title: 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.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
authors.forename: Shashikant
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
authors.forename: Jotam G
authors.initials: JG
authors.lastname: Pasipanodya
authors.affiliation: Tuberculosis Research Center Chennai, India.
authors.forename: Geetha
authors.initials: G
authors.lastname: Ramachandran
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
authors.forename: Devyani
authors.initials: D
authors.lastname: Deshpande
authors.affiliation: KIYATEC Inc., Greenville, SC, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Shuford
authors.affiliation: KIYATEC Inc., Greenville, SC, USA.
authors.forename: Howland E
authors.initials: HE
authors.lastname: Crosswell
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
authors.forename: Kayle N
authors.initials: KN
authors.lastname: Cirrincione
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA.
authors.forename: Carleton M
authors.initials: CM
authors.lastname: Sherman
authors.affiliation: Tuberculosis Research Center Chennai, India.
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Baylor University Medical Center, Dallas, TX, USA; Tuberculosis Research Center Chennai, India. Electronic address: tawanda.gumbo@BSWhealth.org.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
mesh_terms: D000082:Acetaminophen / Q000493:pharmacokinetics / Q000633:toxicity; D000995:Antitubercular Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000503:physiopathology*; D002675:Child, Preschool; D018920:Coculture Techniques; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008954:Models, Biological; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011718:Pyrazinamide / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D018675:Toxicity Tests; D016896:Treatment Outcome; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D000082:Acetaminophen
keywords: 3D liver hollow fiber model; Disseminated tuberculosis; Hepatotoxicity; Pediatric