Antibiotics- PAST-PRESENT AND THE FUTURE

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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 : 

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 : 

The search for antibiotics begins

Bacterial genetic resistance to antibiotics begins to neutralise the beneficial effects. : 

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 : 

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

THE PRESENT : 

THE PRESENT

Antibiotic resistance is rising : 

Antibiotic resistance is rising 80 70 60 50 40 30 20 10 0 1990 1995 2000 2003 Percent of Resistant Strain MRSA QRPSE MRSPN/VRE PRSPN MRSA = methicillin resistant Staphylococcus aureus VRE = vancomycin resistant enterococci MRSPN = macrolide resistant Streptococcus pneumoniae PRSPN = penicillin resistant Streptococcus pneumoniae QRPSE = quinolone resistant Pseudomonas aeruginosa

The number of new antibiotics which reach the market is falling : 

The number of new antibiotics which reach the market is falling

Life-or-death Crisis: The Bacteria are winning : 

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? : 

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 : 

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)

THE FUTURE : 

THE FUTURE

International response to the global spread of antimicrobial resistance : 

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 : 

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)

Methods of generation of new antibiotics : 

Methods of generation of new antibiotics

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 : 

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 Antibiotic Die Multiplying Non-Multiplying Survive Multiplying Clinical Disease

Staphylococcus aureus – stationary phase : 

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) Log CFU/ml Augmentin Levofloxacin Azithromycin Linezolid HT31 HT42 Staphylococcus aureus – stationary phase

Methicillin resistant S. 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) Log CFU/ml Vancomycin HT31 HT42 Methicillin resistant S. aureus – stationary phase

New antimicrobial agents which kill non-multiplying bacteria : 

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 : 

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 : 

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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