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    Rational Antimicrobial

    TherapyRianto Setiabudy

    Department of Pharmacology FMUI Lecture for Infection and Immunology Module

    April, 2010

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    Introduction (1)

    The problems we are facing:The ever increasing problem of bacterialresistance (MRSA, VRE, ESBL producingpathogens, MDR hospital pathogens)Spread of infections in hospital setting

    Cost of treatment Inappropriate use of antimicrobial agents

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    Introduction (2)

    Lack of new antimicrobial agentsdeveloped in recent yearsUnnecessary financial burden to thepatientsScarcity of objective information onappropriate use of antimicrobial agents

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    Outlines (1)

    Pharmacological factors affectingantimicrobial activitySelecting an appropriate antimicrobialagentUse of combinations

    ProphylaxisDuration of antimicrobial treatment

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    Outlines (2)

    Patterns of antimicrobial killingactivity

    Penetration of antimicrobials intoCSFFactors responsible for treatment

    failure

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    Selecting an antimicrobial agent (contd)

    determine the drug of choice

    give the drug

    evaluate the result

    stop or continue or modifythe treatment as necessary

    If in appropriate give a second-line drug. Consider: safety,efficacy, suitability, and cost

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    Tips for selecting an appropriateantimicrobial agent (1)

    If a sensitivity test indicates that a pathogen issensitive to some antibiotics, it does notmean all these agents have equal clinical

    efficacyIf two or more antibiotics are equally safeand effective, choose the one with narrower antibacterial spectrumIn life- threatening condition a de -escalatingtherapy may be applied if the etiology isunknownGeneric antibiotics are not of low quality buttheir price is much more affordable

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    Tips for selecting an appripriateantimicrobial agent (2)

    A new generation antibiotic is not alwayssuperior to its older generations

    A slightly more potent antibiotic shown invitro, is not necessarily associated with better clinical efficacy

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    Use of antimicrobial combinations(1)

    Indications:Empirical therapy of severe infections inwhich cause is unknownTreatment of polymicrobial infectionsEnhancement of antimicrobial activity in

    treatment of specific infectionsPrevention of emergence of resistance

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    Use of antimicrobial combinations(2)

    Examples of appropriate use of AM combinations:Septic shock due to Gram negative pathogens

    Life-threatening infection of undetermined causeEnterococcal endocarditisSerious infections due to P. aeruginosa

    Intra-abdominal infectionTuberculosis and leprosy treatment

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    Use of antimicrobial combinations(3)

    Disadvantages of AM combinations:Increased risk of toxicity

    Selection of multiple-drug-resistantmicroorganismsIncreased cost

    Possibility of unexpected antagonisticeffect

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    Use of antimicrobial combinations(4)

    Examples of possible clinical antagonisticeffect:Lepper & Dowling (Arch Int Med1951;88:489-94)Pneumococcal meningitis treated with:

    Penicillin alone: fatality rate = 21% Penicillin + chlortetracycline: fatality rate =

    79%

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    Prophylaxis

    Characteristics of successful prophylaxis: Aimed at a specific pathogen The pathogen is highly sensitive to the

    prophylactic agent used

    Characteristics of unsuccessfulprophylaxis: Aimed at any or all microorganism in the

    environment of a patient(Chambers, 2001)

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    Duration of therapy (1)

    Determined by:The ability of the pathogens to resisthosts defense mechanism Physical location of the pathogenPotency of the AM agent

    The frequency of development of resistance

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    Duration of therapy (2)

    Examples: Acute uncomplicated cystitis: one dose 3days

    Acute gonococcal urethritis: one dosePneumococcal pneumonia: until afebrile 3days, at least 5 daysBacterial endocarditis: 4 weeksStreptococcal pharyngitis: 10 daysPulmonary tuberculosis: 6 monthsExtra pulmonary tuberculosis: 12-24 months

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    Factors causing failure of treatment (1)

    Poor antibacterial activity of a drugWrong route of administration or wrong dosageThe location of infection isinaccessible by the antimicrobialagent

    Poor hosts defense mechanism Premature discontinuation of treatment

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    Factors causing failure of treatment (2)

    Serious toxicity necessitatesdiscontinuation of therapy

    Resistance of the microorganismSuperinfectionForeign body or necrotic tissues

    Patients incompliance

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    Time-kill curves of P. aeruginosa with exposure to tobramycin

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    0 2 4 6

    Control

    1/4 MIC

    1 MIC4 MIC

    16 MIC

    64 MIC

    L o g

    C F U / m l

    Time (h)

    (Craig, 1991) 20

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    Patterns of antibiotic killing activity(1)

    Pattern 1: concentration-dependentkilling

    E.g.: aminoglycosides,fluoroquinolones Strategy of dosing regimen:

    maximize concentrations Parameters determining efficacy:ratios of Cmax/MIC or AUC/MIC

    (Deziel-Evans, 1986)21

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    Time-kill curves of P. aeruginosa withexposure to ticarcillin

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    2

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    4

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    0 2 4 6 8

    Control1/4 MIC1 MIC4 MIC16 MIC64 MIC

    L o g

    C F U / m

    l

    Time (h)(Craig, 1991)

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    Patterns of antibiotic killing activity(2)

    Pattern 2: time-dependent killingE.g.: betalactams, macrolides,

    oxazolidinedinones Strategy of dosing regimen: maximize

    duration of exposure to antibiotics

    Parameters determining efficacy:length of time of above-MIC antibioticblood level

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    Pharmacokinetic/Pharmaco-dynamic (PK/PD) parameters

    For concentration-dependent killingpattern:

    AUC/MIC (required: 125 and 30for Gram negative and Grampositive pathogens, respectively )

    Cmax/MIC (required: 10)For time-dependent killing pattern: Time above MIC (required: 40%)

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    Penetration of antimicrobials into

    cerebrospinal fluid (1)Excellent:

    Trimethoprim

    Sulfonamides Chloramphenicol INH Rifampicin Flucytocin

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    Penetration of antimicrobials intocerebrospinal fluid (2)

    Good with inflammed meninges: Penicillin G Ampicillin Cloxacillin Ticarcillin Piperacillin

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    Penetration of antimicrobials intocerebrospinal fluid (3)

    Ceftriaxone Ceftazidime Aztreonam Imipenem Fluoroquinolones

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    Penetration of antimicrobials intocerebrospinal fluid (4)

    Poor penetration: Aminoglycosides

    First generation cephalosporins Clindamycin Vancomycin Cefoxitin

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    Factors responsible for treatment

    failure (1)Poor antimicrobial activity

    Active antimicrobial agent fails to bedelivered to the site of infection insufficient concentrationInaccessible site of infection

    Inadequate host body defensesTreatment duration is too short toprevent relapse

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    THANK YOU

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