Botulism

Treatment Overview

Therapy for Botulism

  • Supportive care is the mainstay for treatment of botulism; prolonged intensive care, mechanical ventilation, and parenteral nutrition may be required.
  • Botulinum antitoxin can be administered to treat forms of botulism other than infant botulism and is most effective if given early in the clinical course. Although antitoxin will not reverse existing paralysis, it will prevent additional nerve damage if given before all circulating toxin is bound at the neuromuscular junction.
  • In cases of wound botulism, the wound should be surgically debrided and antibiotics should be administered (usually penicillin).
  • Botulism immune globulin–intravenous (human) (BIG-IV) for treatment of infant botulism was licensed by the FDA in October 2003 as BabyBIG.
    • A recent 5-year randomized, double-blind, placebo-controlled trial of BIG-IV treatment for infant botulism in California demonstrated that it significantly: (1) shortened duration of hospitalization (from a mean of 5.7 weeks to 2.6 weeks), (2) shortened time spent in intensive care (from 5.0 weeks to 1.8 weeks), and (3) decreased mean hospital costs per patient by $88,000 (see References: Arnon 2006).
    • BIG-IV is available as a public-service orphan drug and may be obtained by contacting the California Department of Human Services, Infant Botulism Treatment and Prevention Program (see References: California Department of Health Services, Arnon 2006). The circumstances that enabled the creation of BIG-IV have been presented as a possible paradigm for development of other "orphan" drugs (drugs used to treat relatively few patients) (see References: Arnon 2007).

Availability of botulinum antitoxin

  • Antitoxin should be requested as soon as the diagnosis of botulism is suspected, since confirmation of botulism may take several days and antitoxin is most effective if given within 24 hours after symptom onset (see References: Tacket 1984).
  • Antitoxin for use in the United States is of equine origin and only available through the CDC via state and local health departments (except in California and Alaska, where antitoxin release is controlled by the state health departments).
  • In addition to resources at the state level, epidemiologists at CDC are available 24 hours a day to provide advice regarding use of antitoxin.
  • Antitoxin (supplied by CDC) is maintained at quarantine stations located in airports in various metropolitan areas (eg, New York, Chicago, Atlanta, Miami, Los Angeles, San Francisco, Seattle, Honolulu). Once antitoxin is requested for a patient with suspected botulism, it generally can be delivered within 12 hours (see References: Shapiro 1997).
  • The CDC formulary includes botulinum antitoxin bivalent (equine) for types A and B (produced by Aventis Pasteur and licensed by the FDA) and botulinum antitoxin (equine) type E (an investigational product). In the past, CDC released trivalent ABE antitoxin for treatment of suspected or confirmed botulism cases in the United States; however, the trivalent product is currently not available (see References: CDC: Drug Service: Formulary).
  • The US army has developed an investigational heptavalent botulinum antitoxin (types A, B, C, D, E, F, G). This product could potentially be used during a bioterrorist attack involving aerosolized botulism; however, its efficacy in humans is not yet known (see References: Arnon 2001, Franz 1997).
  • In May 2006, Cangene Corporation was awarded a 5-year development and supply contract by the US Department of Health and Human Services for 200,000 doses of a heptavalent botulism antitoxin (BAT). Cangene announced a substantial delivery of the antitoxin in 2008 (see References: Cangene 2008).

Recommended therapy with botulinum antitoxin

  • If the type of botulinum toxin is not known, all three types of antitoxin should be administered. If the toxin type is known (ie, in an outbreak setting where the toxin type has been previously identified), then either bivalent AB antitoxin or type E antitoxin should be administered on the basis of the identified toxin type.
  • According to the package inserts, each vial of bivalent AB antitoxin contains 7,500 IU of type A antitoxin and 5,500 IU of type B antitoxin. Each vial of type E antitoxin contains 5,000 IU of type E antitoxin. One IU neutralizes 1,000 mouse LD50 of toxin E or 10,000 mouse LD50 of toxins A and B.
  • These amounts are more than adequate to neutralize the amount of toxin likely to be present in the circulation for naturally occurring botulism cases (see References: Hatheway 1984).
  • The circulating equine antitoxins have a half-life of 5 to 8 days (see References: Hatheway 1984).
  • In the setting of a bioterrorist attack, where cases may have been exposed to unusually large amounts of toxin, additional doses of antitoxin may be necessary. According to the package inserts, additional doses may be given (at least 2 to 4 hours after an initial dose or between doses) if the patient's condition continues to deteriorate. Alternatively, the patient's serum could be retested for the ongoing presence of circulating toxin (see References: Arnon 2001); however, this process would take time. The scarcity of antitoxin limits the capacity to provide additional doses.

Administration of botulinum antitoxin

  • The vial(s) should be diluted in 0.9% saline for intravenous infusion at a 1:10 dilution.
  • The preparation should be at ambient temperature before infusion and each diluted vial should be infused slowly (ie, over a minimum of 2 minutes) according to the manufacturer's instructions.

Hypersensitivity reactions to antitoxin

  • According to the package inserts, the following reactions can occur:
    • Anaphylaxis
    • Thermal reactions (usually occurring 20 minutes to 1 hour after administration and characterized by chills, slight dyspnea, and then a rapid rise in temperature)
    • Serum sickness (occurring within 14 days after administration and characterized by fever, urticaria or a maculopapular rash, arthritis or arthralgias, and lymphadenopathy)
  • In one series of 268 patients who received antitoxin between 1967 and 1977 (when the recommended dose of antitoxin was 2 to 4 times higher than it is currently), 24 (9%) had acute (13 patients) or delayed (11 patients) hypersensitivity reactions (see References: Black 1980).
  • Of patients treated with one vial of antitoxin (the current recommended dose), fewer than 1% experienced hypersensitivity reactions (see References: Sobel 2005).
  • Skin testing for sensitivity should be performed on all patients before they receive antitoxin (even if they have received the product at some point in the past). The best method is through a scratch test (outlined in the package insert). If the scratch test is positive, the patient can be desensitized over several hours before the full dose of antitoxin is administered.
  • Diphenhydramine and epinephrine should be available during administration of antitoxin, and the patient should be kept under careful observation for 1 to 2 hours after administration (then under close surveillance for a full 24 hours).
  • A case-control study of 217 botulism patients has provided details about long-term outcome of treated patients. Of the 211 patients who survived, 68% reported having worse health at the time of interview than 6 years earlier, compared with 17% of 656 controls (matched odds ratio, 17.6; 95% confidence interval, 10.9-28.4). Nearly twice as many patients as controls (49% vs 25%) reported their current health as fair or poor. Significantly more botulism patients than controls reported fatigue, dizziness, dry mouth, and difficulty lifting objects. In addition, botulism patients were significantly more likely than controls to report difficulty breathing with moderate exertion and were also more likely to report being limited in vigorous activities, walking 3 blocks, and climbing 3 flights of stairs (see References: Gottlieb 2007).

Botulism immune globulin

  • Isolation of plasma from donors immunized with pentavalent (ABCDE) botulinum toxoid yields botulism immune globulin (BIG). A 2005 hospital-based study in Utah demonstrated that BIG-IV could shorten hospital course and reduce disease complications in patients with infant botulism (see References: Thompson 2005).
Center for Infectious Disease Research & Policy Website. 2007. University of Minnesota. 21 Feb, 2011<http://www.cidrap.umn.edu>.
Supportive care, including prompt respiratory support, can be lifesaving. Respiratory failure due to paralysis of respiratory muscles is the most serious effect and, generally, the cause of death. Reported cases of botulism before 1950 had a mortality rate of 60%. With tracheotomy or endotracheal intubation and ventilatory assistance, fatalities are less than 5 percent today, although initial unrecognized cases may have a higher mortality. Preventing nosocomial infections is a primary concern, along with hydration, nasogastric suctioning for ileus, bowel and bladder care, and preventing decubitus ulcers and deep venous thromboses. Intensive and prolonged nursing care may be required for recovery, which may take up to 3 months for initial signs of improvement, and up to a year for complete resolution of symptoms.

Antitoxin: Early administration of botulinum antitoxin is critical, as the antitoxin can only neutralize the circulating toxin in patients with symptoms that continue to progress. When symptom progression ceases, no circulating toxin remains, and the antitoxin has no effect. Antitoxin may be particularly effective in foodborne cases, where presumably toxin continues to be absorbed through the gut wall. Animal experiments show that after aerosol exposure, botulinum antitoxin is very effective if given before the onset of clinical signs. If the antitoxin is delayed until after the onset of symptoms, it does not protect against respiratory failure.

Several different antitoxin preparations are available in the U.S. A licensed trivalent (types A, B, E) equine antitoxin is available from the Centers for Disease Control and Prevention (the CDC) for cases of foodborne botulism. This product has all the disadvantages of a horse serum product, including the risks of anaphylaxis and serum sickness. A bivalent human intravenous antiserum (types A and B) was licensed in October 2003 by the FDA and is available from the California Department of Health Services for treating infant botulism. Two "despeciated" equine heptavalent antitoxin preparations against all seven serotypes have been prepared by cleaving the Fc fragments from horse IgG molecules, leaving F(ab)2 fragments. The original product was developed by USAMRIID, and is currently available under IND status. It has been effective in animal studies. However, 4% of horse antigens remain, so there is still a risk of hypersensitivity reactions. A newer heptavalent IND preparation by a commercial manufacturer is available through USAMRIID or the CDC.

Use of the equine antitoxin requires compliance with the IND protocol. Administration of the antitoxin may first require skin testing with escalating dose challenges to assess the degree of an individual's sensitivity to horse serum before full dose administration of the vaccine. Skin testing is performed by injecting 0.1 ml of a 1:10 dilution (in sterile physiological saline) of antitoxin intradermally in the patient's forearm with a 26 or 27 gauge needle. The injection site is monitored and the patient is observed allergic reaction for 20 minutes. The skin test is positive if any of these allergic reactions occur: hyperemic areola at the site of the injection > 0.5 cm; fever or chills; hypotension with decrease of blood pressure > 20 mm Hg for systolic and diastolic pressures; skin rash; respiratory difficulty; nausea or vomiting; generalized itching. Equine-derived botulinum F(ab')2 antitoxin is NOT administered if the skin test is positive. If no allergic symptoms are observed, the antitoxin is administered as a single dose intravenously in a normal saline solution, 10 ml over 20 minutes.

With a positive skin test, desensitization can be attempted by administering 0.01 - 0.1 ml of antitoxin subcutaneously, doubling the previous dose every 20 minutes until 1.0 - 2.0 ml can be sustained without any marked reaction. Preferably, desensitization should be performed by an experienced allergist. Medical personnel administering the antitoxin should be prepared to treat anaphylaxis with epinephrine, intubation equipment, and intravenous access.

USAMRIID's Medical Management of Biological Casualities Handbook. Sixth ed. Fort Dietrich, Maryland: U.S. Army Medical Research Institute of Infectious Diseases, 2005. 90-91.
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