期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 62, 期 12, 页码 -出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.01014-18
关键词
Indonesia; Mycobacterium tuberculosis; RCT; meningeal; pharmacokinetics; rifampin; survival; tolerability
资金
- Peer Health (National Academy of Sciences [NAS]United States Agency for International Development [USAID])
- Ministry of Research, Technology and Higher Education, Indonesia (PKSLN grant)
- Direktorat Jenderal Pendidikan Tinggi (BPPLN fellowship)
- Radboud University Medical Center, the Netherlands
High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a doubleblind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 +/- 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC(0-24)], 53.5mg.h/liter versus 170.6mg.h/liter and 293.5 mg.h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial.
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