Polymyxin B protects horses against induced endotoxaemiain vivo

Abstract

Summary Reasons for performing study: A safe, affordable and effective treatment for endotoxaemia in horses is needed in order to reduce the incidence of this potentially fatal condition. Objective: To evaluate the effect of polymyxin B (PMB) on signs of experimentally‐induced endotoxaemia. Hypothesis: PMB ameliorates the adverse effects of endotoxaemia without causing nephrotoxicity. Methods: Four groups of 6 healthy mature horses each received 20 ng endotoxin/kg bwt i.v. over 30 mins. Additionally, each group received one of the following i.v.; 5000 u PMB/kg bwt 30 mins before endotoxin infusion; 5000 u PMB/kg bwt 30 mins after endotoxin infusion; 1000 u PMB/kg bwt 30 mins prior to endotoxin infusion; or saline. Clinical response data and samples were collected to determine neutrophil count, serum tumour necrosis factor (TNF) activity, plasma thromboxane B2 concentration and urine gamma glutamyltranspeptidase (GGT) to creatinine ratio. Results: Treatment with PMB before or after administration of endotoxin significantly reduced fever, tachycardia and serum TNF, compared to horses receiving saline. The differences in response to endotoxin were greatest between horses that received saline vs. those that received 5000 u PMB/kg bwt prior to endotoxin. Urine GGT:creatinine did not change significantly. Conclusions and potential relevance: This study indicates that PMB may be a safe and effective treatment of endotoxaemia, even when administered after onset. Although nephrotoxicity was not demonstrated with this model, caution should be exercised when using PMB in azotaemic patients.

Effects of intravenous administration of polymyxin B in neonatal foals with experimental endotoxemia

“…Similar to previous studies 15,16,18,21 in adult horses and foals, LPS administration in this study resulted in marked leukopenia and neutropenia. In similar LPS studies 15,18 investigating polymyxin B in adult horses, significantly higher neutrophil counts in the polymyxin B-treated horses, compared with control horses, were detected 1 hour after LPS infusion only when polymyxin B was administered prior to LPS infusion.…”

“…29,40 In adult horses, significantly lower serum TNF-α activity was observed in horses that received polymyxin B (5,000 U/kg [2,272.73 U/lb] prior to LPS administration, 1,000 U/kg [454.5 U/lb] prior to LPS administration, and 5,000 U/kg after LPS administration), compared with control horses, with an earlier and more sustained decrease in TNF-α when polymyxin B was administered prior to LPS infusion. 15 Significantly decreased TNF-α concentration was observed in the polymyxin B-treated foals of the study reported here in a similar pattern as the adult horse group that received polymyxin B after LPS infusion. 15 Interestingly, differences in TNF-α concentration between the polymyxin B and control group were not observed until later time points (8 and 24 hours).…”

“…In similar LPS studies 15,18 investigating polymyxin B in adult horses, significantly higher neutrophil counts in the polymyxin B-treated horses, compared with control horses, were detected 1 hour after LPS infusion only when polymyxin B was administered prior to LPS infusion. Although a significant increase in neutrophil counts in the study reported here was detected in the polymyxin B group at 8 hours, compared with the control foals, significantly lower neutrophil counts were reported at 24 and 48 hours.…”

“…Considering the time (8,24, and 48 hours) at which these differences were detected, it is likely that the differences in neutrophil counts were associated with varying degrees of rebound neutrophilia commonly observed after a severe neutropenic episode. 15,39 Thus, it is unlikely that polymyxin B administration had any clinically beneficial effect on the WBC or neutrophil count in this study.…”

“…In addition to having antimicrobial properties, polymyxin B functions as a chelating agent by binding the lipid A portion of LPS in a 1:1 ratio, thus neutralizing LPS and negating the interaction of LPS with cellular receptors that results in inflammation. [13][14][15] Positive effects of IV administration of polymyxin B have been determined in experimental endotoxemia studies [15][16][17][18][19] in adult horses, with significant decreases in concentrations of inflammatory mediators (TNF-α and TXB 2 ) as well as improved clinical attitude (eg, activity level, appetite, and mentation) scores in horses treated with polymyxin B, compared with control horses. Treatment with polymyxin B to attenuate clinical endotoxemia is frequently used in adult horses for conditions such as strangulating intestinal lesions, pleuropneumonia, and postpartum metritis, with purported beneficial effects.…”