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Antimicrobial Agents and Chemotherapy, June 2007, p. 2100-2104, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.00086-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Isoniazid Induces Its Own Resistance in Nonreplicating Mycobacterium tuberculosis{triangledown}

Salman Siddiqi,1* Param Takhar,1 Christian Baldeviano,2 William Glover,2 and Ying Zhang2*

Becton Dickinson Diagnostic Systems, Sparks, Maryland 21152,1 Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland 212052

Received 19 January 2007/ Returned for modification 21 March 2007/ Accepted 5 April 2007

Isoniazid (INH) resistance is most frequent among drug-resistant Mycobacterium tuberculosis clinical isolates. This study was conducted to investigate whether INH could induce its own resistance. During INH susceptibility testing in BACTEC 12B and MGIT 960 media, weekly subcultures were made from the drug-containing media into fresh medium without drug and susceptibility testing was performed. Rifampin (RIF) was used as a control drug. M. tuberculosis H37Rv and three clinical isolates were tested in this study. INH-resistant subcultures were analyzed for catalase activity, INH susceptibility, and mutations associated with INH resistance. With inoculum size (104 bacilli) smaller than a size that contains spontaneously INH-resistant mutants, INH was found to induce resistance to itself in INH-tolerant persisters but not to other drugs. The minimum time required for induction of INH resistance was 5 to 6 days. In contrast, RIF did not induce RIF resistance. Eight subcultures with INH-induced resistance were analyzed, and two had a MIC of 0.4 µg/ml INH and six had MICs of over 2 µg/ml INH. Four of the eight subcultures with INH-induced resistance had lost catalase activity, with three having katG mutations. Despite being a powerful frontline tuberculosis drug, INH has the potential drawback of inducing its own stable genetic resistance in INH-tolerant persisters. This finding helps to explain the higher frequency and prevalence of INH-resistant isolates than isolates with resistance to other drugs in patients.

* Corresponding author. Mailing address for Ying Zhang: Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, 615 N. Wolfe Street, Baltimore, MD 21205. Phone: (410) 614-2975. Fax: (410) 955-0105. E-mail: yzhang{at}jhsph.edu. Mailing address for Salman Siddiqi: Becton Dickinson Diagnostic Systems, 7 Loveton Circle, Sparks, MD 21152. Phone: (410) 316-4319. Fax: (410) 316-4499. E-mail: Salman_Siddiqi{at}bd.com

{triangledown} Published ahead of print on 16 April 2007.

Antimicrobial Agents and Chemotherapy, June 2007, p. 2100-2104, Vol. 51, No. 6
0066-4804/07/$08.00+0     doi:10.1128/AAC.00086-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Rieder, R. J., Zhao, Z., Zavizion, B. (2009). New Approach for Drug Susceptibility Testing: Monitoring the Stress Response of Mycobacteria. Antimicrob. Agents Chemother. 53: 4598-4603 [Abstract] [Full Text]  


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