Isoniazid pharmacokinetics-pharmacodynamics in an aerosol infection model of tuberculosis

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Limited data exist on the pharmacokinetic-pharmacodynamic (PK-PD) parameters of the bactericidal activities of the available antimycobacterial drugs. We report on the PK-PD relationships for isoniazid. Isoniazid exhibited concentration (C)-dependent killing of Mycobacterium tuberculosis H37Rv in vitro, with a maximum reduction of 4 log10 CFU/ml. In these studies, 50% of the maximum effect was achieved at a C/MIC ratio of 0.5, and the maximum effect did not increase with exposure times of up to 21 days. Conversely, isoniazid produced less than a 0.5-logo CFU/ml reduction in two different intracellular infection models (J774A.1 murine macrophages and whole human blood). In a murine model of aerosol infection, isoniazid therapy for 6 days produced a reduction of 1.4 log10 CFU/lung. Dose fractionation studies demonstrated that the 24-h area under the concentration-time curve/MIC (r2 = 0.83) correlated best with the bactericidal efficacy, followed by the maximum concentration of drug in serum/MIC (r2 = 0.73).




Jayaram, R., Shandil, R. K., Gaonkar, S., Kaur, P., Suresh, B. L., Mahesh, B. N., … Balasubramanian, V. (2004). Isoniazid pharmacokinetics-pharmacodynamics in an aerosol infection model of tuberculosis. Antimicrobial Agents and Chemotherapy, 48(8), 2951–2957.

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