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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 selfdefence 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 rising
80
70
MRSA = methicillin resistant Staphylococcus aureus
VRE = vancomycin resistant enterococci
MRSPN = macrolide resistant Streptococcus pneumoniae
PRSPN = penicillin resistant Streptococcus pneumoniae
QRPSE = quinolone resistant Pseudomonas aeruginosa
MRSA
60
Percent
of
Resistant
Strain
50
40
30
QRPSE
MRSPN/VRE
20
PRSPN
10
0
1990
1995
2000 2003
The number of new antibiotics
which reach the market is falling
16
Number of
antibiotics
approved by
FDA (total per
4 years)
10
6
0
1980s
1990s
2000s
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
• 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)
Brand Name
ATC Class
Main Diseases Treated
IV / ORAL
AMOXICILLIN
Amoxil
J1C BROAD SPECTR.PENICILLINS
J06, J02, H66, J03
Oral / IV
RANK
World Wide
No.
Prescriptions
April 2004 to
March 2005)
Rx'000s
192,821
AMOX / CLAVULANIC ACID
Augmentin
J1D CEPHALOSPORINS & COMBS
J1L CARBENICILLIN+SIMIL.TYPE
J03, H66, J06
Oral / IV
136,300
CIPROFLOXACIN
Ciproxin
J1G FLUORO-QUINOLONES
J1C 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
J1M
J1G
J1F
TRIMETHOPRIM COMBS
RIFAMPICIN AND RIFAMYCIN
FLUORO-QUINOLONES
MACROLIDES & SIMILR TYPE
N39, A09, N30
Oral / IV
62,353
SULFAMETHOXAZOLE
Bactrim / Septrin
J1E TRIMETHOPRIM COMBS
J1G FLUORO-QUINOLONES
J1F MACROLIDES & SIMILR TYPE
N39, A09, N30
Oral / IV
55,762
CEFALEXIN
LEVOFLOXACIN
Keflex / Ceporex
Levaquin
J1D CEPHALOSPORINS & COMBS
J1G FLUORO-QUINOLONES
L02, J06, Z09
N39,, J18, N30
Oral / IV
Oral / IV
54,509
41,484
Molecule
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/dalfopristi
n
streptogramin
Gram-positive
(excluding E.
faecalis)
Iv
VRE, cSSTIs,
bloodstream
infections
Marketed
King Pharmaceuticals
(Sanofi-aventis)
Gatifloxacin
Fluoroquinolone
Broad-spectrum
Iv and oral
communityacquired
RTIs SSTIs
UTIs
Marketed
Bristol-Myers Squibb/
Grunenthal (Kyorin)
Iv and oral
Acute otitis
media
Discontinued
Methods of generation of new
antibiotics
Target
Live
Multiplying
Bacteria
Methods
Libraries of natural or derivatives of natural
compounds from fungi, bacteria, plants etc.
Libraries of synthetic compounds
Chemical synthesis
Live
Non-Multiplying
Bacteria
Combinatorial chemistry
Recombinant DNA technology
Genomics
Combinations e.g. Amoxycillin + Clavulanic
acid
Molecule
A new approach: develop antibiotics which
kill non-multiplying bacteria
Non-Multiplying
Multiplying
Antibiotic
Die
Survive
Survive very high concentrations of antibiotics
Source of continuing infection
Multiplying
Clinical
Disease
May be responsible for emergence of genetic resistance
Staphylococcus aureus –
stationary phase
9
8
Log CFU/ml
7
6
5
4
Augmentin
Levofloxacin
Azithromycin
Linezolid
HT31
HT42
3
2
1
0
0
5
10
15
20
25
30
35
40
Concentrations of Drugs (ug/ml)
45
50
Methicillin resistant S. aureus –
stationary phase
8
7
Log CFU/ml
6
5
4
3
2
Vancomycin
HT31
HT42
1
0
0
10
20
30
40
50
60
Concentrations of Drugs (ug/ml)
70
80
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 nonmultiplying bacteria
Acknowledgements
Yanmin Hu
Clive 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.