A Long-term Co-perfused Disseminated Tuberculosis-3D Liver Hollow Fiber Model for Both Drug Efficacy and Hepatotoxicity in Babies.

Abstract

Treatment of disseminated tuberculosis in children≤6years has not been optimized. The pyrazinamide-containing combination regimen used to treat disseminated tuberculosis in babies and toddlers was extrapolated from adult pulmonary tuberculosis. Due to hepatotoxicity worries, there are no dose-response studies in children. We designed a hollow fiber system model of disseminated intracellular tuberculosis with co-perfused three-dimensional organotypic liver modules to simultaneously test for efficacy and toxicity. We utilized pediatric pharmacokinetics of pyrazinamide and acetaminophen to determine dose-dependent pyrazinamide efficacy and hepatotoxicity. Acetaminophen concentrations that cause hepatotoxicity in children led to elevated liver function tests, while 100mg/kg pyrazinamide did not. Surprisingly, pyrazinamide did not kill intracellular Mycobacterium tuberculosis up to fourfold the standard dose as monotherapy or as combination therapy, despite achieving high intracellular concentrations. Host-pathogen RNA-sequencing revealed lack of a pyrazinamide exposure transcript signature in intracellular bacteria or of phagolysosome acidification on pH imaging. Artificial intelligence algorithms confirmed that pyrazinamide was not predictive of good clinical outcomes in children≤6years who had extrapulmonary tuberculosis. Thus, adding a drug that works inside macrophages could benefit children with disseminated tuberculosis. Our in vitro model can be used to identify such new regimens that could accelerate cure while minimizing toxicity.

• Authors: Shashikant Srivastava, Jotam G Pasipanodya, Geetha Ramachandran, Devyani Deshpande, Stephen Shuford, Howland E Crosswell, Kayle N Cirrincione, Carleton M Sherman, Soumya Swaminathan, Tawanda Gumbo
• Journal: EBioMedicine (EBioMedicine) Vol. 6 Pg. 126-138 (Apr 2016) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 27211555 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.

Chemical References

• Antitubercular Agents
• Pyrazinamide
• Acetaminophen

Topics

• Acetaminophen (pharmacokinetics, toxicity)
• Antitubercular Agents (administration & dosage, adverse effects, pharmacokinetics)
• Cell Line
• Chemical and Drug Induced Liver Injury (physiopathology)
• Child, Preschool
• Coculture Techniques
• Humans
• Infant
• Infant, Newborn
• Models, Biological
• Mycobacterium tuberculosis (drug effects)
• Pyrazinamide (administration & dosage, adverse effects, pharmacokinetics)
• Toxicity Tests
• Treatment Outcome
• Tuberculosis (drug therapy)