Drugs, super-bugs and…

1. CHRISTOPHER DYE Drugs, super-bugs and…

2. CHRISTOPHER DYE 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?

3. What is a superbug?

4. 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)

5. Not Ebola, Marburg, rabies, flu, HIV…

6. MRSA: Methicillin resistant Staphylococus aureus

8. 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 infections Of ≈ 20,000 deaths (1 in 5, > HIV/AIDS)

11. VRE: vancomycin resistant Enterococci Urine infections Heart infections Blood poisoning Wound infection

12. Clostridium difficile Diarrhoea Colitis Fever Abdominal cramp Abnormal heart rhythm

14. (M)DR Streptococcus pneumoniae Middle ear infection Sinusitis Bronchitis Pneumonia Meningitis

15. Out of hospitals… MDR Mycobacterium tuberculosis Lung destruction Bloody cough Spine/bone deformity Meningitis

17. MDR-TB among previously treated TB patients < 6% 6 – 20 % 20 – 40% > 40 % No estimate

19. Rapid death of TB XDR patients at Tugela Ferry: 52/53 died, half within 16 days Proportion surviving Days since sputum collected

21. The travels and travails of Andrew Speaker

22. What is an antibiotic?

23. "Antibiosis" Paul Vuillemin (1889) collaborator of Louis Pasteur … life could be used to destroy life….. Bacteriocides Bacteriostatics

24. "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 anthraxLister (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 streptomycinSkin bacteria: protect against pathogenic bacteria and fungi (ringworm)Beer yeast: long-used antibiotic effects

25. Penicillin: the first antibiotic Fleming Chain Florey 1928/41

26. "Hunting a beast through endless forests" (Kafka d. TB 1924) The search for a TB cure

27. Today's antibiotics CLASSSOME EXAMPLES AminoglycosidesStreptomycin AnsamycinsGeldanamycin CephalosporinsCefadroxil GlycopeptidesVancomycin MacrolidesErythromycin PenicillinsPenicillin PolypeptidesBacitracin QuinolonesCiprofloxacin SulfonamidesMafenide TetracyclinesTetracycline OthersChloramphenicol, Isoniazid Metronidazole, Pyrazinamide

28. 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

29. 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

30. Why do bugs turn into (drug resistant) super bugs?

31. "The genetic lending library of evil…" Mutation Conjugation Transduction Transformation

33. Down in the pathospere resistance profiling of soil bacteria D'Costa et al 2006

34. Resistance: complex genetics but a simple selection process

35. Superbugs: not so super Rifampin-resistant mutants of TB from lab are less fit Gagneux, Science 2006

36. Superbugs: overcoming the handicap Rifampin-resistant mutants from patients are not less fit Gagneux, Science 2006

38. Evolution in action: promoting resistance with sub-therapeutic doses • Self-medication • Patients forget to take medication, interrupt treatment, cannot afford full course • Belief in new medications over old • Preferred injections of broad-spectrum drugs • Physicians pressured to prescribe antimicrobials • Pharmaceuticals marketed directly to public • Antibiotics poorly formulated, counterfeit, expired • Hospitals with highly susceptible patients, intensive antimicrobial use, cross-infection • Failure of simple infection controls e.g. handwashing • Veterinary prophylaxis or growth promotion, Salmonella and Campylobacter through food to humans

39. 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!”

40. 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

41. Superbugs: the clean-up

42. "Record numbers of Britons are flying abroad for medical treatment to escape…the rising threat of hospital superbugs...."

43. "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"

44. Superbugs in captivity (hospitals) Handwashing Limiting invasive devices Environmental cleaning Judicious antibiotic use Surveillance --------- hospital

45. 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

46. New antibiotics:hard science or hard sell?

47. Only 2 new classes of antibacterials since 1970s Decade introduced Class of antibacterial 1930s sulphonamides 1940s penicillins, aminoglycosides 1950s chloramphenicol,tetracyclines macrolides, glycopeptides 1960s streptogramins, quinolones lincosamides 1970s trimethoprim 1980s 1990s 2000s oxazolidinones, lipopeptides Other licensed drugs since 1970s in same classes

49. 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

50. 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