pharmacodynamics of antibiotics: correlation between kinetics … · 2020. 2. 16. ·...

Pharmacodynamics of antibiotics:Correlation between kinetics and activity

Paul M. Tulkens

Cellular and Molecular Pharmacology Unit

& Centre for Clinical Pharmacy

Catholic University of Louvain, Brussels, Belgium

International Society for Anti-infective www.facm.ucl.ac.be www.isap.org

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 1

International Society for Anti-infective

Pharmacology (ISAP)

www.facm.ucl.ac.be www.isap.org

Pharmacodynamics of antibiotics:Correlation between kinetics and activity

• Rising resistance and correlation with antibiotic use …

• Did we use antibiotics in a rational way ? …

• What is pharmacodynamics and how can it help you ? …

• Can we prevent (or slow down the emergence of) resistance ? …

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 2

www.facm.ucl.ac.be

• Can we prevent (or slow down the emergence of) resistance ? …

• Can we also reduce health care costs ? …

www.isap.org

Resistance is the problem …

20

25

30

35

40

pe

rce

nta

ge

penicillin* intermediate

tetracyclines

macrolides

penicillin* full resistant

1/3 patients

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 3

0

5

10

15

85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 20

year

pe

rce

nta

ge

Belgian Reference Laboratory for pneumococci, Leuven, 2000

1/5 patients

* all β-lactams (= penicillins, cephalosporins, …)

Overuse is also the problem …

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 4

Risk of resistance to ββββ-lactams among invasive isolates of Streptoccus pneumoniae regressed againstoutpatient sales of beta-lactam antibiotics in 11 European countries• resistance data are from 1998 to 1999; antibiotic sales data 1997. • DDD = defined daily doses

Bronzwaer SL, Cars O, et al. Emerg Infect Dis 2002 Mar;8(3):278-82

How can you be "better" ?

• be globally efficacious

� pharmacodynamics (PK/PD)

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 5

• avoid selection of resistance

� "mutant prevention concentration"

What is Pharmacokinetics / Pharmacodynamics

(PK/PD) ?

• Pharmacokinetics:

what the body does to the drug

� absorption, distribution, serum and tissue levels elimination, …

dose and

schedule

Cmax

t1/2

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 6

• Pharmacodynamics (of AB):

what the drug does to the bacteria

� static vs. bactericidal effect, rate of kill, eradication, prevention of resistance….

clearance

• Emax

• time to Emax

• prevention of

relapses

• maintenance of

susceptibility

The problem as seen from a question of the FDA...

Same dose ??

And what about those ones ?

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 7

Breakpoints tend to set up quantic limits in what is fundamentally a continuous distribution ...

What are "Pharmacodynamic indices" ?

• all drugs have pharmacokinetic properties that describe

the way the body handles them

– antibiotics are no exception …

– you need to consider the Cmax and the clearance (that will result in

a given half-life) to describe the drug exposure

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 8

• a drug needs to bind to its target to act …

– antibiotics are again no exception, but the target is the bacteria …

– the antibiotics can be studied in vitro to look at the extent of their

action at increasing concentrations (like the binding of a ligand to

its receptor in conventional pharmacology). This is

drug pharmacodynamics…

Pharmacokinetics ���� Pharmacodynamics...

Pharmacokineticsconc. vs time

Co

nc.

Time0 25

0.0

0.4

Pharmacodynamicsconc. vs effect

10-3Conc. (log)

Eff

ect

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 9

PK/PDeffect vs time

Time

Eff

ect

0

1

0

Time 10Conc. (log)

Example of a pharmacodynamic relationship

Emin

Emax

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 10Barcia-Macay et al. Antimicrob. Agents Chemother. 2006; 50(3):841-51

MIC

And what if we put pharmacokinetics ?

Emin

Emax

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 11

MIC

Cmin-Cmax

Barcia-Macay et al. Antimicrob. Agents Chemother. 2006; 50(3):841-51

And what if we put pharmacokinetics ?

low concentration dependency

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 12

Cmin-Cmax

high concentration dependency

Barcia-Macay et al. Antimicrob. Agents Chemother. 2006; 50(3):841-51

From Pharmacokinetics to Pharmacodynamics of AB …

Peak / MIC

AUC / MIC

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 13

Time > MIC

AUC / MIC

A simple dynamic model …

Drug Conc.

Inflow = Clearance

Fresh

MediumWaste

Pump

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 14

AUC

TimeV

T1/2 = 0.693 * V/Cl

Sampling of

Drug, Bacteria

Adapted from M.N. Dudley, ISAP / FDA Workshop, March 1st, 1999

Peak

Pharmacodynamics: the basic question …

Which antibiotics are

• time-• AUC• peak-

dependent

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 15

in clinically meaningful

conditions ?

• peak-

Available antibiotics can be divided in 3 groups :

• time - dependent (T > MIC)

• AUC / MIC - dependent

Main PK/PD properties of antibiotics

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 16

• AUC / MIC - dependent

• both AUC / MIC and peak / MIC -dependent

Antibiotics Group # 1 (after W.A. Craig, 2000; revised 2002 and 2003)

1. Antibiotics with time-dependent effects and no or little persistent effects

PK/PD parameter GoalAB

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 17

PK/PD parameter

Time above

MIC

Goal

Maximalizethe exposure

time

AB

β-lactams time above the MIC

How long should you stay above the MIC ?

• cefotaxime

• neutropenic mice

• K. pneumoniae

40 %

Moderate infections

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 18

• K. pneumoniae

• lung infection

100 %

Serious infections

Do all β-lactams have similar PK/PD properties ?...

different pathogens

• same shape of

dose response

• diff. In T > MIC

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 19

• diff. In T > MICfor a static effect

(penicill. > carbap.)

• diff Emax

(penicill. < carbap.)

Andes & Craig Int. J. Antimicrob. Agents 2002, 19: 261-268

Dosing amoxycilline for respiratory tract infections in Belgium

Sensitivity of S. pneumoniae to amoxycillin

cu

mu

lati

ve %

of

str

ain

s

75

100

1000 mg3 x / j

500 mg

Dose and schedule for T > CMI = 50 %

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 20

CMIMIC data: J. Verhaegen et al., 2001

cu

mu

lati

ve %

of

str

ain

s

0.01 0.10 1.000

25

50500 mg3 x / j

500 mg2 x / j

S I R

Antibiotics Group # 2 (after W.A. Craig, 2000; revised 2002 and 2003)

2. Antibiotics with time-dependent effects, no or little influence of concentration, but marked, persistent effects

PK/PD parameter GoalAB

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 21

PK/PD parameter

AUC / MIC

Goal

optimize the amount of

antibiotic

AB

glycopeptides

tetracyclines

macrolides

linezolid

streptogramins

Antibiotics Group # 3 (after W.A. Craig, 2000; revised 2002 and 2003)

3. Antibiotics with concentration-dependent bactericidal activity and prolonged persistent effects (post-antibiotic effects)

PK/PD parameter GoalAB

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 22

PK/PD parameter

Peak andAUC / CMI

Goal

optimize the peak and

the amount of antibiotic

AB

aminoglycosides

fluoroquinolones

daptomycin

ketolides

Aminoglycosides: get a peak !

1. Appropriate mode of

administration

IV route

2. Calculation of the necessary

peak value

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 23

peak value

minimal peak: = MIC / 8

3. Calculation of the adequate dosis

peak = dosis / Vd

dosis = peak x Vd

dosis = MIC x 8 x Vd

Aminoglycosides: why a peak ?

Aminoglycosides are concentration-dependent

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 24

concentration-dependent drugs in the clinically meaningful concentration range ...

Aminoglycosides: why a peak ?

Clinical efficacy

is linked to

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 25

is linked to

peak/MIC ratio

Fluoroquinolones: get a peak and an AUC !C

on

cen

trati

on

increase the amount administered,

in order to optimize AUC/MIC

and peak/MIC

should be > 125 *

should be > 10

Get both a peak and a AUC !!

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 26

Time (h)

Co

ncen

trati

on

MIC

Why an AUC / MIC > 125 for fluoroquinolones ...

AUC / MIC

is

one parameter …

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 27

Forrest et al., AAC, 1993

one parameter …

What do you mean by PEAK /MIC > 10 and AUC / MIC > 100

low ratioMIC

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 28

high ratio

AUC24h = dose / clearance

MIC

AUC/MIC24h =125 : a magical number??

125 was the limit below which failure

rates became unacceptable because of

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 29

rates became unacceptable because of

either

• a large MIC

• or a too low dosage (AUC is proportional to the dosage)

Is 125 good for all ??

80

100

Perc

ent m

ort

alit

y

Mo

rtali

ty (

%) 80

100

The saga of S. pneumoniae ...

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 30

3 30 30010 100 1000

0

20

40

60

24 hr AUC/MICP

erc

ent m

ort

alit

y

neutropenic

Emax at

125 ...

24 Hr AUC/MIC

Mo

rtali

ty (

%)

1 2.5 5 10 25 50 100

0

20

40

60

non-neutropenic

Emax at

30 ...

How to optimize the AUC / MIC ratio ?

AUC = dosis / Cl

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 31

Adjust the daily dosis

~ target AUC

Adapt the number of administrations

~ pharmacokinetics of the drug

10-2

1

10-4

10-6

Mutant Prevention Concentration …

"Classic" bactericidal effect

Su

rviv

ing

bacte

ria

MIC 99 = 0.8

poorly sensitive organisms…

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 32

0.01 0.10 1.00 10.00

concentration

10

10-8

10-10 MPC 10 = 9

Dong et al; AAC 43:1756-1758

Elimination

of resistant

organisms

Su

rviv

ing

bacte

ria

10-2

1

10-4

10-6

Mutant Prevention Concentration …S

urv

ivin

g b

acte

ria

MIC 99 = 0.8

Concentration which

will inhibit the majority

of the organisms

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 33

0.01 0.10 1.00 10.00

concentration

10

10-8

10-10 MPC 10 = 9

Dong et al; AAC 43:1756-1758

Su

rviv

ing

bacte

ria

Concentration

needed to

prevent the

selection of

resistant

organisms

"Window" where selection of mutants/resistants may take place …

MPC

co

nce

ntr

atio

n

Mutation selection window

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 34

Time after administration

MIC

MPC

co

nce

ntr

atio

n

MSW

concept from Drlica & Zhao, Rev. Med. Microbiol. 2004, 15:73-80

Which are the MPC values compared to

- MIC for S. pneumoniae

- Cmax for a standard dose ?

Molecule MIC MPC

levoflox. 1 8

Cmax

≈ 6(500 mg)

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 35

levoflox. 1 8

moxiflox. 0.25 1

Adapted from D. Croisier, 2005, Bondeau et al., 2001, and Hansen et al, 2003

≈ 6

≈ 4

(500 mg)

(400 mg)

So, let us accept values with some degree of precaution

If you wish to prevent resistance

� peak / MIC > 10

(which covers the MPC)

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 36

(which covers the MPC)

If you believe your patient is not a

healthy mouse …

� AUC24h / MIC > 100

A proposal for PK/PD based-breakpoints for fluoroquinolones...

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 37

Van Bambeke F, Michot JM, Van Eldere J, Tulkens PM.

Quinolones in 2005: an update. Clin Microbiol Infect. 2005 Apr;11(4):256-80. PMID: 15760423

PK/PD in action …

Levofloxacin 500 mg

1X / jr

• AUC [(mg/l)xh] 47

• peak [mg/l] 5

� MICmax < 0.5

Moxifloxacin 400 mg60

80

100

% of sensitive strains

moxi

PK/PD breakpoint

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 38

Moxifloxacin 400 mg

1X /jr

• AUC [(mg/l)xh] 48

• peak [mg/l] 4.5

� MICmax < 0.50

20

40

60

0.015 0.03 0.06 0.125 0.25 0.5 1 2 4

MICMIC data: J. Verhaegen et al., 2003

levo

A clinical algorithm ...

Knowledge or ou “educated” suspicion of the causative agent

Pathology andepidemiology

Local MIC data

Is the organism probably highly

susceptible ?

noyes

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 39

susceptible ?

Obtain an MIC

Use common dosage but with attention to PK/PD

Adjust the dosage on a full PK/PD basis

S / I / Ris

insufficient !!

Success ?

re-evaluate• the dosage

no

Consider

yes

A clinical algorithm (follow.) ...

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 40

• the dosage• the therapeutic scheme• the antibiotic classbased on PK/PD properties

step-down therapyif acceptable on a microbiological

point of view

Use these pieces of information to establish recommendations based on local epidemiology and on the knowledge of the

PK/PD properties and of the risk for resistance

And what about health care costs ?

Pharmacoeconomics

Economic

• cost minimization

• cost benefit

• cost effectiveness

Humanistic

• quality of life• patient's preference

• patient's satisfaction

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 41

• Pharmacoeconomics of antibiotics is still largely underdeveloped outside the USA

(but US-based models cannot easily be applied);

• However, comparisons identifying differences in

– amount of money needed to reach a given (better ? ) clinical outcome;

– expenses related to the same (or better) quality of life and patient's satisfaction;

may already suggest interesting avenues for further fine-tuning therapeutic guidelines

• cost effectiveness• cost utility

• patient's satisfaction

L. Sanchez, In Pharmacotherapy, DiPiro et al. eds, p.2, 1999

Rational bases for the choice of an antibiotic

• Know your LOCAL epidemiology

� obtain MIC distributions from your microbiologists…

• know the PK profile of the drugs you consider to purchase

�aim at obtaining > 90 % efficacy against the organisms of interest (AUC, peak, time above MIC) with a standard dosage, …

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 42

dosage, …

• include a safety margin (MPC …)

• Compare products on that basis first …

• Remember that

• no antibiotic (if possible) is the best…

• but that treatment failures (when treatment is needed) cost a lot …

Please, act …

W.A. Craig, MDM.N. Dudley, Pharm.G.L. Drusano, MDJ.J. Schentag, Pharm.A. McGowan, MDX. Zao, PhD

Tunis - 18-04-06PD of antibiotics: correlation between kinetics and activity 43

www.antiinfectieux.org

F. Van Bambeke, Pharm.A. Spinewine, Pharm.S. Carryn, Pharm.H. Chanteux, Pharm.H. Servais, Pharm....

X. Zao, PhDV. Firsov, MDS. Zinner, MDA. Dalhoff, PhD...

www.isap.org