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

• Published in: Intensive care medicine Vol. 38; no. 7; pp. 1118 - 1125
• Main Authors: van Delden, Christian, Köhler, Thilo, Brunner-Ferber, Françoise, François, Bruno, Carlet, Jean, Pechère, Jean-Claude
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 01.07.2012; Springer; Springer Nature B.V
• Subjects: Analysis; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Anesthesiology; Anti-Bacterial Agents - therapeutic use; Antibiotic Prophylaxis; Antibiotics; Antimicrobial agents; Azithromycin; Azithromycin - pharmacology; Azithromycin - therapeutic use; Bacterial infections; Bacterial pneumonia; Biological and medical sciences; Clinical trials; Cloning; Colonization; Critical Care Medicine; Double-Blind Method; Drug resistance; Emergency and intensive respiratory care; Emergency Medicine; Female; Glycolipids - pharmacology; Glycolipids - therapeutic use; Health aspects; Hospitals; Humans; Infection; Intensive; Intensive care medicine; Male; Medical research; Medical sciences; Medicine; Medicine & Public Health; Medicine, Experimental; Middle Aged; Original; Pain Medicine; Pathogens; Pediatrics; Pilot Projects; Pneumology/Respiratory System; Pneumonia; Pneumonia, Ventilator-Associated - drug therapy; Pneumonia, Ventilator-Associated - microbiology; Pneumonia, Ventilator-Associated - prevention & control; Prevention; Pseudomonas aeruginosa; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - pathogenicity; Pseudomonas Infections - drug therapy; Pseudomonas Infections - microbiology; Pseudomonas Infections - prevention & control; quorum sensing; Quorum Sensing - drug effects; rhamnolipids; Risk factors; Risk groups; Statistics; ventilator-associated pneumonia; Ventilators; Virulence; Virulence - drug effects; virulence factors; France; Switzerland; Ventilator-associated pneumonia; Quorum sensing; Rhamnolipids; Virulence; Pseudomonadales; Lung disease; Ventilator; Pneumonia; Intensive care; Respiratory disease; Azithromycin; Macrolide; Antibiotic; Bacteria; Pseudomonadaceae; Pseudomonas aeruginosa; Protein synthesis inhibitor; Antibacterial agent; Resuscitation
• ISSN: 0342-4642; 1432-1238; 1432-1238
• DOI: 10.1007/s00134-012-2559-3

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 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.