Dataset Information

Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis.

ABSTRACT:

Background

Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This K(ATP)-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection.

Methods

We studied a cohort of 1160 patients with gram-negative sepsis caused by a single pathogen (Burkholderia pseudomallei), 410 (35%) of whom were known to have diabetes. We subsequently studied prospectively diabetics with B. pseudomallei infection (n = 20) to compare the gene expression profile of peripheral whole blood leukocytes in patients who were taking glyburide against those not taking any sulfonylurea.

Results

Survival was greater in diabetics than in nondiabetics (38% vs 45%, respectively, P = .04), but the survival benefit was confined to the patient group taking glyburide (adjusted odds ratio .47, 95% confidence interval .28-.74, P = .005). We identified differential expression of 63 immune-related genes (P = .001) in patients taking glyburide, the sum effect of which we predict to be antiinflammatory in the glyburide group.

Conclusions

We present observational evidence for a glyburide-associated benefit during human melioidosis and correlate this with an anti-inflammatory effect of glyburide on the immune system.

SUBMITTER: Koh GC

PROVIDER: S-EPMC3049341 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Publications

Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis.

Koh Gavin C K W GC Maude Rapeephan R RR Schreiber M Fernanda MF Limmathurotsakul Direk D Wiersinga W Joost WJ Wuthiekanun Vanaporn V Lee Sue J SJ Mahavanakul Weera W Chaowagul Wipada W Chierakul Wirongrong W White Nicholas J NJ van der Poll Tom T Day Nicholas P J NP Dougan Gordon G Peacock Sharon J SJ

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20110203 6

<h4>Background</h4>Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This K(ATP)-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host ...[more]

PMID: 21293047

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Project description:BackgroundBurkholderia 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.MethodsMice (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) 1? by bone-marrow-derived macrophages (BMDM).ResultsDiabetic 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 IL1? 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 IL1? by BMDMs in a dose-dependent fashion.ConclusionsDiabetes 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 IL1? 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.

Dataset Information

Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis.

Background

Methods

Results

Conclusions

Publications

Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis.

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