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Journal of Clinical Microbiology, October 2009, p. 3142-3146, Vol. 47, No. 10
0095-1137/09/$08.00+0     doi:10.1128/JCM.00940-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Wild-Type MIC Distribution and Epidemiological Cutoff Values for Aspergillus fumigatus and Three Triazoles as Determined by the Clinical and Laboratory Standards Institute Broth Microdilution Methods{triangledown}

M. A. Pfaller,1,2* D. J. Diekema,1 M. A. Ghannoum,3 J. H. Rex,4 B. D. Alexander,5 D. Andes,6 S. D. Brown,7 V. Chaturvedi,8 A. Espinel-Ingroff,9 C. L. Fowler,10 E. M. Johnson,11 C. C. Knapp,12 M. R. Motyl,13 L. Ostrosky-Zeichner,14 D. J. Sheehan,15 T. J. Walsh,16 for the Clinical and Laboratory Standards Institute Antifungal Testing Subcommittee

Roy J. and Lucille A. Carver College of Medicine,1 College of Public Health, University of Iowa, Iowa City, Iowa 52242,2 Case Western Reserve University, Cleveland, Ohio 44106-5028,3 AstraZeneca, Macclesfield, Cheshire, United Kingdom,4 Duke University Medical Center, Durham, North Carolina 27710,5 University of Wisconsin, Madison, Wisconsin 53792,6 Clinical Microbiology Institute, Wilsonville, Oregon 97070,7 New York State Department of Health, Albany, New York 12201-2002,8 Medical College of Virginia, Richmond, Virginia 23298,9 BioMerieux, Inc., Durham, North Carolina 27712,10 HPA Centre for Infections, Kingsdown, Bristol, United Kingdom,11 Trek Diagnostic Systems, Cleveland, Ohio 44131,12 Merck & Company, Inc., Rahway, New Jersey 07065-0900,13 University of Texas Medical School at Houston, Houston, Texas 77030,14 Pfizer, Inc., New York, NY 10017,15 National Cancer Institute, Bethesda, Maryland 20892,16

Received 12 May 2009/ Returned for modification 29 July 2009/ Accepted 9 August 2009

Antifungal susceptibility testing of Aspergillus species has been standardized by both the Clinical and Laboratory Standards Institute (CLSI) and the European Committee on Antimicrobial Susceptibility Testing (EUCAST). Recent studies suggest the emergence of strains of Aspergillus fumigatus with acquired resistance to azoles. The mechanisms of resistance involve mutations in the cyp51A (sterol demethylase) gene, and patterns of azole cross-resistance have been linked to specific mutations. Studies using the EUCAST broth microdilution (BMD) method have defined wild-type (WT) MIC distributions, epidemiological cutoff values (ECVs), and cross-resistance among the azoles. We tested a collection of 637 clinical isolates of A. fumigatus for which itraconazole MICs were ≤2 µg/ml against posaconazole and voriconazole using the CLSI BMD method. An ECV of ≤1 µg/ml encompassed the WT population of A. fumigatus for itraconazole and voriconazole, whereas an ECV of ≤0.25 µg/ml was established for posaconazole. Our results demonstrate that the WT distribution and ECVs for A. fumigatus and the mold-active triazoles were the same when determined by the CLSI or the EUCAST BMD method. A collection of 43 isolates for which itraconazole MICs fell outside of the ECV were used to assess cross-resistance. Cross-resistance between itraconazole and posaconazole was seen for 53.5% of the isolates, whereas cross-resistance between itraconazole and voriconazole was apparent in only 7% of the isolates. The establishment of the WT MIC distribution and ECVs for the azoles and A. fumigatus will be useful in resistance surveillance and is an important step toward the development of clinical breakpoints.

* Corresponding author. Mailing address: Medical Microbiology Division, C606 GH, Department of Pathology, University of Iowa College of Medicine, Iowa City, IA 52242. Phone: (319) 345-8615. Fax: (319) 356-4916. E-mail: michael-pfaller{at}uiowa.edu

{triangledown} Published ahead of print on 19 August 2009.

Journal of Clinical Microbiology, October 2009, p. 3142-3146, Vol. 47, No. 10
0095-1137/09/$08.00+0     doi:10.1128/JCM.00940-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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