Table of Contents
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PPT Slide
Magic …
The ideal antibiotic ...
Will it always be ideal ?
Main causes of antibiotic failures...
Microbiological evaluation was (classically) static
Static techniques are (partly) inappropriate for
in vivo projections of sensitivities
Breakpoints introduce artificial (and not always
scientific) discontinuties in what is essentially a continuous distribution
PK / PD ...
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Pharmacokinetic/ Pharmacodynamics in Drug Development
and Evaluation of Efficacy
PPT Slide
PK/PD in drug develop-ment A view from FDA
Pharmacokinetic/ Pharmacodynamics and antibiotic
resistance...
PK/PD and drug devlop-ment A view from EMEA
Are PK / PD important in resistance ?
Just a few of them…
Pharmacokinetic/ Pharmacodynamics in Drug Development
and Evaluation
Pharmacokinetic/ Pharmacodynamics: What are the
goals ?
PK / PD of antibiotics in 2001 ?
PPT Slide
PPT Slide
The rest of the talk ...
Methods use to determine which are the pertinent
PK/PD parameters
Methods
In vitro dynamic models
Dilution models
Dilution models: a simple, useful system ...
Dilution models: more sophisticated ones...
PPT Slide
The goal is to mimic potentially useful and achievable
serum concentration variations
Why in vitro dynamic models ...
Methods
Animal models
Dissociating PK covariables
A typical animal model to establish which PK parameters
is associated with efficacy
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End-points of animal models
Relationship between fluoroquinolones 24 Hr AUC
/ MIC and mortality
Relationship Between 24 Hr AUC/MIC and Mortality
for FQs in Immunocompetent Animal Models with Str. pneumoniae infection
(Craig, 2000) *
Known PK problems (with solutions) linked with
animal models
Known PD problems with animal models
Demonstrated advantages of animal models
Methods
PK/PD of fluoroquinolones in clinics
24h AUC / MIC : what were the data ?
24h AUC / MIC : what were the data ?
What is the 24h-AUC / MIC ratio (AUIC) ?
What is the 24h-AUC / MIC ratio (AUIC) ?
Modeling of the clinical data
Medeling of fluoroquinolones clinical outcome
Modeling of fluoroquinolones successes and failures
Why are the conclusions of the clinical trials
apparently (sometimes and apparently) contradictory ?
Methods
Patient care or Drug assessment ?
PK/PD and population-based recommendations : the
issues
Examples of variations
Obtaining population cumulative frequencies
Monte Carlo simulations
PPT Slide
Distribution of AUC: MIC Ratios of Gatifloxacin
and Levofloxacin Against S. pneumoniae: “Monte Carlo” analysis
Monte Carlo simulations of fluoroquinolone AUC
/ MIC against S. pneumoniae
The rest of the talk ...
PK/PD patterns of antimicrobial activity
PPT Slide
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?-lactams : at least 50 % of the time above the
MIC...
PK / PD in action: what can you do with a model
?-lactam *
Improving ?-lactam efficacy by reducing the interval
?-lactam by continuous infusion ?
PPT Slide
?-lactams PK / PD and resistance
PK/PD patterns of antimicrobial activity (2 of
3) (after WA. Craig, 2000)
AUC / MIC - dependent antibiotics and resistance
AUC / MIC - dependent antibiotics and resistance
PK/PD patterns of antimicrobial activity (3 of
3) (after WA. Craig, 2000)
Aminoglycosides : obtain a peak !
PK / PD in action ...
PK /PD in action ...
PK PD in action ...
Fluoroquinolones : get both a peak and an AUC !
24h-AUC / MIC = 125 as a guide to determine acceptable
sensitivities to standard doses of FQ
Peak /MIC = 10 as a guide to determine acceptable
sensitivities to standard doses of FQ
Combining it all … Peak/MIC = 10 and 24h-AUC /
MIC = 125 as predictors of efficacy standard doses of FQ ...
Breakpoint issues ...
Which patient and which value of AUC / MIC ?
To increase efficacy of FQ, you need to increase
both the AUC and the peak …
Breakpoints of FQ: two problems ...
Pharmacokinetics / Pharmacodynamics in action ...
Why should you NOT use low doses ?
Resistance: a global overview...
Mechanisms of resistance to fluoroquinolones
PK/PD and antibiotic efflux pumps...
PK/PD and antibiotic efflux pumps… an example with
RND...
Pharmacokinetics / Pharmacodynamics in action ...
The rest of the talk ...
What does (serious) Industry do ?
PPT Slide
The end of the talk ...
PK / PD in action ...
PK / PD in action ...
Better approaches in antibiotic usage...
Better approaches in antibiotic usage... |