Evaluation of Fungicidal Action in Vitro and in a Skin Model Considering the Influence of Penetration Kinetics of Various Standard Antimycotics

Abstract

Ciclopiroxolamine (Loprox) was the first representative of hydroxpyridones to be developed as a topical antifungal. In the microtitration test and in a skin model using excised skin prices of slaughtered pigs, the fungistatic and fungicidal activity as well as the penetration kinetics of ciclopiroxolamine and ciclopirox were compared with those of the azole compounds bifonazole, clotrimazole, econazole, miconazole, oxiconazole, and tioconazole, and with other antimycotics such as naftifine, sulbentine, tolciclate, and tolnaftate. Clotrimazole had an in vitro inhibitory activity superior to that of the hydroxypyridone ciclopiroxolamine; the latter compound, however, exhibited faster penetration and higher inhibitory or fungicidal activity than the azoles and other antimycotics in the pig skin model. Studies of cream formulations with antimycotics at the bottom layer of the stratum corneum (close to the stratum granulosum) showed that ciclopiroxolamine cream had the most prominent inhibitory effect (93%) and the highest fungicidal activity (98%). The other antimycotics tested exhibited growth inhibition rates of 50% or less and lower fungicidal rates. Inoculated pig skin was treated with lacquer formulations to show that ciclopirox completely inhibited the growth of Trichophyton mentagrophytes, whereas the clotrimazole-treated samples allowed only 0.47% growth. The fungicidal activity of lacquer formulations was 99% for ciclopirox and around 90% for most of the azoles on the pig skin model. The necessity of models tackling the complex penetration kinetics in human skin was discussed.

Ciclopirox olamine: an antifungal alternative against cryptococcosis

“…All the 16 tested strains presented MICs ≤ 1 μg ml −1 and were considered sensitive. Our strains exhibited high sensitivity results when compared to those obtained by Hannel et al. (1988), where the antifungal activity was around 6 μg ml −1 using another method.…”

Experimental Models in Predicting Topical Antifungal Efficacy: Practical Aspects and Challenges

“…Skin models mimic in vivo conditions more closely than any in vitro test [47] , which is why investigators cannot rely on MIC data alone. The studies of Hanel et al [3] show the need for using suitable skin models to better predict the efficacy of topical antifungals in man by addressing the complex percutaneous penetration kinetics in man.…”

“…Therefore, the MIC is an important stepping stone in drug discovery and in predicting the therapeutic outcome of antifungals. However, as Hanel et al [3] state, MICs may not be sufficient to predict topical antifungal efficacy; a more comprehensive test should address penetration kinetics by using membrane models. For example, even though clotrimazole (CLO), an azole, had greater in vitro inhibitory activity than ciclopiroxolamine via MIC data, the latter exhibited greater inhibitory activity in the in vitro pig skin model because as a hydroxypyridone, it penetrates faster and deeper through the stratum corneum and stratum granulosum than CLO in the skin model [44] .…”

“…Allows passage of water equivalent to transepidermal water loss during permeation studies [25][26][27] The transferability of the system to predict the diffusional characteristics of an unknown molecule is questionable; thus, its role is limited [4] 4, 25, 26, 27 Also, the characteristics of the drug formulation such as hydrophobicity, penetration enhancers and acidity can influence the penetration, the retention time and the efficacy of the antifungal in skin [3] . Skin models mimic in vivo conditions more closely than any in vitro test [47] , which is why investigators cannot rely on MIC data alone.…”

“…Using in vitro methods to determine the minimum inhibitory concentration (MIC) value of an antifungal compound helps predict its efficacy, because the success of the antimycotic relies on the maintenance of its MIC in the skin for a prolonged time [2] . However, MIC values alone are not sufficient to predict antifungal action in the stratum corneum and intrafollicular keratin [3] , because much of the efficacy of the drug also relies on its absorption and adsorption in the skin, which is why skin models are needed to evaluate topical drug penetration kinetics as well as MICs.…”