colistin and Endotoxemia

Colistin electrostatically interacts with lipopolysaccharides (LPS). Pre-clinical studies demonstrated beneficial effects of colistin on LPS-induced coagulation and fibrinolysis. The objective of this trial was to investigate the effects of colistin during experimental endotoxaemia. In this randomised, double-blind, placebo-controlled, crossover trial 16 healthy volunteers received a 2 ng/kg LPS bolus after infusion of 2.5 million IU colistin or placebo. Plasma levels of F1+2 prothrombin fragments, thrombin-antithrombin complexes (TAT), von Willebrand factor antigen levels (vWF), E-selectin, plasmin-antiplasmin complexes (PAP), tissue-type plasminogen activator (t-PA) antigen and activity, plasminogen activator inhibitor-1 (PAI-1) were measured. Infusion of colistin significantly reduced peak concentrations of PAP complexes by 70 %, t-PA antigen levels by 63 % and t-PA activity by 48 %, while PAI-1 levels decreased numerically by 63 %. Two hours after the LPS bolus F1+2 levels and TAT complexes were slightly reduced in the colistin period, but peak concentrations were similar in both periods. Colistin blunted the LPS induced four-fold increase in soluble E-Selectin levels by ~50 % and the two-fold increase in vWF antigen levels by ~70 %. The LPS-scavenging actions of colistin significantly reduce endothelial activation and fibrinolytic response in the human endotoxaemia model, while the activation of the coagulation system remains largely unaffected.

Topics: Adult; Anti-Bacterial Agents; Austria; Biomarkers; Blood Coagulation; Colistin; Cross-Over Studies; Double-Blind Method; Endothelium, Vascular; Endotoxemia; Fibrinolysis; Healthy Volunteers; Humans; Infusions, Intravenous; Lipopolysaccharides; Male; Prospective Studies; Time Factors; Treatment Outcome; Young Adult

The previously described anti-endotoxin effect of colistin has not been investigated in humans yet. We performed a randomized, double-blind, placebo-controlled crossover trial to determine the degree of colistin-driven modulation of inflammatory response in blood of lipopolysaccharide (LPS)-challenged healthy volunteers in a human endotoxemia model. After a single intravenous dose of 2.5 million IU colistin methanesulfonate, interleukin (IL)-6, IL-8, tumor necrosis factor alpha (TNF-α), and IL-1β concentrations as well as other biomarkers of inflammation such as C-reactive protein, differential leukocyte counts, and body temperature were measured up to 24 h postdose. Colistin significantly decreased the inflammatory cytokine response to LPS in blood of healthy volunteers. This effect was most evident for IL-6, IL-8, and TNF-α. This study is the first to confirm the anti-endotoxin effect of colistin in humans in vivo. Further studies might increase our knowledge on the interaction between colistin and the effectors of the immune system.

Topics: Adult; Anti-Inflammatory Agents; Biomarkers; Body Temperature Regulation; C-Reactive Protein; Colistin; Cross-Over Studies; Cytokines; Double-Blind Method; Endotoxemia; Healthy Volunteers; Humans; Inflammation; Inflammation Mediators; Infusions, Intravenous; Lipopolysaccharides; Male; Sepsis; Time Factors; Treatment Outcome

To evaluate the possible related factors to endotoxemia and cytokine activation during the ischemic phase of extracorporeal surgery, and the effect of selective digestive decontamination (SDD) as a preventive measure.. Prospective, open, randomized trial.. Two multidisciplinary ICUs (tertiary care hospitals).. One hundred consecutive patients undergoing cardiopulmonary bypass (CPB), randomly allocated to two groups; gut decontamination (group I = 50 cases) and controls (group II = 50 cases).. Preoperative administration of oral non-absorbable antibiotics (polymyxin E, tobramycin and amphotericin B) versus no administration.. The assessment of decontamination by means of the bacteriologic control of rectal swabs. Determinations of gastric intramucosal pH (gastric pHi) and plasma endotoxin, tumor necrosis factor (TNF) aNd interleukin-6 (IL-6) before surgery and during the ischemic and reperfusion phases of bypass. Rectal aerobic Gram-negative bacilli (AGNB) were significantly reduced in the treated patients and in 56% total eradication was achieved. Endotoxin, TNF and IL-6 plasma levels were significantly lower in this group. By contrast, both endotoxin and TNF/IL-6 levels and gastric pHi correlated with the type of surgical flow (pulsatile versus non-pulsatile).. SDD reduces the gut content of enterobacteria. This may explain the lower endotoxin and cytokine levels detected in decontaminated patients. In addition to SDD, the type of flow employed during bypass seems to influence endotoxemia and cytokine levels.

Topics: Amphotericin B; Anti-Bacterial Agents; Antibiotic Prophylaxis; Cardiopulmonary Bypass; Colistin; Cytokines; Endotoxemia; Enterobacteriaceae; Female; Humans; Intestinal Diseases; Intestines; Ischemia; Male; Middle Aged; Prospective Studies; Surgical Procedures, Operative; Tobramycin

The aim of the present work was to evaluate clinical efficacy of the biospecific hemosorbent "Liposorb". The main component of "Liposorb" is polyacrylamide gel containing an immobilized affine ligand (antibiotic polymyxin E-colistyne). 40 patients with abdominal sepsis and peritonitis of different genesis underwent a total of 52 seances of vein-venous extracorporeal hemoperfusion of hemosorbent "Liposorb". Endotoxin level (lipopolysaccharide - LPS) was measured by the turbodimetric method. Blood perfusion through a "Liposorb" column at 50-70 ml/min during 90 minutes permitted to reach stabilization of parameters of systemic hemodynamics. All the patients showed positive dynamics of general well-being, blood gas composition, clinical and biochemical blood analyses. The endotoxin (LPS) level of Gramm-negative flora significantly decreased. It is concluded that hemosorbtion using biospecific polymyxin-containing hemosorbent "Liposorb" effectively removes Gramm-negative endotoxin and leads to stabilization of hemodynamic in patients with Gramm-negative abdominal sepsis.

Topics: Acrylic Resins; Anti-Bacterial Agents; Colistin; Drug Combinations; Endotoxemia; Follow-Up Studies; Gels; Gram-Negative Bacterial Infections; Hemoperfusion; Humans; Middle Aged; Treatment Outcome

This study was conducted to determine the relationship between abnormalities of cell-mediated immunity and gut-derived endotoxemia in rats following burns. Animals were subjected to a 40% full-thickness scald injury, and randomly divided into control and selective decontamination of the digestive tract (SDD) treated groups. It was found that thermal injury resulted in marked reductions in splenocyte proliferative response to concanavalin A or phytohemagglutinin, interleukin 2 (IL-2) production, and T helper/suppressor (Th/Ts) cells ratio. Prophylactic treatment with SDD significantly reduced the incidence of endotoxemia, prevented suppressive mitogenic response and inadequacy in IL-2 production (P < 0.05-0.01), but did not affect the abnormal ratio of Th/Ts in blood (P > 0.05). We conclude that bacteria/endotoxin translocation from the gastrointestinal tract appears to be involved in cellular immune dysfunction after thermal injury. Pretreatment with SDD might attenuate systemic immunosuppression by preventing translocation events.

Topics: Animals; Anti-Bacterial Agents; Bacterial Translocation; Burns; Colistin; Digestive System; Endotoxemia; Immunity, Cellular; Male; Random Allocation; Rats; Rats, Wistar; T-Lymphocyte Subsets