A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients

Abstract

Summary.One hundred and thirty-four adults and 204 children were randomized in two prospective, parallel comparative multicentre trials to receive either conventional amphotericin B 1 mg/kg/d (c-AMB), liposomal amphotericin B 1 mg/kg/d (L-AMB1) or liposomal amphotericin B 3 mg/ kg/d (L-AMB3). Patients were entered if they had a pyrexia of unknown origin (PUO) defined as temperature of 38ЊC or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0 . 5 × 10 9 /l). The safety and toxicity of liposomal amphotericin B was compared with that of conventional amphotericin B. Efficacy of treatment was assessed, with success defined as resolution of fever for 3 consecutive days (< 38ЊC) without the development of any new fungal infection. Clinical and laboratory parameters were collected for safety analysis. In both the paediatric and adult populations, L-AMB treated patients had a 2-6-fold decrease in the incidence (P 4 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 treated patients, in contrast to 12% of patients on c-AMB (P < 0 . 01). Nephrotoxicity, in the patient subset not receiving concomitant nephrotoxic agents, defined as a doubling from the patients baseline serum creatinine 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-AMB (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 all patients randomized. Success was defined by a minimum of 3 consecutive days with fever (< 38ЊC) continuing to study end indicated by recovery of neutrophils to 0 . 5 × 10 9 /l. Addition of systemic antifungal 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 difference was found between c-AMB and L-AMB3 (P ¼ 0 . 03) but a Kaplan-Meier analysis of time to deffervescence of fever showed there was no significant difference between the arms.It was concluded that liposomal amphotericin at either 1 or 3 mg/kg/d was significantly safer than conventional amphotericin B in children and adults. The main aim of this open-label study was to compare safety between the three trial arms. However, we provide evidence for an equivalent or possibly superior efficacy of liposomal amphotericin with regard to resolution of fever of unknown origin. Subsequent trials should compare amphotericin preparations in defined fungal infections.

Amphotericin B-related nephrotoxicity in low-risk patients

“…This practice is based upon the results of clinical trials that have demonstrated reductions of 50-75% in the incidence of ARF [13][14][15][16][17]. In these studies the development of ARF, usually defined as a 50% rise in the basal serum creatinine levels and a peak creatinine level higher than 2.0 mg/dL, occurred in 34% to 49% of the patients.…”

“…Based on the results of clinical trials, liposomal amphotericin has been recommended for the prevention of acute renal failure (ARF) [13][14][15][16][17]. These studies included a largely unselected population of patients, with many of them being treated at intensive care units, using vasoactive drugs, and with multiple risk factors for developing ARF.…”

“…Several studies published during the last two decades have shown that nephrotoxicity can be prevented by the use of sodium loading [4,[7][8][9][10][11], slowing drug infusion [12] and through the use of liposomal or lipid-complex amphotericins [13][14][15][16][17].…”

Pseudohyperphosphatemia associated with high-dose liposomal amphotericin B therapy

“…This lipid formulation has a favorable toxicity profile when compared to conventional amphotericin B deoxycholate [2][3][4] and has been approved for use at dosages ranging from 3 to 6 mg/kg/day for indications including empirical therapy of persistent febrile neutropenia, systemic aspergillus, candida, and cryptococcus infections, visceral leishmaniasis, and cryptococcal meningitis in HIV infected patients. The improved safety and tolerability of this formulation have allowed for the use of increasingly higher dosages for the treatment of refractory infections [5][6][7][8].…”

A prospective randomized controlled trial comparing PCR-based and empirical treatment with liposomal amphotericin B in patients after allo-SCT

“…17 In a further randomized study, liposomal amphotericin B in the empirical setting of fever of unknown origin was shown to be effective even at a dose level of l mg/kg body weight. 18 Furthermore, the dosage of liposomal amphotericin B can be increased safely to dosages higher than 3 mg/kg if necessary. 19 To investigate the impact of PCR as a diagnostic tool for guiding preemptive antifungal therapy, we compared the incidence of IFIs as well as the overall and IFI-related mortality in patients after Allo-SCT randomized to PCRbased preemptive as opposed to empirical treatment with liposomal amphotericin B.…”