Evolution of Envenomation Treatment – The Path Leading to CroFab®

  • Comprehensive snakebite management guidance for North American pit viper envenomation based on current evidence and expert consensus
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  • The first ovine derived, affinity purified Fab fragment antivenom approved for use in the United States
  • Reported crotaline exposures increase from 1,685 in 1999 to 4,023 in 2016, but the incidence of major outcomes within exposures reported decreased from 11% to 5%4,5
  • John Sullivan and Findlay Russell use affinity chromatography to create a highly purified and specific Fab antivenom
  • Dosing to severity of envenomation
  • Acute allergic reactions (~25%), frequent serum sickness (~75%)
  • Fasciotomies are often performed on snakebite victims
  • Research and published data continue to increase
  • C.G. Pope used ammonium sulphate to precipitate out antitoxic proteins from serum of an immunized horses
  • C.G. Pope discovered that antitoxic proteins can be cleaved into fragments with proteolytic enzymes (papain and pepsin) and maintain antitoxin activity
  • First company licensed in the United States to produce and sell polyvalent, equine, whole IgG antivenom for North American pit vipers
  • Vital Brazil demonstrates that antivenom serums are specific to the snakes used to produce the antivenom (prior to that others such as Calmette assumed they were non-specific)
  • Albert Calmette made equine antivenom serum for cobra envenomation
  • Two groups of French researchers are simultaneously credited with the discovery of antivenom serotherapy:
    • Albert Calmette from the Pasteur Institute obtained antiserum from rabbits immunized with cobra venom11
    • Cesaire Auguste Phisalix from the National Museum of Natural History obtained antiserum blood from guinea pigs immunized with heat-inactivated Vipera aspis venom12
  • Von Behring and Kitasato transfer serum from an immunized animal to a non-immune animal providing protection against bacterial toxins (diphtheria)
  • Franz Hofmeister discovered that proteins can be purified out of serum by “salting out”
  • Henry Sewall discovered that pigeons could develop resistance to Crotalus snake venom after injection with increasing doses of venom

1. Gerardo CJ, et al. The Efficacy of Crotalidae Polyvalent Immune Fab (Ovine) Antivenom Versus Placebo Plus Optional Rescue Therapy on Recovery From Copperhead Snake Envenomation: A Randomized, Double-Blind, Placebo-Controlled, Clinical Trial. Ann Emerg Med. 2017;70(2):223-244. 2. Lavonas EJ, Ruha AM, Banner W, et al. Unified treatment algorithm for the management of crotaline snakebite in the United States: results of an evidence-informed consensus workshop. BMC Emerg Med. 2011;11:2. 3. CroFab® Prescribing Information. BTG International Inc.; 2018. 4. Litovitz TL, Klein-Schwartz W, White S, et al. 1999 Annual Report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med. 2000;18(5):517-574. 5. Gummin DD, Mowry JB, Spyker DA, Brooks DE, Fraser MO, Banner W. 2016 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 34th Annual Report. Clin Toxicol. 2017;55(10):1072-1252. 6. Russell FE, Sullivan JB. Preparation of a new antivenin by affinity chromatography. Am J Trop Med Hyg. 1985;34(1):141-150. 7. Dart RC, et al. Efficacy, safety, and use of snake antivenoms in the United States. Ann Emerg Med. 2001;37(2):181-188. 8. Pope CG. The Action of Proteolytic Enzymes on the Antitoxins and Proteins in Immune Sera. III. Further Studies on Enzyme Systems Which Split the Antitoxin Molecule. Br J Exp Pathol. 1951;32(4):314-324. 9. Smithsonian, The National Museum of American History. The Antibody Initiative: Antivenom. http://americanhistory.si.edu/collections/object-groups/antibodyinitiative/ antivenom. Accessed August 2018. 10. Bochner R. Paths to the discovery of antivenom serotherapy in France. J Venom Anim Toxins Incl Trop Dis. 2016;22:20. 11. Calmette, A., Contribution à l'étude du venin des serpents. Immunisation des animaux et 11 traitement de l'envenimation. Annales de l'Institut Pasteur, VIII, 1894: p. 275-291. 12. Alvarenga LM, et al. Engineering venom's toxin-neutralizing antibody fragments and its therapeutic potential. Toxins. 2014;6(8):2541-2567.