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JAC Advance Access published online on August 23, 2006
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkl350
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© The Author 2006. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org
Received May 16, 2006
Revised August 3, 2006
Accepted August 4, 2006

Brief report

Deferiprone iron chelation as a novel therapy for experimental mucormycosis

Ashraf S. Ibrahim 1 *, John E. Edwards Jr 1, Yue Fu 1, and Brad Spellberg 1

1 David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, USA

* To whom correspondence should be addressed.
Ashraf S. Ibrahim, E-mail: ibrahim{at}labiomed.org


  Abstract

Objectives: Patients treated with the iron chelator deferoxamine are known to be more susceptible to mucormycosis. However, while deferoxamine is an iron chelator from the perspective of the human host, deferoxamine actually serves as a siderophore, delivering free iron to Rhizopus oryzae, the major cause of mucormycosis. Other iron chelators, including deferiprone, which do not deliver iron to R. oryzae have been described. We therefore sought to determine whether iron-chelation therapy with deferiprone would effectively treat mucormycosis.

Methods: In vitro MIC and minimum fungicidal concentration (MFC) of the iron chelator, deferiprone, for R. oryzae were determined by microdilution assay. In addition, we compared the efficacy of deferiprone with that of liposomal amphotericin B (LAmB) in treating mucormycosis in diabetic ketoacidotic mice.

Results: Deferiprone demonstrated static activity against R. oryzae at 24 h, but showed cidality at 48 h of incubation. Deferiprone was as effective as LAmB at improving survival and decreasing brain fungal burden, and both drugs were more effective than placebo in non-iron-overloaded animals. Administration of free iron with deferiprone reversed protection, confirming that the mechanism of protection was iron chelation.

Conclusions: Iron chelation is a promising, novel therapeutic strategy for refractory mucormycosis infections. Further studies are warranted to evaluate combination antifungal/iron chelation therapy and to evaluate the efficacy of other iron-chelating agents.

Keywords: zygomycosis; Rhizopus oryzae; mice.
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