Protective Antigen Antibody Augments Hemodynamic Support in Anthrax Lethal Toxin Shock in Canines

Mortality in patients with shock during the 2001 US anthrax outbreak was high [1, 2]. Although the mechanisms and optimal management of this shock remain unclear, the risk of anthrax persists, as demonstrated by recent cases among injection drug abusers in Europe [3, 4]. Seventeen of 52 patients from this outbreak died, many with progressive shock despite standard intensive care unit (ICU) support. Anthrax bacilli produce 2 toxins: lethal toxin (LT) and edema toxin (ET) [5, 6]. Each is composed of a toxic moiety (lethal factor [LF] or edema factor [EF], respectively) and protective antigen (PA), a component necessary for LF or EF uptake by host cells. LF is a zinc endopeptidase that cleaves mitogen-activated protein kinase kinases (MAPKK), whereas EF is a calmodulin-dependent adenyl cyclase. Of the two, LT is the more lethal and thought to play a central role in the pathogenesis of anthrax shock [7–20]. Despite the contribution of LT-induced shock to the pathogenesis of anthrax, its treatment has received little study. Conventional therapy for septic shock (which would include hemodynamic support with fluid and vasopressor administration titrated to physiologic endpoints like mean arterial pressure) has not been investigated in models of anthrax. In rats, fixed (nontitrated) doses of either normal saline or norepinephrine (NE) administered as 24-hour infusions were beneficial against lipopolysaccharide (LPS) or Escherichia coli challenge, but not LT challenge [20, 21]. Notably, however, inability to titrate these therapies in the LT-challenged rodent model may have produced adverse effects that limited benefit. Besides hemodynamic support, toxin inhibition has also been proposed for the treatment of life-threatening anthrax infection. Both polyclonal (Anthrax Immune Globulin Intravenous [AIGIV], Cangene Corp, Winnipeg, Canada) and monoclonal (raxibacumab; Human Genome Sciences, Rockville, MD) antibody preparations, directed in part or solely against PA, have been added to the US Strategic National Stockpile. However, whether such preparations have additive benefit when combined with conventionally titrated hemodynamic support is not clear [21–27]. Defining the effects of titrated hemodynamic support, alone or together with protective antigen–directed monoclonal antibody (PA-mAb), for LT-associated shock is important. We previously developed a sedated, instrumented, and mechanically ventilated canine model in which LT, infused over 24 hours to simulate toxin release during infection, produced progressive hypotension and organ dysfunction [16]. We employed this model to investigate the effects of titrated hemodynamic support and PA-directed monoclonal antibody (raxibacumab) alone or together, for LT-induced shock. Although hemodynamic support was available (if indicated) from the start of toxin infusion, PA-mAb was administered either early at the initiation of toxin (0 hours), or later at 9 or 12 hours to investigate the effect of delayed treatment as might occur clinically.