Understanding the nebulisation of antibiotics: the key role of lung microdialysis studies
Authors: Dhanani Jayesh , Roberts Jason A. , Monsel Antoine , Torres Antoni , Kollef Marin , Rouby Jean-Jacques ,   the European Investigators Network for Nebulized Antibiotics in Ventilator-associated Pneumonia, Arvaniti Kostoula , Assefi Mona , Bassetti Matteo , Blot Stijn , Boisson Matthieu , Bouglé Adrien , Constantin Jean-Michel , Dhanani Jayesh , Dimopoulos George , Dugernier Jonathan , Dureau Pauline , Felton Timothy , Kollef Marin , Koutsoukou Antonia , Kyriakoudi Anna , Laterre Pierre-François , Leone Marc , Lepère Victoria , Bassi Gianluigi Li , Liao Xuelian , Mimoz Olivier , Monsel Antoine , Nair Girish B. , Niederman Michael , Palmer Lucy B. , Pelosi Paolo , Pereira Jose Manuel , Pontikis Konstantinos , Poulakou Garyphalia , Pugin Jérôme , Qian Chuanyun , Qu Jie-ming , Rello Jordi , Roberts Jason , Rouby Jean-Jacques , Routsi Christina , Smaldone Gerald C. , Torres Antoni , Türkoğlu Melda , Welte Tobias , Wolff Michel , Jing Xia , Yang Li , Yang Ting , Zhu Ying-gang 
Published: February 2024

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.