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Drugs, super-bugs and…

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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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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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Out of hospitals… MDR

Mycobacterium tuberculosis

Lung destruction

Bloody cough

Spine/bone deformity

Meningitis

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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

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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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Superbugs: not so super

Rifampin-resistant mutants of TB from lab are less fit

Gagneux, Science 2006

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Superbugs: overcoming the handicap

Rifampin-resistant mutants from patients are not less fit

Gagneux, Science 2006

The spread of "superbugs"

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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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#1 Lipitor lowers

cholesterol$11 billion

#2 NexiumHeartburn

Fastest sales growth

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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