Tomaselli Florian, Dittrich Peter, Maier Alfred, Woltsche Michael, Matzi Veronika, Pinter Johannes, Nuhsbaumer Stephan, Pinter Hans, Smolle Josef, Smolle-Jüttner Freyja M
Department of Surgery, Division of Thoracic and Hyperbaric Surgery, University Medical School of Graz, Graz, Austria.
Br J Clin Pharmacol. 2003 Jun;55(6):620-4. doi: 10.1046/j.1365-2125.2003.01797.x.
The pharmacokinetic profile of antibiotics at the site of anti-infective action is one of the most important determinants of drug response, since it correlates with antimicrobial effect. Up to now, only limited information on the lung tissue pharmacokinetics of antibiotic agents has been available. The aim of this study was to measure, using a new microdialysis-based approach, antibiotic penetration into the extracellular space fluid of pneumonic human lung parenchyma.
The lung penetration of a combination of piperacillin and tazobactam, substances with low protein binding, was determined in five patients suffering from pneumonia and metapneumonic pleural empyema. The condition was treated by decortication after lateral thoracotomy. Intra-, or post-operatively, respectively, two microdialysis probes were inserted into pneumonic lung tissue, and into healthy skeletal muscle to obtain reference values. Serum and microdialysis samples were collected at 20-min intervals for at last 8 h following i.v. administration of a single dose of 4 g piperacillin and 500 mg tazobactam.
The mean free interstitial concentration profiles of piperacillin in infected lung tissue and serum showed a maximal tissue concentration (Cmax) of 176.0 +/- 105.0 mg l-1 and 326.0 +/- 60.6 mg l-1, respectively. The mean AUC (area under the curve) for infected lung tissue was 288.0 +/- 167.0 mg.h l-1 and for serum 470.0 +/- 142.0 mg.h l-1. There was a statistically significant difference between AUC (lung) and AUC (serum) (P = 0.018) as well as between AUC (lung) and AUC (muscle) (P = 0.043). The intrapulmonary concentrations of piperacillin and tazobactam exceeded the minimum inhibitory concentrations (MIC) for most relevant bacteria for 4-6 h. The procedure was well tolerated by all patients and no adverse events or microdialysis-associated side-effects were observed.
This microdialysis technique enabled continuous tissue pharmacokinetic measurement of free, unbound anti-infective agents in the lung tissue of patients with pneumonia. The present data corroborate the use of piperacillin and tazobactam in the treatment of lung infections caused by extracellular bacteria and demonstrate the distribution of piperacillin and tazobactam in the interstitial space of pneumonic lung tissue.
抗生素在抗感染作用部位的药代动力学特征是药物反应的最重要决定因素之一，因为它与抗菌效果相关。到目前为止，关于抗生素药物肺组织药代动力学的信息有限。本研究的目的是使用一种基于微透析的新方法，测量抗生素在肺炎患者肺实质细胞外液中的渗透情况。
在5例患有肺炎和肺炎旁胸腔积脓的患者中，测定哌拉西林和他唑巴坦（两种低蛋白结合物质）联合用药后的肺组织渗透情况。通过侧胸壁切开术后行胸膜剥脱术进行治疗。分别在术中或术后，将两根微透析探针插入肺炎肺组织以及健康骨骼肌中以获取参考值。静脉注射单剂量4g哌拉西林和500mg他唑巴坦后，每隔20分钟采集血清和微透析样本，持续至少8小时。
感染肺组织和血清中哌拉西林的平均游离间质浓度曲线显示，组织最大浓度（Cmax）分别为176.0±105.0mg/L和326.0±60.6mg/L。感染肺组织的平均曲线下面积（AUC）为288.0±167.0mg·h/L，血清为470.0±142.0mg·h/L。AUC（肺）与AUC（血清）之间（P = 0.018）以及AUC（肺）与AUC（肌肉）之间（P = 0.043）存在统计学显著差异。哌拉西林和他唑巴坦的肺内浓度超过了大多数相关细菌的最低抑菌浓度（MIC）达4 - 6小时。所有患者对该操作耐受性良好，未观察到不良事件或与微透析相关的副作用。
这种微透析技术能够连续测量肺炎患者肺组织中游离、未结合抗感染药物的组织药代动力学。目前的数据证实了哌拉西林和他唑巴坦在治疗由细胞外细菌引起的肺部感染中的应用，并证明了哌拉西林和他唑巴坦在肺炎肺组织间质空间中的分布情况。
