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Antimicrobial Agents and Chemotherapy, June 2005, p. 2218-2225, Vol. 49, No. 6
0066-4804/05/$08.00+0     doi:10.1128/AAC.49.6.2218-2225.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Phenotypic and Molecular Characterization of Mycobacterium tuberculosis Isolates Resistant to both Isoniazid and Ethambutol

Linda M. Parsons,^1,2, Max Salfinger,^1,2,3* Anne Clobridge,¹ Jillian Dormandy,¹ Lisa Mirabello,² Valerie L. Polletta,¹ Ahmet Sanic,^1, Oleg Sinyavskiy,¹ Susan C. Larsen,¹ Jeffrey Driscoll,¹ Genet Zickas,¹ and Harry W. Taber^1,2

Wadsworth Center, New York State Department of Health,¹ Department of Biomedical Sciences, School of Public Health, University at Albany,² Department of Medicine, Albany Medical College, Albany, New York³

Received 12 October 2004/ Returned for modification 29 November 2004/ Accepted 23 February 2005

In performing radiometric susceptibility testing on over 2,000 patient isolates of Mycobacterium tuberculosis during the past 6 years, we found that resistance to 7.5 µg/ml ethambutol (EMB) occurred only in isolates that are also resistant to 0.4 µg/ml isoniazid (INH). Using 157 selected isolates in the present study, we performed radiometric and agar proportion susceptibility tests and DNA sequencing of genetic regions associated with resistance to these two drugs. The goal was to study the occurrence of the common mutations associated with resistance to each drug and also to determine whether any particular INH-resistance-associated mutation occurred more often in combination with any particular EMB-resistance-associated mutation. In an analysis of 128 isolates resistant to 0.4 µg/ml INH, we found that a mutation at katG Ser315 was more common in isolates also resistant to 7.5 µg/ml EMB (61 of 67 = 91.0%) than in isolates either susceptible to EMB or resistant to 2.5 µg/ml EMB (39 of 60 = 65.0%). These observations suggest that INH-resistant strains with a mutation at katG Ser315 are more likely to acquire resistance to 7.5 µg/ml EMB than are isolates with INH-resistance-associated mutations at other sites. In addition, we found that 64 of 67 (95.5%) isolates resistant to 7.5 µg/ml EMB contained a mutation in either codon 306 or codon 406 of embB. Met306Val was the most common embB mutation, present in 52 (77.6%) of the 67 isolates. Most occurrences of this mutation (49 of 52 = 94.2%) were found in isolates that also contained the katG Ser315Thr mutation. Finally, sequencing this region of embB appears to be sufficiently sensitive for use as a rapid screening tool for detection of high-level resistance to EMB.

Present address: Global AIDS Program, Centers for Disease Control and Prevention, Atlanta, GA.

Present address: Ondokuz Mayis University, Samsun, Turkey.

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