Optimizing Topical Antifungal Therapy for Superficial Cutaneous Fungal Infections: Focus on Topical Naftifine for Cutaneous Dermatophytosis

clinically relevant, such as inhibition of chemotaxis, reduction in inflammation-associated skin temperature, markedly reduced erythema-wheal formation (intracutaneous histamine test), and inhibition of UV-induced erythema.^26-28,31

Naftifine is highly lipophilic, allowing for efficient penetration into the epidermis and hair follicles that are important target sites for treatment of CDIs and other SCFIs.^31,32 In an animal model of hair root trichophytosis, naftifine 1% cream produced complete organism eradication in 3 days, and was superior to econazole, which produced 80% mycologic clearance in 7 days.³⁴

Systemic absorption of topically administered naftifine is minimal (2%-6%) and no major systemic side effects have been reported.^28,31,32 It is not known whether naftifine is excreted in human milk, and topical naftifine is rated Pregnancy Category B.³⁰

During clinical trials with naftifine 1% cream, the incidence of adverse reactions was as follows: burning/stinging (6%), dryness (3%), erythema (2%), itching (2%), and local irritation (2%).²⁹ Other studies have reported that application site reactions (ie, burning, stinging, itching) are relatively uncommon with topical antifungal agents overall, and were reported in 2% of naftifine-treated patients (n=185) compared with 5% for topical clotrimazole (n=194).^28,35Allergic contact dermatitis has been reported with topical naftifine, with the risk of sensitization estimated to be 1:100,000.^28,31,36

Multiple efficacy studies and comparative studies support the safe and effective use of topical naftifine 1% formulations for CDIs (non-scalp, non-nail) with a usual duration of use of 3 to 4 weeks, which are consistent with studies that have gained FDA-approval with both the 1% gel and 1% cream.^28-32

Many tinea pedis studies with all available topical antifungal agents primarily evaluate interdigital tinea pedis, with fewer patients studied overall for dry plantar (moccasin) tinea pedis.²⁷ Importantly, 1-week duration studies with agents such as topical terbinafine only enrolled subjects treated for interdigital tinea pedis. In contrast, dry plantar tinea pedis is likely to warrant a longer course of topical antifungal therapy to achieve clearance due to the thicker stratum corneum (SC) on plantar skin, wider area of involvement,and a host-related immunologic blind spot against T rubrum in many cases.^{16,18,19,23,27,28}

In patients treated for specific CDIs, based on comparative studies and meta-analyses, allylamines including naftifine 1% (primarily cream) demonstrated superior efficacy regarding faster onset of clinical improvement and symptom reduction, and better sustained cure outcomes, when compared with several imidazole agents, such as econazole, oxiconazole, clotrimazole, and ketoconazole.^26-28,31 The superior sustained cure outcomes with CDIs treated with topical allylamines such as naftifine may be explained by their lipophilicity, keratinophilic properties, fungicidal activity, and persistence of drug levels within the skin after discontinuation of application.^26,37

An in vitro assessment evaluating the possible development of antifungal resistance showed that strains of T rubrum and T mentagrophytes developed no tendency to become resistant to naftifine following repeated exposures.³⁸

Although not FDA-approved for cutaneous yeast infections, topical naftifine has demonstrated clinical efficacy in controlled studies of patients with cutaneous candidiasis and an uncontrolled study of patients with tinea versicolor.³¹

As discussed above, naftifine exhibits fungicidal activity against dermatophytes, with time-kill studies showing dose-dependent activity against T rubrum, T mentagrophytes, and E floccosum. ³⁹ This supported the concept of developing formulations with a higher concentration of naftifine. Naftifine hydrochloride 2% cream gained FDA-approval in adult patients ≥18 years of age for the treatment of interdigital tinea pedis, tinea cruris, and tinea corporis caused by T rubrum using once-daily application for 2 weeks.³⁰ In these trials, multiple endpoints were evaluated. Mycological cure was defined as a negative KOH and dermatophyte culture.^30,40,41 Treatment effectiveness was defined as a negative KOH preparation, a negative dermatophyte culture, and erythema, scaling, and pruritus grades of 0 or 1 (absent or nearly absent).^30,40,41

A randomized, double-blind, vehicle-controlled study of naftifine 2% cream applied once daily for 2 weeks vs naftifine 1% cream applied for 4 weeks vs vehicle for interdigital tinea pedis evaluated efficacy and safety at end of treatment, and at weeks 2 and 4 post-treatment.⁴⁰ Continuous post-treatment improvement was observed in actively treated subjects, suggesting the potential for a “therapeutic reservoir effect” of persistent naftifine in the skin after its application is stopped. At week 6 (4 weeks post-treatment), naftifine-treated subjects achieved 67% mycological cure rate and 57% treatment effectiveness,compared with 21% (P<.001) and 20% (P<.001) in the vehicle group, respectively. The outcomes with naftifine 2% cream used for 2 weeks and naftifine 1% cream used for 4 weeks were equivalent.⁴⁰ Tolerability and safety were favorable in all study arms.

A randomized, double-blind, vehicle-controlled study of naftifine 2% cream applied once daily for 2 weeks vs vehicle for tinea cruris evaluated efficacy and safety at end of treatment, and at 2 weeks post-treatment.⁴¹ At week 4 (2 weeks post-treatment),naftifine-treated subjects achieved 72% mycological cure rate and 60% treatment effectiveness, compared with 16% (P<.001, one-sided) and 10% (P<.001, one-sided) in the vehicle group, respectively. Tolerability and safety were favorable in both study arms.⁴¹