Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis: The Dynamic Duo.
Concentration-Dependent Synergy and Antagonism of Linezolid and Moxifloxacin in the Treatment of Childhood Tuberculosis: The Dynamic Duo.
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DOI：
10.1093/cid/ciw473
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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;Nuermberger E;Pasipanodya JG;Swaminathan S;Gumbo T
背景。目前还没有专门为儿童设计的治疗方案，因为儿童的结核病主要是细胞内的。考虑到利奈唑胺和莫西沙星作为单一疗法的活性，以及它们能够穿透许多弥散性结核病特征的病变解剖部位，它们可以联合使用，形成一种满足这一需求的治疗方案。方法。我们用7 × 7的数学矩阵检测了利奈唑胺和莫西沙星多重暴露对细胞内结核分枝杆菌（Mtb）的微生物杀伤作用。然后，我们使用细胞内结核的中空纤维系统（HFS）模型来确定莫西沙星和利奈唑胺联合使用的最佳剂量计划和暴露。我们模拟了每种药物的儿科半衰期和浓度。我们在第0、7、14、21和28天对外周细胞室取样进行Mtb定量，并根据指数下降回归将这些方案与异烟肼、利福平和吡嗪酰胺标准方案的Mtb微生物杀灭斜率进行比较。结果。全暴露-反应面确定了利奈唑胺-莫西沙星的协同、拮抗和可加性区域。然后在HFS模型中使用基于这些区域的方案，观察到利奈唑胺的半衰期为4.08±0.66小时，莫西沙星的半衰期为3.80±1.34小时。莫西沙星-利奈唑胺可加性区组的杀伤率常数为0.060±0.012 / d，而标准组为0.083±0.011 / d，细菌负荷半衰期分别为11.52天和8.53天。结论。我们确定了利奈唑胺和莫西沙星骨干方案对儿童播散性结核病可能非常有效的剂量和剂量方案。
Background. No treatment regimens have been specifically designed for children, in whom tuberculosis is predominantly intracellular. Given their activity as monotherapy and their ability to penetrate many diseased anatomic sites that characterize disseminated tuberculosis, linezolid and moxifloxacin could be combined to form a regimen for this need. Methods. We examined microbial kill of intracellular Mycobacterium tuberculosis (Mtb) by the combination of linezolid and moxifloxacin multiple exposures in a 7-by-7 mathematical matrix. We then used the hollow fiber system (HFS) model of intracellular tuberculosis to identify optimal dose schedules and exposures of moxifloxacin and linezolid in combination. We mimicked pediatric half-lives and concentrations achieved by each drug. We sampled the peripheral compartment on days 0, 7, 14, 21, and 28 for Mtb quantification, and compared the slope of microbial kill of Mtb by these regimens to the standard regimen of isoniazid, rifampin, and pyrazinamide, based on exponential decline regression. Results. The full exposure-response surface identified linezolid-moxifloxacin zones of synergy, antagonism, and additivity. A regimen based on each of these zones was then used in the HFS model, with observed half-lives of 4.08 ± 0.66 for linezolid and 3.80 ± 1.34 hours for moxifloxacin. The kill rate constant was 0.060 ± 0.012 per day with the moxifloxacin-linezolid regimen in the additivity zone vs 0.083 ± 0.011 per day with standard therapy, translating to a bacterial burden half-life of 11.52 days vs 8.53 days, respectively. Conclusions. We identified doses and dose schedules of a linezolid and moxifloxacin backbone regimen that could be highly efficacious in disseminated tuberculosis in children.
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影响因子：
9.6
作者：
Capitano, B;Mattoes, HM;Nicolau, DP
通讯作者：
Nicolau, DP
DOI：
10.1093/cid/ciw474
发表时间：
2016-11-01
期刊：
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
影响因子：
--
作者：
Deshpande D;Srivastava S;Nuermberger E;Pasipanodya JG;Swaminathan S;Gumbo T
通讯作者：
Gumbo T
DOI：
10.1164/rccm.200210-1125oc
发表时间：
2003-05-15
影响因子：
24.7
作者：
Jindani, A;Doré, CJ;Mitchison, DA
通讯作者：
Mitchison, DA
影响因子：
4.9
作者：
Hu, YM;Coates, ARM;Mitchison, DA
通讯作者：
Mitchison, DA
影响因子：
5.2
作者：
Malincarne, L;Ghebregzabher, M;Baldelli, F
通讯作者：
Baldelli, F