Efflux-pump-derived multiple drug resistance to ethambutol monotherapy in Mycobacterium tuberculosis and the pharmacokinetics and pharmacodynamics of ethambutol.
Efflux-pump-derived multiple drug resistance to ethambutol monotherapy in Mycobacterium tuberculosis and the pharmacokinetics and pharmacodynamics of ethambutol.
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DOI：
10.1086/651377
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发表时间：
2010-04-15
期刊：
影响因子：
--
通讯作者：
Gumbo T
中科院分区：
文献类型：
--
作者：
Srivastava S;Musuka S;Sherman C;Meek C;Leff R;Gumbo T
在肺结核的治疗中，使用异糖二氮二氮二氮二氮在药代动力学 - 抗药性纤维系统中，使用了乙醇二氮二氮的耐药性。
剂量效应的研究和剂量划分研究是用乙酰丁醇和对数期生长的结核分枝杆菌的结核病，以确定与最佳杀伤和抑制作用相关的暴露和时间表，在乙醇酚300毫克/天的耐药性抑制中。
在剂量效应的研究中，排出频率将突变频率降低到64倍。与比例最少的乙硫醇驱动抗性相关，一致随着时间驱动的效应，微生物杀伤是通过浓度曲线与最小抑制作用的面积之比来解释的（R2 = 0.90）。
诱导降低多种药物效应的外排泵的诱导，为在多种耐药性发展中序列地采集突变提供了替代途径。
In the treatment of tuberculosis, ethambutol is used in case there is isoniazid resistance. We examined for the emergence of drug resistance to ethambutol monotherapy in pharmacokinetic-pharmacodynamic studies in the hollow fiber system. Dose–effect studies and dose-scheduling studies were carried out with ethambutol and log-phase growth Mycobacterium tuberculosis to identify exposures and schedules linked to optimal kill and resistance suppression. In one study, after 7 days of ethambutol 300 mg/day isoniazid was administered to each system to determine its early bactericidal activity (EBA). Efflux-pump blockage reduced the mutation frequency to ethambutol 64-fold. In dose-effect studies, ethambutol had a maximal EBA of 0.22 log10 CFU/ml/day, as encountered in patients. By day 7, resistance had arisen to both ethambutol and isoniazid. Prior exposure to ethambutol abolished isoniazid EBA. Daily therapy, as opposed to more intermittent therapy, was associated with the least proportion of efflux-pump driven resistance, consistent with time driven effect. Microbial kill was best explained by the ratio of area under the concentration-time curve to minimal inhibitory effect (r2=0.90). Induction of an efflux-pump that reduces effect to multiple drugs provides an alternative pathway to sequential acquisition of mutations in the development of multiple drug resistance.
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影响因子：
11.8
作者：
Nouvel LX;Kassa-Kelembho E;Dos Vultos T;Zandanga G;Rauzier J;Lafoz C;Martin C;Blazquez J;Talarmin A;Gicquel B
通讯作者：
Gicquel B
影响因子：
9.4
作者：
Madison, B;Robinson-Dunn, B;Ridderhof, J
通讯作者：
Ridderhof, J
影响因子：
2.6
作者：
Jiang, Xin;Zhang, Wenhong;Wang, Honghai
通讯作者：
Wang, Honghai
影响因子：
64.5
作者：
Boshoff, HIM;Reed, MB;Mizrahi, V
通讯作者：
Mizrahi, V
DOI：
10.1073/pnas.0505446102
发表时间：
2005-08-23
影响因子：
11.1
作者：
Morris, RP;Nguyen, L;Thompson, CJ
通讯作者：
Thompson, CJ