Subtherapeutic Rifampicin Concentration Is Associated With Unfavorable Tuberculosis Treatment Outcomes. (10th May 2019)

• Record Type: Journal Article
• Authors: Ramachandran, Geetha; Chandrasekaran, Padmapriyadarshini; Gaikwad, Sanjay; Agibothu Kupparam, Hemanth Kumar; Thiruvengadam, Kannan; Gupte, Nikhil; Paradkar, Mandar; Dhanasekaran, Kavitha; Sivaramakrishnan, Gomathi Narayan; Kagal, Anju; Thomas, Beena; Pradhan, Neeta; Kadam, Dileep; Hanna, Luke Elizabeth; Balasubramanian, Usha; Kulkarni, Vandana; Murali, Lakshmi; Golub, Jonathan; Gupte, Akshay; Shivakumar, Shri Vijay Bala Yogendra; Swaminathan, Soumya; Dooley, Kelly E; Gupta, Amita; Mave, Vidya
• Is Part Of: Clinical infectious diseases. Volume 70:Number 7(2020)
• Page Start: 1463
• Page End: 1470
• Publication Date: 2019-05-10
• Subjects: tuberculosis -- pharmacokinetics -- drug concentrations -- subtherapeutic concentrations -- unfavorable treatment outcomes; Communicable diseases -- Periodicals; 616.905
• DOI: 10.1093/cid/ciz380
• Languages: English
• ISSNs: 1058-4838

Abstract

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. Abstract : In a prospective cohort of patients with newly diagnosed pulmonary tuberculosis receiving standard thrice-weekly antituberculosis treatment in India, lower rifampicin concentration was associated with Human Immunodeficiency Virus coinfection and independently associated with unfavorable treatment outcomes.