Pharmacokinetics and pharmacodynamics for efficacy and prevention of resistance

2d meeting of the Australian Society of Antimicrobials, Melbourne, Victoria, April 6th, 2001

Click here to start

Table of Contents

PPT Slide

The ideal antibiotic ...

Will it always be ideal ?

Main causes of antibiotic failures...

PK / PD ...

PPT Slide

Pharmacokinetic/ Pharmacodynamics in Drug Development and Evaluation of Efficacy

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 and effectiveness: patterns of antimicrobial activity (after WA. Craig, 2000)

PPT Slide

PPT Slide

PPT Slide

PPT Slide

PPT Slide

?-lactams : at least 50 % of the time above the MIC...

PK / PD in action: what can you do with a model ?-lactam *

PK / PD in action... 

Improving ?-lactam efficacy by reducing the interval

PK /PD in action ... 

?-lactams PK / PD and resistance

PK/PD and effectiveness: patterns of antimicrobial activity (after WA. Craig, 2000)

AUC / MIC - dependent antibiotics and resistance

AUC / MIC - dependent antibiotics and resistance

PK/PD and effectiveness: patterns of antimicrobial activity (after WA. Craig, 2000)

Aminoglycosides : obtain a peak !

PK / PD in action ... 

PK /PD in action ... 

PK PD in action ... 

PK/PD of fluoroquinolones

24h AUC / MIC ratio

24h AUC / MIC and FQ effectiveness: in vitro dynamic models

Peak / MIC ratio

Peak / MIC and FQ effectiveness (animal models)

Peak / MIC of FQ: clinical data

Peak / MIC of FQ: clinical data

PK /PD in action ... 

24h-AUC / MIC as a tool to determine acceptable sensitivities to standard doses of FQ

Peak concentrations as a tool to determine acceptable sensitivities to standard doses of FQ

Combining it all (Peak and 24h-AUC / MIC) as predictors of efficacy standard doses of FQ ...

Combining it all (Peak and 24h-AUC / MIC) as predictors of efficacy standard doses of FQ ...

Patients may be treatable because AUC (but not Cmax) increases with decreased drug clearance

PPT Slide

Is a 24h AUC / MIC ratio of 125 necessary ?

PK / PD bkpt for AUC / MIC

To increase both AUC and peak increase the unit dose ...

Breakpoints ??

Why would too high breakpoints favour the emergence of resistance to FQs ?

Resistance to fluoroquinolones: the basics

PK/PD and point mutations ...

PK/PD and point mutation in DNA gyrase...

Cmax and MPC of FQs

Significance of MPC ?

PK/PD and antibiotic efflux pumps...

PPT Slide

Efflux pumps...

Efflux pumps and first mutation may cooperate ... 

Efflux pumps may bring intrabacterial concentrations of FQ < MPC ...

PK/PD and resistance ?

A long way indeed ...

But closer than you tought ...

Author: Paul M. Tulkens 

Email: tulkens@facm.ucl.ac.be

Home Page: http://www.md.ucl.ac.be/facm/facm-conferences.htm

Download the whole presentation (PDF file)