Understanding the nebulisation of antibiotics: the key role of lung microdialysis studies

Abstract

Background: Nebulisation of antibiotics is a promising treatment for ventilator-associated pneumonia (VAP) caused by multidrug-resistant organisms. Ensuring effective antibiotic concentrations at the site of infection in the interstitial space fluid is crucial for clinical outcomes. Current assessment methods, such as epithelial lining fluid and tissue homogenates, have limitations in providing longitudinal pharmacokinetic data.

Main body: Lung microdialysis, an invasive research technique predominantly used in animals, involves inserting probes into lung parenchyma to measure antibiotic concentrations in interstitial space fluid. Lung microdialysis offers unique advantages, such as continuous sampling, regional assessment of antibiotic lung concentrations and avoidance of bronchial contamination. However, it also has inherent limitations including the cost of probes and assay development, the need for probe calibration and limited applicability to certain antibiotics. As a research tool in VAP, lung microdialysis necessitates specialist techniques and resource-intensive experimental designs involving large animals undergoing prolonged mechanical ventilation. However, its potential impact on advancing our understanding of nebulised antibiotics for VAP is substantial. The technique may enable the investigation of various factors influencing antibiotic lung pharmacokinetics, including drug types, delivery devices, ventilator settings, interfaces and disease conditions. Combining in vivo pharmacokinetics with in vitro pharmacodynamic simulations can become feasible, providing insights to inform nebulised antibiotic dose optimisation regimens. Specifically, it may aid in understanding and optimising the nebulisation of polymyxins, effective against multidrug-resistant Gram-negative bacteria. Furthermore, lung microdialysis holds promise in exploring novel nebulisation therapies, including repurposed antibiotic formulations, bacteriophages and immunomodulators. The technique's potential to monitor dynamic biochemical changes in pneumonia, such as cytokines, metabolites and inflammation/infection markers, opens avenues for developing theranostic tools tailored to critically ill patients with VAP.

Conclusion: In summary, lung microdialysis can be a potential transformative tool, offering real-time insights into nebulised antibiotic pharmacokinetics. Its potential to inform optimal dosing regimen development based on precise target site concentrations and contribute to development of theranostic tools positions it as key player in advancing treatment strategies for VAP caused by multidrug-resistant organisms. The establishment of international research networks, exemplified by LUMINA (lung microdialysis applied to nebulised antibiotics), signifies a proactive step towards addressing complexities and promoting multicentre experimental studies in the future.

Keywords: Antibiotic nebulisation; Epithelial lining fluid; Lung microdialysis; Nebulised aminoglycosides; Nebulised polymyxins; Ventilator-associated pneumonia.

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