Anthrax immune globulin improves hemodynamics and survival during B. anthracis toxin-induced shock in canines receiving titrated fluid and vasopressor support

Abstract

BackgroundAlthough anthrax immune globulin (AIG) improved survival in antibiotic-treated Bacillus anthracis-challenged animal models, whether it adds to the benefit of conventional hemodynamic support for B. anthracis toxin-associated shock is unknown.MethodsWe therefore tested AIG in sedated, mechanically ventilated canines challenged with 24-h B. anthracis lethal and edema toxin infusions and supported for 96 h with a previously demonstrated protective regimen of titrated normal saline and norepinephrine.ResultsCompared to controls, proportional survival (%) was increased with AIG treatment started 4 h before (33 vs. 100%, n = 6 each) or 2 h (17 vs. 86%, n = 6 and 7 respectively) or 5 h (0 vs. 67%, n = 3 each) after the start of toxin (p ≤ 0.05) and overall [3 survivors of 15 controls (20%) vs. 14 of 16 AIG animals (88%); p = 0.006]. Averaged across treatment times, AIG increased blood pressure at 48 h and decreased norepinephrine requirements at 72 h (p ≤ 0.02), increased left ventricular ejection fraction at 48 and 72 h (p ≤ 0.02), and increased urine output and decreased net fluid balance at 72 and 96 h (p ≤ 0.04). AIG also reduced acidosis and renal and hepatic injury markers between 24 and 96 h.ConclusionsThese findings further support AIG’s potential benefit for patients with B. anthracis infection and developing toxin-associated shock.Electronic supplementary materialThe online version of this article (10.1186/s40635-017-0159-9) contains supplementary material, which is available to authorized users.

A Review of the Efficacy of FDA-Approved B. anthracis Anti-Toxin Agents When Combined with Antibiotic or Hemodynamic Support in Infection- or Toxin-Challenged Preclinical Models

“…We conducted six studies in a canine model, first examining the effects of LT and ET challenges alone (Study 1) or together (Study 2) on survival, hemodynamic function and organ injury, and then the effects of either Raxibacumab (Studies 3, 4 and 5) or AIG (Study 6) when combined with titrated hemodynamic support (HS) on these same parameters ( Table 4 ) [ 16 , 17 , 18 , 27 ]. Prior studies suggested that these humanized or human antibodies would bind to canine cells and be effective.…”

“…Each study we conducted was approved by the National Institutes of Health Clinical Center’s Animal Care and Use Committee [ 16 , 17 , 18 , 27 ]. In individual weekly experiments comprising the studies, three or four purpose-bred beagles were continuously sedated, mechanically ventilated via tracheostomies and had systemic, pulmonary and urinary catheters in place.…”

“…In Studies 3 to 6, which included titrated hemodynamic support (HS), to ensure all studied animals had similar preloads at the outset before toxin infusion, pulmonary artery wedge pressures (PAWP) were measured and if <10 mmHg, 1 to 3 boluses (20 mL/kg) of normal saline were administered until a PAWP of at least 10 mmHg was achieved [ 17 , 18 , 27 ]. For the remainder of studies, animals assigned to groups with HS received a single bolus of 20 mL/kg of normal saline if the PAWP (checked every 2 h for the first 8 h and every 4 h thereafter) was found to be <10 mmHg ( Figure 4 ).…”

“…Finally, Study 6 examined the effects of AIG or placebo when added to HS in animals challenged with 24 h infusions of LT and ET together [ 18 ]. To reduce hypersensitivity reactions to human protein, AIG and IVIG (the placebo) were administered in gradually escalating doses.…”

“…This supportive measure must be continuously titrated and could not be reliably administered in a live B. anthracis study conducted under Biosafety Level-3 conditions. However, Raxibacumab and AIG have also been shown to be effective when combined with standard hemodynamic support in a 96 h canine model of anthrax toxin-associated shock conducted at Biosafety Level-2 [ 16 , 17 , 18 ].…”