Journal of Intensive Medicine (Jan 2025)
Nebulized aminoglycosides for ventilator-associated pneumonia: Methodological considerations and lessons from experimental studies
- Jean-Jacques Rouby,
- Jing Xia,
- Jayesh Dhanani,
- Gianluigi Li Bassi,
- Antoine Monsel,
- Antoni Torres,
- Kostoula Arvaniti,
- Mona Assefi,
- Matteo Bassetti,
- Stijn Blot,
- Matthieu Boisson,
- Adrien Bouglé,
- Jean-Michel Constantin,
- Jayesh Dhanani,
- George Dimopoulos,
- Jonathan Dugernier,
- Pauline Dureau,
- Stephan Ehrmann,
- Timothy Felton,
- Marin Kollef,
- Antonia Koutsoukou,
- Anna Kyriakoudi,
- Pierre-François Laterre,
- Marc Leone,
- Victoria Lepère,
- Gianluigi Li Bassi,
- Xuelian Liao,
- Shakti Bedanta Mishra,
- Olivier Mimoz,
- Antoine Monsel,
- Girish B Nair,
- Michael Niederman,
- Lucy B Palmer,
- Jose Manuel Pereira,
- Konstantinos Pontikis,
- Garyphalia Poulakou,
- Jérôme Pugin,
- Chuanyun Qian,
- Jie-ming Qu,
- Jordi Rello,
- Jason Roberts,
- Jean-Jacques Rouby,
- Christina Routsi,
- Gerald C. Smaldone,
- Antoni Torres,
- Melda Türkoğlu,
- Tobias Welte,
- Michel Wolff,
- Xia Jing,
- Li Yang,
- Ting Yang,
- Ying-gang Zhu
Affiliations
- Jean-Jacques Rouby
- Department of Anaesthesiology and Critical Care, Sorbonne University, GRC 29, Assistance Publique Hôpitaux de Paris (AP-HP), DMU DREAM, Multidisciplinary Intensive Care Unit, Pitié-Salpêtrière Hospital, Paris, France; Corresponding author: Jean-Jacques Rouby, Sorbonne University, GRC 29, Assistance Publique Hôpitaux de Paris (AP-HP), DMU DREAM, Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, Pitié-Salpêtrière Hospital, Paris 75013, France.
- Jing Xia
- Emergency Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China
- Jayesh Dhanani
- Faculty of Medicine, University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia; Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia
- Gianluigi Li Bassi
- Critical Care Research Group, The Prince Charles Hospital, Chermside, Australia; Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, Australia
- Antoine Monsel
- Department of Anaesthesiology and Critical Care, Sorbonne University, GRC 29, Assistance Publique Hôpitaux de Paris (AP-HP), DMU DREAM, Multidisciplinary Intensive Care Unit, Pitié-Salpêtrière Hospital, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Unité mixte de recherche (UMR)-S 959, Immunology-Immunopathology-Immunotherapy, Paris, Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
- Antoni Torres
- Department of Pneumology, Institut Clinic del Tórax, Hospital Clinic of Barcelona – Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona – SGR 911- Ciber de Enfermedades Respiratorias (Ciberes), Barcelona, Spain
- Kostoula Arvaniti
- Papageorgiou Hospital of Thessaloniki, Intensive Care Unit Department, Thessaloniki, Greece
- Mona Assefi
- Medicine Sorbonne University, Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
- Matteo Bassetti
- Infectious Diseases Clinic, Department of Health Sciences, University of Genoa, Genoa and Hospital Policlinico San Martino – IRCCS, Genoa, Italy
- Stijn Blot
- Department of Internal Medicine and Pediatrics, Ghent University, Ghent, Belgium
- Matthieu Boisson
- University of Poitiers, Anaesthesiology and Intensive Care Department, University hospital of Poitiers, Poitiers, France
- Adrien Bouglé
- Medicine Sorbonne University, Anaesthesiology and Critical Care, Cardiology Institute, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
- Jean-Michel Constantin
- Medicine Sorbonne University, Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
- Jayesh Dhanani
- UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane, QLD, 4029, Australia; Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane. Australia
- George Dimopoulos
- Department of Critical Care Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
- Jonathan Dugernier
- Department of Physiotherapy, Neuchâtel hospital, Neuchâtel, Switzerland
- Pauline Dureau
- Medicine Sorbonne University, Anaesthesiology and Critical Care, Cardiology Institute, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
- Stephan Ehrmann
- Médecine Intensive Réanimation, CIC INSERM 1415, CRICS-TriggerSep network, CHRU Tours, Tours France and Centre d'étude des pathologies respiratoires INSERM U1100, Université de Tours, Tours, France
- Timothy Felton
- The University of Manchester and Manchester University NHS Foundation Trust, Manchester, United Kingdom
- Marin Kollef
- Division of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri, USA
- Antonia Koutsoukou
- Intensive Care Unit, First Department of Respiratory Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Anna Kyriakoudi
- Intensive Care Unit, First Department of Respiratory Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Pierre-François Laterre
- St. Luc Clinical Coordinating Center, Department of Critical Care Medicine, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium
- Marc Leone
- University Aix-Marseille, Department of Anaesthesiology and Critical Care, North Hospital, Marseille, France
- Victoria Lepère
- Medicine Sorbonne University, Anaesthesiology and Critical Care, Cardiology Institute, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
- Gianluigi Li Bassi
- Critical Care Research Group, The Prince Charles Hospital, Brisbane, University of Queensland, Faculty of Medicine, Brisbane, Australia; Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain
- Xuelian Liao
- Department of Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, China
- Shakti Bedanta Mishra
- Department of Critical Care Medicine, Institute and Medical Science and SUM Hospital, Siksha O Anusandhan University, Bhubaneswar, Odisha, India
- Olivier Mimoz
- University of Poitiers, Anaesthesiology and Intensive Care Department, University hospital of Poitiers, Poitiers, France
- Antoine Monsel
- Medicine Sorbonne University, Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; Institut National de la Santé et de la Recherche Médicale (INSERM), Unité mixte de recherche (UMR)-S 959, Immunology-Immunopathology-Immunotherapy (I3), Paris, France (AM); Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France
- Girish B Nair
- Interstitial Lung Disease Program Director Pulmonary Research OUWB School of Medicine, Royal Oak, MI, USA
- Michael Niederman
- Pulmonary and Critical Care, New York Presbyterian/Weill Cornell Medical Center, Weill Cornell Medical College, New York, USA
- Lucy B Palmer
- Stony Brook University Medical Center Pulmonary, Critical Care and Sleep Division, SUNY at Stony Brook, HSC T17-040, Stony Brook, New York, USA
- Jose Manuel Pereira
- Emergency and Intensive Care Department, Centro Hospitalar São João EPE, Faculdade de Medicina da Universidade do Porto, Porto, Portugal
- Konstantinos Pontikis
- Intensive Care Unit, First Department of Respiratory Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Garyphalia Poulakou
- Third Department of Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Jérôme Pugin
- Intensive Care Division, University Hospitals of Geneva, Geneva, Switzerland
- Chuanyun Qian
- Emergency department, The First Affiliated Hospital of Kunming Medical University, Kunming. Yunnan, China
- Jie-ming Qu
- Department of Pulmonary and Critical Care Medicine, Rui-jin Hospital, Shanghai Jiao-tong University School of Medicine, Shanghai, China; Institute of Respiratory Disease, Shanghai Jiao-tong University School of Medicine, Shanghai, China
- Jordi Rello
- Centro de Investigación Biomédica en Red (CIBERES), Instituto de Salud Carlos III, Madrid, Spain; Clinical Research & Innovation in Pneumonia & Sepsis, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain and Clinical Research, CHU Nîmes, Université Montpellier-Nîmes, Nîmes, France
- Jason Roberts
- University of Queensland Centre for Clinical Research, Faculty of Medicine & Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Australia; Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia; Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes France
- Jean-Jacques Rouby
- Medicine Sorbonne University, Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
- Christina Routsi
- First Department of Intensive Care, School of Medicine, Evangelismos Hospital, National and Kapodistrian University of Athens, Athens, Greece
- Gerald C. Smaldone
- Stony Brook University Medical Center Health Sciences Center Stony Brook New York, NY USA
- Antoni Torres
- Department of Pneumology, Institut Clinic del Tórax, Hospital Clinic of Barcelona – Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona – SGR 911- Ciber de Enfermedades Respiratorias (Ciberes), Barcelona. Spain
- Melda Türkoğlu
- Subdivision of Critical Care, Internal Medicine Intensive Care Unit, Department of Internal Medicine, Gazi University Faculty of Medicine, Ankara, Turkey
- Tobias Welte
- University of Hannover, School of Medicine, Hannover, Germany
- Michel Wolff
- Service de Neuro-Réanimation, Groupe Hospitalo-Universitaire Paris Psychiatrie & Neurosciences, Hôpital Ste Anne Paris France
- Xia Jing
- Emergency department, The First Affiliated Hospital of Kunming Medical University, Kunming. Yunnan, China
- Li Yang
- Emergency department, The First Affiliated Hospital of Kunming Medical University, Kunming. Yunnan, China
- Ting Yang
- Emergency department, The First Affiliated Hospital of Kunming Medical University, Kunming. Yunnan, China
- Ying-gang Zhu
- Department of Pulmonary and Critical Care Medicine, Hua-dong Hospital, Fudan University, Shanghai, China
- Journal volume & issue
-
Vol. 5,
no. 1
pp. 12 – 22
Abstract
Aminoglycosides are concentration-dependent antibiotics exerting a bactericidal effect when concentrations at the site of infection are equal to or greater than 5 times the minimum inhibitory concentrations (MIC). When administered intravenously, they exhibit poor lung penetration and high systemic renal and ototoxicity, imposing to restrict their administration to 5 days. Experimental studies conducted in anesthetized and mechanically ventilated sheep and pigs provide evidence that high doses of nebulized aminoglycosides induce a rapid and potent bacterial killing in the infected lung parenchyma. They also confirm that the alveolar-capillary membrane, either normal or injured by the infectious process, restricts the penetration of intravenous aminoglycosides in the infected lung parenchyma, precluding a bactericidal effect at the site of infection. However, injury of the alveolar-capillary membrane promotes the systemic diffusion of nebulized aminoglycosides. Based on experimental data obtained in animals with inoculation pneumonia, it challenges the classical belief that nebulization protects against systemic toxicity. Loss of lung aeration decreases the lung penetration of nebulized aminoglycosides. Nevertheless, lung tissue concentrations measured in non-aerated lung regions with severe and extended pneumonia are most often greater than 5 times the MICs, resulting in a bactericidal effect followed by a progressive pulmonary reaeration. It is likely that the penetration into the consolidated lung, results from the bronchial diffusion of nebulized aminoglycosides toward adjacent non-aerated infected alveolar spaces and their penetration into mechanical ventilation-induced intraparenchymal pseudocysts and distended bronchioles. In animals receiving nebulized aminoglycosides, epithelial lining fluid concentrations grossly overestimate lung interstitial fluid concentrations because of the bronchial contamination of the distal tip of the bronchoscope during the bronchoalveolar procedures. Lung microdialysis is the only technique able to accurately assess lung pharmacokinetics in animals with inoculation pneumonia treated by nebulized aminoglycosides. In 2024, the European Investigators Network for Nebulized Antibiotics in Ventilator-associated Pneumonia (ENAVAP) called for the creation of an international research network for Lung Microdialysis applied to Nebulized Antibiotics (LUMINA) to promote multicentered, experimental, randomized, and controlled studies addressing lung pharmacokinetics of intravenous vs. nebulized antibiotics, using different dosing and ventilator settings.
