Liposomal amphotericin B: a review of its use as empirical therapy in febrile neutropenia and in the treatment of invasive fungal infections.

Liposomal amphotericin B (AmBisome) is a lipid-associated formulation of the broad-spectrum polyene antifungal agent amphotericin B. It is active against clinically relevant yeasts and moulds, including Candida spp., Aspergillus spp. and filamentous moulds such as Zygomycetes, and is approved for the treatment of invasive fungal infections in many countries worldwide. It was developed to improve the tolerability profile of amphotericin B deoxycholate, which was for many decades considered the gold standard of antifungal treatment, despite being associated with infusion-related events and nephrotoxicity. In well controlled trials, liposomal amphotericin B had similar efficacy to amphotericin B deoxycholate and amphotericin B lipid complex as empirical therapy in adult and paediatric patients with febrile neutropenia. In addition, caspofungin was noninferior to liposomal amphotericin B as empirical therapy in adult patients with febrile neutropenia. For the treatment of confirmed invasive fungal infections, liposomal amphotericin B was more effective than amphotericin B deoxycholate treatment in patients with disseminated histoplasmosis and AIDS, and was noninferior to amphotericin B deoxycholate in patients with acute cryptococcal meningitis and AIDS. In adults, micafungin was shown to be noninferior to liposomal amphotericin B for the treatment of candidaemia and invasive candidiasis. Data from animal studies suggested that higher dosages of liposomal amphotericin B might improve efficacy; however, in the AmBiLoad trial in patients with invasive mould infection, there was no statistical difference in efficacy between the standard dosage of liposomal amphotericin B 3 mg/kg/day and a higher 10 mg/kg/day dosage, although the standard dosage was better tolerated. Despite being associated with fewer infusion-related adverse events and less nephrotoxicity than amphotericin B deoxycholate and amphotericin B lipid complex, liposomal amphotericin B use is still limited to some extent by these adverse events. Both echinocandins were better tolerated than liposomal amphotericin B. The cost of liposomal amphotericin B therapy may also restrict its use, but further pharmacoeconomic studies are required to fully define its cost effectiveness compared with other antifungal agents. Based on comparative data from well controlled trials, extensive clinical experience and its broad spectrum of activity, liposomal amphotericin B remains a first-line option for empirical therapy in patients with febrile neutropenia and in those with disseminated histoplasmosis, and is an option for the treatment of AIDS-associated cryptococcal meningitis, and for invasive Candida spp. or Aspergillus spp. infections. Amphotericin B, a macrocyclic, polyene antifungal agent, is thought to act by binding to ergosterol, the principal sterol in fungal cell membranes and Leishmania cells. This results in a change in membrane permeability, causing metabolic disturbance, leakage of small molecules and, as a consequence, cell death. In vitro and in vivo studies have shown that liposomal amphotericin B remains closely associated with the liposomes in the circulation, thereby reducing the potential for nephrotoxicity and infusion-related toxicity associated with conventional amphotericin B. Amphotericin B shows very good in vitro activity against a broad spectrum of clinically relevant fungal isolates, including most strains of Candida spp. and Aspergillus spp., and other filamentous fungi such as Zygomycetes. Liposomal amphotericin B has proven effective in various animal models of fungal infections, including those for candidiasis, aspergillosis, fusariosis and zygomycosis. Liposomal amphotericin B also shows immunomodulatory effects, although the mechanisms involved are not fully understood, and differ from those of amphotericin B deoxycholate and amphotericin B colloidal dispersion. In adult patients with febrile neutropenia, intravenous liposomal amphotericin B has nonlinear pharmacokinetics, with higher than dose-proportional increases in exposure being consistent with reticuloendothelial saturation and redistribution of amphotericin B in the plasma compartment. Liposomal amphotericin B is rapidly and extensively distributed after single and multiple doses, with steady-state concentrations of amphotericin B attained within 4 days and no clinically relevant accumulation of the drug following multiple doses of 1-7.5 mg/kg/day. In autopsy tissue, the highest concentrations of the drug were found in the liver and spleen, followed by the kidney, lung, myocardium and brain tissue. Elimination of liposomal amphotericin B, like that of amphotericin B deoxycholate, is poorly understood; its route of metabolism is not known and its excretion has not been studied. The terminal elimination half-life is about 7 hours. No dosage adjustment is required based on age or renal impairment. In several randomized, double-blind trials (n = 73-1095) in adult and/or paediatric patients, liposomal amphotericin B was effective as empirical therapy or as treatment for confirmed invasive fungal infections, including invasive candidiasis, candidaemia, invasive mould infection (mainly aspergillosis), histoplasmosis and cryptococcal meningitis. All agents were administered as an intravenous infusion; the typical dosage for liposomal amphotericin B was 3 mg/kg/day. Treatment was generally given for 1-2 weeks. Participants in trials evaluating empirical therapy had neutropenia and a persistent fever despite antibacterial treatment and had received chemotherapy or undergone haematopoietic stem cell transplantation. As empirical therapy in adult and paediatric patients, liposomal amphotericin B appeared to be as effective as amphotericin B deoxycholate (approximately 50% of patients in each group achieved treatment success) or amphotericin B lipid complex (approximately 40% of liposomal amphotericin B recipients experienced treatment success). Of note, in the first trial, results of the statistical test to determine equivalence between treatments were not reported. In the second trial, efficacy was assessed as an 'other' endpoint. In another trial, caspofungin was shown to be noninferior to liposomal amphotericin B, with approximately one-third of patients in each group experiencing treatment success. Liposomal amphotericin B was significantly more effective than amphotericin B deoxycholate for the treatment of moderate to severe disseminated histoplasmosis in patients with AIDS, with 88% and 64% of patients, respectively, having a successful response. Liposomal amphotericin B was noninferior to amphotericin B deoxycholate for the treatment of cryptococcal meningitis in terms of mycological success. Micafungin therapy was shown to be noninferior to liposomal amphotericin B for the treatment of adult patients with candidaemia or invasive candidiasis. In a substudy in paediatric patients, which was not powered to determine noninferiority, liposomal amphotericin B was as effective as micafungin for the treatment of candidaemia or invasive candidiasis. In this patient population, within each trial, 90% of adult patients and approximately three-quarters of paediatric patients in both treatment groups experienced a successful response. In patients with invasive mould infection (mainly aspergillosis), there was no difference in efficacy between a higher dosage of liposomal amphotericin B (10 mg/kg/day) and the standard dosage (3 mg/kg/day), with 46% and 50% of patients experiencing a favourable overall response. In well designed clinical trials, liposomal amphotericin B was generally at least as well tolerated as other lipid-associated formulations of amphotericin B and better tolerated than amphotericin B deoxycholate in adult and paediatric patients. Compared with other amphotericin B formulations, liposomal amphotericin B treatment was associated with a lower incidence of infusion-related adverse events and nephrotoxicity. A higher than recommended dosage of liposomal amphotericin B (10 mg/kg/day) was associated with an increased incidence of nephrotoxicity compared with the standard dosage (3 mg/kg/day), although the incidence of infusion-related reactions did not differ between treatment groups. In general, liposomal amphotericin B treatment was not as well tolerated as echinocandin therapy in well designed clinical trials. As empirical therapy or for the treatment of confirmed invasive fungal infections in adult patients, liposomal amphotericin B recipients experienced more infusion-related events and nephrotoxicity than caspofungin or micafungin recipients. There was no difference in the incidence of these adverse events between the liposomal amphotericin B and micafungin groups in a study in paediatric patients.