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Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of quorum sensing: a randomized controlled trial

van Delden, Christian ; Köhler, Thilo ; Brunner-Ferber, Françoise ; François, Bruno ; Carlet, Jean ; Pechère, Jean-Claude

In: Intensive Care Medicine, 2012, vol. 38, no. 7, p. 1118-1125

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    Titre
    • Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of quorum sensing: a randomized controlled trial
    Auteur
    • van Delden, Christian. Service of Infectious Diseases, University Hospital Geneva, 4 Rue Gabrielle-Perret-Gentil, 1211, Geneva, Switzerland
    • Köhler, Thilo. Service of Infectious Diseases, University Hospital Geneva, 4 Rue Gabrielle-Perret-Gentil, 1211, Geneva, Switzerland
    • Brunner-Ferber, Françoise. Brunner Naga, Pfaeffikon-ZH, Switzerland
    • François, Bruno. Intensive Care Unit, CIC-P 0801 Inserm, Dupuytren Hospital Limoges, Limoges, France
    • Carlet, Jean. Groupe Hospitalier Saint Joseph, Paris, France
    • Pechère, Jean-Claude. Department of Microbiology and Molecular Medicine, University of Geneva, Geneva, Switzerland
    Type de document
    • Postprint
    Identifiant OAI-PMH
    • oai:doc.rero.ch:319127
    Summary
    Purpose: Anti-virulence strategies have not been evaluated for the prevention of bacterial infections. Prolonged colonization of intubated patients with Pseudomonas aeruginosa isolates producing high-levels of the quorum sensing (QS)-regulated virulence factor rhamnolipids has been associated with ventilator-associated pneumonia (VAP). In this pathogen, azithromycin reduces QS-regulated virulence. We aimed to assess whether azithromycin could prevent VAP in patients colonized by rhamnolipids producing isolates. Methods: In a randomized, double-blind, multicenter trial, intubated colonized patients received either 300mg/day azithromycin or placebo. Primary endpoint was the occurrence of P. aeruginosa VAP. We further identified those patients persistently colonized by isolates producing high-levels of rhamnolipids and therefore at the highest risk to develop VAP linked to this QS-dependent virulence factor. Results: Ninety-two patients were enrolled; 43 azithromycin-treated and 42 placebo patients were eligible for the per-protocol analysis. In the per-protocol population, the occurrence of P. aeruginosa VAP was reduced in the azithromycin group but without reaching statistical significance (4.7 vs. 14.3% VAP, p=0.156). QS-dependent virulence of colonizing isolates was similarly low in both study groups, and only five patients in each arm were persistently colonized by high-level rhamnolipids producing isolates. In this high-risk subgroup, the incidence of VAP was reduced fivefold in azithromycin versus placebo patients (1/5 vs. 5/5 VAP, p=0.048). Conclusions: There was a trend towards reduced incidence of VAP in colonized azithromycin-treated patients. In addition, azithromycin significantly prevented VAP in those patients at high risk of rhamnolipid-dependent VAP, suggesting that virulence inhibition is a promising anti-microbial strategy