Current And Emerging Agents For Tinea Pedis

There is no shortage of over-the-counter and prescription remedies for tinea pedis. With this in mind, this author takes a look at the research and clinical experience regarding several emerging treatment agents, including new topicals and medical socks. One of the most common infections in the United States, tinea pedis is consistently the result of dermatophytes. These skin, hair and nail-preferring fungi consist of Trichophyton sp., Microsporum sp. and Epidermophyton sp., of which the top pedal pathogen is Trichophyton rubrum. Dermatophytes are highly contagious and may transfer via soil, animals, humans and fomites.    Wearing shoes, sneakers or boots leads to creating a warm and moist environment, which is an optimal place for fungus to thrive. Traditionally, tinea pedis occurs in the pedal interdigital areas, where prolonged moisture will cause macerated tissue to occur. However, it also presents on the plantar surface of the foot as dry, scaly and itchy skin known as the moccasin type. Populations at risk to develop tinea pedis include: those who use communal facilities (pools, dorm showers, gyms); those who wear rubber or non-breathable material shoes at work; and those who have diabetes or are obese, immunocompromised, vascularly compromised and unable to perform regular foot hygiene.    Treatment options have consisted of both prescription and over-the-counter topical medications, such as naftifine (Naftin 1% or 2%, Merz Pharmaceuticals), econazole (Spectazole, Fougera Pharmaceuticals) and ciclopirox (Loprox, Medicis). Oral medications consist of off-label uses for terbinafine (Lamisil, Novartis) and itraconazole (Sporanox, Janssen Pharmaceuticals) and on-label use for griseofulvin ultramicrosize (Grifulvin V, OrthoNeutrogena).    Even after educating the patient on the basics of pedal hygiene (drying between toes, changing socks and shoes daily, disinfecting family showering areas, and wearing shower shoes in communal areas), the physician will typically continue to manage the patient for a persistent and irritating plantar infection weeks to months after treating the initial infection.    Prior to seeking medical attention, the patient will often self-treat with over-the-counter topical preparations that consist of medicated foot powders, sprays and creams, such as Castellani’s paint, gentian violet, undecylenic acid, miconazole, clotrimazole (Canesten, Bayer), tolnaftate (Tinactin, Schering-Plough), butenafine (Lotrimin, Merck) and terbinafine. After a frustrating trial with many of these products, patients will finally seek professional advice. As medical professionals, we often prescribe the same product time and time again, and may be unaware of the emerging treatments available for tinea pedis.

A Closer Look At Emerging Treatments

A member of the allylamine class, naftifine exhibits fungicidal, anti-inflammatory and antibacterial properties.^1-4 In vitro, naftifine exhibits fungicidal activity against the dermatophytes and many Candida species. It stops fungal growth by inhibiting squalene epoxidase in the ergosterol synthesis pathway, which ultimately increases cell membrane fragility and permeability.    The mycological and clinical cure rates for naftifine in the treatment of tinea are superior or equivalent to those of terbinafine, econazole and tolnaftate.⁵ In 2011, Parish and colleagues showed that once-a-day use of naftifine 2% cream for two weeks in the management of interdigital tinea pedis had efficacy responses equivalent to naftifine 1% cream, which patients traditionally used for four weeks for the same infection.⁶    Recently, naftifine 2% gel (Naftin 2% gel, Merz Pharmaceuticals) garnered approval for the same dosing regimen as the 2% cream. The 2% gel was the subject of a randomized, vehicle-controlled clinical trial that enrolled patients who had interdigital tinea pedis or both interdigital and moccasin-type tinea pedis.⁷ The study patients used the medication for two weeks and then researchers followed them for four weeks following discontinuation of the drug. Results of the trial showed that the 2% gel was superior to vehicle at week six (four weeks post-treatment) for complete cure of people who had both interdigital and moccasin-type presentations. The study also showed naftifine 2% gel to be significantly better than vehicle in achieving mycologic cure at week six in those same patients. Overall, naftifine 2% gel was designed to provide a shorter and more convenient regimen while still maintaining the efficacy that practitioners have come to expect with the drug.    In my practice, I often see the presence of hyperkeratotic skin and tinea infection simultaneously. Hyperkeratotic tinea pedis accounts for 2 to 8 percent of tinea cases and presents as moccasin-type tinea with hyperkeratosis confined to the weightbearing areas.⁸ It is typically bilateral and often one only treats it with a topical antifungal. The hyperkeratosis presents a therapeutic challenge to both the patient and the physician. Often, after the tinea infection has resolved, the hyperkeratosis remains, which leads the patient to believe the infection is still present.    There is no combination product targeting both the hyperkeratosis and the tinea available at this time, but there was a pilot study using naftifine and urea on 18 patients.⁹ Researchers evaluated patients for eight weeks. They used the naftifine 2% cream for two weeks in the morning and applied the urea 39% cream to the affected area nightly for eight weeks. Ultimately, the evaluable patients had improvements in hyperkeratosis, the active tinea infection and pruritus. This dual therapy ultimately proved to be efficacious and cosmetically pleasing for the patients to use.    Additionally, luliconazole 1% cream (Luzu, Valeant Pharmaceuticals), a new topical imidazole, recently received approval in the U.S. for the treatment of interdigital tinea pedis. Approved in Japan since 2005, luliconazole is effective against both dermatophytes and Candida albicans, and research has shown it to be as effective as terbinafine in animal studies.¹⁰    Jarratt and colleagues reported the results of applying luliconazole 1% once daily to patients with interdigital tinea for two or four weeks in comparison to the vehicle.¹⁰ Increasing the treatment period from two to four weeks only slightly changed the mycological cure and/or clinical cure rates. This shows the potent activity of the study drug toward the dermatophyte. In addition, this study demonstrated that luliconazole 1% is not only an efficacious topical against tinea, but is also a safe and well-tolerated product. The data of the Phase III study, which supported the new FDA approval for the product, will be published within the next year.

How Effective Are Folk Remedies For Tinea Pedis?

A folk remedy in Japan involves applying green tea leaves to affected skin.¹¹ Green tea leaves contain catechin, which seems to exhibit antioxidant properties. Green tea reportedly has activity against Candida, bacteria and fungus.    A recent study of tinea pedis patients focused on the effects of green tea polyphenol dissolved in lukewarm water foot baths for three months.¹¹ Four bedridden patients who had plantar tinea pedis took once daily foot baths with a green tea polyphenol solution. After 12 weeks, the signs of tinea pedis had improved but researchers could not assess subjective symptoms like pruritus due to the conditions of the patients studied. Patients had no adverse symptoms but further studies will have to assess both the most efficacious concentration of green tea and patient satisfaction.

How Socks Can Help And Hinder Patients With Tinea Pedis

Although topical medications are the mainstay of treatment, recent evidence shows that socks can both hinder and help patients who have tinea pedis. Out of the many reasons for recurrence after treating tinea, Bonifaz and colleagues theorized that fomites, like the patient’s own socks, are a source of re-infection.12 Research has shown that T. rubrum can survive in fabrics washed at 30º C but are inactive at 60º C.¹³ In order to study the viability of dermatophytes in the socks of patients who have both tinea and onychomycosis, Bonifaz and colleagues asked 86 patients with culture positive disease to bring in a pair of used, washed socks. In a controlled environment, researchers took swabs for culture of the socks directly and made serial dilutions of the socks to determine the extent of dermatophyte isolation.    According to the study results, dermatophytes can survive in socks after washing and 10.46 percent of patients were at risk for re-infection by having contact with their socks.¹³ Ultimately, through both direct isolation and isolation from the serial dilutions, the authors showed that dermatophytes can survive in textiles. The study didn’t delve into the possibility of what using bleach or multiple washes would do to dermatophyte viability, but hopefully that will be the grounds for another project.    In contrast, socks impregnated with copper oxide particles have shown promise in the possible treatment and management of those with pedal fungal infections in a most unlikely and unfortunate situation. In August 2010, a mine collapse trapped 33 Chilean miners underground for 69 days.¹⁴ After being underground for two weeks, the miners experienced and complained of pedal skin issues that were most likely secondary to the harsh conditions: 85 percent humidity and greater than 93º F in temperature. Rescuers delivered tubes of clotrimazole to the miners but the medication did not provide any resolution.    Rescuers also delivered three pairs of copper oxide infused socks (Cupron socks, Cupron, Inc.) to the miners after they had been trapped for 30 days.¹⁴ Researchers have documented the fungicidal and antimicrobial properties of copper oxide.¹⁵ Once rescued, the miners reported that their skin condition improved after wearing the socks for four to seven days and only one rescued miner had tinea pedis despite being exposed to the severe conditions underground. Of course, this was not a controlled research study but the results certainly warrant further research and the use of this product on those who are plagued by tinea pedis both consistently and occupationally.    Recurrence due to close contact of continually infected textiles is not only limited to sock use. Shoes are also a constant reservoir for fungus and bacteria. Besides data from Tanaka and coworkers showing that washing sneakers (but not boots) in boiling or cold water was useful in eradicating dermatophytes, some physicians have recommended spraying footwear with various household disinfectants that ultimately might not be shoe- or skin-friendly.¹⁶    Using a commercial ultraviolet shoe sanitizer (SteriShoe, Shoe Care Innovations) with an ultraviolet C lamp, Ghannoum and coworkers first optimized a model of infecting shoes and recovering the dermatophyte, and showed the efficacy of the device to reduce fungal burden in the same footgear.¹⁷ After researchers applied one treatment cycle (45 minutes) of the ultraviolet C shoe sanitizer to the fungally infected shoes in comparison to the growth controls, 88.8 percent of T. rubrum was eradicated along with 83.9 percent of T. mentagrophytes. Researchers applied a second and third cycle of the shoe sanitizer to the shoes, but ultimately, the study showed that the reduction of fungal growth with one treatment cycle is satisfactory.    By addressing the footwear, this ultraviolet C shoe sanitizer has the potential to break the infection cycle in our patients by providing a simple daily protocol. Certainly, future studies using this device in patient-worn shoes will provide an even more compelling argument in recommending this to patients who suffer from recurrent tinea pedis.

Final Words

These new innovations are exciting additions to the fungal treatment armamentarium. They show the commitment of industry in helping podiatric physicians to not only treat tinea with greater patient adherence (a two-week treatment regimen versus four weeks), but also to effectively assist in reducing recurrence by addressing socks and shoes.    Dr. Vlahovic is an Associate Professor and J. Stanley and Pearl Landau Fellow at the Temple University School of Podiatric Medicine in Philadelphia. She is a Fellow on the Faculty of Podiatric Medicine at the Royal College of Physicians and Surgeons in Glasgow, Scotland. References 1. Evans EG, James IG, Seaman RA, Richardson MD. Does naftifine have anti-inflammatory properties? A double-blind comparative study with 1% clotrimazole/1% hydrocortisone in clinically diagnosed fungal infection of the skin. Br J Dermatol. 1993; 129(4):437-442. 2. Merz Pharmaceuticals, LLC. Naftifine product monograph. 2010. 3. Monk JP, Brogden RN. Naftifine: a review of its antimicrobial activity and therapeutic use as in superficial dermatomycoses. Drugs. 1991; 42(4):659-72. 4. Vago T, Baldi G, Columbo D, et al. Effects of naftifine, terbinafine, two allylamine antifungal drugs, on selected functions of polymorphonuclear leukocytes. Antimicrob Agents Chemother. 1994; 38(11):2605-11. 5. Ablon G, Rosen T, Spedale J. Comparative efficacy of naftifine, oxiconazole, and terbinafine in short-term treatment of tinea pedis. Int J Dermatol. 1996; 35(8):591-93. 6. Parish LC, Parish JL, Routh HB, et al. A double-blind, randomized, vehicle-controlled study evaluating the efficacy and safety of naftifine cream, 2% in tinea cruris. J Drugs Dermatol 2011; 10(10):1142-48. 7. Stein Gold L, Parish LC, Vlahovic T, et al. Efficacy and safety of naftifine hcl gel 2% in the treatment of interdigital and moccasin type tinea pedis: pooled results from two multicenter, randomized, double-blind, vehicle-controlled trials. J Drugs Dermatol. 2013; 12(8):911-918. 8. Tanuma H. Pathogenesis and treatment of hyperkeratotic tinea pedis in Japan. Mycoses. 1999; 42(1-2):21-8. 9. Kircik L and Onumah N. Use of naftifine hydrochloride 2% cream and 39% urea cream in the treatment of tinea pedis complicated by hyperkeratosis. J Drugs Dermatol. 2014; 13(2):162-5. 10. Jarratt M, Jones T, Kempers S, et al. Luliconazole for the treatment of interdigital tinea pedis: a double-blind, vehicle-controlled study. Cutis. 2013; 91(4):203-210. 11. Ikeda S, Kanoya Y, Nagata S. Effects of a foot bath containing green tea polyphenols on interdigital tinea pedis. Foot. 2013; 23(2-3):58-62. 12. Bonifaz A, Vazquez-Gonzalez D, Hernandez MA, et al. Dermatophyte isolation in the socks of patients with tinea pedis and onychomycosis. Japan Derm Assoc. 2013; 40(6):504-505. 13. Hammer TR, Mucha H, Hoefer D. Infection risk by dermatophytes during storage and after domestic laundry and their temperature-dependent inactivation. Mycopathologia 2011; 171(1):43-49. 14. Borkow G and Mellibovsky JC. Resolution of skin maladies of the trapped Chilean miners: the unplanned underground copper-impregnated antifungal socks “trial.” Arch Dermatol. 2012; 148(1):134-136. 15. Borkow G, Gabbay J. Copper as a biocidal tool. Curr Med Chem. 2005; 12(18):2163-2175. 16. Tanaka K, Katoh T, IrimajiriI J, et al. Preventive effects of various types of footwear and cleaning methods on dermatophyte adhesion. J Dermatol. 2006; 33(8):528. 17. Ghannoum MA, Isham N, and Long L. Optimization of an infected shoe model for the evaluation of an ultraviolet shoe sanitizer device. J Am Podiatr Med Assoc. 2012; 102(4):309.