Amphotericin B and its new formulations: pharmacologic characteristics, clinical efficacy, and tolerability

Abstract

Amphotericin B (amB) remains the gold standard for the treatment of invasive fungal infections. However, the efficacy is limited, with response rates from 10% to 80%. Moreover, amB is toxic, especially for the kidneys. New formulations have been developed in an attempt to improve both efficacy and tolerability. In an attempt to reduce toxicity, a number of investigators have reconstituted amB in a lipid emulsion, but few data are available on efficacy in documented infections. An improvement in immediate and renal tolerance was obtained with equivalent daily dose regimens, but the therapeutic index does not appear to be improved. This approach cannot be recommended at present. Three lipid formulations have been developed and are now available in most countries: amB colloidal dispersion (ABCD), amB lipid complex (ABLC), and liposomal amB (AmBisome). The efficacy of ABCD on various fungal infections has been assessed in open trials, with a response rate of 49% in aspergillosis, 70% in candidiasis, and 67% in mucormycosis. In two randomized trials comparing ABCD with amB in invasive aspergillosis and in persistent febrile neutropenia, the response rates were equivalent. ABCD was less nephrotoxic. In contrast, immediate reactions to ABCD were as frequent and severe as with amB. These immediate effects are more frequent during the first infusions and lessen as treatment continues. The recommended dose is 3-4 mg/kg/day. ABLC appeared to be effective as rescue therapy in various types of invasive mycoses, with a response rate of 42% in aspergillosis, 67% in candidiasis, and 82% in fusariosis. Efficacy identical to that of amB was demonstrated in a comparative randomized trial involving patients with invasive candidiasis. General and renal tolerability is improved compared with amB. The recommended dose regimen is 5 mg/kg/day. Liposomal amB (AmBisome) is the only truly liposomal formulation. The response rates in preliminary trials were 66% in aspergillosis and 81% in candidiasis. Several comparative studies have confirmed that this formulation has similar or superior efficacy relative to amB in various fungal infections and also in the empirical treatment of febrile neutropenia. Renal and general tolerability is excellent. The optimal dosing remains unclear but is generally between 3 and 5 mg/kg/day. A double-blind trial comparing the tolerance of liposomal amB and ABLC demonstrated that both infusion-related events and nephrotoxicity were significantly lower for liposomal amB. In sum, the new lipid formulations of amB are effective in various invasive fungal infections. The three formulations exhibit reduced nephrotoxicity compared with conventional amB. Large-scale comparative clinical trials may clarify issues of relative efficacy in various forms of mycotic infections.

The role of fat emulsion therapy in a rodent model of propranolol toxicity: A preliminary study

“…A pharmacokinetic mechanism has been hypothesized to explain these effects [5][6][7][8][9][10]. The most impressive report to date involves a canine model of bupivicaine-induced cardiac arrest.…”

“…In the control group, no dogs were successfully resuscitated [6]. Postulated mechanisms for observed effects of lipid emulsions on lipid soluble drug toxicity include creation of an intravascular lipid phase acting either as a drug depot or a conduit to metabolism or redistribution [5][6][7][8][9][10].…”

“…In previous experiments, intravenous lipid emulsions have been shown to ameliorate the toxicity of a number of lipid soluble agents [5][6][7][8][9][10]. A hypothesized mechanism is the formation of a new intravascular lipid phase that affects drug distribution.…”

In vitro activity of Pheroid vesicles containing antibiotics against Plasmodium falciparum

“…Previous studies with poorly water soluble artemisinin derivative artemisone showed similar results, where the Pheroid vesicle formulation significantly increased the bioavailability of artemisone 4.5 times. 36 The IC 50 values of erythromycin and azithromycin entrapped in Pheroid vesicles were compared with other antibiotics and antimalarial drugs entrapped in Pheroid vesicles in a separate experiment (Table 3). Previous studies have indicated IC 50 values of 220 nM of chloroquine against RSA 11 45 and 169.8 nM against K1.…”

“…One of the best examples is amphotericin B formulated in liposomes, which lead to the commercial product Ambisome. 36 Ciprofloxacin and azithromycin has also been successfully formulated in liposomes and proved more successful than the drug alone against Mycobacterium avium infections. 37 The aim of this study was (a) to investigate the in vitro antimalarial effects of erythromycin and azithromycin entrapped in the Pheroid vesicles against a chloroquine-resistant P. falciparum RSA 11 strain; (b) to evaluate whether the drugs entrapped in Pheroid vesicles could influence the time of the antimalarial action and (c) to compare the effects of azithromycin and erythromycin entrapped in Pheroid vesicles with standard antimalarial drugs and other antibiotics.…”