Nebulized aminoglycosides for ventilator-associated pneumonia: Methodological considerations and lessons from experimental studies
Jean-Jacques Rouby
(1, 2)
,
Jing Xia
(3)
,
Jayesh Dhanani
(4, 5)
,
Gianluigi Li Bassi
(6, 7)
,
Antoine Monsel
(1, 8, 2)
,
Antoni Torres
(9, 10, 11, 12)
,
Kostoula Arvaniti
(13)
,
Mona Assefi
(2)
,
Matteo Bassetti
(14)
,
Stijn Blot
(15, 6)
,
Matthieu Boisson
(16, 17)
,
Adrien Bouglé
(1)
,
Jean-Michel Constantin
(2)
,
Jayesh Dhanani
(4, 5)
,
George Dimopoulos
(18, 19)
,
Jonathan Dugernier
,
Pauline Dureau
(1)
,
Stephan Ehrmann
(20, 21)
,
Timothy Felton
,
Marin Kollef
(22)
,
Antonia Koutsoukou
,
Anna Kyriakoudi
,
Pierre-François Laterre
(23)
,
Marc Leone
(24)
,
Victoria Lepère
(1)
,
Gianluigi Li Bassi
(6)
,
Xuelian Liao
,
Shakti Bedanta Mishra
,
Olivier Mimoz
(16, 17)
,
Antoine Monsel
(1, 8, 2)
,
Girish B Nair
,
Michael Niederman
,
Lucy B Palmer
,
Jose Manuel Pereira
,
Konstantinos Pontikis
(19)
,
Garyphalia Poulakou
(19)
,
Jérôme Pugin
(25)
,
Chuanyun Qian
,
Jie-Ming Qu
(26)
,
Jordi Rello
(27, 28, 29, 11, 30)
,
Jason Roberts
(6, 5, 28, 31)
,
Jean-Jacques Rouby
(1, 2)
,
Christina Routsi
,
Gerald C. Smaldone
,
Antoni Torres
,
Melda Türkoğlu
,
Tobias Welte
,
Michel Wolff
,
Xia Jing
,
Li Yang
,
Ting Yang
,
Ying-Gang Zhu
1
CHU Pitié-Salpêtrière [AP-HP]
2 GRC 29 - ARPE - Groupe de Recherche Clinique en Anesthésie Réanimation médecine PEriopératoire
3 KMU - Kunming Medical University
4 CQU - Central Queensland University
5 RBWH - Royal Brisbane and Women's Hospital [Brisbane, Queensland, Australia]
6 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
7 The Prince Charles Hospital
8 I3 - Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière]
9 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
10 UB - Universitat de Barcelona
11 CIBERES - Centro de Investigación Biomédica en Red Enfermedades Respiratorias
12 Clinic Barcelona Hospital Universitari
13 TPGH - The Papageorgiou General Hospital [Thessaloníki, Greece]
14 IRCCS - Centro San Giovanni di Dio, Fatebenefratelli, Brescia
15 UGENT - Universiteit Gent = Ghent University = Université de Gand
16 PHAR2 [Poitiers] - Pharmacologie des anti-infectieux et antibiorésistance [U 1070]
17 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
18 “Attikon” University Hospital
19 NKUA - National and Kapodistrian University of Athens
20 CEPR - Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100
21 CIC - Centre d’Investigation Clinique [Tours] CIC 1415
22 ANZICS Clinical Trials Group
23 Cliniques universitaires St Luc [Bruxelles]
24 Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, Marseille, France
25 HUG - Hôpitaux Universitaires de Genève
26 Shanghai Jiao Tong University School of Medicine
27 VHIR - Vall d’Hebron Research Institute
28 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
29 UIC - Universitat Internacional de Catalunya [Barcelona]
30 ISCIII - Instituto de Salud Carlos III [Madrid]
31 UM - Université de Montpellier
2 GRC 29 - ARPE - Groupe de Recherche Clinique en Anesthésie Réanimation médecine PEriopératoire
3 KMU - Kunming Medical University
4 CQU - Central Queensland University
5 RBWH - Royal Brisbane and Women's Hospital [Brisbane, Queensland, Australia]
6 UQ [All campuses : Brisbane, Dutton Park Gatton, Herston, St Lucia and other locations] - The University of Queensland
7 The Prince Charles Hospital
8 I3 - Immunologie - Immunopathologie - Immunothérapie [CHU Pitié Salpêtrière]
9 IDIBAPS - Institut d'Investigacions Biomèdiques August Pi i Sunyer
10 UB - Universitat de Barcelona
11 CIBERES - Centro de Investigación Biomédica en Red Enfermedades Respiratorias
12 Clinic Barcelona Hospital Universitari
13 TPGH - The Papageorgiou General Hospital [Thessaloníki, Greece]
14 IRCCS - Centro San Giovanni di Dio, Fatebenefratelli, Brescia
15 UGENT - Universiteit Gent = Ghent University = Université de Gand
16 PHAR2 [Poitiers] - Pharmacologie des anti-infectieux et antibiorésistance [U 1070]
17 CHU de Poitiers [La Milétrie] - Centre hospitalier universitaire de Poitiers = Poitiers University Hospital
18 “Attikon” University Hospital
19 NKUA - National and Kapodistrian University of Athens
20 CEPR - Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100
21 CIC - Centre d’Investigation Clinique [Tours] CIC 1415
22 ANZICS Clinical Trials Group
23 Cliniques universitaires St Luc [Bruxelles]
24 Hôpital Nord, Assistance Publique-Hôpitaux de Marseille, Marseille, France
25 HUG - Hôpitaux Universitaires de Genève
26 Shanghai Jiao Tong University School of Medicine
27 VHIR - Vall d’Hebron Research Institute
28 CHU Nîmes - Centre Hospitalier Universitaire de Nîmes
29 UIC - Universitat Internacional de Catalunya [Barcelona]
30 ISCIII - Instituto de Salud Carlos III [Madrid]
31 UM - Université de Montpellier
Jonathan Dugernier
- Fonction : Auteur
Stephan Ehrmann
- Fonction : Auteur
- PersonId : 783648
- ORCID : 0000-0001-6221-4467
- IdRef : 118952900
Timothy Felton
- Fonction : Auteur
Antonia Koutsoukou
- Fonction : Auteur
Anna Kyriakoudi
- Fonction : Auteur
Xuelian Liao
- Fonction : Auteur
Shakti Bedanta Mishra
- Fonction : Auteur
Girish B Nair
- Fonction : Auteur
Michael Niederman
- Fonction : Auteur
Lucy B Palmer
- Fonction : Auteur
Jose Manuel Pereira
- Fonction : Auteur
Chuanyun Qian
- Fonction : Auteur
Christina Routsi
- Fonction : Auteur
Gerald C. Smaldone
- Fonction : Auteur
Antoni Torres
- Fonction : Auteur
Melda Türkoğlu
- Fonction : Auteur
Tobias Welte
- Fonction : Auteur
Michel Wolff
- Fonction : Auteur
Xia Jing
- Fonction : Auteur
Li Yang
- Fonction : Auteur
Ting Yang
- Fonction : Auteur
Ying-Gang Zhu
- Fonction : Auteur
Résumé
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.