New Therapies for Tinea Pedis
Tinea Pedis is an infection of the skin that affects the interdigital areas or soles of the feet and is caused by fungi, particularly dermatophytes and yeasts. Common fungal pathogens frequently associated with this disease include T. rubrum, T. mentagrophytes, and Epidermophyton floccosum. Other etiological agents include Malassezia furfur, Microsporum canis, Coynebacterium minutissium, and Candida spp.18 This condition affects approximately 10-25% of the population worldwide19 and is characterized by pruritus, cracking, maceration, dry scaling, clusters of blisters/pustules, and/or erythema. The disease has various clinical patterns that may affect one or both feet.
Current therapies include a broad range of topical antifungal agents. The majority of topical anti-fungals currently in use are either in the allylamine or azole groups. The allylamine anti-fungals are fungicidal and kill the dermatophytes, whereas azole group anti-fungals mainly work by inhibiting dermatophyte growth as fungistatic agents. While cures can be achieved, reinfection occurs in up to 70% of patients.20 Moreover, the increased use of topical azole antifungals has led to fungal resistance warranting the need for newer, more effective therapies.21 In July 2013, naftifine 2% gel was approved by the US FDA for the treatment of interdigital tinea pedis. Additionally, in November 2013 the US FDA approved luliconazole 1% cream for the topical treatment of interdigital tinea pedis, tinea cruris, and tinea corporis.
Naftifine 2% gel is an allylamine antifungal that exhibits potent fungistatic and fungicidal activity against dermatophytes in vitro, unlike azole anti-fungals, which are only fungistatic. The exact mechanism of action is not yet clear, however naftifine hydrochloride interferes with sterol biosynthesis by inhibiting the enzyme squalene 2,3 epoxidase, depleting ergosterol and accumulating squalene cells, arresting fungal growth and disrupting the stability of the fungal cell membrane.22 Naftifine also has anti-inflammatory effect by inhibiting polymorphonuclear leukocytes (PMN) chemotaxis and neutrophil adhesion23. In vitro antifungal activity of naftifine hydrochloride against dermatophytes demonstrated potent fungistatic and fungicidal activity against all dermatophytes (T. rubrum, T. mentagrophytes, T. tonsurans, M. canis, and Epidermophyton floccosum).24 It has moderate activity against Aspergillus spp, Sporothrix schenckii, and some strains of Candida.25
Two multicenter trials have been conducted to evaluate the efficacy and safety of naftifine 2% gel for interdigital and moccasin-type tinea pedis. Naftifine 2% gel or vehicle was applied once daily for two weeks to the affected area of the foot. The primary endpoint for interdigital tinea pedis indication was the complete cure rate at the four-week follow-up visit after having used the study drug for two weeks (week 6). The complete cure rate, mycological cure rate, and treatment effectiveness at week six are seen in Table 2.26 While local application site reactions occurred, there was no evidence of contact sensitization, phototoxicity, or photoallergenicity.27 Systemic absorption ranged from 2-6%, but systemic adverse effects were not reported and consequently patients do not require laboratory monitoring.28 Naftifine is pregnancy category B, but the safety and effectiveness in nursing women and pediatric patients have not been established.
The most interesting part of these results is continuous improvement during the study after stopping the study drug. For example, complete cure rate of composite scores from two studies increased from 5.4% at week 2 to 21.5% at week 6, four weeks after stopping the study drug; as well the mycologic cure rate increased from 39.1% at week 2 to 62% at week 6.26 This progressive clinical and mycologic improvement over time, after stopping naftifine, implies the depot effect of naftifine in the skin. Furthermore, tape-stripping studies revealed that epidermal level of naftifine at application site remains relatively unchanged for several weeks post treatment.29
Additionally, naftifine 2% gel is the only anti-fungal that has been formally studied in moccasin-type tinea pedis. Although, naftifine 2% gel has not been approved by the FDA for this indication, a randomized double blinded vehicle controlled study showed that complete cure rate for moccasin-type tinea pedis at week 6 was 19.6% for naftifine vs 0.7% for the vehicle group. Treatment effectiveness at week 6 was 51% for naftifine vs 6% for the vehicle group.26
