In Vitro Antifungal Activity of Micafungin (FK463) against Dimorphic Fungi: Comparison of Yeast-Like and Mycelial Forms

Abstract

The characteristics of in vitro micafungin (FK463) antifungal activity against six species of dimorphic fungi were investigated in accordance with the NCCLS M27-A microdilution methods. MICs of micafungin, amphotericin B, itraconazole, and fluconazole for Histoplasma capsulatum var. capsulatum, Blastomyces dermatitidis, Paracoccidioides brasiliensis, Penicillium marneffei, and Sporothrix schenckii were determined both for the yeastlike form and mycelial form. Coccidioides immitis was tested only in its mycelial form. We have clearly demonstrated that the in vitro activity of micafungin depends considerably on the growth form of dimorphic fungi. Micafungin exhibited potent activity against the mycelial forms of H. capsulatum, B. dermatitidis, and C. immitis (MIC range, 0.0078 to 0.0625 g/ml), while it was very weakly active against their yeast-like forms (MIC range, 32 to >64 g/ml). Micafungin was also more active against the mycelial forms than the yeast-like forms of Paracoccidioides brasiliensis, Penicillium marneffei, and S. schenckii. The MICs of amphotericin B were 2 to 5 dilutions lower for the mycelial forms than for the yeast-like forms of B. dermatitidis and Paracoccidioides brasiliensis. There was no apparent difference in the activity of itraconazole between the two forms. The MICs of fluconazole for the yeast-like forms were generally lower than those for the mycelial forms, and considerably so for B. dermatitidis. These results suggest that the growth form employed in antifungal susceptibility testing of dimorphic fungi can considerably influence the interpretation of results. At present, it cannot be judged whether micafungin has clinical usefulness for dimorphic fungus infections, since for most fungi it remains uncertain which growth form correlates better with therapeutic outcome. However, the results of this study warrant further investigations of micafungin as a therapeutic agent for infections caused by dimorphic fungi.

Paracoccidioides brasiliensis: chemical and molecular tools for research on cell walls, antifungals, diagnosis, taxonomy

“…brasiliensis has been reported as resistant to the action of micafungin [68] inasmuch as MIC in seven strains ranged between 4 and 16 lg/ml for the M phase and >64 lg/ml for Y cells of the fungus. These results demonstrated that the antifungal activity of micafungin depended on the growth form, and particularly on the cell wall structure of each morphotype which, as mentioned before, is conformed by b-1,3-glucan -the target of the candin class of compounds-as the sole neutral polysaccharide of the M phase, being substituted by a-1,3-glucan in the Y phase.…”

Treatment of chronic pulmonary blastomycosis with caspofungin

“…Firstly, since B. dermatitidis is a dimorphic fungus, it is unclear which form (mycelium or yeast) should be studied, although the latter is considered pathogenic. As noted by Nakai et al (2003), both forms have markedly different MICs, the yeast being generally less susceptible. Secondly, susceptibility testing for blastomycosis is not standardized and is often derived from Clinical and Laboratory Standards Institute standards for yeasts and filamentous fungi; however, every individual pathogen must undergo a rigorous process to ensure that the method is reproducible.…”

“…Current guidelines also stipulate that echinocandins (caspofungin, micafungin and anidulafungin) should not be used in the treatment of blastomycosis. In the absence of clinical data, this recommendation was extrapolated from two in vitro studies that showed 'poor to intermediate in vitro activity against B. dermatitidis' (Espinel-Ingroff, 1998;Nakai et al, 2003).…”

“…Secondly, susceptibility testing for blastomycosis is not standardized and is often derived from Clinical and Laboratory Standards Institute standards for yeasts and filamentous fungi; however, every individual pathogen must undergo a rigorous process to ensure that the method is reproducible. This can perhaps explain the large discrepancies in the MICs for B. dermatitidis mycelia in the two aforementioned studies (MIC range of micafungin varying from 0.008-0.03 to 0.5-8 mg ml 21 ) (Espinel-Ingroff, 1998; Nakai et al, 2003). Thirdly, echinocandin susceptibility testing itself is incompletely validated for most fungi (including the most common ones).…”

Synergistic Effect of Antituberculosis Drugs and Azoles In Vitro against Histoplasma capsulatum var. capsulatum

“…The results were read visually, and MIC endpoints were determined after 7 days of incubation at 35°C. Broth microdilution assays were performed for H. capsulatum yeast-like form as described by Nakai et al (10), and the readings were conducted after 4 days. All tests were repeated at least twice, and every fungal strain was tested in duplicate.…”