Sulphonylurea usage in melioidosis is associated with severe disease and suppressed immune response

• Published in: PLoS neglected tropical diseases Vol. 8; no. 4; p. e2795
• Main Authors: Liu, Xiang, Foo, Geraldine, Lim, Wan Peng, Ravikumar, Sharada, Sim, Siew Hoon, Win, Mar Soe, Goh, Jessamine Geraldine, Lim, Joan Hui Juan, Ng, Ying Hui, Fisher, Dale, Khoo, Chin Meng, Tan, Gladys, Chai, Louis Yi Ann
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 01.04.2014; Public Library of Science (PLoS)
• Subjects: Asia, Southeastern; Australia; Bacillus; Biology and Life Sciences; Burkholderia pseudomallei; Care and treatment; Cohort Studies; Diabetes; Diabetes Complications - epidemiology; Diabetes Mellitus - drug therapy; Disease susceptibility; Female; Health aspects; Hospitals; Humans; Hypoglycemic Agents - adverse effects; Hypoglycemic Agents - therapeutic use; Immune response; Infections; Length of Stay; Male; Medicine and Health Sciences; Melioidosis - complications; Melioidosis - immunology; Melioidosis - mortality; Melioidosis - pathology; Middle Aged; Mortality; Pseudomonas infections; Retrospective Studies; Risk factors; Sepsis - mortality; Sepsis - pathology; Studies; Sulfonylurea Compounds - adverse effects; Sulfonylurea Compounds - therapeutic use; Surface water; Survival Analysis; Treatment Outcome; Asia, Southeastern; Australia; Length of Stay; Diabetes Complications; Humans; Middle Aged; Male; Treatment Outcome; Diabetes Mellitus; Asia, Southeastern; Melioidosis; Hypoglycemic Agents; Survival Analysis; Female; Sepsis; Retrospective Studies; Sulfonylurea Compounds; Australia; Cohort Studies
• DOI: 10.1371/journal.pntd.0002795
• ISSN: 1935-2735; 1935-2727

Melioidosis is a problem in the developing tropical regions of Southeast Asia and Northern Australia where the the Gram negative saprophytic bacillus Burkholderia pseudomallei is endemic with the risk of fulminant septicaemia. While diabetes mellitus is a well-established risk factor for melioidiosis, little is known if specific hypoglycemic agents may differentially influence the susceptibility and clinical course of infection with B. pseudomallei (Bp). In this cohort study, patients with pre-existing diabetes and melioidosis were retrospectively studied. mortality, length of stay and development of complications (namely hypotension, intubation, renal failure and septicaemia) were studied in relation to prior diabetic treatment regimen. Peripheral blood mononuclear cells (PBMC) from diabetic patients and healthy PBMC primed with metformin, glyburide and insulin were stimulated with purified Bp antigens in vitro. Immune response and specific immune pathway mediators were studied to relate to the clinical findings mechanistically. Of 74 subjects, 44 (57.9%) had sulphonylurea-containing diabetic regimens. Patient receiving sulphonylureas had more severe septic complications (47.7% versus 16.7% p = 0.006), in particular, hypotension requiring intropes (p = 0.005). There was also a trend towards increased mortality in sulphonylurea-users (15.9% versus 3.3% p = 0.08). In-vitro, glyburide suppressed inflammatory cytokine production in a dose-dependent manner. An effect of the drug was the induction of IL-1R-associated kinase-M at the level of mRNA transcription. Sulphonylurea treatment results in suppression of host inflammatory response and may put patients at higher risk for adverse outcomes in melioidosis.