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Immunmodulatory potencies of linezolid in a LPS model of human whole blood

Abstract number: P761

Lambers C., Will M., Wagner C., Zeitlinger M.

Objectives: Gram-negative sepsis resulting in septic shock is one of leading causes of death in critically ill patients. One important determinant of mortality is the release of endotoxin, which is a structural component of LPS. It is generally accepted, that the first mediators in the cascade of LPS-induced events are cytokines, like TNF-alpha and IL-1beta. Because treatment options are limited, a wide range of therapeutic strategies are still under investigation, but convincing reduction of mortality is still lacking. New approaches are focused on immunmodulatory effects of antimicrobials. Several studies investigating Linezolid in different models of Gram-negative sepsis showed significant reduction of pro-inflammatory cytokines but used un-physiologically high doses of LPS. The aim of our study was to characterise the immunmodulatory effects in a model of human whole blood with concentrations of LPS and Linezolid reflecting physiological conditions.

Methods: Whole blood from 10 healthy volunteers was incubated with 50 pg/mL LPS W/o 13 mg/mL Linezolid for 2 and 4 h. RT-PCR was performed from messengerRNA (mRNA) of IL-1b, IL-6 or TNFa, 18sRNA was used as control. Protein levels of the supernatant were measured using ELISA for IL-6 and TNFa.

Results: Incubation of human whole blood with LPS significantly increased mRNA levels of cytokines compared with baseline. The addition of Linezolid significantly reduced mRNA levels of IL-1b (-49%; p < 0.01), IL-6 (-49%; p < 0.01) and TNF-a (-61%; p < 0.02) after 2 hours. In addition, after 4 hours reduction on mRNA levels of IL-1b (-49%; p < 0.01), IL-6 (-25%; p < 0.03) and TNF-a (-32%; p < 0.04) were observed. Although LPS stimulation increased levels of IL-6 and TNFa between 100 and 1000-fold, in contrast to mRNA no reduction by addition of Linezolid was observed on protein level.

Conclusion: The previously assumed immunmodulatory effects of Linezolid were confirmed in our in vitro sepsis model on gene expression level. However, differences to previous findings which have shown significant reduction on protein levels were observed. This discrepancy might be mainly ascribed to methodological differences, since compared to previous work more physiologic conditions were employed in the present setting.

Session Details

Date: 19/04/2008
Time: 00:00-00:00
Session name: 18th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Barcelona, Spain
Presentation type:
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