Evolution of Envenomation Treatment – The Path Leading to CroFab®

2011
  • Comprehensive snakebite management guidance for North American pit viper envenomation based on current evidence and expert consensus
2000
CroFab Logo
  • 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
1985
  • John Sullivan and Findlay Russell use affinity chromatography to create a highly purified and specific Fab antivenom
1954
  • 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
1939
  • 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
1927
  • First company licensed in the United States to produce and sell polyvalent, equine, whole IgG antivenom for North American pit vipers
1898
  • 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)
1895
  • Albert Calmette made equine antivenom serum for cobra envenomation
1894
  • 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
1890
  • Von Behring and Kitasato transfer serum from an immunized animal to a non-immune animal providing protection against bacterial toxins (diphtheria)
1888
  • Franz Hofmeister discovered that proteins can be purified out of serum by “salting out”
1887
  • Henry Sewall discovered that pigeons could develop resistance to Crotalus snake venom after injection with increasing doses of venom
References:

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.