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INTRODUCTION

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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.

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HISTORY

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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.

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PHARMACOLOGY

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Chemistry/Preparation

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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.

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Human whole IgG BIG-IV is derived from cold ethanol precipitation of pooled adult plasma collected from human ...

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