Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated pneumonia by inhibition of quorum sensing

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Intensive Care Med. 2012 Apr 20. [Epub ahead of print]
Azithromycin to prevent Pseudomonas aeruginosa ventilator-associated
pneumonia by inhibition of quorum sensing: a randomized controlled
trial.
van Delden C, Köhler T, Brunner-Ferber F, François B, Carlet J,
Pechère JC.
Source
Service of Infectious Diseases, University Hospital Geneva, 4 Rue
Gabrielle-Perret-Gentil, 1211, Geneva, Switzerland,
Christian...@hcuge.ch.

Abstract
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.