New dosing strategies for liposomal amphotericin B in high-risk patients

ABSTRACTIn recent years, the focus of attention in our understanding of pharmacokinetic antifungal drug efficacy has expanded from the vascular to the tissue compartment, since for moulds in particular, this is the primary point of encounter between the invading fungus and the host. Liposomal amphotericin B (LAB) accumulates in the reticulo-endothelial system and other tissues for several weeks after systemic administration at concentrations exceeding the MICs for many pathogenic fungi. Animal models demonstrate that such tissue depots provide effective prophylaxis and even therapeutic opportunities when LAB is given in high intermittent doses. Efficacy has been shown for even a single high dose of LAB. Human studies have also confirmed retention of amphotericin B in tissues well beyond the last administered dose. Clinical evidence has begun to accrue that suggests prophylactic efficacy in high-risk patients with haematological malignancies who have received intermittent LAB. In an exploratory study of patients with persistent and protracted neutropenic fever, one dose of 10 mg/kg, followed by two doses of 5 mg/kg given on days 1, 3 and 6, respectively, appeared to be as effective as the standard regimen of 3 mg/kg/day given for a longer period. Serum kinetics suggest a large-volume deep tissue compartment for LAB. The drug also appears to accumulate in the tissue, as reflected by bone marrow concentrations. These early observations suggest the potential for intermittent high dosing of LAB for prophylaxis and management of invasive fungal infections, thus providing an alternative option to more frequent and expensive administration of LAB, and daily administration of azoles or candins. This might offer the benefits of lower treatment costs, improved patient compliance and reduced toxicity. Further clinical studies are required to confirm the feasibility of such an approach.