135. Terbinafine & Griseofulvin

Terbinafine! Griseofulvin!

2 weird antifungals that the dermatologists use much more than us! 

But we here at the ID:IOTS Podcast love all our antifungal agents equally so here's an episode on literally everything you need to know about both these agents! 

Transcript

Jame 0:18

Alyssa. Good luck with this one. How are you doing?

Alyssa 0:21

I am good. Thank you. Yeah, how are you?

Jame 0:22

I'm fine,

Alyssa 0:24

Are you

Jame 0:25

Uhhuh.

Alyssa 0:26

Hi, fine.

Jame 0:26

I am I'm.

Alyssa 0:28

Tap.

Jame 0:35

No, that's, oh that's terrible. That's as bad as the time I saw that magic eye poster. And then when you looked at it one way, it looked like it was a, like a seal or something like that. And the other one, it was like a truck filled with stuff, so you didn't know what you were looking at. A gray seal or a full van, and what a coincidence that is today, Alyssa is, what are we discussing today?

Alyssa 0:58

So today we're gonna talk about two antifungal agents. Griz, vin, and ine.

Jame 1:03

One of which I've never given. Have you ever given Grier Fulman?

Alyssa 1:07

No.

Jame 1:08

Okay,

Alyssa 1:08

And only a couple of times.

Jame 1:11

yeah, I've used that much more. I have to say, after researching this episode, I don't think that I'll be using Gris vin very much. The reason that we may not have used it very much is that this is really only used for the treatment of Phyt, which Id don't typically get involved in doing. It's the dermatologists that do this, and in fact, a lot of the information that we are. About to say has been pulled in part from Derm Net, who have some excellent articles on these two agents. But the use of terbinafine I'm more familiar with because I am using it for fungal eradication of nail infection, like oncomycosis in patients who have got cellulitis because they had the nail infection that was a potential site of entry. So I do that a lot. Never use fil for it though.

Alyssa 2:00

Yeah, no, same. Yeah, and if I were to recommend, treatment for on Mycosis or Dermatosis, then generally it's, yeah, tine.

Jame 2:09

Yeah. Which one do you want to start with?

Alyssa 2:12

Why don't we start with quiz four then? So as we've said, Griz is an oral therapy for the treatment of Dermatophytes. The drug is actually a fermentation product from the Fungus Penicillium Griz. It's on the WHO Essential Medicines list. And it's mainly used where topical treatment is ineffective or has failed. Although as we've said, INE is generally the preferred agent now,

Jame 2:42

Yeah, particularly for on Mycosis. How does it work?

Alyssa 2:46

So I can give a very brief overview and then you can give the detail. So my understanding is it disrupts. Tubulin, which is required for forming microtubules and pulling apart the chromosomes in dividing cells. It disrupts mitosis.

Jame 3:06

It does that, but also micro tubals are the thing that gives a cell its structure. So microtubules are going from from one part of the cell membrane to the other, and usually they're ending with A-A-G-P-I anchor protein, which is like sticking it to that part of the cell membrane. Microtubule dysfunction is not just an issue with mitosis and meiosis, but also for the cells basic functions. The vinca alkaloids do this. So Vincristine people might have heard of as a chemotherapeutic agent, vinblastine ezine and vinorelbine. Vinorelbine is more commonly used, I think, than the two in the middle that I've just mentioned. But they are, they're messing with your microtubule function in the cancerous cells, and so that's stopping them from replicating as quickly, and Colchicine also does this. Two is part of its mechanism of action as an anti-inflammatory. How's it doing this it's binding keratin in the keratin precursor cells. So that's why it concentrates disproportionately into hair and skin and nails. These are all just variants of skin cells and slowly the keratin is replaced by a keratin greasy NT complex. So it's bound to the keratin. And then it enters the phy, the fungal cell through energy dependent transports, and then binds onto the fungal microtubule. And at that point, mitosis is stopped. That will then lead to the production of. Multinucleate fungal cells. So they will get bigger and they will have lots and lots of nuclei and you might get sensia, but they're not gonna be able to divide and make copies of themselves. And so the infection can't propagate. It doesn't kill the bug, it just stops it replicating. So when I say phys Alyssa what is it effective against?

Alyssa 4:56

So it has activity against Trico Fightin, epiderm, fightin, and micro spor. But it's. Most active against micropore over the others. And that's where it differs really from tine which has better activity against Trico Fightin.

Jame 5:15

Why you would want to use Turine for a nail infection'cause that's more likely to be caused by Tratton.

Alyssa 5:20

Yeah, so I think the most common cause of Dermatosis is Trico Fightin Rubin.

Jame 5:26

Okay.

Alyssa 5:27

I'm not sure if it's also the most common cause of Oncom Mycosis but I know that in the uk that's the one we most commonly commonly isolate. We need to go back to the the episode, a hundred and twenty three. That was molds, phys, where we talked about the different dermatophytes and and their clinical manifestation. Yeah, more detail. Whereas it doesn't have activity against other, fungal pathogens that can cause oncom, mycosis and fungal skin infections such as can albicans, aspergillus, and malasia. So it's only active against the dermatophytes. And apparently it's efficacy is improved with the couse of selenium sulfide shampoo, head and shoulders. Top tip.

Jame 6:15

Do you want to take us through a detailed breakdown of all the various breakpoints and ecos and tentative ecos for.

Alyssa 6:23

Yes, there aren't any.

Jame 6:24

Okay, fantastic. And therefore no UCA spray points either. I'll talk about the pharmacology now. The dose is very simple. It's 500 milligrams a day for severe infections. You can double that. And you can either give that as a gram once a day or 500 bd. There's also a mention that you might want to use a gram once a daily for trick fight on toran causing tinia capita. It's very rare actually that you know what the organism is. But just to say that there are some dermatosis where you might want to use the higher dosing. It's only oral. And the you give it for varying durations. So between one to three months for hair and skin infections, six to 12 months for nails or other sources have said four months for fingers and six months for toes. And this is related, I think, to the rate at which these nails grow. So the toes grow slower and you need to wait for new uninfected nail to be laid down before you stop therapy. Most places will say something along the lines of continue treatment until two weeks after all signs of infection are resolved. So that's the other way to do it, is to, instead of setting the duration, just say when the nail looks normal, then you stop. But that obviously has the potential to for treatment to continue past the time when it would be giving any benefits. In terms of cost, it's about a pound 13 a day. It's quite expensive given that you're going to be giving it for, six months or so. But I suppose actually the a six month course, say that's 180 days, that would be, 190 ish pounds, less than 200 pounds. Whether or not you want to spend that amount of money to getting rid of a dermatosis I suppose it's up to you. We have some information on the pharmacokinetics. Of vin in the prep notes, if you want to go and have a look at it in brief, it's about 50% bioavailable, but like I say, distributes disproportionately to keratin containing cells and therefore phy deifies themselves hepatically metabolize and is excreted in the urine. Although of course'cause dermatosis don't cause UTIs will be of no use to us in our ongoing struggle against treating fungal urinary tract infections. there's very little data on resistance or anything like that. And there's no TDM either in terms of side effects, Alyssa.

Alyssa 8:52

Yep. Common side effects in include GI upsets, so nausea and vomiting, diarrhea transient headache. Less common side effects include fatigue and a rash. And then more severe side effects are generally very rare. Dermatological issues such as Stephen Johnson syndrome, toxic Epiderm, necrolysis have been reported, but a rare can cause LFT derangement. Although again rare and have, can have some neurological squali such as causing confusion, dizziness, peripheral neuropathy, and d dryness. But again, rare with regard to toxicity it's recommended that it's avoided in liver failure because of the potential for LFT derangement and can also exacerbate systemic lupus erythema ptosis and should be avoided in porphyria.

Jame 9:44

Yeah. It's also a three a four inducer. So it would reduce the levels of things like warfarin the pill they actually recommend using alternative precautions up to a month after stopping ful and cyclosporine and stuff like that. And there have been case reports of a dis suum like reaction with alcohol. But then again, that's also true of metrosol. And that single case report has now managed to make its way into the BNF and every MRCP exam ever. Now that's vin. It's not very commonly used, certainly not by us. Let's talk now about Terbinafine which I do have experience of as you do as well, probably.

Alyssa 10:18

Okay. Yes. So Tine is used for treatment of Dermatosis including Oncom Mycosis. And bitters s Law it was initially discovered in 1991 and it's like Orin. It's on the WHO Essential Medicine list regarding its mechanism of action. So it's a squalene oxidase inhibitor. And essentially squalene oxidase is an enzyme that's important in synthesis of sterol, which is key component of the fungal cell membrane. Tine inhibits squalene oxidase, which prevents the conversion of squalene to Lan Nool, which is the precursor of Ole. And in doing so, disrupts the fungal cell membrane leading to to cell death. So do you wanna tell us what's it active against?

Jame 11:17

Yeah, so this is more active against certain derma fight species, particularly Phyton, but it's also active against candida and malatia. So I dunno if this has got a role in pet versus color. But but maybe useful. It's not really effect against anything. Anything else really. So just phys and other stuff, which can also cause oncomycosis, like candida on occasion. There are no break points. There are no ECCOs, but there are T coffs or tentative ECCOs against phyton, inin and rubrum, which are not 0.1, two, five and not 0.3 respectively. Can understand that ucast are not spending their time concentrating on tine breakpoint and seeing as no antimicrobial testing is done for anyway. These drugs are invariably used empirically.

Alyssa 12:11

I just wanted to flag up tine does have a role in the treatment of rare invasive mold infections. So if you go back to episode 122 we did discuss this that was an episode that we recorded with Neil Stone. So the ECMM have guidelines for the diagnosis of management of rare. Invasive mold, infections some of these infections are incredibly hard to treat with very limited treatment options and ine is used. As an adjunct to other systemic antifungals for the treatment of these. So Lamento Spora it's used first line as an adjunct for a conazole, and then for some of the other mold infections it's used more as a salvage. Alternative first line therapy or a second line or salvage therapy. So that's just to be remembered that it, it does have other applications as well.

Jame 13:07

I've put a link to that in the prep notes while she were talking there, Alyssa.

Alyssa 13:10

Oh, amazing. So dose it's available as a tablet 250 milligrams once a day. It's cheap as chips. So it's about eight pence a day. It's also available in a cream form that can be applied to the skin or to the nails. And then with regard to duration of treatment this really depends on the site of treatment. For, skin infections affecting the body. About four weeks for the groin area. So 10 CROs, two to four weeks for the feet. Like athletes for two to six weeks nails, as we previously said, require longer course of treatment. So between six weeks and three months, generally longer for the toenails. Because these are more slow growing. And then it can also be used topically to treat psis. And that's usually for two or more weeks.

Jame 14:06

So for pharmacokinetics, about 80% bioavailable. But after first pass metabolism that drops to 40, it's very extensively ly metabolized by two C nine three A, four two C 19, and a few others. But those are the big hitters. It's very lipophilic and concentrates into hair and skin and nails. Very protein bound as well, which I thought was a bit surprising considering it's concentrating into these peripheries. And half-life is about 36 hours. So once a day dosing is perfectly fine. For it. 80% eliminated renally and 20% in feces. It's. Penance is good into the skin, hair and nails and its penance is poor to everywhere else. And there's not much more to say about that. There's a little TDM that sometimes people talk about there's no hard and fast guidance about it. Some people recommend checking the LFTs four to six weeks after starting treatment, and that's because. It's uncommonly associated with drug induced liver injury, and that onset is usually at about the 30 day mark, but can be up to three months afterwards, so a four to six week LFT to just make sure that's not the case. There's very little I could find on resistance. There was a trick fight and rubrum isolate that was identified in 2003. There were. 5,000 samples of Tri Phyton that were tested about 0.83%. They had some evidence of resistance on phenotypic testing. And what is the mechanism? About 98% of it is a squalene oxidase gene snip and. The other 2% was a nine base pair deletion leading to a three amino acid deletion in that same enzyme as well. Resistant, not a big issue, although, Alyssa, you've got a little point here on Trix. Fightin in Dein.

Alyssa 16:02

Yes. I guess this is the big news. In the world of phys. So again, we talked about this in episode 123. So Tritin Nin is a novel dite species. It's anthropos, it's spread between, humans and importantly, it's tine resistant, our first line agent for treating phyt. And this is due to mutations in the squalene oxidase gene. So this organism is now really common in Indian Southeast Asia. It causes severe, difficult to treat tenia particularly in the groin also of the face. And body that's characterized by lots of inflammation and itchiness. And there's been evidence of transmission sexually and numbers are increasingly being seen in the uk. So a big area of concern and treatment of these is really challenging.

Jame 16:57

So is there a role there for Aris Vin? Then in, in that kind of infection,

Alyssa 17:03

That's a really good question, actually. It looks like try. Itraconazole is generally the first line therapy for it.

Jame 17:12

I think it's interesting. Most dermatosis in the UK will be treated without the involvement of infectious disease And will only get called to the cases where there's a reason that you can't use the first line therapy. So there's some intolerance or allergy or something to tine or it hasn't worked. And I suppose that TriFit and nin eye infections. Coming into the UK from abroad might be a reason for us to get involved and have to suggest alternative agents. Some loyal listeners may query why we're wasting our time on something as small fry as Garcia Vin.'cause sometimes you might be contacted about it even though you've never used it, and you'll need to give advice on whether or not it is appropriate. Yeah. What about toxicity Alyssa?

Alyssa 17:58

Fairly common side effects include skin rashes GI disturbance, headache myalgia. it can cause a worsening of psoriasis and systemic lupus, erythema ptosis. It can also cause derangement of LFTs so particularly transaminitis. Although there isn't any clear guidance on frequency of LFT monitoring.

Jame 18:23

Yeah. There's a little something. We talked about it in TDM bit up there, maybe you weren't listening.

Alyssa 18:27

I wasn't listening.

Jame 18:28

Fine. What about interactions?

Alyssa 18:29

So it induces cytochrome 2D six. So it can reduce levels of number of drugs including antimicrobials, say Fluconazole and Rifampin. CNS active agents such as Peroxetine and Phenytoin cardiovascular agents such as metoprolol, simvastatin, nifedipine, digoxin, and then other agents include cyclosporine codeine and sedine. So quite a few potential drug interactions there.

Jame 19:01

And that's all that we had to say with Terbinafine and Gren. Not very

Alyssa 19:06

Exciting.

Jame 19:07

exciting drugs and not novel particularly, and not very rarely used to treat anything like invasive disease, but good to get your head around them. I didn't really know very much about either of these drugs. Until I start doing the prep for this episode, so at least it can be a resource to refer back to if you get ever asked about difficult to treat Dermatosis on your on call.

Alyssa 19:31

Amazing, and I hope you're feeling to fine.

Jame 19:34

I'm, I am. Thank you. Thank you, Alyssa. A call back at the end, the loyal listeners will be very happy.