Problems and trends in the therapy with antibacterial drugs

Otto Cars. M.D., Ph.D.Department of Infectious Diseases,

Uppsala University HospitalUppsala,Sweden

Problems and trends in the therapy with antibacterial drugs

Otto Cars. M.D., Ph.D.Department of Infectious Diseases,

Uppsala University HospitalUppsala,Sweden

Natural compounds - screening for microbial metabolites

Chemical synthesis

Semithythetic process - introcuction of new substituents - replacement of side chains

Traditional methods for development of antibacterials

Traditional methods for development of antibacterials

Sulphonamides

Tetracyclines

PenicillinsAminoglycosides

Macrolides

Glycopeptides

Streptogramins

Chloramphenicol

Quinolones

Trimetoprim

Lincosamides

1930´s 1940´s 1950´s 1960´s 1970’s 1980´s 1990´s 2000´s

Oxazolidinones

Introduction of New Antibiotic ClassesIntroduction of New Antibiotic Classes

Development of ß-lactam antibiotics

”One can think of the middle of the 20 th century as the end of one of the most important social events in history : the virtual elimination of the infectious diseases as a significant factor in social life”

Sir MacFarland Burnett, Natural History of Infectious

Diesease, 1962

”One can think of the middle of the 20 th century as the end of one of the most important social events in history : the virtual elimination of the infectious diseases as a significant factor in social life”

Sir MacFarland Burnett, Natural History of Infectious

Diesease, 1962

”The war against infectious diseases has been won ”

U.S. Surgeon General, 1969

”The war against infectious diseases has been won ”

U.S. Surgeon General, 1969

The annual death toll from infectious diseases is now more than 17 million

Many diseases thought to have been brought under control are strongly resurgent

The annual death toll from infectious diseases is now more than 17 million

Many diseases thought to have been brought under control are strongly resurgent

TODAY:

Leading infectious killers

Deaths (millions) <5 years old >5 years old

0

0.5

1

1.5

2

2.5

3

3.5

ARI AIDS Diarrhoea TB Malaria Measles

. 1998 estimate,WHO

• Temperature and moisture• Globalization of food production• Agricultural intensification• Overpopulation, urbanization• Frequency and nature of interpersonal contact• Population mobility• Sanitation, poverty• Access to health care and drugs

Changing epidemiological environmentBiological,social and economical determinants:Changing epidemiological environmentBiological,social and economical determinants:

World Health Organization Working Groups on Anti-infective therapy in collaboration with the Pharmaceutical Industry

• Research& Development

• Drug Quality -Counterfeit medicines

• Drug accessibility

World Health Organization Working Groups on Anti-infective therapy in collaboration with the Pharmaceutical Industry

• Research& Development

• Drug Quality -Counterfeit medicines

• Drug accessibility

”New drugs and vaccines are needed for emerging diseases..”

”Return on capital invested … is often too small to become an incentive for investment by the R&D based pharmaceutical industry”

”…a complex task that cannot be achieved without the cooperation and coordination by the WHO, the international financial institutions, national governments ,bilateral aid agencies ,the private sector and other stakeholders”

Marketing

Use and misuse New antibiotics

Resistance

Antibacterial spectrum

Pharmacokinetics

Toxicity

23F Resistant pneumococcal clones

Tennessee

Cleveland

Mexico

Colombia

Brazil

ArgentinaUruguay

Chile South Africa

SingaporeMalaysia

ThailandPhilippines

Hong KongTaiwan

South KoreaSpain

FranceBM42001978 ?

Finland

The Alexander Project 1998: S. pneumoniae, Pen-I and Pen-R

The Alexander Project 1998: S. pneumoniae, Pen-I and Pen-R

UK 20%UK

20%

Belgium 8%

Belgium 8%

France 53.3%France 53.3%

Germany 7.2%

Germany 7.2%

Czech Rep

7.1%

Czech Rep

7.1%

Poland 9%

Poland 9%

Switzerland 14.5%

Switzerland 14.5%

Italy9%Italy9%

Portugal 17.1%

Portugal 17.1%

Eire 32.8%

Eire 32.8%

Greece 31.6%Greece 31.6%

Netherlands 3.2%

Netherlands 3.2%

Slovakia 51.4%

Slovakia 51.4%

Austria12.4%Austria12.4%

Percentage of hospital Staphylococcus aureus that are multi-drug resistant

0 10 20 30 40 50 60 70 80 90

China, Centre 2

Japan

USA >500 beds

China, Centre 1

Hong Kong

Malaysia

USA, <500 beds

Belgium

Australia

Philippines

Viet Nam

Fiji

New Zealand

Compilation of data from published and unpublished sources ( WHO)

Primary Drug Resistance in Tuberculosis

Dominican RepublicLatvia

Russia (Ivanovo Oblast)Estonia

Sierra LeoneBolivia

Puerto RicoPeru

Portugal

United States of AmericaSwaziland

CubaNepal

RomaniaSpain (Barcelona)

LesothoBrazil

England & Wales

New ZealandBotswanaScotland

Northern IrelandZimbabwe

Czech Republic

Argentina

Kenya

Republic of Korea

China (Henan province)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

MDR

Any other

Susceptible

Engl. &Wales

USA

Latvia

Czech Rep

Anti-tuberculosis drug resistance in the world. WHO 1997

Trends in antimicrobial resistance in Shigella dysenteriae

(type 1 isolates from Bangladesh)

0102030405060708090

100

Percent of resistant isolates

87 88 89 90 91 92

Year

Ampicillin Cotrimoxazole Nalidixic acid

Sack et al. Clin Infect Dis 1997;24(Suppl 1):S102-5

Prognosis and costs for treatment of bacteriemic patients with vancomycin resistant enterococci (VRE) in comparison to susceptible enterococci (VSE)

Prognosis and costs for treatment of bacteriemic patients with vancomycin resistant enterococci (VRE) in comparison to susceptible enterococci (VSE)

VSE VRE

Mortality 41% 76%

Hospital stay (days) 16.7 34.8

Cost per treatment period (USD) 56.707 83.897

Storsor et al Arch Intern Med 1998:158,522

Veterinary medicine

Human medicine

Agriculture

Community

Hospital

ANTIBIOTIC ECOSYSTEMS

Animal feed additives

Plant protection

Treatment & prophylaxis

EnvironmentEnvironment

•Intraspecies•Interspecies•Dynamics

Spread

Selection/Gene amplification

Genetic exchange

Colonization Infection

Host 1 Host 2

•Virulence factors•Host defence•Antibiotics

•Epidemigenicity•Vectors•Fitness cost•Overcrowding

•Antibiotic class•Specific drugs•Dosage regimen

• Variable epidemiology

• Regional differences

• Co-selection

• Clonal spread

• Herd immunity

• Few longitudinal studies

Difficulties in establishing a correlation between levelsof consumption and

resistance

Influence of antibiotic class on PRPcarriage

None - 1.0 - -

-lactam 1 or 2 6.75 1.8–25 0.005 3 6.00 1.4–25 0.013

Co-trimoxazole 1 or 2 7.22 1.7–30 0.007

3 13.14 3.1–55 0.000Erythromycin 1 or 2 8.56 1.1–64 0.037

3 12.16 1.9–75 0.007

The odds for co-trimoxazole and erythromycin being associatedwith PRP carriage were twice that for -lactams in associationwith 3 or more antimicrobial courses

Arason, 1996

Antibiotic Courses in Odds 95% CI p valuelast 12 mos ratio

The association between antibiotic use and resistance

• The introduction of an antibiotic is with few

exceptions followed by an increase in resistance levels

• Antibiotic resistant isolates are selected during therapy

• Higher resistance levels are often found in environments

with high antibiotic exposure (e.g. ICU,day care centres)

• In general, countries with low consumption levels

show lower reistance rates

Development of Resistance During Antimicrobial Therapy

Development of Resistance During Antimicrobial Therapy

•173 clinical studies (U.S. and Europe)• Overall rate of resistance during therapy = 4%

for all organisms• Significantly higher rates: penicillins, aminoglycosides• Significantly lower rates: imipenem, aztreonam

combination therapy• 68.5% of organism developing resistance were

associated with treatment failure

Fish et al, Pharmacotherapy 15, 1995:279

Need for new antibacterial agentsNeed for new antibacterial agents

• Pharmacokinetic/ Pharmacodynamics in drug Development and Evaluation

• Definition of antibotic susceptibility and resistance

• Design of clinical trials

• Pharmacokinetic/ Pharmacodynamics in drug Development and Evaluation

• Definition of antibotic susceptibility and resistance

• Design of clinical trials

Antibiotic Microorganism

Host

PHARMACO-KINETICS

PHARMACO-DYNAMICS

HOST DEFENCE

• A variety of micoorganisms containing the drug receptor

• Misleading kinetics in small animals

• Co-variation between pharmacokinetic parameters

• Poorly discriminating (discontinuous) end-points for efficacy

• Interaction with host defences

• Other patient factors

• Exclusion of resistant bacteria from clinical trials

• Ethical limitations for dose-finding studies

Difficulties in determining of optimal dosage

regimens for for anti-infective agents

Difficulties in determining of optimal dosage

regimens for for anti-infective agents

Pharmacokinetic/ Pharmacodynamics in Drug Development and Evaluation

Pharmacokinetic/ Pharmacodynamics in Drug Development and Evaluation

Over the last 10 years, a series of key concepts have emerged

• Dose -effect relationships are not the same for all anti- infectives

• Some anti-infectives are time dependent, others not

• Subinhibitory effects, post-antibiotic effects, cooperation with host defenses modulate the activity of antiinfective drugs

• Integration of pharmacodynamics/pharmacokinetics is a tool to predict success or failure, and emergence of resistance

Optimal antibiotic dosage

Costs

EfficacyToxicity

Resistance

• Basic in vitro pharmacodynamics • Determination of PK/PD vs efficacy - in vitro models - animal models • Protein binding • Human pharmacokinetics • Exploring tentative dosage regimens based on PK/PD indices and using human kinetics -in vitro models -animal models • Set dose/dosage ranges for Phase II• Validation of PK/PD indices in clinical trials

• Basic in vitro pharmacodynamics • Determination of PK/PD vs efficacy - in vitro models - animal models • Protein binding • Human pharmacokinetics • Exploring tentative dosage regimens based on PK/PD indices and using human kinetics -in vitro models -animal models • Set dose/dosage ranges for Phase II• Validation of PK/PD indices in clinical trials

Daptomycin:Pharmacokinetics/Toxicity RelationshipDaptomycin:Pharmacokinetics/Toxicity Relationship

Is skeletal muscle toxicity related to C max and/or AUC?

What is the safe dosing regimen?

Daptomycin: Effect of Dosing Regimen on Muscle Toxicity in Dogs

Daptomycin: Effect of Dosing Regimen on Muscle Toxicity in Dogs

Dose

(mg/kg)

Frequency ofTreatment

Peak SerumCPK*

MicroscopicMyopathy**

0 q8h 265 0/28

25 q24h 990 3/28

75 q24h 990 8/28

25 q8h 4000 15/28

* Blood samples at time of expected peak muscle toxicity, i.e., 2 hours post-dose** Minimal degeneration/inflammation in skeletal muscle sites; no myopathy in the heart

Selection is a key factor driving the spread of resistant pathogens

Bacteriologicalfailure

Multiresistant strains survive and multiply

Spread ofmultiresistant bacteria

Risk of clinical failureDelayed responseComplications

Low dose and long duration of beta-lactam therapy as risk factors for penicillin-resistant

pneumococcal carriage

Low dose and long duration of beta-lactam therapy as risk factors for penicillin-resistant

pneumococcal carriage

Odds ratio Confidence interval

Oral ß-lactams 3.0 1.1–8.3in past 30 days

Dose lower than 5.9 2.1–16.7 clinically recommended

Treatment >5 days 3.5 1.3–9.8

NB. Data are based on 16 children carrying PRSP (of 864). Ten of these children had low dose, long duration treatment

Guillemot et al. JAMA 1998;279:365–370

• Pharmacokinetically oriented

• Not always taking protein binding into account

• Looking at all antibiotics as one class

• Stay above MIC as long as possible

• But--patients want b.i.d. or once daily!!

Development of antibiotic dosage regimens

Yesterday:

Development of antibiotic dosage regimens

Yesterday:

• Pharmacodynamic goal of therapy

• Develop more precise relationships

between drug exposure and outcome

Development of antibiotic dosage regimens

Tomorrow:

Development of antibiotic dosage regimens

Tomorrow:

• Pharmacokinetic/ Pharmacodynamics in drug Development and Evaluation

• Definition of antibotic susceptibility and resistance

• Design of clinical trials

• Pharmacokinetic/ Pharmacodynamics in drug Development and Evaluation

• Definition of antibotic susceptibility and resistance

• Design of clinical trials

≤0,25 0,5 1 2 4 8 16 32 64 ≤1280

20

40

60

80

100

120

Ceftazidime (mg/l)

SRGA NCCLS

Swedish ICU study 1997

Escherichia coli

Swedish ICU study group

• What is resistance?

• In vitro veritas?

-Microbiological resistance vs clinical resistance

-Interpretataion of susceptibility testing:the breakpoint problem

• What is resistance?

• In vitro veritas?

-Microbiological resistance vs clinical resistance

-Interpretataion of susceptibility testing:the breakpoint problem

• Pharmacokinetic/ Pharmacodynamics in drug Development and Evaluation

• Definition of antibotic susceptibility and resistance

• Design of clinical trials

• Pharmacokinetic/ Pharmacodynamics in drug Development and Evaluation

• Definition of antibotic susceptibility and resistance

• Design of clinical trials

”Clinical trials of efficacy are presently

almost entirely funded by the

pharmaceutical industry and have

objectives largely confined to satisfying

regulatory authorities ”

Opinion of the Scientific Steering Committee on Antimicrobial

Resistance,

28 May 1999

”Clinical trials of efficacy are presently

almost entirely funded by the

pharmaceutical industry and have

objectives largely confined to satisfying

regulatory authorities ”

Opinion of the Scientific Steering Committee on Antimicrobial

Resistance,

28 May 1999

• Poor diagnostic tools

• Poor endpoints in clinical trials

• Poor knowledge about which patients really benefit from antibiotic treatment

• Poor diagnostic tools

• Poor endpoints in clinical trials

• Poor knowledge about which patients really benefit from antibiotic treatment

Slide no 47

Spontaneous cure vs. antibiotic treatment

Spontaneous cure vs. antibiotic treatment

Time

Spontaneous clinical cureCure with antibiotic treatment

0

100

50

% p

atie

nts

Slide no 48

The ‘Pollyanna phenomenon’

20

30

40

50

60

70

80

90

100

Bacteriologic efficacyin bacterial AOM

Clinical efficacyin bacterial AOM

Placebo

Adapted from Marchant et al. J Pediat 1992;120:72–77

Eff

icac

y (%

)

Short Long

where is the balance?

Poor efficacy Emergence of resistance

Treatment time-

Problems related with the discovery and use of new antibacterials

Problems related with the discovery and use of new antibacterials

1. Finding a target for maximal efficacy

2. Avoiding toxicity

3. Optimizing usage

4. Preventing the further emergence of resistance

1. Finding a target for maximal efficacy

2. Avoiding toxicity

3. Optimizing usage

4. Preventing the further emergence of resistance

CLASSIC

ANTIBIOTICS”New” antibiotics

”Genomics”

40´s ???

Approaches for new

antibacterial agents

• Vaccines

• Anti-adhesion

• Inhibition of efflux pumps and bacterial enzymes

• New antibacterial targets

Approaches for new

antibacterial agents

• Vaccines

• Anti-adhesion

• Inhibition of efflux pumps and bacterial enzymes

• New antibacterial targets

It will take at least many years before there might be

antibacterials with new mechanisms of action available.

Our knowledge about and attitudes towards antibiotic

treatment must be radically improved/ changed

to ensure effective antibacterial treatment to patients

with severe bacterial diseases.

Bacteria :• Billions of years of evolutionary experience• Expert survivors• Rapid life-cycle• Intrinsic mechanisms of resistance

Homo sapiens :• Capacity for rapid behavioral change and

cultural evolution

Bacteria :• Billions of years of evolutionary experience• Expert survivors• Rapid life-cycle• Intrinsic mechanisms of resistance

Homo sapiens :• Capacity for rapid behavioral change and

cultural evolution

Academia

IndustryRegulatoryauthorities