THE FUTURE FACE OF INFECTION: Antibiotic Resistance and Phage Therapy Eliot Morrison
description
Transcript of THE FUTURE FACE OF INFECTION: Antibiotic Resistance and Phage Therapy Eliot Morrison
THE FUTURE FACE OF INFECTION:
Antibiotic Resistance and Phage Therapy
Eliot MorrisonFuture Tensing
17.07.14
Karen Kamenetzky, 2008 1/33
2/33
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.
5/33
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
7/33
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
8/33
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
10/33
Boucher et al., IDSA Public Policy, 2013
Our arsenal of antibiotics is not getting larger
11/33
“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
12/33
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
14/33
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
16/33
McNulty et al., Journal of Antimicrobial Chemotherapy, 2007
n = 7120
There is still a lot of misinformation in the general public…
17/33
n = 7120McNulty et al., Journal of Antimicrobial Chemotherapy, 2007
…even among educated people.
18/33
19/33
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
21/33
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
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
23/33
http://www.mansfield.ohio-state.edu/~sabedon/beg_phage_images.htm
Bacteriophages (“phages”):Viruses that specifically target bacteria
24/33
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
27/33
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
28/33
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%
29/33
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
30/33
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
32/33
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