Intensive Care Med
https://doi.org/10.1007/s00134-023-07036-5
WHAT’S NEW IN INTENSIVE CARE
Aerosolised antibiotics in critical care
Jordi Rello1,2,3* , Adrien Bouglé4 and Jean‑Jacques Rouby5
© 2023 Springer-Verlag GmbH Germany, part of Springer Nature
Aerosol therapy in mechanically ventilated patients deliv-
ers drug particles driven by inspiratory gases. Broncho-
dilators, steroids, mucolytics, polymyxins and aminogly-
cosides are the main prescriptions [1]. Lack of knowledge
among practitioners is common regarding differences
between nebulisation, technique and strategies of imple-
mentation in patients with ventilator-associated pneu-
monia (VAP) [1]. The part of the respiratory system to
which aerosolised particles are intended influences aero-
sol effectiveness.
Delivery of aerosols to the tracheobronchial tree is
easy
Delivery of inhaled bronchodilators, steroids and muco-
lytics to the tracheobronchial tree is easy, due to the
proximity of the target organ with ventilator circuits. The
pharmacological effect follows an “on–off ” effect. The
expected bronchodilator effect is obtained whatever the
nebuliser position and the type of nebulisation (breath-
actuated or continuous, Fig. 1a–f ). Inspiratory flow tur-
bulences promote bronchial deposition and there is no
need to modify ventilator settings. Aerosol bronchodi-
lator therapy during high-flow nasal cannula oxygen is
possible with a nebuliser placed at the inlet of the heated
humidifier [2]. Pulmonary drug delivery is limited to < 5%
of the nominal dose placed in the nebuliser [3].
Delivery of inhaled antibiotics to treat ventilator-
associated tracheobronchitis (VAT) or cystic fibrosis
bronchiectasis follows a slightly different rationale. As
aerosolised polymyxins and aminoglycosides are con-
centration-dependent antibiotics, the bactericidal effect
is proportional to the delivered dose. Increasing aerosol
*Correspondence: jrello@crips.es
1
Global Health eCore, Vall d’Hebron Institute of Research (VHIR), Ps. Vall
d’Hebron 129. AMI‑14, 08035 Barcelona, Spain
Full author information is available at the end of the article
delivery to the tracheobronchial tree can be obtained
by maximizing the bolus effect (Fig. 1c, d). Most VAPs
develop after bronchial colonization by continuous
micro-aspiration of contaminated oropharyngeal or gas-
tric content around the tracheal cuff. Antibiotic nebulisa-
tion interfere on tracheobronchial bacterial microbiome,
and might influence the risk of antibiotic resistance and
relapses.
Delivery of aerosols to the infected lung
parenchyma is difficult
Nebulisation of antibiotics for treating VAP is difficult as
aerosolised particles have to go through a complex net-
work of branching air ducts which caliber continuously
decreases towards the alveolar space (left part of Fig. 1).
Bronchial deposition resulting from inspiratory turbu-
lences reduces antibiotic delivery to the infected lung
parenchyma [4–6]. The lung bactericidal effect of amino-
glycosides and polymyxins is concentration-dependent
and, accordingly limiting bronchial deposition is criti-
cal for therapeutic efficiency. Mass median aerodynamic
diameter of aerosolized particles should remain inferior
to 5 µ to penetrate into lung parenchyma. Antibiotic
epithelial lining fluid concentrations obtained by bron-
choalveolar lavage largely overestimate lung interstitial
concentrations as the distal tip of the fiberscope is con-
taminated by high bronchial concentrations and should
be interpreted with caution [5].
During the expiratory phase of continuous nebulisa-
tion, the aerosol accumulates in the inspiratory limb and
this “bolus “is propelled into the respiratory system dur-
ing the next inspiration (Fig. 1a–d). Optimizing aerosol
delivery is achieved by maximizing the “bolus effect”:
use of continuous rather than breath-actuated nebuli-
zation and positioning the nebulizer close to the ven-
tilator (Fig. 1a–d). Limiting inspiratory turbulences is
achieved by delivering a constant inspiratory flow dur-
ing a prolonged inspiratory time and by administering
 Aerosol delivery of
bronchodilators, steroids and
mucolytics to the
tracheobronchial tree is easy.
The pharmacological effect is
always obtained even with
suboptimal conditions of
Aerosol delivery of The bolus effect (ultrasonic and vibrating mesh nebulizers)
antibiotics to the infected
lung parenchyma is difficult.
The bactericidal effect is Continuous nebulisation: the mesh nebuliser is positioned
15 cm to the Y piece. A BOLUS EFFECT is generated
obtained only with optimised
conditions of nebulisation.
Expiratory Expiratory Expiratory

nebulisation. Nebulisers Closed filter filter waste of the

aerosol ++++
expiratory
• Jet nebulisers valve
Closed
Nebulisers • Ultrasonic nebulisers Flow-by 2 L/mn inspiratory
valve
Flow-by 2 L/mn

• Metered-dose inhalers • Vibrating mesh nebulisers Continuous

nebulisation
Ventilator VMN
• Jet nebulisers Humidifier
INSPIRATION
Ventilator
Humidifier
EXPIRATION
• Ultrasonic nebulisers
• Vibrating mesh nebulisers
a. b.
Continuous nebulisation: the mesh nebuliser is positioned
colse to the ventilator. A greater BOLUS EFFECT is generated

Expiratory Expiratory Expiratory

Closed filter filter waste of the
Inspiratory inspiratory
valve
aerosol +

turbulences should Closed

be limited to reduce Flow-by 2 L/mn inspiratory
valve
Flow-by 2 L/mn

bronchial deposition Continuous Continuous

nebulisation nebulisation
Ventilator VMN Ventilator VMN
INSPIRATION EXPIRATION
Humidifier Humidifier

c. d.
S RR VT MV

Breath-actuated nebulisation: the PPDS PDDS mesh

mesh nebuliser
nebuliser is
is
positioned
positioned after
after the
the Y
Y piece.
piece. There
There is
is no
no more
more BOLUS
BOLUS EFFECT
EFFECT
No expiratory waste of the aerosol

Breath-actuated
Breath-actuated Breath-actuated
Breath-actuated
Expiratory nebulisation
nebulisation Expiratory nebulisation
nebulisation
filter Pressure PPDS filter Pressure PPDS
PDDS
Closed sensor
PDDS
sensor
expiratory
valve

Flow-by 2 L/mn Flow-by 2 L/mn

Closed
expiratory
valve
Ventilator Ventilator
INSPIRATION EXPIRATION
Humidifier Humidifier

e. f.
Fig. 1 Specificities of drug aerosol delivery according to the target organ. As shown in the left block, aerosol delivery of bronchodilators, ster‑
oids and mucolytics to the tracheobronchial tree is easy as the target organ (trachea and large-diameter bronchi) begins immediately after the
endotracheal tube. Inspiratory turbulences promote tracheobronchial deposition and therapeutic efficiency. Aerosol delivery of antibiotics to the
lung parenchyma is much more difficult. Infected alveoli (in light brown) are far from the endotracheal tube and aerosolized particles have to move
through a complex network of small-diameter bronchi partially obstructed by purulent plugs. The amount of antibiotic delivered to pneumonic
areas is critical to achieve bactericidal efficiency. Inspiratory flow turbulences promote tracheobronchial impaction and decrease aerosol delivery
to infected areas. They can be limited by using constant inspiratory flow, prolonged inspiratory time and avoiding any discoordination with the
ventilator. The right block shows the “bolus effect” (yellow color) and its components. The bolus effect was first described in 2020 [7]; it is present
during continuous nebulisation (a–d) and is defined as the accumulation of aerosolised particles in the inspiratory tubing during expiration that
are propelled into the respiratory system during the next inspiration. Increasing the bolus effect is essential in maximizing aerosol delivery (a–d).
Positioning the vibrating mesh nebulizer (VMN) 15 cm before the Y piece is associated with a significant (++++) bolus expiratory waste (a,
b). Positioning the VMN close to the ventilator minimises ( +) the expiratory waste, increases the bolus effect and aerosol delivery (c, d). Breath-
actuated nebulization eliminates the bolus effect (e, f). The time of nebulization is a function of inspiratory time over total time of the respiratory
cycle (Ti/Ttot) and is independent of the respiratory frequency: Nebulization time (sec/min) = 60 × 0.75 × Ti/Ttot. Compared to a non-synchronized
mesh nebulizer, the PDDS extends the time of nebulisation by 3 to 9 folds. As it precludes the administration of high dose antibiotics, it should not
be used to deliver inhaled antibiotics to treat ventilator-associated pneumonia [7]. Black arrows indicate inspiratory flow coming from the ventilator.
Red arrows indicate expiratory flow coming from the respiratory system. Blue arrows indicate bias flow

a short-term sedation to avoid patient’s discoordination
with the ventilator [5, 6]. Evidence for optimizing venti-
lator settings is limited to increased aerosol delivery and
reported benefit on therapeutic efficiency is lacking.
Clinical delivery of aerosolized antibiotics
Patients with and without cystic fibrosis bronchiectasis
are affected by chronic bronchial infection frequently
caused by Pseudomonas aeruginosa. Nebulisation of cip-
rofloxacin and aminoglycosides significantly delays the
time to first exacerbation [8, 9] and improves quality of
life in non-cystic fibrosis patients [8]. Definitive microbi-
ological eradication is rarely achieved with the potential
emergence of resistant phenotypes [8].
Polymyxins and aminoglycosides are commonly aero-
solised in critically ill patients in a non-standardized way
[1, 10]. Carbapenem-resistant non-fermentative Gram-
negative bacilli (GNB) are the main target. Due to the
lack of benefit of adjunctive nebulised antibiotics [11], a
position paper of the European Society of Clinical Micro-
biology and Infectious Diseases did not recommend
standard use in VAP [12]. Three randomised controlled
trials (RCTs) confirmed later the lack of benefit [13–15].
A systematic review and meta-analysis [11] reported a
reduced nephrotoxicity risk for inhaled aminoglycosides/
polymyxins administered as a substitutive strategy.
How to address unmet clinical needs from a
research standpoint
Confounding factors and methodological insufficiencies
present in the past RCTs [16] should not be reproduced:
mixing VAP caused by susceptible and XDR GNB; select-
ing multiple antibiotic regimen rather than monotherapy;
selecting breath-actuated rather than continuous nebu-
lisation; nebulising low-doses aminoglycosides/poly-
myxins; and ignoring optimisation of ventilator settings.
Inclusion at an early stage of VAP should be privileged to
avoid extended consolidations that limit antibiotic lung
penetration. Asynchronies with the ventilator should
be avoided by a short-acting propofol sedation [6], the
administration of muscle relaxants being restricted to
refractory asynchronies.
Aerosol delivery provides partial humidification of the
inspiratory gas and using dry carrying gas for less than
60 min does not induce significant tracheobronchial
injury. Further research is needed in ventilated patients
to clarify the impact on lung deposition and therapeutic
efficiency of different type of nebulizers and of using or
not the humidifier. Although mesh nebulizers are pre-
ferred to jet nebulizers [5], the type of nebuliser does not
seem to influence pharmacokinetics.
Conducting RCTs under the substitutive strategy for
treatment of VAP caused by XDR GNB is a priority. The
efficacy of 5-day regimens substitutive polymyxin nebu-
lization regimens should be addressed among patients
with VAP caused by XDR GNB. Lastly, the effect of aero-
sol antibiotic in patients who underwent extracorporeal
membrane oxygenation needs to be evaluated.
In conclusion, aerosol therapy follows different deliv-
ery principles according to the target: the tracheobron-
chial tree or the lung parenchyma. We need to realize
that inspiratory turbulences promote bronchial depo-
sition and limits antibiotic delivery to the infected lung
parenchyma and optimizing the technique of nebulisa-
tion is likely a prerequisite for therapeutic efficiency.
Regulatory agencies’ approval for new antibiotics or new
modes of administration is following non-inferiority tri-
als rules. Future non-inferiority RCTs should focus on
patients with VAP caused by XDR GNB and compare
inhaled polymyxins to intravenous new cephalosporins/
βlactamase inhibitors. Future superiority RCTs should
include patients with VAP caused by XDR GNB and
compare short-course inhaled versus systemic polymyx-
ins. The ENAVAP research network contributes to smart
designs of future RCTs as reported elsewhere [17].
Author details
1
Global Health eCore, Vall d’Hebron Institute of Research (VHIR), Ps. Vall
d’Hebron 129. AMI‑14, 08035 Barcelona, Spain. 2 Centro de Investigacion
Biomedica en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud
Carlos III, Madrid, Spain. 3 Unité de Recherche FOVERA, Réanimation Douleur
Urgences, Centre Hospitalier Universitaire de Nîmes, Nîmes, France. 4 Car‑
diovascular Intensive Care Unit, Department of Anaesthesiology and Critical
Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpitaux de Paris, Paris,
France. 5 Research Department, Departement Médico‑Universitaire DREAM
(DMU DREAM), Sorbonne University of Paris, Paris, France.
Acknowledgements
The following members of the European Investigators Network for Nebulized
Antibiotics in Ventilator-associated Pneumonia (ENAVAP) endorsed the final
manuscript: Kostoula Arvaniti arvanitik@hotmail.com, Papageorgiou Hospital
of Thessaloniki, Intensive Care Unit Department, Thessaloniki, Greece; 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.bassetti@asuiud.sanita.fvg.it, Infectious Diseases Clinic,
Department of Health Sciences, University of Genoa, Genoa and Hospital
Policlinico San Martino – IRCCS, Genoa, Italy; Stijn Blot stijn.blot@UGent.be,
Department of Internal Medicine and Pediatrics, Ghent University, Ghent,
Belgium; Matthieu Boisson matthieu.boisson@chu-poitiers.fr, University of
Poitiers, Anaesthesiology and Intensive Care Department, University hospital
of Poitiers, Poitiers, France; 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; Jayesh Dhanani
jadhanani@hotmail.com, Burns Trauma and Critical Care Research Centre and
Centre for Translational Anti-infective Pharmacodynamics, The University of
Queensland, Butterfield Street, Herston, Brisbane, Australia; George Dimo‑
poulos 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;
Pauline Dureau pauline.dureau@aphp.fr Medicine Sorbonne University, Anaes‑
thesiology and Critical Care, Cardiology Institute, Department of Anaesthesiol‑
ogy and Critical Care, La Pitié-Salpêtrière Hospital, Assistance Publique Hôpi‑
taux de Paris, Paris, France; Timothy Felton timothy.felton@manchester.ac.uk,
The University of Manchester and Manchester University NHS Foundation
Trust, Manchester, United Kingdom; Antonia Koutsoukou koutsoukou@yahoo.
gr, Intensive Care Unit, First Department of Respiratory Medicine, School of
Medicine, Sotiria General Hospital, National and Kapodistrian University of Ath‑
ens, 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 Anaesthesiol‑
ogy 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, Bris‑
bane, Australia, and Institut d’Investigacions Biomèdiques August Pi i Sunyer
(IDIBAPS), Barcelona, Spain; Xuelian Liao xuelianliao@hotmail.com, Depart‑
ment of Critical Care Medicine, West China Hospital of Sichuan University,
Chengdu, China; Olivier Mimoz o.mimoz@chu-poitiers.fr, University of Poitiers,
Anaesthesiology and Intensive Care Department, University hospital of
Poitiers, Poitiers, France; 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 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; Paolo Pelosi ppelosi@hotmail.com Anaesthesiology and Critical
Care, San Martino Policlinico Hospital, IRCCS for Oncology and Neurosciences,
Genoa, Italy. Department of Surgical Sciences and Integrated Diagnostics,
University of Genoa, Genoa, Italy; 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; Kon‑
stantinos Pontikis kostis_pontikis@yahoo.gr, Intensive Care Unit, First Depart‑
ment 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 & 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 Univer‑
sity of Athens, Athens, Greece; 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; Michel Wolff m.wolff@ghu-paris.fr , Service
de Neuro-Réanimation, Groupe Hospitalo-Universitaire Paris Psychiatrie &
Neurosciences, Hôpital Ste Anne Paris France; 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, Kun‑
ming, Yunnan, China; Ting Yang, 459803440@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.
Author contributions
JJR and JR wrote the first draft of the manuscript. JJR conceived and drafted
the figure. AB contributed towards the critical revision of the manuscript for
important intellectual content and confirm the integrity of the work.
Funding
No funding supported this manuscript.
Data availability
Data sharing not applicable to this article as no datasets were generated or
analyzed during the current study.
Declarations
Conflicts of interest
JR served in advisory boards for BAYER, Pfizer, Merck and served in the
speaker’s bureau for Norma-Hellas. AB and JJR declare no conflict of interest.
Ethical approval
An approval by an ethics committee was not applicable.
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in pub‑
lished maps and institutional affiliations.
Received: 31 January 2023 Accepted: 11 March 2023
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