American College of physicians ACP high value care recommendations in rheumat...
ICN Victoria: Grolman on "Antibiotic Future: The Return of the Microbes"
1. THE RETURN OF THETHE RETURN OF THE
MICROBES!MICROBES!
DO ANTIBIOTICS HAVE ADO ANTIBIOTICS HAVE A
FUTURE?FUTURE?
David C GrolmanDavid C Grolman
Medical DirectorMedical Director
Head of Medical Affairs:Head of Medical Affairs:
Global Established PharmaGlobal Established Pharma
Pfizer Australia & Pfizer New ZealandPfizer Australia & Pfizer New Zealand
3. BACTERIABACTERIA
• Are almost all our friends!Are almost all our friends!
• Are themselves the best protection we haveAre themselves the best protection we have
against colonisation with pathogensagainst colonisation with pathogens
• Have survival mechanisms which pre-date usHave survival mechanisms which pre-date us
by billions of yearsby billions of years
• Outnumber our cells in & on our own bodiesOutnumber our cells in & on our own bodies
by at least 10-foldby at least 10-fold
• Outnumber us on the planet by a factor ofOutnumber us on the planet by a factor of
billionsbillions
5. Where have all the antibioticsWhere have all the antibiotics
gone?gone?
Why are there so few antibiotics underWhy are there so few antibiotics under
development by pharmaceuticaldevelopment by pharmaceutical
companies and other stakeholders?companies and other stakeholders?
Do we believe that we are going to ‘runDo we believe that we are going to ‘run
out’ of antibiotic options?out’ of antibiotic options?
What do we mean by ‘antibiotics’?What do we mean by ‘antibiotics’?
Antibacterials v AntimicrobialsAntibacterials v Antimicrobials
(Fungi, viruses, parasites)(Fungi, viruses, parasites)
7. ANTIBIOTICSANTIBIOTICS
WONDER DRUGS of the 20WONDER DRUGS of the 20thth
CENTURYCENTURY
Antimicrobial agents are the single classAntimicrobial agents are the single class
of drugs that have most contributed to theof drugs that have most contributed to the
major improvement in prolonged lifemajor improvement in prolonged life
expectancy achieved over the pastexpectancy achieved over the past
centurycentury
Numerous previously usually fatalNumerous previously usually fatal
infections became treatable –infections became treatable –
Pneumococcal pneumonia, consumption,Pneumococcal pneumonia, consumption,
scarlet fever, diphtheria, wound sepsis,scarlet fever, diphtheria, wound sepsis,
8. ANTIBIOTIC HISTORYANTIBIOTIC HISTORY
1920s = first antibiotics discovered1920s = first antibiotics discovered
1940s = first commercially available1940s = first commercially available
antibioticsantibiotics
RESISTANCE PREDATES THESERESISTANCE PREDATES THESE
EVENTSEVENTS
10. Gram-positive historyGram-positive history
Bacterial response Human response Bacterial response
New pathogens Broad spectrum penicillin Other new pathogens
β-lactamase production β-lactamase inhibitors New β-lactamases
Newer β-lactamases New ‘shaped’ penicillins Altered PBPs
Altered PBPs Glycopeptides Vancomycin-resistance
Vancomycin-resistance Lipopeptides Lipopeptide-resistance
Glycolipopeptide
resistance
Oxazolidinones Enzymatic lysis
11. Gram-negative historyGram-negative history
Bacterial response Human response Bacterial response
New pathogens Broad spectrum penicillin Other new pathogens
β-lactamase production β-lactamase inhibitors New β-lactamases
Newer β-lactamases Cephalosporins Extended spectrum B L
ESBLs Carbapenems New pathogens
ESBLs Carbapenems Carbapenem resistance
-Efflux
-Carbapenemases
Carbapenem resistance Colistin, tigecycline Enzymatic lysis, efflux
12. The ‘Ps’ of resistanceThe ‘Ps’ of resistance
PumpsPumps
PorinsPorins
Penicillin-binding protein (PBP) changePenicillin-binding protein (PBP) change
Proteases (penicillinases to penemases)Proteases (penicillinases to penemases)
Point mutations & target modificationsPoint mutations & target modifications
PRE-DETERMINEDPRE-DETERMINED
PLASMID-MEDIATEDPLASMID-MEDIATED
13. The bacterial armamentariumThe bacterial armamentarium
Resistance genesResistance genes
Virulence factorsVirulence factors
Why don’t all bacteria have all mechanisms?Why don’t all bacteria have all mechanisms?
These are all energy intensive!These are all energy intensive!
However: Resistance + virulence genesHowever: Resistance + virulence genes
have recently been seen in combinationhave recently been seen in combination
14. There will be new antibiotics inThere will be new antibiotics in
the futurethe future
There will be numerous new antimicrobialThere will be numerous new antimicrobial
agentsagents
New pathways and potential targets are beingNew pathways and potential targets are being
discovered dailydiscovered daily
GOAL IS TO FIND AGENTS WHICHGOAL IS TO FIND AGENTS WHICH
ARE:ARE:
SaferSafer
Have less environmental impactHave less environmental impact
Utilise novel pathwaysUtilise novel pathways
15. LpxC-1LpxC-1
Blocks the ability of specificallyBlocks the ability of specifically
Acinetobacter baumaniiAcinetobacter baumanii to activate theto activate the
TLR-4 and hence cause the systemicTLR-4 and hence cause the systemic
inflammatory response usually seen ininflammatory response usually seen in
these infectionsthese infections
Achieved by inhibiting LPS secretionAchieved by inhibiting LPS secretion
Does not actually kill theDoes not actually kill the AcinetobacterAcinetobacter
Has no effect on other receptors orHas no effect on other receptors or
mediators from other bacteriamediators from other bacteria
Lin et al: mBio 3(5):e00312-12. doi:10.1128/mBio.00312-12.Lin et al: mBio 3(5):e00312-12. doi:10.1128/mBio.00312-12.
16. What does cause the emergence ofWhat does cause the emergence of
resistance mechanisms?resistance mechanisms?
Minimal evidence that correct andMinimal evidence that correct and
appropriate antibiotic leads to resistanceappropriate antibiotic leads to resistance
Multitude of evidence that incorrect orMultitude of evidence that incorrect or
inappropriate usage does indeed hasteninappropriate usage does indeed hasten
the development of resistancethe development of resistance
Resistance accelerated by under-dosingResistance accelerated by under-dosing
and excessive duration of therapyand excessive duration of therapy
We should not be using antibiotics whereWe should not be using antibiotics where
not indicated, appropriate or effectivenot indicated, appropriate or effective
17. Historical and ongoingHistorical and ongoing
inappropriate usage of antibioticsinappropriate usage of antibiotics
Gross usage of antibiotics for viral infectionsGross usage of antibiotics for viral infections
where they have no activity, without goodwhere they have no activity, without good
evidence of secondary bacterial infectionevidence of secondary bacterial infection
Use of antibiotics for non-infectiveUse of antibiotics for non-infective
inflammatory conditions (e.g. allergies) andinflammatory conditions (e.g. allergies) and
for non-antimicrobial effects (e.g. prokineticfor non-antimicrobial effects (e.g. prokinetic
factors)factors)
Prolonged usage of antibiotics to ‘prevent’Prolonged usage of antibiotics to ‘prevent’
infectioninfection
19. Ongoing inappropriate use in manyOngoing inappropriate use in many
countries of antibiotics in farmingcountries of antibiotics in farming
Use of antibiotics as an adjunct to animalUse of antibiotics as an adjunct to animal
farming and in agriculturefarming and in agriculture
Usually done in a vain effort to preventUsually done in a vain effort to prevent
infections in livestock (mainly poultry)infections in livestock (mainly poultry)
Real problem is overcrowding of animals byReal problem is overcrowding of animals by
modern farming methods with excessivemodern farming methods with excessive
restriction of free animal movementrestriction of free animal movement
There is scant scientific evidence thatThere is scant scientific evidence that
infections can be prevented by usinginfections can be prevented by using
antibiotics prophylactically in these scenariosantibiotics prophylactically in these scenarios
20. Appropriate human prophylacticAppropriate human prophylactic
antimicrobial useantimicrobial use
There is also scant evidence that humanThere is also scant evidence that human
infections can be prevented antibioticsinfections can be prevented antibiotics
used prophylactically or pre-emptivelyused prophylactically or pre-emptively
Exceptions:Exceptions:
Surgical prophylaxisSurgical prophylaxis
Maximum of 24 hours permissibleMaximum of 24 hours permissible
Fungal prophylaxis in immunosuppressedFungal prophylaxis in immunosuppressed
patientspatients
Fungal sepsis in limited cIAI scenariosFungal sepsis in limited cIAI scenarios
SDD ?SDD ?
25. MORTALITYMORTALITY
Overall for community-acquired infections wasOverall for community-acquired infections was
17,1%17,1%
Overall for nosocomial infections wasOverall for nosocomial infections was 34,3%34,3%
Overall for nosocomial sepsis after initial treatmentOverall for nosocomial sepsis after initial treatment
for a community-acquired infection wasfor a community-acquired infection was 45,2%45,2%
Kollef MH, Sherman G, Ward S, et al:Kollef MH, Sherman G, Ward S, et al:
Inadequate antimicrobial treatment of infections:Inadequate antimicrobial treatment of infections:
A risk factor for hospital mortality among critically ill patients.A risk factor for hospital mortality among critically ill patients.
Chest 1999; 115:462– 474Chest 1999; 115:462– 474
26. MORTALITYMORTALITY
Mortality in group with inadequate antimicrobialMortality in group with inadequate antimicrobial
therapytherapy 42%42%
Mortality in the appropriately treated infection groupMortality in the appropriately treated infection group
17,7%17,7%
(Non-septic patient mortality(Non-septic patient mortality 12,2%12,2%))
Kollef MH, Sherman G, Ward S, et al:Kollef MH, Sherman G, Ward S, et al:
Inadequate antimicrobial treatment of infections: A risk factor for hospital mortalityInadequate antimicrobial treatment of infections: A risk factor for hospital mortality
among critically ill patients.among critically ill patients.
Chest 1999; 115:462– 474Chest 1999; 115:462– 474
27. MORTALITYMORTALITY
INCREASED WITH:INCREASED WITH:
• No. of acquired organ dysfunctionsNo. of acquired organ dysfunctions
• APACHE ScoreAPACHE Score
• Increasing ageIncreasing age
• Need for inotropic supportNeed for inotropic support
• Non-surgical patientsNon-surgical patients
• MalignancyMalignancy
Kollef MH, Sherman G, Ward S, et al:Kollef MH, Sherman G, Ward S, et al:
Inadequate antimicrobial treatment of infections:Inadequate antimicrobial treatment of infections:
A risk factor for hospital mortality among critically ill patients.A risk factor for hospital mortality among critically ill patients.
Chest 1999; 115:462– 474Chest 1999; 115:462– 474
28. APPROPRIATE vs INAPPROPRIATE
ANTIBIOTIC THERAPY:
MORTALITY IN INTRA-ABDOMINAL INFECTION
12%
23%
0.0%
10.0%
20.0%
30.0%
40.0%
Empiric Antibiotic Therapy
Appropriate (n=290)
Empiric Antibiotic Therapy
Inappropriate (n=75)
Mortality,%
Bare M et al. 12th
European Congress of Clinical Microbiology and Infectious
Diseases, 2002.
29. Successful Clinical Outcome withSuccessful Clinical Outcome with
Appropriate AntibioticsAppropriate Antibiotics
in severe IAIin severe IAI
81.9%
58.9%
0.0%
20.0%
40.0%
60.0%
80.0%
100.0%
Empiric Antibiotic
Therapy Appropriate
(n=238)
Empiric Antibiotic
Therapy Inappropriate
(n=56)
Patientswith
ClinicalSuccess,%
p<0.05
*Successful outcome was defined as resolution with no change in treatment.
Davey P et al. Presented at the International Society of Pharmacoeconomics and
Outcomes Research Sixth Annual International Meeting, 2001.
31. APPROPRIATE ANTIBIOTICSAPPROPRIATE ANTIBIOTICS
vs SURVIVALvs SURVIVAL
in SEPTIC SHOCKin SEPTIC SHOCK
Appropriate antibiotic within 1 hour of developingAppropriate antibiotic within 1 hour of developing
shock, survivalshock, survival 79,9%79,9%
SurvivalSurvival droppeddropped by average ofby average of 7,6%7,6% perper
hour thereafter up to 6 hourshour thereafter up to 6 hours
Statistical significance already after 2 hoursStatistical significance already after 2 hours
Survival after starting antibiotics only after 6Survival after starting antibiotics only after 6
hours was onlyhours was only 42%42%
33. WHY SO FEW NEWWHY SO FEW NEW
ANTIBIOTICS?ANTIBIOTICS?
Development costs for a new moleculeDevelopment costs for a new molecule
from preclinical to end phase III nowfrom preclinical to end phase III now
ranging from 700 Million to 1.2 Billion USDranging from 700 Million to 1.2 Billion USD
No guarantees of success along theNo guarantees of success along the
pathwaypathway
Reward for developing a new antimicrobialReward for developing a new antimicrobial
= no-one uses it!= no-one uses it!
34. WHY SO FEW NEWWHY SO FEW NEW
ANTIBIOTICS?ANTIBIOTICS?
Mode of usage is very different to mostMode of usage is very different to most
other drugs, hence profitability almost non-other drugs, hence profitability almost non-
existent:existent:
Standard usage is 5 – 10 daysStandard usage is 5 – 10 days
Compare with medications for diabetes,Compare with medications for diabetes,
hypertension, gout, hyperlipidaemia, etc.hypertension, gout, hyperlipidaemia, etc.
where usage of the drug is for lifewhere usage of the drug is for life
35. WHY SO FEW NEWWHY SO FEW NEW
ANTIBIOTICS?ANTIBIOTICS?
Length of patents are the same forLength of patents are the same for
antibiotics as for all other drugsantibiotics as for all other drugs
A few countries do not respect patentA few countries do not respect patent
rights in any event and allow exportationrights in any event and allow exportation
No other class of medicines is underNo other class of medicines is under
medical pressure to minimise usagemedical pressure to minimise usage
ANTIBIOTICS ARE THE ONLYANTIBIOTICS ARE THE ONLY
MEDICINES THAT WHEN GIVEN TO AMEDICINES THAT WHEN GIVEN TO A
SINGLE PATIENT, MAY AFFECTSINGLE PATIENT, MAY AFFECT
OTHER INDIVIDUALSOTHER INDIVIDUALS
36. WHY SO FEW NEWWHY SO FEW NEW
ANTIBIOTICS?ANTIBIOTICS?
Costs are progressively increasingCosts are progressively increasing
New additional costs becoming necessaryNew additional costs becoming necessary
in many countriesin many countries
Environmental impact studiesEnvironmental impact studies
Very few blockbuster drugs in otherVery few blockbuster drugs in other
therapeutic areas eithertherapeutic areas either
Even biologics soon to be challenged withEven biologics soon to be challenged with
biosimilarsbiosimilars
37. Financial difficulties inherent inFinancial difficulties inherent in
antibiotic developmentantibiotic development
The reward for developing a novel antibiotic is thatThe reward for developing a novel antibiotic is that
it is reserved for later resistant pathogens and isit is reserved for later resistant pathogens and is
hardly used before patent expiryhardly used before patent expiry
Patent lives are not longer for antibiotics than forPatent lives are not longer for antibiotics than for
other drug classesother drug classes
Drugs for chronic illnesses are used for prolongedDrugs for chronic illnesses are used for prolonged
periods and hence R&D costs can be recoupedperiods and hence R&D costs can be recouped
The use of antibiotics is for a very short course ofThe use of antibiotics is for a very short course of
treatmenttreatment
No other drug class has medical restrictions forNo other drug class has medical restrictions for
usage or volume of usageusage or volume of usage
Holding costs for reserved drugs are highHolding costs for reserved drugs are high
38. Are antibiotics a cost-effectiveAre antibiotics a cost-effective
therapeutic intervention?therapeutic intervention?
QALYQALY
ICERICER
NNTNNT
Antibiotics are amongst the most cost-Antibiotics are amongst the most cost-
effective and life-altering medicaleffective and life-altering medical
therapeutic interventions availabletherapeutic interventions available
They are amongst the best value forThey are amongst the best value for
money interventions medical sciencemoney interventions medical science
offers the communityoffers the community
39. Factors influencing antibioticFactors influencing antibiotic
clinical trials for serious infectionsclinical trials for serious infections
Almost all clinical trials for new antimicrobialsAlmost all clinical trials for new antimicrobials
are done in ‘not-so-sick’ patientsare done in ‘not-so-sick’ patients
This follows on trials in human volunteers,This follows on trials in human volunteers,
animal studies and laboratory studiesanimal studies and laboratory studies
The truly ill patient seldom behavesThe truly ill patient seldom behaves
physiologically as the less sick or well personphysiologically as the less sick or well person
Ethical limitations are immense in these trialsEthical limitations are immense in these trials
Statistical significance is near impossible toStatistical significance is near impossible to
achieve (confounding variables)achieve (confounding variables)
40. Clinical trials:Clinical trials:
Exclusions and confoundersExclusions and confounders
Disease aetiologyDisease aetiology
Age extremesAge extremes
Body mass extremesBody mass extremes
PregnancyPregnancy
ChangesChanges
Volume of distributionVolume of distribution
Protein bindingProtein binding
Physiological responsesPhysiological responses
Organ dysfunctionOrgan dysfunction
InterventionsInterventions
Dialysis (IHD / SLEDD / CVVHD)Dialysis (IHD / SLEDD / CVVHD)
Extra-corporeal circulationsExtra-corporeal circulations
Drug-drug interactionsDrug-drug interactions
41. DRUG REGISTRATION ANDDRUG REGISTRATION AND
REIMBURSEMENTREIMBURSEMENT
Complex processes needed to satisfyComplex processes needed to satisfy
regulatorsregulators
Drug registration ⇒ Efficacy and SafetyDrug registration ⇒ Efficacy and Safety
Drug reimbursement ⇒ Cost-effectivenessDrug reimbursement ⇒ Cost-effectiveness
Registration = usually requires provingRegistration = usually requires proving
equivalenceequivalence
Reimbursement = usually requires provingReimbursement = usually requires proving
superioritysuperiority
42. Post-marketingPost-marketing
drug surveillancedrug surveillance
Extremely important for pharmaceuticalExtremely important for pharmaceutical
companies to have strict, well defined andcompanies to have strict, well defined and
comprehensive pharmacovigilancecomprehensive pharmacovigilance
This means dedicated and appropriatelyThis means dedicated and appropriately
staffed drug safety unitsstaffed drug safety units
Many drug toxicities will only becomeMany drug toxicities will only become
evident with prolonged and sustainedevident with prolonged and sustained
usageusage ∝∝ incidence, initial trial designincidence, initial trial design
COST!COST!
43. COST IMPLICATIONS OFCOST IMPLICATIONS OF
ETHICAL DRUG COMPANYETHICAL DRUG COMPANY
FUNCTIONINGFUNCTIONING
Medical Affairs departmentMedical Affairs department
Clinical Development departmentClinical Development department
Medical Compliance divisionMedical Compliance division
Medical Information divisionMedical Information division
Regulatory Affairs departmentRegulatory Affairs department
Patient Access departmentPatient Access department
Drug Safety UnitDrug Safety Unit
44. Pharmaceutical companies:Pharmaceutical companies:
• Are governed by strict regulatory laws in mostAre governed by strict regulatory laws in most
countriescountries
• Are governed by tight Codes of Conduct in mostAre governed by tight Codes of Conduct in most
countriescountries
• Only can promote medications for their licensedOnly can promote medications for their licensed
indicationsindications
• Are subject to major penalties for infringements inAre subject to major penalties for infringements in
the appropriate marketing of their drugsthe appropriate marketing of their drugs
• Have large numbers of doctors, scientists,Have large numbers of doctors, scientists,
lawyers, compliance officers and qualitylawyers, compliance officers and quality
assurance professionals employed fulltime, whoassurance professionals employed fulltime, who
are not accountable to the commercial arms of theare not accountable to the commercial arms of the
businessbusiness
45. DETRACTORS FROM ENABLINGDETRACTORS FROM ENABLING
QUICK AND AFFORDABLE NEWQUICK AND AFFORDABLE NEW
DRUG REGISTRATIONDRUG REGISTRATION
Complexity of new drug registrationComplexity of new drug registration
Needing to repeat the process in everyNeeding to repeat the process in every
country!country!
Near impossibility to do trials in ill patientsNear impossibility to do trials in ill patients
Ethics, consent, enrolment, confounders,Ethics, consent, enrolment, confounders,
exclusions, statistically-significant numbersexclusions, statistically-significant numbers
Near impossibility of proving cost-Near impossibility of proving cost-
effectiveness of novel agentseffectiveness of novel agents
47. FUTURE ANTIBIOTICFUTURE ANTIBIOTIC
DEVELOPMENT WILL NEED:DEVELOPMENT WILL NEED:
LONGTERM:LONGTERM:
Private-public-academic partnershipsPrivate-public-academic partnerships
Government active supportGovernment active support
Cross-country harmonisationCross-country harmonisation
48. THE FUTURETHE FUTURE
SHORT-TERM:SHORT-TERM:
Infection ControlInfection Control
Good habits – cultures, surveillance,Good habits – cultures, surveillance,
source controlsource control
Antimicrobial stewardshipAntimicrobial stewardship
Routine PK / PD considerationsRoutine PK / PD considerations
Early diagnostic markers for sepsis andEarly diagnostic markers for sepsis and
pathogenspathogens
Vaccine researchVaccine research
49. MEDICAL STRATEGIES TO LIMITMEDICAL STRATEGIES TO LIMIT
ANTIBIOTIC PRESCRIPTIONANTIBIOTIC PRESCRIPTION
Antimicrobial stewardshipAntimicrobial stewardship
GuidelinesGuidelines
Formularies?Formularies?
Antibiotic restriction, protocols,Antibiotic restriction, protocols,
cycling, rotationcycling, rotation
51. Early diagnosis will limit inappropriateEarly diagnosis will limit inappropriate
and inadequate antibiotic therapyand inadequate antibiotic therapy
• Early diagnosisEarly diagnosis
– PCRPCR
– MALDI-TOFMALDI-TOF
• Therapeutic drug monitoring (TDM)Therapeutic drug monitoring (TDM)
• Tissue drug levelsTissue drug levels
– Develop indicators of tissue drug levelsDevelop indicators of tissue drug levels
• BiomarkersBiomarkers
– Confirm definite sepsisConfirm definite sepsis
– Exclude non-septic causes of inflammationExclude non-septic causes of inflammation