Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial



Velasquez, Gustavo E, Brooks, Meredith B, Coit, Julia M, Pertinez, Henry, Vasquez, Dante Vargas, Garavito, Epifano Sanchez, Calderon, Roger I, Jimenez, Judith, Tintaya, Karen, Peloquin, Charles A
et al (show 6 more authors) (2018) Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis. A Randomized Controlled Trial. American Journal of Respiratory and Critical Care Medicine, 198 (5). pp. 657-666.

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Abstract

Rationale: We examined whether increased rifampin doses could shorten standard therapy for tuberculosis without increased toxicity. Objectives: To assess the differences across three daily oral doses of rifampin in change in elimination rate of Mycobacterium tuberculosis in sputum and frequency of rifampin-related adverse events. Methods: We conducted a blinded, randomized, controlled phase 2 clinical trial of 180 adults with new smear-positive pulmonary tuberculosis, susceptible to isoniazid and rifampin. We randomized 1:1:1 to rifampin at 10, 15, and 20 mg/kg/d during the intensive phase. We report the primary efficacy and safety endpoints: change in elimination rate of M. tuberculosis log10 colony-forming units and frequency of grade 2 or higher rifampin-related adverse events. We report efficacy by treatment arm and by primary (area under the plasma concentration–time curve [AUC]/minimum inhibitory concentration [MIC]) and secondary (AUC) pharmacokinetic exposure. Measurements and Main Results: Each 5-mg/kg/d increase in rifampin dose resulted in differences of −0.011 (95% confidence interval, −0.025 to +0.002; P = 0.230) and −0.022 (95% confidence interval, −0.046 to −0.002; P = 0.022) log10 cfu/ml/d in the modified intention-to-treat and per-protocol analyses, respectively. The elimination rate in the per-protocol population increased significantly with rifampin AUC0–6 (P = 0.011) but not with AUC0–6/MIC99.9 (P = 0.053). Grade 2 or higher rifampin-related adverse events occurred with similar frequency across the three treatment arms: 26, 31, and 23 participants (43.3%, 51.7%, and 38.3%, respectively) had at least one event (P = 0.7092) up to 4 weeks after the intensive phase. Treatment failed or disease recurred in 11 participants (6.1%). Conclusions: Our findings of more rapid sputum sterilization and similar toxicity with higher rifampin doses support investigation of increased rifampin doses to shorten tuberculosis treatment.

Item Type: Article
Uncontrolled Keywords: tuberculosis, rifampin, randomized controlled trial, treatment efficacy, adverse drug event
Depositing User: Symplectic Admin
Date Deposited: 22 Aug 2018 15:33
Last Modified: 15 Mar 2024 01:49
DOI: 10.1164/rccm.201712-2524OC
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3024697