Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group

Systemic fungal infections are a major problem in bone marrow transplant re cipients who have prolonged neutropenia or who receive high-dose corticoste roids. Prophylaxis with Fluconazole or low-dose amphotericin B reduces, but does not eliminate these infections. To determine which prophylactic agent is better, we performed a prospective randomized study. Patients undergoin g allogeneic (related or unrelated) or autologous marrow or peripheral stem cell transplantation were randomized to receive Fluconazole (400 mg/day p. o, or i.v.) or amphotericin B (0.2 mg/kg/day i.v.) beginning 1 day prior to stem cell transplantation and continuing until recovery of neutrophils to >500/alpha l. Patients were removed from their study drug for drug-associat ed toxicity, invasive fungal infection or suspected fungal infection (defin ed as the presence of fever >38 degrees C without positive culture while on broad-spectrum anti-bacterial antibiotics). Proven or suspected fungal inf ections were treated with high-dose amphotericin B (0.5-0.7 mg/kg/day), Pat ients were randomized at each institution and stratified for the type of tr ansplant. The primary end-point of the study was prevention of documented f ungal infection; secondary endpoints included fungal colonization, drug tox icity, duration of hospitalization, duration of fever, duration of neutrope nia, duration and total dose of high-dose amphotericin B and overall surviv al to hospital discharge. From July 1992 to October 1994, a total of 355 pa tients entered into the trial with 159 patients randomized to amphotericin B and 196 to Fluconazole. Patient groups were comparable for diagnosis, age , sex, prior antibiotic or antifungal therapy, use of corticosteroids prior to transplantation and total duration of neutropenia. Amphotericin B was s ignificantly more toxic than Fluconazole especially in related allogeneic t ransplantation where 19% of patients developed toxicity vs 0% of Fluconazol e recipients (p ( 0.05), Approximately 44% of all patients were removed fro m prophylaxis for presumed fungal infection. Proven fungal infections occur red in 4.1% and 7.5% of Fluconazole and amphotericin-treated patients, resp ectively. Proven fungal infections occurred in 9.1% and 14.3% of related al logeneic marrow recipients receiving Fluconazole or amphotericin B, respect ively, and 2.1% and 5.6% of autologous marrow recipients receiving Fluconaz ole or amphotericin B, respectively (P > 0.05), In this prospective trial, low-dose amphotericin B prophylaxis was as effective as Fluconazole prophyl axis, but Fluconazole was significantly better tolerated.