Efficacy of Amphotericin B or Itraconazole in a Murine Model of Central Nervous System Aspergillus Infection

Abstract

ABSTRACT Given the greater than 90% lethality of clinical central nervous system (CNS) aspergillosis despite current therapies, there is a need for an animal model to study therapeutic strategies. We previously established a model of CNS aspergillosis by intracerebral infection and report here the results of treatment with the two therapies with the greatest clinical experience, i.e., treatments with amphotericin B (AMB) and itraconazole (ITZ). Mice were given cyclophosphamide to produce pancytopenia. AMB was given intraperitoneally (i.p.; 3 mg/kg of body weight) or intravenously (i.v.; 0.8 mg/kg) once daily. ITZ in cyclodextrin was given by gavage once daily at a dose of 100 mg/kg or twice daily at 50 mg/kg. Treatments were started at day 1 postinfection and given for 10 days. At day 15, survivors were euthanatized. Ninety percent of the mice given no treatment died by day 6, and 100% died by day 10. Mice treated with AMB either i.p. or i.v. had 40% survival. Mice treated with ITZ either once or twice per day had a median survival time of 10 days, compared with 4 days for control animals, but a survival rate of only 10%. AMB and ITZ prolonged survival ( P , <0.0001 to <0.05) compared with controls. Brains from surviving mice had CFU of Aspergillus fumigatus . This model can be used to compare newer antifungals and to study combination therapy or immunotherapy to find better therapeutic alternatives.