Empirical Fluconazole versus Placebo for Intensive Care Unit Patients

A Randomized Trial

  1. Mindy G. Schuster, MD;
  2. John E. Edwards, Jr., MD;
  3. Jack D. Sobel, MD;
  4. Rabih O. Darouiche, MD;
  5. Adolf W. Karchmer, MD;
  6. Susan Hadley, MD;
  7. Gus Slotman, MD;
  8. Helene Panzer, PhD;
  9. Pinaki Biswas, PhD; and
  10. John H. Rex, MD
  1. From the University of Pennsylvania School of Medicine, Philadelphia Pennsylvania; Harbor-UCLA Medical Center, Torrance, California; Detroit Medical Center, Wayne State University School of Medicine, Detroit, Michigan; Michael E. DeBakey Veterans Affairs Medical Center, Baylor College of Medicine, and University of Texas Medical School, Houston, Texas; Beth Israel Deaconess Medical Center and Tufts-New England Medical Center, Boston, Massachusetts; University of Medicine and Dentistry of New Jersey, Newark, New Jersey; and Pfizer, New York, New York.

    Abstract

    Background: Invasive infection with Candida species is an important cause of morbidity and mortality in intensive care unit (ICU) patients. Optimal preventive strategies have not been clearly defined.

    Objective: To see whether empirical fluconazole improves clinical outcomes more than placebo in adult ICU patients at high risk for invasive candidiasis.

    Design: Double-blind, placebo-controlled, randomized trial conducted from 1995 to 2000.

    Setting: 26 ICUs in the United States.

    Patients: 270 adult ICU patients with fever despite administration of broad-spectrum antibiotics. All had central venous catheters and an Acute Physiology and Chronic Health Evaluation II score greater than 16.

    Intervention: Patients were randomly assigned to either intravenous fluconazole, 800 mg daily, or placebo for 2 weeks and were followed for 4 weeks thereafter. Two hundred forty-nine participants were available for outcome assessment.

    Measurements: A composite primary outcome that defined success as all 4 of the following: resolution of fever; absence of invasive fungal infection; no discontinuation because of toxicity; and no need for a nonstudy, systemic antifungal medication (as assessed by a blinded oversight committee).

    Results: Only 44 of 122 (36%) fluconazole recipients and 48 of 127 (38%) placebo recipients had a successful outcome (relative risk, 0.95 [95% CI, 0.69 to 1.32; P = 0.78]). The main reason for failure was lack of resolution of fever (51% for fluconazole and 57% for placebo). Documented invasive candidiasis occurred in 5% of fluconazole recipients and 9% of placebo recipients (relative risk, 0.57 [CI, 0.22 to 1.49]). Seven (5%) fluconazole recipients and 10 (7%) placebo recipients had adverse events resulting in discontinuation of the study drug. Discontinuation because of abnormal liver test results occurred in 3 (2%) fluconazole recipients and 5 (4%) placebo recipients.

    Limitations: Twenty-one randomly assigned patients were not included in the analysis because they either did not meet entry criteria or did not have postbaseline assessments. Fewer fungal infections than anticipated occurred in the control group. Confidence bounds were wide and did not exclude potentially important differences in outcomes between groups.

    Conclusion: In critically ill adults with risk factors for invasive candidiasis, empirical fluconazole did not clearly improve a composite outcome more than placebo.

    Article and Author Information

    • Acknowledgment: The authors thank Helen Bhattacharyya and Robert Swanson for help with the data tables.

    • Grant Support: By Pfizer, New York, New York.

    • Potential Financial Conflicts of Interest: Employment: H. Panzer (Pfizer), P. Biswas (Pfizer). Consultancies: J.E. Edwards (Merck & Co., Pfizer, Cerexa, Eisai, Enzon), J.D. Sobel (Merck & Co., Pfizer, Ther-Rx/KV Pharmaceutical), S. Hadley (Pfizer, Schering-Plough). Honoraria: J.D. Sobel (Merck & Co., Pfizer, Astellas). Stock ownership or options (other than mutual funds): H. Panzer (Pfizer). Grants received: M.G. Schuster (Pfizer), J.E. Edwards (Merck & Co., Pfizer, Astellas), J.D. Sobel (Merck, Pfizer), S. Hadley (Pfizer, Astellas). Grants pending: J.E. Edwards (Pfizer). Other: R.O. Darouiche (Pfizer Speakers' Bureau).

    • Reproducible Research Statement: Study protocol: Available from Dr. Schuster (e-mail, schustem{at}mail.med.upenn.edu). Statistical code and data set: Not available.

    • Requests for Single Reprints: Mindy G. Schuster, MD, University of Pennsylvania, Infectious Diseases, 3 Silverstein, Suite E, 3400 Spruce Street, Philadelphia, PA 19104; e-mail, schustem{at}mail.med.upenn.edu.

    • Current Author Addresses: Dr. Schuster: University of Pennsylvania, Infectious Diseases, 3 Silverstein, Suite E, 3400 Spruce Street, Philadelphia, PA 19104.

    • Dr. Edwards: UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509.

    • Dr. Sobel: Wayne State University, 3990 John R, Detroit, MI 48201.

    • Dr. Darouiche: Michael E. DeBakey Veterans Affairs Medical Center, 2002 Holcombe Boulevard, Houston, TX 77030.

    • Dr. Karchmer: Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02215.

    • Dr. Hadley: Tufts-New England Medical Center, 750 Washington Street, Box 41, Boston, MA 02111.

    • Dr. Slotman: 1765 Springdale Road, Cherry Hill, NJ 08003.

    • Drs. Panzer and Biswas: Pfizer, 235 East 42nd Street, New York, NY 10017.

    • Dr. Rex: AstraZeneca Pharmaceuticals, Alderley House, Alderley Park, Macclesfield SK10 4TF, United Kingdom.

    • Author Contributions: Conception and design: M.G. Schuster, J.D. Sobel, R.O. Darouiche, A.W. Karchmer, G. Slotman, H. Panzer, J.H. Rex.

    • Analysis and interpretation of the data: M.G. Schuster, J.E. Edwards, J.D. Sobel, R.O. Darouiche, G. Slotman, J.H. Rex.

    • Drafting of the article: M.G. Schuster, J.E. Edwards, J.D. Sobel, J.H. Rex.

    • Critical revision of the article for important intellectual content: M.G. Schuster, J.E. Edwards, J.D. Sobel, R.O. Darouiche, A.W. Karchmer, G. Slotman, J.H. Rex.

    • Final approval of the article: M.G. Schuster, J.E. Edwards, J.D. Sobel, R.O. Darouiche, A.W. Karchmer, S. Hadley, H. Panzer, J.H. Rex.

    • Provision of study materials or patients: M.G. Schuster, J.D. Sobel, A.W. Karchmer, S. Hadley.

    • Statistical expertise: P. Biswas.

    • Obtaining of funding: J.E. Edwards.

    • Administrative, technical, or logistic support: H. Panzer.

    • Collection and assembly of data: M.G. Schuster, J.D. Sobel.

    Responses to this article

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    • Empirical Fluconazole versus Placebo for Intensive Care Unit Patients: A Randomized Trial
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    1. Ann Intern Med July 15, 2008 vol. 149 no. 2 83-90
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