Vol.56 No.2 March 2008
Paradoxical effect of micafungin on clinically isolated Candida tropicalis
1)Pharmacology Research Laboratories, Astellas Pharma Inc., 2-1-6, Kashima, Yodogawa-ku, Osaka, Japan
2)Medical Information Sciences Division, United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University
Abstract
A strain of Candida tropicalis was isolated from a blood sample of a patient undergoing treatment with micafungin at Gifu University Hospital. Paradoxically, the strain grew in the presence of higher micafungin concentrations than usual. We characterized this strain by several non-clinical experiments, including the response to therapy in animal models of infection, to investigate whether this strain is indeed resistant to micafungin. In the CLSI M27-A2 microdilution assay, growth of this strain was inhibited in the presence of 0.0625 μg/mL or higher concentrations of micafungin at 24 h of incubation. At 48 h, however, slight growth was visible in the range of 8 to 32 μg/mL. The growth was microscopically observed as a grape-like aggregation. This morphology was quite different from that of the untreated control fungus, which was observed as scattered yeast-like cells. When antibiotic medium 3 was used as the test medium, the strain was killed at the MIC or higher, and the paradoxical growth was no longer seen. Micafungin was similarly efficacious against neutropenic murine models of systemic infection caused by both paradoxical effect-positive and -negative strains, with ED50 values of 0.29 and 0.35 mg/kg, respectively (95% confidence interval; 0.18 to 0.41 and 0.26 to 0.48 mg/kg, respectively). These results suggest that this strain should be considered susceptible to micafungin because the paradoxical effect appears only due to varying osmotic resistivity and does not influence the in vivo effect of micafungin.
Key word
micafungin, Candida tropicalis, paradoxical effect
Received
May 15, 2007
Accepted
November 28, 2007
Jpn. J. Chemother. 56 (2): 185-189, 2008
