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Medicine. Past, Present and Future.
ANTIBIOTICS
Professor Anthony Coates
Medical Microbiology
Department of Cellular and Molecular Medicine,
St George’s, University of London.
Microbes kill each other with antibiotics
They have developed self-defence mechanisms:
1. Non-multiplying state
2. Biofilm
3. Genetic resistance
The search for antibiotics begins
Bacterial genetic resistance to antibiotics begins to neutralise
the beneficial effects. 1945, in an interview with The New York Times, Fleming
warned that the misuse of penicillin could lead to selection of resistant forms of bacteria
The solution: Make new antibiotics to replace the old ones to which resistance has emerged.
Antibiotic development 1929-72
• The Antibiotic Paradox, Stuart Levy, New York, Plenum Press, 1992, 4
THE PRESENT
Antibiotic resistance is rising80
70
60
50
40
30
20
10
0
1990 1995 2000 2003
PercentofResistantStrain
MRSA
QRPSE
MRSPN/VRE
PRSPN
MRSA = methicillin resistant Staphylococcus aureusVRE = vancomycin resistant enterococciMRSPN = macrolide resistant Streptococcus pneumoniaePRSPN = penicillin resistant Streptococcus pneumoniaeQRPSE = quinolone resistant Pseudomonas aeruginosa
The number of new antibiotics which reach the market is falling
16
10
6
0
1980s 1990s 2000s
Number ofantibioticsapproved byFDA (total per4 years)
Life-or-death Crisis: The Bacteria are winning
• Emergence of resistance is outpacing the introduction of new antibiotics (2003 Daptomycin; 2004 none; 2005 Tygacil )
• No new agents in clinical development against multi-drug resistant gram-negatives eg Pseudomonas aeruginosa, Acinetobacter spp
Why has the pharmaceutical industry reduced its production of new
antibiotics? • Resistance emerges too quickly and reduces the
effective life of an antibiotic
• Too little profit
• Big Biology has failed to produce new antibiotics
• Increased costs due to more regulation eg EC
• Litigation fears
• Government restrictions on use (Keep in reserve)
Antibiotic use in today’s world
RANKWorld Wide
Molecule Brand Name ATC Class Main Diseases Treated IV / ORAL
No. Prescriptions April 2004 to March 2005) Rx'000s
AMOXICILLIN Amoxil J1C BROAD SPECTR.PENICILLINS J06, J02, H66, J03 Oral / IV 192,821
AMOX / CLAVULANIC ACID AugmentinJ1D CEPHALOSPORINS & COMBSJ1L CARBENICILLIN+SIMIL.TYPE
J03, H66, J06 Oral / IV 136,300
CIPROFLOXACIN CiproxinJ1G FLUORO-QUINOLONESJ1C BROAD SPECTR.PENICILLINS
N39, N30, A09 Oral / IV 80,217
CLARITHROMYCIN Klacid J1F MACROLIDES & SIMILR TYPE J20, J06, J40 Oral / IV 74,689
AZITHROMYCIN Zithromax J1F MACROLIDES & SIMILR TYPE J06, J02, J40 Oral / IV 66,061
TRIMETHOPRIM Bactrim / Septrin
J1E TRIMETHOPRIM COMBSJ1M RIFAMPICIN AND RIFAMYCINJ1G FLUORO-QUINOLONESJ1F MACROLIDES & SIMILR TYPE
N39, A09, N30 Oral / IV 62,353
SULFAMETHOXAZOLE Bactrim / SeptrinJ1E TRIMETHOPRIM COMBSJ1G FLUORO-QUINOLONESJ1F MACROLIDES & SIMILR TYPE
N39, A09, N30 Oral / IV 55,762
CEFALEXIN Keflex / Ceporex J1D CEPHALOSPORINS & COMBS L02, J06, Z09 Oral / IV 54,509 LEVOFLOXACIN Levaquin J1G FLUORO-QUINOLONES N39,, J18, N30 Oral / IV 41,484 CEFACLOR Ceclor J1D CEPHALOSPORINS & COMBS J03, J20, J06 Oral 37,939
DOXYCYCLINE VibramycineJ1A TETRACYCLINES & COMBSJ1F MACROLIDES & SIMILR TYPE
L70, J40, N73 Oral / IV 36,608
CEFUROXIME AXETIL Zinnat J1D CEPHALOSPORINS & COMBS J06, J20, H66 Oral 26,741
ERYTHROMYCIN ErythrocinJ1F MACROLIDES & SIMILR TYPEJ1E TRIMETHOPRIM COMBS
J06, J20, J02 Oral / IV 25,321
CEFADROXIL Oracefal J1D CEPHALOSPORINS & COMBS J06, J02, J03 Oral / IV 23,660 OFLOXACIN Tarivid J1G FLUORO-QUINOLONES N39, N30, A09 Oral / IV 23,121
CEFRADINE VelosefJ1D CEPHALOSPORINS & COMBSJ1G FLUORO-QUINOLONES
J03, J20, R50 Oral / IV 22,003
CEFDINIR Cefzon / Omnicef J1D CEPHALOSPORINS & COMBS J06, J20, H66 Oral 21,646
NORFLOXACIN NoroxinJ1G FLUORO-QUINOLONES J1C BROAD SPECTR.PENICILLINS
N39, N30, A09 Oral 21,273
CEFCAPENE PIVOXIL Flomox J1D CEPHALOSPORINS & COMBS J06, J20, J02 Oral 20,115
PENICILLIN G BenzetacilJ1H MED/NARROW SPECT PENICILJ1K AMINOGLYCOSIDES
J03, J02, J06 Oral / IV 19,775
AMPICILLIN AmpicloxJ1C BROAD SPECTR.PENICILLINSJ1A TETRACYCLINES & COMBSJ1K AMINOGLYCOSIDES
J02, J06, J03 Oral / IV 19,177
ROXITHROMYCIN Rulid J1F MACROLIDES & SIMILR TYPE J20, J06, J40 Oral 18,974 CEFIXIME Suprax J1D CEPHALOSPORINS & COMBS J06, J20, H66 Oral 18,377
PENICILLIN V OspenJ1H MED/NARROW SPECT PENICIILJ1C BROAD SPECTR.PENICILLINS
J03, J02, J06 Oral / IV 17,200
CEFTRIAXONE Rocephin J1D CEPHALOSPORINS & COMBS J18, J20, Z09 IV 15,522 LINCOMYCIN Linocin J1F MACROLIDES & SIMILR TYPE J03, J20, J06 Oral / IV 14,514 CEFPODOXIME PROXETIL Orelox J1D CEPHALOSPORINS & COMBS H66, J02, J20 Oral 13,930
GENTAMICIN GaramycinJ1K AMINOGLYCOSIDESJ1E TRIMETHOPRIM COMBS
N39, N76, A09 Oral / IV 13,076
MOXIFLOXACIN Avelox J1G FLUORO-QUINOLONES J40, J20, J32 Oral / IV 12,707 SULTAMICILLIN Unasyn J1C BROAD SPECTR.PENICILLINS J06, J03, J02 Oral / IV 11,896 CLINDAMYCIN Dalacin C J1F MACROLIDES & SIMILR TYPE L02, J03, J06 Oral / IV 10,787 CEFPROZIL Cefzil J1D CEPHALOSPORINS & COMBS H66, J06, J03 Oral 10,769 TELITHROMYCIN Ketek J1F MACROLIDES & SIMILR TYPE J20, J40, J32 Oral 10,405
• Amoxil and Augmentin 25% of all presciptions• More than $1 billion sales per year for Augmentin,
Klacid, Zithromax and Levaquin. (IMS Health, IMS Midas, www.imshealth.com/globalinsights)
THE FUTURE
International response to the global spread of antimicrobial
resistance
Improve standards of antimicrobial prescribing and so prolong the life of existing antimicrobials
Vaccines
Prevention by improved infection control
Limited impact so far
Production of new antibiotics• GlaxoSmithKline has two in development• Johnson and Johnson active• Pfizer active• Novartis have entered antibiotic R&D (Personal Communication, Halls GA, medical marketing services, [email protected])
Product Class Spectrum Iv/oral Indications
Phase Company (Licensor)
Quinupristin/dalfopristin
streptogramin Gram-positive (excluding E. faecalis)
Iv VRE, cSSTIs, bloodstream infections
Marketed King Pharmaceuticals (Sanofi-aventis)
Gatifloxacin Fluoroquinolone
Broad-spectrum Iv and oral community-acquired RTIs SSTIs UTIs
Marketed Bristol-Myers Squibb/ Grunenthal (Kyorin)
Iv and oral Acute otitis media (paediatric)
Discontinued
Methods of generation of new antibiotics
Target
LiveMultiplyingBacteria
LiveNon-MultiplyingBacteria
Molecule
Methods
Libraries of natural or derivatives of natural compounds from fungi, bacteria, plants etc.
Libraries of synthetic compounds
-
Chemical synthesis
Combinatorial chemistry
Recombinant DNA technology
Genomics
Combinations e.g. Amoxycillin + Clavulanicacid
A new approach: develop antibiotics which kill non-multiplying bacteria
Survive very high concentrations of antibioticsSource of continuing infection
May be responsible for emergence of genetic resistance
Antibiotic
Die
Multiplying Non-Multiplying
Survive
Multiplying
Clinical Disease
0
1
2
3
4
5
6
7
8
9
0 5 10 15 20 25 30 35 40 45 50
Concentrations of Drugs (ug/ml)
Lo
g C
FU
/ml
AugmentinLevofloxacin AzithromycinLinezolidHT31HT42
Staphylococcus aureus – stationary phase
0
1
2
3
4
5
6
7
8
0 10 20 30 40 50 60 70 80
Concentrations of Drugs (ug/ml)
Lo
g C
FU
/ml
VancomycinHT31HT42
Methicillin resistant S. aureus – stationary phase
New antimicrobial agents which kill non-multiplying bacteria
• Potential
Use in combination with anti-multiplying compounds
Will shorten the duration of chemotherapy
May reduce the emergence of resistance
Conclusions• Past
Antibiotics have revolutionised medicine and have saved millions of lives
• Present
Increasing bacterial resistance and falling antibiotic production is reducing the efficacy of antibiotics
• Future
A continuous supply of new antibiotics is needed, with activity against non-multiplying bacteria
Acknowledgements
Yanmin HuClive Page*
Anthony Coates
St George’s, University of London;*Sackler Institute, Kings College, London.
MRC Cooperative Grant(5 year), Burton Programme Grant (5 year),
European Commission (3 year),Helperby Therapeutics plc.
