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.
Botulinum toxin is often cited as the most poisonous substance known; the lethal dose is 1 nanogram/kilogram. In adults, the most common form of transmission is food-borne botulism where the toxin itself is ingested. In wound botulism, bacterial spores find a port of entry and toxin is then produced locally. The aerosolized toxin can potentially be used for biological warfare.
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 cases of botulism reported to 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. The most recent report from the CDC from 2016 shows 29 confirmed foodborne botulism cases, 24 wound-botulism cases, and 3 unknown sources. 18 of the 29 foodborne botulism cases originated in Mississippi, and the confirmed sources were traced back to illicit alcohol made in a correctional facility, 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.
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. It is FDA approved for adult and pediatric patients who have symptomatic foodborne or wound botulism or suspected exposure to botulinum toxin A-G.
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 an investigational monovalent and licensed bivalent antitoxin serotypes which targeted 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. There is a separate trivalent (serotype A, B, and E) formulation, only on the market in Iran currently, that consists of fragmented antibodies. These antibodies are treated with pepsin, which cleaves the antibodies into Fc and Fab fragments, which should result in a lesser chance of inducing severe reactions when administered.
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 there was the declining efficacy of the toxoid.
There are no non-FDA approved indications.
Botulinum toxin binds irreversibly to presynaptic nerve endings at neuromuscular junctions. Through receptor-mediated endocytosis, toxin enters the cell and cleaves SNARE proteins, which are necessary for release of Acetylcholine into the synaptic cleft. 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.
HBAT works via passive immunization. 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 progression of symptoms but does not reverse any paralysis already present.
Prior formulations had non-fragmented antibodies. While these are more potent than the new HBAT formulation, fragmented antibody is less immunogenic and has a decreased risk for serious adverse effects.
Because BAT can only interact with unbound toxin, patients have been shown to have better outcomes the earlier it is administered in a patient’s course. When botulism is suspected, the state health department is notified first. From there, the CDC is contacted for case evaluation and emergency antitoxin dispatch. Because there is a limited quantity of BAT in the National Stockpile, the CDC stores the antitoxin in quarantine stations based in major US airports.
Prior to the administration of BAT, 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 who are at high risk for hypersensitivity should be given BAT at less than .01 mL per minute.
BAT 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.
Important points regarding the handling of the antitoxin from the FDA insert:
Botulinum antitoxin is given in a 1:10 dilution with .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 .5 mL per minute; if 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 .01 mL/kg per minute, can be increased by .01 mL/kg per minute every 30 minutes if tolerated. The maximum infusion rate is .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 .01 mL/kg per minute. Infusion rate can also be titrated by .01 mL/kg per minute if tolerated. Maximum infusion rate is also .03/mL/kg per minute.
The FDA lists the following as major adverse effects that have been documented.
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 may arise weeks after administration is serum sickness. This is a type III hypersensitivity that 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. 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 administration of 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 serum derived from non-human animal sources. Again, treatment includes stopping the infusion, provide airway protection and cardiovascular support. Additionally, steroids and plasmapheresis are other options for treatment that decrease inflammation and clear the vasculature of immune complexes.
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. Having an interprofessional team of toxicologists, emergency medicine physicians, nurses, and pharmacists is important for decreasing time to diagnosis and ensuring patient safety during drug administration. Poison control should immediately be contacted if a patient has suspected botulism.
Poison control, as well as the state health department, will help guide the diagnostic workup in cases where the diagnosis of botulism is not clear. Toxicologists not only consult at presentation; they also 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. When administering anti-toxin, as stated before, the patient should be monitored closely for adverse reactions. Nurses and treating physicians need to have a good understanding of how they will approach resuscitation and for what signs and symptoms they need to look. Pharmacists are needed for guidance on how to correctly administer the anti-toxin as well as 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.
|||Jeffery IA,Karim S, Botulism null. 2018 Jan [PubMed PMID: 29083673]|
|||Horowitz BZ, Botulinum toxin. Critical care clinics. 2005 Oct [PubMed PMID: 16168317]|
|||Shapiro RL,Hatheway C,Swerdlow DL, Botulism in the United States: a clinical and epidemiologic review. Annals of internal medicine. 1998 Aug 1 [PubMed PMID: 9696731]|
|||Fleck-Derderian S,Shankar M,Rao AK,Chatham-Stephens K,Adjei S,Sobel J,Meltzer MI,Meaney-Delman D,Pillai SK, The Epidemiology of Foodborne Botulism Outbreaks: A Systematic Review. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017 Dec 27 [PubMed PMID: 29293934]|
|||Investigational heptavalent botulinum antitoxin (HBAT) to replace licensed botulinum antitoxin AB and investigational botulinum antitoxin E. MMWR. Morbidity and mortality weekly report. 2010 Mar 19 [PubMed PMID: 20300057]|
|||Jones RG,Corbel MJ,Sesardic D, A review of WHO International Standards for botulinum antitoxins. Biologicals : journal of the International Association of Biological Standardization. 2006 Sep [PubMed PMID: 16490362]|
|||Mayers CN,Veall S,Bedford RJ,Holley JL, Anti-immunoglobulin responses to IgG, F(ab')2, and Fab botulinum antitoxins in mice. Immunopharmacology and immunotoxicology. 2003 Aug [PubMed PMID: 19180802]|
|||Notice of CDC's discontinuation of investigational pentavalent (ABCDE) botulinum toxoid vaccine for workers at risk for occupational exposure to botulinum toxins. MMWR. Morbidity and mortality weekly report. 2011 Oct 28 [PubMed PMID: 22031218]|
|||Simpson LL, Identification of the major steps in botulinum toxin action. Annual review of pharmacology and toxicology. 2004 [PubMed PMID: 14744243]|
|||Schussler E,Sobel J,Hsu J,Yu P,Meaney-Delman D,Grammer LC 3rd,Nowak-Wegrzyn A, Workgroup Report by the Joint Task Force Involving American Academy of Allergy, Asthma [PubMed PMID: 29293931]|
|||O'Horo JC,Harper EP,El Rafei A,Ali R,DeSimone DC,Sakusic A,Abu Saleh OM,Marcelin JR,Tan EM,Rao AK,Sobel J,Tosh PK, Efficacy of Antitoxin Therapy in Treating Patients With Foodborne Botulism: A Systematic Review and Meta-analysis of Cases, 1923-2016. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017 Dec 27 [PubMed PMID: 29293927]|
|||Roohi S,Grinnell M,Sandoval M,Cohen NJ,Crocker K,Allen C,Dougherty C,Jolly J,Pesik N, Evaluation of emergency drug releases from the Centers for Disease Control and Prevention Quarantine Stations. American journal of disaster medicine. 2015 [PubMed PMID: 27149310]|
|||Lawley TJ,Bielory L,Gascon P,Yancey KB,Young NS,Frank MM, A prospective clinical and immunologic analysis of patients with serum sickness. The New England journal of medicine. 1984 Nov 29 [PubMed PMID: 6387492]|
|||Sobel J,Rao AK, Making the Best of the Evidence: Toward National Clinical Guidelines for Botulism. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2017 Dec 27 [PubMed PMID: 29293933]|