Raxibacumab augments hemodynamic support and improves outcomes during shock with B. anthracis edema toxin alone or together with lethal toxin in canines

Kenneth E Remy,Yan Li,Stephen H Leppla,Steven B Solomon,Amisha V Barochia,Xizhong Cui,Junfeng Sun,Mahtab Moayeri,Yvonne Fitz,Peter Q Eichacker,Mariam Al-Hamad

doi:10.1186/s40635-015-0043-4

Abstract

BackgroundLethal and edema toxin contribute to shock and lethality with Bacillus anthracis. We showed previously in a 96-h sedated canine model that raxibacumab, a monoclonal antibody against protective antigen, augmented hemodynamic support (HS) and improved survival with lethal toxin challenge. Here we study raxibacumab further. Using this model, we have now studied raxibacumab with 24 h edema toxin challenges (Study 1), and lethal and edema toxin challenges together (Study 2).MethodsUsing our canine model, we have now studied raxibacumab with 24h edema toxin challenges (Study-1), and lethal and edema toxin challenges together (Study-2).ResultsIn Study 1, compared to no treatment, HS (titrated fluid and norepinephrine) increased mean arterial blood pressure (MAP, p ≤ 0.05) but not survival [0 of 10 (0/10) animals survived in each group] or median survival time [43.8 h (range 16.8 to 80.3) vs. 45.2 h (21.0 to 57.1)]. Compared to HS, HS with raxibacumab treatment at or 6 h after the beginning of edema toxin increased MAP and survival rate (6/7 and 7/8, respectively) and time [96.0 h (39.5 to 96.0) and 96.0 h (89.5 to 96.0), respectively]; (p ≤ 0.05). HS with raxibacumab at 12 h increased MAP (p ≤ 0.05) but not survival [1/5; 55.3 h (12.6 to 96.0)]. In Study-2, survival rate and time increased with HS and raxibacumab at 0 h (4/4) or 6 h after (3/3) beginning lethal and edema toxin compared to HS [0/5; 71.5 h (65 to 93)] (p = 0.01 averaged over raxibacumab groups).ConclusionsRaxibacumab augments HS and improves survival during shock with lethal and edema toxin.Electronic supplementary materialThe online version of this article (doi:10.1186/s40635-015-0043-4) contains supplementary material, which is available to authorized users.

Highlights

Lethal and edema toxin contribute to shock and lethality with Bacillus anthracis
B. anthracis produces two binary exotoxins, lethal (LT) and edema toxins (ET) [9,10,11], each consisting of a toxic moiety [lethal factor (LF) and edema factor (EF), respectively] and protective antigen (PA), which mediates transport of the toxic moieties into host cells
We previously developed a 96 h sedated, instrumented, and ventilated canine model of B. anthracis toxin-associated shock in which LT or ET was infused over 24 h to simulate release during infection [18]

Summary

Introduction

Lethal and edema toxin contribute to shock and lethality with Bacillus anthracis. We showed previously in a 96-h sedated canine model that raxibacumab, a monoclonal antibody against protective antigen, augmented hemodynamic support (HS) and improved survival with lethal toxin challenge. Adjunctive therapies that augment conventional hemodynamic support (HS) during B. anthracis shock may improve outcomes from this lethal infection. B. anthracis produces two binary exotoxins, lethal (LT) and edema toxins (ET) [9,10,11], each consisting of a toxic moiety [lethal factor (LF) and edema factor (EF), respectively] and protective antigen (PA), which mediates transport of the toxic moieties into host cells. On a weight basis LT is five to ten times more lethal than ET, both toxins are thought to contribute to shock during infection with B. anthracis [18,19,20]

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Results

Conclusion