Penetration of Anti-Infective Agents into Pulmonary Epithelial Lining Fluid

Abstract

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.

Structure-Based Prediction of Anti-infective Drug Concentrations in the Human Lung Epithelial Lining Fluid

“…Previous reviews on ELF concentrations (7,8) were focused on a more qualitative evaluation, outlining EPR trends between different antibiotic classes. Indeed, such class-based comparisons are relevant based on the visualizations in this article.…”

“…The model training dataset was based on two previously reported systematic reviews of clinical studies quantifying concentrations of anti-infective agents (antibiotics, antifungals and associated agents such as β-lactamase inhibitors) in plasma and ELF (7,8). The original publications included in these two systematic reviews were considered to represent a complete overview of available literature on ELF lung concentrations reported for anti-infective agents up to 2011.…”

“…The alveolar membrane acts as a semi-permeable barrier due to the presence of tight junctions (5) and the presence of drug transporter proteins (6). This results in ELF concentrations that may be several folds lower or higher than the corresponding plasma concentration, as was nicely summarized by Kiem et al (7) and Rodvold et al (8). Therefore, the consideration of ELF concentrations during development of antibiotic agents for lung infections is of considerable importance.…”

“…A more recent and promising technique for measuring ELF concentrations is bronchoscopic microsampling (BMS), which allows for repeated measurement of concentrations over time (11). Considerable variability has been reported for ELF concentrations not only between subjects but also within subjects (7,8). Such variation can be related to the aforementioned methodological issues, the drug-distribution related pharmacokinetics (PK), and potentially other physiological disease related factors such as edema and potential effects of inflammation on membrane permeability.…”

Inhaled Antibiotics for Gram-Negative Respiratory Infections

“…In general, lower respiratory tract infections (LRTIs) are difficult to treat due to the sequestration of microorganisms deep within the airways, where only limited portions of drug gain access after traditional systemic therapy. Systemically delivered antimicrobials, in particular those used to treat LRTIs due to Gram-negative organisms (Gram-negative LRTIs), such as aminoglycosides and ␤-lactams, often have poor pulmonary penetration into the lung parenchyma (10). When hypoxia occurs in response to pneumonia, the pulmonary vasculature vasoconstricts in order to shunt blood away from areas of low oxygen toward areas maintaining adequate ventilation gas exchange (11).…”