Antibiotics- Past-present and the Future

8/3/2019 Antibiotics- Past-present and the Future

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Medicine. Past, Present and Future.

ANTIBIOTICS

Professor Anthony Coates

Medical Microbiology

Department of Cellular and Molecular Medicine,

St Georges, University of London.


2/21

Microbes kill each other with

antibiotics

They have developed self-

defence mechanisms:

1. Non-multiplying state2. Biofilm

3. Genetic resistance


3/21

The search for antibiotics begins


4/21

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 whichresistance has emerged.


5/21

Antibiotic development 1929-72

The Antibiotic Paradox, Stuart Levy, New York, Plenum Press, 1992, 4


6/21

THE PRESENT


7/21

Antibiotic resistance is rising8070

60

50

40

30

20

10

0

1990 1995 2000 2003

PercentofResistantStrain

MRSA

QRPSE

MRSPN/VRE

PRSPN

MRSA = methicillin resistant Staphylococcus aureusVRE = vancomycin resistant enterococciMRSPN = macrolide resistant StreptococcuspneumoniaePRSPN = penicillin resistant StreptococcuspneumoniaeQRPSE = quinolone resistant Pseudomonas aeruginosa


8/21

The number of new antibiotics

which reach the market is falling

16

10

6

0

1980s 1990s 2000s

Number ofantibioticsapproved byFDA (total per4 years)


9/21

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

egPseudomonas aeruginosa, Acinetobacterspp


10/21

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)


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Antibiotic use in todays world

RANK

World Wide

Molecule Brand Name ATC Class Main Diseases Treated IV / ORAL

No.

Prescriptions

April 2004 to

March 2005)

Rx'000s

AMOXICILLIN Amoxil J1C BROAD SPECTR.PENICILLINS J06, J02, H66, J03 Oral / IV 192,821

AMOX / CLAVULANIC ACID AugmentinJ1D CEPHALOSPORINS & COMBS

J1L CARBENICILLIN+SIMIL.TYPEJ03, H66, J06 Oral / IV 136,300

CIPROFLOXACIN CiproxinJ1G 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 TRIMETHOPRIM COMBS

J1M RIFAMPICIN AND RIFAMYCIN

J1G FLUORO-QUINOLONES

J1F 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 Keflex / Ceporex J1D CEPHALOSPORINS & COMBS L02, J06, Z09 Oral / IV 54,509

LEVOFLOXACIN Levaquin J1G FLUORO-QUINOLONES N39,, J18, N30 Oral / IV 41,484

CEFACLOR Ceclor J1D CEPHALOSPORINS & COMBS J03, J20, J06 Oral 37,939

J1A TETRACYCLINES & COMBS

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)


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THE FUTURE


13/21

International response to the

global spread of antimicrobial

resistance

Improve standards of antimicrobialprescribing and so prolong the life of

existing antimicrobials

Vaccines

Prevention by improved infection control

Limited impact so far


14/21

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/dalfopristin streptogramin Gram-positive(excluding E.faecalis)

Iv VRE, cSSTIs,bloodstreaminfections

Marketed King Pharmaceuticals(Sanofi-aventis)

Gatifloxacin Fluoroquinolone Broad-spectrum Iv and oral community-acquired

RTIs SSTIsUTIs

Marketed Bristol-Myers Squibb/Grunenthal (Kyorin)

Iv and oral Acute otitismedia

Discontinued


15/21

Methods of generation of new

antibiotics

Target

L iv e

Mult iplying

Bacteria

L iv e

Non-Mult iplyingBacteria

Molecule

M ethods

L ibraries of natural or derivat ives of natural

compounds from fungi, bacteria, plants etc.

L ibraries of synthetic compounds

-

Chem ical synthes is

Com binator ia l chem ist ryRecom binant DNA technology

Genomics

Com binat ions e.g. Am oxyci ll in + Clavulanic

acid


16/21

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

Antibiotic

Die

Multiplying Non-Multiplying

Survive

Multiplying

Clinical

Disease


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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)

LogCFU

/ml

Augmentin

Levofloxacin

Azithromycin

Linezolid

HT31

HT42

Staphylococcus aureus

stationary phase


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0

1

2

3

4

5

6

7

8

0 10 20 30 40 50 60 70 80

Concentrations of Drugs (ug/ml)

LogCFU/m

l

Vancomycin

HT31

HT42

Methicillin resistant S. aureus

stationary phase


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New antimicrobial agents which kill

non-multiplying bacteria

Potential

Use in combination with anti-multiplyingcompounds

Will shorten the duration of chemotherapy

May reduce the emergence of resistance


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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


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AcknowledgementsYanmin Hu

Clive Page*

Anthony Coates

St Georges, 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.

Antibiotics- Past-present and the Future

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