well.

Alyssa Hudson 11:02

As we've said toxicity is much reduced by using,

Jame 11:05

Me? Okay, fine.

Alyssa Hudson 11:06

formulations,

Jame 11:07

so it's,

Alyssa Hudson 11:41

general rule to, to reduce the nephrotoxicity, it's recommended that patients are pre-hydrated before starting amphotericin B. and that you monitor their-- monitor and supplement low electrolytes so let's talk a bit about resistance.

Jame 11:58

intrinsic resistance in some of the things that you mentioned aspergillus terreus scedosporium some dermatophytes, and some fusarium species. Acquired resistance is actually quite rare and is seen usually after long-term therapy but it does occur. I don't really have a lot more detail than that.

Alyssa Hudson 12:18

Acquired resistance. My understanding is that it is rare but been observed.

Jame 12:23

Yeah. I, I couldn't really find a lot when I was looking looking at up things for this episode. I suppose the only other thing to say about ambrisome is that there is an oral formulation in progress, and that's called MAT2203, and that's being investigated in phase II and III trials for the treatment of cryptococcal meningitis. And if that was beneficial, that would be another tool in the arsenal.

Alyssa Hudson 12:47

Hmm.

Jame 12:48

be nice to have another oral formulation of something, even if it's just a me too or me again drug like a oral formulation of amphotericin.

Alyssa Hudson 12:55

It is currently available under compassionate use programs. And it's, it's quite interesting, its

Jame 13:01

it have a name yet?

Alyssa Hudson 13:03

Pardon?

Jame 13:03

Does it have a name yet, or is it just ambrisome with a different

Alyssa Hudson 13:06

I think it is

Jame 13:07

hat?

Alyssa Hudson 13:07

MAT two two zero three. I think that is the name.

Jame 13:10

It's from Matinas Biopharma. Okay. Oral lipid nanocrystal amphotericin B.

Alyssa Hudson 13:16

Hmm.

Jame 13:16

There you go.

Alyssa Hudson 13:18

So it's absorbed from the tract and then absorbed into the bloodstream, and from there it's taken up by phagocytes at the site of infection. So it really allows the drug to be delivered intracellularly to the site of infection. exciting.

Jame 13:36

Yeah.

Alyssa Hudson 13:36

I feel excited by

Jame 13:38

Okay.

Alyssa Hudson 13:38

it. It'd

Jame 13:38

Okay.

Alyssa Hudson 13:39

interesting to see what the, yeah, what the trial data is.

Jame 13:42

Well, let's see if nystatin can keep the excitement going. One suspects not.

Alyssa Hudson 13:49

So nystatin like amphotericin B, it's a naturally occurring antifungal agent but produced by a different bacteria. So it's produced by Streptomyces nauseae.

Jame 14:01

Okay.

Alyssa Hudson 14:02

And got Great spectrum of activity, but its use has been really disappointingly limited because it, it lacks target specificity. So it is more selective for ergosterol than cholesterol but has significant binding to cholesterol. So it's essentially too toxic to be administered, intravenously or even orally. So its use is limited to trop- topical treatment.

Jame 14:30

There are oral formulations, it's just that it's not getting absorbed in significant doses. It's using to treat like, you know, esophageal candida and stuff like that.

Alyssa Hudson 14:39

Yes.

Jame 14:40

It's interesting 'cause y-when you hear that ambisome or amphotericin and nystatin are in the same drug class, they perhaps don't initially seem to have anything to do with each other. Nystatin's just this thing that you, into a patient's mouth, and ambisome is the, the biggest, baddest antifungal out there. But the reality is that nystatin is the biggest, baddest antifungal out there. It just also kills humans, and so you have to give it in human-friendly doses, and that's what's limiting our use of it.

Alyssa Hudson 15:10

No, exactly. Yeah, so it's just for mucosal candidiasis essentially and comes in oral pessary cream lozenge form for treatment of those infections. Mechanism of action, pretty much the same as amphotericin B. Don't think we've got much else to add to that.

Jame 15:30

No, the spectrum is slightly different. So it's notably active against candida and cryptococcus, aspergillus species, and the dimorphs. But is not active against dermatophytoses. So that, that's sort of a little more of a limited range than, than amphotericin that we just went through a few minutes ago. in terms of indications that we have in the BNF, it's indicated for oral candida, oral or perioral fungal infections, and skin things such as vulvovaginal infections and candida intertrigo. There are no UCAS breakpoints, and it is available topically and orally only. And it is not absorbed orally, so it's essentially an intraoral topical therapy. There is no systemic absorption, like you said. When we think about dosing, it's usually given as one ml, which contains one hundred thousand units. Units of what? I've got no idea. I wasn't able to muster up the wherewithal to find that out. But it's a hundred thousand units or one ml four times a day for seven days or continue until forty-eight hours after the lesions have resolved, whichever you want to say. And the topical formulation is Nystiform one percent cream, and then you just apply that to the affected area. I have very little here in the PK and PD, so maybe I'll just run through that and jump to TDM, which also has nothing there. And Alyssa, why don't you tell us about toxicity?

Alyssa Hudson 16:58

So like we said, the, the toxicity limits its IV use. So IV use is associated with nausea and vomiting, diarrhea rashes, facial edema, angioedema, Stevens-John-Johnson syndrome/uh, toxic epidermal necrolysis. So that's why it's not used IV and is only used topically or, or orally. with regard to the, the topical preparations so they can stain. So they can stain clothes a yellow color. they can also damage the latex used in contraception like condoms and diaphragms. So if somebody is using topical nystatin for vulvovaginal candidiasis, for example alternative contraceptive methods are going to be required. And it can be used in pregnancy, again, because it's used essentially topically. So resistance is, is rare. We send quite a few candida isolates to the reference lab in, in patients who have unresponsive mucosal candidiasis. And they do test the candida against nystatin. Super. So shall we move on to the very exciting polyene called natamycin?

Jame 18:13

Well, actually, for a mechanism of action it is slightly exciting, but yeah, I've never used this. Have you?

Alyssa Hudson 18:20

I'm sure we used it in Exeter for a case of fungal keratitis. I can't remember any more details than that, I'm

Jame 18:27

Yeah. I this has gone under my radar really. I've not really heard very much of this at all before prepping for this episode. Natamycin, it is the third polyene. It is naturally occurring antifungal agent isolated from Streptomyces natalensis. Structurally, its core is a macrolide which contains a polyene segment, which is quite interesting. And unbelievably, it's on the WHO essential medicines list which is quite an achievement for quite a small fry antifungal, and it is used as a food additive. So it is an E number. It is E235, so presumably used for its antifungal properties. I don't know. In terms of mechanism of action, it sort of works the same way as other polyenes but slightly different. So it binds ergosterol, prevents ergosterol-dependent fusion of vacuoles as well as membrane fusion and fission, and that inhibits amino acid and glucose transport proteins, and that results in a loss of nutrient transport across the plasma membrane. So it's not quite the same as the other ones, which are just like poking holes and letting the cells bleed out. What does it work against?

Alyssa Hudson 19:33

So like the other polyenes, it does have very broad antifungal activity. So it's active against yeasts such as Cryptococcus and Candida. And it's active against a wide range of filamentous fungi, so Aspergillus Fusarium some mucorales most dimorphic fungi, I believe according to CUSAs.

Jame 19:55

Oh, yeah.

Alyssa Hudson 19:56

so talaromyces as well as histoplasma, blastomyces coccidioides and sporothrix. But it's rarely used against any of these because it's only available as a, a topical preparation.

Jame 20:12

There, there are no UCAS breakpoints. It is available as topical eye drops, Natacin five percent only. There's no absorption from that, and it is overtly fungicidal. I think that's actually all the information that I had on this. Do you have any toxicity side effects, resistance stuff, Alyssa?

Alyssa Hudson 20:32

So I think the, the toxicity is minimal because it's from topical use, so you might get some minor irritation. But I think that's the only documented toxicity. I think thinking about the clinical uses, it is mainly used for, fungal keratitis, such as, fusarium keratitis. I'm not sure if there are other topical preparations for vaginal or, or anything like that or, or if it's just exclusively used for eye disease.

Jame 21:03

I don't think so. So I guess to sum up, if you're treating some-- If you want to use apoline in the eye, you could use natamycin. If you want to use in the mouth or on the skin, you could use nystatin. If you want to use it anywhere else or inside the human, it's amphotericin liposomal or not liposomal.

Alyssa Hudson 21:20

Yeah. And watch for the future of MAT two two zero three,

Jame 21:24

Yeah. We're rooting for you, buddy.

Alyssa Hudson 21:26

Formulation.