CHRISTOPHER DYE
Drugs, super-bugs and…
Drugs, superbugs and…
What is an antibiotic?
Why do bugs turn into
superbugs?
Superbugs: the clean-up
New antibiotics: science or
economics?
CHRISTOPHER DYE
What is a superbug?
What is a
superbug?
Superbugs, Super at what?
Virulent, drug resistant, hospitals, rich countries
MRSA methicillin resistant Staphylococcus aureus
(UK 7000 cases falling)
GRE Glycopeptide resistant Enterococcus (mostly
vancomycin, 1000 cases rising)
Virulent, hospitals
Clostridium difficile (50,000 cases rising, slowing)
Virulent, drug resistant, community, poor
countries
Resistant Streptococcus pneumonia (100s rising?)
MDR tuberculosis (40 rising? Isoniazid in London)
Not Ebola, Marburg, rabies, flu, HIV…
MRSA: Methicillin resistant
Staphylococus aureus
More MRSA among elderly in UK,
especially men 2006-7
1200
1000
800
600
400
Female
Male
200
Age group (years)
+
80
-7
9
70
-6
9
60
-5
9
50
-4
9
40
-3
9
30
-2
9
20
10
-1
9
0
09
Number of reported
infections
1400
MRSA: coming out (of hospital)
United States 2005
(and soon UK?)
In hospital
In community (after health care)
In community (not after health care)
58%
27%
14%
Of ≈ 100,000 invasive MRSA infections
Of ≈ 20,000 deaths (1 in 5, > HIV/AIDS)
VRE: vancomycin resistant Enterococci
Urine
infections
Heart
infections
Blood
poisoning
Wound
infection
Clostridium difficile
Diarrhoea
Colitis
Fever
Abdominal
cramp
Abnormal
heart
rhythm
Trend in C difficile in UK
patients 65+ years
Number of voluntary reports
50000
40000
30000
20000
10000
0
2000
2001
2002
2003
2004
2005
2006
(M)DR Streptococcus pneumoniae
Middle ear
infection
Sinusitis
Bronchitis
Pneumonia
Meningitis
Out of hospitals… MDR
Mycobacterium tuberculosis
Lung
destruction
Bloody
cough
Spine/bone
deformity
Meningitis
Britain beat TB in the 19th and 20th centuries?
TB deaths England & Wales 1840-1991
300
C Bronte
1855
TB deaths/100,000/yr
250
200
150
Mansfield
1923
Keats
1821
E Bronte
1848
Orwell
1953
Leigh
1967
100
50
Lawrence
1930
0
1820 1840 1860 1880 1900 1920 1940 1960 1980 2000
MDR-TB among previously treated
TB patients
< 6%
6 – 20
%
20 – 40%
> 40 %
No estimate
Proportion surviving
Rapid death of TB XDR patients at Tugela Ferry:
52/53 died, half within 16 days
Days since sputum collected
The travels
and travails of
Andrew
Speaker
What is an
antibiotic?
"Antibiosis"
Paul Vuillemin
(1889)
collaborator of
Louis Pasteur
… life could be
used to destroy
life…..
Bacteriocides
Bacteriostatics
"Antibiosis" before Fleming
Roberts (1874): Penicillium did not become contaminated with
bacteria
Pasteur (1822-95) and Joubert (1834-1910): mould-contaminated
cultures stopped the growth of the anthrax
Lister (1871): urine contaminated with mould did not allow the growth
of bacteria
Duchesne (1897): substance that stopped bacterial growth, penicillin
mould
Acid (lactic) producing bacteria: to treat diphtheria, meningitis,
cystitis and open wounds
Fungus-like bacteria (Actinomycetes): dissolves cell walls of other
bacteria and fungi; used to treat TB and others; origin of
streptomycin
Skin bacteria: protect against pathogenic bacteria and fungi
(ringworm)
Beer yeast: long-used antibiotic effects
Penicillin: the first antibiotic
Fleming
Chain
Florey
1928/41
"Hunting a beast through endless
forests" (Kafka d. TB 1924)
The search for a TB cure
Today's antibiotics
CLASS
Aminoglycosides
Ansamycins
Cephalosporins
Glycopeptides
Macrolides
Penicillins
Polypeptides
Quinolones
Sulfonamides
Tetracyclines
Others
SOME EXAMPLES
Streptomycin
Geldanamycin
Cefadroxil
Vancomycin
Erythromycin
Penicillin
Bacitracin
Ciprofloxacin
Mafenide
Tetracycline
Chloramphenicol, Isoniazid
Metronidazole, Pyrazinamide
How antibiotics work…
and then don't work
Interfering with...
• Making DNA/RNA
rifampicin, chloroquine
• Making proteins
tetracycline, chloramphenicol
• Cell membranes
polyenes, polymyxin
• Enzymes
sulphamethoxazole
• Cell walls
penicillin, vancomycin
Total antibiotic dependency
• 80 million prescriptions
of antibiotics for human
use each year
• 12,500 tons each year
• 50% humans, 50%
animals
• 1 million tons consumed
by humans and animals
in past 50 years
Why do bugs
turn into
(drug resistant)
super bugs?
"The genetic lending library of evil…"
Mutation
Conjugation
Transduction
Transformation
Down in the
pathospere
resistance
profiling
of soil
bacteria
D'Costa et al 2006
Resistance: complex genetics
but a simple selection process
Superbugs: not so super
Rifampin-resistant mutants of TB from lab are less fit
Relative fitness of mutants
1.3
1.2
1.1
Equal fitness
1
0.9
0.8
0.7
0.6
0.5
1
2
3
4
5
6
Resistant mutants
Gagneux, Science 2006
7
8
9
Superbugs: overcoming the handicap
Rifampin-resistant mutants from patients are not less fit
Relative fitness of mutants
1.3
1.2
rpoB S531L m utation
other rpoB mutations
1.1
1
Equal fitness
0.9
0.8
0.7
0.6
0.5
1
2
3
4
5
6
7
Resistant mutants
Gagneux, Science 2006
8
9
10
The spread of "superbugs"
Proportion resistant
1
0.8
Uninfected
0.6
Infected:
drug
sensitive
0.4
Infected:
drug
resistant
0.2
0
0
100
200
Months
300
400
Evolution in action:
promoting resistance with sub-therapeutic doses
1. Self-medication
2. Patients forget to take medication, interrupt treatment,
cannot afford full course
3. Belief in new medications over old
4. Preferred injections of broad-spectrum drugs
5. Physicians pressured to prescribe antimicrobials
6. Pharmaceuticals marketed directly to public
7. Antibiotics poorly formulated, counterfeit, expired
8. Hospitals with highly susceptible patients, intensive
antimicrobial use, cross-infection
9. Failure of simple infection controls e.g. handwashing
10. Veterinary prophylaxis or growth promotion,
Salmonella and Campylobacter through food to humans
The arms race in Wonderland:
at the court of the Red Queen
Red Queen to Alice:
“Now, here, you see, it
takes all the running
you can do, to keep
in the same place. If
you want to get
somewhere else,
you must run at least
twice as fast as
that!”
Loss of resistance is slow
Quickly in, slowly out
Minimal fitness handicap
Plasmids contain several resistance genes
Resistant strains persist at low levels
Finland: restricted macrolide use
Erythromycin resistance in group A
streptococci in Finland cut from 20% to
10% in 2 years
Superbugs:
the clean-up
"Record numbers of Britons are flying
abroad for medical treatment to
escape…the rising threat of hospital
superbugs...."
"We shall fight them with bleaches…
whatever the cost may be"
"A ward at a
time, walls,
ceilings,
fittings and
ventilation
shafts"
"Every hospital will be disinfected and
scrubbed clean over the next year"
Superbugs in captivity (hospitals)
Handwashing
Limiting invasive devices
Environmental cleaning
Judicious antibiotic use
Surveillance
--------- hospital
Assuming superbugs are less fit…
In general
Combination therapy
In the community (>80% most respiratory)
Restrict antibiotics for: coughs, colds, sore
throats (unless strep), otitis media, sinusitis (or
< 3 days)
In hospital
Minimize presumptive treatment, discontinue
treatment asap, withhold key antibiotics
In animals
Minimize use sub-therapeutic dosing
New antibiotics:
hard science or
hard sell?
Only 2 new classes of antibacterials
since 1970s
Decade introduced Class of antibacterial
1930s
1940s
1950s
1960s
sulphonamides
penicillins, aminoglycosides
chloramphenicol,tetracyclines
macrolides, glycopeptides
streptogramins, quinolones
lincosamides
trimethoprim
1970s
1980s
1990s
2000s
oxazolidinones, lipopeptides
Other licensed drugs since 1970s in same classes
big pharma, bad karma?
THE 2006 BITTER PILL AWARDS:
While You Were Sleeping Award
Overmarketing insomnia medications
“Got Cholesterol?” Award
Overpromoting brand-name statins
Driven to Distraction Award
For hawking an Attention Deficit drug
Who will make new drugs?
Mostly Pharma but…
Escalating costs
Net present value
Strict license standards
Post-market surveillance
Resistance
Generics (short patents)
Narrow spectrum
Variable licensure
High purchase price
Low unmet need
Short treatment time
160
0.8
140
0.7
120
0.6
100
0.5
80
0.4
60
0.3
40
0.2
20
0.1
0
2007
0
2009
2011
2013
2015
2017
2019
Probability of one drug
Net cost at present value ($m)
New TB drugs: returns on investment
11 compounds, 73% chance by 2019
yp
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Billions of dollars
Best selling drugs are not antibiotics
40
30
20
10
0
#1 Lipitor
lowers
cholesterol
$11 billion
#2 Nexium
Heartburn
Fastest sales
growth
Hy
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rte
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pr
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Sc
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Ha
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As
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HR
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Drugs per billion dollar sales
Antibiotics are not "blockbusters"
0.4
0.3
0.2
0.1
0
From "market failure" to
market success
Legislation
Intellectual property (extended exclusivity)
Tax incentives for R&D
Guaranteed market
Regulation
Simplify regulation and clinical trials
Financing
Promote translational research and trials:
bench to bedside
Cash prizes (instead of patents)
Surveillance
Present and future drug needs
End of the antibiotic era?
1.
2.
3.
4.
Adjustable balance between
resistance and susceptibility…
Resistance genes are inevitable, but
their spread is preventable
Resistance is reversible, though
slowly
Economic and regulatory levers to
make and distribute new antibiotics
have growing political commitment
Other solutions: prevention, vaccines