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Fluconazole Prophylaxis of Fungal Infections in Patients with Acute Leukemia: Results of a Randomized Placebo-Controlled, Double-Blind, Multicenter Trial

Drew J. Winston, MD; Pranatharthi H. Chandrasekar, MD; Hillard M. Lazarus, MD; Jesse L. Goodman, MD; Jeffrey L. Silber, MD; Harold Horowitz, MD; Richard K. Shadduck, MD; Craig S. Rosenfeld, MD; Winston G. Ho, MD; Muhammed Z. Islam, PhD; and Donald N. Buell, MD
[+] Article and Author Information

For a list of investigators and institutions and Requests for Reprints: Drew J. Winston, MD, Room 42-121 CHS, Department of Medicine, UCLA Medical Center, Los Angeles, CA 90024. Acknowledgments: The authors thank Patrick Robinson, MD, and Katharine Fry for preparation of the manuscript. Grant Support: By grants CA-23175, CA-14548, and P30CA43703 from the National Cancer Institute and research grants from Pfizer Central Research, Groton, Connecticut.


Copyright ©2004 by the American College of Physicians


Ann Intern Med. 1993;118(7):495-503. doi:10.7326/0003-4819-118-7-199304010-00003
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Objective: To evaluate the efficacy and safety of fluconazole for prevention of fungal infections.

Design: A randomized, placebo-controlled, double-blind, multicenter trial.

Patients: Adults (257) undergoing chemotherapy for acute leukemia.

Intervention: Patients were randomly assigned to receive either fluconazole (400 mg orally once daily or 200 mg intravenously every 12 hours) or placebo. The study drug was started at initiation of chemotherapy and continued until recovery of neutrophil count, development of proven or suspected invasive fungal infection, or the occurrence of a drug-related toxicity.

Measurements: Fungal colonization, proven superficial or invasive fungal infection, empiric antifungal therapy with amphotericin B, drug-related side effects, and mortality.

Main Results: Fluconazole decreased fungal colonization (83 of 122 [68%] placebo patients compared with 34 of 119 [29%] fluconazole patients colonized at end of prophylaxis, P < 0.001) and proven fungal infections (27 of 132 [21%] placebo patients compared with 11 of 123 [9%] fluconazole patients infected, P = 0.02). Superficial fungal infections occurred in 20 of 132 (15%) placebo patients but in only 7 of 123 (6%) fluconazole patients (P = 0.01), whereas invasive fungal infections developed in 10 of 132 (8%) placebo patients and in 5 of 123 (4%) fluconazole patients (P = 0.3). Fluconazole was especially effective in eliminating colonization and infection by Candida species other than Candida krusei (66 of 122 [64%] placebo patients colonized at end of prophylaxis compared with 11 of 119 (9%) fluconazole patients, P < 0.001; 22 of 132 (17%) placebo patients infected compared with 7 of 123 [6%] fluconazole patients, P = 0.005). Aspergillus infections were infrequent in both fluconazole (3 cases) and placebo groups (3 cases). The use of amphotericin B, the incidence of drug-related side effects, and overall mortality were similar in both study groups.

Conclusion: Prophylactic fluconazole prevents colonization and superficial infections by Candida species other than Candida krusei in patients undergoing chemotherapy for acute leukemia and is well tolerated. Fluconazole could not be clearly shown to be effective for preventing invasive fungal infections, reducing the use of amphotericin B, or decreasing the number of deaths.

Figures

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Figure 1.
Time to development of fungal infection.P

Kaplan-Meier product-limit estimates of survival distributions of time to development of proven superficial or invasive fungal infection in the fluconazole (F) (———) and placebo (P) (— — —) patients. The difference in time of onset of proven fungal infection between fluconazole and placebo patients has a value of 0.002.

Grahic Jump Location
Grahic Jump Location
Figure 2.
Time to initiation of amphotericin B therapy.P

Kaplan-Meier product-limit estimates of survival distributions of time to initiation of empiric amphotericin B therapy in the fluconazole (F) (———) and placebo (P) (— — —) patients. The difference in time of initiation of empiric amphotericin B between fluconazole and placebo patients has a value of 0.03.

Grahic Jump Location
Grahic Jump Location
Figure 3.
Time to development of invasive fungal infection.P

Kaplan-Meier product-limit estimates of survival distributions of time to development of proven invasive fungal infection in fluconazole (F) (———) and placebo (P) (— — —) patients not receiving empiric amphotericin B for suspected fungal infection. The difference in time of onset of proven invasive fungal infection between fluconazole and placebo patients has a value of 0.03.

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