University of Illinois at Chicago, USA.
Clin Pharmacokinet. 2011 Oct;50(10):637-64. doi: 10.2165/11594090-000000000-00000.
The exposure-response relationship of anti-infective agents at the site of infection is currently being re-examined. Epithelial lining fluid (ELF) has been suggested as the site (compartment) of antimicrobial activity against lung infections caused by extracellular pathogens. There have been an extensive number of studies conducted during the past 20 years to determine drug penetration into ELF and to compare plasma and ELF concentrations of anti-infective agents. The majority of these studies estimated ELF drug concentrations by the method of urea dilution and involved either healthy adult subjects or patients undergoing diagnostic bronchoscopy. Antibacterial agents such as macrolides, ketolides, newer fluoroquinolones and oxazolidinones have ELF to plasma concentration ratios of >1. In comparison, β-lactams, aminoglycosides and glycopeptides have ELF to plasma concentration ratios of ≤1. Potential explanations (e.g. drug transporters, overestimation of the ELF volume, lysis of cells) for why these differences in ELF penetration occur among antibacterial classes need further investigation. The relationship between ELF concentrations and clinical outcomes has been under-studied. In vitro pharmacodynamic models, using simulated ELF and plasma concentrations, have been used to examine the eradication rates of resistant and susceptible pathogens and to explain why selected anti-infective agents (e.g. those with ELF to plasma concentration ratios of >1) are less likely to be associated with clinical treatment failures. Population pharmacokinetic modelling and Monte Carlo simulations have recently been used and permit ELF and plasma concentrations to be evaluated with regard to achievement of target attainment rates. These mathematical modelling techniques have also allowed further examination of drug doses and differences in the time courses of ELF and plasma concentrations as potential explanations for clinical and microbiological effects seen in clinical trials. Further studies are warranted in patients with lower respiratory tract infections to confirm and explore the relationships between ELF concentrations, clinical and microbiological outcomes, and pharmacodynamic parameters.
目前正在重新检查抗感染药物在感染部位的暴露-反应关系。上皮衬里液 (ELF) 已被认为是针对细胞外病原体引起的肺部感染的抗菌活性部位（隔室）。在过去的 20 年中，已经进行了大量研究来确定药物穿透 ELF 的情况，并比较抗感染药物的血浆和 ELF 浓度。这些研究中的大多数通过尿素稀释法来估计 ELF 药物浓度，并且涉及健康成年受试者或接受诊断性支气管镜检查的患者。抗菌药物如大环内酯类、酮内酯类、新型氟喹诺酮类和恶唑烷酮类的 ELF 与血浆浓度比 >1。相比之下，β-内酰胺类、氨基糖苷类和糖肽类的 ELF 与血浆浓度比≤1。需要进一步研究为什么这些抗菌药物类别的 ELF 穿透率存在差异的潜在解释（例如药物转运体、ELF 体积的高估、细胞裂解）。ELF 浓度与临床结果之间的关系尚未得到充分研究。使用模拟 ELF 和血浆浓度的体外药效动力学模型已被用于检查耐药和敏感病原体的清除率，并解释为什么选择的抗感染药物（例如 ELF 与血浆浓度比 >1 的药物）不太可能与临床治疗失败相关。群体药代动力学建模和蒙特卡罗模拟最近已被使用，并允许评估 ELF 和血浆浓度以实现目标达标率。这些数学建模技术还允许进一步检查药物剂量以及 ELF 和血浆浓度的时间过程差异，作为临床试验中观察到的临床和微生物学效果的潜在解释。需要在患有下呼吸道感染的患者中进行进一步的研究，以确认和探索 ELF 浓度、临床和微生物学结果以及药效学参数之间的关系。
