A6: Antidotes in Depth

Antidotal therapies for adult and infant Clostridium botulinum infection are available as equine and human derived immunoglobulin antitoxins. Antitoxins may be beneficial for most clinical forms of botulism, although their utility is restricted to limiting disease progression rather than to reversing clinical manifestations.

Beginning in the 1930s, a formalin-inactivated toxoid against botulinum neurotoxin was first tested in humans, and in 1946 a bivalent (AB) formaldehyde-inactivated toxoid was deployed by the US Department of Defense as prophylaxis for at-risk individuals during the US Offensive Biological Warfare Program.^48,56 By 1999, an equine trivalent antitoxin (ABE) was available to treat botulism.¹³ From 1999 to 2010, equine-derived, licensed bivalent botulinum antitoxin AB (BAT-AB) and investigational monovalent serotype E botulinum antitoxin (BAT-E) were available in the United States as immunoglobulin preparations. BAT-AB was used for patients with presumed wound botulism, and BAT-AB and BAT-E antitoxins were coadministered to patients with food-borne botulism. On March 13, 2010, equine heptavalent botulinum antitoxin (H-BAT, NP-018), the investigational new drug sponsored by the Centers for Disease Control and Prevention (CDC), replaced licensed bivalent BAT-AB and investigational botulinum antitoxin E.² Effective November 30, 2011, the CDC also stopped providing the investigational pentavalent (ABCDE) botulinum toxoid (PBT) for vaccination of workers at risk for occupational exposure.³ BabyBig, or Botulism Immune Globulin Intravenous (Human) (BIG-IV), was created by the California Department of Health Services (CDHS) in 1991 to treat infants afflicted by type A or type B botulism; it received Food and Drug Administration (FDA) approval in 2003.^4,22 On March 22, 2013, the FDA approved H-BAT, equine Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G) which is currently available.

Chemistry/Preparation

A toxoid refers to an inactivated form of a bacterial toxin. An antitoxin is an antibody or antibody fragment capable of neutralizing a toxin. Multiple injections over months of formalin-inactivated toxoid are required to effectively immunize horses against botulinum toxin and to produce equine-derived antitoxins.³¹ The resultant antibotulinum immunoglobulin requires several purification and preparation steps.²⁵ H-BAT is produced by pooling plasma from horses immunized with specific botulinum toxoid subtypes (A–G), followed by pepsin digestion and blending of the seven serotype antitoxins into a heptavalent product.¹² H-BAT contains anti-type A, 4500 international units (IU); anti-type B, 3300 IU; anti-type C, 3000 IU; anti-type D, 600 IU; anti-type E, 5100 IU; anti-type F, 3000 IU; and anti-type G, 600 IU.²⁹ As the equine HBAT is “despeciated” by pepsin enzymatic cleavage and removal of the Fc fragment portion, the result is a product composed of ≥90% Fab and F(ab′)₂ immunoglobulin fragments and less than 2% intact immunoglobulin G (IgG).² This decreases the risk of immediate hypersensitivity reactions and serum sickness.

Human whole IgG BIG-IV is derived from cold ethanol precipitation of pooled adult plasma collected from human donors immunized multiple times with PBT (A–E).^37,52 The reconstituted product (50 ± 10 mg immunoglobulin/mL) contains greater than or equal to 15 IU/mL anti-type A toxin activity and greater than or equal to 4 IU/mL anti-type B toxin activity; antibody titers against botulinum neurotoxins C, D, and E remain undetermined.^22,29

Mechanism of Action

Current antitoxins (whether equine or human derived) bind to and neutralize free botulinum toxin.¹³ Thus, antitoxins are ineffective against toxin bound to presynaptic acetylcholine release sites, toxin endocytosed by peripheral neuronal cells, and intracellular botulinum toxin light chain endopeptidase activity.¹⁰ Affected presynaptic end plates must regenerate in order to regain function.

Pharmacokinetics and Pharmacodynamics

Antidotal antibody fragments (eg, F{ab′}₂, F{ab′}, and single-chain variable fragments {scFv}) demonstrate shorter half-lives compared to whole immunoglobulins.³² Improved renal clearance and uptake by vascular endothelium and surrounding tissues may contribute to this effect.⁴² While linking fragments to polyethylene glycol can extend their half-life,¹⁶ this methodology remains investigational. Compared to the half-lives for antitoxin types A, B, and E of 6.5, 7.6, and 5.3 days measured in a patient provided whole immunoglobulin trivalent antitoxin, clinical trials following single vial administration determined shorter H-BAT antitoxin half-lives of anti-A (8.64 hours), anti-B (34.20 hours), anti-C (29.60 hours), anti-D (7.51 hours), anti-E hours (7.75 hours), anti-F (14.10 hours), and anti-G (11.70 hours).¹¹ These half-lives increased to 10.20 hours, 57.10 hours, 45.60 hours, 7.77 hours, 7.32 hours, 18.20 hours, and 14.70 hours, respectively, when two vials were administered.^11,20,24 The volume of distribution ranges from 1465 mL (anti-D) to 14,172 mL (anti-E), depending on the number of vials.¹¹ The more rapid clearance of Fab and F(ab′)₂ fragments compared to whole IgG may necessitate repeat H-BAT dosing in patients with wound or intestinal colonization or other cases in which in situ botulinum toxin production continues after antitoxin clearance.² Indeed, recurrence of paralysis was reported following H-BAT therapy in a patient with persistent type F intestinal colonization.²⁰

By convention, one IU of botulinum antitoxin neutralizes 10,000 mouse intraperitoneal median lethal doses (MIPLD₅₀) of toxin types A, B, C, D, and F, or 1000 MIPLD₅₀ of toxin type E (the IU for type G remains undefined).¹⁴ Thus, for example, in the doses found in H-BAT, the 4500 IU of anti-A, 3300 IU of anti-B, 3000 IU of anti-C, 600 IU of anti-D, 5100 IUof anti-E, and 3300 IU of anti-F would offset a total of 4.5 × 10⁷ MIPLD₅₀ of botulinum A toxin, 3.3 × 10⁷ MIPLD₅₀ of botulinum B toxin, 3.0 × 10⁷ MIPLD₅₀ of botulinum C toxin, 6.0 × 10⁶ MIPLD₅₀ of botulinum D toxin, 5.1 × 10⁶ MIPLD₅₀ of botulinum E toxin, and 3.0 × 10⁷ MIPLD₅₀ of botulinum F toxin, respectively.⁴⁶ These values would be anticipated to provide significant neutralization; patient serum botulinum toxin concentrations in food-borne botulism are usually less than 10 MIPLD₅₀/mL and rarely exceed 32 MIPLD₅₀/mL, using a plasma volume of 3000 mL reported previously.^5,24,45 In isolated outbreaks, botulinum toxin concentrations in adult serum samples collected less than 18 hours after exposure are reported to be as high as 160 MIPLD₅₀/mL.⁷ Other recent cases have also yielded human serum botulinum toxin concentrations of type A of 1800 MIPLD₅₀/mL.⁴⁶ Following single vial administration, the reported H-BAT maximum concentration values¹² of 2.69 IU/mL for anti-A, 1.90 IU/mL for anti-B, 2.26 IU/mL for anti-C, 0.81 IU/mL for anti-D, 0.94 IU/mL for anti-E, and 2.37 IU/mL for anti-F would be anticipated to neutralize 2.69 × 10⁴ MIPLD₅₀/mL of botulinum A toxin, 1.90 × 10⁴ MIPLD₅₀/mL of botulinum B toxin, 2.26 × 10⁴ MIPLD₅₀/mL of botulinum C toxin, 8.1 × 10³ MIPLD₅₀/mL of botulinum D toxin, 9.4 × 10² MIPLD₅₀/mL of botulinum E toxin, and 2.37 × 10⁴ MIPLD₅₀/mL of botulinum F toxin. One study that measured four patients’ serum antitoxin concentrations following trivalent antitoxin (ABE) administration determined that those patients’ measured antitoxin titers would retain the capability to neutralize 1500, 1000, and 12 times the anticipated toxin concentrations of types A, B, and E, respectively.²⁴ Complexity in anticipating or interpreting absolute neutralization efficacy is due to the fact that animal studies have revealed that the relationship between circulating neutralizing antibody concentrations and the amount of botulinum toxin neutralized is nonlinear, leading to a more efficacious, disproportional increase in botulinum toxin neutralization as antibody concentration is increased.⁴⁵

The half-life of BIG-IV is approximately 28 days.²⁹ BIG-IV anti-A titers were 0.5371 ± 0.2134 IU/mL on day one. Since one IU neutralizes 10,000 mouse intraperitoneal median lethal doses (MIPLD₅₀) of botulinum toxin A, this yields approximately titers of 5370 MIPLD₅₀/mL.^14,29 Thus, a single infusion is anticipated to neutralize all botulinum toxin that might be absorbed from an infant’s colon for several months.⁶

Related Agents

In order to properly interpret earlier botulism studies, it is important to recall that the previously available, equine BAT-AB antitoxin contained 7500 IU of anti-A antitoxin and 5500 IU of anti-B antitoxin.⁴¹ BAT-E contained 5000 IU of antitoxin. Trivalent antitoxin (ABE) contained 7500 IU of anti-A, 5500 IU of anti-B, and 8500 IU of anti-E antitoxins.²⁷ Investigational, whole, and fragment-derived monoclonal antibodies that have been raised in murine and equine species against types A and B are also being explored.^31,32

Investigational PBT vaccine, combining individual monovalent toxoids, was initially manufactured by Parke Davis more than 50 years ago and was subsequently produced by the Michigan Department of Public Health under contract from the US Army.^21,47 A replacement vaccine developed by US Army Medical Research Institute for Infectious Diseases (USAMRIID)—recombinant botulinum vaccine (rBV A/B)—is designed to protect adults 18 to 55 years of age against botulism type A (subtype A1) and type B (subtype B1).²³ It has been studied in animals and, completed human clinical trials await publication, although approval may be pursued under the FDA Animal Rule.^17,23,44 Other recombinant subunit vaccines against C₁, D, E, and F have demonstrated efficacy in animals.⁴⁷ Humanized monoclonal antibodies, small peptides and peptide mimetics, receptor mimics, and small molecules targeting the endopeptidase activity are other avenues being explored for botulism treatment.¹⁰

Rigorous adult morbidity and mortality studies are difficult to perform due to botulism’s rarity, varied exposure and presentation, delayed recognition when bound toxin is no longer removable by antitoxin, and inconsistent clinical care. Given the delay involved in confirmatory testing by the CDC or public health laboratories and the lack of antitoxin reversal potential, the decision to administer H-BAT will often be made on the basis of empirical clinical and epidemiological grounds. Earlier disease recognition and an organized public health approach comprising surveillance, emergency notification, stocking, a release and distribution system, and laboratory confirmation appear to be responsible for decreasing morbidity and increasing survival after typical food-borne botulism.^43,55 Simian experiments demonstrate reduced mortality with antitoxin administration.³⁵ Early antitoxin administration is a critical factor affecting clinical course and outcome. In a 1963 type E outbreak, all three patients who died failed to receive antitoxin, whereas three of five who received botulinum antitoxin survived.³⁰ Trivalent equine antitoxin decreased the fatality rate of botulinum A poisoning in a case series from 1973 to 1980.⁵¹ Patients who received antitoxin within the first 24 hours after symptom onset had a shorter disease course, although their mortality rate was equivalent to those who received antitoxin later. Age over 60 years and being an index patient conferred a greater mortality risk; a shorter incubation period of less than 36 hours (a surrogate measure of toxin dose) increased duration of hospitalization, mechanical ventilation, and time to sustained improvement.⁵¹ The case-fatality rate was 3.5% in patients with type E botulism who were provided antitoxin and 28.9% for untreated control subjects from previous years, although the utilization of supportive measures was uncontrolled.²⁸ In a retrospective review of 29 patients admitted from 1991 to 2005 with type A and a single case of type B wound botulism, a delay in antitoxin administration correlated with increased length of intensive care unit (ICU) stay.³⁶ In 20 patients with type A wound botulism treated from 1991 to 1998, those who received antitoxin within 12 hours of presentation required mechanical ventilation 57% of the time for a median duration of 11 days, compared to those who failed to receive antitoxin within 12 hours in whom 85% require mechanical ventilation for a median duration of 54 days.⁴⁰ Again, a shorter time to presentation heralded more severe disease (respiratory failure). A third wound botulism series (types A and B) with seven patients confirmed the importance of early therapy; those receiving antitoxin more than 8 days from symptom onset faired poorly compared to those receiving it within 4 days of symptom onset.¹⁵ Botulinum antitoxins are also beneficial in cases of iatrogenic botulism.⁴⁹ An earlier despeciated heptavalent botulism immune globulin (dBIG), which was prepared by the University of Minnesota under US Army contract, was deployed in the 1991 Egyptian type E botulism outbreak.²⁵ In a 2006 Thailand type A outbreak, heptavalent antitoxin was administered to 20 patients 5 days after toxin ingestion when respiratory failure was already present. Mechanical ventilation and hospital duration were shorter when compared to a historical study, and there were no deaths in those receiving antitoxin.⁵⁸

The absolute time frame for efficacy remains undetermined. In 109 patients treated under the CDC open-label protocol, H-BAT administration within 2 days after symptom onset (compared to >2 days) was associated with clinically significant, shorter mean durations of hospitalization (12.4 versus 26.1 days), ICU utilization (9.2 versus 15.8 days), and mechanical ventilation (11.6 versus 23.4 days).¹¹ However, circulating toxin can persist for long periods in patients with food-borne botulism. One study reported toxin detection in almost 20% of serum specimens taken greater than or equal to 10 days after toxin ingestion.⁵⁹ Furthermore, persistent, viable organisms or spores were present in stools 40% of the time at 10 days or more after toxin ingestion. A review of laboratory-confirmed botulism cases in Alaska from 1959 to 2007 demonstrated that toxin could be recovered in patients’ sera up to 11 days after ingestion, while no serum specimens collected after antitoxin administration tested positive.¹⁹ In one case, toxin was detected in serum 12 days after the onset of descending paralysis.¹ Another patient in that multinational food-borne outbreak had toxin detected at 25 days after symptom onset.⁴⁶ Other isolated cases detail detectible circulating toxin as late as three and a half weeks after contaminated food consumption.¹⁸ Botulinum toxin–associated ileus might result in prolonged toxin exposure and continued absorption.

Collectively, these factors suggest that H-BAT might still prove clinically useful in patients with delayed presentations or disease recognition, in whom circulating toxins might present a persistent risk. Indeed, one report documented improvement when H-BAT was administered 48 hours after admission and many days after consumption of type-unspecified, botulism-contaminated canned corn.²⁶

A recently discovered, novel, eighth botulinum neurotoxin type H, recovered from an infant botulism patient, cannot be neutralized by any of the currently available antibotulinum therapies.^{7a, 18a} Botulism poisoning does not appear to induce protective immunity or decrease subsequent morbidity or mortality associated with subsequent exposure in food or wound botulism.^8,13,60 Thus, retreatment with antitoxin is required upon reexposure or in recurrent cases.

BIG-IV is approved for treatment of patients younger than one year of age with infant botulism caused by toxin type A or B. BIG-IV does not treat rare serotype F disease, as human donors were vaccinated with PBT (A–E). In a double-blind and subsequent open-label trial, treatment with BIG-IV significantly reduced the overall length of hospital and ICU stay, the duration of mechanical ventilation, tube and intravenous feeding, and the cost of hospitalization.^4,6 A retrospective review of 67 ICU patients with type A or B botulinum toxin from 1976 to 2005 found clinically significant decreases in length of hospital stay, ICU stay, and mechanical ventilation in patients who received BIG-IV versus those who did not.⁵³ Another retrospective review of patients with type A or B botulinum toxin from 1985 to 2005 reported a significant decrease in length of stay, a reduced need for nasogastric feeding, and duration of tracheal intubation in infants treated with botulism immune globulin.⁶⁰

BAT-AB and other equine derived products were rarely used in infants due to concern for anaphylaxis, life long hypersensitivity, and unclear efficacy.¹⁴ However, in situations where BIG-IV was unavailable due to lack of access or cost, BAT-AB treatment within 5 days of symptom onset significantly reduced overall hospital and ICU stays, duration of mechanical ventilation, tube feedings, and incidence of sepsis.⁵⁴

Despite purification, inactivation, and filtration measures, potential transmission of blood-borne infectious agents from animal or human donors (pooled equine or human plasma) may still occur. Treatment with whole equine-derived antitoxins risks hypersensitivity reactions and serum sickness.⁴¹ Early rates of adverse reactions during the first decade during which botulinum antitoxin was available (1967–1977) ranged from 9% to 21%.^9,34 The reported rates of anaphylaxis and serum sickness were 1.9% and 3.7%, respectively.⁹ However, the doses of antitoxin were larger than those subsequently used. H-BAT despeciation further decreases, but does not eliminate, this risk. Use of dBIG produced adverse reactions in 10 of 45 patients when used in one botulism type E outbreak.²⁵ These included nine “mild” reactions (local skin reactions, six; pruritus, one; urticaria, one; shivering, one) and one episode of “suggested serum sickness” without additional detail. The incidence of adverse effects of dBIG was similar to other internationally available antitoxins.²⁵ Healthy subjects administered H-BAT in clinical trails (56 total, of whom 20 received two vials) reported headache, pruritus, nausea, and urticaria at rates of 9%, 5%, 5%, and 5%, respectively.¹¹ Two moderate allergic reactions required treatment. Eleven subjects produced anti-BAT antibodies. The open-label CDC observation study revealed adverse reactions in 10% of 228 assessable patients; pyrexia, rash, chills, nausea, and edema occurred in 4%, 2%, 1%, 1%, and 1%, respectively.¹¹ There were no immediate hypersensitivity reactions, one cardiac arrest, and one episode of serum sickness. H-BAT contains maltose, which may interfere with certain non–glucose-specific blood glucose monitoring systems.

Hypersensitivity reactions might also occur to human BIG-IV, although this was not reported in clinical trials.²⁹ BIG-IV is contraindicated in patients with a prior history of severe reactions to other human immunoglobulin preparations and should be used cautiously in patients with or at risk for kidney dysfunction, because kidney dysfunction has been noted following treatment with other intravenous immunoglobulin products.²⁹ A mild, transient erythematous rash on the face or trunk was the most commonly reported adverse reaction. Potential but unreported adverse events include antibody development to immunoglobin A (IgA) in patients with selective IgA deficiency and anaphylaxis upon subsequent exposure to blood products that contain IgA, aseptic meningitis syndrome, hemolytic anemia, thrombosis, transfusion-related acute lung injury, and hyperviscosity.²⁹ Administration of live virus vaccines (ie, measles, mumps, rubella, varicella) should be delayed for 5 months after infant BIG-IV treatment due to concerns of loss of immunization efficacy.

Although there is limited information regarding H-BAT use in pregnancy, whole equine bivalent and trivalent antitoxins have been previously administered without apparent harm to the mother or the fetus.^33,38,39,50 Pregnancy is not a contraindication to H-BAT. Given botulism’s life-threatening paralysis, treatment benefits would potentially exceed risks of harm, although all decisions are ultimately made on a case-by-case basis. H-BAT’s breast milk distribution is unknown. The labeled indication of BIG-IV for use in patients younger than one year of age does not address administration to pregnant women.²⁹

Close monitoring; medications including epinephrine, diphenhydramine, and corticosteroids, supportive airway modalities; and practitioners who are capable of diagnosing and treating anaphylactic or anaphylactoid reactions (including intubation competence) should be immediately available prior to and during antitoxin administration.

Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)

Unlike prior equine derived products, H-BAT does not require routine sensitivity testing prior to administration, although it may be considered for those at risk of acute hypersensitivity reactions. If required, skin sensitivity testing with H-BAT is performed by administering 0.02 milliliters of 1:1000 saline-diluted BAT intradermally on the volar surface of the forearm (enough to raise a small wheal) with concurrent positive (histamine) and negative (saline) control tests.¹¹ Read after 15 to 20 minutes, a positive test is a wheal with surrounding erythema at least 3 millimeters larger than the negative control test. The histamine control must be positive for valid interpretation. A negative test is followed with repeat testing using a 1:100 dilution and then careful administration if no reaction occurs.

Three separate dosing strategies are recommended for adults, pediatric patients (1–17 years), and infants younger than 1 year. The adult dose is one vial. The vial is diluted 1:10 in 0.9% sodium chloride and administered intravenously via an optional 15-micron in-line filter. Barring any infusion-related safety concerns, the initial rate is 0.5 mL/min for the first 30 minutes, which is increased to 1 mL/min for the next 30 minutes, and then to 2 mL/min until completion of the infusion. For pediatric patients, the dose is a percentage of adult (one vial) dose calculated according to the dosing rule summarized in the package insert. For pediatric patients with a body weight ≤30 kg, the percentage of the adult dose to administer equals twice the body weight (in kg); for patients with a body weight >30 kg, the percentage of the adult dose to administer equals the weight (in kg) + 30. This rule yields the recommended percentages of the adult dose to administer according to the following pediatric weight intervals: 10 to 14 kg, 20%; 15 to 19 kg, 30%; 20 to 24 kg, 40%; 25 to 29 kg, 50%; 30 to 34 kg, 60%; 35 to 39 kg, 65%; 40 to 44 kg, 70%; 45 to 49 kg, 75%; 50 to 54 kg, 80%; and greater than or equal to 55 kg, 100%.¹¹ Without ever exceeding the adult rates, the infusion is initiated at a rate of 0.01 mL/kg/min for the first 30 minutes, which is increased 0.01 mL/kg/min every 30 minutes, to a maximum infusion rate of 0.03 mL/kg/min until completion. Infants (<1 year) receive 10% of the adult dose regardless of body weight. The infusion is initiated at a rate of 0.01 mL/kg/min for the first 30 minutes, which is increased 0.01 mL/kg/min every 30 minutes, to a maximum infusion rate of 0.03 mL/kg/min until completion.

Big-IV

The lyophilized product is reconstituted with 2 mL of sterile water for injection, to obtain a 50 mg/mL BIG-IV solution. The vial should not be shaken; this causes foaming. Infusion should begin within 2 hours of reconstitution. A dedicated intravenous line using low-volume tubing and a constant infusion pump are used to provide 75 mg/kg (1.5 mL/kg of reconstituted 50 mg/mL BIG-IV solution). The BIG-IV solution may be “piggybacked” into a preexisting line if it contains either 0.9% sodium chloride injection, 2.5% dextrose in water, 5% dextrose in water, 10% dextrose in water, or 20% dextrose in water (with or without added sodium chloride). If a preexisting line must be used, BIG-IV should not be diluted more than 1:2 with any of the solutions named above.²⁹ BIG-IV is administered at an initial rate of 25 mg/kg/h (0.5 mL/kg/h of reconstituted 50 mg/mL BIG-IV solution) for the first 15 minutes, which is then increased to 50 mg/kg/h (1 mL/kg/h of reconstituted 50 mg/mL BIG-IV solution), for a total infusion time of 97.5 minutes at the recommended dose.

Other Immunoglobins

In regions where whole, equine-derived antitoxins may still be available, it is important to note that these products required sensitivity testing and potential desensitization. The package inserts should be consulted for specific procedural details for dosing and administration, particularly as titers and volumes may differ by brand.⁴¹ For prophylaxis, the recommended dose of BAT-AB for an individual who had eaten food suspected of being infected with C. botulinum depended on the amount of food eaten and was 1500 to 7500 IU of anti-type A and 1100 to 5500 IU of anti-type B intramuscularly (20% to 100% of one vial). This initial therapy was followed in 12 to 24 hours by the injection of a second vial if any signs or symptoms of botulism developed.⁴¹ In addition, 1000 and 5000 IU (20% to 100% of one vial) of investigational anti-type E, based on the estimated ingested quantity of botulinum toxin, had been used for type E outbreaks.⁵⁷ The BAT-AB and BAT-E treatment doses were one vial of antitoxin diluted 1:10 (vol/vol) in 0.9% sodium chloride solution and administered slowly and intravenously over 30 to 60 minutes.^27,41 Subsequent doses could be provided intravenously every 2 to 4 hours if progression of clinical findings occurred. BAT-AB and BAT-E were administered separately.

H-BAT is supplied in either 20 mL or 50 mL single-dose vials. Despite variable vial filling of 10 to 22 mL/vial, the amount of A, B, C, D, E, F, and G antitoxin contained per vial is fixed: more than 4500 IU of anti-A, more than 3300 IU of anti-B, more than 3000 IU of anti-C, more than 600 IU of anti-D, more than 5100 IU of anti-E, more than 3000 IU of anti-F, and more than 600 IU of anti-G.¹¹ The bulk material contains approximately 30 to 70 mg/mL protein. H-BAT contains 10% maltose and 0.03% polysorbate 80. H-BAT is stored frozen at or below 5°F (–15°C) until used. Thawed H-BAT must be maintained at 36° to 46°F (2°–8°C) and used within 36 months, or until 48 months from the manufacture date, whichever occurs earliest. H-BAT should not be refrozen. Frozen H-BAT can be thawed in a refrigerator at 36° to 46°F (2°–8°C) over approximately 14 hours. Rapid thawing can be achieved by placing at room temperature for one hour, followed by a water bath at 98.6°F (37°C) until thawed. Reconstituted H-BAT may be stored refrigerated for use within 8 to 10 hours.

BIG-IV is formulated as a 6-mL, single-use, solvent-detergent-treated, sterile vial containing 100 ± 20 mg of lyophilized immunoglobin (primarily IgG with trace amounts of IgA and IgM), stabilized with 5% sucrose and 1% albumin (human), without preservative.^22,29

BAT-AB, which may be available outside of the United States, must be maintained at 36° to 46°F (2°–8°C) and not frozen. It contains phenol 0.4% as a preservative.

Medical care providers who suspect botulism should immediately call their local or state health department’s emergency 24-hour telephone service to request release of botulinum antitoxin and comply with legal reporting requirements. When local and state public health authorities are unavailable, the CDC Emergency Operations Center telephone contact is 770-488-7100. The CDC controls H-BAT distribution from stocks located throughout a national network of quarantine stations. The California Infant Botulism Treatment and Prevention Program (510-231-7600) maintains the supply of botulism immune globulin for infant botulism treatment. The Biomedical Advanced Research and Development Authority (BARDA) within the US Department of Health and Human Services has obtained approximately 120,000 H-BAT doses for the Strategic National Stockpile, with anticipated delivery of 80,000 additional doses.⁵⁶

• In conjunction with frequent clinical assessments and aggressive supportive care of respiratory, gastric, and urinary function, provision of botulinum antitoxin appears to decrease morbidity and mortality after typical food borne or wound botulism.

• Preliminary data suggest that early administration of licensed H-BAT decreases the duration of hospitalization, ICU utilization, and mechanical ventilation.

• Current antitoxins cannot neutralize novel botulinum neurotoxin type H.

• Licensed BIG-IV provides effective treatment for infant botulism.

• Early consultation with local health departments, the CDC Emergency Operations Center, or a regional poison center (or other comparable agencies in other parts of the world) should occur to rapidly access effective therapeutic modalities and diagnostic tests for botulism.

References