The Rational Use of The Rational Use of AntibioticsAntibiotics

Victor Lim

International Medical University

Kuala Lumpur, Malaysia

AntibioticsAntibiotics One of the most commonly used One of the most commonly used

group of drugs group of drugs In USA 23 million kg used annually; In USA 23 million kg used annually;

50% for medical reasons50% for medical reasons May account for up to 50% of a May account for up to 50% of a

hospital’s drug expenditurehospital’s drug expenditure Studies worldwide has shown a high Studies worldwide has shown a high

incidence of inappropriate useincidence of inappropriate use

Reasons for appropriate useReasons for appropriate use

Avoid adverse effects on the patientAvoid adverse effects on the patient Avoid emergence of antibiotic Avoid emergence of antibiotic

resistance - resistance - ecological or societal ecological or societal aspect of antibioticsaspect of antibiotics

Avoid unnecessary increases in the Avoid unnecessary increases in the cost of health carecost of health care

Ecological/Societal AspectEcological/Societal Aspect

Antibiotics differ from other classes of Antibiotics differ from other classes of drugs drugs

The way in which a physician and other The way in which a physician and other professionals use an antibiotic can affect professionals use an antibiotic can affect the response of future patientsthe response of future patients

Responsibility to societyResponsibility to society Antibiotic resistance can Antibiotic resistance can spreadspread from from

bacteria to bacteriabacteria to bacteria patient to patientpatient to patient animals to patientsanimals to patients

Prescribing an antibioticPrescribing an antibiotic

Is an antibiotic necessary ?Is an antibiotic necessary ? What is the most appropriate What is the most appropriate

antibiotic ?antibiotic ? What dose, frequency, route and What dose, frequency, route and

duration ?duration ? Is the treatment effective ?Is the treatment effective ?

Is an antibiotic necessary ?Is an antibiotic necessary ?

Useful only for the treatment of Useful only for the treatment of bacterial infectionsbacterial infections

Not all fevers are due to infectionNot all fevers are due to infection Not all infections are due to bacteriaNot all infections are due to bacteria

There is no evidence that antibiotics will There is no evidence that antibiotics will prevent secondary bacterial infection in prevent secondary bacterial infection in patients with viral infectionpatients with viral infection

Arroll and Kenealy, Antibiotics for the common cold. Cochrane Database of Systematic Reviews. Issue 4, 2003

Meta-analysis of 9 randomised placebo controlled trials involving 2249 patients

Conclusions: There is not enough evidence of important benefits from the treatment of upper respiratory tract infections with antibiotics and there is a significant increase in adverse effects associated with antibiotic use.

Is an antibiotic necessary ?Is an antibiotic necessary ?

Not all bacterial infections require Not all bacterial infections require antibioticsantibiotics Consider other options :Consider other options : antisepticsantiseptics surgerysurgery

Choice of an antibioticChoice of an antibiotic

Aetiological agentAetiological agent Patient factorsPatient factors Antibiotic factorsAntibiotic factors

The aetiological agentThe aetiological agent Clinical diagnosisClinical diagnosis

clinical acumenclinical acumen the most likely site/source of infectionthe most likely site/source of infection the most likely pathogensthe most likely pathogens

empirical therapyempirical therapy universal datauniversal data local datalocal data

Importance of local antibiotic Importance of local antibiotic resistance dataresistance data

Resistance patterns vary From country to country From hospital to hospital in the same

country From unit to unit in the same hospital

Regional/Country data useful only for looking at trends NOT guide empirical therapy

The aetiological agentThe aetiological agent Laboratory diagnosisLaboratory diagnosis

interpretation of the reportinterpretation of the report what is isolated is not necessarily what is isolated is not necessarily

the pathogenthe pathogen was the specimen properly was the specimen properly

collected ?collected ? is it a contaminant or coloniser ?is it a contaminant or coloniser ? sensitivity reports are at best a sensitivity reports are at best a

guideguide

Patient factorsPatient factors

AgeAge Physiological functionsPhysiological functions Genetic factorsGenetic factors PregnancyPregnancy Site and severity of infectionSite and severity of infection AllergyAllergy

Antibiotic factorsAntibiotic factors

Pharmacokinetic/pharmacodynamic Pharmacokinetic/pharmacodynamic (PK/PD) profile (PK/PD) profile absorptionabsorption excretionexcretion tissue levelstissue levels peak levels, AUC, Time above MICpeak levels, AUC, Time above MIC

Toxicity and other adverse effectsToxicity and other adverse effects Drug-drug interactionsDrug-drug interactions Cost Cost

PK/PD ParametersPK/PD Parameters

Increasing knowledge on the association between PK/PD parameters on clinical efficacy and preventing emergence of resistance

Enabled doctors to optimise dosage regimens

Led to redefinition of interpretative breakpoints in sensitivity testing

Important PK/PD ParametersImportant PK/PD Parameters

Time above MIC : Proportion of the dosing interval when the drug concentration exceeds the MIC

Time above MIC

Time

An

tib

ioti

c co

nce

ntr

atio

n (

ug

/ml)

2

Drug A

Drug B

A

B

4

6

8

0

Important PK/PD ParametersImportant PK/PD Parameters

Drug A

Drug B

B

Important PK/PD ParametersImportant PK/PD Parameters

AUC/MIC is the ratio of the AUC to MIC

Peak/MIC is the ratio of the peak concentration to MIC

An

tib

ioti

c co

nce

ntr

atio

n

MIC

Time

Area under the curve over MIC

PEAK

PK/PD and Antimicrobial EfficacyPK/PD and Antimicrobial Efficacy

2 main patterns of bacterial killing Concentration dependent

Aminoglycosides, quinolones, macrolides, azalides, clindamycin, tetracyclines, glycopeptides, oxazolidinones

Correlated with AUC/MIC , Peak/MIC

Time dependent with no persistent effect Betalactams Correlated with Time above MIC (T>MIC)

Craig, 4th ISAAR, Seoul 2003

Goal of therapy based on PK/PDGoal of therapy based on PK/PDPattern of Activity Antimicrobials Goal of therapy

and relevant PK/PD Parameter

Concentration dependent killing

AMGs, Quinolones, Daptomycin, ketolides, Macrolides, azithro-mycin, clindamycin, streptogramines,tetracyclines, glycopeptides, oxazolidinones

Maximise concentrations; AUC/MIC, peak/MIC

Use high doses; daily dosing for some agents

Time dependent killing with no persistent effects

Betalactams Maximise duration of exposure; T>MIC

Use more frequent dosing; longer infusion times including continuous infusion

Cost of antibioticCost of antibiotic

Not just the unit cost of the antibioticNot just the unit cost of the antibiotic Materials for administration of drugMaterials for administration of drug Labour costsLabour costs Expected duration of stay in hospitalExpected duration of stay in hospital Cost of monitoring levelsCost of monitoring levels Expected complianceExpected compliance

Choice of regimenChoice of regimen Oral vs parenteralOral vs parenteral Traditional viewTraditional view

““serious = parenteral”serious = parenteral” previous lack of broad spectrum oral previous lack of broad spectrum oral

antibiotics with reliable bioavailabilityantibiotics with reliable bioavailability Improved oral agentsImproved oral agents

higher and more persistent serum and tissue higher and more persistent serum and tissue levelslevels

for certain infections as good as parenteralfor certain infections as good as parenteral

Advantages of oral treatmentAdvantages of oral treatment

Eliminates risks of complications associated with intravascular lines

Shorter duration of hospital stay Savings in nursing time Savings in overall costs

Duration of treatmentDuration of treatment In most instances the optimum In most instances the optimum

duration is unknownduration is unknown Duration varies from a single dose to Duration varies from a single dose to

many months depending on the many months depending on the infectioninfection

Shorter durations, higher dosesShorter durations, higher doses For certain infections a minimum For certain infections a minimum

duration is recommendedduration is recommended

Recommended minimum Recommended minimum durations of treatmentdurations of treatment

Infection Minimum durationTuberculosis 4 - 6 monthsEmpyema/lung abscess 4 - 6 weeksEndocarditis 4 weeksOsteomyelitis 4 weeksAtypical pneumonia 2 - 3 weeksPneumococcal meningitis 7 daysPneumococcalpneumonia

5 days

Monitoring efficacyMonitoring efficacy Early review of responseEarly review of response

Routine early reviewRoutine early review Increasing or decreasing the level of Increasing or decreasing the level of

treatment depending on responsetreatment depending on response change routechange route change dosechange dose change spectrum of antibacterial activitychange spectrum of antibacterial activity stopping antibioticstopping antibiotic

Antimicrobial Resistance:Antimicrobial Resistance: Key Prevention StrategiesKey Prevention Strategies

Optimize Use

PreventTransmission

PreventInfection

EffectiveDiagnosis& Treatment

PathogenAntimicrobial-Resistant Pathogen

Antimicrobial Resistance

Antimicrobial Use

Infection

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Susceptible Pathogen

12 Steps to Prevent Antimicrobial Resistance

12 Break the chain 11 Isolate the pathogen

10 Stop treatment when cured 9 Know when to say “no” to vanco 8 Treat infection, not colonization 7 Treat infection, not contamination

6 Use local data 5 Practice antimicrobial control 4 Access the experts3 Target the pathogen

2 Get the catheters out 1 Vaccinate

Prevent Transmission

Use Antimicrobials Wisely

Diagnose & Treat Effectively

Prevent Infections

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

ConclusionsConclusions Antibiotic resistance is a major Antibiotic resistance is a major

problem world-wideproblem world-wide Resistance is inevitable with useResistance is inevitable with use No new class of antibiotic introduced No new class of antibiotic introduced

over the last two decadesover the last two decades Appropriate use is the only way of Appropriate use is the only way of

prolonging the useful life of an prolonging the useful life of an antibioticantibiotic