effect of increasing concentrations on killing of pneumococci in thighs of neutropenic mice
Post on 02-Jan-2016
23 Views
Preview:
DESCRIPTION
TRANSCRIPT
Pharmacodynamics of Antimicrobialsin Animal Models
William A. Craig, M.D.
University of Wisconsin-Madison
0 2 4 6
2
4
6
8
18.8 mg/kg 4.7 mg/kg 1.17 mg/kg
0 2 4 6
40 mg/kg 10 mg/kg2.5 mg/kg
0 2 4 6
40 mg/kg 10 mg/kg 2.5 mg/kg
CFU = colony-forming unit.
Craig WA, et al. 40th ICAAC Toronto, Ontario, September 17-20, 2000.
Telithromycin Azithromycin Clarithromycin
Time (hours)
Lo
g10
CF
U p
er T
hig
hEffect of Increasing Concentrations
on Killing of Pneumococci 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 C
FU
/Th
igh
3
4
5
6
7
8
9
10
ControlAzi 8 mg/kg
PAE = 11.0 Hrs
T>MIC
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
• 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
Neutropenic Murine Thigh and Lung Infection Models
• 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 Pharmacodynamic Parameters with Efficacy
Correlation of PK/PD Parameters with Efficacy of Temafloxacin against Streptococcus pneumoniae
in Thighs of Neutropenic Mice
24-Hr AUC/MIC
10 100 1000
Log
10 C
FU/T
high
at 2
4 H
rs
0
2
4
6
8
10
Peak/MIC
1 10 100 1000
Time Above MIC
0 25 50 75 100
Craig in Antimicrobial Pharmacodynamics in Theory and Clinical Practice, p 1, 2002
Correlation of PK/PD Parameters and Efficacyfor Ceftazidime against Klebsiella pneumoniae
in a Murine Pneumonia Model
24-Hr AUC/MIC
10 100 1000
Log
10 C
FU
/Thi
gh a
t 24
Hrs
2
3
4
5
6
7
8
9
10
Peak/MIC
1 10 100 1000
Time Above MIC
0 25 50 75 100
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
Nonlinear regression andHill equation to estimate Emax (difference from untreated control), P50 (dose giving 50% ofEmax) and slope (N) of the dose-responserelationship
Dose (mg/kg/6 hrs)10 30 100 300
Lo
g1
0 C
FU
pe
r T
hig
h a
t 2
4 H
rs
5
6
7
8
9
Static Dose
1 Log K ill
P50
Emax
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
Drug q1-2 h q3-4h q6-8h q12-24h Cephalosporins 53 ± 20 43 ± 15 42 ± 14 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 Static Effect After 24-hrs of Therapy with Three
ß-Lactam Classes
Time Above MIC (Percent 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
Time Above MIC Required for a Bacteriostatic Effect with Four Cephalosporins
Time Above MIC (% of Dosing Interval)
Relationship Between MIC and T>MIC for the Static Dose for Cefpodoxime and Cefditoren
with Various Strains of S. pneumoniae
MIC (mg/L)
0.016 0.06 0.25 1 4 16
Tim
e A
bo
ve M
IC (
%)
20
30
40
50
60
70
Cefpodoxime (T)Cefditoren (T)Cefditoren (F)
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
• Mortality 80-100% in untreated controls
• 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
0 20 40 60 80 100M
orta
lity
(%)
0
20
40
60
80
100
Cephalosporins Penicillins
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) Bacteriologic cure for different
ß-lactams with S. pneumoniae and H. influenzae from double tap studies in acute otitis media and acute maxillary sinusitis
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
Time Above MIC (percent)
0 20 40 60 80 100
Bac
teria
l Era
dica
tion
(per
cent
)0
20
40
60
80
100
PSSP
PISP-PRSP
H. influenza
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
0
40
80
120
160
Gati Sita Moxi Gemi Garen Levo Cipro
24-H
r A
UC
/MIC
Total
Free
Andes & Craig 40th and 41st ICAAC, 2000 and 2001
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 gram-negative 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
Andes & Craig, Int J of Antimicrob Agents 19:259, 2002
24-Hr AUC/MIC2.5 10 25 100 250 1000
Mor
talit
y (%
)
0
20
40
60
80
100
Comparison of Relationships Between 24-Hr AUC/MIC and Efficacy against Pneumococci
for Fluoroquinolones in Animals and Patients
• 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/MIC1 2.5 10 25 100 250 1000
Mor
talit
y (%
)
0
20
40
60
80
100
Animals - Literature Review Patients with CAP and AECB
Andes & Craig, Int J of Antimicrob Agents 19:259, 2002 Ambrose et al AAC 45:2793, 2001
Impact of Dosing Interval on Static Dose for Amikacin against K. Pneumoniae and E. coli
in Mice with Normal and Impaired Renal Function
Dosing Interval (Hours)
3 6 12 24Sta
tic D
ose
(mg/
kg/2
4 hr
s)
1
10
100
1000
K. pneumoniaeE. coliNormal T1/2=17 min K. pneumoniae E. coliRenal Impaired T1/2=104 min
Reddington and Craig, JAC 1995
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
(m
g/k
g/2
4 H
rs)
1
2.5
5
10
25
50
100
250
Erythromycin Clarithromycin Azithromycin
Drug
24-Hr AUC/MIC with Total and Free Drug for the Static Dose of Different Macrolides, Ketolides
and Clindamycin with S. pneumoniae ATCC 10813
1
10
100
1000
Erythro Roxi Clari Azi Clinda ABT-773
HMR-6004
24-H
r A
UC
/MIC
Total
Free
Craig et al. 42nd ICAAC, 2002
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
-4
-3
-2
-1
0
1
2
3
MICs (mg/L)
5.6
4.04.0
4.0
2.02.0
1.00.5
0.50.5
0.2
5
0.2
5
0.0
6
0.0
3
0.0
6
0.0
6
0.0
16
Ch
an
ge
in L
og
CF
U
Ove
r 2
4 H
ou
rs
PK/PD ParametersDoes 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
top related