Rational Antimicrobial Therapy

Rianto 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 bacterial resistance (MRSA, VRE, ESBL producing pathogens, MDR hospital pathogens) Spread of infections in hospital setting Cost of treatment Inappropriate use of antimicrobial agents

Introduction (2)
Lack of new antimicrobial agents developed in recent years Unnecessary financial burden to the patients Scarcity of objective information on appropriate use of antimicrobial agents

Outlines (1)
Pharmacological factors affecting antimicrobial activity Selecting an appropriate antimicrobial agent Use of combinations Prophylaxis Duration of antimicrobial treatment

Outlines (2)
Patterns of antimicrobial killing activity Penetration of antimicrobials into CSF Factors responsible for treatment failure

Pharmacologic factors affecting tissue penetration of antimicrobials

Antimicrobial concentration in blood Molecular size of antimicrobials Protein binding Lipid solubility Ionic charge Binding to exudate or tissue Presence of inflammation Active transport mechanism Pathway of excretion
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Selecting an antimicrobial agent

clinical signs & symptoms

clinical diagnosis
Educated guess or Culture and sensitivity test

etiological diagnosis

determine the drug of choice

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Selecting an antimicrobial agent (contd)

determine the drug of choice
If in appropriate give a secondline drug. Consider: safety, efficacy, suitability, and cost

give the drug

evaluate the result

stop or continue or modify the treatment as necessary

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Tips for selecting an appropriate antimicrobial agent (1)

If a sensitivity test indicates that a pathogen is sensitive to some antibiotics, it does not mean all these agents have equal clinical efficacy If two or more antibiotics are equally safe and effective, choose the one with narrower antibacterial spectrum In life-threatening condition a de-escalating therapy may be applied if the etiology is unknown Generic antibiotics are not of low quality but their price is much more affordable
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Tips for selecting an appripriate antimicrobial agent (2)

A new generation antibiotic is not always superior to its older generations A slightly more potent antibiotic shown in vitro, is not necessarily associated with better clinical efficacy

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Use of antimicrobial combinations (1)

Indications: Empirical therapy of severe infections in which cause is unknown Treatment of polymicrobial infections Enhancement of antimicrobial activity in treatment of specific infections Prevention 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 cause Enterococcal endocarditis Serious infections due to P. aeruginosa Intra-abdominal infection Tuberculosis and leprosy treatment

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Use of antimicrobial combinations (3)

Disadvantages of AM combinations: Increased risk of toxicity Selection of multiple-drug-resistant microorganisms Increased cost Possibility of unexpected antagonistic effect

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Use of antimicrobial combinations (4)

Examples of possible clinical antagonistic effect:
Lepper & Dowling (Arch Int Med 1951;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 unsuccessful prophylaxis:

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 resist hosts defense mechanism Physical location of the pathogen Potency of the AM agent The frequency of development of resistance

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Duration of therapy (2)

Examples:
Acute uncomplicated cystitis: one dose 3 days Acute gonococcal urethritis: one dose Pneumococcal pneumonia: until afebrile 3 days, at least 5 days Bacterial endocarditis: 4 weeks Streptococcal pharyngitis: 10 days Pulmonary tuberculosis: 6 months Extra pulmonary tuberculosis: 12-24 months

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Factors causing failure of treatment (1)

Poor antibacterial activity of a drug Wrong route of administration or wrong dosage The location of infection is inaccessible by the antimicrobial agent Poor hosts defense mechanism Premature discontinuation of treatment
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Factors causing failure of treatment (2)

Serious toxicity necessitates discontinuation of therapy Resistance of the microorganism Superinfection Foreign body or necrotic tissues Patients incompliance

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

10 9 8 7 6 5 4 3 2 1 0 0 2 4 6 Control 1/4 MIC 1 MIC 4 MIC 16 MIC 64 MIC

Log CFU/ml

Time (h)
(Craig, 1991)
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Patterns of antibiotic killing activity (1)

Pattern 1: concentration-dependent killing E.g.: aminoglycosides, fluoroquinolones Strategy of dosing regimen: maximize concentrations Parameters determining efficacy: ratios of Cmax/MIC or AUC/MIC
(Deziel-Evans, 1986)
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Time-kill curves of P. aeruginosa with exposure to ticarcillin

10 9 8 7 6 5 4 3 2 1 0 0 2 4 6 8 Control 1/4 MIC 1 MIC 4 MIC 16 MIC 64 MIC

Log CFU/ml

Time (h)

(Craig, 1991)
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Patterns of antibiotic killing activity (2)

Pattern 2: time-dependent killing E.g.: betalactams, macrolides, oxazolidinedinones Strategy of dosing regimen: maximize duration of exposure to antibiotics Parameters determining efficacy: length of time of above-MIC antibiotic blood level
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Pharmacokinetic/Pharmacodynamic (PK/PD) parameters

For concentration-dependent killing pattern: AUC/MIC (required: 125 and 30 for Gram negative and Gram positive pathogens, respectively ) Cmax/MIC (required: 10) For time-dependent killing pattern: Time above MIC (required: 40%)
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Pharmacokinetics and pharmaco-dynamics of antimicrobial agents

CONC. Cmax

AUC/MIC Cmax/MIC Time above MIC

Area Under the Curve

MIC
Time Time above-MIC
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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 into cerebrospinal fluid (2)

Good with inflammed meninges: Penicillin G Ampicillin Cloxacillin Ticarcillin Piperacillin

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Penetration of antimicrobials into cerebrospinal fluid (3)

Ceftriaxone Ceftazidime Aztreonam Imipenem Fluoroquinolones

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Penetration of antimicrobials into cerebrospinal 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 be delivered to the site of infection in sufficient concentration Inaccessible site of infection Inadequate host body defenses Treatment duration is too short to prevent relapse
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Factors responsible for treatment failure (2)

Serious toxicity necessitates discontinuation of therapy Development of resistance Superinfection occurred Foreign body or necrotic tissues Patients incompliance
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THANK YOU

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