Biofilm penetration, triggered release and in vivo activity of inhaled liposomal amikacin in chronic Pseudomonas aeruginosa lung infections
Biofilm penetration, triggered release and in vivo activity of inhaled liposomal amikacin in chronic Pseudomonas aeruginosa lung infections
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DOI：
10.1093/jac/dkn059
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发表时间：
2008-04-01
影响因子：
5.2
通讯作者：
Perkins, W. R.
中科院分区：
文献类型：
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作者：
Meers, P.;Neville, M.;Perkins, W. R.
目的：囊性纤维化患者肺部铜绿假单胞菌的慢性感染由于其生物膜生长模式而成为难治性抗生素靶点。我们已经调查了生物膜渗透，药物释放和体内抗菌活性的一个独特的纳米级脂质体制剂阿米卡星专门设计用于雾化和吸入delivery.Methods：渗透到痰液或铜绿假单胞菌（PA 3064）生物膜的荧光标记脂质体进行监测，通过过滤器测定和荧光或共聚焦扫描激光显微镜。用荧光偏振免疫法测定阿米卡星的体外释放和大鼠吸入后肺内药物浓度。阿14天的琼脂珠模型慢性假单胞菌肺部感染的大鼠被用来评估脂质体阿米卡星与游离氨基糖苷类抗生素在减少细菌计数的疗效。结果：荧光脂质体很容易渗透到生物膜和感染的粘液，而较大的（1 μ m）荧光珠没有。痰液或假单胞菌生物膜上清液介导阿米卡星从脂质体中释放。鼠李糖脂被认为是这些上清液中的主要释放因子，在脂质体内每几百个脂质中有一个鼠李糖脂的活性。吸入脂质体阿米卡星释放在一个缓慢的，持续的方式在正常大鼠肺和数量级更有效的比吸入游离阿米卡星在infected lungs.Conclusions：生物膜的渗透和有针对性的，从脂质体的持续释放可以解释吸入脂质体阿米卡星的上级在体内的疗效与游离药物在14天的感染模型中观察到。阿米卡星脂质体吸入剂可能是治疗慢性肺部感染的一种重要方法。
Objectives: Chronic infections of Pseudomonas aeruginosa in the lungs of cystic fibrosis patients are intractable antibiotic targets because of their biofilm mode of growth. We have investigated the biofilm penetration, mechanism of drug release and in vivo antimicrobial activity of a unique nanoscale liposomal formulation of amikacin designed specifically for nebulization and inhaled delivery.Methods: Penetration of fluorescently labelled liposomes into sputum or P. aeruginosa (PA3064) biofilms was monitored by a filter assay and by epifluorescence or confocal scanning laser microscopy. Amikacin release in vitro and rat lung levels after inhalation of nebulized material were measured by fluorescence polarization immunoassay. A 14 day agar bead model of chronic Pseudomonas lung infection in rats was used to assess the efficacy of liposomal amikacin versus free aminoglycosides in the reduction of bacterial count.Results: Fluorescent liposomes penetrated readily into biofilms and infected mucus, whereas larger (1 mu m) fluorescent beads did not. Amikacin release from liposomes was mediated by sputum or Pseudomonas biofilm supernatants. Rhamnolipids were implicated as the major releasing factors in these supernatants, active at one rhamnolipid per several hundred lipids within the liposomes. Inhaled liposomal amikacin was released in a slow, sustained manner in normal rat lungs and was orders of magnitude more efficacious than inhaled free amikacin in infected lungs.Conclusions: Penetration of biofilm and targeted, sustained release from liposomes can explain the superior in vivo efficacy of inhaled liposomal amikacin versus free drug observed in a 14 day infection model. Inhaled liposomal amikacin may represent an important therapy for chronic lung infections.