Meta-analysis of clinical studies supports the pharmacokinetic variability hypothesis for acquired drug resistance and failure of antituberculosis therapy

Clin Infect Dis. 2012 Jul;55(2):169-77. doi: 10.1093/cid/cis353. Epub 2012 Mar 30.


Background: Using hollow-fiber tuberculosis studies, we recently demonstrated that nonadherence is not a significant factor for ADR and that therapy failure only occurs after a large proportion of doses are missed. Computer-aided clinical trial simulations have suggested that isoniazid and rifampin pharmacokinetic variability best explained poor outcomes. We were interested in determining whether isoniazid pharmacokinetic variability was associated with either microbiological failure or ADR in the clinic.

Methods: Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Prospective, randomized, controlled clinical trials that reported isoniazid acetylation status and microbiological outcomes were selected. The main effects examined were microbiological sputum conversion, ADR, and relapse. Effect size was expressed as pooled risk ratios (RRs) comparing rapid with slow acetylators.

Results: Thirteen randomized studies with 1631 rapid acetylators and 1751 slow acetylators met inclusion and exclusion criteria. Rapid acetylators were more likely than slow acetylators to have microbiological failure (RR, 2.0; 95% confidence interval [CI], 1.5-2.7), ADR (RR, 2.0; CI, 1.1-3.4), and relapse (RR, 1.3; CI, .9-2.0). Higher failure rates were encountered even in drug regimens comprising >3 antibiotics. No publication bias or small-study effects were observed for the outcomes evaluated.

Conclusions: Pharmacokinetic variability to a single drug in the regimen is significantly associated with failure of therapy and ADR in patients. This suggests that individualized dosing for tuberculosis may be more effective than standardized dosing, which is prescribed in directly observed therapy programs.

Publication types

  • Meta-Analysis
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Antitubercular Agents / administration & dosage
  • Antitubercular Agents / pharmacokinetics*
  • Antitubercular Agents / pharmacology*
  • Drug Resistance, Bacterial*
  • Humans
  • Isoniazid / administration & dosage
  • Isoniazid / pharmacokinetics
  • Isoniazid / pharmacology
  • Mycobacterium tuberculosis / drug effects*
  • Mycobacterium tuberculosis / isolation & purification
  • Prospective Studies
  • Randomized Controlled Trials as Topic
  • Recurrence
  • Sputum / microbiology
  • Treatment Failure
  • Tuberculosis, Multidrug-Resistant / drug therapy*
  • Tuberculosis, Multidrug-Resistant / microbiology*


  • Antitubercular Agents
  • Isoniazid