Liposomal amphotericin (AmBisome) in the prophylaxis of fungal infections in neutropenic patients: a randomised, double-blind, placebo-controlled study

Abstract

Summary:Liposomal amphotericin (AmBisome) 2 mg/kg three times weekly was compared with placebo as prophylaxis against fungal infection in patients undergoing chemotherapy or bone marrow transplantation (BMT) for haematological malignancies. Prophylaxis began on day 1 of chemotherapy and continued until neutrophils regenerated or infection was suspected. Of 161 evaluable patients, 74 received AmBisome and 87 received placebo. Proven fungal infections developed in no patients on AmBisome and in three on placebo (3.4%) (P ‫؍‬ NS). Suspected fungal infections requiring intervention with systemic antifungal therapy (usually amphotericin B) occurred in 31 patients on AmBisome (42%) and in 40 on placebo (46%) (P ‫؍‬ NS). Suspected deep-seated infections developed in 21 (28.3%) and 31 (35.6%) patients, respectively (P ‫؍‬ NS). Time to develop a suspected or proven deep-seated infection showed a trend in favour of AmBisome (P ‫؍‬ 0.11). Fifty patients had fungal colonisation (48 with Candida spp, two with Aspergillus spp) of at least one body site during prophylaxis; 15 patients while receiving AmBisome (20%) and 35 while on placebo (40%) (P Ͻ 0.01). Time to colonisation was significantly delayed in the group receiving AmBisome (P Ͻ 0.05). Treatment-related toxicity was modest and no additional toxicity was observed in patients receiving AmBisome. AmBisome 2 mg/kg three times weekly is safe and reduces fungal colonisation in patients receiving intensive chemotherapy or BMT. However, despite encouraging trends, prophylactic AmBisome did not lead to a significant reduction in fungal infection or in requirement for systemic antifungal therapy. Keywords: AmBisome; prophylaxis; neutropenia More than half the fatal infections in neutropenic patients are due to fungi 1 with candida and aspergillus the most commonly-observed pathogens. fungal infection increases with the severity and duration of neutropenia which, in the case of bone marrow transplantation (BMT) or chemotherapy for the treatment of haematological malignancies, can range from a few days to several weeks. The severe immunosuppression induced by high-dose corticosteroids given to recipients of allogeneic BMT to suppress graft-versus-host disease (GVHD) puts them at additional risk of fungal infections 2-4 whereas for patients receiving autologous stem cell support and treatment with growth factors the risk is much lower.5 This provides a rationale for the prophylactic use of antifungal agents.Orally administered agents such as the imidazoles, or non-absorbable amphotericin B, achieve only local decontamination and have little or no impact on invasive fungal infections. 6 A recent meta-analysis 7 has been conducted of 24 trials in which antifungals were used, either as prophylaxis or as empirical therapy, in patients with cancer complicated by neutropenia. This meta-analysis showed that amphotericin B decreased mortality significantly although the studies were small, as was the difference in the number of deaths. Antifungals as a group decreased the incidence of inv...

Primary prophylaxis of invasive fungal infections in patients with hematologic malignancies. Recommendations of the Infectious Diseases Working Party of the German Society for Haematology and Oncology

“…[78][79][80] A second placebo-controlled but underpowered trial also failed to disclose an advantage of liposomal amphotericin B 2 mg/kg/tiw. 81 Recently a randomized clinical trial (n= 132) compared liposomal amphotericin B 50 mg q48h with no prophylaxis in a population with hematologic malignancies. In this reasonably sized and dosed study on the prophylactic properties of the drug the investigators observed a significant reduction in the rates for proven and probable invasive fungal infections as well as IFI-attributable mortality rates.…”

“…82 The results contrast those of a previous placebo controlled trial evaluating a similar approach. 81 A pilot trial evaluated a novel loading dose concept of liposomal amphotericin B 10 mg/kg qw; while the regimen was feasible in acute leukemia, it was associated with adverse events leading to treatment discontinuation in 6 of 8 stem cell recipients. 83 Intravenous Amphotericin B Lipid Complex and Amphotericin B Colloidal Dispersion prophylaxis may be conceivable as well.…”

Amphotericin B lipid complex as prophylaxis of invasive fungal infections in patients with acute myelogenous leukemia and myelodysplastic syndrome undergoing induction chemotherapy

“…6,8 -10,12,15-17 Although amphotericin B prophylaxis has not been evaluated critically evaluated in patients with hematologic malignancies, its efficacy as a prophylactic antifungal agent has been well documented in patients undergoing HSCT-another patient population at high risk for developing fungal infections. 2,18,[25][26][27] The results of 4 randomized, double-blind, placebocontrolled clinical trials comparing low-dose amphotericin B (0.1 mg/kg per day) with L-AmB (1 mg/kg per day or 2 mg/kg 3 times weekly) as antifungal prophylaxis in patients undergoing HSCT showed that both drugs are effective in preventing documented or suspected fungal infections (low-dose amphotericin B, 21-53%; L-AmB, 36 -83%) 18,[25][26][27] ; these infection rates are comparable to the infection rates observed in our study. The rates of documented fungal infections in our historical control study are slightly higher than the rates observed in prospective, controlled clinical trials evaluating low-dose amphotericin B and L-AmB in patients undergoing HSCT (0 -2% vs. 0 -3%, respectively).…”

Antimicrobial prophylaxis in hematopoietic stem cell transplant recipients: heterogeneity of current clinical practice

“…The studies supporting these practices do not always reach a definitive conclusion in terms of modification of existing clinical practice. [1][2][3][4][5][6][7][8][9][10][11][12][13] Therefore, guidelines have been formulated for the prevention of infections following HSCT, 14,15 and have been endorsed by the Centers for Disease Control and Prevention, Infectious Diseases Society of America, and American Society for Blood and Marrow Transplantation. These evidence-based reviews have made weighted recommendations for the use of antimicrobial agents as prophylaxis for bacterial, viral, and fungal pathogens.…”