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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.