The iron chelator deferasirox enhances liposomal amphotericin B efficacy in treating murine invasive pulmonary aspergillosis.
OBJECTIVE
Increased bone marrow iron levels in patients with haematological malignancies is an independent risk factor for developing invasive pulmonary aspergillosis (IPA), suggesting an important role for iron uptake in the pathogenesis of IPA. We sought to determine the potential for combination therapy with the iron chelator deferasirox + liposomal amphotericin B (LAmB) to improve the outcome of murine IPA compared with LAmB monotherapy.


METHODS
In vitro MIC and minimum fungicidal concentration (MFC) values of the iron chelator, deferasirox, for Aspergillus fumigatus were determined by microdilution assay. In addition, we studied the efficacy of deferasirox alone or combined with LAmB in treating immunocompromised mice infected with A. fumigatus via inhalation.


RESULTS
Deferasirox was cidal in vitro against A. fumigatus, with an MIC and MFC of 25 and 50 mg/L, respectively. Deferasirox monotherapy modestly prolonged survival of mice with IPA. Combination deferasirox + LAmB therapy synergistically improved survival and reduced lung fungal burden compared with either monotherapy alone.


CONCLUSIONS
Iron chelation therapy with deferasirox alone or in combination with LAmB is effective in treating experimental IPA. Further study of deferasirox is warranted as adjunctive therapy for IPA infections.
Ibrahim
Ashraf S
AS
Los Angeles Biomedical Research Institute at Harbor-University of California Los Angeles Medical Center, Torrance, CA 90502, USA. ibrahim@labiomed.org
Gebremariam
Teclegiorgis
T
French
Samuel W
SW
Edwards
John E
JE
Spellberg
Brad
B
D000666:Amphotericin B / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000935:Antifungal Agents / Q000627:therapeutic use*; D001232:Aspergillus fumigatus / Q000187:drug effects; D001565:Benzoates / Q000494:pharmacology / Q000627:therapeutic use*; D000077588:Deferasirox; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006801:Humans; D055744:Invasive Pulmonary Aspergillosis / Q000188:drug therapy*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D016019:Survival Analysis; D016896:Treatment Outcome; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use*
D000935:Antifungal Agents; D001565:Benzoates; D014230:Triazoles; C068538:liposomal amphotericin B; D000666:Amphotericin B; D000077588:Deferasirox