Chapter A6: Botulinum Antitoxin

INTRODUCTION

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

HISTORY

Beginning in the 1930s, a formalin-inactivated toxoid against botulinum neurotoxin was first tested in humans, and in 1946, a bivalent (against types A and B) formaldehyde-inactivated toxoid was deployed by the Department of Defense as prophylaxis for at-risk individuals during the US Offensive Biological Warfare Program.^56,65 Before 1999, an equine trivalent antitoxin (BAT-ABE) was used 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. Patients with presumed wound botulism received BAT-AB. BAT-AB and BAT-E antitoxins were coadministered to patients with foodborne botulism. On March 13, 2010, equine heptavalent botulinum antitoxin (H-BAT, NP-018), an investigational new drug sponsored by the Centers for Disease Control and Prevention (CDC), replaced licensed bivalent BAT-AB and investigational BAT-E.¹⁶ 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.¹⁷ Botulism Immune Globulin Intravenous (Human) (BIG-IV), or BabyBIG was created by the California Department of Health Services (CDHS) in 1991 to treat infants affected by type A or type B botulism; it received Food and Drug Administration (FDA) approval in 2003.^2,27 On March 22, 2013, the FDA approved H-BAT, equine Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G), which is currently available.

PHARMACOLOGY

Chemistry and Preparation

A toxoid is an inactivated form of a bacterial toxin. An antitoxin is an antibody or antibody fragment capable of neutralizing a toxin. Multiple injections of formalin-inactivated toxoid are required over months to effectively immunize horses against botulinum toxin and to produce equine-derived antitoxins.³⁷ The resultant antibotulinum immunoglobulin requires several purification and preparation steps.³⁰ Heptavalent botulism antitoxin is produced by pooling plasma from horses immunized with seven specific botulinum toxoid types (A–G) followed by pepsin digestion and blending of the seven unique serotype antitoxins into a heptavalent product.¹¹ The antitoxin potencies for botulism serotypes A to G in H-BAT are provided in Table A6–1. By convention, 1 IU of BAT neutralizes 10,000 mouse intraperitoneal median lethal doses (MIPLD₅₀) of toxin types A, B, C, D, and F and 1,000 MIPLD₅₀ of toxin type E (the IU for type G remains undefined).¹⁵ As the equine H-BAT is “despeciated” by pepsin enzymatic cleavage to remove the Fc fragment portion, the resultant product is composed of 90% or greater Fab and F(ab′)₂ immunoglobulin fragments and less than 2% intact immunoglobulin G (IgG).¹⁶ This decreases ...