william a. craig, md university of wisconsin madison, wisconsin
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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Pharmacodynamics of MASKO Compounds (Macrolides, Azalides,
Streptogramins, Ketolides, and Oxazolidinones)
William A. Craig, MD
University of Wisconsin
Madison, Wisconsin
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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
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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
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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
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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
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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
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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
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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
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-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
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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)
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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
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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
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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
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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
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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
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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
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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
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Impact of Dosing Interval on Static Doses for ABT-773 Against
S. aureus ATCC 29213
1
10
100
q3h q6h q12h q24h
S. aureus
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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
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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
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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
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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%
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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
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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%
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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%
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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%
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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
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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
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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
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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
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RESULTS
Clarithromycin
Strains MICs (mg/L)
MSSP 0.03-0.06
MRSP (Erm) 8->128
MRSP (Mef) 0.5-4
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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.
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-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
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Parmacodynamic Breakpoints forNew Macrolides
Drug Site PD Breakpoint
Clarithromycin Serum 0.5-2
Azithromycin Serum 0.12-0.5
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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
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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%
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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
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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
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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
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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
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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
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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
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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