Title
High-Dose Rifampin Leads to More Rapid Sputum Sterilization in Smear-Positive Pulmonary Tuberculosis without Increased Toxicity
Summarized by
Kelly M. Pennington
Citation
Gustavo E. Velasquez, Meredith B. Brooks, Julia Coit, Henry Pertinez, Dante Vargas Vasquez, Epifanio Sanchez Garavito, Roger I. Calderon, Judith Jimenez, Karen Tintaya, Charles A. Peloquin, Elna Osso, Dylan B. Tierney, Kwonjune J. Seung, Leonid Lecca, Geraint R. Davies, and Carole D. Mitnick. Efficacy and Safety of High-Dose Rifampin in Pulmonary Tuberculosis: A Randomized Controlled Trial. AJRCCM 198(5): 657. 2018
Summary
Mycobacterium tuberculosis continues to be the leading cause of infectious death worldwide. A 6-month, 4 drug regimen is the current standard of care for newly diagnosed pulmonary tuberculosis. Many studies have been completed over the last 20 years in an attempt to shorten the treatment regimen—by adding fluoroquinolones, rifapentine, or identifying low risk individuals. The current study examines the effect of increased daily dose rifampin on time to sputum sterilization and toxicity. Shortening treatment duration by optimizing daily dose rifampin is a potentially valuable intervention as rifampin is an established first-line drug for Tuberculosis and is already available throughout the world.
The current study was a blinded, randomized control trial examining the effect of three different intensive daily doses of rifampin (10, 15, or 20 mg/kg) on sputum eradication and rifampin related toxicities. All participants received standard rifampin dosing (10 mg/kg three times weekly) during the continuation phase. 180 patients were randomized (60 in each arm). Each 5 mg/kg/d increase in rifampin resulted in a statistically significant increase in M. tuberculosis sputum elimination when analyzed by per-protocol analysis. A trend toward significance was noted with the modified intention to treat analysis. The most common rifampin related adverse event were hepatic (24.4%), gastrointestinal (14.4%), musculoskeletal (12.2%), and respiratory (11.7%). Serious adverse events and grade-2 rifampin adverse events were similar amongst all 3 groups.
This study showed that with combination therapy higher doses of rifampin can lead to an increased rate of sputum sterilization without increased rifampin associated toxicities. However, the study was not powered to evaluate 8-week culture conversion and did not find any difference in the 8-week culture conversion. The results of this study, in combination with prior studies such as PanACEA and RIFATOX, suggest that rifampin dosing of 20 mg/kg/d may not be sufficient for treatment shortening. Nonetheless, this study gives reassurance that higher doses of Rifampin may lead to more rapid sputum sterilization without the risk of increased toxicity. Further studies are warranted to examine the effect of higher doses of rifampin on sputum eradication and potential treatment shortening.
