Efficacy and Safety of Topical Antifungals in the Treatment of Dermatomycosis

A Systematic Review

I. Rotta; A. Sanchez; P.R. Gonçalves; M.F. Otuki; C.J. Correr

Disclosures

The British Journal of Dermatology. 2012;166(5):927-933. 

In This Article

Discussion

Our systematic review and meta-analysis indicate that azoles, allylamines and other antifungals, such as butenafine and ciclopiroxolamine, are all efficacious in the management of any dermatomycosis when compared with placebo. The two other published systematic reviews with meta-analysis performed by Hart et al. (1999) and Crawford and Hollis (2007) found similar results for the management of tinea pedis.[8,10]

The duration of treatment with azoles lasted from 2 to 6 weeks and the efficacy of this class seemed to improve over time. Miconazole showed the best success rate for both efficacy outcomes evaluated. Short treatments in the range of 1–2 weeks with naftifine and terbinafine demonstrated the superiority of allylamines in relation to placebo for both outcomes.

Given the strength of evidence obtained from the large number of studies (n = 135) and participants (n = 15 795), placebo-controlled trials evaluating topical antifungals in the treatment of dermatomycosis can no longer be justified, and only clinical trials comparing two active treatments are recommended. In 2008, Crawford et al. published a paper confirming that there is enough evidence to recommend the abandonment of vehicle-controlled trials assessing topical treatments for athlete's foot.[14]

Crawford and Hollis reported that direct comparisons of allylamines and azoles showed allylamines to be more efficacious than azoles. This difference among classes was detected in outcomes assessed 6 weeks after treatment began and appeared to remain over longer periods.[8] A result favouring the use of allylamines was also obtained by Hart et al., although some language bias was detected. Thus eight studies reported in English favoured allylamines, while four foreign language reports showed no difference among azoles and allylamines.[10]

Our meta-analysis of RCTs comparing the mycological cure rate obtained with azoles and allylamines show no significant difference among classes, the same efficacy rate (81%) being found for both. For the sustained cure outcome, however, allylamines were found to be superior to azoles, but the result was inconsistent, due to the high degree of heterogeneity (I2 = 60%) among the selected studies. Following the sensitivity analysis and hypothetical removal from the meta-analysis of the study by Ablon et al.,[13] the heterogeneity became moderate and the difference among classes became nonsignificant. This study was also excluded from the systematic review conducted by Hart et al.,[10] because of an inadequate period of treatment with azoles.

We detected no difference in efficacy among azoles and other antifungals, such as amorolfine, butenafine and ciclopiroxolamine. However, although not significant, the outcome of mycological cure favoured the 'nonallylamine' antifungals. The difference was less obvious when considering sustained cure as the outcome.

No differences were found in the safety or tolerability with any of the antifungal classes. All treatments are generally well tolerated; most of the symptoms reported by patients were mild to moderate and limited to the site of application. It is important to mention that the number of adverse events mentioned in selected studies may be overestimated or underestimated, as the adverse events associated with the use of topical antifungals are also signs and symptoms of the fungal disease, and it is therefore difficult to determine whether these reactions were due to disease or caused by the drug.

Allylamines are considered safe and tolerable. However, the efficacy results showed no conclusive evidence of their superiority compared with azoles. In addition, allylamine treatment is more expensive. As a cost-effective strategy, azoles are recommended as the first-line therapy, followed by allylamines if these are not effective. However, to confirm this recommendation, pharmacoeconomic studies are required to evaluate the real cost-effectiveness ratio of each therapeutic option.[15]

Our study has some limitations. Due to the difficulty of interpolation, the results of the studies were not pooled in the meta-analysis according to the dermatomycosis evaluated. The difficulty of subgroup formation was attributed to the scarceness of studies evaluating the same drug, or antifungals belonging to the same pharmacological class, to treat a specific dermatomycosis. In addition, several studies did not restrict their assessment to a single form of dermatomycosis, as the treatment is similar for all.

Several meta-analysis showed high values of I2 (> 50%), indicating inconsistency in the results of the included studies. However, after conducting sensitivity analysis, involving the hypothetical removal of the studies considered responsible for the high heterogeneity reported, and pooling the studies into subgroups based on the dermatomycosis evaluated, the results remained similar to those found prior to performing such analysis, maintaining their statistical significance. This demonstrates that the wide range of effects in the data collected from many primary studies did not affect the outcomes considered in this study. These findings were similar to those reported in the systematic review conducted by Crawford and Hollis, whose meta-analysis also showed high heterogeneity among the studies selected.[8]

Furthermore, owing to the absence of a sufficient number of good-quality clinical trials that directly compared the antifungal drugs of interest, only 55 comparisons among the 120 possible were found, making the performance of mixed-treatment comparisons necessary in order to establish indirect comparisons among those treatment pairs with common comparators. In the presence of direct and indirect comparisons, these can be interpolated, giving mixed results.[16,17]

In conclusion, our results showed consistent evidence that all topical antifungals are better than placebo. No consistent differences in efficacy were found among classes. Head-to-head clinical trials comparing azoles with allylamines should be conducted to determine the real difference in efficacy among these classes. No differences were found in safety or tolerability in any direct comparisons, allowing us to conclude that topical therapy with antifungal agents is safe and tolerable.

Due to the absence of a sufficient number of direct comparisons among the antifungals, mixed-treatment comparisons were necessary. Finally, given the difference in cost among the antifungals, pharmacoeconomic analysis is required to determine the most cost-effective therapeutic strategy for each condition.

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