Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps.
Linezolid for Infants and Toddlers With Disseminated Tuberculosis: First Steps.
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DOI：
10.1093/cid/ciw482
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发表时间：
2016-11-01
期刊：
影响因子：
--
通讯作者：
Gumbo T
中科院分区：
文献类型：
--
作者：
Deshpande D;Srivastava S;Pasipanodya JG;Bush SJ;Nuermberger E;Swaminathan S;Gumbo T
背景：婴幼儿常表现为播散性和淋巴结结核，其中结核分枝杆菌（Mtb）主要是细胞内的。 利奈唑胺用于治疗成人结核病，尚未在婴儿中进行正式研究。婴儿清除利奈唑胺的速度比成人快5倍，0- 24小时浓度-时间曲线下面积（AUC 0 -24）较低。方法：为了模拟细胞内疾病，我们用结核分枝杆菌感染人源性THP-1巨噬细胞并接种中空纤维系统。 我们进行了剂量效应和剂量安排研究，其中我们概括了婴儿中利奈唑胺的半衰期为3小时。对利奈唑胺药代动力学、Mtb细胞内负荷、活单核细胞计数和RNA测序读数进行了长达28天的重复采样。结果：利奈唑胺的细胞外半衰期为2.64 ± 0.38小时，而细胞内半衰期为8.93 ± 1.30小时（r2 = 0.89）。 利奈唑胺的疗效与AUC 0 -24与最小抑制浓度（MIC）的比值（r2 = 0.98）有关。与最大Mtb杀灭相关的暴露量为AUC 0 -24/MIC 23.37 ± 1.16。我们在暴露于毒性利奈唑胺剂量时鉴定了414基因转录物。最大数量的基因定位于核糖体蛋白，这是迄今为止与利奈唑胺毒性无关的特征。第二大数量的差异表达基因映射到线粒体酶抑制。利奈唑胺AUC 0 -24最好地解释了线粒体基因抑制，在94 mg × h/L时抑制率为50%（最高r2 = 0.98）。结论：我们确定了利奈唑胺的AUC 0 -24/MIC目标值，以获得对儿童细胞内结核病的最佳疗效，并确定了与线粒体抑制相关的AUC 0 -24阈值。 这些构成了结核病儿童中最佳利奈唑胺剂量的治疗窗口。
Background. Infants and toddlers often present with disseminated and lymph node tuberculosis, in which Mycobacterium tuberculosis (Mtb) is predominantly intracellular. Linezolid, used to treat tuberculosis in adults, has not been formally studied in infants. Infants clear linezolid 5 times faster than adults and achieve lower 0- to 24-hour area under the concentration-time curves (AUC0–24). Methods. To mimic intracellular disease, we infected human-derived THP-1 macrophages with Mtb and inoculated hollow fiber systems. We performed dose-effect and dose-scheduling studies in which we recapitulated the linezolid half-life of 3 hours encountered in infants. Repetitive sampling for linezolid pharmacokinetics, Mtb intracellular burden, viable monocyte count, and RNA sequencing reads were performed up to 28 days. Results. The linezolid extracellular half-life was 2.64 ± 0.38 hours, whereas intracellular half-life was 8.93 ± 1.30 hours (r2 = 0.89). Linezolid efficacy was linked to the AUC0–24 to minimum inhibitory concentration (MIC) ratio (r2 = 0.98). The exposure associated with maximal Mtb kill was an AUC0–24/MIC of 23.37 ± 1.16. We identified a 414-gene transcript on exposure to toxic linezolid doses. The largest number of genes mapped to ribosomal proteins, a signature hitherto not associated with linezolid toxicity. The second-largest number of differentially expressed genes mapped to mitochondrial enzyme inhibition. Linezolid AUC0–24 best explained the mitochondrial gene inhibition, with 50% inhibition at 94 mg × hour/L (highest r2 = 0.98). Conclusions. We identified the linezolid AUC0–24/MIC target for optimal efficacy against pediatric intracellular tuberculosis, and an AUC0–24 threshold associated with mitochondrial inhibition. These constitute a therapeutic window to be targeted for optimal linezolid doses in children with tuberculosis.
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