Nebulized aminoglycosides for ventilator-associated pneumonia: Methodological considerations and lessons from experimental studies
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...
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2025-01-01
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| author | 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 |
| author_facet | 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 |
| author_sort | Jean-Jacques Rouby |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-a6ac7fdf2cd642e8ac055e3aeb6c0a1e |
| institution | Kabale University |
| issn | 2667-100X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Intensive Medicine |
| spelling | doaj-art-a6ac7fdf2cd642e8ac055e3aeb6c0a1e2025-01-05T04:28:48ZengElsevierJournal of Intensive Medicine2667-100X2025-01-01511222Nebulized aminoglycosides for ventilator-associated pneumonia: Methodological considerations and lessons from experimental studiesJean-Jacques Rouby0Jing Xia1Jayesh Dhanani2Gianluigi Li Bassi3Antoine Monsel4Antoni Torres5Kostoula Arvaniti6Mona Assefi7Matteo Bassetti8Stijn Blot9Matthieu Boisson10Adrien Bouglé11Jean-Michel Constantin12Jayesh Dhanani13George Dimopoulos14Jonathan Dugernier15Pauline Dureau16Stephan Ehrmann17Timothy Felton18Marin Kollef19Antonia Koutsoukou20Anna Kyriakoudi21Pierre-François Laterre22Marc Leone23Victoria Lepère24Gianluigi Li Bassi25Xuelian Liao26Shakti Bedanta Mishra27Olivier Mimoz28Antoine Monsel29Girish B Nair30Michael Niederman31Lucy B Palmer32Jose Manuel Pereira33Konstantinos Pontikis34Garyphalia Poulakou35Jérôme Pugin36Chuanyun Qian37Jie-ming Qu38Jordi Rello39Jason Roberts40Jean-Jacques Rouby41Christina Routsi42Gerald C. Smaldone43Antoni Torres44Melda Türkoğlu45Tobias Welte46Michel Wolff47Xia Jing48Li Yang49Ting Yang50Ying-gang Zhu51Department 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.Emergency Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, ChinaFaculty of Medicine, University of Queensland Centre for Clinical Research, Brisbane, QLD, Australia; Department of Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, AustraliaCritical Care Research Group, The Prince Charles Hospital, Chermside, Australia; Institute for Molecular Bioscience, University of Queensland, St Lucia, QLD, AustraliaDepartment 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, FranceDepartment 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, SpainPapageorgiou Hospital of Thessaloniki, Intensive Care Unit Department, Thessaloniki, GreeceMedicine Sorbonne University, Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, FranceInfectious Diseases Clinic, Department of Health Sciences, University of Genoa, Genoa and Hospital Policlinico San Martino – IRCCS, Genoa, ItalyDepartment of Internal Medicine and Pediatrics, Ghent University, Ghent, BelgiumUniversity of Poitiers, Anaesthesiology and Intensive Care Department, University hospital of Poitiers, Poitiers, FranceMedicine Sorbonne University, Anaesthesiology and Critical Care, Cardiology Institute, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, FranceMedicine Sorbonne University, Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, FranceUQ 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. AustraliaDepartment of Critical Care Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, GreeceDepartment of Physiotherapy, Neuchâtel hospital, Neuchâtel, SwitzerlandMedicine Sorbonne University, Anaesthesiology and Critical Care, Cardiology Institute, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, FranceMédecine 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, FranceThe University of Manchester and Manchester University NHS Foundation Trust, Manchester, United KingdomDivision of Pulmonary and Critical Care Medicine, Washington University School of Medicine, St. Louis, Missouri, USAIntensive Care Unit, First Department of Respiratory Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, GreeceIntensive Care Unit, First Department of Respiratory Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, GreeceSt. Luc Clinical Coordinating Center, Department of Critical Care Medicine, St Luc University Hospital, Université Catholique de Louvain, Brussels, BelgiumUniversity Aix-Marseille, Department of Anaesthesiology and Critical Care, North Hospital, Marseille, FranceMedicine Sorbonne University, Anaesthesiology and Critical Care, Cardiology Institute, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, FranceCritical 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, SpainDepartment of Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, ChinaDepartment of Critical Care Medicine, Institute and Medical Science and SUM Hospital, Siksha O Anusandhan University, Bhubaneswar, Odisha, IndiaUniversity of Poitiers, Anaesthesiology and Intensive Care Department, University hospital of Poitiers, Poitiers, FranceMedicine 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, FranceInterstitial Lung Disease Program Director Pulmonary Research OUWB School of Medicine, Royal Oak, MI, USAPulmonary and Critical Care, New York Presbyterian/Weill Cornell Medical Center, Weill Cornell Medical College, New York, USAStony Brook University Medical Center Pulmonary, Critical Care and Sleep Division, SUNY at Stony Brook, HSC T17-040, Stony Brook, New York, USAEmergency and Intensive Care Department, Centro Hospitalar São João EPE, Faculdade de Medicina da Universidade do Porto, Porto, PortugalIntensive Care Unit, First Department of Respiratory Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, GreeceThird Department of Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, GreeceIntensive Care Division, University Hospitals of Geneva, Geneva, SwitzerlandEmergency department, The First Affiliated Hospital of Kunming Medical University, Kunming. Yunnan, ChinaDepartment 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, ChinaCentro 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, FranceUniversity 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 FranceMedicine Sorbonne University, Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, FranceFirst Department of Intensive Care, School of Medicine, Evangelismos Hospital, National and Kapodistrian University of Athens, Athens, GreeceStony Brook University Medical Center Health Sciences Center Stony Brook New York, NY USADepartment 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. SpainSubdivision of Critical Care, Internal Medicine Intensive Care Unit, Department of Internal Medicine, Gazi University Faculty of Medicine, Ankara, TurkeyUniversity of Hannover, School of Medicine, Hannover, GermanyService de Neuro-Réanimation, Groupe Hospitalo-Universitaire Paris Psychiatrie & Neurosciences, Hôpital Ste Anne Paris FranceEmergency department, The First Affiliated Hospital of Kunming Medical University, Kunming. Yunnan, ChinaEmergency department, The First Affiliated Hospital of Kunming Medical University, Kunming. Yunnan, ChinaEmergency department, The First Affiliated Hospital of Kunming Medical University, Kunming. Yunnan, ChinaDepartment of Pulmonary and Critical Care Medicine, Hua-dong Hospital, Fudan University, Shanghai, ChinaAminoglycosides 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.http://www.sciencedirect.com/science/article/pii/S2667100X24000975AminoglycosidesVentilator-associated pneumoniaNebulized amikacinNebulized tobramycinLung microdialysisExperimental intensive care unit |
| spellingShingle | 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 Nebulized aminoglycosides for ventilator-associated pneumonia: Methodological considerations and lessons from experimental studies Journal of Intensive Medicine Aminoglycosides Ventilator-associated pneumonia Nebulized amikacin Nebulized tobramycin Lung microdialysis Experimental intensive care unit |
| title | Nebulized aminoglycosides for ventilator-associated pneumonia: Methodological considerations and lessons from experimental studies |
| title_full | Nebulized aminoglycosides for ventilator-associated pneumonia: Methodological considerations and lessons from experimental studies |
| title_fullStr | Nebulized aminoglycosides for ventilator-associated pneumonia: Methodological considerations and lessons from experimental studies |
| title_full_unstemmed | Nebulized aminoglycosides for ventilator-associated pneumonia: Methodological considerations and lessons from experimental studies |
| title_short | Nebulized aminoglycosides for ventilator-associated pneumonia: Methodological considerations and lessons from experimental studies |
| title_sort | nebulized aminoglycosides for ventilator associated pneumonia methodological considerations and lessons from experimental studies |
| topic | Aminoglycosides Ventilator-associated pneumonia Nebulized amikacin Nebulized tobramycin Lung microdialysis Experimental intensive care unit |
| url | http://www.sciencedirect.com/science/article/pii/S2667100X24000975 |
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