Prediction of individual antibiotic dose in the clinic - WorldPharma ...

Prediction of individual
antibiotic dose in the clinic
Professor
Inga Odenholt
Department of Infectious Diseases
Skånes University hospital
Malmö

Concentrationsdependent vs.
timedependent killing

Concentration dependent killing of grepafloxacin against S. pneumoniae ATCC 6306
10
9
8
log10 cfu/ml
7
6
5
4
2xMIC
4xMIC
8xMIC
16xMIX
32xMIC
Control
3
2
1
0
0 3 6 9 12 15 18 21 24 h

Timedependent killing of penicillin against S. pyogenes
10
9
8
log10 cfu/ml
7
6
5
4
2xMIC
4xMIC
8xMIC
16xMIC
64xMIC
Control
3
2
1
0 3 6 9 12 15 18 21 24 h

Intergration between
pharmacokinetics/
pharmacodynamics (PK/PD)

Log conc
Cmax
PK/PD indices
Cmax/MIC
AUC/MIC
T>MIC
AUC= Area under the
Concentration curve
MIC
T>MIC
h

ß-lactam antibiotics
• Efficacy is dependent on T>MIC

Antibiotics dependent on T>MIC
• Penicillins
• Cefalosporins
• Carbapenems
• Monobactam
• Macrolides
• Clindamycin
• Zinezolid

Quiolones och aminoglycosids
• Efficacy is dependent on peak/MIC and
AUC/MIC

How important is T>MIC for
β-lactam antibiotics
How long should it be

Depends on
• How long has the patient been ill
• The immune status
– Immunocompromized or not
• Type of infection
– Simple or severe infection

Piperacillin/tazobactam given every 6 h or
with 4 h infusion every 8 h
Lodise CID 2007
• Patients with APACHE score > 17
14-days mortality was significant lower in
the group of patients that had received 4 h
infusion
12.2 vs 31.6% (p=0.04)

Relationship Between Time Above MIC 90 and Bacteriologic
Cure for S. pneumoniae (pink) & H. influenzae (blue)

Benzylpenicillin
• Spectrum MIC-values
(native)mg/L
• ß-hemolytic
• streptokocker group A 0.008-0.032
• S. pneumoniae 0.008-0.032
• Enterococci 0.5-4
• P. multocida 0.016-0.125
• Meningococci 0.016-0.125

www.eucast.org

S
I
R

MIC MIC-gränser breakpoints
• Pharmacological breakpoints: 0.25/2
• Speciesrelated breakpoints :
• streptococci (0.25/0.25), pneumococci
(0.06/2), enterococci, H. influenzae (IE)

Pharmacokinetics of
benzylpenicillin
• 3g gives a concentration after 4 h of 4 mg/l
• Proteinbindning= 65%.
• Free concentration 1-1.4 mg/l after 4 h
• Half-life= 45 min.
• After 4.45= 0.5 mg/l
• After 5.5 h= 0.25 mg/l
• 3x5.5 h=17.5/24= 69% T>MIC

Dosing
T>MIC;
MIC=0.03 mg/L
T>MIC;
MIC=0.25 mg/L
T>MIC;
MIC=4 mg/L
1g x 3 100% 50% 12.5 %
1g x 4 100% 67% 17%
3g x 3 100% 69% 31%
3g x 4 >100% 92% 42%

Cloxacillin
• Spectrum MIC-values
(native)mg/L
• ß-hemolytic
streptococci group A 0.032-0.125
• Stafylococcus aureus 0.125-0.5
• Coagulasnegative
stafylococci 0.125-1

Pharmacokinetics of cloxacillin
• Cmax after a 30 min infusion=100 mg/l
(2g) Free concentration=6 mg/l
• Proteinbindning= 94%
• T1/2=30 min
• After 2 h conc= 0.35 mg/l
• 2h x 3=6/24= 25% T>MIC!

Dosing
T>MIC; MIC=0.25 mg/L
2g x 3 25%
2g x 4 33%
2g x 6 50%
3g x 4 42%
3g x 6 63%

Piperacillin/tazobactam
Spectrum MIC-values (native)mg/L
• ß-hemolytiska
streptokocker gr. A 0.016-0.064
• pneumokocker 0.008-0.032
• H. influenzae 0.016-0.064
• S. aureus 0.25-1
• E. faecalis 1-8
• E. coli 0.5-4
• Klebsiella 0.5-8
• P. mirabilis 0.125-1
• Enterobacter spp. 0.5-8
• P. aeruginosa 1-8
• Acinetobacter 1-16
• B. fragilis 0.5-8

MIC MIC-gränser breakpoints
• Pharmacological breakpoints: 8/16
• Speciesrelated breakpoints :
Enterobacteriacae 8/16
Pseudomonas 16/16

S I R

S
R

Dosing
T>MIC;
MIC=1 mg/L
T>MIC;
MIC=4 mg/L
T>MIC;
MIC=16 mg/L
4g x 3 69% 47% 25%
4g x 4 92% 63% 33%

Cefotaxim
Spectrum
MIC-values (native)mg/L
• ß-hemolytiska streptokocker 0.008-0.032
• pneumokocker 0.004-0.032
• H. influenzae 0.008-0.032
• M. catarrhalis 0. 032-0.125
• S. aureus 0.5-4
• E. faecalis 2->64
• E. coli 0.016-0.125
• Klebsiella 0.016-0.125
• P. mirabilis 0.008-0.032
• Enterobacter spp. 0.064-0.5
• Acinetobacter 0.5-8

MIC MIC-gränser breakpoints
• Pharmacological breakpoints: 1/2
• Speciesrelated breakpoints :
Enterobacteriacae 1/2

S
I
R

Dosing
T>MIC;
MIC=0.03 mg/
L
T>MIC;
MIC=0,125
mg/L
T>MIC;
MIC=2 mg/L
1g x 2 100% 66% 38%
1 g x 3 >100% 100% 48%