polymyxin for sepsis treatment

What is it about?

Endotoxins are the major components of the outer membrane of most Gram-negative bacteria and are one of the main targets in inflammatory diseases. The presence of endotoxins in blood can provoke septic shock in case of pronounced immune response. Here we show in vitro inactivation of endotoxins by polymyxin B (PMB). The inflammatory activity of the LPS–PMB complex in blood was examined in vitro in freshly drawn blood samples. Plasma protein binding of PMB was determined by ultracentrifugation using membranes with different molecular cut-offs, and PMB clearance during dialysis was calculated after in vitro experiments using the AV1000S filter. The formed LPS–PMB complex has lower inflammatory activity in blood, which results in highly reduced cytokine secretion. According to in vitro measurements, the appropriate plasma level of PMB for LPS inactivation is between 100 and 200 ng/ml. Furthermore, the combination of cytokine removal by adsorbent treatment with LPS inactivation by PMB dosage leads to strong suppression of inflammatory effects in blood in an in vitro model. Inactivation of endotoxins by low-dose intravenous PMB infusion or infusion into the extracorporeal circuit during blood purification can be applied to overcome the urgent need for endotoxin elimination not only in treatment of sepsis, but also in liver failure.

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Why is it important?

As endotoxins induce a strong host immune response, there is an urgent therapeutic need to reduce their activity. As a promising alternative or add-on to endotoxin adsorbents, endotoxin inactivation by low-dose PMB intravenous infusion or infusion into the extracorporeal circuit during blood purification is proposed to reduce considerably endotoxin activity not only in treatment of sepsis, but also in liver failure. However, the findings presented here are based on in vitro experiments. For an optimal and safe endotoxin inactivation therapy by polymyxin administration, further systematic investigations regarding drug monitoring and pharmacokinetic studies, especially in vivo studies, should be conducted.

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