TY - JOUR
T1 - Early Bactericidal Activity of Meropenem plus Clavulanate (with or without Rifampin) for Tuberculosis The COMRADE Randomized, Phase 2A Clinical Trial
AU - the COMRADE Study Team
AU - De Jager, Veronique
AU - Gupte, Nikhil
AU - Nunes, Silvia
AU - Barnes, Grace L.
AU - van Wijk, Rob Christiaan
AU - Mostert, Joni
AU - Dorman, Susan E.
AU - Abulfathi, Ahmed A.
AU - Upton, Caryn M.
AU - Faraj, Alan
AU - Nuermberger, Eric L.
AU - Lamichhane, Gyanu
AU - Svensson, Elin M.
AU - Simonsson, Ulrika S.H.
AU - Diacon, Andreas H.
AU - Dooley, Kelly E.
N1 - Publisher Copyright:
Copyright © 2022 by the American Thoracic Society
PY - 2022/5/15
Y1 - 2022/5/15
N2 - 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) (EBACFU0–14) 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 EBACFU0–14 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 (0.052–0.37), 0.094 (0.034–0.23), and 0.12 (0.04–0.41) (log10 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 al doses, calling into question the utility of this drug in second-line regimens. Clinical trial registered with www.clinicaltrials.gov (NCT03174184).
AB - 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) (EBACFU0–14) 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 EBACFU0–14 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 (0.052–0.37), 0.094 (0.034–0.23), and 0.12 (0.04–0.41) (log10 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 al doses, calling into question the utility of this drug in second-line regimens. Clinical trial registered with www.clinicaltrials.gov (NCT03174184).
KW - carbapenem
KW - early bactericidal activity
KW - meropenem
KW - phase 2A clinical trial
KW - tuberculosis
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UR - http://www.scopus.com/inward/citedby.url?scp=85130634778&partnerID=8YFLogxK
U2 - 10.1164/rccm.202108-1976OC
DO - 10.1164/rccm.202108-1976OC
M3 - Article
C2 - 35258443
AN - SCOPUS:85130634778
SN - 1073-449X
VL - 205
SP - 1228
EP - 1235
JO - American journal of respiratory and critical care medicine
JF - American journal of respiratory and critical care medicine
IS - 10
ER -