Intravenous and oral itraconazole versus intravenous and oral fluconazole for long-term antifungal prophylaxis in allogeneic hematopoietic stem-cell transplant recipients. A multicenter, randomized trial.
BACKGROUND
Allogeneic hematopoietic stem-cell transplant recipients often receive fluconazole or an amphotericin B preparation for antifungal prophylaxis. Because of concerns about fungal resistance with fluconazole and toxicity with amphotericin B, alternative prophylactic regimens have become necessary.


OBJECTIVE
To compare the efficacy and safety of intravenous and oral itraconazole with the efficacy and safety of intravenous and oral fluconazole for long-term prophylaxis of fungal infections.


METHODS
Open-label, multicenter, randomized trial.


METHODS
Five transplantation centers in the United States.


METHODS
140 patients undergoing allogeneic hematopoietic stem-cell transplantation.


METHODS
Itraconazole (200 mg intravenously every 12 hours for 2 days followed by 200 mg intravenously every 24 hours or a 200-mg oral solution every 12 hours) or fluconazole (400 mg intravenously or orally every 24 hours) from day 1 until day 100 after transplantation.


METHODS
Proven invasive or superficial fungal infection, drug-related side effects, mortality from fungal infection, and overall mortality.


RESULTS
Proven invasive fungal infections occurred in 6 of 71 itraconazole recipients (9%) and in 17 of 67 fluconazole recipients (25%) during the first 180 days after transplantation (difference, -16 percentage points [95% CI, -29.2 to -4.7 percentage points]; P = 0.01). Superficial fungal infections occurred in 3 of 71 itraconazole recipients (4%) and in 2 of 67 fluconazole recipients (3%). In a multivariable analysis using factors known to affect the risk for invasive fungal infection after hematopoietic stem-cell transplantation, prophylaxis with itraconazole was still associated with fewer invasive fungal infections (odds ratio, 0.300 [CI, 0.111 to 0.814]; P = 0.02) caused by either yeasts or molds. More fungal pathogens were found to be resistant to fluconazole than to itraconazole. Except for more frequent gastrointestinal side effects (nausea, vomiting, diarrhea, or abdominal pain) in patients given itraconazole (24% vs. 9%; difference, 15 percentage points [CI, 2.9 to 27.0 percentage points]; P = 0.02), both itraconazole and fluconazole were well tolerated. The overall mortality rate was similar in each group (32 of 71 patients in the itraconazole group [45%] vs. 28 of 67 patients in the fluconazole group [42%]; difference, 3 percentage points [CI, -13.2 to 19.8 percentage points]; P > 0.2), but fewer deaths were related to fungal infection in patients given itraconazole (6 of 71 [9%]) than in patients given fluconazole (12 of 67 [18%]) (difference, 9 percentage points [CI, -20.6 to 1.8 percentage points]; P = 0.13).


CONCLUSIONS
Itraconazole is more effective than fluconazole for long-term prophylaxis of invasive fungal infections after allogeneic hematopoietic stem-cell transplantation. Except for gastrointestinal side effects, itraconazole is well tolerated.
Winston
Drew J
DJ
Department of Medicine, UCLA Medical Center, Room 42-121 CHS, 10833 Le Conte Avenue, Los Angeles, California 90095, USA. dwinston@mednet.ucla.edu
Maziarz
Richard T
RT
Chandrasekar
Pranatharthi H
PH
Lazarus
Hillard M
HM
Goldman
Mitchell
M
Blumer
Jeffrey L
JL
Leitz
Gerhard J
GJ
Territo
Mary C
MC
D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000935:Antifungal Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D005260:Female; D015725:Fluconazole / Q000008:administration & dosage* / Q000009:adverse effects; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007275:Injections, Intravenous; D017964:Itraconazole / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood; D008297:Male; D008875:Middle Aged; D009181:Mycoses / Q000517:prevention & control*; D009894:Opportunistic Infections / Q000517:prevention & control; D016019:Survival Analysis
D000935:Antifungal Agents; D017964:Itraconazole; D015725:Fluconazole