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8/10/2019 Rational 2
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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
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“ Medicines are nothing in themselves of not
properly used, but the very hands of Gods,
if employed with reason and prudence..”
- Herophilus
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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
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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.
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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.
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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 !!!
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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
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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.
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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.
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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.
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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…
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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”
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Determinants of irrational use of
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
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Determinants of irrational use of
antibiotics• On the part of policymakers, regulators and
pharmaceutical industry
– Lack of rational drug policy, regulations
– Uncontrolled marketing tactics
– Lack of infrastructure
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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.
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Consequences of IUA
• Antimicrobial resistance
• Adverse Drug Reactions
• Increased cost burden.
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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 !!!
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GENERAL PRINCIPLES INTHE USE OF ANTIBIOTICS
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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?
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General principles
• Clinical assessment
– Type of patient
– Likely infecting organism
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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.
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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.
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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.
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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.
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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.
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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.
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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
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• 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.
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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)
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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.
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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.
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CARAT criteria
• Evidence based results
• Therapeutic benefits
• Safety
• Cost-Effectiveness
• Optimal drug dose and duration
– Shorter course, more aggressive therapy.
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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.
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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.
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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.
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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.
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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.
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• 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
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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
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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.
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• 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
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• 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.
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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.
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•Seminars
•Panel discussion
•Updates
Educating Practitioners
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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?
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Educating Consumers
No own antibiotic kit Emphasis on doseand duration
No self medication
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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.
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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.
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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
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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.
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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.
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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.
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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
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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.
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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.
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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.
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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
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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.
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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
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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.
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• “ 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