title: Serum drug concentrations predictive of pulmonary tuberculosis outcomes.
abstract: BACKGROUND
  Based on a hollow-fiber system model of tuberculosis, we hypothesize that microbiologic failure and acquired drug resistance are primarily driven by low drug concentrations that result from pharmacokinetic variability.
  
  
  METHODS
  Clinical and pharmacokinetic data were prospectively collected from 142 tuberculosis patients in Western Cape, South Africa. Compartmental pharmacokinetic parameters of isoniazid, rifampin, and pyrazinamide were identified for each patient. Patients were then followed for up to 2 years. Classification and regression tree analysis was used to identify and rank clinical predictors of poor long-term outcome such as microbiologic failure or death, or relapse.
  
  
  RESULTS
  Drug concentrations and pharmacokinetics varied widely between patients. Poor long-term outcomes were encountered in 35 (25%) patients. The 3 top predictors of poor long-term outcome, by rank of importance, were a pyrazinamide 24-hour area under the concentration-time curve (AUC) ≤ 363 mg·h/L, rifampin AUC ≤ 13 mg·h/L, and isoniazid AUC ≤ 52 mg·h/L. Poor outcomes were encountered in 32/78 patients with the AUC of at least 1 drug below the identified threshold vs 3/64 without (odds ratio = 14.14; 95% confidence interval, 4.08-49.08). Low rifampin and isoniazid peak and AUC concentrations preceded all cases of acquired drug resistance.
  
  
  CONCLUSIONS
  Low drug AUCs are predictive of clinical outcomes in tuberculosis patients.
authors.affiliation: Office of Global Health, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jotam G
authors.initials: JG
authors.lastname: Pasipanodya
authors.forename: Helen
authors.initials: H
authors.lastname: McIlleron
authors.forename: André
authors.initials: A
authors.lastname: Burger
authors.forename: Peter A
authors.initials: PA
authors.lastname: Wash
authors.forename: Peter
authors.initials: P
authors.lastname: Smith
authors.forename: Tawanda
authors.initials: T
authors.lastname: Gumbo
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000995:Antitubercular Agents / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000097:blood / Q000493:pharmacokinetics*; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011446:Prospective Studies; D011718:Pyrazinamide / Q000097:blood / Q000493:pharmacokinetics*; D012293:Rifampin / Q000097:blood / Q000493:pharmacokinetics*; D016896:Treatment Outcome; D014397:Tuberculosis, Pulmonary / Q000097:blood / Q000188:drug therapy* / Q000401:mortality; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D011718:Pyrazinamide; D007538:Isoniazid; D012293:Rifampin
keywords: classification and regression tree analysis; drug concentrations; hollow-fiber system; nonlinear systems; outcomes; pharmacokinetic variability; tuberculosis
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