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

Abstract

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 increasedmore » 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.« less

Authors:
 [1];  [2];  [3];  [4]
+ Show Author Affiliations
  1. Univ. of Michigan, Ann Arbor, MI (United States); Univ. of Michigan Medical School, Ann Arbor, MI (United States)
  2. The State Univ. of New Jersey, New Brunswick, NJ (United States)
  3. Univ. of Michigan, Ann Arbor, MI (United States)
  4. Univ. of Michigan Medical School, Ann Arbor, MI (United States)
Publication Date:
Research Org.:
Univ. of California (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1241146
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
BMC Systems Biology
Additional Journal Information:
Journal Volume: 9; Journal Issue: 1; Journal ID: ISSN 1752-0509
Publisher:
BioMed Central
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; computational model; pharmacokinetic/pharmacodynamic; isoniazid; Rifampin; tissue distribution

Citation Formats

Pienaar, Elsje, Dartois, Véronique, Linderman, Jennifer J., and Kirschner, Denise E. In silico evaluation and exploration of antibiotic tuberculosis treatment regimens. United States: N. p., 2015. Web. doi:10.1186/s12918-015-0221-8.
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Pienaar, Elsje, Dartois, Véronique, Linderman, Jennifer J., & Kirschner, Denise E. In silico evaluation and exploration of antibiotic tuberculosis treatment regimens. United States. https://doi.org/10.1186/s12918-015-0221-8
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Pienaar, Elsje, Dartois, Véronique, Linderman, Jennifer J., and Kirschner, Denise E. Sat . "In silico evaluation and exploration of antibiotic tuberculosis treatment regimens". United States. https://doi.org/10.1186/s12918-015-0221-8. https://www.osti.gov/servlets/purl/1241146.
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@article{osti_1241146,
title = {In silico evaluation and exploration of antibiotic tuberculosis treatment regimens},
author = {Pienaar, Elsje and Dartois, Véronique and Linderman, Jennifer J. and Kirschner, Denise E.},
abstractNote = {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.},
doi = {10.1186/s12918-015-0221-8},
journal = {BMC Systems Biology},
number = 1,
volume = 9,
place = {United States},
year = {Sat Nov 14 00:00:00 EST 2015},
month = {Sat Nov 14 00:00:00 EST 2015}
}
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Journal Article:
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Publisher's Version of Record
https://doi.org/10.1186/s12918-015-0221-8
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Cited by: 31 works
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Figures / Tables:

Fig. 1 Fig. 1: a Computational model. Granuloma formation and function, plasma pharmacokinetics (PK), tissue PK and pharmacodynamics (PD) are integrated into a single computational framework. Cell recruitment, movement, states (e.g. activated), actions (e.g. tumor necrosis factor secretion), interactions (e.g. macrophage activation) and death of macrophages and T-cells are followed over time,more » with granuloma formation and function as emergent behavior. Bacteria are represented as three subpopulations: intracellular, extracellular replicating and extracellular non-replicating (i.e. residing in caseous areas). Plasma PK equations determine the concentration of antibiotic at vascular source sites on the simulation grid. Antibiotics permeate the vascular wall, diffuse within the granuloma, penetrate host cells and kill bacteria based on local intracellular and extracellular concentrations. Further model details are available in [20]. Artwork in (a) was constructed by combining and modifying artwork elements from Servier Medical Art (http://www.servier.com/Powerpoint-image-bank) provided under the Creative Commons Unported License 3.0. b Simulated antibiotic dosing regimens. Simulated infections are initiated at day 0 and granulomas evolve for the first 100 days (red bars). Regimens 1a, 1b, 2a and 3a, recommended by the CDC/WHO [22], are composed of different doses and frequencies. Regimens 1b and 2a switch from daily to 2 doses per week after 60 and 14 days of treatment, respectively. Each regimen is implemented with INH, RIF and INH + RIF« less
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journal, February 2011

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Differential Risk of Tuberculosis Reactivation among Anti-TNF Therapies Is Due to Drug Binding Kinetics and Permeability
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