THE FUTURE FACE OF
INFECTION:
Antibiotic Resistance and Phage Therapy
Eliot Morrison
Pop Science Cafe
20.01.15
Karen Kamenetzky, 2008
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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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Bacteria have certain unique biochemical mechanisms that can
be targets for antibiotics – while eukaryotic cells are untouched.
Inhibit bacterial cell wall synthesis
Inhibit bacterial protein biosynthesis
Class
Examples
Aminoglycosides
Lincosamides
Macrolides
Kanamycin,
Streptomycin
Clindamycin
Erythromycin
Oxazolidinones
Linezolid
Tetracyclines
Doxycycline,
Tetracycline
Common Use
Gram-negative
bacterial infections
(e.g. E. coli, P.
aeruginosa)
Staph-, pneumoand streptococcal
infections in
penicillin-allergic
patients
Streptococcal
infections, syphilis,
respiratory
infections, Lyme
disease
VRSA
Syphilis, chlamydial
infections, Lyme
disease
Introduce
d
Class
Examples
Carbapenems
Meropenem
Cephalosporins
Cefalexin
1943
Sulfonamides
Examples
Common Use
Sulfa drugs
Urinary tract/eye
infections
http://en.wikipedia.org/wiki/List_of_antibiotics
Introduced
1976
1948
Glycopeptides
Vancomycin
Gram-positive
infections, including
MRSA; oral treatment
of C. difficile
Penicillins
Amoxicillin,
Methicillin,
Penicillin G
Broad spectrum; used
for streptococcal
1942 (mass
infections, sypthilis production)
and Lyme disease
Polypeptides
Bacitracin
1955
1961
1952
1956
1948
Introduce
d
Eye, ear or bladder
infections
1945
Disrupt bacterial membrane potential
Class
Examples
Lipopeptides
Daptomycin
Inhibit bacterial synthesis of folate
Class
Common Use
Broad-spectrum
antibacterial
Gram-positive
infections
Common Use
Gram-positive
infections
Introduced
1987
Inhibit bacterial DNA replication
Class
Examples
Quinolones
Ciprofloxacin
1932
Common Use
Urinary tract
infections,
pneumonia,
gonorrhea
Introduced
1962
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http://en.wikipedia.org/wiki/Natural_selection#mediaviewer/File:Antibiotic_resistance.svg
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Viral
Bacterial
Disease
Agent
Disease
Agent
Anthrax
Bacillus anthracis
Bacterial pneumonia
multiple
AIDS
Chickenpox
Common cold
Dengue fever
Ebola
Hepatitis A-E
Herpes simplex
Influenza
Measles
HIV
Varicella zoster virus
usually rhinoviruses and coronaviruses
Dengue viruses DEN-1-4
Ebolavirus
Hepatitis viruses
Herpes simplex virus 1 and 2
Orthomyxoviridae family
Measles virus
Middle East respiratory syndrome
coronavirus
Mumps virus
Poliovirus
Rabies virus
SARS coronavirus
Variola major/minor
West Nile virus
Yellow fever virus
Botulism
Bubonic plague
Chlamydia
Cholera
Diphtheria
Gonorrhea
Leprosy
Listeriosis
Lyme disease
Pertussis (Whooping
cough)
Salmonellosis
Scarlet fever
Shigellosis (Bacillary
dysentery)
Syphilis
Tetanus
Tuberculosis
Typhoid Fever
Botulinum toxin from
Clostridium botulinum
Enterobacteriaceae family
Chlamydia trachomatis
Vibrio cholerae*
Corynebacterium diphtheriae
Neisseria gonorrhoeae
Mycobacterium leprae
Listeria monocytogenes
Borrelia burgdorferi
Bordetella pertussis
Salmonella genus
Erythrogenic toxin from
Streptococcus pyogenes
Shigella genus
Treponema pallidum
Clostridium tetani
usually Mycobacterium
tuberculosis
Salmonella enterica enterica
serovar Typhi
http://en.wikipedia.org/wiki/List_of_infectious_diseases
MERS
Mumps
Poliomyelitis
Rabies
SARS
Smallpox
West Nile Fever
Yellow fever
Eukaryotic
Disease
Agent
Malaria
Plasmodium genus
Ancylostoma
Hookworm duodenale / Necator
americanus
Scabies
Sarcoptes scabiei
Prionic
Disease
Agent
Bovine spongiform
encephalopathy
(mad cow disease)
prion
Creutzfeldt-Jakob
prion
Kuru
prion
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1900
1997
Diphtheria
HIV Infection
Senility
Chronic Liver Disease
Cancer
Suicide
Injuries
Diabetes
Liver Disease
Pneumonia and Influenza
Stroke
Unintentional Injury
Heart Disease
Chronic Lung Disease
Diarrhea and Enteritis
Stroke
Tuberculosis
Cancer
Pneumonia
Heart Disease
0
5
10
15
20
25
30
35
Percentage
Adapted from CDC: Achievements in Public Health, 1900-1999; July, 1999
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm
0
5
10
15
20
25
30
35
Percentage
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CDC: Achievements in Public Health, 1900-1999; July, 1999
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4829a1.htm
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Our arsenal of antibiotics is not getting larger
WHO, Antimicrobial Resistance Report, 2014
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Our arsenal of antibiotics is not getting larger
Boucher et al., IDSA Public Policy, 2013
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…though this might be changing…
Teixobactin kills
Staphylococcus
aureus after 24 hr…
…and doesn’t
develop resistance
over 25 days
Ling et al., Nature, 2015
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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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“Superbugs”
MRSA:
Methicillin-Resistant
Staphylococcus aureus
CDC/JANICE CARR/DEEPAK MANDHALAPU, M.H.S.
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Elixhauser and Steiner, AHRQ Statistical Brief 35, 2007
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…though we’re improving in this regard as well…
In the US, the CDC reports 30,800 fewer severe MRSA infections and
9000 fewer MRSA-related deaths in 2011 vs. 2005
Office for National Statistics (UK), Aug. 2013; CDC, Active Bacterial Core Surveillance Report, 2012
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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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There is still a lot of misinformation in the general public…
n = 7120
McNulty et al., Journal of Antimicrobial Chemotherapy, 2007
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…even among educated people.
n = 7120
McNulty et al., Journal of Antimicrobial Chemotherapy, 2007
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Mellon et al., Union of Concerned Scientists, 2001
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Steps are being taken to limit prophylactic use…
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
Gilbert, Nature, 2012; Cawood, North Queenland Register, Dec 31 2014
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Horizontal Gene Transfer: harmless bacteria can “share”
resistance genes with harmful bacteria
Larry Frolich, 2006; Gregorious Pilosus 2009
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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.
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 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
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Bacteriophages (“phages”):
Viruses that specifically target and attack bacteria
http://www.mansfield.ohio-state.edu/~sabedon/beg_phage_images.htm
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http://commons.wikimedia.org/wiki/File:Phage.jpg
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106 bacteria / ml seawater
108 phages / ml seawater
70% of all marine bacteria may
be infected by phages
Nicholas Mann, PLOS Biology, 2005
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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 Behältnis.
Woodcut
Sch. IV, 1-178
Harvard Art Museums/Fogg Museum, Gift of Philip Hofer, M3719
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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
Abedon et al., Bacteriophage, 2011; Fruciano and Bourne, Can J Infect Dis Med Microbiol, 2006
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Study
Year
Aim
Etiologic Agent(s)
Peritonitis, osteomyelitis,
lung abscesses,
Staphylococcus,
postsurgical wound
Streptococcus and Proteus
infections
Patients
Success (% w/
cleared bacteria)
236
92%
Sakandelidze and
Meipariani
1974
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 Salmonella
550
92%
Kochetkova et al.
1989
Postoperative wound
infections
Staphylococcus and
Pseudomonas
65 phages; 66
ABs
82% w/ phages,
61% w/ ABs
360 phages;
404 ABs; 576
phage+ABs
86%, 48%, 83%,
respectively
Sakandelidze
1991
Infectious allergoses
Staphylococcus,
Streptococcus, E. coli,
Proteus, enterococci and
P. aeruginosa
Perepanova et al.
1995
Acute and chronic
aurogenital inflammation
E. coli, Proteus and
Staphylococcus
46
92%
Ulcers and wounds
E. coli, Proteus,
Pseudomonas,
Staphylococcus
96
70%
Markoishvili
2002
Abedon et al., Bacteriophage, 2011
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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 selflimiting
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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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 (€8.5–42
million EUR).
•Commercial phage cocktails need to be sequenced,
screened and tested.
•Phage therapies will likely need to be customized for an
individual patient’s needs.
Harald Brussow, Virology, 2012
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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
