Nail fungal disorders are one of the most common problems seen by dermatologists. Although treatments have been available for decades, the best we seem to achieve is about a 50 percent cure rate. Are there options now or in the near future that may improve these statistics? Dr. Boni Elewski sheds light on this subject in an interview with Dr. Norman Levine.
Nail fungal disorders are one of the most common problems seen by dermatologists. Although treatments have been available for decades, the best we seem to achieve is about a 50 percent cure rate. Are there options now or will there be options in the near future that may improve these statistics? Boni E. Elewski, M.D., professor of dermatology at the University of Alabama at Birmingham sheds light on this subject in an interview with Dermatology Times Editorial Advisor, Norman Levine, M.D.
Dr. Levine: What’s your sense of who needs treatment and who does not need treatment for onychomycosis?
Dr. Elewski: That’s a hard question to answer because anyone who wants treatment deserves treatment if they indeed have onychomycosis. But when is it really medically necessary? We know that diabetics have a higher risk of getting onychomycosis. Onychomycosis could be the beginning of complications with a diabetic foot and could lead to cellulitis and other significant conditions. Additionally, fingernail involvement would be concerning and would increase the need for therapy.
Keep in mind, however, that if you have fingernail disease you most likely also have toenail infection. It’s very rare to have dermatophyte onychomycosis of the fingernails without toenails being involved.
Onychomycosis is a progressive infection. If you don’t treat it, it doesn’t go away. It continues to spread. Other nails and body sites develop and the nails continue to thicken and progress over time. Thus, anyone who doesn’t treat the infection at an early stage will eventually have a more severe infection, which is harder to treat - at least with what we have currently available. So, to answer your question, most people should be treated.
Dr. Levine: Some years ago Henry Earl Jones, M.D., talked about the issue of a selective immune response associated with those who get dermatophyte infections[i]. What’s the nature of that?
Dr. Elewski: People who have onychomycosis caused by Trychophyton rubrum may have a hole in their immune system that increases their risk for infection. However, there are other mechanisms to develop disease.
Onychomycosis is an infection. If you put someone in the right environment, like a soldier who marches around in combat boots or those that a share a locker facility, they frequently develop tinea pedis and then onychomycosis. Swimming pools are a particularly risky location for finding infectious fungal particles that may cause tinea pedis.
Everyone may have different degrees of involvement depending on their immune systems. Interestingly, we found that chronic T. rubrum infection may lead to trichophyton anergy and recalcitrant disease, but aggressive therapy with oral terbinafine reversed this response and lead to clearing. Atopics are particularly at risk for infection[ii].
We found that those who were anergic generally had more severe disease for longer time periods, and those who reacted had milder, less severe disease.
We treated all patients for 90 days with terbinafine, per label. Those that were reactive at the beginning of the study had a higher cure rate. Almost all of those patients who were anergic at the beginning of the study, but converted their immune system so they reacted to Trichophyton by the end of the study, went on to be cured. Those people that were anergic at the beginning of the study and never reacted were the ones that failed treatment. So we postulated that aggressive therapy may be indicated in these patients.
NEXT: How efficacious are the new generation of topical therapies?
Dr. Levine: There is now a new generation of topical therapies. What’s the newest on these in terms of their efficacy in a nail fungus infection?
Dr. Elewski: Well there are two topical drugs: Efinaconazole 10 percent solution (Jublia, Valeant Pharmaceuticals) and that is available by prescription and topically applied on, around and under the nail. It was tested in mild to moderate onychomycosis. So these patients weren’t as severe as those treated 20 years ago with oral terbinafine and itraconazole (Sporanox, Janssen Pharmaceuticals). I am very impressed with the results of efinaconazole solution. About 1,236 subjects were treated with drug resulting in 205 complete cures. However, mycologic cure is very important and the mycologic cure rate was about 55 percent, which I think indicates the cure rate we will see in our practices. Best results will be in patients with relatively mild infection, such as nails less than 3 mm thick and involve less than 75 percent of the nail surface.
The second topical, Tavaborole (Kerydin, Anacor Pharmaceuticals), was tested in a similar fashion. There were 795 patients on active drug and 62 were totally cured but the mycologic cure rate was about 35 percent. Again, I feel that this will be an indicator of the likely response in our practices.
Patients will apply either drugs topically until the nail is normal. Given the slow growth of the nail, it will take up to 18 months, but might be much less in mild disease.. The drugs are expensive, so they should not be used unless the diagnosis has been confirmed by KOH, culture or PAS.Persons unable or unwilling to take an oral antifungal are ideal candidates for topical therapy.
Dr. Levine: Let’s talk a little bit about systemic therapies. First, is there any reason in the world for a dermatologist to use oral ketoconazole (Nizoral, McNeil) anymore?
Dr. Elewski: There is absolutely no reason to write a prescription for oral ketoconazole. For those who write it or have written it, say for tinea versicolor, just substitute fluconazole (Diflucan, Pfizer) at 200 milligrams, exactly like you used to give ketoconazole.
Dr. Levine: At the last Academy meeting I heard you say specifically that you used oral fluconazole frequently for nail fungal infection. How do you use it?
Dr. Elewski: The original study for this was published in the Journal of the American Academy of Dermatology[iii]. The study included about 1,000 people and compared the efficacy of 150, 300, and 450 milligrams once a week. It actually had the highest cure rate of any study. The complete cure rate in that 450-milligram group was in the 50 percent range, which was significantly better compared with oral terbinafine at 38 percent. However, they were not toe to toe studies.
Since there’s no pill for 450 milligrams or 300 milligrams, I write a prescription for one 200-milligram tablet per week. I tell the patient to take it every week on “Fungal Friday” or “Toes days - Tuesday”. I have patients take one pill a week, but I give them a loading dose. So whatever day it is that I see them, I will tell them to take one pill today and then one pill every Friday. Fluconazole is relatively safe, with low risk of liver irritation and low risk of skin eruptions. Dosed once weekly, no steady state develops, so drug-drug interactions are unlikely. Keep in mind that it’s not FDA approved for this indication, so using it is off label. It is approved in some countries for onychomycosis, but not the United States.
Dr. Levine: For how long do you use the fluconazole?
Dr. Elewski: You have to use it until the nail is normal. That’s important. Let me give you an example of when I might prescribe this. If I have an older patient who is already on a number of pills per day, I’ll ask them if I can give them just one pill a week. The nail grows slow; so the one pill a week kind of matches the slow growth of nail. I would check baseline labs to be compulsive. I would check a complete blood count, and I would do a baseline measurement of how many millimeters of clear nail are present. Then I would prescribe the patient 12 to 15 pills and have the patient return in three months. At that time, I’ll measure how much clear nail we see compared to the last visit. I’d expect to see a couple of millimeters of clear nail more than the patient had the previous time. Repeat this until the nail is normal.
NEXT: How long should terbinafine be used?
Dr. Levine: For those of us who frequently use terbinafine for this, the conventional wisdom is to use this drug for three months. Is that written in stone or is there a way you alter it?
Dr. Elewski: Well the package label says three months, although the original study compared 12 weeks to 24 weeks and found no statistical difference. However 24 weeks works better than 12 weeks. So what I do in my practice is to begin therapy with three months after obtaining a positive fungal culture and normal baseline labs. Re-evalutate in 3 to 4 months for progress and another 3 month course may be indication if severe nails are still present.
Dr. Levine: What kind of lab monitoring do you use for terbinafine?
Dr. Elewski: I do a baseline liver profile.
Dr. Levine: And do you repeat that after a certain number of weeks?
Dr. Elewski: No. I just repeat it before another course. There was at one point a notation in the package label to monitor at six weeks, but that was removed. So, for a healthy person, I don’t monitor unless there are concerning comorbidities or other drugs that may irritate the liver. For an older patient with polypharmacy I prefer fluconazole, but now I am using the new topical medications for the nail as we discussed.
Dr. Levine: What is the status of laser therapy for nail fungus infection?
Dr. Elewski: The bottom line is that it did not work. Our study, which was published in the Journal of the American Academy of Dermatology, found no clinical improvement and no results in the mycology lab.[iv]
However, there are some studies that show that lasers may be effective. The bottom line is that they may cause some temporary improvement, but no clinical resolution.
As you can see, I am a little skeptical that laser therapy of onychomycosis is worth pursuing.
Dr. Levine: Is there any advantage to avulsing a nail before any of the treatments you have talked about here?
Dr. Elewski: Photodynamic therapy appears to be very effective in onychomycosis, at least with the red light. It is currently unknown if blue light would work. The problem is that the nail must first be avulsed prior to treatment, but urea avulsion seems to suffice.
To be complete, avulsion as a treatment is another option if you have a non-dermatophyte infection, because the oral antifungals are unlikely to be effective. Itraconazole is the best option for oral therapy of nondermatophyte molds.
I want to conclude that I am excited to have two new topical products for onychomycosis. This will improve our options in treating this common, but challenging infection.
[i]Jones HE. Immune response and host resistance of humans to dermatophyte infection. J Am Acad Dermatol. 1993; 28: S12-S18
[ii]Eklewski BE, El Charif M, Cooper KD, Ghannoum M, Birnbaum JE. Reactivity to trichophytin antigen in patients with onychomycosis: effect of terbinafine. J Am Acad Dermatol. 2002; 46(3): 371-375
[iii]Scher RK, Breneman D, Rich P, et al. Once-weekly fluconazole (150, 300, or 450 mg) in the treatment of distal subungual onychomycosis of the toenail. J Am Acad Dermatol. 1998; 38: S77-S86
[iv] Carney C, Cantrell W, Warner J, Elewski B. Treatment of onychomycosis using a submillisecond 1064-nm neodymium:yttrium-aluminum-garnet laser. J Am Acad Dermatol. 2013; 69:578-582