Transcript Pharmacokinetic and Pharmacodynamic Factors in

Pharmacodynamics and the
Dosing of Antibacterials
William A. Craig, MD
University of Wisconsin and
Wm S. Middleton Memorial VA Hospital
Madison, WI USA
PRESENTATION OUTLINE
• History of pharmacodynamics
• Different patterns of antimicrobial activity
• Pharmacodynamic target setting in animal
models
• Identify major factors that alter the
pharmacodynamic target
• Correlation between animal and human
studies
• Uses of pharmacodynamic modeling
• Application to susceptibility breakpoints for
gram-negative bacilli
What is Pharmacodynamics ?
• Relationship between concentration
and pharmacologic and toxicologic
effects of a drug
• Relationship between measures of
in vivo drug exposure and
microbiologic (and clinical) efficacy
Why Interest in Pharmacodynamics?
• Always occurs when there is narrow
difference between MICs and obtainable
drug concentrations
- early days of penicillin in 1940s (low
doses used)
- appearance of pseudomonas infections
in 1960s and 1970s (high MICs)
- appearance of resistant Streptococcus
pneumoniae and other bacteria in
1990s
Log CFU per Thighog
Bactericidal Activity of Tobramycin
and Ticarcillin against
Pseudomonas aeruginosa
9
Tobramycin
Ticarcillin
8
7
6
5
4
0
2
4
4 mg/kg
12 mg/kg
20 mg/kg
6
8
12
0
Time (hours)
Vogelman et al. J Infect Dis 157, 1988
2
4
300 mg/kg
800 mg/kg
2400 mg/kg
1st Pattern of Antimicrobial Activity
 Concentration-dependent killing and
prolonged persistent effects
 Seen with quinolones, aminoglycosides,
ketolides, and daptomycin
 Goal of dosing regimen: maximize
concentrations
2nd Pattern of Antimicrobial Activity
 Time-dependent killing and minimal or
no persistent effects (except with
staphylococci)
 Seen with all beta-lactams
 Goal of dosing regimen: optimize
duration of exposure; maximum killing
when levels constantly above 4-5 times
MIC
3rd Pattern of Antimicrobial Activity
 Time-dependent killing and moderate to
prolonged persistent effects
 Seen with macrolides, azithromycin,
clindamycin, tetracyclines, glycylcyclines,
streptogramins, glycopeptides,
oxazolidinones, deformylase inhibitors
 Goal of dosing regimen: optimize amount
of drug; maximum killing when T>MIC
100%
Major Goal of Pharmacodynamics
Establish the PK/PD TARGET required
for effective antimicrobial therapy
- identify which PK/PD indice (T>MIC,
AUC/MIC, peak/MIC) best predicts in
vivo antimicrobial activity
- determine the magnitude of the
PK/PD parameter required for in vivo
efficacy (static effect, 1 or 2 log kill)
Neutropenic Mouse Thigh-Infection Model
1. Neutropenia induced by 2
injections of cyclophosphamide
on days -4 and -1
4. Thighs removed,
homogenized, serially
diluted and plated for
CFU determinations
2. Bacteria injected into
thighs on day 0 (106-7)
3. Treatment (usually given SQ)
started 2 hr after infection and
continued for 1-5 days
Time Course of Antimicrobial Activity of
Ciprofloxacin Against Klebsiella ATCC 43816
in Lungs of Neutropenic Mice
Log10 CFU/Lung
Death
Death
Death
10
Saline
0.29 q 6h
1.17 q 6h
4.69 q 6h
18.8 q 6h
75.0 q 6h
8
6
4
2
0
1
2
3
Days
4
5
Log10 CFU / Thigh at 24 Hrs
Correlation of PK/PD Parameters with Efficacy
Levofloxacin against Streptococcus
pneumoniae in Thighs of Neutropenic Mice
10
8
6
4
2
0
10
100
1000 1
24-Hr AUC/MIC
10
100
Peak/MIC
Andes & Craig, Int J Antimicrob Agents, 2002
1000 0
25
50
75 100
Time Above MIC
Log10 CFU/Thigh at 24 Hrs
Relationship Between PK/PD Parameters and
Efficacy for Cefpirome against Klebsiella
pneumoniae in Lungs of Neutropenic Mice
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 Antimicrobial Pharmacodynamics in Theory and Practive 2002
Mathematical Analysis of DoseResponse Data from Animal Models
after 24 Hours of Therapy
9
Log 10 CFUperThigat24Hrs
Nonlinear regression
and Hill equation to
S
t
a
t
i
c
D
o
s
e
8
estimate Emax
(difference from
7
untreated control), P50
E
m
a
x
(dose giving 50% of
6
Emax) and slope (N)
P
5
0
of the dose-response
5
1
L
o
g
K
i
l
l
relationship
N
(Emax)
Dose
1
0
3
0
1
0
0
3
0
0
CFU=
D
o
s
e
(
m
g
/
k
g
/
6
h
r
s
)
DoseN + P50N
Craig Diagn Microbiol Infect Dis 1995
Factors That Affect the Magnitude
of PK/PD Parameters
- dosing regimen
- drug class
- protein binding
- infecting pathogen
- presence or absence of neutrophils
- site of infection
Magnitude of PK/PD Parameters
Does the magnitude of the parameter vary with:
1. different dosing regimens? NO, unless the
clearance is too rapid in the animal
model
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
Magnitude of PK/PD Parameters
Does the magnitude of the parameter vary with:
1. different dosing regimens? NO
2. different drugs within the same class?
NO, if free drug levels are used
Protein binding is important !!
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 Levo Cipro
Andes & Craig 40th and 41st ICAAC, 2000 and 2001
Time Above MIC for Total and Free Drug for
the Static Dose of Different Cephalosporins
with Klebsiella pneumoniae ATCC 43816
70
60
50
40
Total
Free
30
20
10
0
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z
a
ft
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Craig Infect Dis Clin N Amer 2003
Magnitude of PK/PD Parameters
Does the magnitude of the parameter vary with:
1. different dosing regimens? NO
2. different drugs within the same class?
NO, if free drug levels are used
3. different organisms ?
Similar for most organisms in
neutropenic mice; less T>MIC with
staphylococci with ß-lactams
Time Above MIC Required for a Static
Effect with 4 Cephalosporins
Time Above MIC (% of Dosing Interval)
Drug
GNB
S. pneumoniae
S.aureus
Ceftazidime
36 (27-42)
39 (35-42)
22 (19-24)
Cefpirome
35 (29-40)
37 (33-39)
22 (20-25)
Cefotaxime
38 (36-40)
38 (36-40)
24 (20-28)
Ceftriaxone
38 (34-42)
39 (37-41)
24 (21-27)
Craig Diagn Microbiol Infect Dis 22:89, 1995
Magnitude of PK/PD Parameters
Does the magnitude of the parameter vary
with:
4. resistant organisms
No
T>MIC for Free Drug for Static Doses with
Cephalosporins, Penicillins and
Carbapenems against Multiple Strains of
S. pneumoniae with Various Penicillin MICs
T>MIC (%)
50
40
30
Cephalosporins
Penicillins
Carbapenems
20
10
0
0.008 0.03
0.12
0.5
2
MIC (mg/L)
8
Free Drug AUC/MIC
24-Hr AUC/MIC of Gemifloxacin (Free Drug)
for the Static Doses with 61 Strains of
S. pneumoniae in Thighs of Neutropenic Mice
80
40
20
10
Wild type
mutants
5
2.5
Efflux
0.008
0.03
0.12
0.5
MIC (mg/L)
2
Magnitude of PK/PD Parameters
Does the magnitude of the parameter vary with:
4. resistant organisms
NO
5. different sites of infection (e.g. blood,
lung, peritoneum, soft tissue)?
NO for most drugs; vancomycin less
potent in lung infection than thigh
Factors That Do Not Affect the
Magnitude of PK/PD Parameters
- resistant organisms
- animal species
Can values obtained in animals be
predictive of efficacy in humans ?
T>MIC for ß-Lactams Versus Mortality
in Animal Models: Literature Review
Mortality (%)
100
Cephalosporins
Penicillins
80
60
40
20
0
0
20
40
60
80
100
Time Above MIC (% of Interval)
Craig Antimicrobial Pharmacodynamics in Theory and Practive 2002
Double Typanocentesis Studies in
Acute Otitis Media
 First tap to identify the causative pathogen
 Second tap at 3-5 days to determine if
organisms had been eradicated
 Techniques first performed by Howie. Most
recent studies with resistant organisms
performed by Dagan.
 Time above MIC calculated from serum levels
and MICs
Craig & Andes, Pediatr Infect Dis J 15:255, 1996;
Multiple studies by Dagan et al
Bacterial Eradication (%)
Relationship Between T>MIC and
Bacterial Eradication with
ß-Lactams in Acute Otitis Media
100
80
60
40
PSSP
PISP-PRSP
H. flu
Best Fit
20
0
0
20
40
60
80
Time Above MIC (%)
Craig Infect Dis Clin N Amer 2003
100
Uses of Pharmacodynamic Studies
• Drug development
- new formulations active against
organisms with high MICS (e.g. high
dose amoxicillin/clavunate)
- dosage regimens for phase II and III
clinical trials
- drug selection for clinical studies
• Optimize dosing regimens
- longer infusions and continuous infusion
of beta-lactams
- once-daily dosing of aminoglycosides
Uses of Pharmacodynamic Studies
• Guidelines for antimicrobial usage
• Reduction of emergence of resistance
organisms
• Modifications of susceptibility and resistance
breakpoints
- oral ß-lactams for S. pneumoniae
- parenteral cephalosporins for S.
pneumoniae
- fluoroquinolones for S. aureus
ESBLs and Clinical Failures
• Emergence of Enterobacteriaceae with
increased MICs due to novel ß-lactamases
(ESBLs)
• Associated with clinical failures and existing
breakpoints fail to detect all these enzymes
• Development by NCCLS of reference
methods for screening and confirmation of
ESBLs in some Enterobacteriaceae; does not
work for all Enterobacteriaceae.
• Elevated MICs in may also arise from
mechanisms not targeted by the current ESBL
test
Pharmacodynamic Studies of ExtendedSpectrum Cephalosporins against
Enterobacteriaceae with and without
ESBLs in Thighs of Neutropenic Mice
Drugs: Cefotaxime, Ceftriaxone, Ceftazidime
and Cefepime
ESBLs: TEM-3, TEM-7, TEM-10, TEM-12,
TEM-26, SHV-2, SHV-4, SHV-5, SHV-7,
CTX-M2, CTX-M3 alone or in combination
with OXA-1, OXA-2, TEM-1, and/or AMP-C
Non-ESBLs: TEM-1, TEM-1 and OXA-1,
AMP-C, wild-type
High inocula – 107-8
Change in Log10 CFU/Thigh
over 24 Hours
Activity of 4 Cephalosporins against Various
Enterobacteriacea with and without ESBLs in
Murine Thigh-Infection Model
3
ESBLs
3
Non-ESBLs
2
2
1
1
0
0
-1
-1
-2
-2
-3
-3
0
20 40 60 80 100
0
20
40
Time Above MIC (percent)
60
80 100
Monte Carlo Simulation
PK Variation
In Normal
Volunteers
or Patients
Simulate
PK Variation in
10,000 Patients
Determine Percentage of Patients
that would meet the PK/PD Target
required for efficacy
Drusano et al
Monte Carlo Simulation: Cefotaxime
Percent of 10,000 Patients Attaining
Indicated PK/PD Exposure Target
MIC
0.5
1
2
4
8
16
30%
100
100
99
98
92
65
T>MIC with 2g every 8 hr
40%
50%
60%
70%
100
99
96
88
99
97
89
73
98
89
71
49
91
67
41
22
62
29
11
4
15
3
0
0
Ambrose & Dudley, ICAAC 2002
Clinical Outcome in 42 Patients with
ESBL-Producing Klebsiella/E. coli
Bacteremia and Treated with
Cephalosporin Monotherapy
Outcome
MIC
<1 ųg/L
MIC
2 ųg/L
MIC
4 ųg/L
MIC
8 ųg/L
Success
13 (81%)
4 (67%)
3 (27%)
1 (11%)
Failure
3 (19%)
2 (33%)
8 (73%)
8 (89%)
Paterson et al J Clin Micro 39:2206, 2001; Kim et al AAC 46:1481,
2002; Wong-Beringer et al Clin Infect Dis 34:135, 2002; Kang et al
AAC In press 2004; Bhavani et al 44rd ICAAC, Abstract K-1588, 2004
Distribution of Enterobacteriacea
with MICs of 4 and 8 mg/L
Total 0f 11, 913 Isolates from ICU Patients
Total
Strains
E. coli
Kleb spp
Other
Ceftazidime
464
89
(19%)
158
(34%)
217
(47%)
Ceftriaxone
532
46
(9%)
169
(32%)
317
(59%)
2002-2003 Sentry Program
Jones, R
Acknowledgements
Pharmacodyamics
Andes DR
Bundtzen R
Ebert S
Fantin B
Gerber A
Gudmundsson S
Kiem S
Leggett J
MacDonald
Mouton J
Redington J
Totska K
Turnidge J
Van Ogtrop M
Vogelman B
Walker R
Watanabe Y
Otitis
Dagan R
ESBLs
Ambrose P
Dudley M
Jones R
It all started with a mouse.
-Walt Disney