Infusion-related toxicity of three different amphotericin B formulations and its relation to cytokine plasma levels

A prospective study was performed to compare the infusion-associated toxicity of three different amphotericin B preparations and to correlate acute side-effects with plasma levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1-RA) during and after the infusions. Six adult neutropenic patients with acute leukaemia suffering from suspected or documented systemic fungal infections were treated on three consecutive days with conventional amphotericin B (AmB), liposomal AmB (AmBisome(R)) and AmB mixed in lipid emulsion (AmB/lipid). Drugs were given over 1-2 h. Drug-induced toxicity was monitored every 30 min for 4 h. Plasma levels of the three cytokines were determined using commercially available enzyme-linked immunosorbent assay (ELISA) techniques. Four of six patients showed toxicity after AmB and AmB/lipid infusions; only one patient reacted to liposomal AmB. Clinical toxicity was associated with increases in TNF-alpha plasma levels during two of four infusions of AmB and three of four infusions of AmB/lipid. Major increases in IL-6 occurred during three of four infusions of AmB and during all four AmB/lipid infusions associated with clinical toxicity. Three of four AmB infusions and all four AmB/lipid infusions accompanied by clinical toxicity were associated with major increases in IL-1-RA plasma concentrations. Liposomal AmB was better tolerated than AmB and AmB/lipid. This formulation also caused the lowest Liberation of all three cytokines tested. The severity of clinical symptoms did not correlate closely with absolute cytokine plasma levels. The findings provide further evidence that expression of TNF-alpha, IL-6 and IL-1-RA plays an important role in mediating AmB-related acute toxicity in vivo.