PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis.
PET/CT imaging reveals a therapeutic response to oxazolidinones in macaques and humans with tuberculosis.
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DOI：
10.1126/scitranslmed.3009500
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发表时间：
2014-12-03
影响因子：
17.1
通讯作者：
Flynn JL
中科院分区：
文献类型：
--
作者：
Coleman MT;Chen RY;Lee M;Lin PL;Dodd LE;Maiello P;Via LE;Kim Y;Marriner G;Dartois V;Scanga C;Janssen C;Wang J;Klein E;Cho SN;Barry CE 3rd;Flynn JL
恶唑烷酮抗生素（如利奈唑胺）在广泛耐药（XDR）结核病（TB）患者中显示出显著的治疗效果，尽管在啮齿动物中的作用中等，并且在人体II期试验中没有可证实的早期杀菌活性。在这里，我们发现利奈唑胺或AZD 5847（第二代恶唑烷酮）单药治疗可降低结核分枝杆菌感染的食蟹猴活动性TB尸检时的细菌载量。这种效应与这些动物肺部FDG PET成像亲合力的下降以及通过连续CT扫描测量的两个月单药治疗的肺部病理学减少相一致。在一项利奈唑胺治疗广泛耐药结核感染患者的平行II期临床研究中，我们还收集了接受利奈唑胺治疗的受试者的PET/CT成像数据，这些受试者已加入失败的治疗方案。这些人类受试者中PET/CT成像变化的定量比较与在猕猴中观察到的变化幅度相似，表明这些恶唑烷酮的治疗效果可以在该实验化疗模型中重现。PET/CT成像可能是有用的，作为一个早期的定量措施，对结核病的药物疗效在人类患者。患有TB的猕猴和人类的PET/CT成像显示利奈唑胺和新型恶唑烷酮抗生素AZD 5847的有益治疗反应。Chen et al.和科尔曼et al.的两篇论文研究了非人类灵长类动物和人类中定量PET/CT扫描的变化如何用作结核病治疗疗效的早期替代标志物。科尔曼等人的研究表明，利奈唑胺和第二代恶唑烷酮AZD 5847治疗结核病感染猕猴导致尸检时细菌负荷降低，FDG PET亲合力和CT定量肺部病理学降低。在感染广泛耐药Mtb并接受利奈唑胺治疗的人类患者中观察到类似的PET/CT变化。Chen等人的伴随研究在耐多药结核病患者的前瞻性分析中证实了这一效应，并证明早期PET/CT变化可预测最终治疗结局。
Oxazolidinone antibiotics such as linezolid have shown significant therapeutic effects in patients with extensively drug-resistant (XDR) tuberculosis (TB) despite modest effects in rodents and no demonstrable early bactericidal activity in human Phase 2 trials. Here, we show that monotherapy with either linezolid or AZD5847, a second-generation oxazolidinone, reduced bacterial load at necropsy in Mycobacterium tuberculosis-infected cynomolgus macaques with active TB. This effect coincided with a decline in FDG PET imaging avidity in the lungs of these animals and with reductions in pulmonary pathology measured by serial CT scans over two months of monotherapy. In a parallel Phase 2 clinical study of linezolid in patients infected with XDR-TB, we also collected PET/CT imaging data from subjects receiving linezolid that had been added to their failing treatment regimens. Quantitative comparisons of PET/CT imaging changes in these human subjects were similar in magnitude to those observed in macaques, demonstrating that the therapeutic effect of these oxazolidinones can be reproduced in this model of experimental chemotherapy. PET/CT imaging may be useful as an early quantitative measure of drug efficacy against TB in human patients. PET/CT imaging in macaques and humans with TB shows a beneficial therapeutic response to linezolid and a new oxazolidinone antibiotic AZD5847. Visualizing Drug Responses in TB A pair of papers by Chen et al. and Coleman et al. investigate how changes in quantitative PET/CT scans in both nonhuman primates and humans can be used as early surrogate markers of treatment efficacy in tuberculosis. The Coleman et al. study shows that treatment of Mtb-infected macaques with linezolid and the second-generation oxazolidinone AZD5847 resulted in a reduced bacterial load at necropsy and reduced FDG PET avidity and CT-quantified lung pathology. Similar PET/CT changes were seen in human patients infected with extensively drug-resistant Mtb and treated with linezolid. The companion study by Chen et al. corroborated this effect in a prospective analysis of patients with multidrug-resistant tuberculosis and demonstrated that early PET/CT changes predicted final treatment outcomes.
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影响因子：
82.9
作者：
Lin, Philana Ling;Ford, Christopher B.;Flynn, JoAnne L.
通讯作者：
Flynn, JoAnne L.
DOI：
10.2147/dddt.s30728
发表时间：
2013
期刊：
Drug design, development and therapy
影响因子：
--
作者：
Urbina O;Ferrández O;Espona M;Salas E;Ferrández I;Grau S
通讯作者：
Grau S
影响因子：
3.1
作者：
Via, Laura E.;Weiner, Danielle M.;Barry, Clifton E., III
通讯作者：
Barry, Clifton E., III
DOI：
10.1073/pnas.1121497109
发表时间：
2012-08-28
影响因子：
11.1
作者：
Lin, Philana Ling;Dartois, Veronique;Flynn, JoAnne L.
通讯作者：
Flynn, JoAnne L.
影响因子：
5.2
作者：
de Steenwinkel, Jurriaan E. M.;de Knegt, Gerjo J.;Bakker-Woudenberg, Irma A. J. M.
通讯作者：
Bakker-Woudenberg, Irma A. J. M.