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 hospital’s 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 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

Antibiotic concentration (ug/ml) Important PK/PD Parameters Important PK/PD Parameters Time above MIC : Proportion of the dosing interval when the drug concentration exceeds the MIC 8 6 Drug A Drug A 4 Drug B Drug B Antibiotic concentration (ug/ml) 2 B B A Time Time above MIC

Area under the curve over MIC Antibiotic concentration Important PK/PD Parameters Area under the curve over MIC AUC/MIC is the ratio of the AUC to MIC Peak/MIC is the ratio of the peak concentration to MIC PEAK Antibiotic concentration 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 and relevant PK/PD Parameter 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, 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 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

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

Antimicrobial-Resistant Pathogen Antimicrobial Resistance Campaign to Prevent Antimicrobial Resistance in Healthcare Settings Antimicrobial Resistance: Key Prevention Strategies Susceptible Pathogen Antimicrobial-Resistant Pathogen Pathogen Infection Prevent Transmission Prevent Infection Antimicrobial Use Antimicrobial Resistance Effective Diagnosis & Treatment Optimize Use

12 Steps to Prevent Antimicrobial Resistance Campaign to Prevent Antimicrobial Resistance in Healthcare Settings 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 experts 3 Target the pathogen 2 Get the catheters out 1 Vaccinate Prevent Transmission Use Antimicrobials Wisely Diagnose & Treat Effectively Prevent Infections

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