Log in | Register

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

Christian van Delden| Thilo Köhler| Françoise Brunner-Ferber| Bruno François| Jean Carlet| Jean-Claude Pechère
Original
Volume 38, Issue 7 / July , 2012

Pages 1118 - 1125

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.

Keywords

References

  1. Van Delden C, Iglewski BH (1998) Cell-to-cell signaling and Pseudomonas aeruginosa infections. Emerg Infect Dis 4:551
    • View reference on PubMed
    • View reference on publisher's website
  2. Smith RS, Iglewski BH (2003) Pseudomonas aeruginosa quorum sensing as a potential antimicrobial target. J Clin Invest 112:1460–1465
    • View reference on PubMed
  3. Rasmussen TB, Givskov M (2006) Quorum sensing inhibitors: a bargain of effects. Microbiology 152:895–904
    • View reference on PubMed
    • View reference on publisher's website
  4. Chastre J, Fagon JY (2002) Ventilator-associated pneumonia. Am J Respir Crit Care Med 165:867
    • View reference on PubMed
  5. Torres A, Ewig S, Lode H, Carlet J (2009) Defining, treating and preventing hospital acquired pneumonia: European perspective. Intensive Care Med 35:9–29
  6. Nguile-Makao M, Zahar JR, Francais A, Tabah A, Garrouste-Orgeas M, Allaouchiche B, Goldgran-Toledano D, Azoulay E, Adrie C, Jamali S, Clec’h C, Souweine B, Timsit JF (2010) Attributable mortality of ventilator-associated pneumonia: respective impact of main characteristics at ICU admission and VAP onset using conditional logistic regression and multi-state models. Intensive Care Med 36:781–789
  7. Hancock RE, Speert DP (2000) Antibiotic resistance in Pseudomonas aeruginosa: mechanisms and impact on treatment. Drug Resist Updat 3:247–255
    • View reference on PubMed
    • View reference on publisher's website
  8. Mesaros N, Nordmann P, Plesiat P, Roussel-Delvallez M, Van Eldere J, Glupczynski Y, Van Laethem Y, Jacobs F, Lebecque P, Malfroot A, Tulkens PM, Van Bambeke F (2007) Pseudomonas aeruginosa: resistance and therapeutic options at the turn of the new millennium. Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 13:560–578
  9. van Delden C (2007) Pseudomonas aeruginosa bloodstream infections: how should we treat them? Int J Antimicrob Agents 30(Suppl 1):S71–S75
    • View reference on PubMed
    • View reference on publisher's website
  10. van Delden C (2004) Virulence factors in Pseudomonas aeruginosa. In: Ramos JL (ed) The Pseudomonads. Kluwer Academic, New York, pp 3–46
  11. Tateda K, Comte R, Pechère JC, Köhler T, Yamaguchi K, Van Delden C (2001) Azithromycin inhibits quorum sensing in Pseudomonas aeruginosa. Antimicrob Agents Chemother 45:1930–1933
    • View reference on PubMed
    • View reference on publisher's website
  12. Favre-Bonté S, Köhler T, Van Delden C (2003) Biofilm formation by Pseudomonas aeruginosa: role of the C4-HSL cell-to-cell signal and inhibition by azithromycin. J Antimicrob Chemother 52:598–604
    • View reference on PubMed
    • View reference on publisher's website
  13. Nalca Y, Jansch L, Bredenbruch F, Geffers R, Buer J, Haussler S (2006) Quorum-sensing antagonistic activities of azithromycin in Pseudomonas aeruginosa PAO1: a global approach. Antimicrob Agents Chemother 50:1680–1688
    • View reference on PubMed
    • View reference on publisher's website
  14. Hoffmann N, Lee B, Hentzer M, Rasmussen TB, Song Z, Johansen HK, Givskov M, Hoiby N (2007) Azithromycin blocks quorum sensing and alginate polymer formation and increases the sensitivity to serum and stationary-growth-phase killing of Pseudomonas aeruginosa and attenuates chronic P. aeruginosa lung infection in Cftr(-/-) mice. Antimicrob Agents Chemother 51:3677–3687
    • View reference on PubMed
    • View reference on publisher's website
  15. Kohler T, Perron GG, Buckling A, van Delden C (2010) Quorum sensing inhibition selects for virulence and cooperation in Pseudomonas aeruginosa. PLoS Pathog 6:e1000883
    • View reference on PubMed
    • View reference on publisher's website
  16. Baldwin DR, Wise R, Andrews JM, Ashby JP, Honeybourne D (1990) Azithromycin concentrations at the sites of pulmonary infection. Eur Respir J Off J Eur Soc Clin Respir Physiol 3:886–890
  17. Pugin J, Auckenthaler R, Mili N, Janssens JP, Lew PD, Suter PM (1991) Diagnosis of ventilator-associated pneumonia by bacteriologic analysis of bronchoscopic and nonbronchoscopic “blind” bronchoalveolar lavage fluid. Am Rev Respir Dis 143:1121
    • View reference on PubMed
  18. Singh N, Rogers P, Atwood CW, Wagener MM, Yu VL (2000) Short-course empiric antibiotic therapy for patients with pulmonary infiltrates in the intensive care unit. A proposed solution for indiscriminate antibiotic prescription. Am J Respir Crit Care Med 162:505–511
    • View reference on PubMed
  19. Kohler T, Buckling A, van Delden C (2009) Cooperation and virulence of clinical Pseudomonas aeruginosa populations. Proc Natl Acad Sci USA 106:6339–6344
    • View reference on PubMed
    • View reference on publisher's website
  20. Kohler T, Guanella R, Carlet J, van Delden C (2010) Quorum sensing-dependent virulence during Pseudomonas aeruginosa colonisation and pneumonia in mechanically ventilated patients. Thorax 65:703–710
    • View reference on PubMed
    • View reference on publisher's website
  21. Kohler T, Donner V, van Delden C (2010) Lipopolysaccharide as shield and receptor for R-pyocin-mediated killing in Pseudomonas aeruginosa. J Bacteriol 192:1921–1928
    • View reference on PubMed
    • View reference on publisher's website
  22. Hauser AR, Cobb E, Bodi M, Mariscal D, Valles J, Engel JN, Rello J (2002) Type III protein secretion is associated with poor clinical outcomes in patients with ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Crit Care Med 30:521
    • View reference on PubMed
    • View reference on publisher's website
  23. Singh G, Wu B, Baek MS, Camargo A, Nguyen A, Slusher NA, Srinivasan R, Wiener-Kronish JP, Lynch SV (2010) Secretion of Pseudomonas aeruginosa type III cytotoxins is dependent on pseudomonas quinolone signal concentration. Microb Pathog 49:196–203
    • View reference on PubMed
    • View reference on publisher's website
  24. Bleves S, Soscia C, Nogueira-Orlandi P, Lazdunski A, Filloux A (2005) Quorum sensing negatively controls type III secretion regulon expression in Pseudomonas aeruginosa PAO1. J Bacteriol 187:3898–3902
    • View reference on PubMed
    • View reference on publisher's website
  25. Tamaoki J, Kadota J, Takizawa H (2004) Clinical implications of the immunomodulatory effects of macrolides. Am J Med 117 Suppl 9A:5S–11S
  26. Amsden GW (2005) Anti-inflammatory effects of macrolides–an underappreciated benefit in the treatment of community-acquired respiratory tract infections and chronic inflammatory pulmonary conditions? J Antimicrob Chemother 55:10–21
    • View reference on PubMed
    • View reference on publisher's website

Sign In

Connect with ICM

Top 5 Articles Editors Picks Supplement