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ARTICLE

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

Drew J. Winston, MD; Richard T. Maziarz, MD; Pranatharthi H. Chandrasekar, MD; Hillard M. Lazarus, MD; Mitchell Goldman, MD; Jeffrey L. Blumer, PhD, MD; Gerhard J. Leitz, MD, PhD; and Mary C. Territo, MD

6 May 2003 | Volume 138 Issue 9 | Pages 705-713

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.

Design: Open-label, multicenter, randomized trial.

Setting: Five transplantation centers in the United States.

Patients: 140 patients undergoing allogeneic hematopoietic stem-cell transplantation.

Intervention: 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.

Measurements: 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).

Conclusion: 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.

Editors' Notes Context Fungal infections after allogeneic hematopoietic stem-cell transplantation are a serious problem. Current prophylactic regimens are limited by toxicity and the emergence of resistant infections. Contribution This open-label randomized trial of 140 patients undergoing stem-cell transplantation found that prophylaxis with itraconazole for 100 days after transplantation prevented more invasive fungal infections than did prophylaxis with fluconazole (absolute difference, –16 percentage points [95% CI, –29 to –5 percentage points]). More fungal pathogens were resistant to fluconazole. Nausea, vomiting, diarrhea, and abdominal pain were more common in patients receiving itraconazole. Implications Itraconazole is better than fluconazole for preventing invasive fungal infections in allogeneic stem-cell transplant recipients but causes more gastrointestinal side effects. –The Editors

 

Author and Article Information

From UCLA Medical Center, Los Angeles, California; Oregon Health and Sciences University, Portland, Oregon; Harper University Hospital, Wayne State University, Detroit, Michigan; Ireland Cancer Center, University Hospitals of Cleveland, Cleveland, Ohio; Indiana University Hospital, Indianapolis, Indiana; and Ortho Biotech, Raritan, New Jersey.

Acknowledgments: The authors thank Ann Gogesch, RN, UCLA Medical Center, Los Angeles, California, and Mary Steigelman, RN, Harper University Hospital, Detroit, Michigan, for their valuable assistance during the study. They also thank Dr. Ronghua Yang, Larry Broach, and Katie Harding for performing data and statistical analyses and Katharine Fry for preparing the manuscript.

Grant Support: By Janssen Research Foundation, Titusville, New Jersey.

Potential Financial Conflicts of Interest:Employment: G.J. Leitz (Ortho Biotech); Consultancies: J.L. Blumer (Pfizer); Honoraria: D.J. Winston (Ortho Biotech and Pfizer), P.H. Chandrasekar (Pfizer), J.L. Blumer (Pfizer); Grants received: D.J. Winston (Janssen Research Foundation, Ortho Biotech, and Pfizer), P.H. Chandrasekar (Pfizer), M. Goldman (Janssen Research Foundation).

Requests for Single Reprints: Drew J. Winston, MD, Department of Medicine, UCLA Medical Center, Room 42-121 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095; e-mail, dwinston{at}mednet.ucla.edu.

Current Author Addresses: Dr. Winston: Department of Medicine, UCLA Medical Center, Room 42-121 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095.

Dr. Maziarz: Oregon Health and Sciences University, 3181 Southwest Sam Jackson Park Road, Portland, OR 97232.

Dr. Chandrasekar: Harper University Hospital, 4 Brush Center, 3990 John R, Detroit, MI 48201.

Dr. Lazarus: Ireland Cancer Center, University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106.

Dr. Goldman: Wishard Memorial Hospital, 430 OPW, 1001 West Tenth Street, Indianapolis, IN 46202.

Dr. Blumer: Rainbow Babies and Children's Hospital, 11100 Euclid Avenue, Cleveland, OH 44106.

Dr. Leitz: Ortho Biotech, 430 Route 22 East, Bridgewater, NJ 08807.

Dr. Territo: Department of Medicine, UCLA Medical Center, Room 42-121 CHS, 10833 Le Conte Avenue, Los Angeles, CA 90095.

Author Contributions: Conception and design: D.J. Winston.

Analysis and interpretation of the data: D.J. Winston, G.J. Leitz.

Drafting of the article: D.J. Winston.

Critical revision of the article for important intellectual content: D.J. Winston, R.T. Maziarz, P.H. Chandrasekar, H.M. Lazarus, M. Goldman, J.L. Blumer.

Final approval of the article: D.J. Winston, R.T. Maziarz, P.H. Chandrasekar, M.C. Territo.

Provision of study materials or patients: R.T. Maziarz, P.H. Chandrasekar, H.M. Lazarus, M. Goldman, J.L. Blumer, M.C. Territo.

Obtaining of funding: D.J. Winston.

Administrative, technical, or logistic support: G.J. Leitz.

Collection and assembly of the data: D.J. Winston.

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