Assessment of Dermatophytosis Treatment Studies: Interpreting the Data

With other dermatomycoses, such as tinea pedis, tinea cruris, and tinea corporis, the longer the interval between cessation of trial drug administration and the final outcome assessment, the more meaningful the result; positive results demonstrated 14 or more days from the conclusion of therapy are considered sustained.²⁰ The most ambitious attempts to compare efficacy between various topical antifungal drugs, as well as between several classes of topical antifungals, found that: 1) There is no significant difference among classes of antifungal drugs in terms of short term efficacy, safety, and tolerability; and 2) The allylamine agents (and related benzylamine, butenafine) show a higher degree of sustained cure compared with classic imidazoles.^17,20 Of course, these analyses included neither newer formulations of older molecules (such as 2% nafitifine and 1% econazole nitrate foam) nor, and most importantly, new molecules (such as luliconazole); thus, while well done and comprehensive, such systematic reviews are already somewhat outmoded.

The trend in recent years has been toward shorter treatment durations for non-onychomycosis dermatophytoses. For example, whereas 4 weeks of topical treatment were once considered necessary to achieve clinically meaningful benefits in tinea pedis, newer agents (1% luliconazole and 2% naftifine) prove satisfactory after only 2 weeks of therapy.^21,24,25 Luliconazole cream has even been successfully administered once daily for only 1 week for the treatment of tinea cruris.³⁷

Participation as a study patient for all clinical trials involving dermatophytes requires clear proof of pre-treatment fungal infection. This generally requires both a positive potassium hydroxide (KOH) preparation and a positive culture. The latter also delineates which species are being treated. There is little controversy in this aspect of antifungal trials. However, the author foresees a day in the not too distant future where molecular diagnosis will be become the gold standard (eg, real time polymerase chain reaction).^40,41 This may facilitate study recruitment and re-define efficacy results due to the greater sensitivity for dermatophyte detection.

At the conclusion of the study, it is standard to report, either as a primary or secondary end point, mycological cure rates. As pointed out by Gupta and co-workers, this may also be called mycologic success, mycologic response, mycologic efficacy, or even “fungus free” or “eradication.”⁴² This efficacy parameter typically implies both negative KOH preparation and negative fungal culture. This definition is fairly straightforward in both tinea and onychomycosis trials. Rarely, mycological cure may be defined as negative culture or negative microscopy alone, a less stringent standard.^43,44

It should also be noted clearly that mycologic cure is not synonymous with visually determined clinical cure. From the perspective of the patient, a normal appearing nail and lack of pain (if present pre-treatment) are the measures of successful onychomycosis treatment. Similarly, from the patient perspective, normal appearing skin (loss of erythema and scaling) and elimination of bothersome itching are the measures of successful therapy for tinea pedis, tinea cruris, and tinea corporis. From the HCP perspective, however, mycologic cure ensures that once-infected skin or nail has been successfully treated.⁴² Thus, it may be advisable to counsel the patient that “successful” therapy, especially of chronic fungal infections such as onychomycosis and tinea pedis, may not result in completely normal appearing nail or skin.

There is a final, perhaps theoretical, issue worth mentioning. In order to achieve mycological cure, both KOH and culture must be negative. How many trial patients fail to achieve this goal because post-treatment specimens fail to grow (negative culture) but still possess demonstrable hyphae microscopically? While this is somewhat speculative, this author suspects that the hyphae which are visible at the end of an antifungal trial may not be viable. In other words, is it possible that the fungal structure is still there, but that the fungus can no longer propagate or cause structural damage? This would lead to lower than real mycologic and complete clinical cure rates. This possibility needs to be addressed in a coherent manner.

It is in this realm where assessment of trial results becomes very difficult. There is simply no standardization across antifungal trials as to what parameters are measured, nor as to the terminology used to describe what was, in fact, measured. Unless nomenclature is defined in an unequivocal manner, interpretation of trial results becomes quite precarious.

Complete cure typically means mycological cure (negative KOH and culture) and total absence of signs (onycholysis, subungual debris, discoloration). While this is the most uniform of all criteria, this may be difficult to achieve, as noted in the previous section of this paper. Thus, it is not surprising that investigators have creatively employed a dazzling and bewildering variety of terms or narrative phrases to express the fact that the patient is “better” than before therapy, if not 100% normal. Historically, for onychomycosis, the most common clinical efficacy measurements have included the items listed in Table 1. This is by no means all-inclusive. Even a cursory glance at Table 1