Univ. of Michigan, Ann Arbor, MI (United States); Univ. of Michigan Medical School, Ann Arbor, MI (United States); Office of Scientific and Technical Information (OSTI)
Univ. of Michigan, Ann Arbor, MI (United States)
Children's Hospital of Pittsburgh of the Univ. of Pittsburgh Medical Center, Pittsburgh, PA (United States)
The State Univ. of New Jersey, Newark, NJ (United States)
Univ. of Pittsburgh, Pittsburgh, PA (United States)
Adventist Univ. of Health Sciences, Orlando, FL (United States)
Univ. of Michigan Medical School, Ann Arbor, MI (United States)
While active tuberculosis (TB) is a treatable disease, many complex factors prevent its global elimination. Part of the difficulty in developing optimal therapies is the large design space of antibiotic doses, regimens and combinations. Computational models that capture the spatial and temporal dynamics of antibiotics at the site of infection can aid in reducing the design space of costly and time-consuming animal pre-clinical and human clinical trials. The site of infection in TB is the granuloma, a collection of immune cells and bacteria that form in the lung, and new data suggest that penetration of drugs throughout granulomas is problematic. In this paper, we integrate our computational model of granuloma formation and function with models for plasma pharmacokinetics, lung tissue pharmacokinetics and pharmacodynamics for two first line anti-TB antibiotics. The integrated model is calibrated to animal data. We make four predictions. First, antibiotics are frequently below effective concentrations inside granulomas, leading to bacterial growth between doses and contributing to the long treatment periods required for TB. Second, antibiotic concentration gradients form within granulomas, with lower concentrations toward their centers. Third, during antibiotic treatment, bacterial subpopulations are similar for INH and RIF treatment: mostly intracellular with extracellular bacteria located in areas non-permissive for replication (hypoxic areas), presenting a slowly increasing target population over time. In conclusion, we find that on an individual granuloma basis, pre-treatment infection severity (including bacterial burden, host cell activation and host cell death) is predictive of treatment outcome.
Pienaar, Elsje, et al. "A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment." Journal of Theoretical Biology, vol. 367, Dec. 2014. https://doi.org/10.1016/j.jtbi.2014.11.021
Pienaar, Elsje, Cilfone, Nicholas A., Lin, Philana Ling, Dartois, Veronique, Mattila, Joshua T., Butler, J. Russell, Flynn, JoAnne L., Kirschner, Denise E., & Linderman, Jennifer J. (2014). A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment. Journal of Theoretical Biology, 367. https://doi.org/10.1016/j.jtbi.2014.11.021
Pienaar, Elsje, Cilfone, Nicholas A., Lin, Philana Ling, et al., "A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment," Journal of Theoretical Biology 367 (2014), https://doi.org/10.1016/j.jtbi.2014.11.021
@article{osti_1344478,
author = {Pienaar, Elsje and Cilfone, Nicholas A. and Lin, Philana Ling and Dartois, Veronique and Mattila, Joshua T. and Butler, J. Russell and Flynn, JoAnne L. and Kirschner, Denise E. and Linderman, Jennifer J.},
title = {A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment},
annote = {While active tuberculosis (TB) is a treatable disease, many complex factors prevent its global elimination. Part of the difficulty in developing optimal therapies is the large design space of antibiotic doses, regimens and combinations. Computational models that capture the spatial and temporal dynamics of antibiotics at the site of infection can aid in reducing the design space of costly and time-consuming animal pre-clinical and human clinical trials. The site of infection in TB is the granuloma, a collection of immune cells and bacteria that form in the lung, and new data suggest that penetration of drugs throughout granulomas is problematic. In this paper, we integrate our computational model of granuloma formation and function with models for plasma pharmacokinetics, lung tissue pharmacokinetics and pharmacodynamics for two first line anti-TB antibiotics. The integrated model is calibrated to animal data. We make four predictions. First, antibiotics are frequently below effective concentrations inside granulomas, leading to bacterial growth between doses and contributing to the long treatment periods required for TB. Second, antibiotic concentration gradients form within granulomas, with lower concentrations toward their centers. Third, during antibiotic treatment, bacterial subpopulations are similar for INH and RIF treatment: mostly intracellular with extracellular bacteria located in areas non-permissive for replication (hypoxic areas), presenting a slowly increasing target population over time. In conclusion, we find that on an individual granuloma basis, pre-treatment infection severity (including bacterial burden, host cell activation and host cell death) is predictive of treatment outcome.},
doi = {10.1016/j.jtbi.2014.11.021},
url = {https://www.osti.gov/biblio/1344478},
journal = {Journal of Theoretical Biology},
issn = {ISSN 0022-5193},
volume = {367},
place = {United States},
publisher = {Elsevier},
year = {2014},
month = {12}}
