THE FUTURE FACE OF INFECTION: Antibiotic Resistance and Phage Therapy

Presentation on theme: "THE FUTURE FACE OF INFECTION: Antibiotic Resistance and Phage Therapy"— Presentation transcript:

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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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2

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Chiras 2007; Pearson Prentice Hall,2005; Sholto Ainslie 2014

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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

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

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http://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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Slide8

Adapted from CDC

: Achievements in Public Health, 1900-1999; July, 1999

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm 8

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Slide9

CDC: Achievements in Public Health, 1900-1999; July, 1999

http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm

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WHO, Antimicrobial Resistance Report, 2014

Our arsenal of antibiotics is not getting larger

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Boucher et al., IDSA Public Policy, 2013

Our arsenal of antibiotics is not getting larger

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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

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

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CDC/JANICE CARR/DEEPAK MANDHALAPU, M.H.S.

“Superbugs”

MRSA:Methicillin-Resistant Staphylococcus Aureus

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Elixhauser and Steiner, AHRQ Statistical Brief 35, 2007

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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

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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… 17/33

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n = 7120

McNulty et al., Journal of Antimicrobial Chemotherapy, 2007

…even among educated people.18/33

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Slide20

Mellon et al., Union of Concerned Scientists, 2001

20

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Larry Frolich

, 2006; Gregorious Pilosus 2009

Horizontal Gene Transfer: harmless bacteria can “share” resistance genes with harmful bacteria21/33

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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

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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 23/33

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http://www.mansfield.ohio-state.edu/~sabedon/beg_phage_images.htm

Bacteriophages (“phages”):

Viruses that specifically target bacteria24/33

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

25

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10

6

bacteria / ml seawater108 phages / ml seawaterNicholas Mann, PLOS Biology, 2005

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Slide27

Anonymous 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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Abedon 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

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Abedon 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

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Antibiotics

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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listex.eu

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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 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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Breakthrough

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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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 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