We have shown previously that high-dose
lipid amphotericin preparations are not more efficacious than lower doses in
aspergillosis. We studied
toxicity, drug concentrations and localization, and quantitative
infection concurrently, using a 4-day model of central nervous system (CNS)
aspergillosis to assess early events. Mice given Aspergillus fumigatus conidia intracerebrally, under a
cyclophosphamide immunosuppressive regimen, were treated for 3 days (
AmBisome at 3 or 10 mg/kg of
body weight,
Abelcet at 10 mg/kg,
amphotericin B deoxycholate at 1 mg/kg,
caspofungin at 5 mg/kg, or
voriconazole at 40 mg/kg). Sampling 24 h after the last treatment showed that
AmBisome at 3 but not
at 10 mg/kg, as well as
Abelcet,
caspofungin, and
voriconazole, reduced brain CFU. All regimens reduced renal
infection. Minor renal tubular changes occurred with
AmBisome or
Abelcet therapy, whereas heart, lung, and brain showed no
drug toxicity.
Amphotericin B tissue and serum concentrations did not correlate with efficacy. Endothelial cell activation (ICAM-1 and
P-selectin in cerebral capillaries) occurred during
infection.
Amphotericin B derived from
AmBisome and
Abelcet localized in activated endothelium and from
Abelcet in intravascular monocytes. In 10-day studies dosing uninfected mice, minor renal tubular changes occurred after
AmBisome or
Abelcet at 1, 5, or 10 mg/kg with or without
cyclophosphamide treatment;
nephrosis occurred only with
Abelcet in
cyclophosphamide-treated mice. Hepatotoxicity occurred with
AmBisome and
Abelcet but was reduced in
cyclophosphamide-treated mice. Marked CFU reduction by
AmBisome at 3 mg/kg occurred in association with relatively more intense
inflammation.
Abelcet renal localization appears to be a precursor to late nephrotoxicity. Hepatotoxicity may contribute to high-dose
Abelcet and
AmBisome failures. Our novel observation of endothelial
amphotericin localization during
infection may contribute to
amphotericin mechanism of efficacy.