THE FUTURE FACE OF INFECTION: Antibiotic Resistance and Phage Therapy Eliot Morrison

1. THE FUTURE FACE OF INFECTION: Antibiotic Resistance and Phage Therapy Eliot Morrison Future Tensing 17.07.14 Karen Kamenetzky, 2008 1/33

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3. 3/33 Chiras 2007; Pearson Prentice Hall,2005; Sholto Ainslie 2014

4. What is an antibiotic? A small molecule of defined chemical structurethat targets a bacterial biochemical process, killing bacteria specifically. For this reason, antibiotics do not affect viruses, nor do they target human (eukaryotic) cells. Penicillin G 4/33

5. Bacteria have certain unique biochemical mechanisms that can be targets for antibiotics. 5/33 http://en.wikipedia.org/wiki/List_of_antibiotics

6. 6/33 http://en.wikipedia.org/wiki/Natural_selection#mediaviewer/File:Antibiotic_resistance.svg

7. 7/33 http://en.wikipedia.org/wiki/List_of_infectious_diseases

8. Adapted from CDC: Achievements in Public Health, 1900-1999; July, 1999 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm 8/33

9. CDC: Achievements in Public Health, 1900-1999; July, 1999 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm 9/33

10. Our arsenal of antibiotics is not getting larger WHO, Antimicrobial Resistance Report, 2014 10/33

11. Our arsenal of antibiotics is not getting larger Boucher et al., IDSA Public Policy, 2013 11/33

12. “The first rule of antibiotics is try not to use them, and the second rule is try not to use too many of them.” -Paul Marino, The ICU Book, 2007 12/33

13. 13/33 http://en.wikipedia.org/wiki/Natural_selection#mediaviewer/File:Antibiotic_resistance.svg

14. “Superbugs” MRSA: Methicillin-Resistant Staphylococcus Aureus CDC/JANICE CARR/DEEPAK MANDHALAPU, M.H.S. 14/33

15. Elixhauser and Steiner, AHRQ Statistical Brief 35, 2007 15/33

16. “The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug make them resistant.” -Alexander Fleming, Penicillin: Nobel Lecture, Dec. 11, 1945 16/33

17. There is still a lot of misinformation in the general public… n = 7120 McNulty et al., Journal of Antimicrobial Chemotherapy, 2007 17/33

18. …even among educated people. n = 7120 McNulty et al., Journal of Antimicrobial Chemotherapy, 2007 18/33

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20. Mellon et al., Union of Concerned Scientists, 2001 20/33

21. Horizontal Gene Transfer: harmless bacteria can “share” resistance genes with harmful bacteria Larry Frolich, 2006; Gregorious Pilosus 2009 21/33

22. The Fundamental Problem with Antibiotics: We use human ingenuity to engineer new or discover ancient, pre-existing antibiotic compounds. Bacteria “use” the principles of environmental pressure and natural selection to develop resistance. We’ve been “winning the race” for the last 70 years – but how long can we keep up? 22/33

23. So, naturalists observe, a flea Has smaller fleas that on him prey; And these have smaller still to bite ‘em, And so proceed ad infinitum. -Jonathan Swift, On Poetry: A Rhapsody, 1733 23/33

24. Bacteriophages (“phages”): Viruses that specifically target bacteria http://www.mansfield.ohio-state.edu/~sabedon/beg_phage_images.htm 24/33

25. http://commons.wikimedia.org/wiki/File:Phage.jpg 25/33

26. 106 bacteria / ml seawater 108 phages / ml seawater Nicholas Mann, PLOS Biology, 2005 26/33

27. Anonymous Germany (Augsburg) 1476 Naaman, a leper who dipped himself 7 times in the River Jordan and became clean 2 Kings 5 Illustrations from Spiegel Menschlicher Behältnis. Woodcut Sch. IV, 1-178 Harvard Art Museums/Fogg Museum, Gift of Philip Hofer, M3719 27/33

28. 1911: d’Herelle successfully stops locust infestation in Argentina using a strain of Cocobacillus 1917: d’Herelle discovers phage activity against dysentery bacteria; develops phage therapies 1934: Phage therapy discredited in a series of articles in JAMA (the Eaton-Bayne-Jones reports) Félix d'Herelle 1873-1949 1934: Joseph Stalin invites d’Herelle to establish Eliava Institute for phage research with George Eliava in Tbilisi, Georgia 1991: Georgian Civil War leaves Institute in ruins 1997: Exposure by the BBC spurs international support for Institute George Eliava 1892-1937 28/33 Abedon et al., Bacteriophage, 2011; Fruciano and Bourne, Can J Infect Dis Med Microbiol, 2006

29. 29/33 Abedon et al., Bacteriophage, 2011

30. 30/33

31. listex.eu 31/33

32. What is needed for phage therapy to become a reality in Western medicine? •Several small clinical trials have taken place in Switzerland and Bangladesh; a trial in the US was approved in 2009 and is currently underway •Attention of pharmaceutical and medical communities has not focused on phage therapy •Commercial phage cocktails need to be sequenced, screened and tested •Minimum investment for a broad-spectrum cocktail similar to a new antibiotic: $10-50 million USD 32/33 Harald Brussow, Virology, 2012

33. … The Progress Bubble: The shape of the 20th/21st centuries? New discovery Calls for moderation / alternatives ??? Irresponsible use accelerates problems Early warnings of unsustainability are outweighed by immediate benefits Rapid growth subsidized by accumulated, ancient resources and/or long-standing environmental niche Breakthroughdiscovery time 33/33

34. Further Reading •Boucher, H. et al. 10 x ‘20 Progress – Development of New Drugs Active Against Gram-Negative Bacilli: An Update from the Infectious Diseases Society of America. CID 56, 2013, 1685-1694 •Brüssow, H. What is needed for phage therapy to become a reality in Western medicine? Virology 434, 2012, 138-142 •Abedon, S. et al. Phage treatment of human infections. Bacteriophage 1:2, 2011, 66-85 •Chanishvili, N. et al. Phages and their application against drug-resistant bacteria. J ChemTechnolBiotechnol 76, 2001, 689-699 •Fruciano, DE and Bourne, S. Phage as an antimicrobial agent: d’Herelle’s heretical theories and their role in the decline of phage prophylaxis in the West. Can J Infect Dis Med Microbiol 18(1), 2007, 19-26