Antibiotic use: making the best of what we have. · Ampicillin. Piperacillin ... Augmented ....

Welcome to this SIRN symposium

Antibiotic use: making the bestof what we have.

SIRN series of symposia

MRSA workshop: John Coia, Jacqui Rielly

Antibiotic use : Ysobel Gourlay, Jeff Edwards, Lesley Frew

C. difficile : Ian Poxton

Pneumococci: Tim Mitchell

Patient’s journey: missing data Fiona Skinner

Others …………………..

‘We are in a situation where infections associated with antibiotic-use and the continued emergence of strains resistant to antibiotics are not being countered by the introduction of novel therapies.

This requires debate and action.’

Programme for today

Three lectures:

The Scottish Antimicrobial Prescribing Group (SAPG) : A National Clinical Forum for Antimicrobial Stewardship

Prof Dilip Nathwani

Guess or get it right –

antimicrobial prescribing in the 21st century?

Dr Bob Masterton

Why its difficult to identify new antibacterial agents

Dr Jeff Edwards

Composite discussion led by Dr Alistair Leanord

Jeff Edwards MSc, PhD

Most of my career in big Pharma

ICI, Zeneca, AstraZeneca

Discovery scientist

Development scientist: cefotetan, ZD0870, meropenem

AstraZeneca Infection Therapy Area Team

strategy, clinical microbiology, in-licensing

Member of ECCMID and ICAAC Programme Committees

Multidrug-resistant Gram-negative infections

What is the unmet medical need?

GEORGE M. ELIOPOULOS, MD; Boston, MA.

What is currently being used?

LOUIS B. RICE, MD; Cleveland, OH.

What's in the pipeline

GEORGE TALBOT, MD; St. Davids, PA.

Why it's difficult to identify new antibacterial agents

JEFFREY R. EDWARDS, PhD; United Kingdom.

Should we rely on government intervention to encourage new solutions?

DAVID SHLAES, MD; Stonington, CT.


GEORGE ELIOPOULOS

spoke of LIN-R S. aureus


LOU RICE

‘Coming to your hospital soon –an untreatable infection’


GEORGE TALBOT

Produced an exhauistive list of on-going clinical studies showing that there was nothing new


DAVE SHLAES

Did not think Government intervention was the way forward

One company used to be 41 !

FDA threatened Bayer: provide cheap CIPRO to be stockpiled re Anthrax or watch your patents!

Why its difficult to identify new antibacterial agents

Jeff Edwards

[email protected]

Why its difficult to find

new antibacterial agents

Why its difficult to find


‘find’: discover by chance

Why its difficult to identify


‘identify’: establish or select by consideration or analysis of the circumstances

John Bell Karen BushGraham Boulnoir Rudolph ThenPaul Newell Richard WhiteBarry MasonBob Nolan Phil Turner George Drusano

Bob Moellering

Phil Edwards Mike DudleyMike Gravestock Ron PalkMark Macielag

David LivermoreFred Tenover

Jason Oliver Al Sheldon

It is not my intention to speak only about the research process but wish to share with you some thoughts, some of which, I hope will be outside your current thinking.

You will, undoubtedly, know some of what I will say, but perhaps you didn’t realise you did!

Also, you may not agree with some of my comments and will wish to discuss. That’s just fine as I come from an environment where any time I spoke from the podium, I expected hearty challenge.

I’ll try to cover ……………….

Evolution of established antibiotic classes and their future

Reduction in choice

Comments on some recent contenders

The Pharmaceutical industry today and the increased power of the Commercial function

Making discovery-life difficult, making mistakes

How about genomics?

Discovering needed agents will be a challenge

Nympholepsy

I’ll try to cover ……………….

Evolution of established antibiotic classes and their future potential

Reduction in choice

Comments on some recent contenders

The Pharmaceutical industry today and the increased power of the Commercial function

Making life difficult, making mistakes

How about genomics?

Discovering needed agents will be a challenge

Nympholepsy: the frenzied pursuit of the unattainable

Also,

You will note that I will continuously make USA-related considerations

- FDA- Hospital Formulary

I do this because without the expectation of registration in the USA, the development of a new anti-bacterial will

NOT BE FINANCIALLY VIABLE.

Penicillin

Penicillin

Nalidixic acid

ErythromycinMethicillin

Vancomycin

Ampicillin

NovobiocinCarbenicillin

Lincomycin

Ticarcillin

Fusidic acid Cephalothin

Rifampacin

Cephaloradine BacitracinGentamicin + PolymyxinTetracyclinesChloramphenicol +NitrofuratoinMetronidazoleSulphanomidesTrimethoprim

β-lactams:

PenicillinMethicillinAmpicillinPiperacillin

Augmented penicillins

Cephalosporins- ceftriaxone - ceftazidime

Carbapenems-imipenem/cil-meropenem

β-lactams:

Quinolones:

Penicillin

Nalidixic acidMethicillinAmpicillin

Norfloxacin

PiperacillinCiprofloxacin

Augmented penicillins

How many other ‘floxacins ?

Cephalosporins -

ceftriaxone

- ceftazidime

Carbapenems- imipenem/cil-

meropenem

β-lactams:

Quinolones:

Others:

Penicillin

Nalidixic acid

MacrolidesMethicillin

Glycopeptides

Ampicillin Norfloxacin Lincomycin+ Piperacillin Aminoglycosides

Ciprofloxacin

PolymyxinTetracyclines

Augmented How many other Nitrofurans

penicillins ‘floxacins ?

MetronidazoleTrimethoprim

Cephalosporins - ceftriaxone - ceftazidime

Carbapenems

Linezolid-

imipenem/cil

Quin+Dalf

- meropenem Daptomycin

Are you really surprised that I defend myself by ‘resisting’ the agents you try to kill me with ?????

All bacterial infections

?

All strains contain 1 or more resistances

Untreatable

Super-R

MR++

MR+

MR

R

Untreatable

Super-R

MR++

MR+

MR

R

?

All strains contain 1 or more resistances

We have progressed through

• a new era of life-saving antibiotics• the discovery of many new series• the exploitation of these series• an era when almost all infections could be treatedwith more than one class of antibiotic.

We are now in a phase when

• many of the best classes have been exhausted or are near to exhaustion

• some older classes have been revisited• new classes are extremely uncommon• a tiny proportion of infections are untreatable• economics do not favour antibacterials and researchis contracting.

β-lactams:

Advances or possibilities

Penicillins

None

Augmented Inhibitors of chromosomal enzymes penicillins

Cephalosporins anti-MRSA activity

Carbapenems

anti-MRSA activity(ertapenem)

Inhibitors of metallo-enzymes and -

(doripenem)

efflux

Current advances are limited to Gm+ve activity and the possibility of inhibitors, particularly, double inhibitors, is a challenge.

Quinolones:

How many others and what can they deliver?

Thus far, attempts to improve properties has had two broad effects

• miscellaneous toxicities

• improved anti Gm+ve potency

Circumventing R mechanisms in Gm-ves

has not been achieved.

Others classes/types

Macrolides/ketolides

Limited advanceGlycopeptides

Exhausted

Daptomycin (lipogly…)

? Quin+dalf

More

Tetracyclines

? advance (tigecycline) Oxazolidinones

? who knows

Trimethoprim

? advance (iclaprim)

Aminoglycosides

NoneNitroimidazoles

None

Lincomycin+

NonePolymyxin NoneChloramphenicol

None

Nitrofurans

None

Cationic peptides

? safety, manufacture FAB (fatty acid biosynthesis)

Whatever the class, most of the recent advances have been directed against Gm+ves.

Most have come from known-series and even if we didn’t realize it, finding anti-Gm-ve

activity,

particularly against non-fermentors, always has been a challenge.

Natural product

Syntheticsorigin

β-lactams

QuinolonesMacrolides

Metronidazole

Aminoglycosides

Oxazolidinone(s)Glyco/lipopeptides

Nitrofurans

Polymyxin TrimethoprimChloramphenicolTetracyclinesQuin+DalfLincomycin+Fusidic acid

Gram +ve

Gram -ve

Physicochemical properties required for Gram+ve and Gram-ve activity are different

ICAAC 2008 symposium

New molecules from ‘old’

classes: Is there still room for improvement?

Quinolones, oxazolidinones, tetracyclines, β-lactams

All speakers are well known academics or from established Pharma companies.

Going forward ……..

We speak about the ‘Pharmaceutical Industry’

but

• this is a composite of independent Companies, each oneserving it’s own share-holders

• as far as I know, there is no integrated approach towards finding defined anti-bacterial agents

• I would not presume to be definitive about any positionin any one Company, we will no doubt agree that infectionresearch in the Pharmaceutical Industry has reduced

• I suggest to you that there are few, if any, of the remainingCompanies, in which effort has not been focused in a mannerwhich is to the detriment of novel research

• The importance of financial return has led to a dominance of the Commercial function in decision-making processes, evenat early stages.

Some realities ……………

• we have many excellent agents

• many of today’s best agents have been used for >10 years

• any new agent must make an acceptable financial return

• the need for speed

• Regulatory requirements must be achievable

• hospital-formulary acceptance is a must for any new agent

• Proposed projects typically are assessed using

Target Product Profiles.

How is financial viability assessed?

What is a financially viable spectrum of antibacterial activity ?

How is financial viability assessed?

Net present value (NPV)

How much profit would be made in today’s-money

Peak-year sales

>US$ 0.5 bn

What is a financially viable spectrum of anti-bacterial activity ?

Aerobes

Anaerobes

Gram+ve

Gram-ve

Staph/strep

Enterococci

Enterobacteriaceae Non-fermenters

++ ++ + ++ + + + + + + + +

World market for anti-infectives is ~$US 37 billion (2002-3)

• anti-bacterials is ~$ 24 bn

• hospital anti-bacterials is $ 8.5 bn

• serious hospital anti-bacterials is $ 2.5 bn

• respiratory is $ 0.7 - 1 bn.

Target Product Profiles (TPPs)

• Used widely across therapeutic areas

• Compiled by scientific/medical/commercial colleagues

• Define the properties required of a new molecule to make it economically viable (worth developing)

Typically very, very challenging targets.

TPP

RTP

Broad spectrum antibacterial agent for hospital use

Registered indication: Parenteral therapy for empiric use in for moderate/severe nosocomial infections.

Customer group: Hospital specialists, ID physicians in general medical/surgical or critical care units, oncologists, haematologists and internists

Promotional claims:

Novel chemical classClinical efficacy against all Gram+ Gram-

aerobic and anaerobic pathogens Improved efficacy over contemporary therapiesPharmacodynamic properties leading to pathogen eradication Active against strains resistant to contemporary therapies Intravenous formulations given bdCompatible with other drugs and fluids given to patient groupWell tolerated

Distinguishing Attributes:

Does not cause CDADOnce daily dosing




Promotional claims:


aerobic and anaerobic pathogensImproved efficacy over contemporary therapiesPharmacodynamic properties leading to pathogen eradication Active against strains resistant to contemporary therapies Intravenous formulations given bdCompatible with other drugs and fluids given to patient groupWell tolerated






Promotional claims:


aerobic and anaerobic pathogens Improved efficacy over contemporary therapiesPharmacodynamic properties leading to pathogen eradicationActive against strains resistant to contemporary therapies Intravenous formulations given bdCompatible with other drugs and fluids given to patient groupWell tolerated






Promotional claims: A novel leanordacycline analogue Clinical efficacy against important

Gram+ Gram-

aerobic and anaerobic pathogens in indications approvedEfficacy comparable

with contemporary therapiesPharmacodynamic properties leading to pathogen eradication Active in vitro against strains resistant to contemporary therapies Intravenous formulations given bdCompatible with other drugs and fluids given to patient groupWell tolerated


Once daily dosing

Will this new analogue of an existing series be good enough to displace the current favoured analogue from formularies ???????

Laboratory activities towards a Research Target Profile


Novel chemical class Active against strains resistant to contemporary therapies

Activity against all Gram+ Gram-

aerobic and anaerobic pathogens

Pharmacodynamic properties leading to pathogen eradication Intravenous formulations given infrequently.

Laboratory activities towards a Research Target Profile


Novel chemical class (novel mode of action) Active against strains resistant to contemporary therapies

Activity against all Gram+ Gram-

aerobic and anaerobic pathogens (appropriate to the indication)

Pharmacodynamic properties leading to pathogen eradication Intravenous formulations given infrequently.

Properties required:

Activity against:

Staphylococci

Enterobacteriaceae

additional barrier

P. aeruginosa / Acinetobacter

additional barrier / mutation

potential for efflux

Super–potency to sustain activity against penetration-mutants

? Efflux inhibition

How to approach this one?

Screening for antibacterial activity

Whole-cell screening

Test a limited range of bacteriafor susceptibility to the action ofa compound collection.

Confirm hits and look for activityagainst a wider range of bacteria.

Progress chemistry.

Target-based screening

Run an HTS (? based on inhibitionof an enzyme function) using acompound collection.

Confirm hits and look for activityagainst bacteria.

Progress chemistry.

Hit-rates from two whole-cell screens

Number of % of hitscompoundstested

S. aureus E. coli

P. aeruginosa

~160,000

3.1

1.1

0

>350,000

? 1





Progress chemistry.




Progress chemistry.

Thus far, modern-day target-based screening has not delivered.

Why?

In my opinion, genomics was oversold and the science inadequately understood

• The expectations was that every target would lead to a new agent with a novel mechanism of action.

However ……………

• when an essential gene (potential target) is identified, many hurdles have to be overcome to allow a HTS to be run

• success from a HTS puts you at the ‘conventional’ starting point for LI and LO chemistry and biology

• as timeframes have been much longer than envisaged, this has not always been acceptable to senior management or Venture Capital providers.

Demonstration of

• essentiality

• possible identification of function

• selectivity

• spectrum

• ability to develop and assay for HTS format

• ability to produce protein or manipulate strainfor assay.

I made a scientific assessment (aka a guess), based on expected attrition rates, that it would take ~ 49 essential genes to have one progressed towards development.

I made a scientific assessment (aka a guess), based on expected attrition rates, that it would take ~ 49 essential gene to have one progressed towards development.

One other colleague was insistent it was 42

I have made a scientific assessment (aka a guess) that it would take ~ 49 essential gene to have one progressed towards the clinic.

One other colleague was insistent it was 42

This is perhaps she was called Jacqui Smith or had read The Hitchers Guide to the Galaxy!

In my opinion, genomics was oversold and the science inadequately understood

• The expectations was that every target would lead to a new agent with a novel mechanism of action.

However ……………

• when an essential gene (potential target) is identified, many hurdles have to be overcome to allow a HTS to be run

• success from a HTS puts you at the ‘conventional’ starting point for LI and LO chemistry and biology

• as timeframes have been much longer than envisaged, this has not always been acceptable to senior management or Venture Capital providers.





Progress chemistry.




Progress chemistry.

Compound libraries (or collections)Company libraries are basically a collection of all molecules made by the Chemists working in all therapeutic areas.

Those used in the good-old-bad-old days had a natural product component.

Over the years, optimised molecules in these collections have become bigger etc and do not represent good starting points for new chemistry.

Perhaps because of the potential difficulties of ‘rediscovery’

and time

in optimising activity, natural products have been less studied.

Therefore, we may question the suitability of such a compound-set even for whole-cell screening.

Hits found in an HTS require much more chemistry and thus start-

molecules should be small and of low lipophylicity to allow chemists the opportunity to design-in the required features.

Molecular weight

500

Lipo

phili

city

(cl

ogP

/ lo

gD)

5

Lipinski: rule of 5

ClogP <5M wt <500n of H bond donor <5n of H bond acceptor <10

Molecular weight

500

Lipo

phili

city

(cl

ogP/

logD

)

5

300

3

Thus, I suspect that we do not have sufficient collections rich in new, appropriately designed entries

and

natural products do not have adequate prominence.


The role of medicinal chemistry in antimicrobial drug discovery:

How can we improve our libraries?

Are natural products still a viable source?

Crystals, chemicals and creativity ………..

Finding a new compound to satisfy this TPP will be exceptionally difficult.

Do we need to find a compound (? exquisitely potent) with all the properties?

Do we first need to find an efflux inhibitor, if one with a sufficient efflux-spectrum can be found, and include it with all early MIC tests to ultimately form part of a combination therapy?

Big challenge …………………





How about a real big challenge and think about in vivo targets which go beyond the in vitro paradigms.


New approaches circumventing classical drug targets:

Virulence factors …………………

Targeting transposition as an anti-virulence approach …..

A novel anti-Gm+ve antibiotic class acting on a non-essential target.

Speakers from academia or biotech.

Concluding commentsWhy is it now difficult to identify the new antibacterial agents

that we really need?

Over the years we have had many new agents introduced which havetaken care of bugs-of-the day; many of these are additional molecules from know series. These series are mostly exhausted.

We have expended a disproportionate effort on these series.

Compound collections are often inappropriate. This is now appreciated

Compounds with a novel mode of action are as common as hens teeth.

Infection-discovery research is much reduced, too heavily controlled by commercial considerations and too heavily influenced by non-research staff.

TPPs are now seen to ‘aspirational’

as opposed to absolute requirements.

If all of that sounds depressing or defeatest, I personally still have great hopes for biochemically-

or target-based programmes. Smaller Biotechs are active in this area and may provide big pharma with franchise-sustainers.

If all else fails, adopt the John Travolta / Mr Micawber last-resort-algorithm:

Keep’em stayin’

alive whilst hoping something will turn up.

Discussion time

Category

Name

Strength

Weakness

Dosing

β-lactam

c’penem

Doripenemβ-lactam

c’penem

tomopenem

MRSA

long t halfRO-4908463

β-lactam

ceph

ceftobiprole

MRSA

Gm negβ-lactam

ceph

ceftaroline

MRSA

Gm negβ-lactam

penem

faropenem

P.aeruginasa

PO

glycopeptide

Oritavancin

MRSA VRE

liver tox

lipo

Dalbavancin

MRSA

VRElipo

Telavancin

MRSA wide

VRE

qolipo

Ramoplanin

C. diff

PO

Macrolide/ketalide

cethromycin

telith

issue

PO

Trimethoprim

Iclaprim

?TPR-R staph

QTc

Misc

OPT80 PAR101 C. diffDifimicin

Misc

Tolevamer

C. diff

toxin binder

PO

Topical

Pleuromutalin

FDA ??

Compound libraries (or collections)

Company libraries are basically a collection of all molecules made by the Chemists working in all therapeutic areas.

Those used in the good-old-bad-old days had a natural product component.

Over the years, optimised molecules in these collections have become bigger etc and these do not represent good starting points for new chemistry. Perhaps because of the potential difficulties and time in optimising activity, natural products have been less studied.

Therefore, we may question the suitability of such a compound-set even for whole-cell screening.

Hits found in an HTS will require much more chemistry and thus start-molecules should be small and of low lypophylicity

to

allow chemists the opportunity to design-in the required features

Thus, I suspect that we do not have sufficient collections rich in new, appropriately designed entries

and

natural products do not have adequate prominence.

What is a financially viable spectrum of anti-bacterial activity ?

Aerobes

Anaerobes

Gram+ve

Gram-ve

Staph/strep

Enterococci

Enterobacteriaceae Non-fermentors

++

++

++ ++ + ++ + + + + + + + +

Strains resistant to current agents are susceptible

Introducing ……………………………….

SIRNocycline (SUREKILL tm

)

The latest and most exciting analogue in the Leanordacycline series

Antibiotic use: making the best of what we have. · Ampicillin. Piperacillin ... Augmented ....

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