title: Glyburide reduces bacterial dissemination in a mouse model of melioidosis.
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.
authors.affiliation: Center for Experimental and Molecular Medicine, Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands ; Warwick Medical School, University of Warwick, Coventry, United Kingdom ; Department of Infection and Tropical Medicine, Heartlands Hospital, Birmingham, United Kingdom ; Department of Medicine, University of Cambridge, Cambridge, United Kingdom ; Mahidol-Oxford Tropical Medicine Research Unit, Mahidol University, Bangkok, Thailand.
authors.forename: Gavin C K W
authors.initials: GC
authors.lastname: Koh
authors.forename: Tassili A
authors.initials: TA
authors.lastname: Weehuizen
authors.forename: Katrin
authors.initials: K
authors.lastname: Breitbach
authors.forename: Kathrin
authors.initials: K
authors.lastname: Krause
authors.forename: Hanna K
authors.initials: HK
authors.lastname: de Jong
authors.forename: Liesbeth M
authors.initials: LM
authors.lastname: Kager
authors.forename: Arjan J
authors.initials: AJ
authors.lastname: Hoogendijk
authors.forename: Antje
authors.initials: A
authors.lastname: Bast
authors.forename: Sharon J
authors.initials: SJ
authors.lastname: Peacock
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.forename: Ivo
authors.initials: I
authors.lastname: Steinmetz
authors.forename: W Joost
authors.initials: WJ
authors.lastname: Wiersinga
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D016957:Burkholderia pseudomallei / Q000187:drug effects*; D002442:Ceftazidime / Q000627:therapeutic use; D048909:Diabetes Complications; D004195:Disease Models, Animal; D005905:Glyburide / Q000627:therapeutic use*; D053583:Interleukin-1beta / Q000378:metabolism; D008554:Melioidosis / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D018805:Sepsis / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D053583:Interleukin-1beta; D002442:Ceftazidime; D005905:Glyburide