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

Methodological Quality

Only studies of medium or high quality according to the Jadad scale[12] were included in the meta-analysis, with an average score of 3·6. Of the 59 trials excluded after full review, 35 did not meet the quality criteria proposed by Jadad et al.[12] Relevant information such as sequence generation and allocation concealment were insufficient in the majority of the studies included. However, the baseline characteristics of patients included in each group were homogeneous, indicating that the absence of information about the allocation should not have affected the confidence of the results obtained. Blinding was reported as satisfactory in almost 53% of the studies included, although we believe that the mycological cure outcome was not likely to be influenced by lack of blinding.

Efficacy

Azoles vs. Placebo Twenty-eight studies, comprising a total of 3044 patients, compared the azoles bifonazole, clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sertaconazole and tioconazole with placebo. The concentration of these drugs was 1% or 2% and they were used for 2–6 weeks. In terms of mycological cure at the end of treatment, meta-analysis of data from 26 RCTs estimated the pooled OR as 10·25 (95% CI 6·88–15·27), favouring azoles. There was a high degree of heterogeneity (I 2 = 71%) among the studies selected for the meta-analysis. Sensitivity analyses were carried out by pooling the studies into subgroups based on the dermatomycosis evaluated. When the heterogeneity remained high, a hypothetical removal of the studies responsible for that heterogeneity was performed. By the sensitivity analyses performed, the I 2 decreased, becoming low or moderate, and the OR value remained statistically significant, favouring treatment with azoles.

Interpolation of the data from 13 RCTs comparing the sustained cure rate among azoles and placebo gave an OR of 7·25 (95% CI 5·15–10·20). There was a low degree of heterogeneity (I 2 = 5%) among the studies selected, indicating consistency in the results. The follow-up period lasted from 2 to 6 weeks after the cessation of treatment.

Allylamines vs. Placebo Naftifine and terbinafine were evaluated in 25 placebo-controlled trials, which included 2001 participants. The concentration of these drugs was 1% or 3% and they were used for 1–4 weeks. In terms of mycological cure at the end of treatment, meta-analysis of data from 20 RCTs estimated the pooled OR as 6·15 (95% CI 3·47–10·91), favouring allylamines. The interpolated results of the individual studies showed considerable variation between studies (I 2 = 75%). Sensitivity analyses were carried out by pooling the studies into subgroups based on the dermatomycosis evaluated. When the heterogeneity remained high, a hypothetical removal of the studies responsible for that heterogeneity was performed. By the sensitivity analyses performed, the I 2 decreased, becoming low or moderate, and the OR value remained statistically significant, favouring the treatment with allylamines.

Of the 25 RCTs found, 23 showed a sustained cure. Combined data from these studies showed a statistically significant difference favouring allylamines (OR 12·67, 95% CI 8·99–17·84). The I 2 value of 42% reflects the moderate heterogeneity between studies. The follow-up period lasted from 2 to 44 weeks after the cessation of treatment.

Other Antifungals vs. Placebo Fourteen RCTs compared other antifungals with placebo. The 12 placebo-controlled trials of butenafine and ciclopiroxolamine yielded a pooled OR of 6·63 (95% CI 4·12–10·67) for mycological cure at the end of treatment. The concentration of these drugs was 0·77% or 1% and they were used for 1–4 weeks. There was a high degree of heterogeneity (I 2 = 67%) among the selected studies.

The results of 12 RCTs were interpolated for the sustained cure outcome, giving an OR of 10·61 (95% CI 6·38–17·64), in favour of the other antifungals. Again, there was a high degree of heterogeneity (I 2 = 74%) among the studies. The follow-up period lasted from 2 to 44 weeks after the cessation of treatment. The results of the studies on topical antifungals vs. placebo are presented in Figure 3.

Figure 3.

Forest plots comparing the efficacy of antifungals vs. placebo for mycological cure at the end of treatment (a) and sustained cure (b) outcomes. The symbols represent the measure of effect (odds ratio) obtained with each drug, the horizontal line indicating the 95% confidence interval (CI) found. The concentrations of drugs reported in the randomized controlled trials are described. The number of studies found for each drug is indicated in parentheses. I 2, inconsistency index, representing the degree of heterogeneity among the studies included in the meta-analysis; N.A., I 2 is not applicable, as only one study for the drug in question was found; BFZ, bifonazole; BTF, butenafine; CPX, ciclopiroxolamine; CTZ, clotrimazole; ECZ, econazole; KTL, ketoconazole; MCZ, miconazole; NFT, naftifine; OCZ, oxiconazole; STZ, sertaconazole; TBF, terbinafine; TCZ, tioconazole.

Azoles vs. Allylamines The meta-analysis included 17 RCTs, with 1781 participants, comparing the allylamines, naftifine and terbinafine (1% or 2%), used for 1–6 weeks with the azoles, bifonazole, clotrimazole, econazole, fenticonazole, miconazole and oxiconazole (1% or 2%), used for 2–6 weeks. In terms of mycological cure at the end of treatment, 15 trials showed a small and not statistically significant difference in favour of allylamines (0·78, 95% CI 0·48–1·24). The same efficacy rate (81%) was obtained for both classes. There was moderate heterogeneity in the results of the individual trials (I 2 = 45%), indicating that high-quality evidence was obtained.

Although the meta-analysis of 15 trials comparing the sustained cure obtained following the use of azoles and allylamines showed a significant result in favour of allylamines (0·55, 95% CI 0·33–0·89), there was evidence of inconsistency, due to the high heterogeneity among trials (I2 = 60%). This inconsistency may be attributed to one study in particular (Ablon et al. 1999).[13] The hypothetical removal of this study decreased the I 2 to 50% and changed the results of the analysis, such that there was no difference in efficacy among classes.

Azoles vs. Other Antifungals We identified 11 studies, containing a total of 952 patients, comparing the azoles, bifonazole, clotrimazole and fenticonazole (1% or 2%), with antifungals other than allylamines, both used for 2–5 weeks. In terms of mycological cure at the end of treatment, 10 RCTs produced a pooled OR of 0·64 (95% CI 0·40–1·01), favouring the other antifungals, although the difference was not significant. There was consistency among the studies selected (I 2 = 7%).

In terms of sustained cure, the combined data from 10 RCTs showed an OR of 0·79 (95% CI 0·50–1·26), again not reaching statistical significance. The I 2 was 0%.

For details about the sensitivity analysis performed for each meta-analysis with an I 2 > 50%, see Appendix S4 (see Supporting information).

Safety and Tolerability

No differences were found in safety or tolerability in all direct comparisons made between antifungals and placebo or among antifungals. Table 1 presents the results obtained regarding comparisons among antifungals and placebo for safety outcome.

As expected, few serious adverse events were reported with the use of any topical antifungal. The adverse events most commonly reported by patients were burning, stinging and itching, all confined to the site of application.

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