Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis.
Linezolid Dose That Maximizes Sterilizing Effect While Minimizing Toxicity and Resistance Emergence for Tuberculosis.
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DOI：
10.1128/aac.00751-17
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发表时间：
2017-08
影响因子：
4.9
通讯作者：
Gumbo T
中科院分区：
文献类型：
--
作者：
Srivastava S;Magombedze G;Koeuth T;Sherman C;Pasipanodya JG;Raj P;Wakeland E;Deshpande D;Gumbo T
利奈唑胺对肺结核患者具有良好的杀菌效果，但不良事件发生率较高。最大化疗效和最小化毒性的剂量是未知的。我们在结核病中空纤维系统模型（HFS-TB）中进行了利奈唑胺剂量效应和剂量调度研究，以获得灭菌效果。HFS-TB单位用几种剂量处理，以模拟人样利奈唑胺肺内药代动力学，并在2个月内重复采样用于药物浓度、总细菌负荷、利奈唑胺耐药亚群和RNA测序。对利奈唑胺耐药分离株进行全基因组测序。前1 - 2周编码外排泵的基因表达显示与利奈唑胺耐药亚群相同的抑制-应答模式。治疗第2个月的利奈唑胺耐药分离株显示几种外排泵/转运蛋白基因和LuxR家族转录调节因子突变。利奈唑胺的灭菌作用与未结合0- 24 h浓度-时间曲线下面积（AUC 0 -24）与MIC的比值相关。在AUC 0 -24/MIC比为119时达到最佳微生物杀灭效果。使用Monte Carlo模拟确定了临床使用的最佳灭菌效果剂量。300和600 mg/天（或每隔一天加倍剂量）的临床剂量分别在87%和>99%的10，000例患者中达到了这一目标。确定的敏感性折点为2 mg/L。模拟发现，300 mg/天剂量未达到与利奈唑胺毒性相关的AUC 0 - 24 s，而600 mg/天剂量在<20%的受试者中达到这些AUC 0 - 24 s。利奈唑胺300 mg/天剂量表现良好，应在临床试验中与600 mg/天或1，200 mg每隔一天进行比较。
Linezolid has an excellent sterilizing effect in tuberculosis patients but high adverse event rates. The dose that would maximize efficacy and minimize toxicity is unknown. We performed linezolid dose-effect and dose-scheduling studies in the hollow fiber system model of tuberculosis (HFS-TB) for sterilizing effect. HFS-TB units were treated with several doses to mimic human-like linezolid intrapulmonary pharmacokinetics and repetitively sampled for drug concentration, total bacterial burden, linezolid-resistant subpopulations, and RNA sequencing over 2 months. Linezolid-resistant isolates underwent whole-genome sequencing. The expression of genes encoding efflux pumps in the first 1 to 2 weeks revealed the same exposure-response patterns as the linezolid-resistant subpopulation. Linezolid-resistant isolates from the 2nd month of therapy revealed mutations in several efflux pump/transporter genes and a LuxR-family transcriptional regulator. Linezolid sterilizing effect was linked to the ratio of unbound 0- to 24-h area under the concentration-time curve (AUC0–24) to MIC. Optimal microbial kill was achieved at an AUC0–24/MIC ratio of 119. The optimal sterilizing effect dose for clinical use was identified using Monte Carlo simulations. Clinical doses of 300 and 600 mg/day (or double the dose every other day) achieved this target in 87% and >99% of 10,000 patients, respectively. The susceptibility breakpoint identified was 2 mg/liter. The simulations identified that a 300-mg/day dose did not achieve AUC0–24s associated with linezolid toxicity, while 600 mg/day achieved those AUC0–24s in <20% of subjects. The linezolid dose of 300 mg/day performed well and should be compared to 600 mg/day or 1,200 mg every other day in clinical trials.