title: Drug Concentration Thresholds Predictive of Therapy Failure and Death in Children With Tuberculosis: Bread Crumb Trails in Random Forests.
abstract: BACKGROUND
  The role of drug concentrations in clinical outcomes in children with tuberculosis is unclear. Target concentrations for dose optimization are unknown.
  
  
  METHODS
  Plasma drug concentrations measured in Indian children with tuberculosis were modeled using compartmental pharmacokinetic analyses. The children were followed until end of therapy to ascertain therapy failure or death. An ensemble of artificial intelligence algorithms, including random forests, was used to identify predictors of clinical outcome from among 30 clinical, laboratory, and pharmacokinetic variables.
  
  
  RESULTS
  Among the 143 children with known outcomes, there was high between-child variability of isoniazid, rifampin, and pyrazinamide concentrations: 110 (77%) completed therapy, 24 (17%) failed therapy, and 9 (6%) died. The main predictors of therapy failure or death were a pyrazinamide peak concentration <38.10 mg/L and rifampin peak concentration <3.01 mg/L. The relative risk of these poor outcomes below these peak concentration thresholds was 3.64 (95% confidence interval [CI], 2.28-5.83). Isoniazid had concentration-dependent antagonism with rifampin and pyrazinamide, with an adjusted odds ratio for therapy failure of 3.00 (95% CI, 2.08-4.33) in antagonism concentration range. In regard to death alone as an outcome, the same drug concentrations, plus z scores (indicators of malnutrition), and age <3 years, were highly ranked predictors. In children <3 years old, isoniazid 0- to 24-hour area under the concentration-time curve <11.95 mg/L × hour and/or rifampin peak <3.10 mg/L were the best predictors of therapy failure, with relative risk of 3.43 (95% CI, .99-11.82).
  
  
  CONCLUSIONS
  We have identified new antibiotic target concentrations, which are potential biomarkers associated with treatment failure and death in children with tuberculosis.
authors.affiliation: National Institute for Research in Tuberculosis, Chennai, India.
authors.forename: Soumya
authors.initials: S
authors.lastname: Swaminathan
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, Texas.
authors.forename: Jotam G
authors.initials: JG
authors.lastname: Pasipanodya
authors.affiliation: National Institute for Research in Tuberculosis, Chennai, India.
authors.forename: Geetha
authors.initials: G
authors.lastname: Ramachandran
authors.affiliation: National Institute for Research in Tuberculosis, Chennai, India.
authors.forename: A K
authors.initials: AK
authors.lastname: Hemanth Kumar
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, Texas.
authors.forename: Shashikant
authors.initials: S
authors.lastname: Srivastava
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, Texas.
authors.forename: Devyani
authors.initials: D
authors.lastname: Deshpande
authors.affiliation: Center for Tuberculosis Research, Department of Medicine Department of International Health, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors.forename: Eric
authors.initials: E
authors.lastname: Nuermberger
authors.affiliation: Center for Infectious Diseases Research and Experimental Therapeutics, Baylor Research Institute, Dallas, Texas Department of Medicine, University of Cape Town, Observatory, South Africa.
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
mesh_terms: D000293:Adolescent; D000995:Antitubercular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D015415:Biomarkers; D002648:Child; D002675:Child, Preschool; D060085:Coinfection; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000188:drug therapy; D006801:Humans; D007223:Infant; D000069550:Machine Learning; D008297:Male; D015233:Models, Statistical; D011379:Prognosis; D012680:Sensitivity and Specificity; D017211:Treatment Failure; D016896:Treatment Outcome; D014376:Tuberculosis / Q000175:diagnosis / Q000188:drug therapy* / Q000401:mortality*
chemical_list: D000995:Antitubercular Agents; D015415:Biomarkers
keywords: boosted classification and regression tree analyses; childhood tuberculosis; drug concentration thresholds; pharmacokinetic variability; random forests