The iron chelator deferasirox enhances liposomal amphotericin B efficacy in treating murine invasive pulmonary aspergillosis.

OBJECTIVES 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.

[1]  K. Zarember,et al.  Antifungal Activities of Natural and Synthetic Iron Chelators Alone and in Combination with Azole and Polyene Antibiotics against Aspergillus fumigatus , 2009, Antimicrobial Agents and Chemotherapy.

[2]  Russell E. Lewis,et al.  Increased bone marrow iron stores is an independent risk factor for invasive aspergillosis in patients with high‐risk hematologic malignancies and recipients of allogeneic hematopoietic stem cell transplantation , 2007, Cancer.

[3]  B. Spellberg,et al.  The iron chelator deferasirox protects mice from mucormycosis through iron starvation. , 2007, The Journal of clinical investigation.

[4]  B. Spellberg,et al.  Deferiprone iron chelation as a novel therapy for experimental mucormycosis. , 2006, The Journal of antimicrobial chemotherapy.

[5]  M. Moore,et al.  The Aspergillus fumigatus Siderophore Biosynthetic Gene sidA, Encoding l-Ornithine N5-Oxygenase, Is Required for Virulence , 2005, Infection and Immunity.

[6]  J. Briones,et al.  Frequent severe liver iron overload after stem cell transplantation and its possible association with invasive aspergillosis , 2004, Bone Marrow Transplantation.

[7]  S. Filler,et al.  Novel Inhalational Murine Model of Invasive Pulmonary Aspergillosis , 2004, Antimicrobial Agents and Chemotherapy.

[8]  Richard Sylvester,et al.  Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. , 2002, The New England journal of medicine.

[9]  D. Kontoyiannis,et al.  Invasive Aspergillosis in 2002: An Update , 2002, European Journal of Clinical Microbiology and Infectious Diseases.