The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomized controlled trial comparing standard treatment with a regimen intensified by rifampin 15 mg/kg and levofloxacin for the first 60 days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic/pharmacodynamic study in 237 trial participants to define exposure-response relationships that might explain the trial results and improve future therapy. Rifampin 15 mg/kg increased plasma and cerebrospinal fluid (CSF) exposures compared with 10 mg/kg: day 14 exposure increased from 48.2 hour·mg/L (range 18.2-93.8) to 82.5 hour·mg/L (range 8.7-161.0) in plasma and from 3.5 hour·mg/L (range 1.2-9.6) to 6.0 hour·mg/L (range 0.7-15.1) in CSF. However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death, and was linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.

中文翻译：

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强化抗结核治疗结核性脑膜炎的药代动力学和药效学。

结核性脑膜炎最有效的抗结核药物治疗方案尚不确定。我们进行了一项随机对照试验，比较标准治疗与头60天以rifampin 15 mg / kg和左氧氟沙星加强治疗的方案。强化治疗不能改善生存或任何其他结果。因此，我们在237名试验参与者中进行了嵌套的药代动力学/药效学研究，以定义可能解释试验结果并改善未来治疗的暴露-反应关系。与10 mg / kg相比，利福平15 mg / kg的血浆和脑脊液（CSF）暴露增加：第14天的暴露从48.2小时·mg / L（范围18.2-93.8）增加到82.5小时·mg / L（范围8.7-161.0） ）和血浆中的3.5小时·mg / L（范围1.2-9.6）至6.0小时·mg / L（范围0.7-15.1）。然而，利福平暴露与生存率之间没有关系。相反，我们发现异烟肼暴露与生存相关，低暴露可预示死亡，并且与快速代谢者表型有关。应该研究更高剂量的异烟肼，尤其是在快速代谢者中。