Amphotericin B preparations: a maximum tolerated dose in severe invasive fungal infections?

Abstract

Availability of lipid formulations of amphotericin B has opened up the possibility of treating invasive fungal infections in immunocompromised patients with high doses of this antifungal agent. Evidence is emerging to suggest that lipid formulations may have heightened efficacy compared to conventional amphotericin B. The issue of optimal dosage has been a neglected area. This article reviews published data accrued from clinical, open-label, salvage, and other studies, and finds little support that the use of high doses of lipid formulations are more efficacious than lower doses. The response rates for invasive fungal infection from most studies are predictably around 56%, irrespective of the lipid formulation and dose used. Animal models provide evidence that low doses of a lipid formulation are as successful in reducing fungal dissemination and in prolonging survival as higher doses, although concomitant tissue fungal eradication is not as effectively achieved by the lower doses (survival-mycologic eradication dissociation). Kinetic studies performed in the clinically relevant setting of critically ill patients give further support to the use of low doses, since levels of liposomal amphotericin B at all dosages between 1 and 4 mg/kg/day are similar and above maximum inhibitory concentrations for commonly encountered fungi. There has only been one prospective randomised study designed with the primary end-point of comparing two dosages of an amphotericin B lipid formulation on clinical response and survival. That European Organization for Research and Treatment of Cancer (EORTC) study concluded that liposomal amphotericin B given at 1 mg was as efficacious as 4 mg/kg/day in treating neutropenic patients with invasive pulmonary aspergillosis. There are a multitude of unanswered questions concerning dosing, and their answers are confounded by difficulties in performing clinical trials and the multiplicity of factors other than antifungal chemotherapy that influence outcome. Maximum tolerated dose studies using existing lipid formulations, or perhaps with the newer formulations such as pegylated immunoliposomal amphotericin B, could be performed to shed light on this difficult area.