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Antimicrobial Agents and Chemotherapy, July 2007, p. 2329-2336, Vol. 51, No. 7
0066-4804/07/$08.00+0     doi:10.1128/AAC.00185-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Isoniazid Bactericidal Activity and Resistance Emergence: Integrating Pharmacodynamics and Pharmacogenomics To Predict Efficacy in Different Ethnic Populations

Divison of Infectious Diseases, UT Southwestern Medical Center, Dallas, Texas 75390,¹ Emerging Infections and Host Defense Section,² Institute for Clinical Pharmacodynamics, Ordway Research Institute, Albany, New York 12208³

Received 7 February 2007/ Returned for modification 20 March 2007/ Accepted 9 April 2007

Isoniazid, administered as part of combination antituberculosis therapy, is responsible for most of the early bactericidal activity (EBA) of the regimen. However, the emergence of Mycobacterium tuberculosis resistance to isoniazid is a major problem. We examined the relationship between isoniazid exposure and M. tuberculosis microbial kill, as well as the emergence of resistance, in our in vitro pharmacodynamic model of tuberculosis. Since single-nucleotide polymorphisms of the N-acetyltransferase-2 gene lead to two different clearances of isoniazid from serum in patients, we simulated the isoniazid concentration-time profiles encountered in both slow and fast acetylators. Both microbial kill and the emergence of resistance during monotherapy were associated with the ratio of the area under the isoniazid concentration-time curve from 0 to 24 h (AUC_0-24) to the isoniazid MIC. The time in mutant selection window hypothesis was rejected. Next, we utilized the in vitro relationship between the isoniazid AUC_0-24/MIC ratio and microbial kill, the distributions of isoniazid clearance in populations with different percentages of slow and fast acetylators, and the distribution of isoniazid MICs for isonazid-susceptible M. tuberculosis clinical isolates in Monte Carlo simulations to calculate the EBA expected for 10,000 patients treated with 300 mg of isoniazid. For those patient populations in which the proportion of fast acetylators and the isoniazid MICs were high, the average EBA of the standard dose was 0.3 log₁₀ CFU/ml/day and was thus suboptimal. Our approach, which utilizes preclinical pharmacodynamics and the genetically determined multimodal distributions of serum clearances, is a preclinical tool that may be able to predict the EBAs of various doses of new antituberculosis drugs.

Published ahead of print on 16 April 2007.

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