Time-kill kinetics of anti-tuberculosis drugs, and emergence of resistance, in relation to metabolic activity of Mycobacterium tuberculosis
Time-kill kinetics of anti-tuberculosis drugs, and emergence of resistance, in relation to metabolic activity of Mycobacterium tuberculosis
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DOI：
10.1093/jac/dkq374
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发表时间：
2010-12-01
影响因子：
5.2
通讯作者：
Bakker-Woudenberg, Irma A. J. M.
中科院分区：
文献类型：
--
作者：
de Steenwinkel, Jurriaan E. M.;de Knegt, Gerjo J.;Bakker-Woudenberg, Irma A. J. M.
应进一步探索结核病治疗的药效学，以防止耐药性的出现、治疗失败和感染复发。指导结核病治疗的诊断药物敏感性试验研究的是静态条件下代谢活跃的结核分枝杆菌 (Mtb) 分离株，因此对于抗结核药物的时间杀灭动力学以及代谢低活性甚至休眠的分枝杆菌细胞中耐药性的出现并无提供信息。在代谢高活性和代谢低活性的 Mtb 细胞中进行了研究。异烟肼对高活性分枝杆菌表现出快速且高的杀伤能力，但由于耐药性的出现，无法消除 Mtb。外排泵介导的异烟肼耐药性占主导地位。利福平显示出相对缓慢且具有时间依赖性的杀灭能力，但实现了消除所有分枝杆菌。乙胺丁醇没有杀菌作用。阿米卡星表现出高且极快的杀灭活性，不依赖于时间，并且可以消除所有分枝杆菌。低活性结核分枝杆菌群体接触异烟肼、利福平或阿米卡星会导致耐药突变体的出现。与高活性分枝杆菌相比，消除易受影响的低活性分枝杆菌需要异烟肼浓度增加64倍，利福平浓度增加4倍，而无论分枝杆菌的代谢状态如何，阿米卡星都同样有效。抗结核药物的时间杀灭动力学存在显着差异。此外，结核分枝杆菌的代谢状态显着影响其对抗菌药物的敏感性，阿米卡星除外。需要优化抗结核药物的剂量，以在感染部位达到最大药物浓度，从而最大限度地减少结核分枝杆菌负荷并最大限度地减少耐药性的出现和选择。
The pharmacodynamics of tuberculosis (TB) treatment should be further explored, to prevent emergence of resistance, treatment failure and relapse of infection. The diagnostic drug susceptibility tests guiding TB therapy investigate metabolically active Mycobacterium tuberculosis (Mtb) isolates under static conditions and as such are not informative with respect to the time-kill kinetics of anti-TB drugs and the emergence of resistance in metabolically lowly active or even dormant mycobacterial cells.In vitro, the killing capacity of rifampicin, isoniazid, ethambutol and amikacin regarding the degree of killing, killing rate and selection of resistant mutants was investigated in metabolically highly active versus metabolically lowly active Mtb cells.Isoniazid showed rapid and high killing capacity towards highly active mycobacteria, but due to the emergence of resistance could not eliminate the Mtb. Efflux pump-mediated isoniazid resistance was predominant. Rifampicin revealed a relatively slow and time-dependent killing capacity, but achieved elimination of all mycobacteria. Ethambutol was not bactericidal. Amikacin showed a high and extremely rapid killing activity that was not time dependent and could eliminate all mycobacteria. Exposure of lowly active Mtb populations to isoniazid, rifampicin or amikacin led to the emergence of resistant mutants. Compared with the highly active mycobacteria, elimination of the susceptible lowly active mycobacteria required a 64-fold increased isoniazid concentration and a 4-fold increased rifampicin concentration, whereas amikacin was equally effective irrespective of the metabolic state of the mycobacteria.The anti-TB drugs differ significantly regarding their time-kill kinetics. In addition, the metabolic state of Mtb significantly affects its susceptibility to antimicrobials, with the exception of amikacin. Optimization of dosage of anti-TB drugs is required to achieve maximum drug concentrations at the site of infection in order to maximize reduction in Mtb load and to minimize the emergence and selection of resistance.