Continuing Education Activity

Botulinum antitoxin, also known as botulism antitoxin, is comprised of antibodies or antibody antigen-binding fragments that block the neurotoxin produced by the bacterial species Clostridium botulinum. Botulinum toxin causes botulism, a paralytic syndrome classically characterized by symptoms of descending symmetric muscle weakness. Symptoms can include blurry vision, inability to speak or swallow, and weakness in the bilateral upper extremities with progression to the chest and lower extremities. This activity reviews the mechanism of action, adverse event profile, toxicity, dosing, pharmacodynamics, and monitoring of botulism antitoxin, pertinent for interprofessional team members for the treatment of patients with botulism poisoning.

Objectives:

• Summarize the mechanism of action of botulism antitoxin.
• Describe the potential adverse effects of botulism antitoxin.
• Review the indication(s) for the therapeutic use of botulism antitoxin.
• Discuss interprofessional team strategies for improving care coordination and communication to advance the treatment of botulism poisoning and improve outcomes when using botulinum antitoxin.

Indications

Botulinum antitoxin, also known as botulism antitoxin, is comprised of antibodies or antibody antigen-binding fragments that block the neurotoxin produced by the bacterial species Clostridium botulinum. Botulinum toxin causes botulism, a paralytic syndrome classically characterized by symptoms of descending symmetric muscle weakness. Symptoms can include blurry vision, inability to speak or swallow, and weakness in the bilateral upper extremities with progression to the chest and lower extremities.[1]

Botulinum toxin is often cited as the most poisonous substance known; the lethal dose is 1 nanogram/kilogram.[2] The most common form of transmission in adults is food-borne botulism, where the toxin itself is ingested. In wound botulism, bacterial spores find a port of entry, and the toxin is then produced locally.[3] The aerosolized toxin can potentially be used for biological warfare.[4] Another form is infant botulism which occurs when young children, usually below the age of 1-year-old, ingest Clostridium botulinum. This can generate botulism in the immature gastrointestinal tract and cause a "floppy" baby. It is treated with a different form of antitoxin and discussed in a review of neonatal botulism.

The Center for Disease Control and Prevention (CDC) publishes yearly surveillance data on laboratory-confirmed reports of botulism in the United States; from 2001 to 2016, there have been 100 to 200 confirmed botulism cases reported by the CDC. In one systematic review specifically looking at foodborne botulism from 1920 through 2014, there were 197 reported outbreaks, with 2 to 97 cases per outbreak.[5] The most recent report from the CDC from 2016 shows 29 confirmed foodborne botulism cases, 24 wound-botulism cases, and 3 unknown sources. Also, 18 of the 29 foodborne botulism cases originated in Mississippi. The confirmed sources were traced back to illicit alcohol made in a correctional facility (a.k.a. pruno), home-canned food, and the third outbreak has an unknown source. Wound botulism cases had an overwhelming majority originate from black tar heroin injection, one from methamphetamine injection, and the last from a gunshot wound. Of the 3 cases with unknown sources of botulinum toxin, 2 are believed to have had intestinal colonization.

Indications

As of March 13, 2010, the heptavalent botulinum antitoxin (HBAT) replaced all other non-infant botulinum antitoxins. This formulation contains fragments of immunoglobulin, Fab, and F(ab')2, that are active against 7 botulinum toxin subtypes. Only A, B, and E are naturally occurring types that cause disease in humans, but the other types potentially could be used as a weaponized biologic agent, so all 7 forms are used in HBAT. HBAT is FDA approved for adult and pediatric patients who have symptomatic foodborne or wound botulism or suspected exposure to botulinum toxin A-G.[6]

The first botulinum antitoxin was developed in the 1970s by the US Army Medical Research Institute of Infectious Diseases (USAMRIID). This antitoxin serum was developed from First Flight, a thoroughbred horse that was the only source of the United States botulinum antitoxin until the 1990s.

Prior to HBAT, formulations included investigational monovalent and licensed bivalent antitoxin serotypes targeting toxin types E and AB, respectively. Serotype AB was used for wound botulism cases, whereas foodborne botulism was treated with serotype AB and E. Both of these preparations of antitoxin are whole immunoglobulins.[7] [8]Before HBAT was approved, there was a trivalent (serotypes A, B, and E) formulation in the U.S. that has since been withdrawn from the market and is only used in Iran currently. In order to produce HBAT, horses are inoculated with all 7 serotypes of botulism, and serum is harvested to obtain antibodies. These antibodies are treated with pepsin, which cleaves the antibodies into Fc and Fab fragments, which reduces the chance of inducing severe allergic reactions when administered.[9]

There is also an investigational pentavalent toxoid vaccine, which differs from the other antitoxins as it is comprised of the inactivated toxin. Previously, it was reserved for pathologists and other personnel who work closely with C. botulinum or those who are first responders in a biological warfare threat. However, in 2011, the CDC discontinued offering this vaccine completely as new data suggested a declining efficacy of the toxoid.[10]

There are no non-FDA-approved indications.

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]