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.

Ehrlichs 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 pneumoniae
and 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 such
dramatic 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 Darwins theory of
Survival of the fittest, the
bacteria underwent a rapid
hitherto unprecedented evolution
to circumvent this menace to
their survival.
Being single celled and endowed
with the ability to multiply
rapidly, the change was almost
natural and spontaneous.

RESISTANCE !!!

Mechanism of resistance and its transfer

Major mechanisms of resistance by antimicrobial class:
1. Enzymatic alteration
Lactams,
Aminoglycosides,
2. Decreased permeability
Macrolides,
3. Efflux
Quinolones,
Chloramphenicol
4. Alteration of target site
5. Protection of target site- tetracycline, quinolones
6. Overproduction of target- sulphonamides,
trimethoprim, glycopeptide
7. Bypass of inhibited process- sulphonamides,
trimethoprim
8. Bind up antibiotic- glycopeptide

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 suboptimal
antibiotic is prescribed.

AMR
In addition, antibiotics are now included in
many animal feeds, which are given to
promote growth in animals not otherwise
known 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, in
wrong 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

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

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

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 IN
THE 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 are
needed?

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 the
teeth.
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 be
used 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 and
macrolides 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, necrotic
material 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 drug
reactions, 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 these
organisms..
Laboratory investigations supports to
establish a definitive microbiological
diagnosis.

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 more
effective 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 the
appropriate and accurate use of antibiotics.
CARAT has developed 5 criteria to assist
healthcare 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 should
consider the clinical evidence demonstrating
that the drug is clinically and microbiologically
appropriate, the efficacy of the drug in welldesigned 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 patients
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 drug
treatment.
If possible, the clinician should identify the
causative 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 blackbox warnings and 16 (2.9%) were withdrawn from the
market 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 suited
to 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 gramnegative?
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 patients medical history, including
recent antibiotic exposure.

 Optimal duration means prescribing the

selected drug for the shortest amount of
time required for clinical and microbiologic
efficacy.

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 in
overall costs of medical care because of
treatment failures and adverse events.

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 nonprotein-bound serum concentration
of drug exceeds its minimum inhibitory
concentration(MIC);
the ratio between peak serum concentration (Cmax) and
MIC;
the ratio between drug exposure, measured as area under
the serum 24-hour concentration-time curve (AUC24),
and MIC (AUC24MIC) ratio.

 These parameters have been shown to be coordinated

with clinical outcome.
E.g. at a free-drug AUC24MIC ratio 33.7, the
microbiological response of S pneumoniae to
fluoroquinolones is 100%.
An AUC24MIC 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 be
administered 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 with
rifampicin.
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 ?

Educating Practitioners
Seminars
Panel discussion

Updates

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 self medication

No own antibiotic kit

Emphasis on dose
and duration

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 specific
clinical 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 STGs
Introduce in pre-service training
(Internship/House job)
Dynamic (regular updates)
Handy pocket books

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 antibiotic
is 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 microbiological
labs.
Ministry of Health & Family Welfare
recommends for increase in the
utilization 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.

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 of
reporting, regular issue of
resistance/susceptibility patterns and active
consultations.
Establishment of an antibiotic advisory service in
the hospital.
Publication of consensual antibiotic policy for
special 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 and
the relative lack of newer antimicrobial
agents to combat these multi-resistant
organisms.

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 one
of the most serious difficulties with which
we have to contend
- Sir William Osler (1894)

Antibiotics

Microbes

Past

Present

Future

Thank You !!!