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THE FUTURE FACE OF INFECTION: Antibiotic Resistance and Phage Therapy Eliot Morrison Pop Science Cafe 20.01.15 Karen Kamenetzky, 2008 1/35

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Chiras 2007; Pearson Prentice Hall,2005; Sholto Ainslie 2014 3/35

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What is an antibiotic? A small molecule of defined chemical structure that 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 4/35

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http://en.wikipedia.org/wiki/List_of_antibiotics Inhibit bacterial protein biosynthesis ClassExamplesCommon Use Introduce d Aminoglycosides Kanamycin, Streptomycin Gram-negative bacterial infections (e.g. E. coli, P. aeruginosa) 1943 LincosamidesClindamycin Staph-, pneumo- and streptococcal infections in penicillin-allergic patients 1961 MacrolidesErythromycin Streptococcal infections, syphilis, respiratory infections, Lyme disease 1952 OxazolidinonesLinezolidVRSA1956 Tetracyclines Doxycycline, Tetracycline Syphilis, chlamydial infections, Lyme disease 1948 Inhibit bacterial cell wall synthesis ClassExamplesCommon UseIntroduced CarbapenemsMeropenem Broad-spectrum antibacterial 1976 CephalosporinsCefalexin Gram-positive infections 1948 GlycopeptidesVancomycin Gram-positive infections, including MRSA; oral treatment of C. difficile 1955 Penicillins Amoxicillin, Methicillin, Penicillin G Broad spectrum; used for streptococcal infections, sypthilis and Lyme disease 1942 (mass production) PolypeptidesBacitracin Eye, ear or bladder infections 1945 Disrupt bacterial membrane potential ClassExamplesCommon UseIntroduced LipopeptidesDaptomycin Gram-positive infections 1987 Inhibit bacterial DNA replication ClassExamplesCommon UseIntroduced QuinolonesCiprofloxacin Urinary tract infections, pneumonia, gonorrhea 1962 Inhibit bacterial synthesis of folate ClassExamplesCommon Use Introduce d SulfonamidesSulfa drugs Urinary tract/eye infections 1932 Bacteria have certain unique biochemical mechanisms that can be targets for antibiotics while eukaryotic cells are untouched. 5/35

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http://en.wikipedia.org/wiki/Natural_selection#mediaviewer/File:Antibiotic_resistance.svg 6/35

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http://en.wikipedia.org/wiki/List_of_infectious_diseases Viral DiseaseAgent AIDSHIV ChickenpoxVaricella zoster virus Common coldusually rhinoviruses and coronaviruses Dengue feverDengue viruses DEN-1-4 EbolaEbolavirus Hepatitis A-EHepatitis viruses Herpes simplexHerpes simplex virus 1 and 2 InfluenzaOrthomyxoviridae family MeaslesMeasles virus MERS Middle East respiratory syndrome coronavirus MumpsMumps virus PoliomyelitisPoliovirus RabiesRabies virus SARSSARS coronavirus SmallpoxVariola major/minor West Nile FeverWest Nile virus Yellow feverYellow fever virus Eukaryotic DiseaseAgent MalariaPlasmodium genus Hookworm Ancylostoma duodenale / Necator americanus ScabiesSarcoptes scabiei Prionic DiseaseAgent Bovine spongiform encephalopathy (mad cow disease) prion Creutzfeldt-Jakobprion Kuruprion Bacterial DiseaseAgent AnthraxBacillus anthracis Bacterial pneumoniamultiple Botulism Botulinum toxin from Clostridium botulinum Bubonic plagueEnterobacteriaceae family ChlamydiaChlamydia trachomatis CholeraVibrio cholerae* DiphtheriaCorynebacterium diphtheriae GonorrheaNeisseria gonorrhoeae LeprosyMycobacterium leprae ListeriosisListeria monocytogenes Lyme diseaseBorrelia burgdorferi Pertussis (Whooping cough) Bordetella pertussis SalmonellosisSalmonella genus Scarlet fever Erythrogenic toxin from Streptococcus pyogenes Shigellosis (Bacillary dysentery) Shigella genus SyphilisTreponema pallidum TetanusClostridium tetani Tuberculosis usually Mycobacterium tuberculosis Typhoid Fever Salmonella enterica enterica serovar Typhi 7/35

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Adapted from CDC: Achievements in Public Health, 1900-1999; July, 1999 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm 8/35

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CDC: Achievements in Public Health, 1900-1999; July, 1999 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm 9/35

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WHO, Antimicrobial Resistance Report, 2014 Our arsenal of antibiotics is not getting larger 10/35

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Boucher et al., IDSA Public Policy, 2013 Our arsenal of antibiotics is not getting larger 11/35

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Ling et al., Nature, 2015 though this might be changing 12/35 Teixobactin kills Staphylococcus aureus after 24 hr and doesnt develop resistance over 25 days

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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 13/35

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http://en.wikipedia.org/wiki/Natural_selection#mediaviewer/File:Antibiotic_resistance.svg 14/35

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CDC/JANICE CARR/DEEPAK MANDHALAPU, M.H.S. Superbugs MRSA: Methicillin-Resistant Staphylococcus aureus 15/35

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Elixhauser and Steiner, AHRQ Statistical Brief 35, 2007 16/35

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Office for National Statistics (UK), Aug. 2013; CDC, Active Bacterial Core Surveillance Report, 2012 though were improving in this regard as well 17/35 In the US, the CDC reports 30,800 fewer severe MRSA infections and 9000 fewer MRSA-related deaths in 2011 vs. 2005

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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 18/35

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McNulty et al., Journal of Antimicrobial Chemotherapy, 2007 n = 7120 There is still a lot of misinformation in the general public 19/35

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n = 7120 McNulty et al., Journal of Antimicrobial Chemotherapy, 2007 even among educated people. 20/35

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Mellon et al., Union of Concerned Scientists, 2001 22/35

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Gilbert, Nature, 2012; Cawood, North Queenland Register, Dec 31 2014 23/35 2011: EU voted to ban prophylactic use of antibiotics in agriculture 2012: FDA in US bans prophylactic use of 2 cephalosporin antibiotics in livestock; currently considering expanding ban Nevertheless, worldwide, 70-80% of all antibiotics produced are still used in livestock Steps are being taken to limit prophylactic use

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Larry Frolich, 2006; Gregorious Pilosus 2009 Horizontal Gene Transfer: harmless bacteria can share resistance genes with harmful bacteria 24/35

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The Fundamental Problem with Antibiotics: We use human ingenuity to engineer new or discover ancient, pre-existing antibiotic compounds. There compounds are static tools. Bacteria use the principles of environmental pressure and natural selection to develop resistance. This a dynamic process. Weve been winning the race for the last 70 years but how long can we keep up? 25/35

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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 26/35

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http://www.mansfield.ohio-state.edu/~sabedon/beg_phage_images.htm Bacteriophages (phages): Viruses that specifically target and attack bacteria 27/35

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http://commons.wikimedia.org/wiki/File:Phage.jpg 28/35

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10 6 bacteria / ml seawater 10 8 phages / ml seawater 70% of all marine bacteria may be infected by phages Nicholas Mann, PLOS Biology, 2005 29/35

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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 Behltnis. Woodcut Sch. IV, 1-178 Harvard Art Museums/Fogg Museum, Gift of Philip Hofer, M3719 30/35

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Abedon et al., Bacteriophage, 2011; Fruciano and Bourne, Can J Infect Dis Med Microbiol, 2006 Flix d'Herelle 1873-1949 1911: dHerelle successfully stops locust infestation in Argentina using a strain of Cocobacillus George Eliava 1892-1937 1934: Joseph Stalin invites dHerelle to establish Eliava Institute for phage research with George Eliava in Tbilisi, Georgia 1917: dHerelle 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) 1991: Georgian Civil War leaves Institute in ruins 1997: Exposure by the BBC spurs international support for Institute 31/35

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Abedon et al., Bacteriophage, 2011 StudyYearAimEtiologic Agent(s)Patients Success (% w/ cleared bacteria) Sakandelidze and Meipariani 1974 Peritonitis, osteomyelitis, lung abscesses, postsurgical wound infections Staphylococcus, Streptococcus and Proteus 23692% Meladze et al.1982Lung/pleural infectionsStaphylococcus 223 phages; 117 ABs 82% w/ phages; 64% w/ ABs Slopek et al.1987 Gastrointestinal tract, skin, head and neck infections Staphylococcus, Pseudomonas, E. coli, Klebsiella and Salmonella 55092% Kochetkova et al.1989 Postoperative wound infections Staphylococcus and Pseudomonas 65 phages; 66 ABs 82% w/ phages, 61% w/ ABs Sakandelidze1991Infectious allergoses Staphylococcus, Streptococcus, E. coli, Proteus, enterococci and P. aeruginosa 360 phages; 404 ABs; 576 phage+ABs 86%, 48%, 83%, respectively Perepanova et al.1995 Acute and chronic aurogenital inflammation E. coli, Proteus and Staphylococcus 4692% Markoishvili2002Ulcers and wounds E. coli, Proteus, Pseudomonas, Staphylococcus 9670% 32/35

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AntibioticsPhage Therapy Kill broad spectrum of bacteria (including beneficial gut flora) Specifically targets infectious bacterial strain Broad spectrum activity allows for trivial widespread use Most successful phage treatments must be bred specifically for each patient Potential for allergic response Only minor side effects seen; no immune response reported Dose-dependent Self-multiplying and self- limiting Static; if bacteria develop resistance, new antibiotic must be developed Dynamic; can evolve in parallel with bacteria to thwart resistance 33/35

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listex.eu 34/35

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Harald Brussow, Virology, 2012 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 phase I clinical trial (Intralytix) in the US was successful in 2009. Others are currently underway. Minimum investment for a broad-spectrum cocktail similar to a new antibiotic: $10-50 million USD (8.542 million EUR). Commercial phage cocktails need to be sequenced, screened and tested. Phage therapies will likely need to be customized for an individual patients needs. 35/35

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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 Brssow, 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 Chem Technol Biotechnol 76, 2001, 689-699 Fruciano, DE and Bourne, S. Phage as an antimicrobial agent: dHerelles 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