8th isap symposium can pk/pd be used in everyday clinical practice? francesco scaglione department...
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8th ISAP Symposium
Can PK/PD be used in everyday clinical practice?
Francesco Scaglione Department of Pharmacology, Toxicology and Chemotherapy, University of Milan, Milan, Italy
PK/PD results and evolution
2000
Persistend effect
Time/Conc. dependent activity
}Improvement of dose and intervals
}Outcome
resistance
?
Effect overEffect over the time;the time;
Peculiar EffectsPeculiar Effects
Effect overEffect over the time;the time;
Peculiar EffectsPeculiar Effects
AADDMMEE
AADDMMEE
In VitroIn Vitroand in vivoand in vivo
activityactivity
In VitroIn Vitroand in vivoand in vivo
activityactivity
Pharmacology : what for physician?
0
2
4
6
810
12
1416
18
20
0 1 2 3 4 5 6 7 8 9 10 11 12time h
conc
entr
atio
n (µ
g/m
l)
Optimizing antimicrobial therapy
Concentration at infection
site
PathogenMIC
DRUGPK
Pharmacodynamics = relationship between
concentration and effect
Bacterialkill
PK/PD parameters determining efficacy AbsorptionAbsorption Serum levelsSerum levels Distribution and penetration to site of Distribution and penetration to site of
infectioninfection Intracellular penetrationIntracellular penetration Relationship of PK parameters to MICRelationship of PK parameters to MIC
Trauma
FACTORS INVOLVED IN INLAMMATION
Complement
Necrosis
Bacteria
PMNMN
Lymphocytes
TNF- IL - 1IL - 6
PAFPGELTCTXA
Protease
oxygen Radicals
endothelialDamage
Increase of capillary
permeability
Oedema
THEORETICAL CONCENTRATION OF AN ANTIBIOTIC
Time
Serum
Interstitial fluid
Con
cent
ratio
n Large volume compartment
‘‘Time above MIC’Time above MIC’
Co
nce
ntr
atio
nC
on
cen
trat
ion
M ICM IC11
TimeTime
M ICM IC22
Time Over MICPeak/MIC
Ideal approach to adjust the doseInitial dosing regimen(chosen by patient’s physician)
Blood sampling( two or more post-distributional sample)
Pharmacokinetic analysis (peak,AUC,CL)
Adjust dose or/and intervals (PK/PD)
Redetermine concentrations
Adjust again ?
First problemPK approach to adjust the dose is poor applicable for routinely use (at moment)
N°samples Personnel Costs
second problemPK/PD breakpoints
betalactams (ceftriaxone)
aminoglicosides
quinolones
glicopeptides
macrolides
tetraciclines
Program to customize the therapyin our hospital
Isolation of the pathogen and MIC
Design therapy traditionally(by patient’s physician)
Pharmacokinetic
Adjust dose or interval using PK/PD
Redetermine concentrations
PK/PD values adopted
•Aminoglicosides Peak/MIC 8•Quinolones peak/MIC 10 •Betalactams peak/MIC 4
and T>MIC 70%
same value for monotherapy or combination
Sampling time
•Aminoglicosides Peak : 0.5 h from end 30 min infusion•Quinolones peak : 0.5 h from end 60 min infusion•Betalactams peak :0.5 h from end 30 min infusionAnd T>MIC : 5.6 hours from start infusion
Concentrations of ceftazidime and cefotaxime in serum
05
101520253035404550556065
mg
/L
C 0.5 h C 5.6 h
PK/PD dose adjustment
Levofloxacin 500 mg to 750 OD or BID
Ciprofloxacin 500mg to 750 BID
Cefotaxime-Ceftazidime 2g q 8 to 2g q6
Amikacin 10 mg/kg OD to 15 mg/kg OD
preliminary results
October 2000 – April 2001
Patients included 680
Evaluated for PK/PD 223 (32.8%)
Dose or interval adjusted 84 (37.7%)
Adjustment failed in 6 (5 cipro -1 amikacin)
Organisms isolated
Pseudomonas aeruginosa 87
Staphylococcus aureus 42
Enterobacter species 33
Klebsiella species 15
Escherichia coli 14
Haemophilus influenzae 11
Serratia marcescens 7
Streptococcus pneumoniae 4
Stenotrophomonas spp 4
Legionella species 2
Citrobacter species 2
Acinetobacter 1
Proteus species 1
AminoglicosidesDose adjusted according to creatinine clearance
Creatinine clearance % of initial dose at mL/min 24h dosing interval:
40 92% 30 86 25 81 20 75 17 70 15 67 12 61 10 56
Ceftazidime-Cefotaxime-LevofloxacinDose adjusted according to creatinine clearance
>50 mL/min: normal dose 20-50 mL/min: 1/2-3/4 normal dose <20 mL/min: 1/4-1/2 normal dose
Ciprofloxacin Dose adjusted according to creatinine clearance
> 20 mL/min: normal dose <20 mL/min: 1/2 normal dose
outcome
Length Length hospitalizationhospitalization
- days- days**
failurefailure mortalitymortality
PK/PD PK/PD analysedanalysed
11 (7-16)11 (7-16) 39/223 39/223 (17.5%)(17.5%)
11 11
(4.9%)(4.9%)
PK/PDPK/PD
Not Not analysedanalysed
16 (9-23 )16 (9-23 ) 147/457147/457
(31.9 %)(31.9 %)
4646
(10.1%)(10.1%)
*From the diagnosis of infection
0 25 50 75 100 125 150 1750
5
10
15
20
hours to adjust doses
ho
spit
aliz
atio
n d
ays
correlation between time to adjust the dose and hospitalisation days
Conclusions I
The PK/PD approach may:
improve the outcome
shorten the time to clinical improvement
Reduce the length of hospitalisation
Conclusions II
The initial higher costs for analysis and personnel are compensate for the reduction of the hospitalisation, with a financial gain
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