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Antimicrobial Agents and Chemotherapy, January 2003, p. 82-86, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.82-86.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Clinical Trichophyton rubrum Strain Exhibiting Primary Resistance to Terbinafine

Pranab K. Mukherjee,1 Steven D. Leidich,1 Nancy Isham,1 Ingrid Leitner,2 Neil S. Ryder,2 and Mahmoud A. Ghannoum1*

Center for Medical Mycology, Department of Dermatology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, Ohio,1 Novartis Forschungsinstitut, Vienna, Austria2

Received 25 April 2002/ Returned for modification 17 June 2002/ Accepted 18 September 2002

The in vitro antifungal susceptibilities of six clinical Trichophyton rubrum isolates obtained sequentially from a single onychomycosis patient who failed oral terbinafine therapy (250 mg/day for 24 weeks) were determined by broth microdilution and macrodilution methodologies. Strain relatedness was examined by random amplified polymorphic DNA (RAPD) analyses. Data obtained from both broth micro- and macrodilution assays were in agreement and revealed that the six clinical isolates had greatly reduced susceptibilities to terbinafine. The MICs of terbinafine for these strains were >4 µg/ml, whereas they were <0.0002 µg/ml for the susceptible reference strains. Consistent with these findings, the minimum fungicidal concentrations (MFCs) of terbinafine for all six strains were >128 µg/ml, whereas they were 0.0002 µg/ml for the reference strain. The MIC of terbinafine for the baseline strain (cultured at the initial screening visit and before therapy was started) was already 4,000-fold higher than normal, suggesting that this is a case of primary resistance to terbinafine. The results obtained by the broth macrodilution procedure revealed that the terbinafine MICs and MFCs for sequential isolates apparently increased during the course of therapy. RAPD analyses did not reveal any differences between the isolates. The terbinafine-resistant isolates exhibited normal susceptibilities to clinically available antimycotics including itraconazole, fluconazole, and griseofulvin. However, these isolates were fully cross resistant to several other known squalene epoxidase inhibitors, including naftifine, butenafine, tolnaftate, and tolciclate, suggesting a target-specific mechanism of resistance. This is the first confirmed report of terbinafine resistance in dermatophytes.

* Corresponding author. Mailing address: Center for Medical Mycology, 11100 Euclid Ave., Cleveland, OH 44106-5028. Phone: (216) 844-8313. Fax: (216) 844-1076. E-mail: mag3{at}po.cwru.edu.

Antimicrobial Agents and Chemotherapy, January 2003, p. 82-86, Vol. 47, No. 1
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.1.82-86.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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