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Medicine. Past, Present and Future. ANTIBIOTICS

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:

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Medicine. Past, Present and Future. ANTIBIOTICS

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  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 MRSA 60 50 Percent of 40 Resistant QRPSE Strain 30 MRSPN/VRE 20 PRSPN 10 0 2000 2003 1990 1995

  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; 2005 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, www.imshealth.com/globalinsights)

  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. 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 Linezolid Oxazolidinone Gram-positive Iv and oral RTIs SSTIs VRE Bloodstream infections Marketed Pharmacia Telithromycin Ketolide Gram-positive, Respiratory tract infection pathogens oral community-acquired RTIs Marketed Aventis Ertapenem Carbapenem Broad-spectrum (excluding non-fermenters) Iv CAP, intra-abdominal infection, acute gynae infections USA + Europe. cSSTI, cUTI USA Marketed Merck & Co Moxifloxacin Fluoroquinolone Broad-spectrum Iv and oral RTIs, Marketed; Bayer cSSTIs Approved in EU & USA intra-abdominal infections Filed Gemifloxacin Fluoroquinolone Broad-spectrum Iv and oral 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 community-acquired RTIs Pre-reg EU Co-marketing partner not yet announced Daptomycin lipopeptide Gram-positive Iv (oral development discontinued) cSSTIs 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 Iv cSSTI, HAP, CAP, intra-abdominal infections, cUTI, VRE, Marketed USA; filed EU Wyeth Dalbavancin Glycopeptide Gram-positive Iv; once-weekly cSSTI, Filed USA Vicuron Ceftobiprole Cephalosporin Gram-positive (including MRSA) + Gram-negative Iv cSSTI, HAP, catheter-related bacteraemia (and probably CA P) Phase III; FDA fast tracked for HAP/VAP Basilea Pharmaceutica/J&J (Roche) Telavancin Glycopeptide Gram-positive (including MRSA) Iv cSSTI and HAP Phase III; FDA fast tracked Theravance Doripenem (S-4661) Carbapenem Broad -spectrum, including resistant Gram-negatives Iv cUTI. cIAI, HAP/VAP Phase III; FDA fast tracked for HAP/VAP J&J (Shionogi) Garenoxacin Des F(6) quinolone Broad-spectrum Iv and oral 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 Gram-positive Oral non-absorbed Prevention of VRE bacteraemia in neutropenic patients Discontinued Oscient (Vicuron) C. difficile-associated diarrhoea Phase II/III RO4908463 (R1558/CS-023) Carbapenem Gram-positive including MRSA and Gram-negative including P. aeruginosa Iv CAP; nosocomial bacterial infections CAP Phase II Roche (Sankyo) CX-0903 (PPI-0903/TAK-599) Cephalosporin (Resistant) Gram-positive + Gram-negative Iv cSSTI, HAP, CAP Phase I completed; Phase II cSSTI planned Q2 2005 Cerexa (Peninsula/Takeda) DX-619 Des F(6) quinolone Gram-positive and Gram-negative (excluding P. aeruginosa) Iv and oral life- threatening infections caused by MDR Gram+ Iv Phase I Oral pre-clinical Daiichi WCK 771 Fluoroquinolone Gram-positive Iv and oral cSSTI Phase I Wockhardt GSK-565154 Pleuromutilin (new class) susceptible and resistant Gram positive & Gram negative RTI pathogens; and –multi-resistant MRSA (inc. VRSA) oral RTIs Phase I GlaxoSmithKline LBM415 Deformylase inhibitor Gram-positive and Respiratory tract pathogens iv and oral community-acquired RTIs Phase I (but to be replaced by new molecule due Phase I Q4 2005) Novartis (Vicuron) AZD2563 Oxazolidinone Gram-positive Iv and oral RTIs SSTIs VRE Bloodstream infections Discontinued AstraZeneca Faropenem penem Broad-spectrum Oral RTIs SSTIs Discontinued Bayer Oritavancin Glycopeptide Gram-positive Iv cSSTI, HAP bloodstream infections Discontinued InterMune (Lilly) ABT-773 ketolide Gram-positive, Respiratory tract infection pathogens Iv and oral community-acquired RTIs Discontinued Abbott BB 83698 Deformylase inhibitor Gram-positive Respiratory tract infection pathogens iv and oral community-acquired RTIs Discontinued British Biotech 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, ghalls@btconnect.com) 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; ghalls@btconnect.com

  15. Methods of generation of new antibiotics

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

  17. Staphylococcus aureus – stationary phase 9 8 7 6 5 Log CFU/ml 4 Augmentin Levofloxacin 3 Azithromycin Linezolid 2 HT31 1 HT42 0 0 5 10 15 20 25 30 35 40 45 50 Concentrations of Drugs (ug/ml)

  18. Methicillin resistant S. aureus – stationary phase 8 7 6 5 Log CFU/ml 4 3 2 Vancomycin HT31 1 HT42 0 0 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.

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