The Rational Use of Antibiotics

Victor Lim International Medical University Kuala Lumpur, Malaysia

Antibiotics

One of the most commonly used group of drugs In USA 23 million kg used annually; 50% for medical reasons May account for up to 50% of a hospitals drug expenditure Studies worldwide has shown a high incidence of inappropriate use

Reasons for appropriate use

Avoid adverse effects on the patient Avoid emergence of antibiotic resistance - ecological or societal aspect of antibiotics Avoid unnecessary increases in the cost of health care

Ecological/Societal Aspect

Antibiotics differ from other classes of drugs The way in which a physician and other professionals use an antibiotic can affect the response of future patients Responsibility to society Antibiotic resistance can spread from

bacteria to bacteria patient to patient animals to patients

Prescribing an antibiotic

Is an antibiotic necessary ? What is the most appropriate antibiotic ? What dose, frequency, route and duration ? Is the treatment effective ?

Is an antibiotic necessary ?
Useful only for the treatment of bacterial infections Not all fevers are due to infection Not all infections are due to bacteria
There is no evidence that antibiotics will prevent secondary bacterial infection in patients 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 ?
Not all bacterial infections require antibiotics Consider other options : antiseptics surgery

Choice of an antibiotic

Aetiological agent Patient factors Antibiotic factors

The aetiological agent

Clinical diagnosis
clinical acumen
the most likely site/source of infection the most likely pathogens

empirical therapy
universal data local data

Importance of local antibiotic resistance 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 agent

Laboratory diagnosis
interpretation of the report what is isolated is not necessarily the pathogen was the specimen properly collected ? is it a contaminant or coloniser ? sensitivity reports are at best a guide

Patient factors

Age Physiological functions Genetic factors Pregnancy Site and severity of infection Allergy

Antibiotic factors
Pharmacokinetic/pharmacodynamic (PK/PD) profile
absorption excretion tissue levels peak levels, AUC, Time above MIC

Toxicity and other adverse effects Drug-drug interactions Cost

PK/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 Parameters Important PK/PD Parameters

Time above MIC : Proportion of the dosing interval when the drug concentration exceeds the MIC
6 4
Antibiotic concentration (ug/ml)

Drug A Drug A Drug B Drug B

B B A
Time above MIC Time

Important PK/PD Parameters

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

Area under the curve over MIC

PEAK

MIC

Time

PK/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/PD

Pattern of Activity Antimicrobials Goal of therapy and relevant PK/PD Parameter

Concentration dependent killing

AMGs, Quinolones, Daptomycin, ketolides, Macrolides, azithromycin, clindamycin, streptogramines,tetracyc lines, glycopeptides, oxazolidinones

Maximise concentrations; AUC/MIC, peak/MIC Use high doses; daily dosing for some agents
Maximise duration of exposure; T>MIC Use more frequent dosing; longer infusion times including continuous infusion

Time dependent killing Betalactams with no persistent effects

Cost of antibiotic

Not just the unit cost of the antibiotic Materials for administration of drug Labour costs Expected duration of stay in hospital Cost of monitoring levels Expected compliance

Choice of regimen
Oral vs parenteral Traditional view
serious = parenteral previous lack of broad spectrum oral antibiotics with reliable bioavailability

Improved oral agents

higher and more persistent serum and tissue levels for certain infections as good as parenteral

Advantages 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 treatment

In most instances the optimum duration is unknown Duration varies from a single dose to many months depending on the infection Shorter durations, higher doses For certain infections a minimum duration is recommended

Recommended minimum durations of treatment

Infection Tuberculosis Empyema/lung abscess Endocarditis Osteomyelitis Atypical pneumonia Pneumococcal meningitis Pneumococcal pneumonia Minimum duration 4 - 6 months 4 - 6 weeks 4 weeks 4 weeks 2 - 3 weeks 7 days 5 days

Monitoring efficacy
Early review of response
Routine early review

Increasing or decreasing the level of treatment depending on response

change route change dose change spectrum of antibacterial activity stopping antibiotic

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

Antimicrobial Resistance:

Key Prevention Strategies

Susceptible Pathogen Pathogen Antimicrobial-Resistant Pathogen
Prevent Transmission
Prevent Infection

Antimicrobial Resistance
Optimize Use

Infection
Effective Diagnosis & Treatment

Antimicrobial Use

Campaign to Prevent Antimicrobial Resistance in Healthcare Settings

12 Steps to Prevent Antimicrobial Resistance

12 Break the chain Prevent Transmission 11 Isolate the pathogen 10 Stop treatment when cured 9 Know when to say no to vanco 8 Treat infection, not colonization Use Antimicrobials Wisely 7 Treat infection, not contamination 6 Use local data 5 Practice antimicrobial control 4 Access the experts Diagnose & Treat Effectively 3 Target the pathogen 2 Get the catheters out Prevent Infections 1 Vaccinate

Conclusions

Antibiotic resistance is a major problem world-wide Resistance is inevitable with use No new class of antibiotic introduced over the last two decades Appropriate use is the only way of prolonging the useful life of an antibiotic