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Release Date: 03/16/2018 Expiration Date: 12/31/2020
Warren Joseph, DPM
Roxborough Memorial Hospital
Editor - Journal of the APMA
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Warren Joseph Warren S Joseph, DPM, FIDSA has disclosed that he receives Honorarium/Expenses, is a Consultant to and serves on the Speaker's Bureau for Pfizer and Merck.
Warren Joseph: Listen. People, why are you doing fungus? Why are you talking about fungus? Frankly, I talk about fungus because I look at fungus differently than most people. Whenever you go to most meetings or you read most of the papers on tinea pedis onychomycosis, they’re all written by what specialty? Dermatology. Most people look at fungal infections as skin conditions, nail conditions. See, I don’t. I look at a fungal infection, I approach the fungal infection as an infection. As an infection, it’s something that should be treated with anti-infectives as opposed to just treating palliatively or ignoring. I use the example of my son, he’s now 22 years old, my younger son, when he was in elementary school. He came home from school one day with a note from the nurse saying, “Your son has ringworm of the arm. He will not be allowed back into school unless we have a letter from the doctor saying that the ringworm is being treated and it’s no longer contagious.” Well, what’s ringworm of the arm? Tinea corporis. It’s T. rubrum. It’s the exact same infection, the exact same organism that you see on the foot in both tinea pedis and onychomycosis. The difference is you don’t see it on the foot, because it’s under the shoe and the sock. We really need to look at this and get serious about this that this is not some minor little irritation or minor little skin condition. This is an infection and as an infection, we need to treat it with some sort of anti-infective treatment. Alright, just from some disclosures, because I will be actually mentioning specific drugs here unlike with the last lecture. I’m a consultant and sit on the scientific advisory board for Valeant and Pedinol, a division of Valeant. We’re consulting on a speaker for MERS. Actually the proper German pronunciation is “mers” [Phonetic]. And I am consulting for Anacor who has one of the new topical onychomycosis drugs. Why do I talk about these two conditions together? Because you can’t separate them. You can’t separate them. There’s really an inextricable link between onychomycosis and tinea pedis. That is because it has to do with the natural history of onychomycosis. Onychomycosis begins as tinea pedis. Then there’s some sort of trauma to break the hyponychial seal, which then allows the organism to get from the skin up under the toenail and into the nail bed stratum corneum. The two are really the same. Essentially, all patients with onychomycosis either currently have or had one time have had tinea pedis. You really can’t treat one without the other. Just think about it. There are lots of good topicals for tinea pedis. We’re going to talk about them. If you got the patient with onychomycosis, what’s going to happen if you treat its skin but not the nail? The nail acts as a reservoir to re-infect the skin. Likewise, let’s say you use a topical for the treatment of onychomycosis but you don’t treat the tinea pedis. What’s going to happen? You can clear the onychomycosis but the tinea is going to act to re-infect the nail. You really can’t treat one without the other. This is just showing you what I mean by this connection and you’ve got that typical serpiginous lesion that you find with tinea pedis. You have the break in hyponychial seal here which has allowed the fungus to migrate up under the toenail and cause what we now know as distal lateral subungual onychomycosis. Just looking at this schematic cartoon, you see infection on the skin. Now it gets up under the toenail. Now you treat the skin so the skin is clear but the nail is still infected, it just serves to re-infect the skin. You can’t treat one without the other. Now when we talk about epidemiology, we talk about their three aspects. The public health people are big on this. They talk about epidemiology. They talk about the host, the pathogen, and the environment. Let’s look first at the pathogen. Because this is really one of the few things we can talk about, I mean we can do something about. The pathogen we know almost all onychomycosis and almost all tinea pedis is caused by dermatophytes and the primary dermatophyte causing both? T. rubrum. Yes, you can also get T. mentagrophytes in some but T. rubrum is number is one.
Microsporum, Epidermophyton have all been found as potential pathogen or dermatophytes that can cause skin and nail infection. In the United States, at least by far the major causes are T. rubrum and T. mentag. Now there’s different types of tinea pedis. You got moccasin tinea pedis. This is by far the most common. This is what we see everyday. This is usually caused by T. rubrum. Vesicular tinea pedis, almost always caused by T. mentagrophytes and then the interdigital. Back in the 1980s, early 1990s, Jim Layne [Phonetic], the dermatologist at that time at the University of Pennsylvania actually came up with a classification system for interdigital tinea. He broke interdigital tinea down into two categories, dermatophytosis simplex and dermatophytosis complex. I’ll show you those in a bit. This is your classic tinea pedis, your moccasin presentation. You can see here that the dorsal skin, the skin of the ankle here or anywhere on the foot, the dorsal skin is spared. In a moccasin distribution, you get all of the scaling. You notice these little papules here. Basically, what that is, that’s the primary infection, that’s the fungus. Because there’s an autosomal dominant trait that confers a cell-mediated immune deficit in these patients and it has been mapped in families. Zaias has shown this. A couple of others, recently [indecipherable] [06:29] has shown thus where they actually follow families and they can do genetic mapping. I don’t even need genetic mapping. I look at myself. I mean, I’ve got tinea pedis, onychomycosis. Anyone else? Anyone? You know, all good to go? I mentioned before, my son has it. Actually, both my sons have it. My wife does not. We’ve been together 28 plus years. She does not have it. There is definitely a genetic predisposition to it. In this case, because of the cell-mediated immune deficit, the patients can’t mount a response that gets rid of the fungus that’s in the stratum corneum so it just starts chronically pumping out this hyperkeratosis and you get this peripheral scale. What about this? Is this dry skin or is this tinea pedis? A lot of patients come in and say, “I’ve got dry skin, I’ve been using moisturizer.” When this first really came to me that most dry skin in the foot is really tinea pedis, when the first oral anti-fungals came out. Back in the early 1990s, mid 1990s when Lamisil came out and Sporanox, terbinafine, itraconazole came out. We would give our drug or these drugs to our patients and we’d have them back in six weeks just for the blood work. What’s the first thing the patient would say? He’s a practicing doctor, remember this. “Patient never said my toenail looks better.” It’s six weeks the patient would always say, “Doc, my skin has never looked this good. I had this dry skin, I used to put all sort s of moisturizer on it every night, and nothing works.” This pill is taking care of it. It really drove home the point that you have to make the correct diagnosis because a lot of cirrhosis is really tinea and needs to be treated with an anti-fungal. This is the vesicular type of tinea pedis caused by T. mentagrophytes. Now notice here, it’s a very distinctive looking bullet. Number one, it starts from the inner space but you almost see like these punctate little dots on the roof of the blister. As you deroof this blister, this bulla, you’ll see little septae that run from the base of the ulcer up to the roof of the blister. As you pull it away, those septic kind of retract back into foot and you get this reticulated pattern and you can see here, this is reticulated pattern that you get. Let’s open it up a little bit more and there are the septae that were up against the blisters and bulla roof that have now come down and are on the base of the ulcer. This is your interdigital vesicular tinea pedis. Getting back to Leyden and is in dermatophytosis simplex. This is interdigital dermatophytosis simplex. White, dry, scaly, seen in every patient you’re probably treating. What he did is he took a bunch of college students and he took students, I’m sorry, that had that and he wrapped their feet in Saran Wrap, plastic wrap to change the environment. Because remember, epidemiology, pathogen-environment-host, we can’t do anything about the host but we can treat the pathogen and change the environment. On this particular case, he changed the environment and after just a couple of days of having those feet wrapped up in plastic wrap, that interdigital or dermatophytosis simplex became this dermatophytosis complex.
You’ve all seen this. And usually there’s a lot of inflammation, it’s foul-smelling. You take bacterial cultures because you’re freaked out and there are gram-negatives growing and some gram-positive rods, and all sorts of different organism. And you start pumping the patient full of antibiotics. No need. What caused this? The environment. How do you reverse them? The environment. And that’s what Leyden show. By simply reversing the environment, drying this out, he was able to convert the complex back to a simplex, without all the antifungals and antibiotics and everything. How do we approach treatment of tinea pedis? Well, make the correct diagnosis. We talked about that. The dry skin is probably tinea and you have to get a proper sample. You’ve got two pathology labs here that I’m sure would be more than happy to take your pathologic specimens and do fungal testing for you. Treat the onychomycosis if it’s there. And there are all sorts of topicals. We’ve got creams, we’ve got gels, we’ve got solutions. Interestingly enough, almost every single clinical trial, with one exception, have looked at interdigital tinea, not moccasin tinea. Because up to this point the FDA has only approved antifungals for interdigital tinea. Yet the tinea we see most commonly, moccasin tinea pedis, none of them are indicated for moccasin. They’re only indicated for interdigital. And then there’s also oral therapies we could use. I checked clinicaltrials.gov when I first put this lecture together a couple of months ago. I found there were 39 trials for tinea pedis. Only two were currently recruiting and most were just updated formulations of older drugs or the case on head-to-head comparison against small drugs. There were no orals being studied for tinea pedis at this point. There were some new topicals, luliconazole, which is going to be available both for tinea pedis and onychomycosis. It’s Valeant’s drug for tinea pedis. It’s topical drug for onychomycosis. And albaconazole, I don’t know whose got that particular product. And there’s some new delivery systems, different foams, sprays, all of them are microcapsules. It’s actually antifungals and these little capsules that when you rub them on the foot, the capsule burst and lets out the antifungal. There’s not really a lot going on in the tinea pedis world. Why? We’ve got good antifungals for tinea pedis. We really do. The options, we’ve got prescription, we’ve got OTC, we got lots of drugs at work. Of course, the azoles are the most common. They’re probably the earliest also. These are primarily fungistatic, they inhibit our gastro synthesis, and you can see lots of different agents here. The only one of these that’s fungicidal is the sertaconazole, all the others are considered fungistatic. The side of the static make a difference in tinea pedis. Well, I’m here, tell you right now, it makes no difference at all in bacterial infections. We talked diabetic foot, we can talk other bacterial infections, I never once given consideration to either antibiotics, bactericidal, bacteriostatic. Makes no difference to me. There have been a couple of studies that have proven that. But, in tinea pedis, I think it’s a different story. Because unlike bacterial there may actually be a difference. Theoretically, and there not a lot of good studies to prove this, theoretically, you could use suicidal agent for shorter period of time. Since, remember, the skin takes 30 days to cycle through and replace itself. If you use a static agent, and let’s say you stop after two weeks, that gives the fungus two more weeks to start regrowing again and reinfecting the skin. Whereas, if you use suicidal agent for two weeks, if the organism is killed, it’s dead, it doesn’t matter if it takes another couple of weeks for the skin to flake off and new skin to form. Theoretically, you can use the cidal agent for shorter period of time. The allylamines are cidal agents, they are newer class of antifungal, they inhibit squalene epoxidase. And like I said, they’re fungicidal. Three of them that are available, terbinafine, is now, that’s Lamisil, that’s over-the-counter, naftifine is Naftin and butenafine is also over-the-counter as, I believe, Lotrimin Ultra. There was a study that looked at these and they did find that overall the allylamines may be slightly more effective than the azoles. Another website I want you to become intimately familiar with, you got idsociety.org. I would give you mine but I’m guilty I haven’t updated it in about four months and a couple of residents came up to me and asked me about that.
I promise I got next week or two free, I will update my website with leinfections.com. There are some really cool stuff that’s just come out recently, really neat stuff. There’s something about quinolones. I mean, I hated quinolones. I’m not big quinolone fan. But FDA just came up with a new warning on quinolones, a nonreversible peripheral neuropathy. How many of you have ever been asked by your patients when you give them an antibiotic, can I take yogurt or should I eat yogurt with this? Anybody? How many of you have told you patients take yogurt? Yeah. A new study just came out, they found probiotics make no difference in antibiotic-associated diarrhea. Just cool stuff. This is just cool stuff I need to blog about. Let me do it. But anyway, this is the other website I want you to know, cochrane.org. I don’t know if you’re familiar with it and if you read my book I quote a lot of the Cochrane collaborative reviews. These are systematic reviews of the literature and they come up with opinions, evidence-based opinions on all sorts of different treatments, surgical, medical, wound care, advice on wound care, all based on what medical evidence is out there. So this was a Cochrane review in 2009. Naftifine, okay, I’m talking about naphthalene, there’s some new formulations and I am consultant to MERS. It’s the first allylamine available for tinea pedis. Most people thought it was terbinafine, it was not, naphthalene actually predated it. Once daily cream or twice daily gel. That’s actually now changed just as of like the last two or three weeks. There is now a once daily 2% gel also. The new 2% formulation, originally it was just a 2% cream, which was once a day for two weeks, there’s now a 2% gel also once a day for two weeks. It’s got some anti-inflammatory effect and in vitro it’s been shown to be more effective against dermatophytes in either keto or oxiconazole. And there’s some activity against molds, yeast, and bacteria both in vitro and in vivo. This is their clinical trials. This just shows the different endpoint definitions they had, complete cure always low or always a high hurdle to jump over low numbers. All shows statistically significant difference between the active drug and the placebo or, excuse me, vehicle. These are all vehicle-controlled studies. Now, I put this study in because what this shows is in the Quinn study there was actually 15 patients included with moccasin tinea pedis. Alright, that’s not a lot. And it did shows there was efficacy versus vehicle which was 0%, not enough to come up with any significance. I will tell you they have not formally release it yet but I’ve seen a naftifine gel data. And if I remember correctly, there actually a couple hundred people with moccasin tinea pedis. That would be really cool. They don’t have the indication yet if that drug becomes the first drug indicated for moccasin tinea pedis. As I mentioned before, giving shorter courses of therapy of a cidal drug, it’s possible that you can do well. This is a two weeks, four weeks and six weeks. You only give the drug for two weeks. Notice that two weeks, numbers are pretty dismal. But what happens as time goes on? You see the stair stepping here? As time goes on the organism is dead so the patients continue to get better. And you got that same effect with onychomycosis. If you’re giving a cidal drug or using a device that kills the organism, it’s possible that you can use shorter courses of therapy. And if the organism is dead it just takes time for either the skin in this case or the nail to grow out. Well, here is going to be a shock to you. Patients don’t always follow your instructions. Now we used to call that noncompliance. That is no longer politically correct. We now have to call it nonadherence. Nonadherent, to me that sounds like a Band-Aid. It’s like I refuse to use it. But this is what your public health people wants you to do. These patients are not noncompliance, they are nonadherent. Well, I will tell you that adherence to topical therapies hasn’t been particularly great. There’s an entire science of adherence. It’s called pharmionics. So there’ve been some interesting things looking just a topical therapies. And just a couple of review articles that looked at this, they find shorter, easier to understand courses of therapy may improve adherence. Of course, this is not just for topicals. Try giving a patient a four-time-a-day drug, a four-time-a-day pill, how many of them actually take a four-time-a-day pill?
The first day they do, after that, never, alright. What are some of the barriers to adherence? Inconvenient to apply, cost to the medication, vagueness of application terms. How many of you, when you give patient a tube of some antifungal for tinea pedis, have ever told them how much to put on the foot? If you say, do one knuckles worth, or do like one inch per foot, you are the best ever with this. Most of the residents are too young, some of the other attendings might remember when becaplermin came out, Regranex, that had the best description ever on how to apply it. Anyone remember what they told you or what you had to tell your patients? The thickness of a dime. Cover the ulcer with a thickness of a dime. That’s specific. That makes sense. But if you give somebody a tube of cream and say apply it to your feet twice a day, what are they going to do? How much are they going to use? They don’t really know. You got to make sure it’s short term, not frequently applied, and you get specific with how to instruct them. This is a really cool study. Because what they did here is they looked at 17 patients and they found applied dose versus the expected dose and they defined the 80% rate that the patient applied the drug they were supposed to apply 80% of the time. They were considered adherent. One out of 17 patients was found to be adherent. One out of 17. And I love this slide. This slide is just wild. This is incredible. What they did in this study is they gave patients a cream and the cream had a special lid, a special cap to it. But every time they squeeze out the cream it measured how much cream they squeezed out and when they squeezed it out. They had a cream measuring lid and they told the patients to diary when they put on the cream. Well, if you look at this top line, according to the diary, these patients were adherent almost 90% of the time. But when they actually took the tubes and look at the patient’s adherence over days, by the end of treatment less than 50% of patients were actually putting the medication when they were supposed to put on. By shortening courses, by decreasing amount of courses, both in numbers and time, you can at least, theoretically, increase the adherence. Oral antifungals, yes we can use them for tinea pedis. When would I use it for tinea pedis? A patient has been recalcitrant to topical therapy, maybe a severe moccasin or maybe even in combination. So inside out, outside in that we apply to onychomycosis also. Here’s a Cochrane review. The review compared different oral antifungal drugs and found that terbinafine and itraconazole were both more effective than placebo. Terbinafine worked faster and was more effective than griseofulvin in the treatment of tinea pedis. Again, this is when I use an oral moccasin tinea in response to the topicals, severe interdigital possibly in combination with topicals, and when there are patient adherence issues. You can get them on a week or two weeks of once a day, terbinafine 250 milligrams as opposed to applying a cream once or twice a day. Alright, any questions on any of this? Instead of going into onychomycosis now I wish my main topic was tinea. Anyway, I figured with five minutes after it. Any questions on this or the diabetic foot talk? Or, even the life thing talk I was giving you?
Male Speaker 2: Hey Warren, what do you do as far as the environment that you choose?
Male speaker 1: What about environment? Well, it’s a great question. When you deal with onychomycosis or tinea pedis, I mean we know the organisms are everywhere and these are your ubiquitous organisms. Any of you staying at the hotel here, you can probably culture your carpets in your room. Boni Elewski, who in the world of dermatology is like Dr. Fungus did a study where she cultured hotel carpets. When she talks about it, she jokes around about how she was going to call it. Like there’s a four dime, the triple A diamond rating, there’s this four-diamond hotel or three-diamond hotel. She was going to come up with the Elewski’s spore rating. This is a one spore hotel, a two spore hotel. Any of you from Florida? I mean the present guys are from Florida.
And whenever you walk into a hotel in Florida, any of you have noticed, do you ever notice what I call the Florida hotel smell? It’s a very distinctive odor whenever you walk into a hotel in Florida. And what is that? That’s mold. There’s stuff all over the place, there’s all over the floors. I mean, hell, think about it, I stay in hotels probably 70 nights a year. I don’t walk around in slippers or shoes or socks, I already have tinea pedis why do I care, right? But you come into the room after me. Do you think that vacuum cleaner got it all up? I think we have to address the environment. What about shoes and socks, alright? At the APMA National I just noticed they have these new copper socks. They have socks with actually copper threads impregnated into them. I’m not a consultant. I honestly don’t even remember their name. I think it was Cupron. They gave me a couple. I haven’t put them on yet because they’re really thick, they’re kind of like athletic socks. But they’re kind of black, their color, black athletic socks. It’s like my shoes I wear for dress wouldn’t fit those thick socks but I’m not that much of a nerd that I’m going to go exercising in black socks. I haven’t quite found a place to use them yet. But that’s one way to maybe treat the environment. What about the shoe? Well, I will tell you, I am a consultant to them but SteriShoe. It’s a UV shoe tray. Basically, you put it in and then use this UV light. I give these guys props. Again, full disclosure, I am a consultant and I don’t get paid for speaking for them or anything. I’m not sponsored for mine either. But they actually commissioned one of the top mycologists in the world, Mahmoud Ghannoum, up in Ohio in Cleveland. And Mahmoud who is brilliant guy, a nice guy, I’ve known him for number of years, actually designed a study for them which was a shoe infection model, where he actually came up with a model to infect shoes with T. rubrum. And then they treated it with the SteriShoe. They did find that there was significant decreases in the amount of fungus found in the shoe after using the UV light in the shoe. There are ways, spraying Lysol in the shoes, I’m not a big fan of that, antifungal powders. Some of us at a certain age remember the shoeminator. It was like when the “Terminator” movies came out some podiatrists actually invented the shoeminator, which was like a thing you could spray antifungals into shoes with. I think it is important that you do handle as much as you can handle the environment not just the pathogen. Other questions? Thanks very much.