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

Departments of Surgery and Anesthesiology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston Massachusetts, USA

L. Lögdberg

Sandoz Research Institute, East Hanover, New Jersey, USA

P. Lake

Sandoz Research Institute, East Hanover, New Jersey, USA

V.A. Larkin

Departments of Surgery and Anesthesiology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston Massachusetts, USA

M.P. Fink

Departments of Surgery and Anesthesiology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston Massachusetts, USA

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.

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