1. Medicine. Past, Present and Future. ANTIBIOTICS
Professor Anthony Coates
Medical Microbiology
Department of Cellular and Molecular Medicine,
St George’s, University of London.

2. Microbes kill each other with antibiotics
They have developed self-defence mechanisms:
1. Non-multiplying state
2. Biofilm
3. Genetic resistance

3. The search for antibiotics begins

4. 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.

5. Antibiotic development 1929-72
The Antibiotic Paradox, Stuart Levy, New York, Plenum Press, 1992, 4

6. THE PRESENT

7. Antibiotic resistance is rising
MRSA = methicillin resistant Staphylococcus aureus
VRE = vancomycin resistant enterococci
MRSPN = macrolide resistant Streptococcus pneumoniae
PRSPN = penicillin resistant Streptococcus pneumoniae
QRPSE = quinolone resistant Pseudomonas aeruginosa 80 70 60
MRSA 50
Percent of 40
Resistant
QRPSE
Strain 30
MRSPN/VRE 20
PRSPN 10
1990
1995
2000
2003

8. The number of new antibiotics which reach the market is falling

9. Life-or-death Crisis: The Bacteria are winning
Emergence of resistance is outpacing the introduction of new antibiotics (2003 Daptomycin; 2004 none; Tygacil )
No new agents in clinical development against multi-drug resistant gram-negatives eg Pseudomonas aeruginosa, Acinetobacter spp

10. 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)

11. 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,

12. THE FUTURE

13. 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

14. 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,
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
Bristol-Myers Squibb/ Grunenthal (Kyorin)
Acute otitis media (paediatric)
Discontinued
Linezolid
Oxazolidinone
Gram-positive
RTIs SSTIs VRE Bloodstream infections
Pharmacia
Telithromycin
Ketolide
Gram-positive, Respiratory tract infection pathogens
oral
community-acquired RTIs
Aventis
Ertapenem
Carbapenem
Broad-spectrum (excluding non-fermenters)
CAP, intra-abdominal infection, acute gynae infections USA + Europe. cSSTI, cUTI USA
Merck & Co
Moxifloxacin
RTIs,
Marketed;
Bayer
cSSTIs
Approved in EU & USA
intra-abdominal infections
Filed
Gemifloxacin
AECB; mild-moderate CAP
Oral Marketed; iv late-pre-clinical USA
Oscient(LG Chemical)
5-day treatment of CAP; acute bacterial sinusitis
Phase III complete USA; filing expected by end 2005
Pre-reg EU
Co-marketing partner not yet announced
Daptomycin
lipopeptide
Iv (oral development discontinued)
Marketed USA, filed EU
Cubist USA; Chiron Europe and ROW (Lilly)
Bacteraemia/ endocarditis
Pre-reg USA
Tigecycline (GAR 936)
Glycylcycline
Gram-positive, Gram-negative and anaerobes
cSSTI, HAP, CAP, intra-abdominal infections, cUTI, VRE,
Marketed USA; filed EU
Wyeth
Dalbavancin
Glycopeptide
Iv; once-weekly
cSSTI,
Filed USA
Vicuron
Ceftobiprole
Cephalosporin
Gram-positive (including MRSA) + Gram-negative
cSSTI, HAP, catheter-related bacteraemia (and probably CA P)
Phase III; FDA fast tracked for HAP/VAP
Basilea Pharmaceutica/J&J (Roche)
Telavancin
Gram-positive (including MRSA)
cSSTI and HAP
Phase III; FDA fast tracked
Theravance
Doripenem (S-4661)
Broad -spectrum, including resistant Gram-negatives
cUTI. cIAI, HAP/VAP
J&J (Shionogi)
Garenoxacin
Des F(6) quinolone
community-acquired RTIs SSTIs UTIs; intra-abdominal infection
Phase III
Schering Plough (Toyama)
AR-100
Diaminopyrimidine
Gram-positive (including MRSA), Respiratory tract infection pathogens IV
MRSA, RTIs, SSTIs
IV Phase III; oral Phase I
Arpida Ltd (Roche)
Ramoplanin
Glycolipo-depsipeptide
Oral non-absorbed
Prevention of VRE bacteraemia in neutropenic patients
Oscient (Vicuron)
C. difficile-associated diarrhoea
Phase II/III
RO (R1558/CS-023)
Gram-positive including MRSA and Gram-negative including P. aeruginosa
CAP; nosocomial bacterial infections
CAP Phase II
Roche (Sankyo)
CX-0903 (PPI-0903/TAK-599)
(Resistant) Gram-positive + Gram-negative
cSSTI, HAP, CAP
Phase I completed; Phase II cSSTI planned Q2 2005
Cerexa (Peninsula/Takeda)
DX-619
Gram-positive and Gram-negative (excluding P. aeruginosa)
life- threatening infections caused by MDR Gram+
Iv Phase I
Oral pre-clinical
Daiichi
WCK 771
cSSTI
Phase I
Wockhardt
GSK
Pleuromutilin (new class)
susceptible and resistant Gram positive & Gram negative RTI pathogens; and –multi-resistant MRSA (inc. VRSA)
RTIs
GlaxoSmithKline
LBM415
Deformylase inhibitor
Gram-positive and Respiratory tract pathogens
iv and oral
Phase I (but to be replaced by new molecule due Phase I Q4 2005)
Novartis (Vicuron)
AZD2563
AstraZeneca
Faropenem
penem
Oral
RTIs SSTIs
Oritavancin
cSSTI, HAP bloodstream infections
InterMune (Lilly)
ABT-773
ketolide
Abbott
BB 83698
Gram-positive Respiratory tract infection pathogens
British Biotech
ROW = rest of world; CAP = community-acquired pneumonia; cSSTI = complicated skin and skin structure infections; VAP = ventilator-associated pneumonia
Ref: Personal Communication Halls GA, medical marketing services, 34 Ledborough Lane, Beaconsfield, Bucks HP9 2DD, UK;

15. Methods of generation of new antibiotics

16. A new approach: develop antibiotics which kill non-multiplying bacteria Survive very high concentrations of antibiotics Source of continuing infection May be responsible for emergence of genetic resistance
Multiplying
Non-Multiplying
Antibiotic
Die
Survive
Multiplying
Clinical Disease

17. Staphylococcus aureus – stationary phase9 8 7 6 5
Log CFU/ml 4
Augmentin
Levofloxacin 3
Azithromycin 2
Linezolid
HT31 1
HT42 5 10 15 20 25 30 35 40 45 50
Concentrations of Drugs (ug/ml)

18. Methicillin resistant S. aureus – stationary phase8 7 6 5
Log CFU/ml 4 3 2
Vancomycin
HT31 1
HT42 10 20 30 40 50 60 70 80
Concentrations of Drugs (ug/ml)

19. 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

20. 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

21. 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.