Colistin methanesulfonate is an inactive prodrug of colistin against Pseudomonas aeruginosa
Colistin methanesulfonate is an inactive prodrug of colistin against Pseudomonas aeruginosa
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DOI：
10.1128/aac.00035-06
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发表时间：
2006-06-01
影响因子：
4.9
通讯作者：
Nation, Roger L.
中科院分区：
文献类型：
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作者：
Bergen, Phillip J.;Li, Jian;Nation, Roger L.
尽管“粘菌素”越来越多地被用作治疗由多重耐药革兰氏阴性菌引起的感染的最后一道防线，但有关“粘菌素”的药效学信息仍然匮乏。通过研究每种粘菌素和甲磺酸粘菌素 (CMS) 对阳离子调节 Mueller-Hinton 肉汤中铜绿假单胞菌典型培养物的时间杀灭动力学，研究了粘菌素和甲磺酸粘菌素 (CMS) 的抗菌活性。通过高效液相色谱法测量 CMS 中粘菌素浓度为 8.0 和 32 毫克/升的情况，生成粘菌素浓度-时间曲线。这些浓度-时间曲线随后在独立于 CMS 的其他培养中通过逐渐添加粘菌素来模拟。当向培养物中添加任一浓度的 CMS 时，杀灭作用的开始会出现显着延迟，直到 CMS 水解产生的粘菌素浓度达到约 0.5 至 1 毫克/升（即，类似于粘菌素 MIC 的 0.5 至 1 倍）时才明显。当逐渐添加粘菌素以达到从 CMS 水解观察到的相同粘菌素浓度-时间过程时，杀灭效果的时间过程相似。鉴于 CMS 的杀灭动力学可以通过粘菌素的出现来解释，CMS 是一种无活性的粘菌素前药，具有对抗铜绿假单胞菌的活性。这是第一项证明粘菌素在含有 CMS 的微生物介质中形成的研究，并证明 CMS 是粘菌素的无活性前药。这些发现对于涉及“粘菌素”的药敏试验具有重要意义，特别是对于 MIC 测量、微生物测定以及药代动力学和药效学研究。
There is a dearth of information on the pharmacodynamics of "colistin," despite its increasing use as a last line of defense for treatment of infections caused by multidrug-resistant gram-negative organisms. The antimicrobial activities of colistin and colistin methanesulfonate (CMS) were investigated by studying the time-kill kinetics of each against a type culture of Pseudomonas aeruginosa in cation-adjusted Mueller-Hinton broth. The appearance of colistin from CMS spiked at 8.0 and 32 mg/liter was measured by high-performance liquid chromatography, which generated colistin concentration-time profiles. These concentration-time profiles were subsequently mimicked in other incubations, independent of CMS, by incrementally spiking colistin. When the cultures were spiked with CMS at either concentration, there was a substantial delay in the onset of the killing effect which was not evident until the concentrations of colistin generated from the hydrolysis of CMS had reached approximately 0.5 to 1 mg/liter (i.e., similar to 0.5 to 1 times the MIC for colistin). The time course of the killing effect was similar when colistin was added incrementally to achieve the same colistin concentration-time course observed from the hydrolysis of CMS. Given that the killing kinetics of CMS can be accounted for by the appearance of colistin, CMS is an inactive prodrug of colistin with activity against P. aeruginosa. This is the first study to demonstrate the formation of colistin in microbiological media containing CMS and to demonstrate that CMS is an inactive prodrug of colistin. These findings have important implications for susceptibility testing involving "colistin," in particular, for MIC measurement and for microbiological assays and pharmacokinetic and pharmacodynamic studies.