Emerging Concepts In Treating Onychomycosis
Given the significant prevalence of onychomycosis that podiatrists see in practice, these authors review current treatments and offer a closer look at emerging topicals, orals and devices that may hold promise in treating this disease.
Since the drug companies’ fungal wars of the 1990s, many podiatrists have lost interest in the treatment of onychomycosis and have settled into their own particular treatment paradigm. However, emerging technologies and new drug delivery systems have again brought the treatment of onychomycosis to the forefront of our profession.
Onychomycosis is still the number one disease diagnosed and treated by podiatric physicians in the United States.1 While researchers have estimated that 2 to 3 percent of the U.S. population has onychomycosis, this number seems dynamic and growing with time as the infection spreads in a pandemic fashion. Onychomycosis currently affects up to 20 percent of individuals between 40 and 60 years old. Thirty-two percent of individuals 60 to 70 years old have it and over 50 percent of those over the age of 70 are infected.2,3
Army research from 1965 stated that fungus is contagious to others and can also spread to other locations in the patient’s own body. Nail trauma and longer exposure to fungus contribute to higher infection rates. Still, many clinicians wonder why certain patients acquire fungal infections and others do not. Some researchers have postulated that an autosomal gene defect produces an immune sensitivity that allows infection.1,3
The infection of the nail may be caused by dermatophytes, saprophytes and/or Candida. Most studies suggest Trichophyton rubrum is the most common organism.
The nail is made up of three layers. The nail plate acts as a button, opposing the force that places pressure on the finger or toe. This increases the discrimination ability of the acral pulp and skin wherever the skin feels the object. When a fungal infection occurs, the intermediate layer hypertrophies and distorts the nail. Since the ventral layer stays intact, the nail is usually still attached to the nail bed by a specialized onychodermal band known as the sole horn.4-6
The treatment of onychomycosis centers on five basic modalities: debridement, surgical removal, topical medications, oral medications and emerging technologies.
What You Should Know About Debridement And Surgical Options
For podiatric physicians, debridement of the fungal nails is a common practice, one that many other specialists overlook. Although debridement does not treat the infection, it can decrease the fungal load of the nail and can complement medical therapy. It can also reduce pressure necrosis and improve the nail’s overall cosmetic appearance.7
The treatment is noninvasive and is therefore safe for all patients, including those with advanced peripheral vascular disease and diabetes. Another debridement technique other than use of the nail nipper is 40% urea. Over time, the urea eats away at the keratin, providing chemical debridement of the nail area.8
Surgical removal of the nail by matrixectomy can be effective in eliminating the infection. However, surgical avulsion is another matter altogether. The first problem with avulsion is one of possible re-infection as the nail returns.
The second problem that can arise is that the distal dorsal tuft of the distal phalanx can hypertrophy, preventing the nail from completing its full excursion past the hyponychium. This will lead to a dorsal deformity of the distal toe. Eventually this can lead to distally infected ingrown nails requiring matrixectomy for resolution of the problem.
A Guide To Current And Emerging Topical Treatments
In the early 1990s, the Food and Drug Administration (FDA) stated that no topical remedy could claim efficacy against onychomycosis. Currently, only ciclopirox lacquer (Penlac, Sanofi Aventis) is approved for mild to moderate onychomycosis of the fingers or toenails.
Ciclopirox is a hydroxypyridone with a unique mechanism of action. It works by chelating the polyvalent cations (Fe+3 or Al+3), resulting in the inhibition of metal dependent enzymes that degrade the toxic peroxides within the fungal cell. Mycological cure rates have been good but clinical cure rates are approximately one-quarter that of oral medications.9
Other medications that have shown anecdotal success are tea tree oil, Vicks Vapor rub, Listerine and oral medications dissolved in different mediums including dimethyl sulfoxide (DMSO). None of these have FDA approval or are substantiated by evidence-based medicine.9-11
In regard to new topical agents, Schering Plough has acquired AN2690, a new topical antifungal that targets fungal protein synthesis. An essential enzyme in fungal synthesis is leucyl-transfer RNA synthetase (LeuRS). AN2690 inhibits protein synthesis by denaturing LeurRS, which leads to the termination of cell growth or cell death.12 This inhibition requires a boron molecule to be replaced with a carbon molecule. In theory, this will eliminate fungal infection.
When it comes to possible side effects for AN2690, initial phase II trials led to little or no detectable drug exposure in urine or blood, negating possible systemic issues. The main side effect was mild to moderate local skin reaction. Schering-Plough will begin phase III clinical trials in 2009. The company claims that this new topical treatment will be 250 times more powerful than Penlac, the only currently approved topical therapy for onychomycosis in the U.S.12
Another way to improve topical medications is to improve transport technology. Current work is centering on an iontophoretic control device that delivers an electrical current with a dose of terbinafine (Lamisil, Novartis) to the nail bed by electrode. The goal is to drive the drug through the nail as well as saturate the nail and nail bed. This will create a reservoir of antifungal medication, which will allow continual release of terbinafine to the underside of the nail where onychomycosis develops.
The same features that make drug delivery to the nail difficult (i.e. a lack of blood vessels and a waxy, impermeable surface) improve the half-life of drugs that do penetrate. Also bear in mind that the structure of the nail creates an excellent reservoir for holding drugs and releasing them over time. This will help eliminate high systemic concentrations and drug interaction concerns.
A double-blind, randomized pilot study of 28 patients using iontophoresis with terbinafine hydrochloride showed a 64 percent clinical improvement in comparison to the placebo group at week 24. Final data is not available at this time.13
NanoBio Corporation is developing NB-002, a new topical treatment for onchomycosis. This oil-in-water emulsion is currently in phase II development. With this treatment, high-energy nano-sized particles penetrate the skin pores and diffuse through the skin that surrounds the entire nail plate, according to a study by NanoBio Corporation.14 Upon contact with the pathogen, the highly charged particles release their energies to the pathogen’s outer membranes, disrupting the fungus.
NanoBio states that NB-002 is able to achieve 50 times the minimum drug concentration needed to kill the fungus in the center of the nail bed. Studies conducted in vitro demonstrate that NB-002 has antifungal activity against the organisms (including T. rubrum, T. mentagrophytes, Epidermophyton floccosum and Candida albicans) that cause nail fungus.14
MacroChem Corporation is currently in the midst of a phase II open-label trial of EcoNail (econazole 5%/SEPA 18% nail lacquer), a topical lacquer with SEPA (2-n-1,3 dioxolane) as a drug release enhancer to increase the delivery of econazole to the nail matrix. A total of 37 patients with mild to moderate great toenail infection underwent treatment for 48 weeks with the topical nail lacquer. After 48 weeks of once-a-day treatment, 100 percent of patients had cultures that were negative for dermatophyte growth.15
Pertinent Insights On Oral Medications
Griseofulvin (Gris-PEG, Pedinol) was introduced in 1958. It is fungistatic and effective against dermatophytes. However, due to low cure rates, high relapse rates and poor safety profile, the use of griseofulvin has been limited.
The azoles are a drug class that includes itraconazole, ketoconazole and fluconazole. This drug group is effective against dermatophytes, yeast and other fungi. Ketoconazole (Nizoral) fell out of favor due to its high toxicity rates. Fluconazole (Diflucan, Pfizer) never was approved for toenails and has a high rate of resistance.
Itraconazole (Sporanox, Ortho-McNeil) was approved for continuous therapy for onychomycosis and has proven effective when physicians use it in a pulsing fashion as well.16 Recently, itraconazole received a black box warning due to cardiac concerns.16
The best of the oral antifungals is terbinafine, the first oral antifungal approved for treatment of onychomycosis. Unlike the other antifungals, it is fungicidal and is currently the most effective of the antifungal oral medications.
Before starting any oral antifungal, it is important to take into account the other medications a patient is taking due to the fact that azoles inhibit P-450 cytochrome, which could interfere with other medications. Also, a past history of liver dysfunction may preclude the patient from taking these medications due to the fact that the medications are metabolized in the liver and could lead to further liver damage.17-19
There are a plethora of new triazoles at different stages of clinical trial. These include voriconazole (Vfend, Pfizer), isavuconazole (Basilea Pharmaceutica), ravuconazole (Eisai/Bristol-Myers Squibb), pramiconazole (Barrier Therapeutics/Stiefel Laboratories), posaconazole (Schering-Plough) and albaconazole (Stiefel Laboratories).20
One promising new azole is pramiconazole. This new addition to the family of triazole antifungal agents works by inhibiting fungal cell membrane ergosterol synthesis, thereby leading to increased cell permeability and cell destruction.21 In pre-clinical studies, pramiconazole showed similar or superior antifungal activity to ketoconazole and itraconazole. This new azole was absorbed rapidly and had a long half-life, allowing for once-daily dosing.21 Promising pre-clinical and early phase II clinical data warrant further development.
Can New Devices Have An Impact For Onychomycosis?
Noveon (Nomir Technologies) is a low power laser that is currently in use for dental work, cataract surgery and even hair removal. The laser beam has two different wavelengths of near-infrared light, which causes photo inactivation of the fungi that cause onychomycosis. The device uses specific infrared wavelengths that have the ability to cause photo damage to microbes.
In a pilot study, Noveon treatment had a 76 percent clinical improvement. At this time, Nomir Medical has a FDA 510(k) clearance for the Noveon laser and is pursuing approval for onychomysosis.23
PinPointe FootLaser (Patholase) is a new high powered pulse laser that targets the fungus responsible for causing onychomycosis and related fungal infections. According to Patholase, usually only one treatment is necessary although further study is ongoing. No anesthesia or other drugs are necessary. Patients who have undergone the treatment report very little pain and promising results have been reported.24 A new trial will evaluate the efficacy and safety of this new modality.
PinPointe FootLaser has received FDA approval for use in podiatry, dermatology and plastic surgery but it does not have a specific indication for onychomycosis at this time. However, in Europe, it recently received the CE Mark approval (certifying that it has met EU consumer and health safety standards) for the treatment of toenail fungus. The cost of the procedure is approximately $1,000.24
Transungual laser therapy (TLT, Arpida) is a new device which makes partial micro-holes to the dorsal nail plate. This facilitates the permeation of terbinafine to the ventral side of the nail.25 Patients then apply a daily topical formulation of a terbinafine lacquer solution and ethanolic liquid on a daily basis. A European regulatory agency has initiated a phase III clinical trial to evaluate the efficacy, safety and tolerability of the TLT therapy.
Keraderm is creating a UVC device that offers two to four phototherapy treatments using a germicidal light. The treatment uses UVC rays, which are shorter than UVA and UVB rays. Microorganisms are very sensitive to UVC light and therefore only small amounts of UVC light can make microorganisms harmless. The radiation that the nail bed experiences is approximately equal to 20 minutes of sun exposure.
With respect to current clinical trials, the FDA has designated this device as having a non-significant risk. In the pilot trial, there were no significant side effects and 73 percent of those treated showed significant improvement in their nails.26
The device will be introduced in 2010 at approximately $100 for several treatments. The goal is to eventually only need one treatment for about $100. Keraderm’s research with this device has been published in the peer-reviewed British Journal of Dermatology and presented at the 2007 World Congress of Dermatology.26,27
Talima Therapeutics is working on a micro-implant to deliver a broad-acting time release antifungal molecule to the site of the nail infection. One would place the implant in a non-invasive manner with an applicator at the target site.28 Phase III clinical trials are currently underway in the U.S. to determine the safety and efficacy of the micro-implant. This technology has the potential to deliver high and sustained therapeutic levels of drug to the diseased area, thereby minimizing blood levels of the drug by up to a thousand-fold in comparison to conventional administration.
A new device called the Toemate (Innovation Biomedical Devices) reportedly treats onychomycosis by heating (40ºC max) a viscous antifungal liquid through the keratin in the nail plate. The theory is that heat will increase kinetic energy and facilitate drug absorption.
When keratin is heated, it has a tendency to absorb water into its structure and will absorb antifungal medication attached to absorbed fluid. Applying heat increases the rate and depth of this absorption by increasing the space between molecular bonds. This device is currently undergoing clinical trials at Temple University.29
Dr. Mozena is in private practice at the Town Center Foot Clinic in Portland, Ore. He is a Fellow of the American College of Foot and Ankle Surgeons and is board certified in foot and ankle surgery.
Dr. Mitnick is in private practice at Town Center Foot Clinic in Portland, Ore.
For further reading, see “Treating Fungal Infections,” a March 2004 supplement to Podiatry Today, “Managing Onychomycosis,” a June 2004 supplement, or “A Guide To Treatments For Onychomycosis” in the August 2003 issue.
For other related articles, please visit the archives at www.podiatrytoday.com.
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2. Mozena JD. Why onychomycosis can no longer be dismissed as a cosmetic problem. Podiatry Today 2000; 13(2):29-34.
3. Charis MA, Elewski BE. Historical perspective on onychomycosis. Dermatological Therapy 1997; 3:43.
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12. Available from: http//www.anacor.com/an2690.php
13. Boker A, Bae YS, Gowrishankar TR, et al. A double-blind, placebo-controlled pilot study of 1% terbinafine cream delivered via toenail microconduits for the treatment of subungual onychomycosis. Poster presented at the 65th annual meeting of the American Academy of Dermatology, Washington, DC, Feb. 2-6, 2007.
14. Jones T, Ijzerman, Flack M, Baker JR. Tolerability, safety and pharmacokinetics of topical nanoemulsion (NB-002) in patient with onychomycosis. Poster presented at Interscience conference on antimicrobial agents and chemotherapy, 17-20 Sept. 2007, Chicago, IL, USA
15. Available from: http://www.medicalnewstoday.com/articles/116086.php
16. Itraconazole (package insert). Ortho-McNeil, Raritan, NJ, 2009.
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18. Elewski B. Mechanisms of action of systemic antifungal agents. J Am Acad Dermatol 1993; 28(5 Pt 1):S28-S34.
19. Terbinafine (package insert). Medical Economics Company, Inc., Montvalle, NJ, 1999.
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21. Geria AN, Scheinfeld NS. Pramiconazole, a triazole compound for the treatment of fungal infections. IDrugs 2008; 11(9):661-70.
22. Available from: www.nomirmedical.com/news2.pdf
23. Available from: www.nomirmedical.com/news1.pdf
24. Available from: www.patholase.com/news/multi-center-trial
25. Arpida reports progress in pivotal Phase III trial with TLT treat treatment in onychomycosis. Available from: www.arpida.ch/1/content/arpida-tlt-phiii.pdf
26. Boker A, Cumbie B, Kimball AB. A single-center, prospective, open-label, pilot study of the safety, local tolerability, and efficacy of ultraviolet-C (UVC) phototherapy for the treatment of great toenail onychomycosis. Poster presented at the World Congress of Dermatology, Buenos Aires, Argentina, Sept. 30-Oct. 5, 2007.
27. Dai T, Tegos GP, Rolz-Cruz G, Cumbie WE, Hamblin MR. Ultraviolet C inactivation of dermatophytes: implications for treatment of onychomycosis. Br J Dermatol 2008 Jun; 158(6):1239-46.
28. Available from: www.talima.com/technology.html
29. Correspondence with Todd Weinfield, CEO, Innovation Biomedical Devices, Inc., 2009.