Anti-endotoxin Properties of Polymyxin B-immobilized Fibers

Abstract

Polymyxin B is an antibiotic that shows strong bactericidal activity against Gram-negative bacteria, by binding to and inactivating endotoxin. Systemic administration of polymyxin B in humans is restricted because of its nephrotoxicity and neurotoxicity, and this compound was therefore considered a strong candidate ligand for the extracorporeal selective adsorption of circulating endotoxin in the blood. Toraymyxin® is a direct hemoperfusion column that uses polymyxin B attached to an insoluble carrier to bind endotoxin in the blood. In 1994, the Japanese National Health Insurance system approved the use of Toraymyxin for the treatment of endotoxemia and septic shock.In this chapter, we will review the development, clinical use, and efficacy of Toraymyxin, examine the structure of the Toraymyxin column, and comment on the current position of Toraymyxin in the treatment of severe sepsis and septic shock. We will also highlight some potential new applications of Toraymyxin for pulmonary diseases.

Keywords: Endotoxemia; Lipopolysaccharide; Polymyxin; Septic shock; Toraymyxin.

Fig. 19.1

History of the development of Toraymyxin EUPHAS: Early use of polymyxin B hemoperfusion in abdominal sepsis ABDO-MIX trial: Effects of hemoperfusion with a polymyxin B membrane in peritonitis with septic shock EUPHRATES trial: Evaluating the use of polymyxin B hemoperfusion in a randomized controlled trial of adults treated for endotoxemia and septic shock

Fig. 19.2

Physical structure of a Toraymyxin cartridge and of the knitted fabric roll of polymyxin B-immobilized fibers. (Provided by Toray Medical Co., Ltd.) The Toraymyxin cartridge contains a roll of knitted fibers. Each fiber consists of a bundle of ultra-fine fibers with a diameter of approximately 20 μm. The polymyxin B molecules are covalently bound onto the fiber surface and therefore do not leak into the patient Molecular conformation is shown. Polymyxin B was covalently bound to polystyrene-based fibers

Fig. 19.3

Endotoxin adsorption capacity of polymyxin B-immobilized fiber or IRA-938 data from Shoji et al. [24]. Two grams of polymyxin B-immobilized fibers (polymyxin B-immobilized fibers, solid line) or ion-exchange resin (IRA-938, dotted line) were incubated with 30 mL of various concentrations of endotoxin in (a) aqueous solution or (b) bovine serum solution

Fig. 19.4

Relationship between the residual number of primary amino groups in the immobilized polymyxin B molecule (a) Relationship between the residual number of primary amino groups in the immobilized polymyxin B molecule and its detoxification capacity Polymyxin B-immobilized fibers were added to a bovine serum solution containing lipopolysaccharides, and incubated with continuous stirring for 2 h. Endotoxin concentration was measured via limulus amebocyte lysate assay. Polymyxin B-immobilized fibers had the best endotoxin detoxification capacity when three amino groups were left in the immobilized polymyxin B molecule bound to the carrier fiber. (Reproduced from Shoji et al. [24]) (b) Relationship between the number of residual amino groups in fixed immobilized polymyxin B and the rate of survival in endotoxin-challenged dogs The number of residual primary amino groups in the immobilized polymyxin B had a greater overall effect on the survival of dogs than did the quantity of immobilized polymyxin B used. (Reproduced from Shoji et al. [24])

Fig. 19.5

Endotoxin removal by polymyxin B-immobilized fibers examined in a rabbit pyrogen test Polymyxin B-immobilized fibers (PMX-F) were incubated with various concentrations of endotoxin in an aqueous solution at 37 °C for 120 min, and then intravenously administered to rabbits. Treatment with polymyxin B-immobilized fibers suppressed the elevation of body temperature

Fig. 19.6

The endotoxin adsorption ability and bactericidal activity of polymyxin B-immobilized fibers. (Reproduced from Shoji et al. [24]) (a) Alteration in lipid A concentration by polymyxin B-immobilized fibers Polymyxin B-immobilized fibers (PMX-F) were incubated with a bovine serum solution containing 20 ng/mL of synthetic Escherichia coli lipid A with continuous stirring. Lipid A concentration was measured via limulus amebocyte lysate assay (b) Detoxification of endotoxin extracted from different species or strains of Gram-negative bacteria by use of polymyxin B-immobilized fibers (c) Bactericidal activity of polymyxin B-immobilized fibers against Pseudomonas aeruginosa Polymyxin B-immobilized fibers (PMX-F) or carrier fibers alone were incubated with a solution of Pseudomonas aeruginosa for 9 h and residual bacterial numbers were assessed

Fig. 19.7

Endotoxin adsorption by polymyxin B-immobilized fibers in an endotoxemia dog model. (Reproduced from Kodama et al. [25]) (a) Schematic of the experimental model: endotoxin was infused intravenously to dogs. Extracorporeal direct-hemoperfusion with a polymyxin B-immobilized fiber (PMX-F) column or control column was initiated (b) Survival rates after PMX-F treatment were compared with those after treatment with a PMX-F column, or a charcoal, resin, or carrier fiber column

Fig. 19.8

Efficacy of polymyxin B-immobilized fibers in a dog bacterial infusion model. (Reproduced from Hanasawa et al. [9]) (a) Schematic of the experimental model: the solution containing Escherichia coli was infused intravenously to dogs. Extracorporeal direct-hemoperfusion with a polymyxin B-immobilized fiber (PMX-F) column or control column was initiated (b) Alteration in mean aortic blood pressure: mean aortic blood pressure after PMX-F treatment increased compared to that after treatment with the control column (c) Alteration in platelet counts: platelet count significantly decreased following PMX-F treatment compared that following treatment with the control column (d) Alteration in blood lactate levels: blood lactate levels significantly decreased following PMX-F treatment compared to those following treatment with the control column

Fig. 19.9

The inside structure and endotoxin adsorption capacity of the Toraymyxin cartridge (a) Structure of a Toraymyxin cartridge and schematic of the blood flow inside the adsorption cartridge. (Provided by Toray Medical Co., Ltd.) (b) Endotoxin adsorption capacity of the Toraymyxin cartridge compared with the carrier fiber cartridge alone. Bovine serum solution containing 10 ng/mL of endotoxin was circulated through the Toraymyxin and carrier fiber cartridges. (Reproduced from Shoji et al. [11])

Fig. 19.10

The specifications of the Toraymyxin cartridge (a) Overview of the three Toraymyxin cartridges currently available for clinical use. (Provided by Toray Medical Co., Ltd.) (b) Schematic of direct hemoperfusion with a Toraymyxin cartridge. (Provided by Toray Medical Co., Ltd.)

Fig. 19.11

Results from the first clinical trial of Toraymyxin in Japan (a) Endotoxin concentrations before and after Toraymyxin treatment (b) Systemic vascular resistance (SVR) before and after Toraymyxin treatment. Toraymyxin treatment decreased the concentration of endotoxin in the blood and improved hemodynamic status in patients with severe sepsis and septic shock. (Reproduced from Aoki et al. [10])

Fig. 19.12

Main results of a meta-analysis of Toraymyxin treatment. (Provided by Toray Medical Co., Ltd.) MAP mean arterial pressure, PaO ₂ /FIO ₂ ratio of partial pressure arterial oxygen and fraction of inspired oxygen, CI confidence interval

Fig. 19.13

Use of Toraymyxin in combination with continuous hemodiafiltration (a) Survival of patients receiving Toraymyxin therapy in combination with continuous hemodiafiltration. (Reproduced from Suzuki et al. [57]) The use of this combination significantly improved survival rate in patients with sepsis and acute renal failure (b) Schematic of the combination of direct hemoperfusion with Toraymyxin and continuous hemodiafiltration in a series-parallel circuit