16/04/2013 1 PK-PD of ANTIBIOTICS N A F R I A L D I Department of Pharmacology Faculty of Medicine, University of Indonesia Jakarta Antimicrobial Update April 12, 2013 INTRODUCTION Successful antibiotic (AB) treatment depends on: • Intrinsic sensitivity of bacteria to AB • Sufficient AB concentration at the site of infection for a sufficient duration. • But must remain below toxic level 3 INTRODUCTION • In vitro activity is only a guide as to whether an AB is likely to be effective for an infection. • Pharmacokinetics describes the time course of drug concentration in plasma or other body fluid
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16/04/2013
1
PK-PD of ANTIBIOTICS
N A F R I A L D IDepartment of Pharmacology
Faculty of Medicine, University of Indonesia
Jakarta Antimicrobial UpdateApril 12, 2013
INTRODUCTION
Successful antibiotic (AB) treatment depends on:
• Intrinsic sensitivity of bacteria to AB• Sufficient AB concentration at the site of
infection for a sufficient duration.• But must remain below toxic level
3
INTRODUCTION
• In vitro activity is only a guide as to whether an AB is likely to be effective for an infection.
• Pharmacokinetics describes the time course of drug concentration in plasma or other body fluid
ØPK parameter: T > MIC (Time above MIC) ØEffective T > MIC : 40-50% (mostly for Gr +)ØGoal of treatment: maximize duration of exposureØSlow infusion is betterØIf using T > MIC, a value of 70% may be needed
Percentage bacteriologic cure for ß-lactam agents against Streptococcus pneumoniae (black circle) and Haemophilus influenzae (white circle) in children with acute otitis media
Craig WA, Andes W.. Pediatr Infect Dis J 1996;15:255-9.
Time above MIC vs Bacteriologic cure
3. Time-dependent Killing(with minimal to moderate persistent effects)
Ø PK parameter: AUC24h/MICØ Goal of treatment: optimize amount of
• Unlike the sensitivity test, the data of Cmaxand AUC is not routinely performed in patient setting.
• It needs serial measures of drug concentration• Thus, PK-PD is normally performed in animal
model• The magnitude of PK/PD parameters required
for efficacy is relatively similar in different animal species and human being
Strategies to Increase % Time>MIC (Example of Doripenem)
vGive a higher dose
v Increase duration of infusionØProlonged infusion
• Same dose and dosing interval, but prolong the duration of infusion
ØContinuous infusion• Loading dose, followed by total daily dose over 24
hours infusion
Nicolau DP. Pharmacodynamic optimization of beta-lactams in the patient care setting. Crit Care. 2008;12 Suppl 4:S2. Epub 2008 May 21.
vDoripenem is the only approved carbapenem for 1-hour and 4-hour extended infusion1
vHighest Cummulative Fraction Response (CFR) against P. aeruginosa in comparison with imipenem and meropenem2
vSuperior stability vs. other carbapenems for extended infusion3,4,5
CFR : Cumulative Fraction of Response
1. DORIBAX Prescribing Information (Malaysia) 2008.2. Roberts JA, Kwa A, Montakantikul P, Gomersall C, Kutie JL, Nicolau DP. Pharmacodynamic profiling of intravenous antibiotics against prevalent Gram-negative organisms across the
globe: the PASSPORT Program—Asia Pacific Region. International Journal of Antimicrobial Agents 37 (2011) 225–229.3. DORIBAX (doripenem for injection) [European Public Assessment Report]. Janssen-Cilag International NV., Beerse, Belgium.4. Meronem® I.V. (meropenem for injection) [Summary of Product Characteristics]. AstraZeneca UK Ltd., Luton, UK.5. Primaxin® I.V. (imipenem and cilastatin for injection) [Summary of Product Characteristics]. Merck Sharp & Dohme Ltd., Hoddesdon, UK.
Strategies to Increase % Time>MIC (Example of Doripenem)
DORIBAX IS THE ONLY APPROVED CARBAPENEM FOR 1-HOUR INFUSION AND 4-HOUR EXTENDED INFUSION4-Hour Infusion Allows Targeting of Higher MICs
Without Increasing the Dose
*Optional infusion time for NP/VAP patients who are at risk for infections with less susceptible pathogens.
DORIBAX Prescribing Information (Malaysia) 2008.
500 mg IV administered over 1 h500 mg IV administered over 4 h*
25
20
15
10
5
00 1 2 3 4 5 6 7 8
Time (hours)
Concentration (µg/mL)
DORIBAX Prescribing Information (Malaysia) 2008.
Improved Doripenem Targeting of Higher MICs with 4-hour Infusion
100%
0
20
40
60
80
100
MIC, µg/mL
Target Attainment,
%
0.06 0.12 0.25 0.5 1 2 4 8 16
Doripenem 500 mg q8h, 1-h infusion
Doripenem 500 mg q8h, 4-h infusion
35%
78%
95%
CUMULATIVE FRACTION OF RESPONSE (CFR)
PASSPORT: Probability of target attainment of Antibacterial agents Studied for Susceptibility and Pharmacodynamic Optimization in Regional Trials
Roberts JA, Kwa A, Montakantikul P, Gomersall C, KutieJL, Nicolau DP. Pharmacodynamic profiling of intravenous antibiotics against prevalent Gram-negative organisms across the globe: the PASSPORT Program—Asia Pacific Region. International Journal of Antimicrobial Agents 37 (2011) 225–229.
vCFR is the possibility that the antibiotic regimen will reach its pharmacodynamic index against the entire population of organismsvThe PASSPORT analysis showed that doripenem has
the highest CFR against P. aeruginosa in comparison with imipenem and meropenemvAgainst P. aeruginosa, doripenem 1 gm and 2 gm
Doripenem has the highest CFR against P. Aeruginosa
Roberts JA, Kwa A, Montakantikul P, Gomersall C, Kutie JL, Nicolau DP. Pharmacodynamic profiling of intravenous antibiotics against prevalent Gram-negative organisms across the globe: the PASSPORT Program—Asia Pacific Region. International Journal of Antimicrobial Agents 37 (2011) 225–229.
1. DORIBAX (doripenem for injection) [European Public Assessment Report]. Janssen-Cilag International NV., Beerse, Belgium.2. Meronem® I.V. (meropenem for injection) [Summary of Product Characteristics]. AstraZeneca UK Ltd., Luton, UK.3. Primaxin® I.V. (imipenem and cilastatin for injection) [Summary of Product Characteristics]. Merck Sharp & Dohme Ltd., Hoddesdon, UK.
DORIPENEM Provides a Favourable Stability Following Reconstitution
Stability Time, h
Diluent Room Temperature
2-80C(Refrigerator)
DORIPENEM Normal Saline 12 72*
Imipenem Normal Saline 3 24
Meropenem Normal Saline 8 48
Doripenem 5% Dextrose 4 24*
Imipenem 5% Dextrose 3 24
Meropenem 5% Dextrose 3 14
* Once removed from the refrigerator, infusions should be completed within the room temperature stability time,provided the time does not exceed refrigeration stability time.
Keel RA, Sutherland CA, Crandon JL, Nicolau DP. Stability of doripenem, imipenem and meropenem at elevated room temperatures. Int J AntimicrobAgents. 2011 Feb;37(2):184-5. Epub 2010 Aug 10.
DORIPENEM Has Superior Stability at Elevated Room Temperatures