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Antimicrobial Agents and Chemotherapy, November 2003, p. 3592-3597, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3592-3597.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Attenuation of Itraconazole Fungicidal Activity following Preexposure of Aspergillus fumigatus to Fluconazole

Wei Liu,1 Michail S. Lionakis,1 Russell E. Lewis,1,2 Nathan Wiederhold,1,2 Gregory S. May,3 and Dimitrios P. Kontoyiannis1,2*

Department of Infectious Diseases, Infection Control and Employee Health,1 Department of Laboratory Medicine, The University of Texas M. D. Anderson Cancer Center,3 University of Houston College of Pharmacy, Houston, Texas2

Received 17 June 2003/ Returned for modification 26 June 2003/ Accepted 11 July 2003

Fluconazole (FLC), a triazole with limited activity against Aspergillus species, is frequently used as prophylaxis in leukemia patients and bone marrow transplant recipients. Prior FLC use has been associated with an increasing incidence of invasive aspergillosis in these patients. We hypothesized that prior exposure of Aspergillus fumigatus to FLC could result in altered in vitro susceptibility of this fungus to other, more active triazoles. Thus, we performed serial passages of conidia of 10 clinical isolates of A. fumigatus (all itraconazole [ITC] susceptible) on FLC-containing yeast agar glucose plates. The MICs and minimal fungicidal concentrations (MFCs) of amphotericin B, FLC, ITC, and voriconazole (VRC) for A. fumigatus conidia were measured following four passages on FLC-containing medium according to the National Committee for Clinical Laboratory Standards microdilution method. Serial passages on FLC-containing plates resulted in a fourfold increase in the MFCs (but not the MICs) of ITC for nine isolates. The attenuated ITC fungicidal activity against A. fumigatus following FLC preexposure was medium independent and was also observed against FLC-preexposed A. fumigatus hyphae with the viability staining FUN-1 dye. Moreover, FLC preexposure of A. fumigatus conidia resulted in an analogous increase in the MFCs (but not the MICs) of VRC. Our findings suggest that preexposure of A. fumigatus to FLC attenuates the in vitro fungicidal activity of subsequent ITC use against it. This phenotypic adaptation is not captured by a routine MIC determination but requires MFC measurement. The in vivo significance of this in vitro phenomenon requires further investigation.

* Corresponding author. Mailing address: Department of Infectious Diseases, Infection Control and Employee Health, Unit 402, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: (713) 792-6237. Fax: (713) 745-6839. E-mail: dkontoyi{at}mdanderson.org.

Antimicrobial Agents and Chemotherapy, November 2003, p. 3592-3597, Vol. 47, No. 11
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.11.3592-3597.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

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  • Gil-Lamaignere, C., Salvenmoser, S., Hess, R., Muller, F.-M. C. (2004). Micafungin Enhances Neutrophil Fungicidal Functions against Candida Pseudohyphae. Antimicrob. Agents Chemother. 48: 2730-2732 [Abstract] [Full Text]  


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