Warren S Joseph, DPM reviews the different types of tinea pedis and discusses the most current treatment available to eradicate each variety. Dr Joseph also reviews the efficacy of these medications, specifically topical vs oral options.
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Warren Joseph, DPM
Roxborough Memorial Hospital
Editor - Journal of the APMA
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Male Speaker: Our next speaker loves to come to Desert Foot to speak. I almost fell over, I almost thought that I saw him actually wear a tie but I was wrong. I was wrong so he didn’t surprise me. Probably the infection that is inadequately treated or one of the infections is inadequately treated is tinea pedis. A chronic problem for patients with diabetes especially those with autonomic neuropathy and dry skin and can lead to fissuring and some very significant problems especially with people in PAD. We’ve asked our friendly podiatrist, Dr. Warren Joseph to come and speak with us. He’s pretty happy to come to Phoenix now because he’s just finished building his house up in Sedona, one of our favorite places in the world. He knew I like to go there so he went there and he started to build the house up there because I can’t afford to build a house up there.
Warren Joseph: Because you work for the VA.
Male Speaker: Because I work for the VA. But I get to go there whenever I want to. Okay, so let’s welcome Dr. Joseph. Tinea Pedis: You Need to Treat It. Dr. Joseph.
Warren Joseph: Thank you. Well, we’re still planning on that clinic treating onychomycosis with crystals right? We have to lay those crystals on, the vortex is in the crystals, yes. It’s a very Sedona thing to talk about. The reason I do not wear a tie is basically because they’ve been found to be vectors from MRSA. I do treat patient sir, I was in the hospital yesterday. The other reason I don’t wear a tie is because frankly I’m too fat for my collars to close over my neck. I’m sorry by that’s the way it is. Anyway, I got a couple of talks here at Desert Foot, three of them are on fungus and one is on diabetic foot infections and bacterial infections. The first one we’re going to talk about is tinea pedis and why this is an infection and you need to treat it. Now, I usually talk about this when I talk about onycho also and when I say onychomycosis, I say tinea pedis I mean the same thing because as you’ll say these two are very closely linked. I don’t come to this as the average person comes to tinea pedis and onychomycosis. I mean, if you read the literature on onychomycosis and tinea pedis, what especially usually write dermatology. Why does dermatology write it? Because they look at this as a skin condition. They look at this as a disease of skin and nail. See I don’t do that. I come with the infectious disease bias. I look at this as an infection of skin and nail and subungual stratum corneum. And therefore you need to treat it with an anti-infective. I don’t care if you have got an antibiotic, if you got a bacterial infection you need an antibiotic. If you got a fungal infection you need an antifungal. That’s why I look at this as being an infection and you need to treat infections. Just as a disclosure coming from the antifungal side I’ve been a speaker and a consultant to Valeant which used to had Pedinol but it is now just Valeant. The learning objectives we’re going to recognize tinea pedis as an infection that can have significant sequelae, understand the differences between various classes of antifungals and then talk about use of antifungals and we’re going to finish off talking about pharmionics which is the study of adherence, patient adherence. Let’s first talk about this onychomycosis and tinea pedis connection. Some of you will be in my lecture tomorrow on onycho, I’ll touch on this again. These two are inexorably linked because it’s the natural history of the disease. See, onychomycosis starts as tinea pedis. The fungus infects the skin, there’s some trauma to the hyponychial seal which allows the fungus then to invade up under the nail and invade the subungual or nail bed stratum corneum setting up onychomycosis. You really can’t have one without the other. All patients who have onychomycosis either have had or do currently have tinea pedis. But this is where that becomes important. You can’t treat one without treating the other. We’ve got lots of topicals we’re going to talk about today for both onychomycosis and tinea pedis. My onycho lecture when I talk about the two new topicals that are out. Well, let’s say you use one of those topicals we’re going to talk about now on tinea pedis. Well, what happens if the nails are still infected? The nail access a reservoir to reinfect the skin. Likewise, if you use one of the new topicals we’re going to talk about later this evening on the toenail and you clear the toenail, often you clear toenail with an oral antifungal but you haven’t clear the skin then you go back to this natural history situation where the skin is going to reinfect the nail.
This is just a picture of one of my patients where you can see that classic serpiginous lesion with a peripheral scale in the central clearing and you could see the break in the hyponychium, you can see obviously how the fungus is going to invade up under the toenail. This is just a cartoon I had drawn up, here you see tinea pedis comes up under the toenail, this is the moccasin distribution of tinea pedis. Now you’ve cleared the tinea pedis with the topical antifungal but the nail is still infected, the nail now access the reservoir to reinfect the skin. You always have to treat both. Now that was always really nice about the oral antifungals because when we’re using the oral antifungals let’s say terbinafine or terconazole you use the pill and that takes care both of them. But if you’re only using the topicals, make sure you’re going to treat both. I know you hear the word epidemiology and your eyes all glaze over and I apologize for that but if we look at epidemiology, we have to talk about the pathogen. The pathogen and tinea pedis is going to be the same pathogen as onychomycosis and that is the dermatophyte. The dermatophyte by definition is a fungus that’s capable of digesting human keratin and by digesting human keratin it leaves off of that and can sustain itself by just eating up the stratum corneum. The organisms to do that in particular are Trichophyton rubrum and to a lesser degree in tinea pedis and onychomycosis Trichophyton mentagrophytes which is now called T. interdigitale. They change the name of that a little bit. There are also other dermatophytes, microsporum, epidermophyton frankly, I don’t think they cause much. I don’t remember the last time I’ve seen a microsporum or epidermophyton infection. Types of tinea pedis. Well, I do a lot of the speaking engagements for the different companies with tinea pedis drugs and in the commercial decks that they always give you, they are often vetted by the crack legal team from whatever company. They always talk about interdigital tinea pedis is the most common form of tinea pedis. I don’t buy that. I think moccasin is far more common than interdigital. Why do you always here that interdigital tinea pedis is the most common? Because every antifungal that’s out there is FDA approved for the treatment of interdigital. Alright, none of them are approved specifically for the treatment of moccasin tinea pedis even though it’s the most common. Now, I will show you some data. At least one study has finally collected some data on moccasin tinea pedis and that’s the naftifine 2% and I’ll show you that data in a little bit. Vesicular tinea pedis are aggressive disease as usually caused by the T. interdigitale is a more aggressive organism. In fact in all tests that used to be used in the laboratory to differentiate T. rubrum from T. mentagrophytes was called the hair penetration test. What they would do is they would take some liquid media and they would have either T. menta or T. rubrum in there and they will put a human hair in. If the fungus grew around the human hair on the surface, that was T. rubrum. If it actually penetrated the human hair, that was T. mentagrophytes now T. interdigitale. It’s a more aggressive organism that attacks the stratum corneum more aggressively. Then there’s interdigital tinea. Now, back in the late 1980s, Jim Leyden of University of Pennsylvania came up with a classification of interdigital tinea pedis that he called either dermatophytosis simplex or dermatophytosis complex. I’ll show you the differentiation of those in a second. This is your classic moccasin tinea, you can see the scale, you can see here these little almost like papules, what’s happening is this patient have a genetic predisposition to not be able to fight off the fungus and we’ll talk about that when we talk about more about onychomycosis as an infection tomorrow. What happens here is it just causes hyperkeratosis. You can see all of that scale. But notice the dorsal skin. The dorsal skin tends to look fairly normal therefore it is not xerosis. Many patients came in saying, “I’ve got dry skin.” Well, it’s not dry skin, in fact it’s tinea pedis. And this is just an example. Is this dry skin or is it tinea? How did we know for the first time for sure that this was tinea pedis? When we started using the antifungals. Patients would come in and what’s the first thing the patient would say, “Doc, my skin looks great. I’ve been using all these moisturizers on my skin for all these years and nothing helps.”
“Now that I’m finally using this antifungal, look at how good my skin looks.” That’s because the dry skin was in fact a fungal infection. This is vesicular tinea pedis. Now, notice this is a very classic appearance. It’s almost pathognomonic where you get the roof of the bulla with lots of these little punctate dots all over the place. As you de-roof this bulla, you see septate that run from the roof of the blister down to the base of the blister. As you pull that away, those septate, we track into the base of the blister and you got a very interesting reticulated pattern. Here is an interdigital and you can see where you’re starting to get that little reticulated pattern and then we débrided the rest of this away here. You could see all of these. These are the septate that were attached to the roof of the blister that once you pulled it off, come down and just settling on the floor. This would be your T. interdigitale sort of vesicular tinea pedis. Now, I mentioned Jim Leyden, Dermatologist at Pen. He did a study where he took college students and with these college students, first thing he did is he diagnosed this dry scaling interdigital infection. He called that dermatophytosis simplex. Then what he did is he took these feet and wrapped them in occlusive wrap like Saran Wrap. What he found is this dermatophytosis simplex would convert to a dermatophytosis complex. This is where you got the runny, smelly inflamed sort of interdigital infection. Well, we see this and what do we do? We jump on antibiotics and all sorts of oral antifungals. Well, Leyden said is if we create this complex, just by occluding the environment, let’s change the environment and reverse it. In fact, what he did by reversing the environment, by drying out the interspaces, he was able to convert a dermatophytosis complex back to a dermatophytosis simplex. When you see this, you don’t necessarily have to freak out and start using all these oral antibiotics and oral antifungals and topical creams. You can basically just turn around the environment and convert it to back to a simplex and then treat the simplex. Alright, treatment of onychomycosis or excuse me, tinea pedis, you have to make the correct diagnosis, that so called dry skin as I mentioned is probably actually tinea, treat the onychomycosis if it is there. Then there are all sorts of topicals, creams, gels, solutions. Most of those clinical trials as I’ve mentioned before look at interdigital and not plantar moccasin tinea pedis. At the end, we’ll just touch on where you would use orals. I love clinicaltrials.gov. It’s a cool website. Basically, you can just put in a search term and you can search every study pretty much as being done anywhere in the world. And I did this about a year or so ago on tinea pedis. I did it just yesterday on onychomycosis. I’ll show you those results in a little bit of the next lecture. But back then, what we found, what I found was that there were 40 clinical trials listed for tinea pedis. Of those, only one was currently recruiting, so there’s really not a lot of activity in the tinea pedis world. Most of the ones that were completed or terminated were updated formulations, older drugs, or head to head comparisons and a very few had that comparisons. There were some topicals like luliconazole which I’ll talk about. It’s now been FDA approved and albaconazole, it’s not out there yet. There were number of new delivery systems such as sprays and foams and something called a microcapsule. There is not all that much going on in the world of tinea pedis from a research standpoint right now. It’s probably because there is lot of drugs out there that we have that are effective in the treatment. Let’s look at the drugs that are available for tinea pedis. The original class of drugs, the oldest class of antifungals we have were the azoles. Right. They are earliest and by far the most common. They work by inhibiting ergosterol synthesis. Alright. All of the antifungals that we’re going to talk about, the azoles and the allylamines, both work on the ergosterol synthesis pathway. Ergosterol is necessary for a healthy cell membrane. A healthy fungal cell membrane. If you inhibit the formation of ergosterol anywhere along the synthesis pathway, you’re going to end up with some distraction of the fungal cell. Now, most of these azoles have been classified as fungistatic, miconazole, clotrimazole, econazole, you can read them as easily as I can read them to you. Sertaconazole has been considered fungicidal and luliconazole is also possibly being considered fungicidal.
Cidal versus static those two drugs of the azoles are the ones that may have some fungicidal activity. What about the whole issue of cidal versus static? You’ve heard me talk about antibiotics for years. I’ve said it makes no difference. It does not make a difference whether it’s cidal or static. I can quote those references for you. There have been a number that have been done, unlike bacterial infections, there may actually be a clinical difference with the cidal versus static fungal drug. Why? Because the skin on the plantar aspect of the foot can take 30 plus days to turn over. If you use a drug that static, you may have to continue to use it over the full 30 days until the skin totally turns over and sheds the fungus. If you use a cidal drug, by killing the fungus, you may be able to use it for shorter period of time. Again, theoretically, you can use cidal agent for a shorter period of time. We’re going to finish up other that the talk on pharmionics, on a couple of slides, I want to concentrate tonight on two antifungals that are the newest antifungals in the market place. These are both prescription drugs. The first one to talk about is luliconazole 1%. This was approved in 2013. It is a topical azole antifungal. Its dose once a day for two weeks. Now think of that. Once a day for two weeks. How many total doses is that? Fourteen. Some of these older antifungals we are talking about before, you have to give up to 56 doses of drug. This is 14 doses of drug, once a day for two weeks. The clinical trials, two randomize multi-centered double blind vehicle controlled study, once daily luliconazole cream for two weeks. Now, the FDA, when you’re looking at a topical antifungal for tinea pedis, the FDA says, you have to give the drug for two weeks and then you have to watch for four weeks after you stopped giving the drugs. The primary endpoint of all antifungal studies is six weeks. Two weeks on, in this case, four weeks off, alright. The assessment was done. The complete cure or the efficacy the primary endpoint in this particular case was what is known as complete clearance. Complete clearance said at six weeks, so four weeks after you stopped therapy. You have a zero score in erythema scaling and pruritus. Zero scores, and you have mycologic cure. Mycologic cure same with onychomycosis, negative KOH, negative culture. Of course, there were safety assessments. Two identical pivotal trials. As you see in just about every study the FDA requires two of them. Study number one, the mean age was 38, they were slightly older and study number two, this is interesting though. You start seeing this in not only the tinea pedis trials but also the onychomycosis studies. Look what they were done. Study one was all US, 100% US. Study two where a third of the patients were in Central America. In Central America, it seems to be topped off again with the fungus. Just like in one of the onychomycosis class studies, I’m going to show you a little bit later, a good number of the patients in one of the studies were in Japan. Japan actually clears onychomycosis better than in the US. There are geographic differences in how patients respond to therapy. Here is the endpoint. We talked about it. Six weeks, four weeks after treatment, you have to have complete clearance. The rates here, you see a 28 days, and then at the six-week period, day 42, 26% in study one, 14% in study two. That’s a fairly large difference and complete cure between study one and study two. Two identical studies. Could it be slightly older patients and the patients in Central America, I don’t know. It’s just you have to look at these studies and look at this data and just wonder. Here are some of the other endpoints, mycologic cure 66% in study one, 60% in study two. These are fairly close, effective treatment, again much higher in study one than in study two. Overall, effective drug, statistically significantly better than the vehicle and because of that, the drug got its approval because it was superior to the vehicle. That’s the azole. The azole again working on inhibiting lanosterol 14 alpha-demethylase, which produces or stops the production of a gastral. Now, allylamines, they are newer class of antifungal, they worked one step up. They stop the production in the ergosterol pathway.
They stop the production of a squalene to lanosterol by inhibiting squalene epoxidase. These tend to be considered fungicidal across the board. These are the agents that are available, terbinafine, naftifine and butenafine. There was a Cochrane review on another page, just I like clinicaltrials.gov, I really Cochrane. I quote Cochrane a lot in my book. I quote Cochrane a lot in my blog. They’ve done some really cool reviews. Overall, they found that the allylamines maybe slightly more effective than the azoles. Well, one of the allylamines we have out there, the newest one that’s being marketed right now is naftifine in particular the 2%. It’s the first allylamine actually available for tinea pedis. Most people think it was terbinafine but it’s actually naftifine. It’s available in a once daily cream or gel and then 2% formulation is two-week therapy. Now we have two drugs. We have luliconazole, once a day for two weeks. Now we have naftifine 2% once day for two weeks. We’ve got two drugs now, short courses of therapy, 14-day courses, 14 applications. The allylamines tend to have an anti-inflammatory effect. According to this paper on mycosis, they found in-vitro that it was more effective against dermatophytes than ketoconazole or oxiconazole. There is also some activity against molds, yeasts, bacteria, both i- vitro and in-vivo. Well, the same thing with this study as you saw with a luliconazole study. Basically, two weeks on, four weeks off, for a primary endpoint at six weeks. Two double blind randomized vehicle controlled trials, 47 sites, 1,715 patients. But what’s interesting about this study is the first study that I actually included a moccasin tinea arm. Here’s the schematic of the study. Again, wash up if needed, treatment for two weeks, follow up for four weeks, primary endpoint is right here at week six, complete clearance. Let’s look at the data. This is interdigital tinea. What you find is complete cure at week two is only 5%. But look what happens if you wait. Now, you’ve only treated to two weeks. Don’t keep treating, single luliconazole, don’t keep treating. Stop the therapy at two weeks. And you’ll see, what happens is the cure rates go up. Up to 22% here, you can see mycologic cure, 39% at two weeks, up to 62% four weeks later. The drugs persist in the stratum corneum, they stall the activity and you can see increasing efficacy. This is their moccasin data. Now, relatively small numbers in their moccasin trial or moccasin arm, but you can see here complete cure 2%, lower than interdigital which you would expect, but goes as high as 20% at week six. The drug does have moccasin data. Now, they do not have enough patients to make this FDA approved from moccasin tinea pedis but I just find it interesting that they actually included a moccasin arm. I would have finished the last three or four slides just talking about adherence to topical therapies. Again, there’s an entire science of this, it’s called pharmionics, or the study of adherence. Shorter, easier to understand course of therapies may improve adherence. How do we tell patients to apply antifungals? Smear a little bit on. Put on or apply liberally, put a thick layer on, put a thin layer on. We don’t have that standardized. Nobody has ever standardized how to really instruct people to apply drugs for tinea pedis. Keep the courses short. Keep them easy to understand. That’s going to improve adherence. What are some of the barriers to adherence? If they are time consuming, inconvenient to apply. That’s why ointments have never been particularly successful because ointments are tough thing to sell. They are not a particularly elegant solution, cost of medication. Cost of medication, you have look at two things. This becomes important not only in tinea pedis but also onychomycosis. There is the cost of the drug and then there is the cost to the patient. Can the patient access the drug at a zero co-pay, how much cash out of pocket, first is the cost actually of the drug. But the cost of medication or lack of access can be a barrier to adherence. The use of application terms, I said that before, how do you tell them to apply it. You have to really give simple instructions. Well, there’d been a couple of studies and look at this. This is an interesting one. It’s not my favorite. My favorite is the next one. This is 17 patients were treated and I believe this was for psoriasis. They were treated with topical therapies.
They defined 80% following instructions and 80% application as the way they were supposed to as being adherence. They found in this study, basically one out of 17 patients were adherent. Not only one out of 17 patients were adherent, two of 17 didn’t even bother filling their prescription, five of 17 say they’d never intended to apply it and this is my favorite here. Six of 15 responded that they have not applied the prescribed medication the previous day. They know they’re coming back to see you the next day and they can’t be bothered putting on the medication. If you think to ask them, this is my all time favorite study. This is a study that they did where they gave patients a tube of antifungal and that tube had a computerized cap on it. They measured how much antifungal or it wasn’t antifungal in this case, I forgot what the medication is, how much of the topical was squeezed out. They also then asked the patient to keep a log of how they followed instructions and how they applied the medication. News flash, ladies and gentlemen, patients sometimes stretch the truth a little bit. Okay. If you look at the patient log, they found the patient’s average about 90, 95% adherence. But if they actually look at the computerized tube cap, they found that by the end of the study, patients were only adherent 50% of the time. Patients were not particularly good at following instructions. Keep it easy. Keep it short. Keep it simple. Oral antifungals are only recalcitrant cases. Basically tinea pedis is common and frequently misdiagnosed. There are many effective topical in oral therapies. We now have the two newly approved shorter course once a day for 14-day therapies, the naftifine 2% and the luliconazole. Thank you very much.