Comparison of the toxicity of amphotericin B in 5% dextrose with that of amphotericin B in fat emulsion in a randomized trial with cancer patients. Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Administration of lipid-emulsion versus conventional amphotericin B in patients with neutropenia. Low-dose amphotericin B lipid complex vs. conventional amphotericin B for empirical antifungal therapy of neutropenic fever in patients with hematologic malignancies--a randomized, controlled trial. Use of amphotericin B colloidal dispersion in children. Pharmacoeconomic analysis of liposomal amphotericin B versus conventional amphotericin B in the empirical treatment of persistently febrile neutropenic patients. Amphotericin B in children with malignant disease: a comparison of the toxicities and pharmacokinetics of amphotericin B administered in dextrose versus lipid emulsion. Trial of glucose versus fat emulsion in preparation of amphotericin for use in HIV infected patients with candidiasis. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia.
A multicentric randomized trial was undertaken to compare the toxicity of amphotericin B in 5% dextrose with that of amphotericin B in a fat emulsion (Intralipid) in cancer patients. Group 1 (n = 33) received amphotericin B diluted in 5% dextrose with premedication consisting of promethazine plus an antipyretic. Group 2 (n = 28) received amphotericin B diluted in 20% Intralipid without premedication. Amphotericin B was infused daily at a dose of 1 mg/kg of body weight over a 1-h period to members of both groups for empirical antifungal therapy (in neutropenic patients) or for the treatment of documented fungal infections. The majority of patients (80%) received empirical amphotericin B treatment. The two groups were comparable with regard to age, gender, underlying disease, and the following baseline characteristics: use of other nephrotoxic drugs and serum levels of potassium and creatinine. The median cumulative doses of amphotericin B were 240 mg in group 1 and 245 mg in group 2 (P = 0.73). Acute adverse events occurred in 88% of patients in group 1 and in 71% of those in group 2 (P = 0.11). Forty percent of the infusions in group 1 were associated with fever, compared to 23% in group 2 (P < 0.0001). In addition, patients in group 2 required less meperidine for the control of acute adverse events (P = 0.008), and fewer members of this group presented with hypokalemia (P = 0.004) or rigors (P < 0.0001). There was no difference in the proportions of patients with nephrotoxicity (P = 0.44). The success rates of empirical antifungal treatment were similar in the two groups (P = 0.9). Amphotericin B diluted in a lipid emulsion seems to be associated with a smaller number of acute adverse events and fewer cases of hypokalemia than amphotericin B diluted in 5% dextrose. In patients with persistent fever and neutropenia, amphotericin B is administered empirically for the early treatment and prevention of clinically occult invasive fungal infections. However, breakthrough fungal infections can develop despite treatment, and amphotericin B has substantial toxicity.
                We conducted a randomized, double-blind, multicenter trial comparing liposomal amphotericin B with conventional amphotericin B as empirical antifungal therapy.
                The mean duration of therapy was 10.8 days for liposomal amphotericin B (343 patients) and 10.3 days for conventional amphotericin B (344 patients). The composite rates of successful treatment were similar (50 percent for liposomal amphotericin B and 49 percent for conventional amphotericin B) and were independent of the use of antifungal prophylaxis or colony-stimulating factors. The outcomes were similar with liposomal amphotericin B and conventional amphotericin B with respect to survival (93 percent and 90 percent, respectively), resolution of fever (58 percent and 58 percent), and discontinuation of the study drug because of toxic effects or lack of efficacy (14 percent and 19 percent). There were fewer proved breakthrough fungal infections among patients treated with liposomal amphotericin B (11 patients [3.2 percent]) than among those treated with conventional amphotericin B (27 patients [7.8 percent], P=0.009). With the liposomal preparation significantly fewer patients had infusion-related fever (17 percent vs. 44 percent), chills or rigors (18 percent vs. 54 percent), and other reactions, including hypotension, hypertension, and hypoxia. Nephrotoxic effects (defined by a serum creatinine level two times the upper limit of normal) were significantly less frequent among patients treated with liposomal amphotericin B (19 percent) than among those treated with conventional amphotericin B (34 percent, P<0.001).
                Liposomal amphotericin B is as effective as conventional amphotericin B for empirical antifungal therapy in patients with fever and neutropenia, and it is associated with fewer breakthrough fungal infections, less infusion-related toxicity, and less nephrotoxicity. To evaluate the usefulness of a 20% lipid emulsion as a delivery system for amphotericin B (1 mg/mL) administered over 1 hour to patients with neutropenia with hematologic malignancies compared with amphotericin B (0.1 mg/mL) administered in dextrose 5% solution over the same time.
                A prospective, comparative, randomized, labeled study.
                Hematology unit, pharmacy service, university general hospital.
                Twenty patients with neutropenia with hematologic malignancies and proven or suspected fungal infections, 10 in the fat emulsion group (group 1) and 10 in the dextrose 5% group (group 2).
                Clinical tolerance (i.e., fever, shaking chills, nausea, blood pressure, pulse rate) and biologic tolerance (i.e., urea, creatinine, sodium, potassium).
                Clinical tolerance was comparable in both groups although amphotericin B in fat emulsion was better tolerated. Medication for symptoms related to the administration of amphotericin B was given in 6 cases in group 1 and in 8 cases in group 2. There was a statistically significant difference in the urea concentrations between the 2 groups (p = 0.023); there was an observed increase between the initial and the final serum urea (56.8 mg/d in group 1, 79.8 mg/dL in group 2). Statistically significant differences in creatinine serum concentrations (84.9 mumol/L in group 1, 123.8 mumol/L in group 2) (p = 0.047) were found. No differences were found in the antifungal efficacy of the treatment. However, as amphotericin B was started in the majority of cases (75%) as empiric treatment for fever unresponsive to antibiotic therapy, it is difficult to compare the efficacy of both preparations.
                The clinical tolerance of lipid-emulsion infusions is similar to that of conventionally administered amphotericin B therapy. Renal toxicity appears to be decreased when the drug is administered in a fat emulsion. This type of preparation permits the reduction of the volume and the time of administration for amphotericin B therapy. Conventional amphotericin B (c-AmB) remains the empirical antifungal treatment of choice for neutropenic patients with persistent fever of unknown origin (FUO). Unfortunately, empirical treatment with c-AmB is hampered by its safety profile, with frequent infusion-related adverse events (IRAEs) and renal toxicity. Amphotericin B lipid complex (ABLC) has been investigated for this indication due to its low toxicity profile. The recommended dose of ABLC is 5 mg/kg/d, which is five to seven times higher than the recommended dose of c-AmB.
                This randomized, controlled trial includes 105 adult patients with hematologic malignancies and with FUO after receiving chemotherapy or autologous stem cell transplantation. Patients were randomly allocated to receive ABLC at 1 mg/kg/d or c-AmB at 0.6 mg/kg/d for empirical antifungal therapy.
                The incidence of renal toxicity was significantly lower in the ABLC group, compared with c-AmB group: 8% vs. 32%, respectively (P = 0.003). The rates of IRAEs were similar in both groups (73% for ABLC vs. 77% for c-AmB). The overall response rate was 72% for ABLC compared with 48% for c-AmB (P = 0.018). This difference was mainly due to the significantly higher renal toxicity in the c-AmB group. The number of emergent fungal infections and overall mortality were similar in both groups.
                This randomized trial suggests that ABLC at 1 mg/kg/d produces less nephrotoxicity than c-AmB, without differences in the incidence of IRAEs and with similar efficacy.
                Copyright Blackwell Munksgaard 2004. To describe the experience with a new lipid-based amphotericin product (amphotericin B colloidal dispersion or ABCD) in children with fever and neutropenia who are at high risk for fungal infection.
                Forty-nine children with febrile neutropenia were treated in a prospective, randomized trial comparing ABCD with amphotericin B. An additional 70 children with presumed or proven fungal infection were treated with 5 different open-label studies of ABCD. Patients were registered into these studies for reasons of: 1) failure to respond to amphotericin B; 2) development of nephrotoxicity or preexisting renal impairment; or 3) willingness to participate in a dose-escalation study. Extensive data detailing response and toxicity were collected from each patient.
                In the randomized trial, there was significantly less renal toxicity in the children receiving ABCD than in those receiving amphotericin B (12.0% vs. 52.4% [P = 0.003]). Other adverse symptoms were not significantly different. In the additional open-label studies, although 80% of patients receiving ABCD reported some adverse symptom, the majority of these were infusion related, and nephrotoxicity was reported in only 12% of these patients.
                ABCD was well-tolerated at doses up to 5 times greater then those usually tolerated with amphotericin B. Renal toxicity was markedly less than expected, and there were no other unexpected severe toxicities. Further randomized studies are needed to further define the role of this and other liposomal products in children. In a randomized, double-blind, comparative, multicenter trial, liposomal amphotericin B was equivalent to conventional amphotericin B for empirical antifungal therapy in febrile neutropenic patients, using a composite end point, but was more effective in reducing proven emergent fungal infections, infusion-related toxicities, and nephrotoxicity. The purpose of this study was to compare the pharmacoeconomics of liposomal versus conventional therapy.
                Itemized hospital billing data were collected on 414 patients from 19 of the 32 centers that participated in the trial. Hospital length of stay and costs from the first dose of study medication to the time of hospital discharge were assessed.
                Hospital costs from the time of first dose to discharge were significantly higher for all patients who received liposomal amphotericin B ($48,962 v $43,183; P =.022). However, hospital costs were highly sensitive to the cost of study medication ($39,648 v $43,048 when drug costs were not included; P =.416). Using decision analysis models and sensitivity analyses to vary the cost of study medications and the risk of nephrotoxicity, the break-even points for the cost of liposomal therapy were calculated to range from $72 to $87 per 50 mg for all patients and $83 to $112 per 50 mg in allogeneic bone marrow transplant patients.
                The cost of liposomal amphotericin B and patient risk for developing nephrotoxicity play large roles in determining whether liposomal amphotericin B is cost-effective as first-line empirical therapy in persistently febrile neutropenic patients. In a prospective, randomized clinical trial, the toxicity of 1 mg of amphotericin B (AmB) per kg of body weight per day infused in 5% dextrose was compared with that of AmB infused in lipid emulsion in children with malignant disease. In an analysis of 82 children who received a full course of 6 days or more of AmB (117 courses), it was shown that there were significant increases in plasma urea and creatinine concentrations and in potassium requirement after 6 days of therapy with both AmB infused in dextrose and AmB infused in lipid emulsion, with there being no difference between the two methods of AmB administration. An intent-to-treat comparison of the numbers of courses affected by acute toxicity (fever, rigors) and chronic toxicity (nephrotoxicity) also indicated that there was no significant difference between AmB infused in dextrose (78 courses) and AmB infused in lipid emulsion (84 courses). The pharmacokinetics of AmB were investigated in 20 children who received AmB in dextrose and 15 children who received AmB in lipid emulsion. Blood samples were collected up to 24 h after administration of the first dose, and the concentration of AmB in plasma was analyzed by a high-performance liquid chromatography assay. The clearance (CL) of AmB in dextrose (0.039 +/- 0.016 liter. h-1. kg-1) was significantly lower (P < 0.005) than the CL of AmB in lipid emulsion (0.062 +/- 0. 024 liter. h-1. kg-1). The steady-state volume of distribution for AmB in dextrose (0.83 +/- 0.33 liter. kg-1) was also significantly lower (P < 0.005) than that for AmB in lipid emulsion (1.47 +/- 0.77 liter. kg-1). Although AmB in lipid emulsion is apparently cleared faster and distributes more widely than AmB in dextrose, this study did not reveal any significant advantage with respect to safety and tolerance in the administration of AmB in lipid emulsion compared to its administration in dextrose in children with malignant disease. To compare the tolerance, efficacy, and pharmacokinetics of amphotericin deoxycholate (Fungizone) prepared in a parenteral fat emulsion (Intralipid 20%) or glucose in HIV patients with candidiasis.
                Non-blind randomised controlled trial.
                University hospital; tertiary clinical care.
                22 HIV positive patients with oral candidiasis.
                Amphotericin 1 mg/kg/day given on four consecutive days as a one hour infusion dissolved in either 5% glucose (amphotericin-glucose) or parenteral fat emulsion at a final concentration of 2 g/l fat emulsion (amphotericin-fat emulsion).
                Clinical tolerance (fever, chills, sweats, nausea, arterial pressure, and pulse rate); biological tolerance (serum creatinine, electrolyte, and magnesium values); clinical score of candidiasis; and serum concentrations of amphotericin.
                11 patients were enrolled in each group. All the amphotericin-fat emulsion infusions were given without serious problem whereas four amphotericin-glucose infusions were stopped because of renal impairment (n = 3) or severe chills (n = 2), or both. For patients completing the amphotericin-glucose treatment creatine concentration increased by 42 mumol/l; four of seven patients had at least one creatinine value > or = 133 mumol/l versus one of 11 receiving amphotericin-fat emulsion. Magnesium concentration fell significantly with amphotericin-glucose but not with amphotericin-fat emulsion. Clinical side effects were noted in 36/38 infusions with amphotericin-glucose but 10/44 with amphotericin-fat emulsion. Oral candidiasis score was reduced similarly in both groups. Serum amphotericin concentrations were significantly lower and the volume of distribution of the drug higher after infusion of amphotericin-fat emulsion than after amphotericin-glucose.
                Clinical and renal toxicity of amphotericin are reduced when the drug is prepared in fat emulsion. Preparation is simple and cost effective. Its efficacy is similar to that of conventional amphotericin. 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 38 degrees C or more, not responding to 96 h of systemic broad-spectrum antibiotic treatment, and neutropenia (< 0.5 x 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 (< 38 degrees C) 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 < or = 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 (< 38 degrees C) continuing to study end indicated by recovery of neutrophils to 0.5 x 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 = 0.03) but a Kaplan-Meier analysis of time to differvescence 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. We conducted a prospective, randomized, double-blind study comparing amphotericin B colloidal dispersion (ABCD) with amphotericin B in the empirical treatment of fever and neutropenia. Patients with neutropenia and unresolved fever after > or = 3 days of empirical antibiotic therapy were stratified by age and concomitant use of cyclosporine or tacrolimus. Patients were then randomized to receive therapy with ABCD (4 mg/[kg.d]) or amphotericin B (0.8 mg/[kg.d]) for < or = 14 days. A total of 213 patients were enrolled, of whom 196 were evaluable for efficacy. Fifty percent of ABCD-treated patients and 43.2% of amphotericin B-treated patients had a therapeutic response (P = .31). Renal dysfunction was less likely to develop and occurred later in ABCD recipients than in amphotericin B recipients (P < .001 for both parameters). Infusion-related hypoxia and chills were more common in ABCD recipients than in amphotericin B recipients (P = .013 and P = .018, respectively). ABCD appeared comparable in efficacy with amphotericin B, and renal dysfunction associated with ABCD was significantly less than that associated with amphotericin B. However, infusion-related events were more common with ABCD treatment than with amphotericin B treatment.
It is not clear whether there are any advantages of lipid-based formulations if conventional amphotericin B is administered under optimal circumstances and their high cost prohibits routine use in most settings. There is a need for large trials comparing lipid-based formulations of amphotericin B with conventional amphotericin B given in the same dose, with routine premedication for prevention of infusion-related toxicity, and with supplementation with fluid, potassium and magnesium for prevention of nephrotoxicity.