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Antimicrobial Agents and Chemotherapy, August 2006, p. 2897-2898, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00687-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

LETTER TO THE EDITOR

A New Calcineurin Inhibitor, Pimecrolimus, Inhibits the Growth of Malassezia spp.


   LETTER
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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 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).


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  		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.


   ACKNOWLEDGMENTS
 
This study was supported in part by research grants from the Japan Society for the Promotion of Science (no. 16590127), the Ministry of Education, Culture, Sports, Science, and Technology of Japan for an Open Research Centre Project, and the IFO Foundation (T.S.).


   REFERENCES
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 References
 

  1. Faergemann, J. 2002. Atopic dermatitis and fungi. Clin. Microbiol. Rev. 15:545-563.[Abstract/Free Full Text]
  2. Fox, D. S., and J. Heitman. 2002. Good fungi gone bad: the corruption of calcineurin. Bioessays 24:894-903.[CrossRef][Medline]
  3. Gupta, A. K., Y. Kohli, A. Li, J. Faergemann, and R. C. Summerbell. 2000. In vitro susceptibility of the seven Malassezia species to ketoconazole, voriconazole, itraconazole and terbinafine. Br. J. Dermatol. 142:758-765.[CrossRef][Medline]
  4. Nikkels, A. F., and G. E. Pierard. 2003. Framing the future of antifungals in atopic dermatitis. Dermatology 206:398-400.[CrossRef][Medline]
  5. Sugita, T., H. Suto, T. Unno, R. Tsuboi, H. Ogawa, T. Shinoda, and A. Nishikawa. 2001. Molecular analysis of Malassezia microflora on the skin of atopic dermatitis patients and healthy subjects. J. Clin. Microbiol. 39:3486-3490.[Abstract/Free Full Text]
  6. Sugita, T., M. Tajima, T. Ito, M. Saito, R. Tsuboi, and A. Nishikawa. 2005. Antifungal activities of tacrolimus and azole agents against the eleven currently accepted Malassezia species. J. Clin. Microbiol. 43:2824-2829.[Abstract/Free Full Text]
  7. Wolff, K. 2005. Pimecrolimus 1% cream for the treatment of atopic dermatitis. Skin Ther. Lett. 10:1-6.
Takashi Sugita*
Department of Microbiology
Meiji Pharmaceutical University
2-552-1 Noshio, Tokyo
204-8588 Japan,1

Mami Tajima
Department of Dermatology
Tokyo Medical University
Shinjuku, Tokyo
160-0023 Japan,2

Hisae Tsubuku
Department of Dermatology
Japan Self Defence Forces Central Hospital
Setagaya, Tokyo
154-8532 Japan,3

Ryoji Tsuboi Akemi Nishikawa
Department of Immunobiology
Meiji Pharmaceutical University
2-552-1 Noshio, Tokyo
204-8588 Japan,4

* Phone: 81-424-95-8762, Fax: 81-424-95-8762, E-mail: sugita{at}my-pharm.ac.jp

Antimicrobial Agents and Chemotherapy, August 2006, p. 2897-2898, Vol. 50, No. 8
0066-4804/06/$08.00+0     doi:10.1128/AAC.00687-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.




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