Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis The COMRADE Randomized, Phase 2A Clinical Trial

Rationale: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain. Objectives: To evaluate the 14-day bactericidal activity of meropenem, at different doses, with or without rifampin. Methods: Individuals with drug-sensitive pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), 2 g TID plus rifampin at 20 mg/kg once daily (arm D), 1 g TID (arm E), or 3 g once daily (arm F). All participants received amoxicillin/clavulanate with each meropenem dose. Serial overnight sputum samples were collected from baseline and throughout treatment. Median daily fall in colony-forming unit (CFU) counts per milliliter of sputum (solid culture) (EBA(CFU0-14)) and increase in time to positive culture (TTP) in liquid media were estimated with mixed-effects modeling. Serial blood samples were collected for pharmacokinetic analysis on Day 13. Measurements and Main Results: Sixty participants enrolled. Median EBA(CFU0-14) counts (2.5th-97.5th percentiles) were 0.22 (0.12-0.33), 0.12 (0.057-0.21), 0.059 (0.033-0.097), and 0.053 (0.035-0.081); TTP increased by 0.34 (0.21-0.75), 0.11 (0.052-037), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log(10) h), for arms C-F, respectively. Meropenem pharmacokinetics were not affected by rifampin coadministration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events. Conclusions: Bactericidal activity was greater with the World Health Organization-recommended total daily dose of 6 g daily than with a lower dose of 3 g daily. This difference was only detectable with solid culture. Tolerability of intravenous meropenem, with amoxicillin/clavulanate, though, was poor at all doses, calling into question the utility of this drug in second-line regimens.