Therapeutic evaluation of free and liposome-encapsulated amphotericin B in the treatment of systemic candidiasis in mice

Abstract

Various doses of amphotericin B encapsulated into unilamellar vesicles of 0.1 micron diameter (lip-AMB) (1.0 to 20.0 mg/kg of body weight) were compared with free amphotericin B (AMB) (0.5 to 2.0 mg/kg of body weight) in a murine model of disseminated candidiasis. CD2F1 mice injected intravenously with 3 x 10(5) Candida albicans cells were treated with either single- or multiple-dose regimens. Untreated infected mice had a median survival of 7 days, with all mice dead by 12 days. Single doses of AMB resulted in a median survival range from 18 to 23.5 days, with less than or equal to 38% survival by day 42. Single doses of lip-AMB resulted in 88 to 100% survival by day 42. The multiple-dose AMB regimen provided median survival of only 30 to 33 days, with less than or equal to 38% survival by day 42. The multiple-dose lip-AMB regimen resulted in greater than 90% survival by day 42. With single-dose regimens, lip-AMB levels in plasma were severalfold higher than AMB levels in plasma. By 10 h, at equivalent doses, lip-AMB levels in plasma were much higher, whereas AMB levels in plasma were not detectable. Compared with normal values, the blood urea nitrogen, serum glutamic pyruvic transaminase, serum glutamic oxaloacetate transaminase, and serum lactate dehydrogenase levels were not significantly altered by high doses of lip-AMB treatment. Viable C. albicans was recoverable from the kidneys of some of the lip-AMB-treated mice at day 42. Thus, encapsulation into unilamellar liposomes enhances the antifungal efficacy of amphotericin B while reducing the toxicity normally associated with administration of free amphotericin B.