THE FUTURE FACE OF INFECTION:

Antibiotic Resistance and Phage Therapy

Eliot MorrisonFuture Tensing

17.07.14

Karen Kamenetzky, 2008 1/33

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

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 G4/33

http://en.wikipedia.org/wiki/List_of_antibiotics

Inhibit bacterial protein biosynthesisClass Examples Common Use Introduce

d

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

Macrolides Erythromycin

Streptococcal infections, syphilis,

respiratory infections, Lyme

disease

1952

Oxazolidinones Linezolid VRSA 1956

Tetracyclines Doxycycline, Tetracycline

Syphilis, chlamydial infections, Lyme

disease1948

Inhibit bacterial cell wall synthesisClass Examples Common Use Introduced

Carbapenems Meropenem Broad-spectrum antibacterial 1976

Cephalosporins Cefalexin Gram-positive infections 1948

Glycopeptides VancomycinGram-positive

infections, including MRSA; oral treatment

of C. difficile1955

PenicillinsAmoxicillin, Methicillin, Penicillin G

Broad spectrum; used for streptococcal

infections, sypthilis and Lyme disease

1942 (mass production)

Polypeptides Bacitracin Eye, ear or bladder infections 1945

Disrupt bacterial membrane potentialClass Examples Common Use Introduced

Lipopeptides Daptomycin Gram-positive infections 1987

Inhibit bacterial DNA replicationClass Examples Common Use Introduced

Quinolones CiprofloxacinUrinary tract

infections, pneumonia, gonorrhea

1962

Inhibit bacterial synthesis of folateClass Examples Common Use Introduce

d

Sulfonamides Sulfa drugs Urinary tract/eye infections 1932

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 6/33

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

ViralDisease Agent

AIDS HIVChickenpox Varicella zoster virus

Common cold usually rhinoviruses and coronavirusesDengue fever Dengue viruses DEN-1-4

Ebola EbolavirusHepatitis A-E Hepatitis viruses

Herpes simplex Herpes simplex virus 1 and 2Influenza Orthomyxoviridae familyMeasles Measles virus

MERS Middle East respiratory syndrome coronavirus

Mumps Mumps virusPoliomyelitis Poliovirus

Rabies Rabies virusSARS SARS coronavirus

Smallpox Variola major/minorWest Nile Fever West Nile virus

Yellow fever Yellow fever virus

EukaryoticDisease AgentMalaria Plasmodium genus

HookwormAncylostoma

duodenale / Necator americanus

Scabies Sarcoptes scabiei

PrionicDisease Agent

Bovine spongiform encephalopathy

(mad cow disease) prion

Creutzfeldt-Jakob prion

Kuru prion

BacterialDisease AgentAnthrax Bacillus anthracis

Bacterial pneumonia multiple

Botulism Botulinum toxin from Clostridium botulinum

Bubonic plague Enterobacteriaceae familyChlamydia Chlamydia trachomatis

Cholera Vibrio choleraeDiphtheria Corynebacterium diphtheriaeGonorrhea Neisseria gonorrhoeae

Leprosy Mycobacterium lepraeListeriosis Listeria monocytogenes

Lyme disease Borrelia burgdorferiPertussis (Whooping

cough) Bordetella pertussis

Salmonellosis Salmonella genus

Scarlet fever Erythrogenic toxin from Streptococcus pyogenes

Shigellosis (Bacillary dysentery) Shigella genus

Syphilis Treponema pallidumTetanus Clostridium tetani

Tuberculosis usually Mycobacterium tuberculosis

Typhoid Fever Salmonella enterica enterica serovar Typhi

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

Pneumonia

Tuberculosis

Diarrhea and Enteritis

Heart Disease

Stroke

Liver Disease

Injuries

Cancer

Senility

Diphtheria

0 5 10 15 20 25 30 35

1900

Percentage

Heart Disease

Cancer

Stroke

Chronic Lung Disease

Unintentional Injury

Pneumonia and Influenza

Diabetes

Suicide

Chronic Liver Disease

HIV Infection

0 5 10 15 20 25 30 35

1997

Percentage

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

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 13/33

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 15/33

“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…

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n = 7120McNulty et al., Journal of Antimicrobial Chemotherapy, 2007

…even among educated people.

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

Larry Frolich, 2006; Gregorious Pilosus 2009

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

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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?

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So, naturalists observe, a fleaHas 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

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

Bacteriophages (“phages”):Viruses that specifically target bacteria

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

106 bacteria / ml seawater108 phages / ml seawater

Nicholas Mann, PLOS Biology, 2005 26/33

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'Herelle1873-1949

1911: d’Herelle successfully stops locust infestation in Argentina using a strain of Cocobacillus

George Eliava1892-1937

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 ruins

1997: Exposure by the BBC spurs international support for Institute

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Abedon et al., Bacteriophage, 2011

Study Year Aim Etiologic Agent(s) Patients Success (% 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 ABs

82% w/ phages; 64% w/ ABs

Slopek et al. 1987 Gastrointestinal tract, skin, head and neck infections

Staphylococcus, Pseudomonas, E. coli,

Klebsiella and Salmonella550 92%

Kochetkova et al. 1989 Postoperative wound infections

Staphylococcus and Pseudomonas

65 phages; 66 ABs

82% w/ phages, 61% w/ ABs

Sakandelidze 1991 Infectious allergosesStaphylococcus,

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 46 92%

Markoishvili 2002 Ulcers and woundsE. coli, Proteus, Pseudomonas, Staphylococcus

96 70%

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Antibiotics Phage TherapyKill 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 31/33

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 niche

Early 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 20th/21st centuries?

time 33/33

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