Canisius-Wilhelmina HospitalNijmegen, The Netherlands

Johan W Mouton

Pharmacodynamic Indices

MIC

PEAK

PEAK / MICAUC / MICTIME > MIC

AUC

TIME > MIC

PK/PD

• Neutropenic mouse thigh model

• Various doses and dosing regimens (q1 to q24)

• Outcome parameter: cfu counts after 24 h

• Plot PD index (AUC, Peak T>MIC) to effect

K. pneumoniae, imipenem

For K.pneumoniae, there is no clear relation

between total daily dose of imipenem and

efficacy in an in vivo model of infection

K. pneumoniae, imipenem

For beta-lactams, there is a direct

relation between

Time > MIC and efficacy

Scaglione et al, ICAAC 1999

Pharmacodynamic Indicespredictive for efficacy

T>MIC AUC (Peak)/MIC

Penicillins Aminoglycosides

Cephalosporins Fluoroquinolones

Carbapenems Metronidazole

Monobactams Daptomycin

Tribactams Ketolides

Clindamycin Macrolides

Oxazolidinones Azithromycin

Clindamycin Streptogramins

Glycopeptides

Glycylcyclines Tetracyclines

Kill curves of ceftazidime, P. aeruginosa

tobramycin

-2 -1 0 1 2 3-2

3

8

13

18

10log (conc tobramycin) mg/lki

llrat

e h

-1

meropenem

-3 -2 -1 0 1 2-2

-1

0

1

2

3

4

5

10log (conc meropenem) mg/l

killr

ate

h-1

Mouton & Vinks, 2003

Kill curves of tobramycin, P. aeruginosa

•Antibiotics showing increasing effect (killing) over a wide range of concentrations are called ‘concentration dependent’. In vivo effects are usually AUC and/or Peak related.

•Those with a limited range of increasing effect are called (wrongly) ‘concentration-independent’. In vivo effects are usually Time >MIC related.

Pharmacodynamic index

Pharmacokinetic parameter MIC

The MIC

The MIC is a result of :

•kill over time (kill rate) by the antibiotic •growth over time (growth rate) •for a certain number of micro-organisms (the inoculum)

MIC

AT STATIC CONCENTRATIONS

•Growth and/or kill rate dependent :–strain, species–medium composition, brand

–MH, supplements, ISO–number of bacteria–inoculum

–5.105 (NCCLS) vs 105 (BSAC)–temperature (35o vs 37o)–growth phase–CO2

–etc.

0.0 0.5 1.0 1.5 2.0-6

-5

-4

-3

-2

-1

0

microdilution

e-test

10log MH dilution

2lo

g n

orm

aliz

ed M

IC

r²

2log mic

0.9457

2log etest

0.9507

Mouton, icaac 2000

The MIC of the control strain should be within one two-fold dilution of the expected MIC

PHARMACOKINETICparameters

Definition :The Area under the Concentration-time curve over 24 hours.Note: ….. It should be stated how the AUC is determined : based on (log) linear trapezoideal rule, based on clearance, or based on microconstants.

Dimensions : concentration x time e.g. mg.h/L or g.h/mL

Mouton et al, Int J Antimicrob Agents april 2002

AUC 0-24 = 3033 AUC inf = 5100AUC 0-24 sd = 1361AUC inf sd =1700

0 10 20 30 400

100

200

time

con

cen

trat

ion

Mg.h/L

WHICH AUC?

•AUC 0-24h or AUC

•Steady State?

• (log) trapezodeal rule?

•Derived ? (A/ +B/ or other)

Peak/MICDefinition : the peak level divided by the MIC.

Dimensions : no dimensions.

Mouton et al, Int J Antimicrob Agents april 2002

WHICH PEAKLEVEL?

•After the 1st, 2nd or later dose?

•If more than one compartment, the peak level in compartment 1, 2 or even 3?

simulation of 1.25 mg/kg q1h

0 1 2 3 4 5 6 7 80.0

0.5

1.0

1.5

2.0simulated conc.measured conc.

time (h)

con

cen

trat

ion

mg

/Lsimulation 10 mg/kg +

1.25 mg/kg q1h

0 4 8 12 16 20 240

2

4

6

8

10

simulated conc.

time (h)

con

cen

trat

ion

mg

/L

simulation 10 mg/kg + 1.25 mg/kg q1h

0 4 8 12 16 20 240

2

4

6

8

10

simulated conc.

time (h)

con

cen

trat

ion

mg

/L

fig 2a

fig 2b

fig 2c

Scaglione et al, icaac 1999

0.1 1 10 1000.6

0.7

0.8

0.9

1.0

fu levfu cip

concentration mg/l

frac

tio

n u

nb

ou

nd

fig 1

Scaglione et al, unpubl.

Time > MICDefinition : the % of time above the MIC over a period of 24 hours.Note : if the period is other than 24 h, this should be stated explicitly.

Dimensions : %.

Mouton et al, Int J Antimicrob Agents april 2002

Concentration-time profile of beta-lactamVd = 20 L, Ka = 1.2 h-1, Ke = 0.3 h-1

0.20

1.20

2.20

3.20

4.20

5.20

6.20

7.20

8.20

9.20

10.20

11.20

12.20

13.20

14.20

15.20

16.20

17.20

18.20

19.20

0.00

1.25

2.50

3.75

5.00

6.25

7.50

8.75

10.0

0

11.2

5

12.5

0

13.7

5

15.0

0

16.2

5

17.5

0

18.7

5

20.0

0

21.2

5

22.5

0

23.7

5

0.95-1.00

0.90-0.95

0.85-0.90

0.80-0.85

0.75-0.80

0.70-0.75

0.65-0.70

0.60-0.65

0.55-0.60

0.50-0.55

0.45-0.50

0.40-0.45

0.35-0.40

0.30-0.35

0.25-0.30

0.20-0.25

0.15-0.20

0.10-0.15

0.05-0.10

0.00-0.05

Conc

Time

Prob

Monte Carlo Simulation of beta-lactamVd = 20 L, Ka = 1.2 h-1, Ke = 0.3 h-1, VC=20%

4h

10h

Mouton, Int J Antimicrob Agents april 2002

Mouton et al, Clin Pharmacokin 2000

Mouton & Punt, JAC 2001

Amoxicillin/clavulanic acid

For all indices :

how are they determinedhow are they calculated

what is the error?