Efficacy of amphotericin B or itraconazole in a murine model of central nervous system Aspergillus infection

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.

FIG. 1.

Survival of groups of 10 male 5-week-old immunosuppressed CD-1 mice infected intracerebrally with A. fumigatus and left untreated, given D5W, or treated with AMB at a dose of 3 mg/kg i.p. (a) or 0.8 mg/kg i.v. (b). Treatments were started on day 1 postinfection and continued for 10 days.

FIG. 2.

Survival of groups of 10 male 5-week-old immunosuppressed CD-1 mice infected intracerebrally with A. fumigatus and left untreated, given CDX, or treated with ITZ orally at a dose of 100 mg/kg QD (a) or 50 mg/kg BID (b). Treatments were started on day 1 postinfection and continued for 10 days.