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Semin Respir Crit Care Med 2022; 43(02): 255-270
DOI: 10.1055/s-0041-1740340
Review Article

Nebulized Antibiotics for Healthcare- and Ventilator-Associated Pneumonia

Matthieu Boisson
1   INSERM U1070, Université de Poitiers, UFR de Médecine Pharmacie, Poitiers, France
2   Service de Prévention et de Contrôle de l'Infection, Hôpitaux Universitaires de Genève, Genève, Suisse
,
Adrien Bouglé
3   Medicine Sorbonne University, Anaesthesiology and Critical Care, Cardiology Institute, Paris, France
4   Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
,
Candela Sole-Lleonart
5   Intensive Care Unit, Consorci Hospitalari de Vic (CHV), The University of Vic – Central University of Catalonia (UVic-UCC), Vic, Barcelona, Spain
,
Jayesh Dhanani
6   Department of Intensive Care Medicine, Centre for Clinical Research, The University of Queensland, The Royal Brisbane and Women's Hospital Herston, Brisbane, Australia
,
Kostoula Arvaniti
7   Intensive Care Unit Department, Papageorgiou Hospital of Thessaloniki, Thessaloniki, Greece
,
Jordi Rello
8   Centro de Investigación Biomédica en Red (CIBERES), Instituto de Salud Carlos III, Madrid, Spain
9   Clinical Research and Innovation in Pneumonia and Sepsis, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain
10   Clinical Research, CHU Nîmes, Université Montpellier-Nîmes, Nîmes, France
,
Jean-Jacques Rouby
11   Department of Anaesthesiology and Critical Care, Medicine Sorbonne University, Multidisciplinary Intensive Care Unit, La Pitié Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
,
Olivier Mimoz
12   INSERM U1070 Université de Poitiers, UFR de Médecine Pharmacie and Service des Urgences Adultes & SAMU 86, Centre Hospitalier Universitaire de Poitiers, Poitiers, France
,
On Behalf of the European Investigator Network for Nebulized Antibiotics in Ventilator-Associated Pneumonia (ENAVAP)› Author Affiliations
Funding M.B. is currently receiving a mobility grant from the Société Française d'Anesthésie et Réanimation for his fellowship in Geneva.
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Abstract

Global emergence of multidrug-resistant and extensive drug-resistant gram-negative bacteria has increased the risk of treatment failure, especially for healthcare- or ventilator-associated pneumonia (HAP/VAP). Nebulization of antibiotics, by providing high intrapulmonary antibiotic concentrations, represents a promising approach to optimize the treatment of HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria, while limiting systemic antibiotic exposure. Aminoglycosides and colistin methanesulfonate are the most common nebulized antibiotics. Although optimal nebulized drug dosing regimen is not clearly established, high antibiotic doses should be administered using vibrating-mesh nebulizer with optimized ventilator settings to ensure safe and effective intrapulmonary concentrations. When used preventively, nebulized antibiotics reduced the incidence of VAP without any effect on mortality. This approach is not yet recommended and large randomized controlled trials should be conducted to confirm its benefit and explore the impact on antibiotic selection pressure. Compared with high-dose intravenous administration, high-dose nebulized colistin methanesulfonate seems to be more effective and safer in the treatment of ventilator-associated tracheobronchitis and VAP caused by multidrug resistant and extensive-drug resistant gram-negative bacteria. Adjunctive nebulized aminoglycosides could increase the clinical cure rate and bacteriological eradication in patients suffering from HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria. As nebulized aminoglycosides broadly diffuse in the systemic circulation of patients with extensive bronchopneumonia, monitoring of plasma trough concentrations is recommended during the period of nebulization. Large randomized controlled trials comparing high dose of nebulized colistin methanesulfonate to high dose of intravenous colistin methanesulfonate or to intravenous new β-lactams in HAP/VAP due to multidrug-resistant and extensive drug-resistant gram-negative bacteria are urgently needed.

Keywords

nebulized antibiotics - healthcare-associated pneumonia - ventilator-associated pneumonia - colistin - aminoglycosides - antibiotic resistance

Members of the European Investigators Network for Nebulized Antibiotics in Ventilator-Associated Pneumonia

Mona Assefi (mona.assefi@aphp.fr), 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 (matteo.bassetti70@gmail.com), Infectious Diseases Clinic, Department of Health Sciences, University of Genoa, Genoa, and Hospital Policlinico San Martino – IRCCS, Genoa, Italy; Deborah Benchetrit (deborah.benchetrit@aphp.fr), Medicine Sorbonne University, Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; Stijn Blot (stijn.blot@UGent.be), Department of Internal Medicine, Faculty of Medicine and Health Science, Ghent University, Ghent, Belgium; Jean-Michel Constantin (jean-michel.constantin@aphp.fr), Medicine Sorbonne University, Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; George Dimopoulos (gdimop@med.uoa.gr), Department of Critical Care Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Jonathan Dugernier (jonathan.dugernier@rhne.ch), Department of Physiotherapy, Neuchâtel Hospital, Neuchâtel, Switzerland; Stephan Ehrmann (stephanehrmann@gmail.com), 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 (timothy.felton@manchester.ac.uk), The University of Manchester and Manchester University NHS Foundation Trust, Manchester, United Kingdom; Dimitrios Karakaxas (dimitrios.karakaksas@gmail.com), Department of Critical Care Medicine, Attikon University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece; Antonia Koutsoukou (koutsoukou@yahoo.gr), Intensive Care Unit, First Department of Respiratory Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, Greece; Anna Kyriakoudi (Annkyr@gmail.com), 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 (pierre-francois.laterre@uclouvain.be), St. Luc Clinical Coordinating Center, Department of Critical Care Medicine, St Luc University Hospital, Université Catholique de Louvain, Brussels, Belgium; Marc Leone (marc.leone@ap-hm.fr), University Aix-Marseille, Department of Anaesthesiology and Critical Care, North Hospital, Marseille, France; Victoria Lepère (victoria.lepere@aphp.fr), 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 (g.libassi@uq.edu.au), Critical Care Research Group, The Prince Charles Hospital, Brisbane, University of Queensland, Faculty of Medicine, Brisbane, Australia, and Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; Xuelian Liao (xuelianliao@hotmail.com), Department of Critical Care Medicine, West China Hospital of Sichuan University, Chengdu, China; Antoine Monsel (antoine.monsel@aphp.fr), (1) Medicine Sorbonne University, Multidisciplinary Intensive Care Unit, Department of Anaesthesiology and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris, France; (2) 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), and Biotherapy (CIC-BTi) and Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Hôpital Pitié-Salpêtrière, Assistance Publique-Hôpitaux de Paris, Paris, France; Girish B. Nair (Girish.Nair@beaumont.org), Interstitial Lung Disease Program Director, Pulmonary Research OUWB School of Medicine, Royal Oak, MI, USA; Michael Niederman (msn9004@med.cornell.edu), Pulmonary and Critical Care, New York Presbyterian/Weill Cornell Medical Center, Weill Cornell Medical College, New York, USA; Lucy B. Palmer (lucy.b.palmer@stonybrook.edu), 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 (jmcrpereira@yahoo.com), Emergency and Intensive Care Department, Centro Hospitalar São João EPE, Faculdade de Medicina da Universidade do Porto, Porto, Portugal; Konstantinos Pontikis (kostis_pontikis@yahoo.gr), Intensive Care Unit, First Department of Respiratory Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, Greece; Garyphalia Poulakou (gpoulakou@gmail.com), Third Department of Medicine, School of Medicine, Sotiria General Hospital, National and Kapodistrian University of Athens, Athens, Greece; Jérôme Pugin (jerome.pugin@unige.ch), Intensive Care Division, University Hospitals of Geneva, Geneva, Switzerland; Chuanyun Qian (qianchuanyun@126.com), Emergency department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; Jie-ming Qu (jmqu0906@163.com), 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; Jason Roberts (j.roberts2@uq.edu.au), (1) University of Queensland Centre for Clinical Research, Faculty of Medicine and Centre for Translational Anti-infective Pharmacodynamics, School of Pharmacy, The University of Queensland, Brisbane, Australia; (2) Departments of Pharmacy and Intensive Care Medicine, Royal Brisbane and Women's Hospital, Brisbane, Australia; (3) Division of Anaesthesiology Critical Care Emergency and Pain Medicine, Nîmes University Hospital, University of Montpellier, Nîmes France; Christina Routsi (chroutsi@hotmail.com), First Department of Intensive Care, School of Medicine, Evangelismos Hospital, National and Kapodistrian University of Athens, Athens, Greece; Antoni Torres (atorres@clinic.cat), 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 (meldaturkoglu@yahoo.com.tr), Subdivision of Critical Care, Internal Medicine Intensive Care Unit, Department of Internal Medicine, Gazi University Faculty of Medicine, Ankara, Turkey; Tobias Welte (welte.tobias@mh-hannover.de), University of Hannover, School of Medicine, Hannover, Germany; Jing Xia (xiajing@kmmu.edu.cn), Emergency Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; Li Yang (1197815424@qq.com), Emergency Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; Ting Yang (yangtingkm@qq.com), Emergency Department, The First Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, China; Ying-gang Zhu (robinzyg@gmail.com), Department of Pulmonary and Critical Care Medicine, Hua-Dong Hospital, Fudan University, Shanghai, China.


Authors' Contributions

M.B., O.M., and J.-J.R. wrote the draft of the manuscript. M.B. and J.-J.R. designed the illustrations. A.B., C.S.-L., J.D., K.A., M.N., and J.R. contributed toward the critical revision of the manuscript for important intellectual content. Each member of the European Investigators Network for Nebulized Antibiotics in Ventilator-Associated Pneumonia contributed to the final manuscript and approved its content. All authors have read and agreed to the published version of the manuscript.




Publication History

Article published online:
18 January 2022

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