The Effect of Anti-lethal Toxin Antibodies on Anthrax Mortality
By Amesh A. Adalja, MD, FACP, April 13, 2012
The traditional mortality from inhalational anthrax at the beginning of the 20th century was often reported as 90%, but it was 45% following the 2001 anthrax letter attacks. This marked reduction in mortality likely occurred because of improvements in the care of critically ill patients. That a high mortality rate persists despite aggressive care suggests that there is room for further improvements in treatment. Two areas for improvement are mitigation of the effects of toxins and reducing or eliminating the bacterial and toxin burden via pleural cavity drainage.
Septic shock, with its characteristic unresponsive hypotension and multi-organ failure, is one of the features of fatal cases of anthrax. The profound nature of this premorbid clinical state of shock that occurs during anthrax infection is thought to be mediated by lethal toxin (LT), one of the 2 toxins secreted by Bacillus anthracis. Because of this role, therapeutics that neutralize LT are considered to be a leading means for combating anthrax-induced shock. Both polyclonal and monoclonal antibodies targeted against the protective antigen (PA) portion of LT have been developed for this purpose. A team from the U.S. National Institutes of Health (NIH) and Human Genome Sciences recently published the results of a study in which PA-targeted monoclonal antibodies (raxibacumab) along with hemodynamic support were administered to beagles in experimental LT-induced shock. Their findings suggest that monoclonal antibodies and fluid resuscitation together decrease the mortality of anthrax.
24 Hour LT-infusion Protocol with 4 Study Groups
In the study, Barochia and colleagues gave 40 beagles a dose of LT (infused over 24 hours) that was calibrated to produce a morality rate > 50%. Study groups included a control arm, hemodynamic support alone, hemodynamic support plus monoclonal antibody, and monoclonal antibody alone. Hemodynamic support consisted of normal saline infusions to keep pulmonary artery occlusion pressure > 10 mm Hg and norepinephrine infusions to keep mean arterial pressure (MAP) > 80 mm Hg. The monoclonal antibody was administered at 0, 9, or 12 hours.
Combination Treatment Beneficial
All control canines died, with a median time to death of 48-72 hours. Only 25% of those receiving hemodynamic support alone survived—a marginal but statistically significant benefit. Other notable results are summarized in the table below
+ hemodynamic support
|0||All survived||80% survived|
|9||66% survived||All survived|
|12||None survived||75% survived|
Statistical analysis revealed that monoclonal antibody effectiveness diminished with increasing time of administration in those who did not receive hemodynamic support. Combined therapy revealed a statistically significant increase in survival rate with better hemodynamic parameters (MAP, central venous pressure, left ventricular ejection fraction, urine output, and heart rate) as well as decreased requirements for norepinephrine and lower 96 hour lactate levels.
Early Antitoxin Plus Hemodynamic Support May Be Optimal
Generalized to humans, the results of this study indicate that an optimal therapy for severe anthrax infection would include hemodynamic support coupled with antitoxin therapy administered as soon as possible after diagnosis. Indeed, the treatment of recent human cases of anthrax has included the administration of a polyclonal antibody preparation (AIGIV), and the Strategic National Stockpile (SNS) contains both AIGIV and raxibacumab. If the results of this study are in fact valid in humans, the use of antitoxin antibodies would be recommended, not just for those recalcitrant to standard therapy, but for all cases of anthrax that progress to septic shock. If this treatment does prove optimal for humans, then a robust supply of these products will be needed for the SNS.
One major caveat: Because shock was induced with a 24-hour LT infusion—as opposed to by a genuine bacterial infection—true anthrax shock might be more complex. True anthrax shock may have characteristics mediated by edema toxin, other bacterial factors, and in vivo LT production and may last longer than 24 hours. Also, the effects of adding antitoxin therapy to antimicrobial therapy, which is the mainstay of treatment for anthrax, could not be addressed in this study. Nevertheless, hemodynamic support and antimicrobial therapy plus the use of an antitoxin therapy may well prove optimal.
Reference: Barochia AV, Cui X, Sun J, et al. Protective antigen antibody augments hemodynamic support in anthrax lethal toxin shock in canines. J Infect Dis 2012;818-829.