DELAYED THERAPY WITH A POLYMYXIN B-DEXTRAN CONJUGATE (PMX-622) IMPROVES SURVIVAL IN RABBITS WITH GRAM-NEGATIVE PERITONITIS

Polymyxin B (PMB) is an amphipathic nephrotoxic antibiotic, which has been shown to neutralize the effects of endotoxin both in vitro and in vivo. PMB-D70 (PMX-622), a covalent conjugate of PMB with dextran 70 (D70), is less nephrotoxic than the parent compound. We sought to dete rmine whether therapy with PMB-D70, in addition to conventional antimi crobial chemotherapy, could improve survival in a model of Gram-negati ve peritonitis. At T = 0 h, New Zealand white rabbits were implanted i ntraperitoneally with 10 mi of a suspension containing hemoglobin (40 mu g/ml), mucin (150 mu g/ml), and 1.0 +/- 0.2 x 10(4) cfu/kg of viabl e Escherichia coli (018:K1). Beginning at T = 4 h, the rabbits were tr eated with gentamicin (5 mg/kg every 12 h) for five doses or until dea th, and infused for 24 h or until death with either D70 or PMB-D70. Tw o pairs of groups were studied (doses indicate cumulative amounts infu sed over 24 h). The PMB-D70 (low dose) group received PMB-D70 (5 mg/kg of the PMB component) and the D70 (low dose) group received an equiva lent dose of D70. The PMB-D70 (high dose) group received PMB-D70 (10 m g/kg of the PMB component) and the D70 (high dose) group received an e quivalent dose of D70. Results for the two PMB-D70 groups, on the one hand, and the two D70 group, on the other hand, were statistically ind istiguishable and, accordingly, were pooled for all analyses. Survival at 7 days was 11/25 (44%) for rabbits treated with PMB-D70 as compare d to 2/23 (9%) for animals treated with D70 (P = 0.007). We conclude t hat adjuvant treatment with PMB-D70 improves survival in a clinically relevant model of Gram-negative sepsis.