137. Flucytosine

Flucytosine. A much maligned antifungal, consigned to adjuvant use in Cryptococcus... 

WELL THAT CHANGES... well not today because the resistance barrier is shockingly low, but at least in 20m time you'll know all you need to about 5-FC! 

Transcript

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Jame 0:18

Alyssa, how are you doing?

Alyssa 0:21

Hi,

Jame 0:21

Hi, Jane. I'm

Alyssa 0:22

I'm

Jame 0:22

good, thank you. How

Alyssa 0:23

How are

Jame 0:23

you? I'm fine. Have you received that periodical about pandemic outbreaks of viruses and where they are? It's a really, it is a really important flu site. Oozine. I'm surprised you're not on the mailing list, but what a coincidence that is, Alyssa. 'cause what are we discussing today?

Alyssa 0:41

So today we are gonna be talking about the antifungal drug flu.

Jame 0:46

Right now, have you ever used this in anger, Alyssa?

Alyssa 0:48

So I've only ever used it for cryptococcal meningitis. And also an interesting case that we had down here in Devon of a patient with invasive f Aosis of the spine that was very resistant. and we ended up treating them with Fluconazole and flu. Citabine was recommended. As a potential agent with Synergy. So that was quite an interesting case, but I think quite an unusual use of Flucytosine.

Jame 1:18

How about you? I have considered using it a lot. I've considered using it for urinary tract infection because it's one of the few antifungals that has decent urine penetrance, but I have shied away from doing it at the last minute, multiple times because of resistance issues that we will talk about momentarily. I've used it in a couple of cases of cryptococcal meningitis as well as you have done, and that's about it really. I, this is not uncommon usage, but I wonder if as time goes on and we get more and more antifungal resistance that we will return to Flucytosine more and more. And also from pharmacological pharmacokinetic point of view, this is by far and away my favorite antifungal. I had an absolute blast researching all this, and I can't wait to get into it.

Alyssa 2:06

He is such a geek.

Jame 2:10

Why don't you get started with a little potted history of flu citabine which now the loyal listener knows I wrote. But it's nice to have a little back and forth. Okay?

Alyssa 2:19

Flucytosine is a fluorine,

Jame 2:24

Yep. So it's tine, but with a fluoride group stuck on the end.

Alyssa 2:28

Okay. So it's essentially, my understanding is it's

Jame 2:32

A synthetic analog.

Alyssa 2:33

of cytokine. And it causes mischief RNA and DNA synthesis

Jame 2:41

Yeah.

Alyssa 2:41

disrupts, Protein synthesis. So it's an anti metabolite essentially. And it was initially used as cancer chemotherapy but toxicity limited its use. And then in about the 1950s, its antifungal properties were discovered and the drug was repurposed and licensed as an antifungal in the 1970s. It's mainly active against yeasts. So its main uses are for treating cryptococcal meningitis. And this is in combination predominantly with liposomal amphotericin B but also in combination with Fluconazol. And it can also be used

Jame 3:22

Treating

Alyssa 3:23

candida

Jame 3:24

infections

Alyssa 3:26

and

Jame 3:26

and

Alyssa 3:26

of infections of deep cyto endocarditis, osteomyelitis endophthalmitis.

Jame 3:31

I will take the mechanism of action now. I've been looking forward to this for weeks. So five fc Why is it so interesting? It's an analog of five FU, which is a more commonly used anti anti-cancer agent there. And what five FU is doing in. Human cells five FC is doing in fungal cells. So what is it doing? It doesn't have any antifungal activity on its own, and it is imported into the cell by transport protein called cytosine permease. And so once it gets into the cell, it then gets deaminated. It's converted by Cytosine Dease into its active form five FU five fluoro, uridine tri phosphate, and humans don't have this cytosine dease enzyme, unlike fungi and precarious. So that explains its specificity for fungi, but not humans. And why it wasn't a particularly good anti-cancer agent in humans. Presumably they were having to use absolutely massive doses to get any effect. So it's derated into five FU. It's then incorporated into fungal RNA, a bit like five FU would be incorporated into human RNA where it replaces uracil or UMP. And that inhibits protein synthesis. Also the conversion of five FU into fluro UMP, which I'll talk about in a sec. Blocks di eight synthesis and therefore the the. Synthesis of DNA. So that enzyme is important for DNA synthesis, and that results in unbalanced growth and the death of the fungal organism. And what's the difference between UMP and uracil? Uracil is the nitrogenous base. So the PERINE and UMP or uridine monophosphate is a nucleotide. The uracil bonded to a ribo sugar and a phosphate group. So basically, UMP is the phosphorylated form of uracil, so we'll use them interchangeably. Specifically to annoy all the geneticists in the audience. But functionally these are as far as an infectious disease doctor goes the same thing. And already judging from the lone your face far too much detail.

Alyssa 5:34

Yes.

Jame 5:34

Okay.

Alyssa 5:35

yeah, that's, it's quite complicated, but there's a really good flow chart in the show notes which. Of explains

Jame 5:42

And linked to the paper that it got stolen from as well which I'm trying to do more of. Do you want to tell us about the spectrum?

Alyssa 5:48

So the spectrum of activity, so it's mainly active against yeast. So predominantly it has very good activity against candida. and crypto occus less so potentially against Candida, Orus and Candida. But good activity against the other candida species. It also has some activity against Demetrious. Fungi. So these are filamentous fungi that have melanin in their cell walls and give them a dark brown black color. So examples of these are Claudia Spora OPH, Fiala and these are the organisms that cause fao Hy Mycosis. So infections such as a chromo blasts mycosis But aside from that, it doesn't really have activity against other filamentous fungi, so it's not active against aspergillus mu the dimorphic fungal pathogens.

Jame 6:46

So with those exceptions, it's not mold active really. So if your mold is Highline then. Forget about it. You're not gonna be able to use it.

Alyssa 6:53

Yeah. I think the main thing to think of is that it's always used in combination with another fungal agent. And we'll come on a bit about why later, but it's not used as a monotherapy even for treating. Yeast infections.

Jame 7:07

Let me chat a little bit specifically about Aspergillus. 'cause occasionally it gets muted as a potential additional therapy or combination. Therapy for Aspergillus, its efficacy seems to depend on. The pH. So I've taken Asperger's fag as an example. So if the pH is seven, the MI cyl flut will be quite high. But if the pH is five, it will be lower. And this has led to the idea that in low pH environments, five FC might have some benefits. If added to another effective therapy. There has been a small study actually on patients with invasive aspergillosis, hematology oncology patients where five FC was added or not added to Amerin B, but that study didn't show any benefit. So I think the jury is very much out on this, but my inclination would be not to use it. The only indications in the BNF. Are for systemic fungal infections and cryptococcal meningitis as an adjunct to terin. That's all it says, really. So you already know more than you would find if you were reading the BNF break points Alyssa,

Alyssa 8:14

so there aren't any clinical breakpoints but there are some tentative ECCOs given by Ucast. And James included a table of those in the show notes.

Jame 8:27

Yeah. Most of these are t coffs as well indicated by the brackets. The only one that isn't is the EEC O for candid albicans and iris, which is not 0.5. So yeah, not very much. To base yourself off there. And in fact, susceptibility testing for flutes is very difficult, so we have to send it to our ref lab down the road. I don't know if you are able to do it locally.

Alyssa 8:49

No,, it would be to Bristol.

Jame 8:50

Yeah. Let's talk about the pharmacology now. So in terms of. Availability is available, IV or oral. And the oral is available as either tablets or oral solution. The dose is either 100 to 200 milligrams per kilogram per day, and usually that's split into four doses. So if you were giving 25 to 50 milligrams per kilogram four times a day. And if you're giving it an IV infusion, the infusion would usually go over 30 minutes. We've got some doses that I pulled from the E-C-M-M-A-S-M-I sham guideline for invasive candidiasis and for CS infection, they. Advise 37.5 milligrams per kilogram, six hourly. So that's halfway between the 25 and the 50. And then for endocarditis, it's 25 milligrams per kilogram, six hourly in combination with amphotericin. So if you're using it, you're using it for, a candal. Endocarditis. I've never heard of a cryptococcus endocarditis. I don't know if it can do it, but yeah, you would be giving the lower dose, a hundred milligrams per kilogram per day. In terms of the pk, it's between 70 80 to 89% bioavailable, which is highly buy available. If you can get it. Orally, then I think that would be okay as long as the patient could take it. The disadvantage in the UK is that we don't have easy or ready access to the oral formulation. We only have it available iv, and if you were wanting the tablets, you would have to import them.

Alyssa 10:18

Just talking about availability globally, I think one of the major issues with Flucytosine is that it doesn't have, availability across wide parts of the world including in countries where, there's a higher incidence of. A critical disease. So lots of parts of Africa doesn't have access to IV formulations. And I

Jame 10:41

So they have the opposite problem to us is that they can get the pills. They just can't give it to somebody who can't swallow.

Alyssa 10:46

Yeah,

Jame 10:47

I think

Alyssa 10:47

I

Jame 10:47

it's,

Alyssa 10:47

an issue with, lots of antifungal drugs globally, that there isn't global access to all of these formulations.

Jame 10:55

yeah. In terms of distribution, it's very highly water soluble, so it gets very good penetrance into the tissues. It's about 28 to 30% protein bound, giving a volume of distribution of between 40. Two to 63 liters. It is not very well metabolized at all. It's essentially mostly excreted unchanged unless you give absolutely massive doses, in which case the bacteria in your gut will deaminate the five FC to convert it to five FU. Give you human toxicity because if you get absorb a load of five FU after the bacteria have done all the converting for you, you'll get five FU related side effects that explains some of the toxicity with higher doses. In terms of excretion, it's about 90% excreted renally. And that gives a halflife of between 2.4 to 4.8 hours. In terms of pd your PD target is time over MIC of about 45% in UCaaS Monte Carlo simulations at least. And the penance is said to be good into the urine vitreous fluid, where it's about a hundred percent of plasma. And the CSF. But poorly penetrant into lipid and fat. And presumably also the intracellular compartment. Yeah. What about the TDM Alyssa?

Alyssa 12:11

So TDM is recommended in certain high risk groups for flucytosine. In pediatrics patients with chronic kidney disease or if toxicity is suspected. And in these high risk groups, it's usually done within 72 hours of starting therapy. And it's also recommended that EUIs and LFTs are monitored weekly whilst patients are receiving flucytosine. So the target levels are 20 to 50. Milligrams per liter for pred and 50 to a hundred milligrams per liter for post dose. And low pred dose concentrations are associated with treatment failure and emergence of resistance. pred dose less than 20 and high post dose concentrations over a hundred have been associated with toxicity. and generally the re assay interval is every four to eight days. That's when you're gonna send your repeat levels. Yeah, and I guess that interval depends on, if it was in range or not in range when you first

Jame 13:17

Yeah so I guess if you're worried about toxicity, you may just want to do a post dose or if you were worried about the efficacy as well a trough as well. But let's talk about that now, because the loyal listener may be listening loyally to all this thinking, this seems like a great drug. Why am I not using it more and more? Because the resistance is really easy to acquire. That's why. So it's got a very low resistance barrier So baseline in vitro resistance by species it's about. 7.5% for candida albicans, 22% for other candida species, 45 to 60% for candida Iris. So very rarely would you be able to use it for Iris. For cryptococcus, it's much lower. It's about one to 2%. But the issue is that there are lots of ways that you can become. Resistant to octine. And the main two methods are mutations in the enzyme responsible for the uptake in metabolism of flu citabine, or increased production of perine, which then competes with five U and overcomes the mechanism. Increased perine synthesis by the fungal cell, but taking the other taking the first mechanism for a moment. There's the FCY one gene, it encodes cytosine dase and that limits the co conversion of five FC to five fu. There's the FCY two gene, which is a purine cytokine permease, which reduces the uptake of five FC into candida, and about 10% of candida albicans resistance is explained by that mechanism. And lastly, there's FUR one, which is Sal phospho rib oal transferase. And that reduces the conversion of five FC to five UMP. And there's a couple of different ways they can do it. Candid Iris does that due to a missense mutation in FUR one. But those are the main resistance mechanisms that I was able to find. And then this means that when you use it particularly as monotherapy, you really have to watch out for resistance erging. So if you use it for a Candida UTI, it'll fail about a quarter of the time. As monotherapy. So it'll be successful three courses of the time. So it's not to be completely ignored, but a 25% fail rate is not to be sniffed at candida. Glabrata is less common and apparently that's partially explained by the fact that Candida GTA is haid. So it's only got half the DNA that the other candidates have. So mutations and resistance are a bit less common there with. Crypto Occus, we just said that you need to watch out for it being below the MIC, but when resistance does occur, it can occur in crypto Occus even when the FC levels are above the MIC. So even if you're within the therapeutic range, you can still get resistance emerging. So that is what happens if your flu tine level is too low. What about if it's too high? Alyssa, tell me about toxicity.

Alyssa 16:08

So it's generally a well tolerated drug. And I think the most common side effects are GI related, so nausea and diarrhea. But other potential complications are blood disorders. So it can cause a degree of myelosuppression confusion. Cardiotoxicity. And as we've said, GI disturbance.

Jame 16:32

And all of these are things that Five U gives you. So I'm presuming that this is all five U conversion. If you give the dose, if the dose is too high.

Alyssa 16:40

Yeah, toxicity is particularly seen if the level is over a hundred milligrams per liter. And again, this is mainly GI disturbance, but also liver toxicity and myelosuppression.

Jame 16:54

And the last thing to mention, if you look this up in the BNF, they'll mention something about DPD toxicity. This is a dihydropyridine dehydrogenase and this is a thing which metabolizes five U in humans and. DPD deficiency is not very common, but is associated with life-threatening toxicity. So if those bacteria in your gut metabolize five FFC to five FU for you, you better have a way of dealing with it. And if you don't, you're going to get an acute myelosuppression GI disturbance, diarrhea neutropenia and neurotoxicity and DPD enzyme activity varies in humans, in Caucasians. There's a complete deficiency in not point, not one to not 0.5% and a partial deficiency in three to 8%. So that's just something to watch out for. And in fact, I think that BNF. And there's been an MHRA alert about this as well, advises testing for DPD deficiency if you're going to use flu tine for more than a few days. So I'm not sure if the treatment for cryptococcal meningitis, if it would really be worth doing that, but if you're going to use it for longer than that, yes, you do have to think about that at least

Alyssa 18:05

Ah, interesting. Okay. I hadn't heard about that at all.

Jame 18:08

And that is that,

Alyssa 18:09

Super. Fantastic.

Jame 18:11

Do you think you'll be using this,

Alyssa 18:12

obviously in the guideline context for, Crile meningitis but. I think outside of that I probably only use it in discussion with the experts. So the ology reference lab I think, like you said, a really interesting potential use is in a canida urinary tract infection where organisms fluconazole are resistant. so it is a potential option there. But with the caveat that it would be used essentially, I guess as monotherapy. So then resistance would likely build up or develop.

Jame 18:52

Yeah

Alyssa 18:53

what about you? Do you think you'll be,

Jame 18:55

I will

Alyssa 18:56

it?

Jame 18:56

consider using it multiple times. But I don't think I'll be using it very commonly, let's put it that way. So I had a difficult case. It was candida, zi eye, I forget which. But anyway, it was in a urinary tract and it was very difficult to get rid of, and it kept on coming back. And I considered it using it for that case. And it, it turned out actually that the patient had stones in the urinary tract that were untreated. So if I had used it in that case, I have no doubt that the bugs that were sticking to the outside of that stone would've simply acquired resistance to flucytosine carried on with their day. So it would've only worked once or twice. So if you are going to use it in the urinary tract. You better make sure that there's no NIUs of infection remaining. No stones, no metal, no abscesses, because if you do, and the bus can hide temporarily, they're just going to acquire resistance and then come right back at you. So you will have just wasted your time and your pharmacist time because you will not. Likely have this in the hospital unless you work in a big tertiary center. I'm sure you use it for cryptococcus a lot, but for other stuff, maybe not. I guess the CNS infection, it might be worth considering if your back is to a wall and I note here at the end a little thing, seeing that. There have been reports of reducing RO toxicity when used in combination with amphotericin, and people aren't too sure as to why, but they think it's just that if you're giving IV flutes, you're actually giving quite a lot of sodium chloride, so you're giving it in saline, and so maybe that's got a partially renal protective effect.

Alyssa 20:33

And the review article that James included a link to in the show notes has a really nice sort of summary overview of Flucytosine and also the different uses of Flucytosine. So said the main one being Cryp Cocal meningitis. But also candida of deep sites where Flucytosine has good concentration and penetration such as the nu tract CNS. The eye is another one. So well worth having a read, and particularly if you're considering using flucytosine.

Jame 21:05

Yeah, so that's RA and Denning 2023 in therapeutic advances in infectious Disease. Worth a look there.