Liposomal amphotericin B for empirical therapy in patients with persistent fever and neutropenia. National Institute of Allergy and Infectious Diseases Mycoses Study Group. Micafungin versus liposomal amphotericin B for pediatric patients with invasive candidiasis: substudy of a randomized double-blind trial. A randomized comparison of liposomal versus conventional amphotericin B for the treatment of pyrexia of unknown origin in neutropenic patients. Use of amphotericin B colloidal dispersion in children. Randomized comparison between fluconazole and itraconazole for the treatment of candidemia in a pediatric intensive care unit: a preliminary study. Randomized, double-blind clinical trial of amphotericin B colloidal dispersion vs. amphotericin B in the empirical treatment of fever and neutropenia.
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. Invasive candidiasis is increasingly prevalent in premature infants and seriously ill children, and pediatric data on available antifungal therapies are lacking.
                We conducted a pediatric substudy as part of a double-blind, randomized, multinational trial to compare micafungin (2 mg/kg) with liposomal amphotericin B (3 mg/kg) as first-line treatment of invasive candidiasis. Treatment success was defined as clinical and mycologic response at the end of therapy. Statistical analyses were descriptive, as the sample size meant that the study was not powered for hypothesis testing.
                One hundred six patients were included in the intent-to-treat population; and 98 patients-48 patients in the micafungin group and 50 patients in the liposomal amphotericin B group-in the modified intent-to-treat population. Baseline characteristics were balanced between treatment groups. Overall, 57 patients were <2 years old including 19 patients who were premature at birth; and 41 patients were 2 to <16 years old. Most patients (91/98, 92.9%) had candidemia, and 7/98 (7.1%) patients had other forms of invasive candidiasis. Treatment success was observed for 35/48 (72.9%) patients treated with micafungin and 38/50 (76.0%) patients treated with liposomal amphotericin B. The difference in proportions adjusted for neutropenic status was -2.4% [95% CI: (-20.1 to 15.3)]. Efficacy findings were consistent, independent of the neutropenic status, the age of the patient, and whether the patient was premature at birth. Both treatments were well tolerated, but with a lower incidence of adverse events that led to discontinuation in the micafungin group (2/52, 3.8%) compared with the liposomal amphotericin B group (9/54, 16.7%) (P = 0.05, Fisher exact test).
                Micafungin seems to be similarly effective and as safe as liposomal amphotericin B for the treatment of invasive candidiasis in pediatric patients. (ClinicalTrials.gov number, NCT00106288). 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. 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. Candida bloodstream infections have shown an increase in hospitalized patients, especially those receiving intensive care. The effectiveness of various azoles, especially itraconazole, in treatment of candidemia has not been fully evaluated. Our objective was to compare the efficacy and safety of enterally administered itraconazole vs. fluconazole in treatment of candidemia.
                Randomized, double-blind, controlled trial.
                Pediatric intensive care unit of a referral and teaching hospital.
                Forty-three pediatric patients with candidemia,
                Patients received either fluconazole (n = 22) or itraconazole (n = 21), about 10 mg/kg orally or through a gastric tube, and were monitored for clinical and mycological cure (sterile fungal blood culture), blood counts, and liver and renal functions.
                The clinical characteristics of two groups were comparable. The cure rate was similar in both the groups: itraconazole 17 of 21 (81%) and fluconazole 18 of 22 (82%). Crude mortality rate (itraconazole 9.5% and fluconazole 13.6%) was also comparable in two groups of patients. The frequency of electrolyte disturbance was very low and similar in both the groups. Blood urea, creatinine, liver enzymes, and serum bilirubin were not adversely affected.
                Itraconazole was as effective as fluconazole in nosocomial candidiasis in children receiving intensive care and was devoid of serious side effects. 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.
Limited paediatric data are available comparing antifungal agents in children with proven, probable or suspected invasive fungal infection. No differences in mortality or treatment efficacy were observed when antifungal agents were compared. Children are less likely to develop nephrotoxicity with a lipid preparation of amphotericin B compared with conventional amphotericin B. Further comparative paediatric antifungal drug trials and epidemiological and pharmacological studies are required highlighting the differences between neonates, children and adults with invasive fungal infections.