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Clinical Microbiology Reviews, January 2005, p. 163-194, Vol. 18, No. 1
0893-8512/05/$08.00+0     doi:10.1128/CMR.18.1.163-194.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Combination Treatment of Invasive Fungal Infections

Pranab K. Mukherjee,1 Daniel J. Sheehan,2 Christopher A. Hitchcock,3 and Mahmoud A. Ghannoum1*

Center for Medical Mycology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio,1 Pfizer Global Pharmaceuticals, Pfizer Inc., New York, New York,2 Exploratory Development, Pfizer Global Research & Development, Sandwich Laboratories, Sandwich, United Kingdom3

The persistence of high morbidity and mortality from systemic fungal infections despite the availability of novel antifungals points to the need for effective treatment strategies. Treatment of invasive fungal infections is often hampered by drug toxicity, tolerability, and specificity issues, and added complications often arise due to the lack of diagnostic tests and to treatment complexities. Combination therapy has been suggested as a possible approach to improve treatment outcome. In this article, we undertake a historical review of studies of combination therapy and also focus on recent studies involving newly approved antifungal agents. The limitations surrounding antifungal combinations include nonuniform interpretation criteria, inability to predict the likelihood of clinical success, strain variability, and variations in pharmacodynamic/pharmacokinetic properties of antifungals used in combination. The issue of antagonism between polyenes and azoles is beginning to be addressed, but data regarding other drug combinations are not adequate for us to draw definite conclusions. However, recent data have identified potentially useful combinations. Standardization of assay methods and adoption of common interpretive criteria are essential to avoid discrepancies between different in vitro studies. Larger clinical trials are needed to assess whether combination therapy improves survival and treatment outcome in the most seriously debilitated patients afflicted with life-threatening fungal infections.

* Corresponding author. Mailing address: Center for Medical Mycology, Department of Dermatology, Case Western Reserve University and University Hospitals of Cleveland, 11100 Euclid Ave., LKS-5028, Cleveland, OH 44106-5028. Phone: (216) 844-8580. Fax: (216) 844-1076. E-mail: mahmoud.ghannoum{at}case.edu.

Clinical Microbiology Reviews, January 2005, p. 163-194, Vol. 18, No. 1
0893-8512/05/$08.00+0     doi:10.1128/CMR.18.1.163-194.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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