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Rational Use Of Antibiotics

Guided By Presented by

Dr V M Motghare Dr Rushikesh Deshpande

Prof & Head Junior Resident

Department of Pharmacology

Swami Ramanand Teerth Rural Medical College, Ambajogai



“ Medicines are nothing in themselves of not

properly used, but the very hands of Gods,

if employed with reason and prudence..”

- Herophilus



History of chemotherapy

• Period of empirical use: – E.g. mouldy curd by Chinese in boils,

– Choulmoogra oil by Hindus in leprosy

– Mercury by paracelsus in syphilis .

– Lime in prevention of Pregnancy induced hypertension by pregnant mothers in Guatemala.

• Ehrlich’s phase of dyes and organometallic compounds.

E.g. methylene blue, tryptan red , arsenic for sleeping

scikness etc.

• Modern era of antibiotics



Pre-antibiotic era

• Era of pus drainage, amputations and

laudable pus…

• Wards full of suppurating wounds…

• Mortuary filled with victims who had been

felled by organisms that we often disregard

these days e.g. Streptococcus pneumoniaeand Streptococcus pyogens.



Antibiotic Era

• Antibiotics were hailed as

“miracle drugs” after their initial

introduction in 1940s.• Penicillin, the wonder drug, saved millions of lives in

the 2nd world war and many mothers were saved from

puerperal sepsis.

• Their widespread availability and success led to suchdramatic reduction in the morbidity and mortality

caused by infectious diseases that many thought it was

time to “close the book” on infectious diseases.



Introduction

• As if proving Darwin’s theory of

“Survival of the fittest”, the

bacteria underwent a rapid

hitherto unprecedented evolution

to circumvent this menace totheir survival.

• Being single celled and endowed

with the ability to multiplyrapidly, the change was almost

natural and spontaneous.

RESISTANCE !!!



Mechanism of resistance and its transfer

• Major mechanisms of resistance by antimicrobial class:

1. Enzymatic alteration

2. Decreased permeability

3. Efflux

4. Alteration of target site

5. Protection of target site- tetracycline, quinolones

6. Overproduction of target- sulphonamides,

trimethoprim, glycopeptide7. Bypass of inhibited process- sulphonamides,

trimethoprim

8. Bind up antibiotic- glycopeptide

β Lactams,

Aminoglycosides,

Macrolides,

Quinolones,

Chloramphenicol



Antimicrobial Resistance (AMR)

• 3 methods:• Transformation

– Naked DNA from dead bacteria

• Transduction

– By phages

• Conjugation

– F factor

• The latest in genetic transfer is Transposon;- jumps form bacteria to bacteria, carrying

chains of resistance genes leading to Multi

Drug Resistance (MDR) organisms.



AMR

• Though there are many causes of

developing resistance, 2 key factors are

overuse and misuse of antibiotics.

• Antibiotics are frequently prescribed for

indications in which their use is not

warranted, or an incorrect or suboptimalantibiotic is prescribed.



AMR

• In addition, antibiotics are now included in

many animal feeds, which are given to

promote growth in animals not otherwiseknown to be bacterially infected !

• Many of these antibiotics are then ingested

by humans through consuming animal products.



What is irrational use of

antibiotics (IUA) ?

• IUA means use of wrong antibiotics, inwrong dose, by wrong route of

administration, for wrong interval and

duration and in wrong dosage form…



Determinants of irrational use of

antibiotics• Physician related

– Lack of knowledge

– Delayed lab results, fear of clinical failure

– Inappropriate peer norms,

– local medical culture

– Economic incentives

– Patient demand of “quick fix”




antibiotics• On the part of pharmacist/dispenser

– Economic incentives

– Lack of regulations and enforcements

– Unclear role as health providers

• On the part of patients

– Lack of access to proper health care

– Beliefs and traditions

– Marketing pressures

– Economic considerations




antibiotics• On the part of policymakers, regulators and

pharmaceutical industry

– Lack of rational drug policy, regulations

– Uncontrolled marketing tactics

– Lack of infrastructure



4 Es of IUA

• Lack of Education – Suboptimal approach to diagnosis and Rx.

– Lack of knowledge of natural course of viral

diseases.• Experience

– Diagnostic and prescribing habits of doctors.

• Expectations – Belief that patient expects antibiotics.

• Economics

– Time pressures, need to return to work.



Consequences of IUA

• Antimicrobial resistance

• Adverse Drug Reactions

• Increased cost burden.



What is Rational Use of Drugs?

Requires that patients receive medicines

appropriate to their clinical needs

in doses to meet individual requirements

for an adequate period of time

at the lowest cost to them.

(WHO 1988)

Correct Drug; Correct Dose; Correct Duration !!!



GENERAL PRINCIPLES INTHE USE OF ANTIBIOTICS



Appropriate Antibiotic Therapy

1. Perception of need

– Is an antibiotic necessary?

2. Choice of antibiotic – What is the most appropriate antibiotic?

3. Choice of regimen

– What dose, route, frequency and duration areneeded?

4. Monitoring efficacy

– Is the treatment effective?



General principles

• Clinical assessment

– Type of patient

– Likely infecting organism



A) Host factors

• Age

– Some drugs are contraindicated in children like

tetracycline, because they may discolor theteeth.

– Quinolones are used with precaution because of

concerns over arthropathy.

– Renal function and creatinine clearance reduced

in elderly, doses need to be reduced.



Host factors

• Renal and hepatic function:

– Alters the pharmacokinetics of the drugs.

– Aminoglycosides and glycopeptides need to beused very carefully even in mild renal failure.

– Beta lactams precipitates seizures in renal

impairment.

– Macrolides, cloramphenicol, metronidazole,

rifampicin and isoniazid ; doses need to be

reduced in liver failure.



Host factors

• Pregnancy

– Aminoglycosides and tetracyclines should be

avoided – Penicillins, cephalosporins and macrolides

appear to be safe.

– Drugs like trimethoprim, metronidazole andmacrolides enter breast milk.



Host factors

• Site of infection

– Antibiotics need to achieve sufficeint local

concentration at the infected site for effective

microbial killing to occur.

– Abscesses will require drainage, necroticmaterial to me debrided.

• Immune status – AIDS, hematological malignancies ; influence

both the likelihood of an infection and its likely

etiology.



Host factors

• Presence of prosthetic material

– Rarely respond to antibiotic therapy

– Usually require removal of device

• Allergy

– Determination of previous allergic drugreactions, including antimicrobial agents.

– Failure to do so can have catastrophic

consequences.



B) Likely infecting agent

• Clinical assessment may allow a likely

source of infection.

• Empirical treatment is aimed at theseorganisms..

• Laboratory investigations supports to

establish a definitive microbiologicaldiagnosis.



Other considerations• Routes of administration:

– Parenteral therapy:

• Seriously ill patient, where effective drug concentrations are

required rapidly at the site of infection.

• Drugs not orally absorbed e.g. aminoglycosides,

glycopeptides

• Oral route is contraindicated

• Patient usually switched to oral formulation after 48-72

hours.

– Oral therapy

– Topical

• Superficial skin infections, mucosal candidiasis, middle ear

and superficial ocular infections



• Dosage regimens

– Dose influenced by severity of infection, age and

weight of the patient. – Standard treatment guidelines should be followed.

• Encouraging compliance – Less frequency improves compliance

• Length of treatment – Depends upon site and severity of infections,

causative organisms and patients response to the

treatment.



Combination therapy – High risk of toxicity, interactions

– High cost, Less compliance

Useful in

• Empirical therapy to cover several pathogens – E.g. Severe community acquired pneumonia; combination

of beta lactam and macrolide is used.

– Brain abscesses; ceftriaxone + metronidazole

• Treatment of mixed infections – E.g. intra-abdominal infections

– Gram negative agent (Ceftriaxone/aminoglycoside) +

Metronidazole (broad spectrum anaerobic) + Amoxycillin

(against enterococci)



Combination therapy• Synergy :

– E.g. beta lactams + Aminoglycosides moreeffective than penicillin alone in streptococcal

endocarditis.

• Broadening of antimicrobial activity – Combination of antibiotic + Enzyme inhibitor

e.g. amoxicillin + clavulanic acid.

– Inhibitors against human enzymes, to reduce

metabolism of antibiotics. E.g imipenam +

cilastin.

• Avoiding drug resistance

– E.g. quadruple therapy for tuberculosis.



The Council for Appropriate and

Rational Antibiotic Therapy (CARAT)• CARAT is an independent, multidisciplinary

panel of healthcare professionals, clinicians as

well as scientists, established to advocate theappropriate and accurate use of antibiotics.

• CARAT has developed 5 criteria to assisthealthcare providers in selecting the most

appropriate and accurate treatment regimens.



CARAT criteria

• Evidence based results

• Therapeutic benefits

• Safety

• Cost-Effectiveness

• Optimal drug dose and duration

– Shorter course, more aggressive therapy.



Evidence based results

• In choosing an antibiotic, clinicians shouldconsider the clinical evidence demonstrating

that the drug is clinically and microbiologically

appropriate, the efficacy of the drug in well-

designed clinical trials and the antibiotic

resistance pattern of local region.

• Well conducted, randomized, controlled clinical

trials provide the highest quality information for

making decisions.



Therapeutic Benefits

• The key to applying evidence-based results and making

appropriate therapeutic choices for each patient involves

determining the correct diagnosis and analyzing the

therapeutic benefits of possible treatments.

• To maximize patient health and reduce unnecessary

prescribing, the therapeutic benefits of each drug should be considered relative to the status of the patient’s

infection.



Therapeutic Benefits

• The clinician must consider any evidence that a particular antibiotic can result in a, clinical and

microbiologic cure as well as the treatment

failures associated with the absence of drugtreatment.

• If possible, the clinician should identify thecausative pathogen and use surveillance data on

regional antibiotic resistance patterns in

selecting the optimal therapeutic agent.



Safety

• In treating patients with a particular drug, safety must be

weighed against efficacy.

• Clinically applicable treatment strategies should be

chosen to maximize efficacy while minimizing side

effects.

• In a study of the period between 1975 and 2000, 548

new chemical entities were approved for use in the

United States; 45 of these (8.2%) acquired new black-

box warnings and 16 (2.9%) were withdrawn from themarket during this time.

• Of the 16 withdrawn from the market, 8 were withdrawn

within 2 years after their introduction.



Optimal Drug for Optimal Duration• Optimal drug selection requires finding the antimicrobial

class and the specific member of that class that is best suitedto treat a particular infection.

• Because empiric therapy is necessary in most cases, multiple

factors have to be considered.

– Whether the etiologic agent is gram-positive or gram-

negative?

– whether a narrow or broad-spectrum agent should be

chosen, – the resistance patterns of the likely pathogen to this drug,

both nationally and regionally, and

– the individual patient’s medical history, including

recent antibiotic exposure.



• Optimal duration means prescribing the

selected drug for the shortest amount of

time required for clinical and microbiologicefficacy.

– Decreased side effects

– Increased patient adherence – Decreased promotion of resistance

– Decreased cost



Cost effectiveness

• Choosing inappropriate therapy is

associated with increased costs, including

the cost of the antibiotic and increases inoverall costs of medical care because of

treatment failures and adverse events.

h ki i id i



Pharmacokinetic considerations• Pharmacokinetic properties differentiate among classes of

antibiotics, and even among antibiotics within the same

class, in their ability to eradicate bacteria at drug

concentrations attained during therapy.

• Among these properties are :

– time for which non – protein-bound serum concentration

of drug exceeds its minimum inhibitory

concentration(MIC);

– the ratio between peak serum concentration (Cmax) andMIC;

– the ratio between drug exposure, measured as area under

the serum 24-hour concentration-time curve (AUC24),

and MIC (AUC24 – MIC) ratio.



• These parameters have been shown to be coordinated

with clinical outcome.

– E.g. at a free-drug AUC24 – MIC ratio 33.7, the

microbiological response of S pneumoniae to

fluoroquinolones is 100%.

– An AUC24 – MIC ratio of 125 predicts an 85.4%microbiologic response to levofloxacin and an 81.5%

response to ciprofloxacin

– For optimal reduction of bacterial load, antibiotics

like beta lactams and macrolides; should beadministered such that drug concentrations exceed

the MIC for 40% of dosing interval i.e. time

dependent efficacy



• Concentration dependent bactericidal

activity; drugs like aminoglycosides,

macrolides and lincosamides.

– The efficacy of these drugs has been found to

correlate with Cmax-MIC and AUC24-MIC

ratios. – E.g. AUC24-MIC ration of 25 to 40 is thought to

predict optimal bactericidal activity of

Fluoroquinolones against S. pnumoniae.

– Thus for these class of drug, administration of

maximum dose for a shorter time would be

optimal in the absence of adverse effects.



Prophylactic use of antibiotics

• Long acting Penicillin (Benzathine Penicillin) for

prevention of recurrent attack of group A beta

hemolytic streptococcal infection.

• Children and other susceptible contacts of open case of

tuberculosis – INH alone or in combination withrifampicin.

• Malaria – before visit from non endemic area to

endemic area, chloroquine or sulphamethoxazole +

Pyrimethamine propbhylaxis.

• Meningococcal meningitis prophylaxis particularly

during epidemic for close contacts- sulphadiazine,

Rifampicin, Ciprofloxacin.



WHAT WE CAN DO ?



•Seminars

•Panel discussion

•Updates

Educating Practitioners



Let the advertisements

not block your intelligence!

* Reading the fine print!

1. The drug is 10 times more potent

but may cause renal damage in some

2. The most effective antibiotic for what?

At what cost?

What duration?



Educating Consumers

No own antibiotic kit Emphasis on doseand duration

No self medication



Essential drug list

Essential drugs are those that satisfy the

needs of the majority of the population.

They should therefore be available at all

times, in adequate amounts, and in the

appropriate dosage forms.



Standard Treatment Guidelines

A systematically developed statement to

assist practitioners in making decisions

about appropriate health care for specificclinical conditions

• These guidelines should be tailored to the

local situations and specific to levels of care• From national level to hospital level.



Key features of STGs

• Simplicity

• Credibility

• Same standard for all levels

• Drug supply based on STG’s

• Introduce in pre-service training

(Internship/House job)• Dynamic (regular updates)

• Handy pocket books

S ill



Surveillance

• Two complementary types of surveillance are

recommended

– Surveillance for antibiotic resistance

– Surveillance for antibiotic use

• Knowing resistance levels and tracking them

over a period of time is a powerful tool to

support real changes.

• Once the link between resistance and antibioticis accepted, tracking antibiotic use can be used

as a surrogate for changes in antibiotic

resistance.



Increasing the use of diagnostic tests

• Lack of adequate, well equipped

laboratory facilities.

• Under-utilization of microbiologicallabs.

• Ministry of Health & Family Welfare

recommends for increase in theutilization of diagnostic tests in

the clinical practice.



Antibiotic policy

• A corporate document that is designed to

further the aim of the hospital to provide a

high standard of patient care.• The principles of antibiotic policy were laid

down in the 1980s.



Objectives of the Antibiotic Policy

• To provide the most effective and empirical

treatment for individual patient with

minimal adverse reactions.

• To motivate the rational use of antibiotics

• To prevent the development of drug

resistance by judicious and timely use of

relevant antibiotics.

• Cost effective and rational use of drugs for

treatment.

A tibi ti li



Antibiotic policy

• Educational programs designed to improve

antibiotic uses.

• Controls operated through the Pharmacy

department.

– Creation of hospital pharmacopeia.

– Written justification for the costlier and broader

spectrum of antibiotics.

– Introduction of concept of stop orders

– Sponsoring of antibiotics according to their usage

e.g. prophylaxis, specific therapy, therapeutic trials

etc.



Antibiotic policy

• Controls through the laboratory in the form ofreporting, regular issue of

resistance/susceptibility patterns and active

consultations.• Establishment of an antibiotic advisory service in

the hospital.

• Publication of consensual antibiotic policy forspecial use e.g. prophylaxis and specialized

clinical units.



Antibiotic policy

– Audit of antibiotic usage; antibiotics as a class of

drugs accounts for the largest expenditure in health

care system.

– Promotion of ethical relationship between the pharmaceutical companies, prescribers and

pharmacists.



Antimicrobial Management Team

• To design and implement antibiotic policy.

• Composition

– Infectious disease physician (Member secretary)

– Infection control officer- a senior microbiologist.

– Clinical microbiologist

– Surgeon – Clinical pharmacologist

– Clinical pharmacist



Antimicrobial Management Team

• Functions-

– Providing high standard of patient care

– Improving rational utilization of antibiotic. – Pharmacovigilance of antimicrobial

– Effective utilization of financial resources in

purchase of antimicrobials – Curbing emergence of microbial resistance.



Summary

Infectious diseases are still a serious problem,

compounded by the development of

antibiotic resistance in many bacteria andthe relative lack of newer antimicrobial

agents to combat these multi-resistant

organisms.

S mmar



Summary

• Appropriate aggressive short-course

treatment is recommended for ensuring clinical and

microbiologic cure, optimal patient adherence, and

minimal generation of antibiotic resistance.

• Ideally, institution of the 5 CARAT criteria will

optimize safe and well-tolerated treatment regimens,

curb unnecessary prescribing of antibiotics, decrease

treatment costs, and increase adherence.



• “ The desire to take medicines is one

feature which distinguishes man, the

animal from his fellow creatures. It is oneof the most serious difficulties with which

we have to contend ”

- Sir Wil l iam Osler (1894)

Antibiotics Microbes



Past

Present

Future



Thank You !!!

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