A RANDOMIZED COMPARISON OF LIPOSOMAL VERSUS CONVENTIONAL AMPHOTERICIN-B FOR THE TREATMENT OF PYREXIA OF UNKNOWN ORIGIN IN NEUTROPENIC PATIENTS

One hundred and thirty-four adults and 204 children were randomized in two prospective, parallel comparative multicentre trials to receive e ither conventional amphotericin B I mg/kg/d (c-AMB), liposomal amphote ricin B 1 mg/kg/d (L-AMB1) or liposomal amphotericin B 3 mg/kg/d (L-AM B3). Patients were entered if they had a pyrexia of unknown origin (PU O) defined as temperature of 38 degrees C or more, not responding to 9 6 h of systemic broad-spectrum antibiotic treatment, and neutropenia ( <0.5x10(9)/l). The safety and toxicity of liposomal amphotericin B was compared with that of conventional amphotericin B. Efficacy of treatm ent was assessed, with success defined as resolution of fever for 3 co nsecutive days (<38 degrees C) without the development of any new fung al infection. Clinical and laboratory parameters were collected for sa fety analysis. In both the paediatric and adult populations, L-AMB tre ated patients had a 2-6-fold decrease in the incidence (P less than or equal to 0.01) of test-drug-related side-effects, compared to c-AMB. Severe trial-drug-related side-effects were seen in 1% of L-AMB treate d patients, in contrast to 12% of patients on c-AMB (P<0.01). Nephroto xicity, in the patient subset not receiving concomitant nephrotoxic ag ents, defined as a doubling from the patients baseline serum creatinin e level, was not observed in the L-AMB1 arm whereas the incidence was 3% in patients on L-AMB3 and 23% in those on c-AMB (P<0.01). Moreover, time to develop nephrotoxicity was longer in both L-AMB arms than c-A MB (P<0.01). Severe hypokalaemia was observed less frequently in both L-AMB arms (P<0.01). Analysis was by intention-to-treat and included a ll patients randomized; Success was defined by a minimum of 3 consecut ive days with fever (<38 degrees C) continuing to study end indicated by recovery of neutrophils to 0.5x10(9)/l. Addition of systemic antifu ngal therapy or development of systemic fungal infection were failures as was persistent fever to study end. Efficacy assessments indicated success in 49% of the total group treated with c-AMB. 58% of patients responded to L-AMB1 and 64% to L-AMB3. A statistically significant dif ference was found between c-AMB and L-AMB3 (P=0.03) but a Kaplan-Meier analysis of time to deffervescence of fever showed there was no signi ficant difference between the arms. It was concluded that liposomal am photericin at either 1 or 3 mg/kg/d was significantly safer than conve ntional amphotericin B in children and adults. The main aim of this op en-label study was to compare safety between the three trial arms. How ever, we provide evidence for an equivalent or possibly superior effic acy of liposomal amphotericin with regard to resolution of fever of un known origin. Subsequent trials should compare amphotericin preparatio ns in defined fungal infections.