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

• DOI: 10.1164/rccm.202108-1976oc
• Publication Date: 2022-03-08T14:58:13Z
• Authors: Veronique De Jager; Nikhil Gupte; Silvia Nunes; Grace L. Barnes; Rob Christiaan va...; Joni Mostert; Susan E. Dorman; Ahmed A. Abulfathi; Caryn M. Upton; Alan Faraj; Eric L. Nuermberger; Gyanu Lamichhane; Elin M. Svensson; Ulrika S. H. Simo...; Andreas H. Diacon; Kelly E. Dooley
• Keywords: Antitubercular Agents; Radboud University Medical Center; Amoxicillin; Clinical Pharmacy - Radboud University Medical Center; Meropenem; 16. Peace & justice; 3. Good health; 03 medical and health sciences; 0302 clinical medicine; Isoniazid; Humans; Drug Therapy, Combination; Rifampin; Radboudumc 4: lnfectious Diseases and Global Health RIHS: Radboud Institute for Health Sciences; Tuberculosis, Pulmonary; Clavulanic Acid

Rationale: Carbapenems are recommended for treatment of drug-resistant tuberculosis. Optimal dosing remains uncertain. Objectives: To evaluate the 14-day bactericidal activity meropenem, at different doses, with or without rifampin. Methods: Individuals drug-sensitive pulmonary tuberculosis were randomized to one four intravenous meropenem-based arms: 2 g every 8 hours (TID) (arm C), TID plus rifampin 20 mg/kg once daily D), 1 E), 3 F). All participants received amoxicillin/clavulanate each meropenem dose. Serial overnight sputum samples collected from baseline and throughout treatment. Median fall in colony-forming unit (CFU) counts per milliliter (solid culture) (EBACFU0–14) increase time positive culture (TTP) liquid media estimated mixed-effects modeling. blood pharmacokinetic analysis on Day 13. Measurements Main Results: Sixty enrolled. EBACFU0–14 (2.5th–97.5th percentiles) 0.22 (0.12–0.33), 0.12 (0.057–0.21), 0.059 (0.033–0.097), 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), (0.04–0.41) (log10 h), arms C–F, respectively. Meropenem pharmacokinetics not affected coadministration. Twelve withdrew early, many whom cited gastrointestinal adverse events. Conclusions: Bactericidal was greater World Health Organization–recommended total dose 6 than a lower daily. This difference only detectable solid culture. Tolerability amoxicillin/clavulanate, though, poor all calling into question utility this drug second-line regimens. Clinical trial registered www.clinicaltrials.gov (NCT03174184).