Transcript What the @*#! is Pharmacodynamics??

Antimicrobial Pharmacodynamics:
Concepts for Rational Selection
and Dosing of Antibiotics
Effect of Adequate Antimicrobial Therapy For
Bloodstream Infections on Mortality
P<0.001
Hospital Mortality, %
80
70
60
50
40
30
20
10
0
Adequate
Inadequate
Initial Antimicrobial Treatment
Ibrahim E, et al. Chest 2000; 118: 146-155.
Effect of Adequate Antimicrobial Therapy For
Bloodstream Infections on Mortality
OSSA
Hospital Mortality
E. Coli
Inadequate Antimicrobial Therapy
Pathogens
Enterococcus spp.
Klebsiella spp.
P. aeruginosa
CNS
ORSA
Candida spp.
VRE
0
20
40
60
80
100
Percent
OSSA=oxacillin-susceptible S. aureus; CNS=coagulase-negative staphylococci;
VRE=vancomycin resistant enterococci
Ibrahim E, et al. Chest 2000; 118: 146-155.
What does “S” Mean?
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Susceptible - Isolates are inhibited by the usually
achievable concentrations of antimicrobial agent
when the recommended dose is used for the site of
infection.
Intermediate – Implies clinical efficacy in the areas
where drugs are physiologically concentrated or
when higher than normal dosages of drugs can be
used
Resistant – Isolates are not inhibited by the usually
achievable concentrations of the agent with normal
dosage schedules
CLSI. M-100-S16. January 2006
Pharmacokinetics
•
•
•
•
Absorption
Distribution
Metabolism
Elimination
“PK is what the body does to the drug”
Pathogen
Susceptibility
MIC/MBC
Pharmacokinetics
Serum/Tissue
Concentrations
Half-Life
Pharmacodynamics
Peak/MIC
AUC/MIC
Time > MIC
Eradication/Cure
Pharmacodynamic Interactions
Concentration
Peak/MIC
AUC/MIC
MIC
Time>MIC
Time
Concentration Dependent vs.
Concentration Independent Bacterial
Killing
Log10 Colony Forming Units/ml
Tobramycin
Ticarcillin
Ciprofloxacin
9
Control
8
1/8 MIC
1/2 MIC
7
1 MIC
6
4 MIC
5
16 MIC
4
64 MIC
3
2
0
2
4
6
8
0
2
4
6
8
0
2
4
6
8
Time (hours)
Craig WA, et al. Scand J Infect Dis, 1991; Suppl (74)
Optimizing Antimicrobial Therapy
PK
Concentration
at Infection
Site
Antibiotic
Pathogen
MIC/MBC
Host Factors
PD
Bacterial
Killing
Outcome
Pharmacokinetic-Pharmacodynamic Indices
Correlating with Efficacy
Antimicrobial Agent
Bactericidal
Pattern of invitro Activity
Aminoglycosides
Concentration
PK-PD
measure(s)
AUC0-24:MIC,
Cmax:MIC
b-Lactams
Antimicrobial
Agent
Bactericidal
Pattern of in-vitro
Activity
PK-PD measure(s)
Macrolides
Concentration
AUC0-24:MIC,
Cmax:MIC
Azithromycin
Time
AUC0-24:MIC
Penicillins
Time
T>MIC
Clarithromycin
Time
AUC0-24:MIC
Cephalosporins
Time
T>MIC
Telithromycin
Concentration
AUC0-24:MIC
Carbapenems
Time
T>MIC
Concentration
Monobactams
Time
T>MIC
AUC0-24:MIC,
Cmax:MIC
Doxycycline
Time
AUC0-24:MIC
Tigacycline
Time
AUC0-24:MIC
Time
AUC0-24:MIC
Time
AUC0-24:MIC
Glycopeptides/
Lipopeptides
Metronidazole
Tetracyclines
Daptomycin
Concentration
AUC0-24:MIC,
Cmax:MIC
Oritavancin
Concentration
T>MIC
Vancomycin
Time
AUC0-24:MIC
Oxazolidinones
Concentration
AUC0-24:MIC,
Cmax:MIC
Linezolid
Fluoroquinolone
Clindamycin
In-vitro Pharmacodynamic Models
Murine Thigh Infection
Pharmacodynamic Model
Cyclophosphamide
Antimicrobial
Organism
107 CFU
CFU
determination
Bacteriostatic
dose
Pharmacokinetic
parameters
2 hours
Vesga A, et al. 37th ICAAC. 1997.
b-lactams
Correlation of PK/PD Parameters With Effect of
Cefotaxime Against K. pneumoniae in Lungs of
Neutropenic Mice
CFU/Thigh at 24 Hr
10
9
8
7
6
5
1
10
100 1000
Peak/MIC
1
10
100 1000
24-Hr AUC/MIC
0
25
50
75
100
T>MIC
Craig WA. Diagn Microbiol Infect Dis 1995: 22:89-96
Relationship Between Time Serum Levels
Exceed the MIC and Mortality for B-Lactams
Against S. pneumoniae
Mortality (%)
100
Penicillins
80
Cephalosporins
60
40
20
0
0
20
40
60
80
100
Time above MIC (%)
Craig WA. Diagn Microbiol Infect Dis 1996:25:213-7
Craig WA. Diagn Microbiol Infect Dis 1996:25:213-7
Relation Between PD Parameters and
Efficacy for Ticarcillin against P. aeruginosa
CFU/Thigh at 24 Hr
10
8
6
4
2
0
1
10
100 1000
24-Hr AUC/MIC
1
10
100 1000
Peak/MIC
0
25
50
75
100
T>MIC
Vogelman B., et al. J Infect Dis 1988. 158(4).
What %T>MIC is our target for βlactams?
“Static” dose
1 log
CFU/Thigh at 24 Hr
10
2 log
8
3 log
6
4
2
0
1
10
100 1000
24-Hr AUC/MIC
1
10
100 1000
Peak/MIC
0
25
50
75
100
T>MIC
Vogelman B., et al. J Infect Dis 1988. 158(4).
b-lactam Pharmacodynamics
Antibiotic
Organism/Class
Outcome Parameter
and Value
Source
Cefazolin
E. coli, Klebsiella
T>MIC
IVPDM
Ceftriaxone
S. pneumoniae
T>MIC=100%
Rabbit meningitis model
Cefazolin
E. coli
IVPDM
Cephalosporins
Enterobacteriacae
Streptococci
S. aureus
E. coli
S. aureus
P. aeruginosa
S. pneumoniae
T>MIC, max effect
4xMIC
T>MIC 60-70%
T>MIC 60-70%
T>MIC 40-50%
T>MIC 100%
T>MIC 55%
T>MIC 100%
T>MIC 100%
Gram-negative
T>DRC
Human, nosocomial
pneumonia
Cefazolin, ticarcillin,
penicillin
Cefmenoxime
Animal data review
Neutropenic murine thigh
infection model
Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S
Concentration Time Profile:
Antibiotic Y
MIC=2
Antibiotic Y Concentration (ug/ml)
%T>MIC >90% DI
100
10
1
0
4
8
12
Time (hours)
16
20
24
Concentration Time Profile:
Antibiotic Y (q12h)
Antibiotic Y Concentration (ug/ml)
MIC=8
%T>MIC=50% DI
100
10
1
0
4
8
12
Time (hours)
16
20
24
Concentration Time Profile:
Antibiotic Y (q8h)
Antibiotic Y Concentration (ug/ml)
MIC=8
%T>MIC>90% DI
100
10
1
0
4
8
12
Time (hours)
16
20
24
Beta-lactam Serum Concentrations
Continuous Infusion Beta-lactams
Intermittent
Continuous
MIC
MIC
Time (h)
Cefamandole: Continuous vs.
Intermittent infusion
60%
Cure Rate
50%
40%
30%
20%
10%
0%
Cefamandole CI
Cefamandole II
p=NS
Bodey, GP, et al. Am J Med 1979. 67.
Cure Rate of Infections in Persistently
Febrile Neutropenic Patients
70
60
Cure Rate
50
40
30
20
10
0
Cefamandole CI
p=0.03
Cefamandole II
Bodey, GP, et al. Am J Med 1979. 67.
Fluoroquinolones
Correlation of PK/PD Parameters With Effect of
Levofloxacin Against S. pneumoniae in Thighs of
Neutropenic Mice
CFU/Thigh at 24 Hr
10
8
6
4
2
0
1
10
100 1000
24-Hr AUC/MIC
1
10
100 1000
Peak/MIC
0
25
50
75
100
T>MIC
Handbook of Experimental Pharmacology. Vol 127: Quinolone Antibacterials. 1998
Pharmacodynamic Interactions
Concentration
Peak/MIC
AUC/MIC
MIC
Time>MIC
Time
Relationship Between 24-Hour AUC/MIC and
Mortality for Fluoroquinolones Against
S. pneumoniae
100
% Mortality
80
60
40
20
0
2.5
10
25
100
250
24-Hour AUC/MIC
Craig, WA 37th IDSA, 1999
Clin Infect Dis. (in press)
Relationship Between 24-Hour AUC/MIC and Mortality
for Fluoroquinolones Against Gram-Negative Bacilli in a
Murine Model
100
% Mortality
80
60
40
20
0
2.5
10
25
100
250
24-Hour AUC/MIC
Craig, WA 37th IDSA, 1999
Clin Infect Dis. (in press)
Relationship Between AUC24/MIC and Efficacy
of Ciprofloxacin in Patients with Serious Bacterial
Infections
% Efficacy
100
80
60
40
20
0
0-62.5
62.5-125 125-250
250-500
>500
24-Hour AUC/MIC
Clinical
Microbiologic
Forrest A, et al. AAC, 1993; 37: 1073-1081
Fluoroquinolone Pharmacodynamics:
S. pneumoniae
Antibiotic
Outcome Parameter
and Value
Source
Levoflooxacin, ciprofloxacin, trovafloxacin
AUC:MIC > 35
IVPDM
Ciprofloxacin, levofloxacin
AUC:MIC 30-35
IVPDM
Ciprofloxacin, ofloxacin, trovafloxacin
AUC:MIC 44-49
IVPDM
Ciprofloxacin, levovfloxacin
AUC:MIC 32-64
IVPDM
Quinolones
AUC:MIC > 40
IVPDM
Sitafloxacin
AUC:MIC = 37
Murine thigh and lung
infection model
Gatifloxacin
AUC:MIC = 52
Murine thigh and lung
infection model
Gemifloxacin
AUC:MIC = 35
Murine thigh and lung
infection model
Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S
Fluoroquinolone Pharmacodynamics:
Gram Negative Bacilli
Antibiotic
Organism/Class
Outcome Parameter
and Value
Source
Enoxacin
P. aeruginosa, E. coli
Cmax:MIC>8
IVPDM
Ciprofloxacin
P. aeruginosa
Cmax:MIC>8
IVPDM
Ciprofloxacin, ofloxacin
P. aeruginosa
AUC:MIC>100
IVPDM
Lomefloxacin
P. aeruginosa
Cmax:MIC>10
Neutropenic rat sepsis
model
Gatifloxacin
Enterobacteriacae
AUC:MIC=48
Murine thigh and lung
infection model
Sitafloxacin
Enterobacteriacae
AUC:MIC=43
Murine thigh and lung
infection model
Ciprofloxacin
GNR, mostly LRTI
AUC:MIC>125
Human, retrospective
Ciprofloxacin
GNR, vent dependent
AUC:MIC>100
Human, retrospective
Gunderson BW, et al. Pharmacotherapy. 2001 Nov;21(11 Pt 2):302S-318S
Aminoglycosides
Response Rate (%)
Max Peak/MIC Ratio and Clinical
Response with Aminoglycosides
100
90
80
70
60
50
2
4
6
8
10
12+
Maximum Peak / MIC ratio
Moore,et al. J Inf Disease, 1987; 155(1): 93-98
Pharmacodynamic Interactions
Concentration
Peak/MIC
AUC/MIC
MIC
Time>MIC
Time
Aminoglycoside Pharmacodynamics: Human
Studies
Antibiotic
Organism
Outcome Parameter
and Value
Gent, Tob,
Amik
GNR(63% E. coli, 27%
Klebsiella); UTI, LRTI,
bacteremia, SSI
Cmax:MIC>10
Gent, Tob,
Amik
GNR; UTI, LRTI, URTI,
SSI, Sepsis
Cmax:MIC>8
Gent, Tob
GNR
Cmax:MIC>10
Moore,et al. J Inf Disease, 1987; 155(1): 93-98
Deziel-Evans LM, et al. Clin Pharm 1986; 5:319-324
Nicolau DP, et al. Antimicrob Agents Chemother 1995; 39:650-5
Methods for AG Dosing
Serum Concentration (mg/L)
25
20
15
10
5
0
1
2
3
4
5
6
7
8
9
10 12 14 16 17 18 20 22 24
Time
Extended Interval Dosing
Traditional Dosing
Single Daily Dosing Aminoglycosides: Efficacy
Bailey TC, et al. Clin Infect Dis 1997; 24: 786-95.
Zaki M, Goetz MB. Clin Infect Dis 1997; 24: 796-809
Single Daily Dosing Aminoglycosides: Toxicity
Bailey TC, et al. Clin Infect Dis 1997; 24: 786-95.
Zaki M, Goetz MB. Clin Infect Dis 1997; 24: 796-809
Extended Interval Dosing of
Aminoglycosides
Clin Infect Dis 2000 Mar;30(3):433-9
National survey of extended-interval aminoglycoside dosing (EIAD).
Chuck SK, Raber SR, Rodvold KA, Areff D.
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500 acute care hospitals in the United States
EIAD adopted in 3 of every 4 acute care hospitals
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rationale
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4-fold increase since 1993
written guidelines for EIAD in 64% of all hospitals
87.1% : equal or less toxicity,
76.9% : equal efficacy
65.6% :cost-savings
dose: > 5 mg/Kg
47% used extended interval in case of decline in renal function (38% with
Hartford nomogram)
Optimal Pharmacodynamic Indices
Drug Class
% T>MIC
Cephalosporins
60 – 70%
Penicillins
40 – 50%
Carbapenems
30 – 40%
AUC/MIC
Peak/MIC
Fluoroquinolones
Gram +
30 - 50
Gram -
125
Aminoglycosides
10
Craig WA. Infect Dis Clin N Am 2003. 17:479-501
Gunderson BW, et al. Pharmacotherapy 2001. 21: 302S-318S
Conclusions
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There are associations between antibiotic concentrations and microbiologic
effects.
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These associations are dependent on the organisms and the antibiotic class.
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“WHAT CONCENTRATION AM I GOING TO ACHIEVE WITH A GIVEN
DOSE AND HOW DOES THIS CONCENTRATION RELATE TO THE
CONCENTRATION NEEDED TO INHIBIT/KILL IN VITRO”
GN vs GP
CEPHALOSPORINS/PENICILLINS/CARBAPENEMS
Investigations have led to new knowledge and application of these principles
to optimizing antibiotic doses.
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NEW DRUGS COMING TO MARKET
WHAT ABOUT OLDER DRUGS??
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Organisms can be susceptible (by MIC) to an antibiotic that can not kill the
organism.
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AMINOGLYCOSIDES
CONTINUOUS INFUSION B-LACTAMS
P. AERUGINOSA
FLUOROQUINOLONES & PIPERACILLIN/TAZOBACTAM
Additional studies evaluating the outcome of patients are needed to refine
these principles.
Selection of Antimicrobial Therapy
I think your patient needs
Imipenem 1gmq6h
Impact of PD on Outcomes
Examples of Drug-Bug Combinations with Low
Conc:MIC Ratios
Staphylococcus sp.
cephalosporins, FQ, vancomycin
Streptococcus sp.
FQ, oral beta-lactams
Enterobacter sp.
3rd Generation cephalosporins
Pseudomonas sp.
Beta-lactams, FQ,
aminoglycosides
Acinetobacter sp.
Beta-lactams, FQ
* May be unlikely to achieve optimal PD targets
Mathematical Expression of
Pharmacodynamic Indices
Dose
t1/2
100
%T>MIC = ln ----------- * ------ * ------Vd * MIC 0.693
DI
Dose
t1/2
24
AUC24/MIC = ----------- * ------ * ------Vd * MIC 0.693 DI
Dose (mg)
DI = Dosing Interval (q6h, DI=6)
t1/2 = Half life of the Drug (hr)
Vd = Apparent Volume of Distribution (Liters/kg)
MIC = Minimum Inhibitory Concentration (mg/L)
Pharmacokinetic Changes in
Critically Ill
Critically Ill
Vd
(L/kg)
0.31
0.31
T1/2
(hr)
2.5
1.5
0.4
0.27
2
1.5
2.5
3.3
Normal Patients
Cefepime
P/T
Imipenem
Meropenem
Ciprofloxacin
Vd
(L/kg)
0.22
0.14
T1/2
(hr)
2
0.75
0.16
0.17
1.3
1
1
3.3
Cefepime Pharmacokinetics in
Critically Ill Adults with Sepsis
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13 patients with CrCl>50
Received Cefepime 2gm x 1
dose
Vd
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Mean: 21.8 + 5.1 L
Range: 16.2 L – 31.4 L
t1/2
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Mean: 3 + 1.2 hours
Range: 1.5 – 5.6 hrs
Monte Carlo Simulation: Applied to
Pharmacokinetic-Pharmacodynamic Models
Random
pharmacokinetics
and MIC values
from data set
AUC
MIC
Calculate
pharmacodynamic
parameter
Plot results in
a probability chart
AUC:MIC
Dudley MN, Ambrose PG. Curr Opin Microbiol. 2000;3:515-521.
Pharmacodynamics of Ciprofloxacin 400mg IV q8H Against P.
aeruginosa in Critically Ill Patients
100
20
CLSI BP =1 ug/ml
90
69% Susceptible
80
MIC Frequency (%)
70
15
60
56% Ciprofloxacin Optimized
10
50
40
30
5
20
Probability of Achieving Dynamic Target
25
10
0
0
0.008 0.015
0.03
0.06
0.12
0.25
0.5
1
2
4
8
16
32
64
128
256
MIC
MIC Distribution
AUC/MIC > 125 By MIC
AUC/MIC > 125 Cumulative
MIC Distributions adapted from Mystic Surveillance Network, http://www.infectionacademy.org/mystic.asp
Ciprofloxacin PK adapted from Lipman J, et al. Antimicrob Agents Chemother 1998; 42(9): 2235-2239.
Craig WA. Infect Dis Clin N Am 2003. 17:479-501
Pharmacodynamics of Cefepime 2gm q12h against P.
aeruginosa in Critically Ill Patients
35
100
80
MIC Frequency (%)
25
70
60
20
50
15
40
30
10
20
Probability of Achieving Dynamic Target
90
CLSI BP = 8 ug/ml
84% Susceptible
30
5
10
0
0
0.12
0.25
0.5
1
2
4
8
16
32
64
128
256
MIC
MIC Distribution
T>MIC 70% DI
T>MIC 50% DI
MIC Distributions adapted from Mystic Surveillance Network, http://www.infectionacademy.org/mystic.asp
Cefepime PK adapted from Lipman, et al. Antimicrob Agents Chemother 1999; 43: 2559-2561
Craig WA. Infect Dis Clin N Am 2003. 17:479-501
Probability of 50% T>MIC (Free) for
Piperacillin/Tazobactam
3.375 Gm Q6h
3.375 Gm Q4h
Probability of Target
Attainment
100
80
60
40
20
0
0.25
0.5
1
2
4
8
16
32
64
MIC
Lomaestro BM, Drusano GL. 41st Annual ICAAC 2002. Abstract A-2190
Meropenem
Cefepime
100
80
60
40
20
0
0.25
0.5
1
2
MIC
1 Gm q8h (0.5 hr inf.)
0.5 Gm q6h (0.5 hr inf.)
1 Gm q8h (3 hr inf.)
4
Probability T>MIC 70% (free drug)
Probability T>MIC 40% (free drug)
Optimizing b-lactam Antibiotics
100
90
80
70
60
50
40
30
20
10
0
0.25
0.5
1
2
4
8
MIC
2 Gm q12h (0.5 hr inf.)
1 Gm q6h (0.5 hr inf)
4 Gm CI over 24 hours
Lomaestro BM, Drusano GL. Antimicrob Agents Chemother 2005; 49:461-3.
Mohr JF, et al. 41st IDSA 2003. Abstract# 34.
In-vitro Pharmacodynamic Models
Minimum-inhibitory concentrations
(MICs) of P. aeruginosa tested in an
in-vitro Pharmacodynamic Model
Organism #
Cefepime
Meropenem
Piperacillin/ Tazobactam
2
32 (H)
>32 (H)
>256 (H)
25
2 (L)
0.25 (L)
4 (L)
29
8 (M)
0.25 (L)
64 (M)
31
4 (L)
4 (M)
8 (L)
35
64 (H)
4 (M)
>256 (H)
40
4 (L)
0.5 (L)
32 (M)
53
2 (L)
16 (H)
32 (M)
62
0.5 (L)
0.5 (L)
1 (L)
68
8 (M)
1 (L)
4 (L)
H = “Resistant” strains
M = “Moderately Susceptible” strains
L = “Susceptible” strains
Mohr et al, Submitted ICAAC 2007
Effect of meropenem 1 gm q8h on P. aeruginosa that are resistant (MPMH), moderately susceptible (MPM-M) and susceptible (MPM-L) in an invitro pharmacodynamic model
2
Change Log CFU/ml
1
0
-1
-2
-3
-4
0
6
12
18
24
30
36
42
48
Hours
MPM-H
MPM-M
MPM-L
Mohr et al, Submitted ICAAC 2007
Effect of cefepime 2 gm q12h on P. aeruginosa that are resistant (CPMH), moderately susceptible (CPM-M) and susceptible (CPM-L) in an invitro pharmacodynamic model of bacteremia.
2
Change Log CFU/ml
1
0
-1
-2
-3
-4
0
6
12
18
24
30
36
42
Hours
CPM-H
CPM-M
CPM-L
48
Effect of piperacillin/tazobactam 4.5 gm q6h on P. aeruginosa that are
resistant (PT-H), moderately susceptible (PT-M) and susceptible (PT-L) in
an in-vitro pharmacodynamic model of bacteremia.
2
Change Log CFU/ml
1
0
-1
-2
-3
-4
0
6
12
18
24
30
36
42
Hours
PT-H
PT-M
PT-L
48
Pharmacokinetic Parameters
Concentration
Peak (Cmax)
Cmin
AUC
(Area Under the Curve)
Time
Pharmacodynamics
• Describes the relationship between drug
concentration and pharmacologic effect
“PD is what the drug does in the body”
Antimicrobial Therapy:
Appropriate vs. Adequate

Appropriate therapy—antimicrobial treatment
selected for efficacy based on:
Presumptive identification of causative pathogen
 Antimicrobial agent’s spectrum of activity
 Local microbial resistance patterns

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Adequate therapy—microbiological documentation
of an infection that was being effectively treated at
the time of its identification
Kollef MH. Clin Infect Dis. 2000;31:S131–S138.