Delayed therapy with a polymyxin B-dextran conjugate (PMX-622) improves survival in rabbits with Gram-negative peritonitis

Abstract

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 determine whether therapy with PMB-D70, in addition to conventional antimicrobial chemotherapy, could improve survival in a model of Gram-negative peritonitis. At T = 0 h, New Zealand white rabbits were implanted intraperitoneally with 10 ml of a suspension containing hemoglobin (40 μg/ml), mucin (150 μg/ml), and 1.0 ± 0.2 x 104 cfu/kg of viable Escherichia coli (O18:K1). Beginning at T = 4 h, the rabbits were treated with gentamicin (5 mg/kg every 12 h) for five doses or until death, and infused for 24 h or until death with either D70 or PMB-D70. Two pairs of groups were studied (doses indicate cumulative amounts infused 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 equivalent dose of D70. The PMB-D70 (high dose) group received PMB-D70 (10 mg/kg of the PMB component) and the D70 (high dose) group received an equivalent 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 indistiguishable and, accordingly, were pooled for all analyses. Survival at 7 days was 11/25 (44%) for rabbits treated with PMB-D70 as compared to 2/23 (9%) for animals treated with D70 (P = 0.007). We conclude that adjuvant treatment with PMB-D70 improves survival in a clinically relevant model of Gram-negative sepsis.