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Drugs, super-bugs and…
C
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Drugs, superbugs and…
What is a superbug?
What is an antibiotic?
Why do bugs turn into superbugs?
Superbugs: the clean-up
New antibiotics: science or economics?
What is a superbug?
Superbugs, Super at what?
Virulent, drug resistant, hospitals, rich countriesMRSA methicillin resistant Staphylococcus aureus (UK 7000 cases falling)GRE Glycopeptide resistant Enterococcus (mostly vancomycin, 1000 cases rising)
Virulent, hospitalsClostridium difficile (50,000 cases rising, slowing)
Virulent, drug resistant, community, poor countriesResistant 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
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Age group (years)
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Male
MRSA: coming out (of hospital)
United States 2005(and soon UK?)
In hospital 58%In community (after health care) 27%In community (not after health care) 14%
Of ≈ 100,000 invasive MRSA infectionsOf ≈ 20,000 deaths (1 in 5, > HIV/AIDS)
VRE: vancomycin resistant Enterococci
Urine infections
Heart infections
Blood poisoning
Wound infection
Clostridium difficileDiarrhoea
Colitis
Fever
Abdominal cramp
Abnormal heart rhythm
Trend in C difficile in UKpatients 65+ years
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2000 2001 2002 2003 2004 2005 2006
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Middle ear infection
Sinusitis
Bronchitis
Pneumonia
Meningitis
(M)DR Streptococcus pneumoniae
Out of hospitals… MDR
Mycobacterium tuberculosis
Lung destruction
Bloody cough
Spine/bone deformity
Meningitis
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1820 1840 1860 1880 1900 1920 1940 1960 1980 2000
TB
dea
ths/
100,
000/
yrBritain beat TB in the 19th and 20th centuries?
TB deaths England & Wales 1840-1991
Keats1821
E Bronte1848
C Bronte1855
Mansfield1923
Lawrence1930
Orwell1953
Leigh1967
MDR-TB among previously treated
TB patients
No estimate
< 6%6 – 20
%20 – 40%> 40 %
Rapid death of TB XDR patients at Tugela Ferry: 52/53 died, half within 16 days
Days since sputum collected
Pro
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urv
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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 antibioticsCLASS SOME EXAMPLES
Aminoglycosides Streptomycin
Ansamycins Geldanamycin
Cephalosporins Cefadroxil
Glycopeptides Vancomycin
Macrolides Erythromycin
Penicillins Penicillin
Polypeptides Bacitracin
Quinolones Ciprofloxacin
Sulfonamides Mafenide
Tetracyclines Tetracycline
Others Chloramphenicol, Isoniazid
Metronidazole, Pyrazinamide
Interfering with... • Making DNA/RNA
rifampicin, chloroquine • Making proteins
tetracycline, chloramphenicol • Cell membranes
polyenes, polymyxin • Enzymes
sulphamethoxazole • Cell walls
penicillin, vancomycin
How antibiotics work… and then don't work
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 pathospereresistance profiling
of soil bacteria
D'Costa et al 2006
Resistance: complex genetics but a simple selection process
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Resistant mutants
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Equal fitness
Superbugs: not so super
Rifampin-resistant mutants of TB from lab are less fit
Gagneux, Science 2006
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Resistant mutants
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Equal fitness
rpoB S531L mutation other rpoB mutations
Superbugs: overcoming the handicap
Rifampin-resistant mutants from patients are not less fit
Gagneux, Science 2006
The spread of "superbugs"
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Infected:drugsensitive
Infected:drugresistant
Evolution in action: promoting resistance with sub-therapeutic doses
1. Self-medication2. Patients forget to take medication, interrupt treatment,
cannot afford full course3. Belief in new medications over old4. 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 outMinimal fitness handicapPlasmids contain several resistance genesResistant strains persist at low levels
Finland: restricted macrolide useErythromycin 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...."
"Every hospital will be disinfected and scrubbed clean over the next year"
"A ward at a time, walls, ceilings, fittings and ventilation shafts"
"We shall fight them with bleaches…
whatever the cost may be"
Superbugs in captivity (hospitals)
Handwashing
Limiting invasive devices
Environmental cleaning
Judicious antibiotic use
Surveillance
--------- hospital
Assuming superbugs are less fit…
In generalCombination 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 animalsMinimize use sub-therapeutic dosing
New antibiotics:hard science or
hard sell?
Decade introduced Class of antibacterial1930s sulphonamides1940s penicillins, aminoglycosides1950s chloramphenicol,tetracyclines
macrolides, glycopeptides1960s streptogramins, quinolones
lincosamides1970s trimethoprim1980s1990s2000s oxazolidinones, lipopeptidesOther licensed drugs since 1970s in same classes
Only 2 new classes of antibacterials since 1970s
big pharma, bad karma?
THE 2006 BITTER PILL AWARDS: While You Were Sleeping AwardOvermarketing insomnia medications “Got Cholesterol?” AwardOverpromoting brand-name statinsDriven to Distraction AwardFor hawking an Attention Deficit drug
Who will make new drugs?
Mostly Pharma but…Escalating costsNet present valueStrict license standardsPost-market surveillanceResistanceGenerics (short patents) Narrow spectrum Variable licensureHigh purchase priceLow unmet needShort treatment time
New TB drugs: returns on investment11 compounds, 73% chance by 2019
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Bill
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olla
rsBest selling drugs are not antibiotics
#1 Lipitor lowers
cholesterol$11 billion
#2 NexiumHeartburn
Fastest sales growth
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on
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Haemato
logy
Asthm
a
Lipid
lower
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Acid d
isord
ers
Throm
bosis
Antibio
tics
HR/ost
eo
Dru
gs
pe
r b
illio
n d
olla
r s
ale
sAntibiotics are not "blockbusters"
From "market failure" to market success
Legislation Intellectual property (extended exclusivity)Tax incentives for R&DGuaranteed marketRegulationSimplify regulation and clinical trialsFinancingPromote translational research and trials:
bench to bedsideCash prizes (instead of patents)SurveillancePresent and future drug needs
End of the antibiotic era?
Adjustable balance between resistance and susceptibility…
1. Resistance genes are inevitable, but their spread is preventable
2. Resistance is reversible, though slowly
3. Economic and regulatory levers to make and distribute new antibiotics have growing political commitment
4. Other solutions: prevention, vaccines