Penetration of Antibacterial Agents into Pulmonary Epithelial Lining Fluid: An Update

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 beta-lactam agents, including those in combination with beta-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 beta-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.

Automated summary

The review summarizes studies on drug penetration into pulmonary epithelial lining fluid, focusing on comparisons of plasma and ELF concentrations of antibacterial agents in healthy adult subjects and critically ill patients. The significance of changes in intrapulmonary penetration and the need for further studies relating ELF concentrations to clinical response are highlighted. Studies are warranted to evaluate the relationship between intrapulmonary penetration and clinical and microbiological outcomes in critically ill patients with lower respiratory tract infections.