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Antimicrobial Agents and Chemotherapy, October 2008, p. 3504-3511, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00190-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Establishing In Vitro-In Vivo Correlations for Aspergillus fumigatus: the Challenge of Azoles versus Echinocandins

Maiken Cavling Arendrup,^1* Susanne Perkhofer,² Susan J. Howard,³ Guillermo Garcia-Effron,⁴ Aimanianda Vishukumar,⁵ David Perlin,⁴ and Cornelia Lass-Flörl²

Unit of Mycology and Parasitology, Statens Serum Institut, Copenhagen, Denmark,¹ Department of Hygiene and Medical Microbiology, Innsbruck Medical University, Innsbruck, Austria,² School of Translational Medicine, The University of Manchester, Manchester, United Kingdom,³ Public Health Research Institute, New Jersey Medical School, UMDNJ, Newark, New Jersey,⁴ Unité des Aspergillus, Institut Pasteur, Paris, France⁵

Received 11 February 2008/ Returned for modification 2 March 2008/ Accepted 9 July 2008

Two clinical isolates of Aspergillus fumigatus, designated AT and DK, were recently obtained from patients failing caspofungin and itraconazole therapy, respectively. The isolates were tested by microdilution for susceptibility to itraconazole, voriconazole, posaconazole, ravuconazole, and caspofungin and by Etest for susceptibility to amphotericin B and caspofungin. Susceptibility testing documented that the DK isolate was azole resistant (itraconazole and posaconazole MICs, >4 µg/ml; voriconazole MIC, 2 µg/ml; ravuconazole MIC, 4 µg/ml), and the resistance was confirmed in a hematogenous mouse model, with mortality and the galactomannan index as the primary and secondary end points. Sequencing of the cyp51A gene revealed the M220K mutation, conferring multiazole resistance. The Etest, but not microdilution, suggested that the AT isolate was resistant to caspofungin (MIC, >32 µg/ml). In the animal model, this isolate showed reduced susceptibility to caspofungin. Sequencing of the FKS1 gene revealed no mutations; the enzyme retained full sensitivity in vitro; and investigation of the polysaccharide composition showed that the β-(1,3)-glucan proportion was unchanged. However, gene expression profiling by Northern blotting and real-time PCR demonstrated that the FKS gene was expressed at a higher level in the AT isolate than in the susceptible control isolate. To our knowledge, this is the first report to document the presence of multiazole-resistant clinical isolates in Denmark and to demonstrate reduced susceptibility to caspofungin in a clinical A. fumigatus isolate with increased expression of the FKS gene. Further research to determine the prevalence of resistance in A. fumigatus worldwide, and to develop easier and reliable tools for the identification of such isolates in routine laboratories, is warranted.

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* Corresponding author. Mailing address: Unit of Mycology and Parasitology (43/117), Statens Serum Institut. Artillerivej 5, DK-2300 Copenhagen S, Denmark. Phone: 45 22 63 27 85. Fax: 45 3268 8180. E-mail: mad{at}ssi.dk

Published ahead of print on 21 July 2008.

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Antimicrobial Agents and Chemotherapy, October 2008, p. 3504-3511, Vol. 52, No. 10
0066-4804/08/$08.00+0     doi:10.1128/AAC.00190-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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