Inhaled amikacin versus placebo to prevent ventilator-associated pneumonia: the AMIKINHAL double-blind multicentre randomised controlled trial protocol

Elsa Tavernier, Francois Barbier, Ferhat Meziani, Jean-Pierre Quenot, Jean-Etienne Herbrecht, Mickael Landais, Damien Roux, Philippe Seguin, David Schnell, Anne Veinstein, Benoît Veber, Sigismond Lasocki, Qin Lu, Gaetan Beduneau, Martine Ferrandiere, Claire Dahyot-Fizelier, Gaetan Plantefeve, Mai-Anh Nay, Hamid Merdji, Pascal Andreu, Laurent Vecellio, Grégoire Muller, Maria Cabrera, Deborah Le Pennec, Renaud Respaud, Philippe Lanotte, Nicolas Gregoire, Marie Leclerc, Julie Helms, Thierry Boulain, Jean-Claude Lacherade, Stephan Ehrmann, REVA network and the CRICS-TRIGGESEP F-CRIN network, Elsa Tavernier, Francois Barbier, Ferhat Meziani, Jean-Pierre Quenot, Jean-Etienne Herbrecht, Mickael Landais, Damien Roux, Philippe Seguin, David Schnell, Anne Veinstein, Benoît Veber, Sigismond Lasocki, Qin Lu, Gaetan Beduneau, Martine Ferrandiere, Claire Dahyot-Fizelier, Gaetan Plantefeve, Mai-Anh Nay, Hamid Merdji, Pascal Andreu, Laurent Vecellio, Grégoire Muller, Maria Cabrera, Deborah Le Pennec, Renaud Respaud, Philippe Lanotte, Nicolas Gregoire, Marie Leclerc, Julie Helms, Thierry Boulain, Jean-Claude Lacherade, Stephan Ehrmann, REVA network and the CRICS-TRIGGESEP F-CRIN network

Abstract

Introduction: Pre-emptive inhaled antibiotics may be effective to reduce the occurrence of ventilator-associated pneumonia among critically ill patients. Meta-analysis of small sample size trials showed a favourable signal. Inhaled antibiotics are associated with a reduced emergence of antibiotic resistant bacteria. The aim of this trial is to evaluate the benefit of a 3-day course of inhaled antibiotics among patients undergoing invasive mechanical ventilation for more than 3 days on the occurrence of ventilator-associated pneumonia.

Methods and analysis: Academic, investigator-initiated, parallel two group arms, double-blind, multicentre superiority randomised controlled trial. Patients invasively ventilated more than 3 days will be randomised to receive 20 mg/kg inhaled amikacin daily for 3 days or inhaled placebo (0.9% Sodium Chloride). Occurrence of ventilator-associated pneumonia will be recorded based on a standardised diagnostic framework from randomisation to day 28 and adjudicated by a centralised blinded committee.

Ethics and dissemination: The protocol and amendments have been approved by the regional ethics review board and French competent authorities (Comité de protection des personnes Ouest I, No.2016-R29). All patients will be included after informed consent according to French law. Results will be disseminated in international scientific journals.

Trial registration numbers: EudraCT 2016-001054-17 and NCT03149640.

Keywords: adult intensive & critical care; clinical trials; infectious diseases; respiratory infections.

Conflict of interest statement

Competing interests: SE declares consultancies from Aerogen, La Diffusion Technique Française; unrestricted research grants from Fisher & Paykel Healthcare, Aerogen Ltd, Hamilton Medical; travel reimbursements from Aerogen and Fisher & Paykel Healthcare.

© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Figures

Figure 1
Figure 1
Study outline.

References

    1. Torres A, Niederman MS, Chastre J, et al. . International ERS/ESICM/ESCMID/ALAT guidelines for the management of hospital-acquired pneumonia and ventilator-associated pneumonia: Guidelines for the management of hospital-acquired pneumonia (HAP)/ventilator-associated pneumonia (VAP) of the European Respiratory Society (ERS), European Society of Intensive Care Medicine (ESICM), European Society of Clinical Microbiology and Infectious Diseases (ESCMID) and Asociación Latinoamericana del Tórax (ALAT). Eur Respir J 2017;50:1700582. 10.1183/13993003.00582-2017
    1. Kalil AC, Metersky ML, Klompas M, et al. . Management of adults with hospital-acquired and ventilator-associated pneumonia: 2016 clinical practice guidelines by the infectious diseases Society of America and the American thoracic Society. Clin Infect Dis 2016;63:e61–111. 10.1093/cid/ciw353
    1. Koulenti D, Tsigou E, Rello J. Nosocomial pneumonia in 27 ICUs in Europe: perspectives from the EU-VAP/CAP study. Eur J Clin Microbiol Infect Dis 2017;36:1999–2006. 10.1007/s10096-016-2703-z
    1. Papazian L, Klompas M, Luyt C-E. Ventilator-associated pneumonia in adults: a narrative review. Intensive Care Med 2020;46:888–906. 10.1007/s00134-020-05980-0
    1. Nseir S, Martin-Loeches I, Makris D, et al. . Impact of appropriate antimicrobial treatment on transition from ventilator-associated tracheobronchitis to ventilator-associated pneumonia. Crit Care 2014;18:R129. 10.1186/cc13940
    1. Melsen WG, Rovers MM, Groenwold RHH, et al. . Attributable mortality of ventilator-associated pneumonia: a meta-analysis of individual patient data from randomised prevention studies. Lancet Infect Dis 2013;13:665–71. 10.1016/S1473-3099(13)70081-1
    1. Schreiber PW, Sax H, Wolfensberger A, et al. . The preventable proportion of healthcare-associated infections 2005-2016: systematic review and meta-analysis. Infect Control Hosp Epidemiol 2018;39:1277–95. 10.1017/ice.2018.183
    1. Pozuelo-Carrascosa DP, Herráiz-Adillo Ángel, Alvarez-Bueno C, et al. . Subglottic secretion drainage for preventing ventilator-associated pneumonia: an overview of systematic reviews and an updated meta-analysis. Eur Respir Rev 2020;29:190107. 10.1183/16000617.0107-2019
    1. Wittekamp BHJ, Oostdijk EAN, Cuthbertson BH, et al. . Selective decontamination of the digestive tract (SDD) in critically ill patients: a narrative review. Intensive Care Med 2020;46:343–9. 10.1007/s00134-019-05883-9
    1. de Smet AMGA, Kluytmans JAJW, Cooper BS, et al. . Decontamination of the digestive tract and oropharynx in ICU patients. N Engl J Med 2009;360:20–31. 10.1056/NEJMoa0800394
    1. de Jonge E, Schultz MJ, Spanjaard L, et al. . Effects of selective decontamination of digestive tract on mortality and acquisition of resistant bacteria in intensive care: a randomised controlled trial. Lancet 2003;362:1011–6. 10.1016/S0140-6736(03)14409-1
    1. Bergmans DC, Bonten MJ, Gaillard CA, et al. . Prevention of ventilator-associated pneumonia by oral decontamination: a prospective, randomized, double-blind, placebo-controlled study. Am J Respir Crit Care Med 2001;164:382–8. 10.1164/ajrccm.164.3.2005003
    1. Verwaest C, Verhaegen J, Ferdinande P, et al. . Randomized, controlled trial of selective digestive decontamination in 600 mechanically ventilated patients in a multidisciplinary intensive care unit. Crit Care Med 1997;25:63–71. 10.1097/00003246-199701000-00014
    1. Plantinga NL, de Smet AMGA, Oostdijk EAN, et al. . Selective digestive and oropharyngeal decontamination in medical and surgical ICU patients: individual patient data meta-analysis. Clin Microbiol Infect 2018;24:505–13. 10.1016/j.cmi.2017.08.019
    1. Plantinga NL, de Smet AMGA, Oostdijk EAN, et al. . Selective digestive and oropharyngeal decontamination in medical and surgical ICU patients: individual patient data meta-analysis. Clin Microbiol Infect 2018;24:505–13. 10.1016/j.cmi.2017.08.019
    1. Lim CLL, Chua AQ, Teo JQM, CLL L, JQM T, et al. . Importance of control groups when delineating antibiotic use as a risk factor for carbapenem resistance, extreme-drug resistance, and pan-drug resistance in Acinetobacter baumannii and Pseudomonas aeruginosa: a systematic review and meta-analysis. Int J Infect Dis 2018;76:48–57. 10.1016/j.ijid.2018.05.017
    1. Luyt C-E, Clavel M, Guntupalli K, et al. . Pharmacokinetics and lung delivery of PDDS-aerosolized amikacin (NKTR-061) in intubated and mechanically ventilated patients with nosocomial pneumonia. Crit Care 2009;13:R200. 10.1186/cc8206
    1. Niederman MS, Chastre J, Corkery K, et al. . BAY41-6551 achieves bactericidal tracheal aspirate amikacin concentrations in mechanically ventilated patients with gram-negative pneumonia. Intensive Care Med 2012;38:263–71. 10.1007/s00134-011-2420-0
    1. Petitcollin A, Dequin P-F, Darrouzain F, et al. . Pharmacokinetics of high-dose nebulized amikacin in ventilated critically ill patients. J Antimicrob Chemother 2016;71:3482–6. 10.1093/jac/dkw313
    1. Ehrmann S, Mercier E, Vecellio L, et al. . Pharmacokinetics of high-dose nebulized amikacin in mechanically ventilated healthy subjects. Intensive Care Med 2008;34:755–62. 10.1007/s00134-007-0935-1
    1. Lu Q, Yang J, Liu Z, et al. . Nebulized ceftazidime and amikacin in ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Am J Respir Crit Care Med 2011;184:106–15. 10.1164/rccm.201011-1894OC
    1. Koerner RJ. Contribution of endotracheal tubes to the pathogenesis of ventilator-associated pneumonia. J Hosp Infect 1997;35:83–9. 10.1016/S0195-6701(97)90096-7
    1. Mah TF, O'Toole GA. Mechanisms of biofilm resistance to antimicrobial agents. Trends Microbiol 2001;9:34–9. 10.1016/S0966-842X(00)01913-2
    1. Póvoa FCC, Cardinal-Fernandez P, Maia IS, et al. . Effect of antibiotics administered via the respiratory tract in the prevention of ventilator-associated pneumonia: a systematic review and meta-analysis. J Crit Care 2018;43:240–5. 10.1016/j.jcrc.2017.09.019
    1. Palmer LB, Smaldone GC. Reduction of bacterial resistance with inhaled antibiotics in the intensive care unit. Am J Respir Crit Care Med 2014;189:1225–33. 10.1164/rccm.201312-2161OC
    1. Kidney disease: improving global outcome. acute kidney injury work group KDIGO clinical practice guideline for acute kidney injury. Kidney Int 2012;2:S1–138.
    1. Acute Respiratory Distress Syndrome Network, Brower RG, Matthay MA, et al. . Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301–8. 10.1056/NEJM200005043421801
    1. Ehrmann S, Chastre J, Diot P, et al. . Nebulized antibiotics in mechanically ventilated patients: a challenge for translational research from technology to clinical care. Ann Intensive Care 2017;7:78. 10.1186/s13613-017-0301-6
    1. American Thoracic Society, Infectious Diseases Society of America . Guidelines for the management of adults with hospital-acquired, ventilator-associated, and healthcare-associated pneumonia. Am J Respir Crit Care Med 2005;171:388–416. 10.1164/rccm.200405-644ST
    1. Nseir S, Di Pompeo C, Pronnier P, et al. . Nosocomial tracheobronchitis in mechanically ventilated patients: incidence, aetiology and outcome. Eur Respir J 2002;20:1483–9. 10.1183/09031936.02.00012902
    1. EUCAST . The European Committee on antimicrobial susceptibility testing. breakpoint table v5.0, 2015. Available:
    1. Fartoukh M, Maitre B, Honoré S, et al. . Diagnosing pneumonia during mechanical ventilation: the clinical pulmonary infection score revisited. Am J Respir Crit Care Med 2003;168:173–9. 10.1164/rccm.200212-1449OC
    1. Pugin J, Auckenthaler R, Mili N, et al. . Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic "blind" bronchoalveolar lavage fluid. Am Rev Respir Dis 1991;143:1121–9. 10.1164/ajrccm/143.5_Pt_1.1121
    1. Singh N, Rogers P, Atwood CW, et al. . Short-Course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. Am J Respir Crit Care Med 2000;162:505–11. 10.1164/ajrccm.162.2.9909095
    1. Centre for disease control . Surveillance for ventilator-associated events, 2015. Available:
    1. Magiorakos A-P, Srinivasan A, Carey RB, et al. . Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: an international expert proposal for interim standard definitions for acquired resistance. Clin Microbiol Infect 2012;18:268–81. 10.1111/j.1469-0691.2011.03570.x
    1. QIIME . Quantitative insights into microbial ecology, 2020. Available:
    1. RD pipeline . Center for microbial ecology. Michigan university, 2020. Available:
    1. Reignier J, Mercier E, Le Gouge A, et al. . Effect of not monitoring residual gastric volume on risk of ventilator-associated pneumonia in adults receiving mechanical ventilation and early enteral feeding: a randomized controlled trial. JAMA 2013;309:249–56. 10.1001/jama.2012.196377
    1. Surveillance des infections nosocomiales en réanimation adulte . Réseau REA-Raisin, France, résultats 2013, 2013. Available:
    1. Schulgen G, Olschewski M, Krane V, et al. . Sample sizes for clinical trials with time-to-event endpoints and competing risks. Contemp Clin Trials 2005;26:386–96. 10.1016/j.cct.2005.01.010
    1. Lozupone C, Lladser ME, Knights D, et al. . UniFrac: an effective distance metric for microbial community comparison. Isme J 2011;5:169–72. 10.1038/ismej.2010.133
    1. Boisson M, Jacobs M, Grégoire N, et al. . Comparison of intrapulmonary and systemic pharmacokinetics of colistin methanesulfonate (CMS) and colistin after aerosol delivery and intravenous administration of CMS in critically ill patients. Antimicrob Agents Chemother 2014;58:7331–9. 10.1128/AAC.03510-14
    1. ICMJE . International Committee of medical journal editors, 2020. Available:
    1. Niederman MS, Alder J, Bassetti M, et al. . Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with gram-negative pneumonia (inhale): a double-blind, randomised, placebo-controlled, phase 3, superiority trial. Lancet Infect Dis 2020;20:330–40. 10.1016/S1473-3099(19)30574-2
    1. Kollef MH, Ricard J-D, Roux D, et al. . A randomized trial of the amikacin fosfomycin inhalation system for the adjunctive therapy of gram-negative ventilator-associated pneumonia: IASIS trial. Chest 2017;151:1239–46. 10.1016/j.chest.2016.11.026
    1. Wittekamp BHJ, Oostdijk EAN, Cuthbertson BH, et al. . Selective decontamination of the digestive tract (SDD) in critically ill patients: a narrative review. Intensive Care Med 2020;46:343–9. 10.1007/s00134-019-05883-9

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