Central nervous system (CNS)
aspergillosis is a severe disease that responds poorly to current
therapies. The current studies examined the efficacies of several
antifungal agents alone or in combination with a murine model of CNS
aspergillosis. Immunosuppressed mice were infected intracerebrally with Aspergillus fumigatus and treated with an
amphotericin B preparation, an
echinocandin, or
voriconazole (VCZ) given alone or in combination. Monotherapy studies showed that
micafungin (
MICA),
caspofungin (CAS), VCZ, conventional
amphotericin B (AMB),
Abelcet (ABLC) (a
lipid-carried AMB formulation; Enzon
Pharmaceuticals, Inc.), and
AmBisome (AmBi) (liposomal AMB; Gilead Sciences, Inc.) were efficacious. However, doses of AmBi above 15 mg/kg of
body weight showed reduced efficacy. Neither
MICA nor CAS showed dose responsiveness at the doses tested (1, 5, or 10 mg/kg). Only the 40-mg/kg dose of VCZ was effective. AmBi and ABLC showed dose responsiveness, with 10-mg/kg doses causing a significant reduction in fungal burden; they had equivalent activities at the 10-mg/kg dose. Suboptimal dosages of AmBi in combination with
MICA, CAS, or VCZ were effective in prolonging survival. However, significantly enhanced activity was demonstrated only with AmBi and VCZ in combination. AmBi in combination with
MICA or CAS showed a trend toward enhanced activity, but the combination was not significantly superior to monotherapy. The use of AmBi with CAS or VCZ at optimal doses did not improve efficacy. Cure was not attained with any dosage combinations. These results indicate that AmBi in combination with VCZ may be superior for treatment of CNS
aspergillosis; combinations of AmBi and
MICA or CAS were not antagonistic and may have a slight benefit.