Bronchoscopic Microsampling Method for Measuring Drug Concentration in Epithelial Lining Fluid

Abstract

Direct measurement of the concentration of antimicrobial agents in bronchial epithelial lining fluid (ELF) would allow for a more informed approach to appropriate dosing of antimicrobial agents for respiratory tract infections. In this study, we determined the time versus concentration profile in ELF after an oral administration of levofloxacin, using recently developed bronchoscopic microsampling probes. These probes could be repeatedly and safely inserted through the fiberoptic bronchoscope in normal healthy volunteers. The concentration of levofloxacin in ELF was 43.4% of the corresponding serum value at 1 hour, reached the same level at 2 hours, decreased in a similar manner as that in serum, and returned to undetectable levels at 24 hours. It exceeded minimal inhibitory concentrations of Staphylococcus aureus (0.25 g/ml), Klebsiella species (0.5 g/ml), and Haemophilus influenzae (0.06 g/ml) after 6 hours. The experimental procedure was well tolerated, and no complications were observed. In conclusion, bronchoscopic microsampling is a feasible and promising method for measuring antimicrobial concentrations in the target sites of respiratory tracts directly and repeatedly.Keywords: bronchoscopy; antimicrobial agents; respiratory tract infection; time versus concentration profile; levofloxacin Community-acquired bacterial pneumonia and ventilatorassociated pneumonia in critically ill patients remain frequent causes of death worldwide (1-3). Although the introduction of recently developed antimicrobial agents has substantially improved the outcome of respiratory tract infections (4), the number of cases in which antimicrobial therapy fails to be effective remains high. Some therapeutic failures are attributed to drugresistant pathogens (5, 6). Therapeutic failures may also be related to an inability of antibiotics to penetrate target sites such as bronchoalveolar spaces sufficiently (7,8). Thus, direct measurement of antimicrobial concentrations in bronchoalveolar space fluid may lead to a critical reappraisal of current antimicrobial dosing guidelines (9). To date, drug concentrations at the site of infection in the respiratory tracts of humans have been estimated by assaying whole-lung tissue, collecting sputum or sampling bronchoalveolar lavage (BAL) fluid (10)(11)(12)(13)(14). However, at least two methodologic problems hamper a correct interpretation of data derived from these techniques: (1 ) the concentration in the collected samples might not necessarily reflect the concentration at the anatomic target site, and (2 ) it would be impossible to obtain samples easily and repeatedly from the same subject. Herkner and colleagues recently introduced flexible microdialysis catheters, which were implanted during lung surgery for (Received in original form January 28, 2003; accepted in final form August 4, 2003) Correspondence and requests for reprints should be addressed to Koichi Yamazaki, First Department of Medicine, Hokkaido University School of Medicine, North 15, West 7, Kitaku, Sapporo 060-8638, Japan...

Pharmacokinetics of telithromycin using bronchoscopic microsampling after single and multiple oral doses

“…BMS is useful for measuring the concentrations of biochemical substances, such as KL-6, albumin, and tumor markers, in bronchial ELF [4,5]. We have also used this technique to obtain bronchial ELF on the airway surface and determine the time versus concentration profile of levofloxacin, a model antibiotic [6].…”

“…Bronchial ELF sampling was performed with the BMS probe under bronchoscopy [3,6]. In vitro studies showed that more than 90% recovery could be obtained after 1 mg/l of telithromycin or 2-20 ml of human serum was absorbed to the BMS probe.…”

“…Since the bronchial ELF sampled by BMS probe was diluted with 2 ml of saline, the concentration of antibiotics in bronchial ELF (ABX br-ELF ) was determined as follows: ABX br-ELF = ABX BMS x (2 + V br-ELF ) / V br-ELF , where ABX BMS was the measured concentration of antibiotic in the saline-diluted sample, and V br-ELF was the volume of bronchial ELF recovered by the BMS probe [3,6].…”

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

“…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).…”

Active Uptake of Ulifloxacin from Plasma to Lung That Controls Its Concentration in Epithelial Lining Fluid

“…We also aimed to elucidate the feature of ulifloxacin uptake in rat lung and human lung adenocarcinoma cells (Calu-3). Sparfloxacin 16) and levofloxacin 17) are the quinolones with high and low penetration into the ELF, respectively. Azithromycin is a macrolide which highly penetrates into the ELF.…”