Prediction of individual antibiotic dose in the clinic - WorldPharma ...
Prediction of individual antibiotic dose in the clinic - WorldPharma ...
Prediction of individual antibiotic dose in the clinic - WorldPharma ...
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<strong>Prediction</strong> <strong>of</strong> <strong><strong>in</strong>dividual</strong><br />
<strong>antibiotic</strong> <strong>dose</strong> <strong>in</strong> <strong>the</strong> cl<strong>in</strong>ic<br />
Pr<strong>of</strong>essor<br />
Inga Odenholt<br />
Department <strong>of</strong> Infectious Diseases<br />
Skånes University hospital<br />
Malmö
Concentrationsdependent vs.<br />
timedependent kill<strong>in</strong>g
Concentration dependent kill<strong>in</strong>g <strong>of</strong> grepafloxac<strong>in</strong> aga<strong>in</strong>st S. pneumoniae ATCC 6306<br />
10<br />
9<br />
8<br />
log10 cfu/ml<br />
7<br />
6<br />
5<br />
4<br />
2xMIC<br />
4xMIC<br />
8xMIC<br />
16xMIX<br />
32xMIC<br />
Control<br />
3<br />
2<br />
1<br />
0<br />
0 3 6 9 12 15 18 21 24 h
Timedependent kill<strong>in</strong>g <strong>of</strong> penicill<strong>in</strong> aga<strong>in</strong>st S. pyogenes<br />
10<br />
9<br />
8<br />
log10 cfu/ml<br />
7<br />
6<br />
5<br />
4<br />
2xMIC<br />
4xMIC<br />
8xMIC<br />
16xMIC<br />
64xMIC<br />
Control<br />
3<br />
2<br />
1<br />
0 3 6 9 12 15 18 21 24 h
Intergration between<br />
pharmacok<strong>in</strong>etics/<br />
pharmacodynamics (PK/PD)
Log conc<br />
Cmax<br />
PK/PD <strong>in</strong>dices<br />
Cmax/MIC<br />
AUC/MIC<br />
T>MIC<br />
AUC= Area under <strong>the</strong><br />
Concentration curve<br />
MIC<br />
T>MIC<br />
h
ß-lactam <strong>antibiotic</strong>s<br />
• Efficacy is dependent on T>MIC
Antibiotics dependent on T>MIC<br />
• Penicill<strong>in</strong>s<br />
• Cefalospor<strong>in</strong>s<br />
• Carbapenems<br />
• Monobactam<br />
• Macrolides<br />
• Cl<strong>in</strong>damyc<strong>in</strong><br />
• Z<strong>in</strong>ezolid
Quiolones och am<strong>in</strong>oglycosids<br />
• Efficacy is dependent on peak/MIC and<br />
AUC/MIC
How important is T>MIC for<br />
β-lactam <strong>antibiotic</strong>s<br />
How long should it be
Depends on<br />
• How long has <strong>the</strong> patient been ill<br />
• The immune status<br />
– Immunocompromized or not<br />
• Type <strong>of</strong> <strong>in</strong>fection<br />
– Simple or severe <strong>in</strong>fection
Piperacill<strong>in</strong>/tazobactam given every 6 h or<br />
with 4 h <strong>in</strong>fusion every 8 h<br />
Lodise CID 2007<br />
• Patients with APACHE score > 17<br />
14-days mortality was significant lower <strong>in</strong><br />
<strong>the</strong> group <strong>of</strong> patients that had received 4 h<br />
<strong>in</strong>fusion<br />
12.2 vs 31.6% (p=0.04)
Relationship Between Time Above MIC 90 and Bacteriologic<br />
Cure for S. pneumoniae (p<strong>in</strong>k) & H. <strong>in</strong>fluenzae (blue)
Benzylpenicill<strong>in</strong><br />
• Spectrum MIC-values<br />
(native)mg/L<br />
• ß-hemolytic<br />
• streptokocker group A 0.008-0.032<br />
• S. pneumoniae 0.008-0.032<br />
• Enterococci 0.5-4<br />
• P. multocida 0.016-0.125<br />
• Men<strong>in</strong>gococci 0.016-0.125
www.eucast.org
S<br />
I<br />
R
MIC MIC-gränser breakpo<strong>in</strong>ts<br />
• Pharmacological breakpo<strong>in</strong>ts: 0.25/2<br />
• Speciesrelated breakpo<strong>in</strong>ts :<br />
• streptococci (0.25/0.25), pneumococci<br />
(0.06/2), enterococci, H. <strong>in</strong>fluenzae (IE)
Pharmacok<strong>in</strong>etics <strong>of</strong><br />
benzylpenicill<strong>in</strong><br />
• 3g gives a concentration after 4 h <strong>of</strong> 4 mg/l<br />
• Prote<strong>in</strong>b<strong>in</strong>dn<strong>in</strong>g= 65%.<br />
• Free concentration 1-1.4 mg/l after 4 h<br />
• Half-life= 45 m<strong>in</strong>.<br />
• After 4.45= 0.5 mg/l<br />
• After 5.5 h= 0.25 mg/l<br />
• 3x5.5 h=17.5/24= 69% T>MIC
Dos<strong>in</strong>g<br />
T>MIC;<br />
MIC=0.03 mg/L<br />
T>MIC;<br />
MIC=0.25 mg/L<br />
T>MIC;<br />
MIC=4 mg/L<br />
1g x 3 100% 50% 12.5 %<br />
1g x 4 100% 67% 17%<br />
3g x 3 100% 69% 31%<br />
3g x 4 >100% 92% 42%
Cloxacill<strong>in</strong><br />
• Spectrum MIC-values<br />
(native)mg/L<br />
• ß-hemolytic<br />
streptococci group A 0.032-0.125<br />
• Stafylococcus aureus 0.125-0.5<br />
• Coagulasnegative<br />
stafylococci 0.125-1
Pharmacok<strong>in</strong>etics <strong>of</strong> cloxacill<strong>in</strong><br />
• Cmax after a 30 m<strong>in</strong> <strong>in</strong>fusion=100 mg/l<br />
(2g) Free concentration=6 mg/l<br />
• Prote<strong>in</strong>b<strong>in</strong>dn<strong>in</strong>g= 94%<br />
• T1/2=30 m<strong>in</strong><br />
• After 2 h conc= 0.35 mg/l<br />
• 2h x 3=6/24= 25% T>MIC!
Dos<strong>in</strong>g<br />
T>MIC; MIC=0.25 mg/L<br />
2g x 3 25%<br />
2g x 4 33%<br />
2g x 6 50%<br />
3g x 4 42%<br />
3g x 6 63%
Piperacill<strong>in</strong>/tazobactam<br />
Spectrum MIC-values (native)mg/L<br />
• ß-hemolytiska<br />
streptokocker gr. A 0.016-0.064<br />
• pneumokocker 0.008-0.032<br />
• H. <strong>in</strong>fluenzae 0.016-0.064<br />
• S. aureus 0.25-1<br />
• E. faecalis 1-8<br />
• E. coli 0.5-4<br />
• Klebsiella 0.5-8<br />
• P. mirabilis 0.125-1<br />
• Enterobacter spp. 0.5-8<br />
• P. aerug<strong>in</strong>osa 1-8<br />
• Ac<strong>in</strong>etobacter 1-16<br />
• B. fragilis 0.5-8
MIC MIC-gränser breakpo<strong>in</strong>ts<br />
• Pharmacological breakpo<strong>in</strong>ts: 8/16<br />
• Speciesrelated breakpo<strong>in</strong>ts :<br />
Enterobacteriacae 8/16<br />
Pseudomonas 16/16
S I R
S<br />
R
Dos<strong>in</strong>g<br />
T>MIC;<br />
MIC=1 mg/L<br />
T>MIC;<br />
MIC=4 mg/L<br />
T>MIC;<br />
MIC=16 mg/L<br />
4g x 3 69% 47% 25%<br />
4g x 4 92% 63% 33%
Cefotaxim<br />
Spectrum<br />
MIC-values (native)mg/L<br />
• ß-hemolytiska streptokocker 0.008-0.032<br />
• pneumokocker 0.004-0.032<br />
• H. <strong>in</strong>fluenzae 0.008-0.032<br />
• M. catarrhalis 0. 032-0.125<br />
• S. aureus 0.5-4<br />
• E. faecalis 2->64<br />
• E. coli 0.016-0.125<br />
• Klebsiella 0.016-0.125<br />
• P. mirabilis 0.008-0.032<br />
• Enterobacter spp. 0.064-0.5<br />
• Ac<strong>in</strong>etobacter 0.5-8
MIC MIC-gränser breakpo<strong>in</strong>ts<br />
• Pharmacological breakpo<strong>in</strong>ts: 1/2<br />
• Speciesrelated breakpo<strong>in</strong>ts :<br />
Enterobacteriacae 1/2
S<br />
I<br />
R
Dos<strong>in</strong>g<br />
T>MIC;<br />
MIC=0.03 mg/<br />
L<br />
T>MIC;<br />
MIC=0,125<br />
mg/L<br />
T>MIC;<br />
MIC=2 mg/L<br />
1g x 2 100% 66% 38%<br />
1 g x 3 >100% 100% 48%