title: Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of quorum sensing: a randomized controlled trial.
abstract: OBJECTIVE
  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 300 mg/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.
authors.affiliation: Service of Infectious Diseases, University Hospital Geneva, 4 Rue Gabrielle-Perret-Gentil, 1211, Geneva, Switzerland. Christian.vandelden@hcuge.ch
authors.forename: Christian
authors.initials: C
authors.lastname: van Delden
authors.forename: Thilo
authors.initials: T
authors.lastname: Köhler
authors.forename: Françoise
authors.initials: F
authors.lastname: Brunner-Ferber
authors.forename: Bruno
authors.initials: B
authors.lastname: François
authors.forename: Jean
authors.initials: J
authors.lastname: Carlet
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Pechère
mesh_terms: D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D019072:Antibiotic Prophylaxis; D017963:Azithromycin / Q000494:pharmacology / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D006017:Glycolipids / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010865:Pilot Projects; D053717:Pneumonia, Ventilator-Associated / Q000188:drug therapy / Q000382:microbiology / Q000517:prevention & control*; D011552:Pseudomonas Infections / Q000188:drug therapy / Q000382:microbiology / Q000517:prevention & control*; D011550:Pseudomonas aeruginosa / Q000187:drug effects* / Q000472:pathogenicity; D053038:Quorum Sensing / Q000187:drug effects; D014774:Virulence / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D006017:Glycolipids; C418382:rhamnolipid; D017963:Azithromycin