Pharmacodynamic Indices

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Pharmacodynamic Indices. Johan W Mouton. Canisius-Wilhelmina Hospital Nijmegen, The Netherlands. PEAK / MIC AUC / MIC TIME > MIC. PEAK. AUC. MIC. TIME > MIC. PK/PD. Neutropenic mouse thigh model Various doses and dosing regimens (q1 to q24) Outcome parameter: cfu counts after 24 h - PowerPoint PPT Presentation

Text of Pharmacodynamic Indices

  • Pharmacodynamic IndicesCanisius-Wilhelmina HospitalNijmegen, The NetherlandsJohan W Mouton

  • MICPEAKPEAK / MICAUC / MICTIME > MICAUCTIME > MIC

  • PK/PDNeutropenic mouse thigh model

    Various doses and dosing regimens (q1 to q24)

    Outcome parameter: cfu counts after 24 h

    Plot PD index (AUC, Peak T>MIC) to effect

  • K. pneumoniae, imipenem

  • For K.pneumoniae, there is no clear relation

    between total daily dose of imipenem and

    efficacy in an in vivo model of infection

  • K. pneumoniae, imipenem

  • For beta-lactams, there is a direct

    relation between

    Time > MIC and efficacy

  • Scaglione et al, ICAAC 1999

  • Pharmacodynamic Indicespredictive for efficacy

    T>MICAUC (Peak)/MICPenicillinsAminoglycosidesCephalosporinsFluoroquinolonesCarbapenemsMetronidazoleMonobactamsDaptomycinTribactamsKetolidesClindamycin Macrolides Oxazolidinones AzithromycinClindamycinStreptogramins GlycopeptidesGlycylcyclinesTetracyclines

  • Kill curves of ceftazidime, P. aeruginosa

  • Mouton & Vinks, 2003

  • Kill curves of tobramycin, P. aeruginosa

  • Antibiotics showing increasing effect (killing) over a wide range of concentrations are called concentration dependent. In vivo effects are usually AUC and/or Peak related.

    Those with a limited range of increasing effect are called (wrongly) concentration-independent. In vivo effects are usually Time >MIC related.

  • Pharmacodynamic index Pharmacokinetic parameterMIC

  • The MIC

  • MICThe MIC is a result of :

    kill over time (kill rate) by the antibiotic growth over time (growth rate) for a certain number of micro-organisms (the inoculum)

    AT STATIC CONCENTRATIONS

  • Growth and/or kill rate dependent :strain, speciesmedium composition, brandMH, supplements, ISOnumber of bacteriainoculum5.105 (NCCLS) vs 105 (BSAC)temperature (35o vs 37o)growth phaseCO2etc.

  • Mouton, icaac 2000

  • The MIC of the control strain should be within one two-fold dilution of the expected MIC

  • PHARMACOKINETICparameters

  • Definition :The Area under the Concentration-time curve over 24 hours.Note: .. It should be stated how the AUC is determined : based on (log) linear trapezoideal rule, based on clearance, or based on microconstants.

    Dimensions : concentration x time e.g. mg.h/L or g.h/mLMouton et al, Int J Antimicrob Agents april 2002

  • AUC 0-24 = 3033 AUC inf = 5100AUC 0-24 sd = 1361AUC inf sd =1700Mg.h/L

  • AUC 0-24h or AUC Steady State? (log) trapezodeal rule?Derived ? (A/ +B/ or other)

    WHICH AUC?

  • Peak/MICDefinition : the peak level divided by the MIC.

    Dimensions : no dimensions.

    Mouton et al, Int J Antimicrob Agents april 2002

  • After the 1st, 2nd or later dose?

    If more than one compartment, the peak level in compartment 1, 2 or even 3?WHICH PEAKLEVEL?

  • Scaglione et al, icaac 1999

  • Scaglione et al, unpubl.

  • Time > MICDefinition : the % of time above the MIC over a period of 24 hours.Note : if the period is other than 24 h, this should be stated explicitly.

    Dimensions : %.

    Mouton et al, Int J Antimicrob Agents april 2002

  • Concentration-time profile of beta-lactamVd = 20 L, Ka = 1.2 h-1, Ke = 0.3 h-1

    About

    SimLab

    Monte Carlo Analysis Tool

    MEDIMATICS

    N.C. Punt

    March 2001

    TitleSimLab

    AuthorN.C. Punt

    Revision1.000

    Date09-01-2000

    StatusProject Approved

    Simulation

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