3 years ago

Combined Antibacterial Effect of Isoniazid and Rifampicin on Four Mycobacterium tuberculosis Strains: in Vitro Experiments and Response-Surface Modeling.

Florence Ader, Catherine Pichat, Gérard Lina, Sylvain Goutelle, Charlotte Genestet, Oana Dumitrescu
While isoniazid and rifampicin have been the cornerstone of tuberculosis therapy caused by drug-susceptible Mycobacterium tuberculosis for more than 40 years, their combined action has never been thoroughly assessed by modern quantitative pharmacology approaches.The aims of this work were to perform in vitro experiments and mathematical modeling of the antibacterial effect of isoniazid and rifampicin alone and in combination against various strains of Mycobacterium tuberculosisAfter MIC determination of H37Rv and three strains belonging to the, Beijing, Euro-American and Indo-Oceanic lineages, the antibacterial effects of isoniazid and rifampicin alone and in combination were studied in static time-kill experiments. A sigmoidal maximum effect model (Hill equation) and a response-surface model were used to describe the effect the drugs alone and in combination, respectively.The killing effect of isoniazid and rifampicine alone were well described by the Hill equation. Rifampicin displayed a more concentration dependent effect than isoniazid around the MIC. The pharmacodynamics parameters of each drug (maximal effect, median effect concentration and coefficient of sigmoidicity) were quite similar between the four strains. The response-surface model from Minto et al. fit data of combined effect very well with low bias and imprecision. Response surface modeling showed that the combined action of isoniazid and rifampicin was synergistic for the H37Rv, Beijing and Euro-American strains, but only additive for the Indo-Oceanic strain.This study can serve as a motivating example for pre-clinical evaluation of combined action of antituberculous drugs.

Publisher URL: http://doi.org/10.1128/AAC.01413-17

DOI: 10.1128/AAC.01413-17

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