Activated Protein C Substantially Improves Survival in a Baboon Model of Anthrax-Mediated Sepsis
DJ Stearns-Kurosawa, V Collins, S Freeman, S Kurosawa. Boston University School of Medicine, Boston, MA
Background: A fulminant septic response contributes to the lethality of toxigenic, Gram positive, Bacillus anthracis, the cause of clinical anthrax, but few studies address adjunctive therapeutics that might influence disease severity and mortality after infection. In ongoing studies, this model recapitulates the coagulopathic, inflammatory and metabolic pathophysiological changes in a manner similar to humans, with the lung as a primary target organ. The current study evaluates whether pre-treatment with recombinant activated protein C, a potent anti-coagulant and anti-inflammatory drug, influences outcome or disease severity in this model of anthrax bacteremia.
Design: Anesthetized nonhuman primates (Papio c. cynocephalus; n=40; 6-8kg) were pre-treated with recombinant activated protein C (DAA, drotrecogin alfa (activated)) followed by challenge with i.v. bacteria infusion. Some baboons were challenged with B.anthracis Sterne strain which produces anthrax toxins (n=32; toxemia + sepsis); some were challenged with B.anthracis Delta Sterne strain which does not produce toxins (n=8; sepsis only). The effect of DAA on baboon septic responses was determined by monitoring on-line physiologic responses, inflammation, coagulation, organ responses and survival.
Results: All baboons challenged with lethal doses of B. anthracis Delta Sterne strain survived as a result of DAA treatment (p<0.01). Challenge with Delta Sterne strain induced a typical septic response and DAA pre-treatment was accompanied by reduced coagulopathy, inflammation and pulmonary injury. The influence of DAA pre-treatment on animal responses after challenge with toxigenic Sterne strain was related to whether lethality was driven by sepsis or acute pulmonary injury. DAA ameliorated the later responses (>24hrs) due to sepsis and these animals survived (p<0.05), but treatment did not influence the early pulmonary failure (<24 hrs) which may be governed by exotoxin activities.
Conclusions: Death due to infection with B. anthracis is governed by both septic responses and the activities of anthrax exotoxins. Pre-treatment with DAA was highly effective in preventing death due to anthrax-mediated sepsis, but did not alter the very early deaths that may be attributable to exotoxins and/or other bacterial virulence factors. Thus, an effective therapeutic approach for treatment of B.anthracis infection will need to provide relief for the pathogenic effects of both anthrax toxins and host septic responses. [NIH RO1AI058107, U19AI062629 (SK)]
Monday, March 9, 2009 1:00 PM
Poster Session II # 200, Monday Afternoon