The efficacy of a novel
sterol-complexed preparation of
amphotericin B,
amphotericin B colloidal dispersion, was compared with that of
deoxycholate-complexed
amphotericin B in an acute murine model of systemic
coccidioidomycosis. Mice (CD-1, female) were infected intravenously with 180 or 200 arthroconidia of Coccidioides immitis, and intravenous
therapy was begun 3 days later. Six doses in various regimens of either preparation were given over 14 days, and deaths were tallied for an additional 35 days. All regimens that were not acutely lethal prolonged the survival of mice over that of controls (P less than 0.001). Quantitative determination of residual burdens of C. immitis in the spleen, liver, and lungs of survivors revealed that the colloidal dispersion was not as effective as the
deoxycholate suspension on a milligram-per-kilogram basis.
Deoxycholate suspension at 1.3 mg/kg cleared the organs in all mice, whereas colloidal dispersion at 5.0 mg/kg was the lowest dose that cleared organisms from all animals. Lower doses cleared organisms from fewer animals or cleared only selected organs.
Deoxycholate suspension was more efficacious than colloidal dispersion in clearing C. immitis from the liver or lungs (P less than 0.05 to 0.01, dose and organ dependent) at identical doses. No overt toxicity was observed in mice treated with colloidal dispersion
at 10 mg/kg. In contrast,
deoxycholate suspension at 2.0 mg/kg was acutely toxic; 50% of the treated mice died
after treatment. The two complexes were not equivalent on a milligram-per-kilogram basis; the
deoxycholate suspension was three to four times more efficacious and also greater than 5- to greater than or equal to 8-fold more toxic. Thus, the therapeutic index of the colloidal dispersion complex is greater than that of the
deoxycholate complex. The amount of
amphotericin B per dose could also be increased when given as a colloidal dispersion to an optimally level.
Amphotericin B colloidal dispersion shows promise for the
therapy of disseminated
coccidioidomycosis and should be tested in other animal models and in humans.