College of Pharmacy, University of Illinois Chicago, m/c 886, 833 South Wood Street, Room # 164, Chicago, IL, 60612, USA.
College of Medicine, University of Illinois Chicago, Chicago, IL, USA.
Clin Pharmacokinet. 2022 Jan;61(1):17-46. doi: 10.1007/s40262-021-01061-7. Epub 2021 Oct 15.
A comprehensive review of drug penetration into pulmonary epithelial lining fluid (ELF) was previously published in 2011. Since then, an extensive number of studies comparing plasma and ELF concentrations of antibacterial agents have been published and are summarized in this review. The majority of the studies included in this review determined ELF concentrations of antibacterial agents using bronchoscopy and bronchoalveolar lavage, and this review focuses on intrapulmonary penetration ratios determined with area under the concentration-time curve from healthy human adult studies or pharmacokinetic modeling of various antibacterial agents. If available, pharmacokinetic/pharmacodynamic parameters determined from preclinical murine infection models that evaluated ELF concentrations are also provided. There are also a limited number of recently published investigations of intrapulmonary penetration in critically ill patients with lower respiratory tract infections, where greater variability in ELF concentrations may exist. The significance of these changes may impact the intrapulmonary penetration in the setting of infection, and further studies relating ELF concentrations to clinical response are needed. Phase I drug development programs now include assessment of initial pharmacodynamic target values for pertinent organisms in animal models, followed by evaluation of antibacterial penetration into the human lung to assist in dosage selection for clinical trials in infected patients. The recent focus has been on β-lactam agents, including those in combination with β-lactamase inhibitors, particularly due to the rise of multidrug-resistant infections. This manifests as a large portion of the review focusing on cephalosporins and carbapenems, with or without β-lactamase inhibitors, in both healthy adult subjects and critically ill patients with lower respiratory tract infections. Further studies are warranted in critically ill patients with lower respiratory tract infections to evaluate the relationship between intrapulmonary penetration and clinical and microbiological outcomes. Our clinical research experience with these studies, along with this literature review, has allowed us to outline key steps in developing and evaluating dosage regimens to treat extracellular bacteria in lower respiratory tract infections.
先前于 2011 年发表了一篇关于药物渗透到肺部上皮衬液（ELF）的综合综述。此后，大量比较抗菌药物血浆和 ELF 浓度的研究已经发表，并在本综述中进行了总结。本综述中包含的大多数研究使用支气管镜和支气管肺泡灌洗来确定抗菌药物的 ELF 浓度，本综述重点关注健康成人研究或各种抗菌药物的药代动力学模型中确定的肺内穿透比。如果有，还提供了从评估 ELF 浓度的临床前鼠感染模型中确定的药代动力学/药效学参数。也有一些关于患有下呼吸道感染的危重症患者肺内穿透的最新研究，其中 ELF 浓度可能存在更大的变异性。这些变化的意义可能会影响感染时的肺内穿透，需要进一步研究 ELF 浓度与临床反应的关系。I 期药物开发计划现在包括在动物模型中评估相关病原体的初始药效学靶值，然后评估抗菌药物渗透到人体肺部，以协助为感染患者的临床试验选择剂量。最近的重点一直是β-内酰胺类药物，包括与β-内酰胺酶抑制剂联合使用的药物，特别是由于多药耐药感染的增加。这表现为综述的很大一部分重点关注头孢菌素和碳青霉烯类药物，无论是否有β-内酰胺酶抑制剂，在健康成年受试者和患有下呼吸道感染的危重症患者中。需要进一步研究患有下呼吸道感染的危重症患者，以评估肺内穿透与临床和微生物学结果之间的关系。我们在这些研究中的临床研究经验，以及本文献综述，使我们能够概述开发和评估治疗下呼吸道感染中细胞外细菌的剂量方案的关键步骤。
