Male Speaker: E-learning lecture. We’re going to talk about tinea pedis. I’m going to update you on some of the new drugs that are out there. This gives you my philosophy on why and how we have to treat tinea pedis. The learning objectives for this particular talk are we’re going to recognize the tinea pedis as an infection that can have significant sequelae. We’re going to understand the difference between various classes of topical and oral antifungals and where to use each of this. Going to go into the background on how to select an appropriate antifungal given at patient’s presentation. When I spend a little bit of time on this first objective about recognizing the tinea pedis is an infection. Those of you who have heard me lecture on the topic of onychomycosis know that I take a very strong position with any of these fungal infections that these are infectious diseases that need to be treated with an anti-infective. Just like we have bacterial infections, we don’t think twice about treating with an antibiotic. When you have a fungal infection, why do we hesitate to treat it with an antifungal? It doesn’t matter whether we’re talking about onychomycosis or tinea pedis, and these are very, very closely linked and I’m going to go into that and show you how they're linked. We need to get more serious about understanding the pathophysiology and the treatment of these infectious diseases. Well, let’s talk about this connection between tinea pedis and onychomycosis because the two really are inexorably linked. You can’t have one without the other. That gets to the whole background of the natural history of onychomycosis because it starts as tinea pedis. The patient develops a skin infection of the foot, the tinea pedis. There are some trauma to the hyponychial seal which allows the fungus to invade up under the toenail and then cause onychomycosis. Likewise or therefore, you have to assume that every patient with onychomycosis either currently has or has had in the recent past some tinea pedis and you can’t treat one without the other. You really have to treat both. Now, from using an oral, this is not an issue. If you’re using an oral, it’s going to work against both to tinea and the onychomycosis. But if you use a topical, let’s say use a topical to clear the tinea pedis. Well, if you don’t treat the onychomycosis, the nail is just going to act as a reservoir to reinfect the skin. Likewise, if you treat the nail with one of the new antifungals we have for onychomycosis but you don’t treat the skin, the skin is just going to reinfect the nail as it started initially in the natural history of the disease. Remember, if you’ve got them both, which you're going to have in most patients, you really need to treat both. This is just a little picture of one of my patients showing the classic serpiginous lesion of tinea pedis of the distal aspect of the toe and you can see how there’s been a break in the hyponychial seal. You can almost imagine looking at this how the fungus will just migrate, just crawl up under that toenail and set up shop in the nail, bed stratum corneum. You really do need to address both of these and see how they’re connected. This is just a little cartoon I have drawn up. It shows here, we have tinea pedis. Tinea pedis can crawl up under the toenail especially as it gets worse and you get in your digital involvement. Now, you treat the tinea pedis with a topical antifungal. The skin is clear but the toenail is going to act as a reservoir to reinfect the skin. Again, always consider the two together, look for the two together and treat the two together. Let’s talk about the epidemiology. Now, I know it’s a little boring but when we talk about epidemiology, we have to think about the pathogen, the host and the environment. Well, let’s first look at the pathogen. It is very clear that almost all tinea pedis is caused by the dermatophytes. In particular, you’ve got T. rubrum, Trichophyton rubrum. Now, with some types of interdigital vesicular tinea pedis, you may have a T. mentagrophytes which is now called T. interdigitale because it causes interdigital infection. But these two organisms cause the vast majority, probably 95 plus percent of tinea pedis is caused by T. rubrum and T. mentagrophytes. Much less commonly, you may see other dermatophytes such as microsporum and epidermophyte. I will tell you, I personally have not seen these and then you can certainly get interdigital infections with the yeast in particular Candida, C. albicans, krusei, parapsilosis can all also cause interdigital infections. There are a number of different types of tinea pedis. I think by far the most common is moccasin.

[04:56]

Now, moccasin tinea pedis usually caused by T. rubrum is that classic presentation where you get scaling on the plantar aspect of the foot that comes up around the sides of the foot in a moccasin distribution. You can tell this because the dorsum of the foot is spare. That’s how we differentiate it from just dry skin or psoriatic skin. The plantar skin looks dry and scaly, whereas the dorsal skin looks normal. That’s a moccasin tinea pedis. Then we have vesicular tinea pedis generally found interdigitally but you can also find that plantarly. That is usually caused by the T. interdigitale or the T. mentagrophytes, and it’s the old name used to be. Then back in the late 1980s, early 1990s, Dr. Jim Leyden at the University of Pennsylvania came up with a classification system with interdigital tinea pedis, where he divided interdigital into two types, dermatophytosis simplex and dermatophytosis complex. We’re going to take a look at both of those and how they occur. Well, this is a classic presentation of a severe moccasin tinea pedis. You can see that outside of the moccasin distribution there's really no scaling but this is pretty nasty scaling. You can see the papules that are forming, those little red dots all around and that’s actually how it starts. It starts as these little red dots that causes hyperkeratotic reaction and you get the scaling of the skin. That’s why when you go to harvest a culture, you should be harvesting from the peripheral scale because it moves outward. But this is fairly classic. You can see in the plantar aspect of the foot, one of those classic scales with the serpiginous or snake-like look to it and this is fairly classic severe moccasin tinea pedis. Now, when you look at this foot, you might look at this and say, “This patient doesn’t have tinea pedis, they just have dry skin.” Well, if you actually were to scrape the skin and culture the skin, you would find that the patient does in fact have tinea pedis. You have to be very careful with that. You have to be very careful with the diagnosis. It’s not uncommon for patients to come in and say, "Doc, you know, I have this dry skin on the bottom of my foot and I’ve been using moisturizer and nothing seems to work." Well, it’s because it’s not dry skin, it’s tinea. Where we really first came to know this? We’re the point really got driven home to me was when the oral antifungals first came out, terbinafine, itraconazole because we would put the patients on these drugs and have them back in about six weeks or two months for blood testing and the first thing the patient will tell you, because it was too early for their nails to look better. But the first thing the patients would tell you is, "Doc, my skin really looks great. I mean, it looks like a baby’s behind it. I’ve never seen anything like this." That is because the skin cleared because it was tinea pedis and not dry skin. Make the correct diagnosis. This is your classic vesicular tinea pedis that started interdigitally. You could see the big vesicle formation. Now, what I want to point out to you is if you look at the roof of the vesicle, you can see almost like a punctate sort of look, a little pinpoint look, a little dotted look on the top. That I found to be very almost pathognomonic, very fungal infection and as you deroof this, you’ll see that there are septate that run from the bullae roof, the vesicle roof right down to the base of what’s now an ulcerated area. As you pull the roof away, those septed break and fall back into the base and you end up with these very reticulated looking base of the ulceration. Let me show you that in this particular picture of an interdigital vesicle. Here you can see where there was some interdigital vesicular tinea pedis and you can make out that reticulated sort of look in the base. Just to give you a bigger picture, I debrided up on the medial aspect of the fifth toe a little bit and you can see that white foamy look that’s running around in different directions on the base of the ulceration. I think that’s just the septate that have come off of the roof as you deroofed it and fallen back into the base of the wound. A very classic appearance for a vesicular tinea pedis. Now, to get back to that classification system that Leyden came up with, he identified two types of interdigital tinea. This is dermatophytosis simplex. Now, dermatophytosis simplex can be very, very benign-looking. You look between the toes and it may just look like there's a little scaling in there, a little dry skin in there, a little flaking, but that in fact is a fungal infection. There’s just another picture, a little more severe case of some dermatophytosis simplex.

[09:55]

Now, what he found in his experiment is when he took patients with dermatophytosis simplex and he put those feet under occlusion and he did this by using a plastic wrap, like a surround wrap around the foot to put the toes under occlusion, he found that that dermatophytosis simplex could turn into a dermatophytosis complex. In other words, a draining, smelly bacterially-colonized, very significant looking condition where the skin is rather eaten away and at least, the superficial layers of the skin are eaten away, and this is what you end up seeing. This is the dermatophytosis complex. Now, he did find that there was not only fungus here but there were bacteria here and a lot of people jump on the use of antibiotics in these cases. But what Leyden showed in his experiment was that in order to convert a dermatophytosis complex back to a dermatophytosis simplex, you don’t need antibiotics, you don’t need even antifungals. You need to reverse the situation that cause the problem in the firsthand and that was the environment. Again, remember when we look at epidemiology, you’ve got the host, the environment and the pathogen. This is the environment. By separating these toes and drying them out, he was able to revert dermatophytosis complex back to dermatophytosis simplex. Let’s now talk about some of the treatment options we have for tinea pedis. Well, I’ve said it already a couple of times and need various repeating, you need to make the diagnosis that dry skin probably has tinea pedis. You need to get that proper sample, get as much of that peripheral scale as you can because that’s where the live fungus is going to be, send that off to the lab and just like you would do for onychomycosis, you can order KOH, you can order PIS staining, you can order fungal cultures or nowadays even we have the new molecular techniques that could be used to help diagnose the tinea pedis along with the onychomycosis. If there’s onychomycosis as I stated in one of my first slides, treat it. Then, consider which topical or oral you are going to use. We’ll talk about when to use the orals towards the end of the lecture but the top of those you then have to look at their different sorts of vehicles. You’ve got creams, you’ve got gels and you got solutions. Now, traditionally, the thinking and the dermatology world has been that solutions dry and creams can help moisturize. If it’s a wet area, then you want to dry it out with a solution or a gel. The gel is going to be alcohol based. Or if it’s a dry area, maybe moisturizing it a little bit with the cream will help. I'm not sure that it makes all that much of a difference. [indecipherable] [12:53] fungal activity is as important. Just be aware with some of the gels especially if they’re highly alcohol based and you’ve got any sort of fissuring between the toes, that can actually sting the patient. Now, you also have to be aware, the clinical trials that have been looked at in tinea pedis actually look at interdigital tinea pedis. Now, we said earlier that moccasin tinea pedis is the most common presentation. I think that’s true in podiatric practice. But the studies, the guidance for industry that the FDA has for tinea pedis only looks at interdigital. I will show you one study that did start looking at moccasin tinea pedis also but overall is interdigital, so we don’t really know how that translates to moccasin. Moccasin tinea pedis does tend to be more difficult to treat. Does intend to be refractory and in longer courses of therapy than the interdigital may. If you look at clinicaltrials.gov to see what is going on in the world of tinea pedis, it’s very easy, you just go to the website and you just type in under the search box tinea pedis. As I did back in March of this year, I found there were 44 trials when I entered the term tinea pedis. Now, of those 44 trials, actually none of them were currently recruited because clinicaltrials.gov will keep studies often that have been completed in the past couple of years. There were no drug studies currently recruiting in tinea pedis. There's not going to be a lot of new drug coming out in this field. All the rest were completed and really none of them were exciting new products. So you had some updated formulations of older drugs, there were a few head-to-head comparisons which is always good to see but really no new drug therapy at all, which does not bode well for the field of new discovery. Either that or it means that we’ve got everything we already need, we don’t need anything more. We’ve got the drugs that worked very well. There was a new oral that was being looked at, albaconazole, I don’t know how far along that is. I don’t know whether that’s going to be developed.

[15:01]

Quite frankly when you’re looking at the orals, I think the terbinafine or the itraconazole work very, very well. I don’t know that a new oral is going to make that much of a difference in the treatment of tinea pedis. Then there were some new delivery systems. There were some foams, sprays, I like these microcapsules whatever that means, I guess burst upon application. There’s some interesting delivery systems. The one that is missing to me and it’s unfortunate because I really think it’s a fascinating product is a product that's found only in Europe and it’s called terbinafine or Lamisil Once. It’s a film-forming gel. It’s actually a gel that you put on the foot and it forms a film that then leaches the drug out for the next seven days. You only have to apply it one time. Unfortunately, I do not believe that they’ve ever considered bringing that into the United States but that’s only mean by the new or unique delivery systems. Interesting to see if anything interesting comes out of these experiments. But let’s look at the classes of antifungals that we currently have available to us. The azoles are probably the oldest, the most common, the most familiar class of the antifungals. They tend to be primarily fungistatic even though a couple of the newer azoles could also be considered fungicidal. They all work the same way. They inhibit ergosterol synthesis. Now, ergosterol is necessary for healthy fungal cell wall. If you inhibit the development of ergosterol, then the cell wall is disruptive and the cell is going to end up dying. That’s where these antifungals all work. They inhibit the production of the ergosterol and that reduces ergosterol levels and disrupts the cell. These are the agents you’ve seen around forever, miconazole, clotrimazole, econazole oxiconazole and some of the newer agents, sertaconazole and probably the newest agent in the azole family is luliconazole. Of these last two, the sertaconazole and the luliconazole, some people will consider them mixed with fungicidal and have some fungistatic activity. Well, does just make a difference, the cidal versus static question. I’ve preached for years in the world of bacteria that it does not. That in fact, it doesn’t matter if something cidal versus static, there have been studies that have shown this and antibiotic can be static and the skin-skin structure infection work just as well as the cidal antibiotic in the skin-skin structure infection. Well, theoretically at least in tinea pedis, that may not be the case. In fact, it may make a difference if a drug is cidal versus static. Because unlike bacterial infections, it unusually go away in just a couple of days, you need to treat fungal infections for at least two weeks period of time per long periods of time. The skin can take up to a month to totally turn over. If the skin takes a month to turn over, if the antifungal is being applied for only two weeks but the organism is just stunned if it’s a static drug and not dead if it’s a cidal drug and the following two weeks where the skin has to turn over, the organism may come back to life and reinfect the patient or cause a recurrence action in the patient. However, if the drug is cidal and you use it for one of the shorter periods of time, let’s say two weeks, then theoretically of this, the organism is dead from the two weeks of therapy. Therefore, you can wait another two weeks post therapy and the patient should continue to improve as the skin clears and you have a fungus, an either dead fungus that was left in the scales. At least theoretically, cidal may make a difference in tinea pedis treatment. Well, let’s finish up talking about the two newest antifungals. The two bit are being the most heavily marketed in podiatry right now. This one is luliconazole 1%. Now, this was improved in November of 2013. It’s a topical azole antifungal and it’s dosed once daily for two weeks, once daily for two weeks. Now, that’s to me one of the benefits of this drug because if you look at some of the other drugs from the older drugs out there, they can be once daily for four weeks, some are as much as twice daily for four weeks. Basically, you’re looking at 14 applications versus some of the older drugs that could be as many as 56 applications. That’s going to lead to improve patient adherence. We’ll end the lecture talking about patient adherence. This study for luliconazole as with any clinical trial that’s going to be looked at by the FDA, you have to do for drug approvals, you have to do two randomized control, double blind studies and these were vehicle controlled trials and what they found was, the luliconazole was applied once daily for two weeks. And the efficacy evaluation on each visit was a clinical assessment, so they looked at erythema, scaling and itching, pruritus on a zero to three severity scale.

[20:08]

Then they looked at the mycology through KOH and culture, and then safety assessments were done looking for it for events throughout the study and laboratory tests were done at the baseline and in day 14. The study demographics, the average age of the patient was in the late 30s, early 40s, males tend to as with onychomycosis study significantly higher than females. Well, what's interesting here is the two studies were done in two different locations. You need to be aware of this because the FDA does allow this one study to be done in part x US. Study number one was all US, 100% of patients we’re in the US. Study number two, about 1/3 of the patients were actually in Central America. Now, if you think about the climate in Central America, that could certainly lead to less good results because of the extra heat and humidity that you may run into. Let’s see if that plays out in the efficacy evaluations. Efficacy endpoints, the primary endpoint just like you’ve heard me talk about when I talked about onychomycosis is that you have to have negative KOH and negative cultures so the nail has to be mycologically cured, or the skin has to be mycologically cured and the foot has to be 100% normal looking. No more erythema, scaling or itching. In this particular study, the patients were treated for two weeks with drug therapy and then the primary endpoint was determined at day 42, which was four weeks after stopping the therapy. Again, to get that straight, patients were treated for two weeks and then evaluated for the primary endpoint at six weeks, four weeks after the patient stopped therapy. The secondary endpoints, there was affected treatment which was defined as a negative KOH and negative culture, so mycologic cure and in most mild erythema of scaling and no itching at four weeks post treatment. Clinical cured four weeks post treatment, mycological cured four weeks post treatment and clinical clearance at two weeks post treatment. Just like with all the other studies, everybody has secondary endpoints. But the FDA primarily looks at that number one endpoint, that primary endpoint which is complete clearance, negative KOH and negative culture and perfectly normal-looking skin with no redness, scale or itch. How did this drug do? Well, if you look at study one, at day 28, the numbers are relatively low. That’s when the patient stopped therapy, but at day 42, you can see that the numbers are much higher. It’s almost a stair step appearance, day 28 and day 42. Actually, 28 is two weeks after therapy. It’s not when the patient stopped therapy, which shows you that the organism was probably dead and the skin just continued to shed the organism overtime. You can’t evaluate these patients right at the end when they stopped using their drug. You have to wait at least a couple of weeks to give the skin a chance to turn over and become more normal appearing. Now, we talked about the demographics and the study, study one versus study two. Study one was just in the US. You could see that they have complete clearance of the interdigital tinea at 26%. Where study two that included Central America, we have 14%. Now, it’s lower than the 26%, still significantly higher however than the vehicle, therefore, the drug was considered superior to vehicle and that allowed its FDA approval. But be aware again when you look at the studies, when you evaluate studies where they were done and what the demographics may have been. These are some of the secondary endpoints. There's other endpoints we’ve talked about, effective treatment, 48% of patients were considered to have effective treatment in the first study, 35% in the second. Clinical cure, 31 and 60 and mycologic cure, almost 2/3 of the patients were mycologically cured at the end of the study, which I think is a pretty good number when you got 2/3 don’t have any fungus, through negative KOH and negative culture. Now, let’s switch gears and talk about the allylamines. The allylamines are slightly newer class of antifungal than the azoles. They work a little bit differently, although they still work on the ergosterol pathway, they don’t directly inhibit ergosterol synthesis rather, they inhibit the enzyme squalene epoxidase, which occurs a little bit earlier in the ergosterol pathway. Bottom line is still the same. No ergosterol, no healthy cell wall.

[24:56]

These drugs overall are considered to be fungicidal and therefore, at least in the past have been thought to be able to be used for shorter periods of time. The most common agents we have include terbinafine, naftifine and butenafine. If you look at the Cochrane Collaborative, I’m a big believer in looking at Cochrane in Cochrane.org. Now they really do nice synthesis on the scientific evidence on any particular area of interest, what they did find is overall, the allylamines may be slightly more effective than the azoles. That was from the Cochrane review that was published in 2009. The allylamine that’s most commonly being talked about now in the profession is naftifine. Naftifine was the first available allylamine for tinea pedis even though it’s not thought of as that way because most people think of the terbinafine being available before the naftifine. The naftifine actually did come out first. It’s available in either a once daily cream or gel and with a newer 2% formulation, it is also now available for two-week therapy. Once a day for two weeks just like we were talking about with the luliconazole earlier. Naftifine is thought to have some anti-inflammatory effect. I really am not a fan in using combinations of antifungals and steroids, that is traditionally something called a tinea incognito where the steroid can masks the signs of the tinea pedis. I think if you kill the organism, you'll get rid of the inflammatory reaction and in the case of the naftifine, you have some inherent anti-inflammatory activity. In vitro, it’s more effective in dermatophytes in either keto or oxiconazole, that was a paper published in the journal Mycoses in 2007. Not only that, the naftifine does have activity not only against the dermatophytes. It also has activity to get some molds, yeast and bacteria both in vitro and in vivo. Well what about the clinical trials? The clinical trials on this were very similar to other clinical trials in that they were both done with two weeks of therapy and four weeks of followup. There were two six week double blind randomized vehicle controlled studies, in this particular case, over 1700 patients were randomized to receive either the naftifine, they have 1100 versus the vehicle, 570. Now, what’s interesting about this study is this was the first study that actually did include some moccasin-type tinea pedis. Unfortunately, even though the results were promising for the moccasin tinea pedis, there were not enough numbers in order to allow the FDA to give an indication for the moccasin. Again, just like all the other antifungals we have, this is approved for interdigital tinea pedis. Here is the study design. You have the patients randomized to receive either the naftifine or the vehicle. Patients treated for two weeks and then a four-week followup. Here, you see the numbers. The complete cure at week two and the mycologic cure at week two on the left hand graph versus at week six or four weeks post treatment, you see a significant increase that goes from two to 20% on the one, on the mycologic here goes from 28 to 65% on the other. Again, you don’t judge these patients when you stop the therapy. You stop the therapy and let the body do its thing and then four weeks out and you can judge whether the patient received an efficacious treatment. Well, let's finish by talking about adherence to topical therapies because we all know that adherence becomes a major, major issue. There’s actually a science to the study of adherence called pharmionics. It’s really very interesting because as we would suspect, patients aren’t necessarily follow the instructions that you give them. What they do find is that shorter and easier to understand courses of therapy may improve adherence and the barriers to adherence include time consuming or inconvenient to apply medications, cost of medication and access of that medication, vagueness of the application terms. How often do you say, here, "Wrap this on your foot twice a day?" Well, how much do you put on your foot twice a day? Instructions that are complicated, difficult to remember or inconvenient, do it after a shower, do it before bed. Do it on dry skin, do it on damp skin. It just complicates it. Anything that complicates it makes the patient less adherent. I like to think back to probably the best application instruction of any topical I can think of. It’s not onychomycosis product. It’s becaplermin Regranex for wounds. So how do you remember how that was always taught that you should apply it?

[29:59]

You should apply a dime thickness to cover the wound, a dime thickness. Patients can visualize that. You can visualize that. Whereas if you just say, put this on the wound, put a little bit on the gauze, just smear it around. No one really understands what that means. Well, this is an interesting study. It looked at 17 patients in the particular study and found that in fact, only one patient was considered adherent, one out of 17. In fact, two of 17 patients didn’t even bother to fill their prescriptions, five of 17 say they never really intended to apply the medication anyway and six out of 15 had not even bothered to apply the prescribed dose the day before they came in to be evaluated for the study. If they can’t even follow instructions when participating in a study, you can imagine what they’re doing in real life. But this is really my favorite study. This was very interesting. What they did here is they tricked the patient a little bit. They gave the patient a topical medication that had a computerized cap on it. It measured every time the drug was squeezed out. They also had the patients keep a logbook of how often they were applying the medication. If you look here, look at that top line, that the orange line, that’s the logbook. The patients admitted to be compliant about 90% of the time or I should say, excuse me, it’s politically incorrect to say compliant. I should say, they admitted to being adherent about 90% of the time. Yet, when the computerized caps were looked at, they found in fact, the patients were only adherent about 50% of the time. Here's a newsflash to you, patients may not always be telling you the complete truth. Oral antifungals certainly do have a role in tinea pedis treatment. Cochrane did review oral antifungal for tinea pedis. What they found is, and this is direct quote, this review compared different oral antifungals and found that terbinafine and itraconazole were both more effective than placebo. Terbinafine works faster and it’s more effective than griseofulvin. I think the short course of terbinafine, maybe two weeks of terbinafine, even one week of terbinafine, may be adequate to treat orally tinea pedis. Well, when are you going to use an oral? Moccasin tinea pedis I mentioned before tends to be more recalcitrant and unresponsive to therapy. If you have a moccasin that’s not responding to topical therapy, if you’ve got a severe interdigital, maybe using it in combination to topical will work from the outside in. The oral will work from the inside out. Then if you’ve got those adherence issues, a good chance the patient can take one pill for seven to 14 days, whereas they might not even be able to apply a medication and smear cream on their foot once a day for 14 days. In conclusion, tinea pedis is common and frequently misdiagnosed. Fortunately, there are many effective drugs, both topical and oral, and we have both OTC and prescription drugs. Then there are two more relatively newly approved drugs that are being marketed in the profession. They are luliconazole and naftifine. These are interesting drugs because they are both given once or applied once a day for 14 days. Theoretically, you should have patient adherence improvement. Thank you.