Ceftazidime-avibactam has potent sterilizing activity against highly drug-resistant tuberculosis.
Ceftazidime-avibactam has potent sterilizing activity against highly drug-resistant tuberculosis.
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Ceftazidime-avibactam对高度耐药性结核病具有有效的消毒活性。
DOI：
10.1126/sciadv.1701102
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发表时间：
2017-08
期刊：
影响因子：
13.6
通讯作者：
Gumbo T
中科院分区：
文献类型：
--
作者：
Deshpande D;Srivastava S;Chapagain M;Magombedze G;Martin KR;Cirrincione KN;Lee PS;Koeuth T;Dheda K;Gumbo T
头孢他啶-阿巴坦对广泛耐药和多重耐药的结核分枝杆菌菌株非常有效。目前有许多患者患有多药耐药和广泛耐药结核病。尽管接受了治疗，但高度耐药菌株的持续传播和高死亡率仍然是问题所在。目前的药物发现和开发战略需要长达十年的时间才能将一种新药投入临床使用。我们启动了一项战略，对目前使用的所有抗生素进行筛选，并检查它们是否用于结核病。我们发现，已经用于临床治疗耐多药革兰氏阴性杆菌感染的头孢他啶-阿维巴坦在中空纤维系统模型中对快速生长的、细胞内的和半正常的结核分枝杆菌有明显的杀灭作用。此外，多重耐药和广泛耐药的临床分离株表现出良好的头孢他啶-阿维巴坦敏感性谱，并被临床可达到的浓度所抑制。耐药性的产生是因为青霉素结合蛋白ponA1的转肽酶结构域发生了突变，这表明该药物通过干扰细胞壁的重塑来杀死结核分枝杆菌。我们确定了结核病最佳效果的浓度(暴露目标)，并将其与计算机辅助临床试验模拟中的敏感性结果一起使用，以确定立即用于成人和儿童抢救治疗的临床剂量。此外，这项工作为有效和及时地评估抗生素和优化临床相关的给药方案提供了路线图。
Ceftazidime-avibactam is highly efficacious against extensive- and multidrug-resistant strains of Mycobacterium tuberculosis. There are currently many patients with multidrug-resistant and extensively drug-resistant tuberculosis. Ongoing transmission of the highly drug-resistant strains and high mortality despite treatment remain problematic. The current strategy of drug discovery and development takes up to a decade to bring a new drug to clinical use. We embarked on a strategy to screen all antibiotics in current use and examined them for use in tuberculosis. We found that ceftazidime-avibactam, which is already used in the clinic for multidrug-resistant Gram-negative bacillary infections, markedly killed rapidly growing, intracellular, and semidormant Mycobacterium tuberculosis in the hollow fiber system model. Moreover, multidrug-resistant and extensively drug-resistant clinical isolates demonstrated good ceftazidime-avibactam susceptibility profiles and were inhibited by clinically achievable concentrations. Resistance arose because of mutations in the transpeptidase domain of the penicillin-binding protein PonA1, suggesting that the drug kills M. tuberculosis bacilli via interference with cell wall remodeling. We identified concentrations (exposure targets) for optimal effect in tuberculosis, which we used with susceptibility results in computer-aided clinical trial simulations to identify doses for immediate clinical use as salvage therapy for adults and young children. Moreover, this work provides a roadmap for efficient and timely evaluation of antibiotics and optimization of clinically relevant dosing regimens.
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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
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
影响因子：
3.2
作者：
Flores, AR;Parsons, LM;Pavelka, MS Jr
通讯作者：
Pavelka, MS Jr
影响因子：
4.9
作者：
Gumbo, Tawanda;Louie, Arnold;Drusano, George L.
通讯作者：
Drusano, George L.
DOI：
10.1016/s2213-2600(14)70031-1
发表时间：
2014-04
期刊：
The Lancet. Respiratory medicine
影响因子：
--
作者：
Dheda K;Gumbo T;Gandhi NR;Murray M;Theron G;Udwadia Z;Migliori GB;Warren R
通讯作者：
Warren R