Effect of Polymyxin B Sulfate on Endotoxin Activity in a Gram-Negative Septicemia Model

Abstract

Summarv polymyxin B has antiendotoxin activity which is distinct from itsThe antiendotoxin effect of polymyxin B was investigated in experimentally induced septicemia in rabbits. The Pasteurella multocida organisms were sensitive to the antibacterial action of penicillin but not to polymyxin B. Animals pre-treated with polymyxin showed positive blood cultures and significantly reduced plasma endotoxin levels (Limulus test) with normal white blood cell and platelet counts when analyzed 6 hr after the injection of live organisms. Polymyxin therapy given after the animals had LntibLterial power. Heretofore, all ofthe studies that have been reported have employed either the purified lipopolysaccharide or dead gram-negative organisms. The purpose of this study was to investigate the effect of polymyxin B on endotoxin activity in a rabbit model of gram-negative septicemia. The endotoxin effects investigated were the changes in plasma endotoxin activity, and the white blood cell and platelet counts in animals who were treated with polymyxin B sulfate.established septicemia-endotoxemia reduced the plasma endotoxin levels and improved the survival, but had no effect on the leuko-MATERIALS AND METHODS penia and thrombocytopenia. The best survival data were obtained White rabbits of both sexes, California strain, weighing 1.0 kg in rabbits who were treated with both penicillin and polymyxin. were used. They were housed in an air-conditioned isolated animal The data suggest that polymyxin is effective in neutralizing the room and fed antimicrobial free rabbit chow and water ad libitum. endotoxic effects from live organisms and that the timing and The production of gram-negative septicemia in these rabbits was perhaps duration of the polymyxin treatment is of critical impor-by methods previously described (4). In essence, the animals were tance. In addition, a modified Limulus lysate method was devel-given 2 x 10"ive P. multocida organisms per kg body wt ip. The oped which showed that quantitative plasma endotoxin determi-animals regularly became clinically ill and had positive blood nation could be made more sensitive by prior heating of the plasma cultures and Limulus lysate tests 4-6 hr after the injection. Seto remove the natural inhibitors.quential blood samples were obtained from the heart and were used for blood cultures, endotoxin assay and leukocyte and platelet Speculation counts. Quantitative colony counts using heparinized whole blood were performed by pour plate technique on 5% blood agar plates his investigation and other reports have shown that ~o l~m~x i n (h4icro-~ech Diagnostics, Tucson, AZ). The plates were incubated B sulfate neutralized endotoxin effects in animals given purified at 370 and 24 hr later the small, mucoid gray, nonhemolytic endotoxin, dead endotoxin-containing organisms, and gram-nega-colonies were counted, tive septicemic animals (3,6,8,(12)(13)(14)(15). The antiendotoxin effect ~~~~~i~i~~d plasma was obtained by ofthe blood of the antibiotic appears to be separate from its antimicrobial ...

Inhibition of endotoxin-induced priming of human neutrophils by lipid X and 3-Aza-lipid X.

“…Because of the presumed role of endotoxin in septic shock, investigators have studied therapeutic interventions aimed at alleviating the effects of endotoxin or its secondary mediators. Corticosteroids, naloxone, cyclooxygenase inhibitors, endotoxin inhibitors (polymyxin B), and anti-core endotoxin antibodies have been investigated, but their use and efficacy in human septic shock remain controversial (8)(9)(10)(11)(12)(13)(14)(15)(16).…”

Effect of Hemoperfusion Using Polymyxin B-Immobilized Fiber on IL-6, HMGB-1, and IFN Gamma in a Neonatal Sepsis Model

“…Thus, polymyxin B prevents the generation of superoxide production by macrophages in vitro (11). Furthermore, it prevented endotoxininduced mortality of mice (12) and rabbits (13). Applying PMX-DHP, where polymyxin-B is attached to polystyrene fiber with covalent bonding without its release, has shown to be effective in the clearance of LPS and yields a significant improvement of the survival rate in septic shock adult patients (14).…”

POLYMYXIN B SULPHATE PROTECTS CATS AGAINST THE HAEMODYNAMIC AND METABOLIC EFFECTS OF E. coli ENDOTOXIN

“…The initial pulmonary hypertension was completely prevented ( Figure 1); systemic arterial pressure was well maintained into the severe and delayed shock phase ( (Corrigan & Kiernat, 1979), whilst in a canine endotoxin shock model, pretreatment with polymyxin B largely prevented the delayed hypotensive phase and decreased lethality but did not modify either the early hypotensive phase (cf. Figure 1 of the present results) or the decreases in blood platelets and serum cc mplement (From, Fong & Good, 1979).…”

“…Our own initial studies (Madan and Parratt, unpublished) and those of others (Craig, Turner & Kunin, 1974;Corrigan & Kiernat, 1979) have shown that the timing of the polymyxin administration is crucial in modifying the biological effects of endotoxin. This could suggest that there is a chemical interaction between the two molecules.…”