Efficacy of colistin combination therapy in a mouse model of pneumonia caused by multidrug-resistant Pseudomonas aeruginosa
Efficacy of colistin combination therapy in a mouse model of pneumonia caused by multidrug-resistant Pseudomonas aeruginosa
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DOI：
10.1093/jac/dkn530
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发表时间：
2009-03-01
影响因子：
5.2
通讯作者：
Yamaguchi, Keizo
中科院分区：
文献类型：
--
作者：
Aoki, Nobumasa;Tateda, Kazuhiro;Yamaguchi, Keizo
多重耐药铜绿假单胞菌（MDRP）正在成为医院的一个严重问题，特别是在使用呼吸机的患者中。最近的数据表明，粘菌素可能对这些患者有效，尽管体外和体内数据有限。本研究采用药敏试验、时间杀灭试验、脂多糖（LPS）阻断试验和小鼠肺炎模型，观察了黏菌素单独或与其他抗生素联合应用对MDRP临床菌株的作用。对于肺炎模型，小鼠鼻内感染细菌并保持在高氧条件下以模拟呼吸机相关性肺炎。在组合中，用粘菌素加利福平观察到最大协同作用。正如预期的那样，细菌培养物上清液与粘菌素的共孵育显著降低LPS活性，并伴随细胞毒性的相关降低。在肺炎模型中，鼻内而非静脉内，粘菌素联合利福平产生最大的生存保护。粘菌素的药代动力学分析证明了鼻内给药的优越性，从肺中的高浓度和长半衰期判断。此外，粘菌素治疗显着降低炎症细胞因子和LPS活性的生产，即使在剂量影响没有变化的细菌负荷在lung.These数据强烈表明，粘菌素可能是一个重要的选择，联合治疗对关键MDRP感染。特别是对于肺炎，鼻内粘菌素与利福平可能不仅有利于协同抗菌活性，而且有利于阻断LPS。
Multidrug-resistant Pseudomonas aeruginosa (MDRP) is becoming a serious problem in hospitals, especially in patients on ventilators. Recent data demonstrate that colistin may be effective for these patients, although limited in vitro and in vivo data are available. Our aim was to identify further characteristics of colistin for the therapy of pneumonia caused by MDRP.The effects of colistin on clinical strains of MDRP were examined by susceptibility test, time-kill assay, lipopolysaccharide (LPS)-blocking assay and a mouse pneumonia model, alone or in combination with other antibiotics. For the pneumonia model, mice were intranasally infected with bacteria and kept in hyperoxic conditions to mimic ventilator-associated pneumonia.As a single agent, colistin exhibited the strongest activity of the antimicrobial agents tested. In combination, maximum synergy was observed with colistin plus rifampicin. As expected, co-incubation of bacterial culture supernatants with colistin significantly reduced LPS activities with an associated decrease in cellular cytotoxicity. In the pneumonia model, intranasal, but not intravenous, colistin combined with rifampicin produced maximum survival protection. Pharmacokinetic analysis of colistin demonstrated the superiority of intranasal administration, judging from the compartmentalized high concentration and the long half-life in the lungs. Moreover, colistin therapy significantly decreased both production of inflammatory cytokines and LPS activity, even at a dose effecting no change in the bacterial burden in the lung.These data strongly suggest that colistin may be an important option for combination therapy against critical MDRP infections. For pneumonia especially, intranasal colistin with rifampicin may be beneficial not only for synergistic antibacterial activity, but also for blocking LPS.