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Effects of Proanthocyanidins on Adhesion, Growth, and Virulence of Highly Virulent Extraintestinal Pathogenic Escherichia coli Argue for Its Use to Treat Oropharyngeal Colonization and Prevent Ventilator-Associated Pneumonia

Margetis, Dimitri MD, MSc1,2,3; Roux, Damien MD, PhD1,2,3; Gaudry, Stéphane MD, MSc3,4,5; Messika, Jonathan MD, MSc1,2,3; Bouvet, Odile PharmD, PhD1,2; Branger, Catherine PharmD, PhD1,2,6; Ponnuswamy, Padmapriya PhD7,8; Oufella, Hafid Ait MD, PhD7,8; Dreyfuss, Didier MD1,2,3; Denamur, Erick MD, PhD1,2; Ricard, Jean-Damien MD, PhD1,2,3

doi: 10.1097/CCM.0000000000000972
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Objective: In the context of increasing microbial resistance and limited new antimicrobials, we aimed to study the antimicrobial effects of cranberry proanthocyanidin extracts on Escherichia coli growth, adhesion to epithelial cells, and lung infection.

Design: Experimental in vitro and in vivo investigation.

Setting: University research laboratory.

Subjects: Seventy-eight 6- to 8-week-old male Balb/C mice.

Interventions: In vitro, the effect of increasing concentrations of cranberry proanthocyanidin on bacterial growth of different clinical E. coli isolates was evaluated. Ex vivo, adhesion of E. coli to fresh human buccal epithelial cells was measured in the presence or absence of cranberry proanthocyanidin using microscopy. In vivo, lung bacterial count, pulmonary immune response (neutrophil murine chemokine keratinocyte-derived cytokine measurement and polymorphonuclear recruitment in bronchoalveolar lavage fluid), and lethality were evaluated in a pneumonia mouse model with E. coli precultured with or without cranberry proanthocyanidin. E. coli isolates originated from ventilated ICU patients with respiratory tract colonization or ventilator- associated pneumonia. They differed in number of virulence genes.

Measurements and Main Results: A significant inhibition of bacterial growth was observed with increasing concentration of cranberry proanthocyanidin, affecting both time to maximal growth and maximal growth rate (p < 0.0001 for both). The minimal concentration at which this effect occurred was 250 μg/mL. Cranberry proanthocyanidin significantly reduced E. coli adhesion to fresh buccal epithelial cells by up to 80% (p < 0.001). Bacterial counts in homogenized lungs and bronchoalveolar lavage fluid were decreased after cranberry proanthocyanidin exposition (p < 0.05 and p < 0.01, respectively). Cranberry proanthocyanidin also decreased KC concentrations and polymorphonuclear cell recruitment in bronchoalveolar lavage fluid (p < 0.05 for both). At identical inoculum, mortality was reduced by more than half in mice inoculated with E. coli exposed to cranberry proanthocyanidin (p < 0.01).

Conclusion: Cranberry proanthocyanidins exhibit potent effects on growth, adhesion, and virulence of oropharyngeal and lung isolates of E. coli, suggesting that cranberry proanthocyanidin could be of clinical interest to reduce oropharyngeal colonization and prevent lung infection.

1Institut National de la Santé et de la Recherche Médicale, INSERM, IAME, UMR 1137, Paris, France.

2Univ Paris Diderot, Sorbonne Paris Cité, IAME, UMR 1137, Paris, France.

3AP-HP, Service de Réanimation Médico-Chirurgicale, Hôpital Louis Mourier, Colombes, Paris, France.

4Institut National de la Santé et de la Recherche Médicale, INSERM, ECEVE, UMR 1123, Paris, France.

5Univ Paris Diderot, Sorbonne Paris Cité, ECEVE, UMR 1123, Paris, France.

6AP-HP, Service de Microbiologie, Hôpital Louis Mourier, Colombes, Paris, France.

7Institut National de la Santé et de la Recherche Médicale, INSERM, Cardiovascular Research Center, UMR 970, Paris, France.

8Univ Paris Descartes, Sorbonne Paris Cité, Paris, France.

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Dr. Margetis was a recipient of a grant from le Fonds d’Etude et de Recherche du Corps Médical des Hôpitaux de Paris and received grant support from Assistance Publique - Hôpitaux de Paris. Dr. Roux’s institution received grant support from the Hearst Foundation–Harvard Medical School. Dr. Gaudry received support for travel. Dr. Dreyfuss provided expert testimony 2,000 euros for counseling (Institut National de la Santé et de la Recherche Médicale [INSERM] Transfert) for the development of a novel antisepsis drug. Dr. Ricard has disclosed other support from INSERM (a patent is being filed regarding the use of proanthocyanidin to prevent or treat nosocomial pneumonia [#14305539.0]), served as a board member for Covidien, and received support for travel from Fisher&Paykel (2012 American Thoracic Society and European Society of Intensive Care Medicine meetings and 2013 World Federation of Societies of Intensive and Critical Care Medicine). The remaining authors have disclosed that they do not have any potential conflicts of interest.

For information regarding this article, E-mail: jean-damien.ricard@lmr.aphp.fr

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