In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

Pienaar, Elsje; Dartois, Véronique; Linderman, Jennifer J.; Kirschner, Denise E.

doi:10.1186/s12918-015-0221-8

Title: In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

Journal Article · Sat Nov 14 00:00:00 EST 2015 · BMC Systems Biology

DOI:https://doi.org/10.1186/s12918-015-0221-8· OSTI ID:1241146

Pienaar, Elsje ^[1]; Dartois, Véronique ^[2]; Linderman, Jennifer J. ^[3]; Kirschner, Denise E. ^[4]

Univ. of Michigan, Ann Arbor, MI (United States); Univ. of Michigan Medical School, Ann Arbor, MI (United States)
The State Univ. of New Jersey, New Brunswick, NJ (United States)
Univ. of Michigan, Ann Arbor, MI (United States)
Univ. of Michigan Medical School, Ann Arbor, MI (United States)

Improvement in tuberculosis treatment regimens requires selection of antibiotics and dosing schedules from a large design space of possibilities. Incomplete knowledge of antibiotic and host immune dynamics in tuberculosis granulomas impacts clinical trial design and success, and variations among clinical trials hamper side-by-side comparison of regimens. Our objective is to systematically evaluate the efficacy of isoniazid and rifampin regimens, and identify modifications to these antibiotics that improve treatment outcomes. We pair a spatio-temporal computational model of host immunity with pharmacokinetic and pharmacodynamic data on isoniazid and rifampin. The model is calibrated to plasma pharmacokinetic and granuloma bacterial load data from non-human primate models of tuberculosis and to tissue and granuloma measurements of isoniazid and rifampin in rabbit granulomas. We predict the efficacy of regimens containing different doses and frequencies of isoniazid and rifampin. We predict impacts of pharmacokinetic/pharmacodynamic modifications on antibiotic efficacy. We demonstrate that suboptimal antibiotic concentrations within granulomas lead to poor performance of intermittent regimens compared to daily regimens. Improvements from dose and frequency changes are limited by inherent antibiotic properties, and we propose that changes in intracellular accumulation ratios and antimicrobial activity would lead to the most significant improvements in treatment outcomes. Results suggest that an increased risk of drug resistance in fully intermittent as compared to daily regimens arises from higher bacterial population levels early during treatment. In conclusion, our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.

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Research Organization:: Univ. of California (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1241146

Journal Information:: BMC Systems Biology, Vol. 9, Issue 1; ISSN 1752-0509

Publisher:: BioMed CentralCopyright Statement

Country of Publication:: United States

Language:: English

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Cited by: 31 works

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In silico evaluation and exploration of antibiotic tuberculosis treatment regimens [Supplementary Data] Pienaar, Elsje; Dartois, VĂŠronique; Linderman, Jennifer https://doi.org/10.6084/m9.figshare.c.3602969 The current record is supplemented by this dataset	dataset	November 2015
In silico evaluation and exploration of antibiotic tuberculosis treatment regimens [Supplemental Data] Pienaar, Elsje; Dartois, Véronique; Linderman, Jennifer https://doi.org/10.6084/m9.figshare.c.3602969.v1 The current record is supplemented by this dataset	dataset	November 2015
Additional file 1: Figure S1. of In silico evaluation and exploration of antibiotic tuberculosis treatment regimens Pienaar, Elsje; Dartois, VĂŠronique; Linderman, Jennifer https://doi.org/10.6084/m9.figshare.c.3602969_d1 The current record is supplemented by this text	text	January 2015
Additional file 1: Figure S1. of In silico evaluation and exploration of antibiotic tuberculosis treatment regimens Pienaar, Elsje; Dartois, Véronique; Linderman, Jennifer https://doi.org/10.6084/m9.figshare.c.3602969_d1.v1 The current record is supplemented by this figure	figure	November 2015