Pharmacodynamics of MASKO Compounds (Macrolides, Azalides,

Streptogramins, Ketolides, and Oxazolidinones)

William A. Craig, MD

University of Wisconsin

Madison, Wisconsin

Pharmacodynamics• Pattern of killing

• PAEs, PA-SMEs, and PALEs

• PK/PD parameters determining efficacy (dose fractionation studies)

• Magnitude of PK/PD targets (importance of protein binding)

• Comparison of different sites of infection

• Effect of neutrophils

Pattern of Bacterial Killing• Except for the ketolides, the MASKO

compounds show very little concentration-dependent killing both in vitro and in vivo in neutropenic animals

• Killing with concentration-independent drugs is always maximal when levels are above 1-4 times the MIC for 100% of the dosing interval

• In animals with neutrophils, there is a tendency for more concentration-dependent killing

Impact of Increasing Doses on Killing of Streptococcus pneumoniaeStreptococcus pneumoniae ATCC 10813 ATCC 10813

Time (Hours)

0 2 4 6

Log

10 C

FU

per

Thi

gh

2

4

6

8

18.8 mg/kg 4.7 mg/kg 1.17 mg/kg

0 2 4 6

40 mg/L 10 mg/L2.5 mg/L

Telithromycin Azithromycin

Impact of Increasing Doses on Killing of Streptococcus pneumoniae CDC 140

Time (Hours)

0 2 4 6

Lo

g 10

CF

U p

er

Th

igh

2

4

6

8

18.8 mg/kg 4.7 mg/kg 1.17 mg/kg

0 2 4 6

40 mg/L 10 mg/L2.5 mg/L

Telithromycin Azithromycin

Impact of Increasing Doses on Killing of Streptococcus pneumoniae ATCC 10813

Time (Hours)

0 2 4 6

Lo

g 10

CF

U p

er

Th

igh

2

4

6

816 mg/kg 4 mg/kg 1 mg/kg

0 2 4 6

40 mg/L 10 mg/L2.5 mg/L

Clarithromycin

ABT-773

Log

s of

Kil

ling

at

6 H

r

1.2 mg/kg 4.7 mg/kg 18.8 mg/kg

ATCC 10813

CDC 140

CDC 141

Impact of Increasing Doses of Telithromycin on Killing of Streptococcus pneumoniae

in Thighs of Neutropenic Mice

Log

s of

Kil

ling

at

6 H

r

0.6 mg/kg 2.5 m/kg 10 mg/kg

ATCC 10813

CDC 140

CDC 141

Impact of Increasing Doses of ABT 773 on Killing of Streptococcus pneumoniae

in Thighs of Neutropenic Mice

-5.0

-4.0

-3.0

-2.0

-1.0

0.0

1.0

Log

s of

Kill

ing

at 6

Hrf

2.5 mg/L 10 mg/L 40 mg/L

ATCC 10813CDC 140CDC 141

Impact of Increasing Doses of Azithromycin on Killing of Streptococcus pneumoniae

in Thighs of Neutropenic Mice

Persistent Effects

MASKO compound produce moderate to prolonged persistent effects wiith various bacteris both in vitro and in vivo– moderate to prolonged in-vitro PAEs– moderate to prolonged PA-SMEs– moderate PALEs– moderate to prolonged in vivo PAEs

(prolonged even longer by the presence of neutrophils)

Pharmacodynamics of Linezolid

• Time-Dependent Killing Pattern

• Modest In-Vivo PAEs 3.6-3.8 hrs with PSSP

3.7-3.9 hrs with MSSA

PAE Against S. pneumoniae

Time (hours)3 6 9 12 15 18

Log

10 C

FU/T

high

5

6

7

8

9

10

Control20 mg/kg80 mg/kg

In Vivo PAE of Clarithromycin with Streptococcus pneumoniae ATCC 10813

in Thighs of Neutropenic Mice

Time (Hours)

0 2 4 6 9 12 18 24

Log 1

0 C

FU

/Th

igh

3

4

5

6

7

8

9

10

ControlClar 40 mg/kg

PAE = 4.8 Hrs

T>MIC

Time (Hours)

0 4 8 12 16 20 24

Lo

g 10

CF

U p

er

Th

igh

0

2

4

6

8

10

Control Tel 18.8 mg/kg

T>MIC

PAE = 5.8 Hrs

In Vivo PAE of Telithromycin withStreptococcus pneumoniae ATCC 10813

in Thighs of Neutropenic Mice

In Vivo PAE for Azithromycin with Streptococcus pneumoniae ATCC 10813

in Thighs of Neutropenic Mice

Time (Hours)

0 2 4 6 8 12 18 24

Lo

g 10

CF

U/T

hig

h

3

4

5

6

7

8

9

10

ControlAzi 8 mg/kg

PAE = 11.0 Hrs

T>MIC

Pharmacodynamic Characterisitics Persistent

Drug Killing Pattern Effects

Macrolides Time-Dependent Moderate

Azithromycin Time-Dependent Prolonged

Ketolides Conc-Dependent Moderate

Streptogramins Time-Dependent Mod-prolonged

Oxazolidinones Time-Dependent Mod-prolonged

Impact of Dosing Frequency on Static Dose for Macrolides and Azalides with

Streptococcus pneumoniae ATCC 10813

Dosing Interval (Hours)

3 6 12 24

Sta

tic D

ose

(mg/

kg/2

4 H

rs)

1

2.5

5

10

25

50

100

250

Erythromycin Clarithromycin Azithromycin

Drug

Impact of Dosing Frequency on Static Dose for Macrolides, Azalides and Ketolides with Streptococcus pneumoniae ATCC 10813

Dosing Interval (Hours)

3 6 12 24

Sta

tic D

ose

(mg/

kg/2

4 H

rs)

1

2.5

5

10

25

50

100

250

ABT-773Telithromycin

Impact of Dosing Interval on Static Doses for ABT-773 Against

S. aureus ATCC 29213

1

10

100

q3h q6h q12h q24h

S. aureus

Impact of Dosing Interval on Doseof Synercid (Quinupristin + Dalfopristin)

Required for Efficacy in Neutropenic Mice

1

10

100

1000

Dai

ly D

ose

(mg/

kg)

6-Hr12-Hr24-Hr

S.aureus S. pneumoniae

Craig and Ebert, ICAAC 1996

Impact of Dosing Interval on Dose of Linezolid Required for Efficacy in

Neutropenic Mice

1

10

100

1000

Dai

ly D

ose

(mg/

kg)

1-Hr3-Hr6-Hr12-Hr24-Hr

S.aureus S. pneumoniae

Andes et al, ICAAC 1996

Pharmacokinetics of Macrolides, Azalides and Ketolides in Infected Neutropenic Mice

at a Dose of 18.8 mgkg

Drug Cmax Half-life AUC

Erythromycin 2.8 0.8 4.0

Roxithromycin 2.7 0.8 3.9

Clarithromycin 3.0 1.1 5.5

Azithromycin 1.9 1.8 4.1

Telithromycin 8.5 2.5 30

HMR 3004 6.2 0.9 10

ABT-773 7.2 2.6 28

Relationships Between PK/PD Parameters and Efficacy of ABT-773 with

Streptococcus pneumoniae ATCC 10813

Peak/MIC

1 10 100 1000 10000

Time Above MIC (%)

0 20 40 60 80 100

AUC/MIC

10 100 1000 10000

Log

10 C

FU

/Thi

gh

2

4

6

8R2 = 88%

R2 = 78%

R2 = 64%

Relationship Between PK/PD Parameters and Efficacy of Clarithromycin with

Streptococcus pneumoniae ATCC 10813

24-Hr AUC/MIC

10 100 1000

Lo

g 10

CF

U p

er

Th

igh

at

24

Ho

urs

4

5

6

7

8

9

10

11

Time Above MIC (%)

0 20 40 60 80 100

4

6

8

10

Relationship Between PK/PD Parameters and Log10 CFU/Thigh After 24 Hrs of Therapy with

Linezolid at Different Dosing Intervals

Time Above MIC (%)

0 20 40 60 80 100

Cha

nge

in L

og C

FU

/Thi

gh

-6

-4

-2

0

2

4

R2 = 84%

Relationship Between PK/PD Parameters and Log10 CFU/Thigh After 24 Hrs of Therapy with

Linezolid at Different Dosing Intervals

AUC/MIC

1 10 100 1000Cha

nge

in L

og C

FU

/Thi

gh

-6

-4

-2

0

2

4

R2 = 42%

Relationship Between PK/PD Parameters and Efficacy of AZD2562

Figure 4. Relationships Between PK/PD Parameters and CFU/Thigh of S. pneumoniae ATCC 10813

AUC/MIC

10 100 1000

CF

U/T

HIG

H a

t 24

Hrs

4

5

6

7

8

9

10

Peak/MIC

1 10 100

T>MIC

0 25 50 75 100

R2=94% R2=59% R2=46%

PK/PD Parameters and Efficacy

Drug PK/PD Parameter

Macrolides Time above MIC

Azithromycin 24-Hr AUC/MIC

Ketolides 24-Hr AUC/MIC

Streptogramins 24-Hr AUC/MIC

Oxazolidinones Time above MIC - 24-Hr AUC/MIC

Impact of DosingFrequency on Static Dose for Macrolides, Azalides and Ketolides with Streptococcus pneumoniae ATCC 10813

Dosing Interval (Hours)

3 6 12 24

Sta

tic D

ose

(mg/

kg/2

4 H

rs)

1

2.5

5

10

25

50

100

250

ABT-773Telithromycin Erythromycin Clarithromycin Azithromycin

PK/PD Parameters and Efficacy

Drug PK/PD Parameter

Macrolides 24-hr AUC/MIC

Azithromycin 24-Hr AUC/MIC

Ketolides 24-Hr AUC/MIC

Streptogramins 24-Hr AUC/MIC

Oxazolidinones 24-Hr AUC/MIC

24-Hr AUC/MIC with Total and Free Drug for the Static Dose of Different Macrolides

with S. pneumoniae ATCC 10813

0

20

40

60

80

100

120

140

Erythro Roxi Clari Azi

24-H

r A

UC

/MIC

for

Sta

tic D

ose

TotalFree

RESULTS

Clarithromycin

Strains MICs (mg/L)

MSSP 0.03-0.06

MRSP (Erm) 8->128

MRSP (Mef) 0.5-4

Change in CFU/Thigh with Strains of CSSP after 24 Hrs of Treatment (48 mg/kg/6 hrs)

and in Control Neutropenic Mice

-5

-4

-3

-2

-1

0

1

2

3

Lo

g C

FU

/Th

igh

CSSP-1 CSSP-2 CSSP-3 CSSP-4

Strain

Treated

Control

Change in CFU/Thigh with Strains of CRSP (due to Erm) after 24 Hrs of Treatment (48

mg/kg/6 hrs) and in Control Neutropenic Mice

0

0.5

1

1.5

2

2.5

3

Ch

ang

e in

Lo

g C

FU

per

T

hig

h o

ver

24 H

rs

CRSP-1 CRSP-2 CRSP-3 CRSP-4

Strain

Treated

Control

Change in CFU/Thigh with Strains of CRSP (due to Mef) after 24 Hrs of Treatment (48

mg/kg/6 hrs) and in Control Neutropenic Mice

-0.5

0

0.5

1

1.5

2

2.5

Ch

ang

e in

Lo

g C

FU

p

er T

hig

h o

ver

24

Hrs

1 2 3 4 5 6 7 8 9

CRSP Strain

Treated Control

24-Hr AUC/MIC for Free Drug with Susceptible and Resistant Strains

of Streptococcus pneumoniae

Drug None ERM MEF

Clarithromycin 24(13-34) NM 27 (NM)

Azithromycin 24(13-31) NM 20 (NM)

Telithromycin 121(66-182) 132(74-228) 86(16-164)

ABT-773 34(26-40) 50(34-58) 56(10-108)

NM = not measurable

Static Doses (mg/kg/24 hrs) in Lungs and Thigh with Azithromycin

Organism MIC Thigh Lung

ATCC 10813 0.06 12.2 14.3

3427 1.0 134 NM

Static Doses (mg/kg/24 hrs) in Lung and Thigh with Clarithromycin

Organism MIC Thigh Lung

ATCC 10813 0.03 3.6 5.7

3427 1.0 182 163

Impact of Resistance to Quinupristin or Dalfopristin on Activity in Animal Models

• Dalfopristin Resistance: No reduction in in-vivo activity with staphylococci (rabbit endocarditis and thigh infection) or pneumococci (thigh infection)

• Quinupristin Resistance: Reduced in-vivo activity (2- to 4-fold) with staphylocci (rabbid endocarditis and thigh infection) and pneumococci (thigh infection)

Fantin et al AAC 39:400, 1995Zarrouk et al AAC 44:1168, 2000Vesga et al ICAAC 1996

Impact of Neutrophils on Activity of Macrolides, Azalides, Ketolides and

Oxazolidinones with Strains of Streptococcus pneumoniae

Drug Normal Neutropenic Difference

Roxithromycin 5.0, 10 23, 29 4.6, 2.9

Clarithromycin 1.6, 8.2 11, 18 6.7, 2.2

Azithromycin 2.3, 4.2 7.4, 14 3.2, 3.4

Telithromycin 1.2, 4.4 5.5, 11 4.6, 2.5

HMR 3004 2.4, 4.4 7.9, 17 3.3, 3.9

ABT-773 1.5 3.9 2.6

24-Hr AUC/MIC with Total and Free Drug for the Static Dose of Different Macrolides

with S. pneumoniae ATCC 10813

0

20

40

60

80

100

120

140

Erythro Roxi Clari Azi

24-H

r A

UC

/MIC

for

Sta

tic D

ose

TotalFree

Conclusions

• For most drugs the 24-hr AUC/MIC of free drug is 20-35 for the static doses in neutropenic mice and 5-15 in normal mice

• This is equivalent to averaging 1-1.5 times the MIC over 24 hrs in neutropenic mice and 0.2-0.6 times the MIC over 24 hrs in normal mice.

• 90-100% survival is associated with a 2-2.5 log drop in CFU at 24 hours.

-lactams

Intracellular

Tissue conc’n (µg/ml)

0.5

12 12

0.5

<1.0

>40

Interstitial

S. pneumoniaeH. influenzaeM. catarrhalis

L. pneumophilaC. pneumoniae

Serum conc’n(mg/L)

Macrolides

Pathogens

Distribution of Antibiotics in the Body Affects Bacteriological Efficacy

M. pneumoniae

Parmacodynamic Breakpoints forNew Macrolides

Drug Site PD Breakpoint

Clarithromycin Serum 0.5-2

Azithromycin Serum 0.12-0.5

Clarithromycin and Azithromycin Levels in Plasma and Epithelial Lining

Fluid (ELF) of Healthy Adults

Clarithromycin Azithromycin

Time Plasma ELF Plasma ELF

4 Hrs 2.0 34.5 0.08 1.0

8 Hrs 1.6 26.1 0.09 2.2

12 Hrs 1.2 15.1 0.04 1.0

24 Hrs 0.2 4.6 0.05 1.2

AUC 25 550 1.4 28

Rodvold et al. Antimicrob Agents Chemother 41:1399, 1997

Relationship Between Epithelial Lining Fluid/Serum Ratio and

Alveolar Macrophage/Serum Ratio

Epithelial Lining Fluid/Serum

0.1 1 10 100

Alv

eola

r M

acro

phag

e/S

erum

0.01

0.1

1

10

100

1000

10000

R2=83%

Problems in Evaluating Macrolides in Animal Models

• Do not know if rodent models have the same magnitude of ELF/serum levels as seen in humans

• Many of the pneumococcal strains studied are also penicillin-resistant

• Penicillin-resistant pneumococci are less virulent in non-neutropenic rodents

Parmacodynamic Breakpoints forNew Macrolides

Drug Site PD Breakpoint

Clarithromycin Serum 0.5-2

Azithromycin Serum 0.12-0.5

Clarithromycin ELF 16-64

Azithromycin ELF 1-4

Relationship Between Magnitude of PK/PD Parameter and Efficacy in Double Tap Studies

in Otitis Media due to S. pneumoniae

Magnitude of Bacteriologic Drug MIC PK/PD Parameter Cure

Erythromycin S AUC/MIC=124 14/15 (93%)

Clarithromycin S AUC/MIC=250 12/12 (100%)

Azithromycin S AUC/MIC=50 15/16 (94%)

R AUC/MIC<0.1 3/14 (21%)

Klein Ped Inf Dis 12:973, 1993; Dagan et al AAC 44:43, 2000, Dagan et al

Ped Inf Dis 19:95, 2000

Relationship Between Magnitude of PK/PD Parameter and Efficacy in Double Tap Studies

in Otitis Media due to H. influenzae

Magnitude of Bacteriologic

Drug MIC PK/PD Parameter Cure

Erythromycin R AUC/MIC = 0.8 3/20 (15%)

Clarithromycin S (4) ? AUC/MIC = 2 3/15 (20%)

Azithromycin S (2) ? AUC/MIC = 1.5 13/35 (37%)

Klein Ped Inf Dis 12:973, 1993; Dagan et al AAC 44:43, 2000, Dagan et al

Ped Inf Dis 19:95, 2000

Pneumococcal Breakthrough Bacteremia

in Patients Treated with Macrolidesfor Community-Acquired Pneumonia

• 10% (4/41) outpatients treated with macrolides for CAP due to S. pneumoniae S. pneumoniae had breakthrough bacteremia - all strains had moderate resistance (efflux mechanism)

• 20-22% of cases of pneumococcal bacteremia due to macrolide-resistant strains occurred while on treatment with macrolides - about half these strains had moderate resistance (efflux mechanism)

Kelley et al Clin Infect Dis 31:1008, 2000Garau & Mederios ICMASKO, 2000

Resistance and Efficacy in CAP

• MICs of failures have been 4 mg/L or higher

• Values are close to predicted ELF values for azithromycin and lower than predicted ELF values for clarithromycin

• Protein present in ELF; could reduce efficacy of clarithromycin

Increasing Macrolide Resistance in Eight Counties Surrounding Atlanta

0%

20%

40%

60%

80%

100%

1994 1995 1996 1997 1998 1999

>=16

8

4

2

1

0.5

0.25

0.12

<=0.06