Transcript Pharmacodynamics of Antimicrobials in Animal Models

Pharmacodynamics of Antimicrobials
in Animal Models
William A. Craig, M.D.
University of Wisconsin-Madison
Effect of Increasing Concentrations
on Killing of Pneumococci
in Thighs of Neutropenic Mice
Telithromycin
Log10 CFU per Thigh
8
Azithromycin
Clarithromycin
6
4
40 mg/kg
10 mg/kg
2.5 mg/kg
18.8 mg/kg
4.7 mg/kg
1.17 mg/kg
2
0
2
4
CFU = colony-forming unit.
6
0
2
4
40 mg/kg
10 mg/kg
2.5 mg/kg
6
0
2
Time (hours)
Craig WA, et al. 40th ICAAC Toronto, Ontario, September 17-20, 2000.
4
6
In Vivo PAE for Azithromycin with
Streptococcus pneumoniae ATCC 10813
in Thighs of Neutropenic Mice
Log10 CFU/Thigh
10
9
8
PAE = 11.0 Hrs
7
6
5
4
Control
Azi 8 mg/kg
T>MIC
3
0
2
4
6
8
12
Time (Hours)
18
24
Patterns of Antimicrobial Activity
 Concentration-dependent killing and prolonged
persistent effects
 Seen with aminoglycosides, quinolones, daptomycin,
ketolides, amphotericin B and echinocandins
 Goal of dosing regimen: maximize concentrations
 AUC/MIC and Peak/MIC major parameters
correlating with efficacy
Patterns of Antimicrobial Activity
 Time-dependent killing and minimal or no
persistent effects
 Seen with all beta-lactams and flucytosine
 Goal of dosing regimen: optimize duration of
exposure
 Time above MIC major parameter correlating
with efficacy
Patterns of Antimicrobial Activity
 Time-dependent killing and moderate to prolonged
persistent effects
 Seen with macrolides, azithromycin, clindamycin,
tetracyclines, oxazolidinones, streptogramins,
glycopeptides and azoles
 Goal of dosing regimen: optimize amount of drug
 AUC/MIC major parameter correlating with efficacy
Neutropenic Murine Thigh and
Lung Infection Models
• Cyclophosphamide 150 and 100 mg/kg at 4 and 1
day before infection
• Thigh infection produced by injection of 0.1 ml of
107 CFU/ml 2 hrs before treatment
• Lung infection produced by 45 min aerosol of 109
CFU/ml 14 hrs before treatment
• 107-8 CFU/g in thigh or lung at start of therapy
Correlation of Pharmacodynamic Parameters
with Efficacy
• Use neutropenic murine thigh-and lung-infection models
• Evaluate 20-30 different dosing regimens (5 different
total doses given at 4-6 different dosing intervals)
• Measure efficacy from change in Log10 CFU per thigh or
lung at the end of 24 hours of therapy
• Correlate efficacy with various pharmacodynamic
parameters (Time above MIC, peak/MIC, 24-Hr
AUC/MIC)
Correlation of PK/PD Parameters with Efficacy of
Temafloxacin against Streptococcus pneumoniae
in Thighs of Neutropenic Mice
Log10 CFU/Thigh at 24 Hrs
10
8
6
4
2
0
10
100
1000
24-Hr AUC/MIC
1
10
100
Peak/MIC
1000 0
25
50
75
100
Time Above MIC
Craig in Antimicrobial Pharmacodynamics in Theory and Clinical Practice, p 1, 2002
Correlation of PK/PD Parameters and Efficacy
for Ceftazidime against Klebsiella pneumoniae
in a Murine Pneumonia Model
Log10 CFU/Thigh at 24 Hrs
10
9
8
7
6
5
4
3
2
10
100
1000
24-Hr AUC/MIC
1
10
100
1000
Peak/MIC
0
25
50
75
100
Time Above MIC
Craig in Antimicrobial Pharmacodynamics in Theory and Clinical Practice, p 1, 2002
PK/PD Parameters
Does the magnitude of the parameter vary markedly with:
1. different animal species
2. the dosing regimen?
3. different drugs within the same class?
4. different organisms ?
5. different sites of infection (e.g. blood, lung,
peritoneum, soft tissue)?
6. the presence of neutrophils?
Mathematical Analysis of
Dose-Response Data from Animal Models
after 24 Hours of Therapy
9
S
t
a
t
i
c
D
o
s
e
8
7
Log 10 CFUperThigat24Hrs
6
E
m
a
x
P
5
0
5
1
0
1
L
o
g
K
i
l
l
3
0
1
0
0
D
o
s
e
(
m
g
/
k
g
/
6
h
r
s
)
Nonlinear regression and
Hill equation to estimate
Emax (difference from
untreated control), P50
(dose giving 50% of
Emax) and slope (N) of
the dose-response
relationship
3
0
0
CFU=
(Emax) DoseN
DoseN + P50N
PK/PD Parameters: -Lactams
 Time above MIC is the important parameter
determining efficacy of the -Lactams
 T>MIC required for static dose vary from 25-40% of
dosing interval for penicillins and cephalosporins to
10-25% for carbapenems
 Free drug levels of penicillins and cephalosporins
need to exceed the MIC for 40-50% of the dosing
interval to produce maximum survival
Time Above MIC Required for a Static
Effect After 24-hrs of Therapy with Three
ß-Lactam Classes
Time Above MIC (Percent of Dosing Interval)
Drug
Cephalosporins
q1-2 h
53 ± 20
q3-4h
43 ± 15
q6-8h
42 ± 14
q12-24h
35 ± 11
Penicillins
29 ± 10
31 ± 14
34 ± 16
31 ± 12
Carbapenem
20 ± 4
26 ± 10
23 ± 6
20 ± 4
Craig et al 33rd ICAAC, 1993 (Abstract 86)
Time Above MIC Required for a Bacteriostatic
Effect with Four Cephalosporins
Time Above MIC (% of Dosing Interval)
Drug
Enterobacteriaceae S. pneumoniae
S.aureus
Ceftazidime
36 (27-42)
39 (35-42)
20,25
Cefepime
35 (29-40)
37 (33-39)
21,24
Cefotaxime
38 (36-40)
38 (36-40)
22,25
Ceftriaxone (T)
62 (56-69)
64 (59-68)
46,69
Ceftriaxone (F)
38 (34-42)
39 (37-41)
24,26
Relationship Between MIC and T>MIC for the
Static Dose for Cefpodoxime and Cefditoren
with Various Strains of S. pneumoniae
Time Above MIC (%)
70
Cefpodoxime (T)
Cefditoren (T)
Cefditoren (F)
60
50
40
30
20
0.016 0.06
0.25
1
MIC (mg/L)
4
16 Urban et al. 19th ICC 1995
(Abstract 2229); Craig, Andes
40th ICAAC (Abstract 2248);
Literature Review for T>MIC for Beta-Lactams
Versus Mortality in Animal Models
• At least 48 hrs of treatment
• Pharmacokinetics provided
to calculate magnitude of
PK/PD parameter
• Mortality recorded within 24
hrs after last dose of drug
• Data from 3 animal species
and 4 sites of infection
Mortality (%)
• Mortality 80-100% in
untreated controls
100
Cephalosporins
Penicillins
80
60
40
20
0
0
20
40
60
80
100
Time Above MIC (% of Interval)
Craig CID 26:1, 1998; Nicolau et al. AAC 44:1291, 2000
Relationship Between T>MIC and Bacterial
Eradication with Beta-Lactams in Otitis Media
(Circles) and Maxillary Sinusitis (Squares)
 Time above MIC calculated
from serum levels and MICs
for different organisms
Craig & Andes, Pediatr Infect Dis J
15:255, 1996; Dagan et al JAC
47:129, 2001;Dagan et al Pediatr
Infect Dis J 20:829, 2001
100
Bacterial Eradication (percent)
 Bacteriologic cure for different
ß-lactams with S. pneumoniae
and H. influenzae from double
tap studies in acute otitis media
and acute maxillary sinusitis
80
60
40
PSSP
PISP-PRSP
H. influenza
20
0
0
20
40
60
80
Time Above MIC (percent)
100
PK/PD Paramters with Fluoroquinolones
•
24-hr AUC/MIC is the parameter that best
predicts activity of fluoroquinolones.
• 24-hr AUC/MIC (using free drug levels) for
static dose range from 25-50 for most
organisms in neutropenic mice
24-Hr AUC/MIC with Total and Free Drug for
the Static Dose of Different Fluoroquinolones
with S. pneumoniae ATCC 10813
24-Hr AUC/MIC
160
120
Total
Free
80
40
0
Gati
Sita
Moxi
Gemi
Garen
Andes & Craig 40th and 41st ICAAC, 2000 and 2001
Levo
Cipro
Pharmacodynamics of Fluoroquinolones
 Magnitude of 24-Hr AUC/MIC in serum required
for 90-100% survival in animal infection models
varies from about 25 in immunocompentent
animals for Streptococcus pneumoniae to about
100 in immunocompromised animals for gramnegative bacilli
 24-Hr AUC/MIC values of 25 and 100 are
equivalent to averaging one and four times the
MIC over a 24-hr period
Relationship Between 24 Hr AUC/MIC
and Mortality in Animals for Fluoroquinolones
against Gram-Negative Bacilli
Mortality (%)
100
80
60
40
20
0
2.5
10
25
100
250
24-Hr AUC/MIC
Andes & Craig, Int J of Antimicrob Agents 19:259, 2002
1000
Comparison of Relationships Between 24-Hr
AUC/MIC and Efficacy against Pneumococci
for Fluoroquinolones in Animals and Patients
Animals - Literature Review
Patients with CAP and AECB
Mortality (%)
100
80
60
40
20
0
1
2.5
10
25
100 250
1000
• 58 patients enrolled in a
comparative trial of
levofloxacin vs gatifloxacin
• Free-drug 24-hr AUC/MIC
<33.7, the probability of a
microbiologic cure was 64%
• Free-drug 24-hr AUC/MIC
>33.7, the probability of a
microbiologic cure was 100%
24-Hr AUC/MIC
Andes & Craig, Int J of Antimicrob Agents
19:259, 2002
Ambrose et al AAC 45:2793, 2001
Static Dose (mg/kg/24 hrs)
Impact of Dosing Interval on Static Dose
for Amikacin against K. Pneumoniae and E. coli
in Mice with Normal and Impaired Renal Function
1000
K. pneumoniae
E. coli
Normal
T1/2=17 min
100
K. pneumoniae
E. coli
Renal Impaired
T1/2=104 min
10
1
3
6
12
24
Dosing Interval (Hours)
Reddington and Craig, JAC 1995
Static Dose (mg/kg/24 Hrs)
Impact of Dosing Frequency on Static Dose
for Macrolides and Azalides with
Streptococcus pneumoniae ATCC 10813
250
100
50
Drug
25
Erythromycin
Clarithromycin
Azithromycin
10
5
2.5
1
3
6
12
24
Dosing Interval (Hours)
24-Hr AUC/MIC with Total and Free Drug for
the Static Dose of Different Macrolides, Ketolides
and Clindamycin with S. pneumoniae ATCC 10813
24-Hr AUC/MIC
1000
100
Total
Free
10
1
Erythro
Roxi
Craig et al. 42nd ICAAC, 2002
Clari
Azi
Clinda
ABT773
HMR6004
Animal Models for Susceptibility
Breakpoint Determinations
• Simulate human pharmacokinetics in animals
(induce renal impairment with uranyl nitrate)
• Infect groups of animals with organisms with
varying MICs
• Treat the animals for at least 24 hours with
dosage regimen used to treat human infections
• Find the MIC value that separates bacterial
killing from bacterial growth
Effect of Amoxicillin (7 mg/kg) on 17 Strains of
S. pneumoniae in Thighs of Neutropenic Mice
3
2
1
0
ChangeiLogOCvFeUr24Hours
1
2
3
0.160.3
00..66
00..256
0.250.5
00..55
12..00
24..00
44..00
5.6
4
M
I
C
s
(
m
g
/
L
)
PK/PD Parameters
Does the magnitude of the parameter vary markedly with:
1. different animal species NO
2. the dosing regimen? NO
3. different drugs within the same class? NO
providing free drug levels are used
4. different organisms ? Some (S. aureus-ß-lactams)
5. different sites of infection (e.g. blood, lung,
peritoneum, soft tissue)? NO
6. the presence of neutrophils? YES, some drugs
more than others