Botulism Antitoxin

Mechanism of Action

Botulinum toxin binds irreversibly to presynaptic nerve endings at neuromuscular junctions. Through receptor-mediated endocytosis, the toxin enters the cell and cleaves SNARE proteins, which are necessary for releasing acetylcholine into the synaptic cleft.[11]  Blockade of voluntary motor and autonomic cholinergic junctions leads to xerostomia (dry mouth), blurry vision, diplopia, dysphonia, dysarthria, dysphagia, and other muscle weakness. The most concerning clinical manifestation is when blockade affects respiratory muscles leading to respiratory failure.[1]

HBAT works by binding botulism toxin in the blood. In the Clinical Pharmacology Review submitted by Cangene, the reported that the polyclonal antibody fragments (F(ab’)2 and Fab) bind free botulinum toxin, which then prevents the toxin from being internalized at the post-synaptic cholinergic receptor. Because antitoxin only binds free botulinum toxin, it prevents the progression of symptoms but does not reverse any paralysis already present.[12]

Prior formulations had non-fragmented antibodies derived from inoculated horses. While these are larger molecules than the new HBAT formulation, the fragmented antibody is less immunogenic and has less risk for serious adverse effects.[9]

Administration

Because HBAT can only interact with the unbound toxin, patients have been shown to have better outcomes the earlier it is administered in a patient’s course.[13] When botulism is suspected, the state health department is notified first. From there, the CDC is contacted for a case evaluation and emergency antitoxin dispatch. Because there is a limited quantity of HBAT in the National Stockpile, the CDC stores the antitoxin in quarantine stations based in major US airports.[14]

Before the administration of HBAT, the CDC recommends a skin test to evaluate for hypersensitivity. In all cases, epinephrine and other supportive measures for allergic reactions should be readily available. However, in the packaging insert, the FDA suggests that patients at high risk for hypersensitivity should be given HBAT at less than 0.01 mL per minute.

HBAT is delivered as a vial that must be thawed and prepared prior to administration. If the vial is frozen upon receiving it from the CDC, there are two ways of thawing the contents.

1. Place in the refrigerator at 2 to 8 C for about 14 hours (not recommended as the time to administer the antitoxin is critical)
2. Place at room temperature for 1 hour and then in a water bath at 37 C (more rapid)

Important points regarding the handling of the antitoxin from the FDA insert: 

• Once thawed, the antitoxin may not be refrozen.
• Do not use if the vial has discolored or turbid fluid, and look for particles other than “a few translucent-to-white proteinaceous particulates.”
• As soon as the vial is opened, anti-toxin must be used as quickly as possible.
• Do not shake the vial.
• Discard any excess antitoxin.

Botulinum antitoxin is given in a 1 to 10 dilution with 0.9% normal saline only by IV through a continuous pump. FDA specifies using a 15 micron sterile, non-pyrogenic, low protein binding in-line filter. When drawing up antitoxin, each vial must be evaluated closely as vials with different lot numbers will contain different volumes. The FDA recommends that when diluting the antitoxin, even if the pediatric dosing calls for a percentage of the vial, to withdraw the entire volume in the vial to ensure the dose administered is the most accurate.

Dosing per FDA Botulinum Antitoxin Insert 

Adults (17 years old and up) have a starting infusion of 0.5 mL per minute; if the infusion rate is tolerated, the rate can be doubled every 30 minutes. The maximum infusion rate is 2 mL per minute. The dose is 1 vial.

Pediatric patients (age 1 to younger than 17 years old) have a starting rate of 0.01 mL/kg per minute, which can be increased by 0.01 mL/kg per minute every 30 minutes if tolerated. The maximum infusion rate is 0.03 mL/kg per minute, and the rate is not to exceed the adult rate.

In infants (younger than 1 year of age), the dose is 10% of the adult dose with a starting infusion rate of 0.01 mL/kg per minute. The infusion rate can also be titrated by 0.01 mL/kg per minute if tolerated. The maximum infusion rate is also 0.03/mL/kg per minute. There is a separate product available to treat infant botulism, and it must be obtained from the California Health Department, not the CDC.

Adverse Effects

The FDA lists the following as major adverse effects that have been documented.[12]

1. Infusion reactions
2. Type I hypersensitivity: Patients with a history of allergic reactions to horses, hay fever, have had issues with other equine-derived sera, or have asthma are at increased risk for this complication.
3. Serum sickness syndrome

Monitoring

Because HBAT is an infused equine-derived medication, patients should be monitored closely for infusion, hypersensitivity, and delayed serum sickness reactions.

During and immediately after administration of HBAT, flu-like symptoms, such as fevers, chills, malaise, myalgias, lightheadedness, indicate an infusion reaction. Treatment includes slowing the infusion rate or discontinuing HBAT completely if symptoms persist as well as supportive care.

The most serious adverse effect of antitoxin is anaphylaxis. Per the FDA insert, patients should be carefully monitored for signs of Type I hypersensitivity reactions, especially if they have a history of asthma, hay fever, or allergic reaction to horses. Symptoms to watch for during and immediately following administration of HBAT include respiratory distress, wheezing, angioedema, hypotension, tachycardia, rashes, or hives. If these occur, stop the infusion and provide airway protection and cardiovascular support. Supplies necessary for intubation and epinephrine administration should be at the bedside before starting HBAT.

Lastly, a more delayed reaction that may arise weeks after administration is serum sickness. This type III hypersensitivity is induced when a patient is exposed to proteins derived from animal (non-human) sources. Patient antibodies bind the foreign proteins, and these complexes deposit in locations not easily cleared by the reticuloendothelial system, such as in vessel walls or joint spaces.[15] The deposits cause inflammation and can easily interact with complement. If the patient is naive to the anti-serum, the reaction will typically occur 1 to 2 weeks after administering the drug. Symptoms may be difficult to distinguish from type I hypersensitivity as patients may experience fever, chills, rash, itching, and even cardiovascular collapse. With type III hypersensitivity, patients may also develop vasculitis, glomerulonephritis, or arthritis as a result of immune complex deposition. Because HBAT is made from fragmented equine antibodies, an immunogenic response should be less of a risk. However, you should always anticipate serum sickness as a complication of treatment with antibodies derived from non-human animal sources. Serum sickness is typically delayed in onset by several days. Treatment includes oral steroids and supportive care.

Enhancing Healthcare Team Outcomes

An interprofessional approach to the use of botulinum anti-toxin is recommended.

Treatment of botulism is time-sensitive, the antitoxin takes time to be dispatched from the CDC, and it can cause serious side effects.[14] Having an interprofessional team of toxicologists, emergency medicine physicians, other clinicians, nurses, and pharmacists is important for decreasing the time to diagnosis and ensuring patient safety during drug administration. Poison control should immediately be contacted if a patient has suspected botulism.

Poison control and the state health department will help guide the diagnostic workup in cases where the diagnosis of botulism is not clear. Toxicologists can consult at presentation and follow-up numerous times throughout the progression of patient care. Next, the state health department needs to be contacted when botulism is suspected. They assist with mobilizing anti-toxin from the CDC and will investigate potential outbreaks. They may also isolate and test the food source in case of foodborne disease, and if needed, provide help with food recall if a potential commercial source is identified.

When administering anti-toxin, as stated before, the patient should be monitored closely for adverse reactions. Nurses and treating clinicians need to understand how they will approach resuscitation and what signs and symptoms may present. Pharmacists are needed for guidance on how to administer the anti-toxin correctly and how to step down treatment if reactions do occur. Treatment with botulinum anti-toxin is time-sensitive and not without major risks. Having effective interprofessional communication affords patients the best chance of correctly diagnosing and treating Botulism while minimizing harm. Finally, the public should be educated about the hazards of consuming improperly or poorly packaged canned or preserved foods. Pregnant mothers should be told not to offer any honey to infants, as this is a risk for the infant form of botulism.[16]