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Rontgene M. Solante, MD
Infectious Disease Specialist
Pharmacodynamics
Three different classes depending on the
PK/PD indices associated with their optimal killing activity
Plasma
conc
Target
site
conc
Pharma
effects
PK
Drug
Adherence
[C] @
Infection
Site
Pathogen
MIC
Drug
Dosing
Pharmacodynamics
In Vivo Potency
Outcome
Clinical
Success/failure
Rate of response
Microbiologic
Economic
Antibiotic (C)
MIC
T>MIC
Time (h)
Chest 2011;139;1210-1220
Insufficient beta-lactam
concentrations in the early phase of
severe sepsis and septic shock
Higher dose
Increased dosing frequency
Increased duration of infusion
a. Prolonged infusion
- Same dose and dosing interval,
however, change duration of
infusion (0.5 hr 3hr)
b. Continuous infusion
- Administer loading dose, then use
pump to give total daily dose IV
over 24 hr period
Improved Potency
(In Vivo Exposure)
Consensus Principles
on Specific Antimicrobial Use
Cefepime 1 gm q 8H
67.1
72.1
Cefepime 2 gm q 8H
74.4
79.2
Imipenem 1 gm q 8H
69.3
72.0
Meropenem 1 gm q 8H
77.1
83.8
Meropenem 2 gm q 8H
84.1
88.1
Pipera/Tazo 4.5 gm q 8H
56.4
80.7
Pipera/Tazo 4.5 gm q 6H
72.4
81.3
All refernces are from latest Infectious Disease Society of America Guidelines
Data c/o Vitas Gupta, PharmD, BCPS, Director, CareFusion Medmined, USA
Susceptible
<8 ug/ml
Intermediate or
SDD
16 ug/ml
CLSI (current)
1gm q 8H/2gm
q 12H
Resistant
>32 ug/ml
CLSI (proposed)
<2 ug/ml
4-8 ug/ml
>16 ug/ml
EUCAST
<1 ug/ml
2-4 ug/ml
>8 ug/ml
current
1-2 gm every 8-12 hours
= 50% T>MIC
8
6
4
2
0
MIC
T>MIC
Break
point
CLSI
(current)
1gm q
8H/2gm
q 12H
Time (h)
Drusano GL Clin Infect Dis. 2007 Jul 15;45 Suppl 1:S89-95
McKinnon PS, Davis SL Eur J Clin Microbiol Infect Dis. 2004;23:271-88
16
ug/ml
>32
ug/ml
Break
point
current
Suscep
Intermed Resistant
tible
iate or
2 gm every 12 hours
SDD
CLSI
<2
(proposed) ug/ml
EUCAST
8
6
4
2
0
proposed
1-2 gm every 8-12 hours
= >65% T>MIC
( greater exposure of
organism to cefepime
Higher killing rate)
= 50% T>MIC
4-8
ug/ml
>16
ug/ml
<1
T>MIC 2-4
ug/ml ug/ml
MIC
>8
ug/ml
T>MIC
MIC
2
Time (h)
Drusano GL Clin Infect Dis. 2007 Jul 15;45 Suppl 1:S89-95
McKinnon PS, Davis SL Eur J Clin Microbiol Infect Dis. 2004;23:271-88
current
proposed
2 gm every 12 hours
= 65% T>MIC
( greater exposure of
organism to cefepime
Higher killing rate)
2 gm every 12 hours
= 50% T>MIC
8
6
4
2
0
MIC
T>MIC
T>MIC
MIC
2
Time (h)
Time (h)
Monte Carlo
Simulation of
PK/PD Data
Clinical
Outcome
Dose
N/A
Susceptible
Breakpoint
1 ug/ml
1g 12hours
1 g 8hours
2 ug/ml
2-4 ug/ml
2 g 12 hours
4 ug/ml
2 g 8hours
8ug/ml
1 g 8 hours
2-4 ug/ml
Comment
Based upon a
target attainment
of 50% T>MIC for
90% of the
population
Monte Carlo
Simulation of
PK/PD Data
Clinical
Outcome
Dose
N/A
Susceptible
Breakpoint
1 ug/ml
1g 12hours
1 g 8hours
2 ug/ml
2-4 ug/ml
2 g 12 hours
2 g 8hours
4 ug/ml
8ug/ml
1 g 8 hours
2-4 ug/ml
Comment
Mild-moderate
infection
Moderate to
severe infection
Dose
Frequency
0.5 1 gram
Every 12 hours
Total Daily
Dose
1-2 grams
2 grams
1-2 grams
Every 12 hours
Every 12 hours
4 grams
2-4 grams
2 grams
Every 12 hours
4 grams
2 grams
Every 12 hours
4 grams
2 grams
Every 8 hours
6 grams
Dose
Frequency
Total Daily
Dose
Mild to
Moderate UTI
0.5 1 gram
Every 12 hours
1-2 grams
Severe UTI
2 grams
Every 12 hours
4 grams
Mild to Severe
Pneumonia
1-2 grams
Every 12 hours
2-4 grams
Mild to Severe
SSTI
2 grams
Every 12 hours
4 grams
Complicated
Intra-abdominal
infections
2 grams
Every 12 hours
4 grams
Neutropenic
fever
2 grams
Every 8 hours
6 grams