A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way.
A Faropenem, Linezolid, and Moxifloxacin Regimen for Both Drug-Susceptible and Multidrug-Resistant Tuberculosis in Children: FLAME Path on the Milky Way.
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DOI：
10.1093/cid/ciw474
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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：利奈唑胺和氟诺沙星的治疗方案在儿童细胞内结核的中空纤维系统模型中被发现是有效的。 然而，其杀灭率低于标准的异烟肼、利福平和吡嗪酰胺3药方案。我们想检查在这种双重组合中加入第三种口服药物法罗培南的效果。方法：通过模拟每种抗生素的儿科药代动力学，我们在细胞内结核分枝杆菌的中空纤维系统模型中进行了一系列研究。 首先，我们改变了法罗培南在利奈唑胺方案中持续高于最低抑菌浓度（TMIC）的时间百分比。在选择最佳法罗培南暴露后，我们进行了实验，其中我们改变了三联方案中的氟沙星和利奈唑胺剂量。最后，我们进行了更长时间的治疗验证实验。使用每毫升菌落形成单位（CFU/mL）和阳性时间（TTP）定量细菌负荷。使用指数回归对杀灭斜率进行建模。结果：TTP是一个比CFU/mL更敏感的细菌负荷指标。 法罗培南TMIC > 62%与最陡的微生物杀灭斜率相关。标准利奈唑胺和利奈沙星+法罗培南TMIC > 60%的方案以及更高剂量的利奈沙星在28天的治疗期间达到了与基于TTP和CFU/mL的标准方案相当的斜率。结论：我们已经开发了一种口服法罗培南-利奈唑胺-阿氟沙星（FLAME）方案，该方案不含一线药物。 该方案对儿童耐多药结核病和药物敏感结核病均有效。
Background. The regimen of linezolid and moxifloxacin was found to be efficacious in the hollow fiber system model of pediatric intracellular tuberculosis. However, its kill rate was slower than the standard 3-drug regimen of isoniazid, rifampin, and pyrazinamide. We wanted to examine the effect of adding a third oral agent, faropenem, to this dual combination. Methods. We performed a series of studies in the hollow fiber system model of intracellular Mycobacterium tuberculosis, by mimicking pediatric pharmacokinetics of each antibiotic. First, we varied the percentage of time that faropenem persisted above minimum inhibitory concentration (TMIC) on the moxifloxacin-linezolid regimen. After choosing the best faropenem exposure, we performed experiments in which we varied the moxifloxacin and linezolid doses in the triple regimen. Finally, we performed longer-duration therapy validation experiments. Bacterial burden was quantified using both colony-forming units per milliliter (CFU/mL) and time to positivity (TTP). Kill slopes were modeled using exponential regression. Results. TTP was a more sensitive measure of bacterial burden than CFU/mL. A faropenem TMIC > 62% was associated with steepest microbial kill slope. Regimens of standard linezolid and moxifloxacin plus faropenem TMIC > 60%, as well as higher-dose moxifloxacin, achieved slopes equivalent to those of the standard regimen based by both TTP and CFU/mL over 28 days of treatment. Conclusions. We have developed an oral faropenem-linezolid-moxifloxacin (FLAME) regimen that is free of first-line drugs. The regimen could be effective against both multidrug-resistant and drug-susceptible tuberculosis in children.
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影响因子：
3.7
作者：
Mac Kenzie WR;Heilig CM;Bozeman L;Johnson JL;Muzanye G;Dunbar D;Jost KC Jr;Diem L;Metchock B;Eisenach K;Dorman S;Goldberg S
通讯作者：
Goldberg S
DOI：
10.1093/cid/ciw473
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
影响因子：
5.8
作者：
Marais, Ben J.;Pai, Madhukar
通讯作者：
Pai, Madhukar
影响因子：
3.6
作者：
Jungbluth, GL;Welshman, IR;Hopkins, NK
通讯作者：
Hopkins, NK
影响因子：
9.4
作者：
ABE, C;HOSOJIMA, S;MORI, T
通讯作者：
MORI, T