A New Calcineurin Inhibitor, Pimecrolimus, Inhibits the Growth of Malassezia spp (2006)

Malassezia spp. are a component of the cutaneous microflora that colonizes lipid-rich areas, especially the head and neck, because the microorganisms require a lipid for its growth. An anti-Malassezia-specific immunoglobulin E antibody is produced in patients with atopic dermatitis who have disrupted skin barrier function, while healthy subjects do not produce the immunoglobulin E antibody. In addition, antifungal agents can improve the symptoms of atopic dermatitis. Based on this evidence, Malassezia spp. are considered one of the factors involved in exacerbating atopic dermatitis (1, 4). The genus Malassezia consists of 11 species (M. dermatis, M. globosa, M. furfur, M. japonica, M. obtusa, M. restricta, M. slooffiae, M. sympodialis, M. yamatoensis, M. nana, and M. pachydermatis), although the last two species show affinities to nonhuman animals. Of the 11 species, M. globosa and M. restricta have been isolated from almost all patients with atopic dermatitis, while the other species are found in fewer than 60% of patients, suggesting that M. globosa and M. restricta play a major role in atopic dermatitis (5).

Pimecrolimus, an ascomycin macrolactam derivative, is a new calcineurin inhibitor that binds to the cytosolic receptor macrophilin-12 with high affinity, inhibiting the calcium-dependent phosphatase calcineurin, an enzyme required for the dephosphorylation of the cytosolic form of the nuclear factor of the activated T cell. Therefore, it targets T-cell activation and proliferation by blocking the release of both TH1 and TH2 cytokines (7). Previously, we demonstrated that the calcineurin inhibitor tacrolimus, which has a similar chemical structure, inhibits the growth of Malassezia in vitro (6). Therefore, we postulated that pimecrolimus might have an antifungal effect.

In this study, we examined the in vitro drug susceptibility to pimecrolimus of 109 strains of the nine human-related Malassezia species. The strains were isolated from patients with atopic dermatitis or from healthy subjects. Pimecrolimus was kindly supplied by Novartis (Basel, Switzerland). In vitro drug susceptibility was determined according to the method of Gupta et al. (3), with slight modification (6). Drug susceptibility testing was conducted at least three times.

The MICs of pimecrolimus are shown in Table ​Table1.1. Pimecrolimus had an antifungal effect against the 109 Malassezia strains, with MICs ranging from 16 to 64 μg/ml. It inhibited the growth of approximately 90% of the strains at a concentration of 16 or 32 μg/ml. No differences in MICs were seen across the Malassezia species. The calcineurin inhibitor tacrolimus, which has a similar chemical structure, also inhibited the growth of Malassezia in vitro, with MICs of 16 to 32 μg/ml, which were the same as the MICs of pimecrolimus (6). Interestingly, fungal cells also contain a calcineurin homologue, although its function is unknown. Recent studies indicate that cyclosporine and tacrolimus are toxic to the pathogenic fungi Candida albicans and Cryptococcus neoformans (2).



TABLE 1.

Antifungal susceptibilities of Malassezia strains to pimecrolimus



Malassezia spp. are one of the factors that exacerbate atopic dermatitis. The growth-inhibitory effect of pimecrolimus might contribute to improving the symptoms of atopic dermatitis in addition to the inhibitory effect of calcineurin as its main action. A 1% concentration of pimecrolimus is used for clinical purposes, which sufficiently exceeds the growth-inhibitory concentration for Malassezia.