Preexposure of A. fumigatus to Fluconazole (FLU) Induces Tolerance to Itraconazole (Itra) In Vitro

Ref ID: 2813

Author:

W. LIU 1, R. E. LEWIS 2, G. S. MAY 2, D. P. KONTOYIANNIS1

Author address:

1The University of Texas M. D. Anderson Cancer Center, Houston, TX, 2University of Houston, Houston, TX.

Full conference title:

42nd Interscience Conference on Antimicrobial Agents and Chemotherapy

Abstract:

Background: Prior use of FLU resulted in an increase in invasive aspergillosis (IA) in high risk patients. We hypothesized that FLU, despite its lack of significant activity against A. fumigatus, could result in changes in antifungal resistance and/or tolerance of that fungus (CID 2002;34:1281). Methods: We performed 4 serial passages of 10 clinical isolates of A. fumigatus (all Itra-susceptible) in YAG, YAG + FLU 8mg/ml, YAG+FLU 64mg/ml plates. Conidia were collected every 3 days and replated on the corresponding media. We measured (in duplicate) the MIC and MFC to FLU, Itraconazole (Itra) and amphotericin B (AMB) by the NCCLS M-38P microdilution method both at baseline and after 4 passages on FLU-containing media. Two serial passages in drug-free YAG plates was then performed. Growth on alternative media (RPMI 1640+FLU plates) was used as an additional control in a subset of representative isolates. Finally, the MIC and MFC to voriconazole (Vori) were determined in the same subset of isolates. Results: Serial passages on FLU resulted in a 4-fold increase in Itra MFC (but not Itra MIC) in 9/10 of isolates and it was more marked after preexposure to YAG+FLU 64mg/ml compared to YAG+FLU 8 mg/ml plates. Strain to strain variation was seen, with 6/10 isolates exhibiting marked increases in Itra MFC (>16mg/L). The increase in Itra MFC in FLU-preexposed isolates was specific to triazoles (Itra, Vori) and it was not medium-dependent since it was also observed on RPMI+FLU plates. Finally, 8/9 isolates with increased Itra MFC after preexposure to FLU had a 4 fold decrease in Itra MFC following 2 passages in drug-free YAG plates. Conclusion: Pre-exposure of A. fumigatus to FLU affects the fungicidal effect of subsequent Itra. This phenotypic adaptation is not captured by routine MIC determination but requires measurement of MFC. This observation could have implications in the efficacy of triazoles when used sequentially in IA.

Abstract Number: M-852

Conference Year: 2002

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