In silico evaluation and exploration of antibiotic tuberculosis treatment regimens

Elsje Pienaar, Jennifer J. Linderman, Denise E. Kirschner

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Background: 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. Results: 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. Conclusions: Our systems pharmacology approach complements efforts to accelerate tuberculosis therapeutic development.

Original languageEnglish (US)
Article number79
JournalBMC Systems Biology
Volume9
Issue number1
DOIs
StatePublished - Nov 14 2015

Fingerprint

Tuberculosis
Antibiotics
Computer Simulation
Granuloma
Isoniazid
Rifampin
Anti-Bacterial Agents
Pharmacokinetics
Evaluation
Pharmacodynamics
Efficacy
Clinical Trials
Dose
Pharmacology
Drug Resistance
Spatio-temporal Model
Predict
Bacterial Load
Immunity
Rabbit

All Science Journal Classification (ASJC) codes

  • Applied Mathematics
  • Molecular Biology
  • Structural Biology
  • Computer Science Applications
  • Modeling and Simulation

Keywords

  • Computational model
  • Isoniazid
  • Pharmacokinetic/Pharmacodynamic
  • Rifampin
  • Tissue distribution

Cite this

Pienaar, Elsje ; Linderman, Jennifer J. ; Kirschner, Denise E. / In silico evaluation and exploration of antibiotic tuberculosis treatment regimens. In: BMC Systems Biology. 2015 ; Vol. 9, No. 1.
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In silico evaluation and exploration of antibiotic tuberculosis treatment regimens. / Pienaar, Elsje; Linderman, Jennifer J.; Kirschner, Denise E.

In: BMC Systems Biology, Vol. 9, No. 1, 79, 14.11.2015.

Research output: Contribution to journalArticle

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