cream has a wide range of indication. Nonetheless, this simply defies logic and common sense. In a similar manner, 2% naftifine gel is approved only for the treatment of interdigital tinea pedis. Considering that 1% naftifine gel is indicated for management of tinea corporis and cruris, is there any reason why the 2% formulation lacks the same indication, other than the fact that this study was not done? As another example of a glaring anomaly, consider the only current FDA-approved indication for sertaconazole cream: interdigital tinea pedis. Yet, in the European Union, sertaconazole is indicated for the treatment of tinea corporis, tinea cruris, tinea manum, tinea barbae, and tinea pedis, as well as both cutaneous candidiasis and pityriasis versicolor.21 Should we believe that this agent somehow works less well in North America than in Europe, especially for the same causative fungi?
FDA-approved indication also does not address relative (comparative) efficacy, safety, and tolerability. While tonaftate is “approved†for the treatment of tinea corporis, cruris, and pedis due to an extended range of dermatophyte species, clinical experience dictates that both azole and allylamine agents are more efficacious. When comparing the relative efficacy of azoles and allylamines, the situation becomes considerably less clear despite comprehensive and thoughtful attempts to do so. In such systematic and meta-analyses, the authors concluded two important things: 1. Allylamine, benzylamine, azole, hydroxypyridone, and thiocarbamate agents are all routinely superior to placebo and 2. Since no trials sort subjects who failed treatment by etiologic species, no conclusions can be drawn about clinical susceptibility of various fungi to individual drugs in a manner that meaningfully impacts decision making.22-25 A few additional pearls can be gleaned from these heroic attempts to compare different topical agents. In a systematic review of 67 randomized-controlled trials (RCTs) of topical tinea pedis treatment, authors concluded that: allylamines produce slightly higher complete cure rates than do azoles, and that, for the same agent, longer durations of therapy tend to work somewhat better than shorter durations of therapy.22 In a systematic review of 129 RCTs of topical treatments for tinea corporis and cruris, the authors concluded that naftifine and terbinafine were very effective, but that other classes (such as azoles and hydroxypyridones) are also quite beneficial.25 Finally, in a pair of reports representing the most ambitious attempts to compare efficacy between various topical antifungal drugs, as well as between classes of topical antifungals, Rotta and co-wokers23,24 concluded that: 1. There is no significant and consistent difference between classes of antifungal drugs in terms of short-term efficacy 2. Safety and tolerability is excellent across all classes of topical antifungals, with adverse events (burning, stinging, pruritus, true allergic contact dermatitis) being reported in about 1-3% of treated patients and 3. Allylamine agents (and the related benzylamine, butenafine) show a higher degree of sustained cure compared to classic imidazoles. It is noted that these exhaustive reviews included many RTC which were sub-optimally designed, inadequately reported, subject to considerable heterogeneity, and at risk for bias; none included newer formulations or concentrations of older agents or recently released agents (eg, luliconazole).
What is the clinical relevance of the foregoing? Basically, assuming diligent patient adherence to the prescribed treatment regimen, any approved agent will work for common dermatophyte infections due to the most common pathogens.11 However, some interventions may be more “appealing†to both HCP and patient because they require fewer applications per day, fewer total applications, and/or shorter duration of therapy. For example, whereas four weeks of topical antifungal therapy were once considered required to achieve clinical benefit in tinea pedis, newer agents (1% luliconazole cream and 2% naftifine cream/gel) prove satisfactory after only two weeks of therapy.26-28 Luliconazole cream has even been successfully administered once daily for only one week for tinea cruris.29
Although not apparent in large scale retrospective analysis, there is some evidence that dermatomycoses due to Microsporum species (in particular M. canis) may be somewhat less responsive to topical azole agents compared to topical allylamines, especially if one utilizes the older azoles such as clotrimazole.30,31
With respect to cutaneous candidiasis, the various approved azoles and ciclopirox are considered superior to allylamines and are deemed the appropriate drugs of choice.32 That said, in contrast to accepted dogma and FDA approved indication, both butenafine and terbinafine have proven modestly successful (efficacy rates ranging from 73-85%) in the treatment of interdigital and intertriginous candidiasis.33,34 Butenafine is particularly interesting in that it may not only block squalene epoxidase, but also possess a direct membrane damaging effect on Candida albicans.35 Due to its potent anti-inflammatory effects and relative low cost (now being available OTC), butenafine may be a viable (off-label) alternative for rapid relief of symptomatic cutaneous candidiasis. Nystatin is the only specific topical anti-Candidal agent, and is available as a powder, cream and ointment (100,000 units per gram). The powder may be untenable in the face of excessive exudation, but may be an optimal method of topical prophylaxis in cases of recurrent intertriginous candidiasis. Nystatin regularly demonstrates a
