Early Bactericidal Activity of Meropenem Plus Clavulanate (+/-Rifampin) For TB: The COMRADE Randomized, Phase 2 Trial

Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain.Evaluate the fourteen-day bactericidal activity of meropenem, at different doses, with or without rifampin,.Individuals with pulmonary tuberculosis were randomized to one of four intravenous meropenem-based arms: 2 grams 8 hourly (Arm C), 2 grams 8 hourly plus rifampin 20 mg/kg once daily (Arm D), 1 gram 8 hourly (Arm E) or 3 grams 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 mL of sputum (solid culture)(EBACFU0-14) and increase in time to liquid culture positivity (TTP) were estimated with mixed-effects modelling. Serial blood samples were collected for pharmacokinetic analysis on Day 13.Sixty participants enrolled. Median (2.5th-97.5th percentiles) EBACFU0-14 was 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 (0.052-0.37), 0.094 (0.034-0.23), and 0.12 (0.04-0.41) (log10h), for Arms C, D, E, and F, respectively. Meropenem pharmacokinetics were not impacted by rifampin co-administration. Twelve participants withdrew early, many of whom cited gastrointestinal adverse events.Bactericidal activity was greater with the World Health Organization recommended total daily dose of 6 grams daily than a lower dose of 3 grams 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. Clinical trial registration available at www.gov, ID: NCT03174184.