Subtherapeutic rifampicin concentration is associated with unfavorable tuberculosis treatment outcomes

for the Cohort for Tuberculosis Research by the Indo-US Partnership (CTRIUMPh) Team

Research output: Contribution to journalArticle

Abstract

Background: The relationships between first-line drug concentrations and clinically important outcomes among patients with tuberculosis (TB) remain poorly understood. Methods: We enrolled a prospective cohort of patients with new pulmonary TB receiving thrice-weekly treatment in India. The maximum plasma concentration of each drug was determined at months 1 and 5 using blood samples drawn 2 hours postdose. Subtherapeutic cutoffs were: rifampicin <8 μg/mL, isoniazid <3 μg/mL, and pyrazinamide <20 μg/mL. Factors associated with lower log-transformed drug concentrations, unfavorable outcomes (composite of treatment failure, all-cause mortality, and recurrence), and individual outcomes were examined using Poisson regression models. Results: Among 404 participants, rifampicin, isoniazid, and pyrazinamide concentrations were subtherapeutic in 85%, 29%, and 13%, respectively, at month 1 (with similar results for rifampicin and isoniazid at month 5). Rifampicin concentrations were lower with human immunodeficiency virus coinfection (median, 1.6 vs 4.6 μg/mL; P =. 015). Unfavorable outcome was observed in 19%; a 1-μg/mL decrease in rifampicin concentration was independently associated with unfavorable outcome (adjusted incidence rate ratio [aIRR], 1.21 [95% confidence interval {CI}, 1.01-1.47]) and treatment failure (aIRR, 1.16 [95% CI, 1.05-1.28]). A 1-μg/mL decrease in pyrazinamide concentration was associated with recurrence (aIRR, 1.05 [95% CI, 1.01-1.11]). Conclusions: Rifampicin concentrations were subtherapeutic in most Indian patients taking a thrice-weekly TB regimen, and low rifampicin and pyrazinamide concentrations were associated with poor outcomes. Higher or more frequent dosing is needed to improve TB treatment outcomes in India.

Original languageEnglish (US)
Pages (from-to)1463-1470
Number of pages8
JournalClinical Infectious Diseases
Volume70
Issue number7
DOIs
StatePublished - Mar 17 2020

Keywords

  • drug concentrations
  • pharmacokinetics
  • subtherapeutic concentrations
  • tuberculosis
  • unfavorable treatment outcomes

ASJC Scopus subject areas

  • Microbiology (medical)
  • Infectious Diseases

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    for the Cohort for Tuberculosis Research by the Indo-US Partnership (CTRIUMPh) Team (2020). Subtherapeutic rifampicin concentration is associated with unfavorable tuberculosis treatment outcomes. Clinical Infectious Diseases, 70(7), 1463-1470. https://doi.org/10.1093/cid/ciz380