The first rule of antibiotics is try not to use them and the second rule is try not to use too many of them brPaul Marino The ICU Book 2007 ID: 776711
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THE FUTURE FACE OF INFECTION:
Antibiotic Resistance and Phage Therapy
Eliot MorrisonFuture Tensing17.07.14
Karen Kamenetzky, 2008
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Slide22
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Slide3Chiras 2007; Pearson Prentice Hall,2005; Sholto Ainslie 2014
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Slide4What 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
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Slide5http://en.wikipedia.org/wiki/List_of_antibiotics
Inhibit bacterial protein
biosynthesisClassExamples
Common Use
Introduced
Aminoglycosides
Kanamycin, Streptomycin
Gram-negative bacterial infections (e.g.
E. coli, P. aeruginosa
)
1943
Lincosamides
Clindamycin
Staph-, pneumo- and streptococcal infections in penicillin-allergic patients
1961
MacrolidesErythromycinStreptococcal infections, syphilis, respiratory infections, Lyme disease1952OxazolidinonesLinezolidVRSA1956TetracyclinesDoxycycline, TetracyclineSyphilis, chlamydial infections, Lyme disease1948
Inhibit bacterial cell wall synthesisClassExamplesCommon UseIntroducedCarbapenemsMeropenemBroad-spectrum antibacterial1976CephalosporinsCefalexinGram-positive infections1948GlycopeptidesVancomycinGram-positive infections, including MRSA; oral treatment of C. difficile1955PenicillinsAmoxicillin, Methicillin, Penicillin GBroad spectrum; used for streptococcal infections, sypthilis and Lyme disease1942 (mass production)PolypeptidesBacitracinEye, ear or bladder infections 1945
Disrupt bacterial membrane potentialClassExamplesCommon UseIntroducedLipopeptidesDaptomycinGram-positive infections1987
Inhibit bacterial DNA replicationClassExamplesCommon UseIntroducedQuinolonesCiprofloxacinUrinary tract infections, pneumonia, gonorrhea1962
Inhibit bacterial synthesis of folateClassExamplesCommon UseIntroducedSulfonamidesSulfa drugsUrinary tract/eye infections1932
Bacteria have certain unique biochemical mechanisms that can be targets for antibiotics.
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Slide6http://en.wikipedia.org/wiki/Natural_selection#mediaviewer/File:Antibiotic_resistance.svg
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Slide7http://en.wikipedia.org/wiki/List_of_infectious_diseases
Viral
DiseaseAgentAIDS
HIV
Chickenpox
Varicella zoster virus
Common cold
usually rhinoviruses and coronaviruses
Dengue fever
Dengue viruses DEN-1-4
Ebola
Ebolavirus
Hepatitis A-E
Hepatitis
viruses
Herpes simplexHerpes simplex virus 1 and 2InfluenzaOrthomyxoviridae familyMeaslesMeasles virusMERSMiddle East respiratory syndrome coronavirusMumpsMumps virusPoliomyelitisPoliovirus
RabiesRabies virusSARSSARS coronavirusSmallpoxVariola major/minorWest Nile FeverWest Nile virusYellow feverYellow fever virusEukaryoticDiseaseAgentMalariaPlasmodium genusHookwormAncylostoma duodenale / Necator americanusScabiesSarcoptes scabieiPrionicDiseaseAgentBovine spongiform encephalopathy (mad cow disease) prion
Creutzfeldt-JakobprionKuruprionBacterialDiseaseAgentAnthraxBacillus anthracis
Bacterial pneumoniamultipleBotulismBotulinum toxin from Clostridium botulinumBubonic plagueEnterobacteriaceae familyChlamydiaChlamydia trachomatisCholeraVibrio cholerae
DiphtheriaCorynebacterium diphtheriaeGonorrheaNeisseria gonorrhoeaeLeprosyMycobacterium lepraeListeriosisListeria monocytogenesLyme diseaseBorrelia burgdorferiPertussis (Whooping cough)
Bordetella pertussis
Salmonellosis
Salmonella genus
Scarlet fever
Erythrogenic toxin from
Streptococcus pyogenes
Shigellosis (Bacillary dysentery)
Shigella genus
Syphilis
Treponema pallidumTetanusClostridium tetaniTuberculosisusually Mycobacterium tuberculosisTyphoid FeverSalmonella enterica enterica serovar Typhi
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Slide8Adapted from CDC
: Achievements in Public Health, 1900-1999; July, 1999
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm 8
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Slide9CDC: Achievements in Public Health, 1900-1999; July, 1999
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm
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Slide10WHO, Antimicrobial Resistance Report, 2014
Our arsenal of antibiotics is not getting larger
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Slide11Boucher et al., IDSA Public Policy, 2013
Our arsenal of antibiotics is not getting larger
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Slide12“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
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Slide13http://en.wikipedia.org/wiki/Natural_selection#mediaviewer/File:Antibiotic_resistance.svg
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Slide14CDC/JANICE CARR/DEEPAK MANDHALAPU, M.H.S.
“Superbugs”
MRSA:Methicillin-Resistant Staphylococcus Aureus
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Slide15Elixhauser and Steiner, AHRQ Statistical Brief 35, 2007
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Slide16“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
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Slide17McNulty et al., Journal of Antimicrobial Chemotherapy, 2007
n = 7120
There is still a lot of misinformation in the general public… 17/33
Slide18n = 7120
McNulty et al., Journal of Antimicrobial Chemotherapy, 2007
…even among educated people.18/33
Slide1919/33
Slide20Mellon et al., Union of Concerned Scientists, 2001
20
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Slide21Larry Frolich
, 2006; Gregorious Pilosus 2009
Horizontal Gene Transfer: harmless bacteria can “share” resistance genes with harmful bacteria21/33
Slide22The 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
Slide23So, 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
Slide24http://www.mansfield.ohio-state.edu/~sabedon/beg_phage_images.htm
Bacteriophages (“phages”):
Viruses that specifically target bacteria24/33
Slide25http://commons.wikimedia.org/wiki/File:Phage.jpg
25
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Slide2610
6
bacteria / ml seawater108 phages / ml seawaterNicholas Mann, PLOS Biology, 2005
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Slide27Anonymous Germany (Augsburg)
1476Naaman
, a leper who dipped himself 7 times in the River Jordan and became clean2 Kings 5Illustrations from Spiegel Menschlicher Behältnis. WoodcutSch. IV, 1-178Harvard Art Museums/Fogg Museum, Gift of Philip Hofer, M3719
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Slide28Abedon et al., Bacteriophage,
2011; Fruciano and Bourne, Can J Infect Dis Med Microbiol, 2006
Félix d'Herelle1873-19491911:
d’Herelle successfully stops locust infestation in Argentina using a strain of Cocobacillus
George Eliava
1892-1937
1934:
Joseph
Stalin invites d’Herelle to establish Eliava Institute for phage research with George Eliava in Tbilisi,
Georgia
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)1991: Georgian Civil War leaves Institute in ruins1997: Exposure by the BBC spurs international support for Institute28/33
Slide29Abedon et al., Bacteriophage, 2011
Study
YearAimEtiologic Agent(s)
PatientsSuccess (% w/
cleared bacteria)
Sakandelidze and Meipariani
1974
Peritonitis, osteomyelitis, lung abscesses, postsurgical wound infections
Staphylococcus, Streptococcus and Proteus
236
92%
Meladze et al.
1982
Lung/pleural infections
Staphylococcus
223 phages; 117 ABs82% w/ phages; 64% w/ ABsSlopek et al.1987Gastrointestinal tract, skin, head and neck infectionsStaphylococcus, Pseudomonas, E. coli, Klebsiella and Salmonella55092%Kochetkova et al.1989Postoperative wound infectionsStaphylococcus and Pseudomonas65 phages; 66 ABs
82% w/ phages, 61% w/ ABsSakandelidze1991Infectious allergosesStaphylococcus, Streptococcus, E. coli, Proteus, enterococci and P. aeruginosa360 phages; 404 ABs; 576 phage+ABs86%, 48%, 83%, respectivelyPerepanova et al.1995Acute and chronic aurogenital inflammationE. coli, Proteus and Staphylococcus4692%Markoishvili2002Ulcers and woundsE. coli, Proteus, Pseudomonas, Staphylococcus9670%29/33
Slide30Antibiotics
Phage 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
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Slide31listex.eu
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Slide32Harald 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 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
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Slide33Breakthrough
discovery
Rapid growth subsidized by accumulated, ancient resources and/or long-standing environmental nicheEarly warnings of unsustainability are outweighed by immediate benefits
Irresponsible use accelerates problems
Calls for moderation / alternatives
New discovery
???
…
The Progress Bubble:
The shape of the 20
th
/21st centuries?
time
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Slide34Further 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 Chem
Technol Biotechnol 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