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Comparison of 8 versus 15 days of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia in adults: a randomized, controlled, open-label trial

Intensive Care Medicine (2022)Cite this article

A Correction to this article was published on 21 June 2022

This article has been updated

Abstract

Purpose

Duration of antibiotic therapy for ventilator-associated pneumonia (VAP) due to non-fermenting Gram-negative bacilli (NF-GNB), including Pseudomonas aeruginosa (PA) remains uncertain. We aimed to assess the non-inferiority of a short duration of antibiotics (8 days) vs. prolonged antibiotic therapy (15 days) in VAP due to PA (PA-VAP).

Methods

We conducted a nationwide, randomized, open-labeled, multicenter, non-inferiority trial to evaluate optimal duration of antibiotic treatment in PA-VAP. Eligible patients were adults with diagnosis of PA-VAP and randomly assigned in 1:1 ratio to receive a short-duration treatment (8 days) or a long-duration treatment (15 days). A pre-specified analysis was used to assess a composite endpoint combining mortality and PA-VAP recurrence rate during hospitalization in the intensive care unit (ICU) within 90 days.

Results

The study was stopped after 24 months due to slow inclusion rate. In intention-to-treat population (n = 186), the percentage of patients who reached the composite endpoint was 25.5% (N = 25/98) in the 15-day group versus 35.2% (N = 31/88) in the 8-day group (difference 9.7%, 90% confidence interval (CI) −1.9%–21.2%). The percentage of recurrence of PA-VAP during the ICU stay was 9.2% in the 15-day group versus 17% in the 8-day group. The two groups had similar median days of mechanical ventilation, of ICU stay, number of extra pulmonary infections and acquisition of multidrug-resistant (MDR) pathogens during ICU stay.

Conclusions

Our study failed to show the non-inferiority of a short duration of antibiotics in the treatment of PA-VAP, compared to a long duration. The short duration strategy may be associated to an increase of PA-VAP recurrence. However, the lack of power limits the interpretation of this study.

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Acknowledgements

We wish to thank Moreno Ursino, Ph.D., from the Clinical Research Unit of Robert-Debré hospital (AP-HP), Inserm CIC-EC 1426, for the post hoc Bayesian analysis. The iDIAPASON Trial Investigators: Adrien Bouglé: Hôpitaux Universitaires Pitié-Salpêtrière, APHP, Paris; Julien Amour: Hôpitaux Universitaires Pitié-Salpêtrière, APHP, Paris; Thomas Dessalle: Hôpitaux Universitaires Pitié-Salpêtrière, APHP, Paris; Florence Bellenfant Zegdi : Hôpital Européen Georges Pompidou, APHP, Paris; Bernard Cholley ; Julien Massot: Hôpital Européen Georges Pompidou, APHP, Paris; Jean-Michel Constantin: CHU Clermont-Ferrand, Clermont-Ferrand; Alexandre Demoule; Julien Mayaux : Hôpitaux Universitaires Pitié-Salpêtrière, APHP, Paris; Vincent Dubée: Hôpital Saint-Antoine, APHP, Paris; Hervé Dupont : CHU Amiens, Amiens; Jacques Duranteau : Hôpital Bicêtre, APHP, Paris; Laura Federici : Centre Hospitalier Sud Francilien, Corbeil; Arnaud Foucrier: Hôpital Beaujon, APHP, Paris; Thomas Geeraerts : CHU Toulouse, Toulouse; Céline Guichon : Hôpital Croix Rousse, CHU Lyon, Lyon; Pierre Kalfon : Hôpital Louis Pasteur, CH de Chartres, Chartres; Éric Kipnis: CHRU Lille, Lille; Sigismond Lasocki : CHU Angers, Angers; Jean-Yves Lefrant: CHU Nîmes, Nîmes; Matthieu Legrand : Groupe Hospitalier Lariboisière – Saint Louis, APHP, Paris; Marc Leone: CHU Hôpital Nord, APHM, Marseille; Thomas Lescot : Hôpital Saint-Antoine, APHP, Paris; Bruno Lévy : CHU Nancy Brabois, Nancy; Joël Cousson: CHU Reims, Reims; Philippe Montravers, Sébastien Tanaka: Hôpital Bichat, APHP, Paris; Emmanuel Novy : CHU Nancy Brabois, Nancy; Alexandre Ouattara : CHU Bordeaux, Bordeaux; Jean-François Payen: CHU Grenoble, Grenoble; Walter Picard: Centre Hospitalier de Pau, Pau; Pascale Poète: Hôpitaux Universitaires Pitié-Salpêtrière, APHP, Paris; Julien Pottecher : Nouvel Hôpital Civil, CHRU Strasbourg, Strasbourg; Christophe Quesnel, Muriel Fartoukh: Hôpital Tenon, APHP, Paris; Anoine Tesniere, Mélanie Fromentin: Hôpital Cochin, APHP, Paris; Jean-Jacques Rouby, Qin Lu, Olivier Langeron: Hôpitaux Universitaires Pitié-Salpêtrière, APHP, Paris; Pierre Squara: Clinique Ambroise Paré, Neuilly-sur-Seine; Eric Levesque: Hôpital Henri Mondor, APHP, Créteil; Nicolas Mongardon: Hôpital Henri Mondor, APHP, Créteil. Methodology and biostatistics team: Tabassome Simon, Laurence Berard, Marine Cachanado, Nora Soussi: Unité de Recherche Clinique du GH HUEP (URC-Est), Hôpital Saint-Antoine, APHP, Paris

Funding

The sponsor was Assistance Publique – Hôpitaux de Paris (Département de la Recherche Clinique et du Développement, Clinical Research and Development Department). The research was funded by a grant from Programme Hospitalier de Recherche Clinique—PHRC 2014 (Ministère de la Santé).

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Authors and Affiliations

  1. Department of Anesthesiology and Critical Care Medicine, Cardiology Institute, Sorbonne University, GRC 29, AP-HP, Pitié-Salpêtrière Hospital, 47-83 Boulevard de l’Hôpital, 75013, Paris, France

    Adrien Bouglé, Thomas Dessalle & Julien Amour

  2. Department of Clinical Pharmacology-Clinical Research Platform, Sorbonne University, AP-HP, Paris, France

    Sophie Tuffet, Alexandra Rousseau & Tabassome Simon

  3. Service de Réanimation Polyvalente, Centre Hospitalier Sud Francilien, Corbeil, France

    Laura Federici

  4. Service d’anesthésie et de réanimation, Hôpital Nord, Assistance Publique Hôpitaux de Marseille, Aix Marseille Université, Marseille, France

    Marc Leone

  5. Multidisciplinary Intensive Care Unit, Department of Anesthesioloy and Critical Care, Sorbonne University, GRC 29, AP-HP, Pitié-Salpêtrière Hospital, Paris, France

    Antoine Monsel & Olivier Langeron

  6. Department of Anaesthesia and Intensive Care, University Hospital of Poitiers, Poitiers, France

    Claire Dahyot-Fizelier

  7. Service de Médecine Intensive-Réanimation, Centre Hospitalier Régional d’Orléans, 14, avenue de l’Hôpital, 45100, Orléans, France

    François Barbier

  8. Medical Intensive Care Unit, Pitié-Salpêtrière Hospital, Sorbonne University, AP-HP, Paris, France

    Charles-Edouard Luyt

  9. Service de Médecine Intensive Et Réanimation (Département R3S), APHP-Sorbonne Université, Site Pitié-Salpêtrière, Paris, France

    Alexandre Demoule

  10. Département d’Anesthésie et Réanimation, Hôpital Européen Georges Pompidou, APHP, Paris, France

    Bernard Cholley

  11. Anaesthesiology, Critical Care and Perioperative Medicine, Strasbourg University Hospital-EA3072, FMTS, Strasbourg, France

    Julien Pottecher

  12. General Intensive Care Unit, Sud-Essonne Hospital, Étampes, France

    Tarik Hissem

  13. Service des Réanimations, Pôle Anesthésie Réanimation Douleur Urgence, CHU Nîmes, Nîmes, France

    Jean-Yves Lefrant

  14. Department of Anesthesiology, Critical Care and Perioperative Medicine, Rouen University Hospital, Rouen, France

    Benoit Veber

  15. Department of Anaesthesiology and Critical Care and Burn Unit, Groupe Hospitalier Lariboisière-Saint Louis, APHP, Paris, France

    Matthieu Legrand

  16. Service de Réanimation Polyvalente, Hôpital Louis Pasteur, CH de Chartres, Chartres, France

    Pierre Kalfon

  17. Department of Perioperative Medicine, University Hospital of Clermont-Ferrand, Clermont-Ferrand, France

    Jean-Michel Constantin

  18. Department of Anaesthesiology and Critical Care, Beaujon Hospital, DMU Parabol, AP-HP Nord, Université de Paris, Clichy, France

    Arnaud Foucrier

Authors
  1. Adrien Bouglé
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  2. Sophie Tuffet
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  3. Laura Federici
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  4. Marc Leone
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  5. Antoine Monsel
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  6. Thomas Dessalle
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  7. Julien Amour
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  8. Claire Dahyot-Fizelier
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  9. François Barbier
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  10. Charles-Edouard Luyt
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  11. Olivier Langeron
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  12. Bernard Cholley
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  13. Julien Pottecher
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  14. Tarik Hissem
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  15. Jean-Yves Lefrant
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  16. Benoit Veber
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  17. Matthieu Legrand
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  18. Alexandre Demoule
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  19. Pierre Kalfon
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  20. Jean-Michel Constantin
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  21. Alexandra Rousseau
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  22. Tabassome Simon
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  23. Arnaud Foucrier
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Consortia

the iDIAPASON Trial Investigators

  • Adrien Bouglé
  • , Julien Amour
  • , Thomas Dessalle
  • , Florence Bellenfant Zegdi
  • , Bernard Cholley
  • , Julien Massot
  • , Jean-Michel Constantin
  • , Alexandre Demoule
  • , Julien Mayaux
  • , Vincent Dubée
  • , Hervé Dupont
  • , Jacques Duranteau
  • , Laura Federici
  • , Arnaud Foucrier
  • , Thomas Geeraerts
  • , Céline Guichon
  • , Pierre Kalfon
  • , Éric Kipnis
  • , Sigismond Lasocki
  • , Jean-Yves Lefrant
  • , Matthieu Legrand
  • , Marc Leone
  • , Thomas Lescot
  • , Bruno Lévy
  • , Joël Cousson
  • , Philippe Montravers
  • , Sébastien Tanaka
  • , Emmanuel Novy
  • , Alexandre Ouattara
  • , Jean-François Payen
  • , Walter Picard
  • , Pascale Poète
  • , Julien Pottecher
  • , Christophe Quesnel
  • , Muriel Fartoukh
  • , Anoine Tesniere
  • , Mélanie Fromentin
  • , Jean-Jacques Rouby
  • , Qin Lu
  • , Olivier Langeron
  • , Pierre Squara
  • , Eric Levesque
  • , Nicolas Mongardon
  • , Tabassome Simon
  • , Laurence Berard
  • , Marine Cachanado
  •  & Nora Soussi

Corresponding author

Correspondence to Adrien Bouglé.

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The authors declare no conflict of interests.

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A complete list of iDIAPASON Trial Investigators is provided in the Acknowledgements section.

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Bouglé, A., Tuffet, S., Federici, L. et al. Comparison of 8 versus 15 days of antibiotic therapy for Pseudomonas aeruginosa ventilator-associated pneumonia in adults: a randomized, controlled, open-label trial. Intensive Care Med (2022). https://doi.org/10.1007/s00134-022-06690-5

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  • DOI: https://doi.org/10.1007/s00134-022-06690-5

Keywords

  • Ventilator-associated pneumonia
  • Pseudomonas aeruginosa
  • Antibiotic therapy
  • Recurrence
  • Survival