In vitro antifungal activity of Isavuconazole to Madurella mycetomatis, the causative agent of black-grain mycetoma

W. Kloezen, J. F. Meis, I. Curfs-Breuker, A. H. Fahal and W. W. J. van de Sande

Abstract: 

Introduction: Madurella mycetomatis is the most prevalent causative agent of eumycetoma. This chronic, granulomatous infection is frequently found in the lower extremities, initially as a small subcutaneous nodule, which slowly progresses into swollen lesions and sinuses that discharge black grains. To date, treatment of eumycetoma in endemic areas still consists of a combination of extensive surgery with removal of infected tissue or amputation of the limb and prolonged antifungal therapy with ketoconazole or itraconazole. Although successful cases have been reported, eumycetoma is associated with high recurrence rates, even after amputation of the affected limb. Isavuconazole is an intravenous and oral broad-spectrum triazole, currently studied in Phase III trials, which has predictable dose proportional pharmacokinetics, a long plasma half-life, good tissue penetration and is shown to have good in vitro antifungal activity to several other causative agents of black-grain mycetoma. Previous in vitro studies have shown that M. mycetomatis is susceptible to several azoles. Therefore, the antifungal activity to M. mycetomatis of the new azole Isavuconazole (BAL4815) was explored.
Methods: In this study, the susceptibility of 22 M. mycetomatis isolates (obtained from 21 patients in the Mycetoma Research Centre, University of Khartoum, Sudan in 1999 and 2000) to Isavuconazole was determined. A standardized hyphal suspension of M. mycetomatis was prepared in RPMI and exposed to 0.031–16 lg ml-1 of Isavuconazole, ketoconazole or itraconazole for 7 days at 37_ C. To facilitate endpoint reading 2,3-bis (2-methoxy-4-nitro-5-sulfophenyl)-5-[(phenylamino) carbonyl]-2H-tetrazolium hydroxide (XTT) was added.
Results: MICs ranged from 0.031–1 lg ml-1, from £0.016 - 0.25 lg ml-1, and from £0.016 - 0.125 lg ml-1 for ketoconazole, itraconazole, and Isavuconazole, respectively. The MIC90 of Isavuconazole was 0.063 lg ml-1, which was lower than the MIC90 of ketoconazole (0.25 lg ml-1) and itraconazole (0.125 lg ml-1).
Conclusion: In vitro, M. mycetomatis appears to be highly susceptible to Isavuconazole. These properties make Isavuconazole a potentially promising antifungal agent in the treatment of mycetoma caused by M. mycetomatis.

    • ISHAM 18th (2012)