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Glyburide reduces bacterial dissemination in a mouse model of melioidosis.

Koh, Gavin C K W and Weehuizen, Tassili A and Breitbach, Katrin and Krause, Kathrin and de Jong, Hanna K and Kager, Liesbeth M and Hoogendijk, Arjan J and Bast, Antje and Peacock, Sharon J and van der Poll, Tom and Steinmetz, Ivo and Wiersinga, W Joost (2013) Glyburide reduces bacterial dissemination in a mouse model of melioidosis. PLoS neglected tropical diseases, 7 (10). e2500. ISSN 1935-2735.

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Official URL: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC379843...

Abstract

BACKGROUND

Burkholderia pseudomallei infection (melioidosis) is an important cause of community-acquired Gram-negative sepsis in Northeast Thailand, where it is associated with a ~40% mortality rate despite antimicrobial chemotherapy. We showed in a previous cohort study that patients taking glyburide ( = glibenclamide) prior to admission have lower mortality and attenuated inflammatory responses compared to patients not taking glyburide. We sought to define the mechanism underlying this observation in a murine model of melioidosis.

METHODS

Mice (C57BL/6) with streptozocin-induced diabetes were inoculated with ~6 × 10(2) cfu B. pseudomallei intranasally, then treated with therapeutic ceftazidime (600 mg/kg intraperitoneally twice daily starting 24 h after inoculation) in order to mimic the clinical scenario. Glyburide (50 mg/kg) or vehicle was started 7 d before inoculation and continued until sacrifice. The minimum inhibitory concentration of glyburide for B. pseudomallei was determined by broth microdilution. We also examined the effect of glyburide on interleukin (IL) 1β by bone-marrow-derived macrophages (BMDM).

RESULTS

Diabetic mice had increased susceptibility to melioidosis, with increased bacterial dissemination but no effect was seen of diabetes on inflammation compared to non-diabetic controls. Glyburide treatment did not affect glucose levels but was associated with reduced pulmonary cellular influx, reduced bacterial dissemination to both liver and spleen and reduced IL1β production when compared to untreated controls. Other cytokines were not different in glyburide-treated animals. There was no direct effect of glyburide on B. pseudomallei growth in vitro or in vivo. Glyburide directly reduced the secretion of IL1β by BMDMs in a dose-dependent fashion.

CONCLUSIONS

Diabetes increases the susceptibility to melioidosis. We further show, for the first time in any model of sepsis, that glyburide acts as an anti-inflammatory agent by reducing IL1β secretion accompanied by diminished cellular influx and reduced bacterial dissemination to distant organs. We found no evidence for a direct effect of glyburide on the bacterium.

Item Type: Article
Subjects: WC Communicabable diseases > WC680 Tropical medicine
Divisions: Clinical Support > Infectious Diseases
Related URLs:
Depositing User: Preeti Puligari
Date Deposited: 28 Nov 2014 13:33
Last Modified: 28 Nov 2014 13:33
URI: http://www.repository.heartofengland.nhs.uk/id/eprint/698

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