Pharmacokinetic/ Pharmacodynamics in Antibiotic Evaluation, Clinical use, and Management of Resistance ... or PK/PD like Magic !

(Fourth Annual Conference of Infectious Diseases Pharmacotherapy, May 3d,  2001, Orlando, Fla)

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Table of Contents

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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

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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 ?

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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...

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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

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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

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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 ?

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?-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 ?

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The end of the talk ...

PK / PD in action ...

PK / PD in action ...

Better approaches in antibiotic usage...

Better approaches in antibiotic usage...

Author: Paul M. Tulkens 

Email: tulkens@facm.ucl.ac.be

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