Fig. 1

Lung microdialysis for nebulised antibiotics: principles, technique of implementation, assessment of interstitial antibiotic concentrations, advantages over epithelial lining fluid concentrations. a A microdialysis probe (0.6 × 50 mm) with a semi-permeable membrane is positioned into the lung parenchyma. A physiologic solution is flushed through the probe using a microdialysis pump (saline yellow filled circle at a flow rate of 0.1–10 µL/min) and the unbound fraction of the antibiotic (red filled circle) present in the interstitium diffuses through the semi-permeable membrane (proteins cannot pass through the membrane). The collected microdialysate containing the antibiotic is analysed by liquid chromatography tandem mass spectrometry; b and c after thoracotomy, microdialysis probes are inserted under direct vision in the upper and lower lobes of anaesthetised ewes. An intercostal catheter is placed on each side, after incision closure; d and e combined lung and intravascular microdialysis allows estimation of intravenous and nebulised unbound antibiotics concentrations in the lung and intravascular compartments. As colistimethate sodium (polymyxin E) (green filled circle) has a limited endothelial diffusion, its interstitial and alveolar antibiotic concentrations are low after intravenous administration and high after nebulisation. Conversely, intravascular colistimethate sodium concentrations are low after nebulisation and high after intravenous administration; f and g total versus regional lung and plasma concentration–time profiles after the administration of 400 mg tobramycin by nebulisation or intravenously. The mean concentrations measured from four probes implemented in upper and lower lobes are represented in (f) and regional concentrations in (g). High lung and low plasma concentrations of nebulised tobramycin are evidenced by lung microdialysis; h distribution of tobramycin concentrations between proximal and distal airways immediately after the nebulisation of 600 mg in patients with cystic fibrosis. Aerosol concentrations in the central and more distal airways were computed using airway models reconstructed from computed tomography scans of patients with cystic fibrosis, in combination with computational fluid dynamic simulations. Proximal airways defined as bronchi with an internal diameter greater than 1 mm are represented as the tracheal bronchial tree, whereas distal airways are represented as lung parenchyma; i during the bronchoalveolar lavage performed to collect the epithelial lining fluid, the bronchoscope is heavily contaminated by the antibiotic deposited on bronchial walls during the nebulisation (red colour); j box plots showing higher epithelial lining fluid (ELF) than interstitial space fluid (ISF) tobramycin concentrations for nebulised tobramycin compared to intravenous (IV) tobramycin at a dose of 400 mg. The dots indicate the values that are outside the box plots. ELF concentrations are measured by bronchoalveolar lavage and ISF concentrations by lung microdialysis. b, g and j are reproduced from [13] and with permission of the publisher; f is reproduced from [12] with permission of the publisher; h and i are reproduced from reference [10] with permission of the publisher