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microorganisms with multiply resistance

MRSA - methicillin/oxacillin-resistant Staphylococcus

VISA - vancomycin intermediate resistant
VRE - vancomycin-resistant enterococci
ESBLs - extended-spectrum beta-lactamases
(microorganisms resistant to cephalosporins and
PRSP - penicillin-resistant Streptococcus pneumoniae
1952 100 % Staphylococcus infections were cured by penicillin
1982 only 10 % infections
At nowadays ?........
MRSA causes 19 000 deaths annually in USA (more than VIL)
Beta-lactam antibiotics:
- Penicillins
- Inhibitors of beta-lactamases and combined drugs,
- Cephalosporins
- Monobactams
- carbapenems
Macrolides, azalides, streptogramins, prystinamycines.
Cyclic polipeptides (polimixins).
Other antibiotics
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.
Mechanism of resistance and its transfer
Major mechanisms of resistance by antimicrobial class:
1. Enzymatic alteration
2. Decreased permeability Macrolides,
3. Efflux Quinolones,
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,
Antimicrobial Resistance (AMR)
3 methods:
Naked DNA from dead bacteria
By phages
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.
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
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

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

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
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.
Diagnostic and prescribing habits of doctors.
Belief that patient expects antibiotics.
Time pressures, need to return to work.
Consequences of IUA

Antimicrobial resistance

Adverse Drug Reactions

Increased cost burden.

What is Rational Use of Drugs?

Rational use of drugs requires that patients

receive medications appropriately to their
clinical needs, in doses that meet their own
individual requirements for an adequate
period of time, at the lowest cost to them and
their community
(WHO 1988)

Correct Drug; Correct Dose; Correct Duration !!!

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
4. Monitoring efficacy
Is the treatment effective?
Antibiotic choice:
Antibiotic-related factors
(PK/PD) profile
tissue levels, peak levels, AUC,
Time above MIC
Toxicity and other adverse effects
Drug-drug interactions
Pharmacokinetic (PK)/
pharmacodynamic (PD) factors
Increasing knowledge on the association
between PK/PD parameters on
clinical efficacy
preventing emergence of resistance
Enables optimization of dosage regimens
In some instances this has led to a
redefinition of interpretative breakpoints in
sensitivity testing
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
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.
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
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.
Antimicrobial activity
Drug Concentration Peak (Peak/MIC)

Area Under the Curve (AUC/MIC)


Time above
Pharmacodynamic properties of
Type of bactericidal Important
Dosage optimization
profile parameter

Dose-dependent Cmax / MIC

Aminoglycosides, Single daily dose
Prolonged PAE

Time-dependent Multiple DD or
Penicillin, cephalosporins continuous infusion

dependent AUC / MIC Total dose and
Clarithromycin, Prolonged PAE duration

PAE: Post-Antibiotic Activity


Dose-dependent Time-dependent

Antibacterial effect directly Effectiveness depends on a

depends on their period of time, during which
concentrations in the locus of concentration in blood
inflammation overwhelms MIC for a
(high doses 1-2 times/24h) particular causative agent
(constant i.v. infusion or 3-6

Aminoglycosides Beta-lactames
Fluoroqinolones Glycopeptides
Metronidazol Macrolides
Amphotericin B Linkozamides
General principles

Clinical assessment

Type of patient

Likely infecting organism

A) Host factors
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
Macrolides, cloramphenicol, metronidazole,
rifampicin and isoniazid ; doses need to be
reduced in liver failure.
Host factors
Aminoglycosides and tetracyclines should be
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 sufficient 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

Determination of previous allergic drug reactions,
including antimicrobial agents.
Failure to do so can have catastrophic
B) Likely infecting agent
Clinical assessment may allow a likely source
of infection.
Empirical treatment is aimed at these
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,
Oral route is contraindicated
Patient usually switched to oral formulation after 48-72
Oral therapy
Superficial skin infections, mucosal candidiasis, middle ear
and superficial ocular infections
Dosage regimens
Lowest dose that is effective
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
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.
Indifference Synergism Antagonism
Log of number if viable bacteria/mL

No drug No drug No drug

Drug A
Drug A
Drug C
Drug B
Drug B
A+ C
A+ B

I A+ B Drug A

Hours after inoculation

Antibiotic-related factors: Synergy
Synergy against Gram-negatives
Treating CF chest exacerbations with combinations of
Ticarcillin-clavulanate and tobramycin
Neutropenic patients with Gram-negative infections
Severe invasive Group-A streptococcal infections
Penicillin and clindamycin
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
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 well-designed clinical trials
and the antibiotic resistance pattern of local
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
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.
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
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 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 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 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
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.
Prophylactic use of antibiotics
Long acting Penicillin (Benzathine Penicillin) for prevention
of recurrent attack of group A beta hemolytic streptococcal
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
Meningococcal meningitis prophylaxis particularly during
epidemic for close contacts- sulphadiazine, Rifampicin,
Educating Practitioners

Panel discussion

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 (SGTs)
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
Same standard for all levels
Drug supply based on STGs
Introduce in pre-service training
Dynamic (regular updates)
Handy pocket books
Two complementary types of surveillance are
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
1996 WHO
Respiratory Infections
Urinary Tract Infections
Skin and Soft Tissue Infections
Musculosketel Infections
Gastrointestinal Infections
Genitourinary Infections (Including Sexually Transmitted
Central Nervous System Infections
Cardiovascular Infections
Bacteraemia And Septicaemia
Other Infections
Infections Associated With Pregnancy
Chemoprophylaxis For Selected Medical Condition
Condition 1st Choice 2nd Choice Notes
antibiotic(s) antibiotic(s)

Acute Penicillin V Erythromycin The majority of sore

pharyngitis/tonsillitis throats are viral in
, scarlet fever origin and antibiotics
(Streptococcus are not indicated for
pyogenes suspected treatment or
or proven) prevention of
secondary bacterial
Diphtheria Benzylpenicillin Antibiotics are not
(Corynebacterium the mainstay of
diphtheriae) treatment. Antitoxin
and supportive
treatment are critical
in management.
Close contacts should
receive erythromycin.
contacts should be
Condition 1st Choice 2nd Choice Notes
antibiotic(s) antibiotic(s)
Acute urinary tract Cotrimoxa- 1o/2o cephalo-sporin Many hospital acquired
infection zole pathogens are now
(E. coli, or resistant to ampicillin.
Staphylococcus Trimethoprim In uncomplicated cystitis
saprophyticus) in adults 4 tabs
or cotrimoxazole in a single
Ampicillin dose has been shown to
or be effective.
Nitrofurantoi In pregnancy ampicillin
n should be given for 10
Pyelonephritis and 2o Cephalo- In all cases an attempt
complicated urinary sporin should be made to
tract infection and exclude any underlying
(E. coli, Gentamicin abnormality
otherEnterobacteriac or
eae) a quinolone
Increasing the use of diagnostic tests

Lack of adequate, well equipped

laboratory facilities.
Under-utilization of microbiological labs.
Ministry of Health 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
Cost effective and rational use of drugs for
Antibiotic policy
Educational programs designed to improve
antibiotic uses.
Controls operated through the Pharmacy
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
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
WHO treatment revised and to be linked to Model
List of Essential Drugs
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Med 1976; 89 : 802 - 805.
2. Lim V K E, Cheong Y M and Suleiman A B. Pattern of antibiotic usage in hospitals
in Malaysia. Singapore Med J 1993; 34 : 525 - 528.
3. Ackerman V P, Pritchard R C, Groot Obink D J, Bradbury R and Lee A.
Consumer survey on microbiology reports. Lancet 1979; i : 199 - 203.
4. Cooke D, Salter A J and Phillips I. Antibiotic misuse, antibiotic policies and
information resources. J Antimicrob Chemother 1980; 6 : 435 - 443.
5. Obaseiki-Ebor E E, Akerele J O and Ebea P O. A survey of outpatient prescribing
and antibiotic self medication. J Antimicrob Chemother 1987; 20 : 759 -763.
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wards of a University Hospital, Bangkok, Thailand. Rev Infect Dis 1990; 12 : 136 -
7. Cheong YM, Lim VKE, Jegathesan M and Suleiman AB. Med J Malaysia 1994; 47
8. Kunin C M, Lipton H L, Tupasi T, Sacks T, Scheckler W E, Jivani A, Goic A,
Martin R R, Guerrant R L and Thamlikitkul V. Social, behavioural and practical
factors affecting antibiotic use worldwide: Report of task force 4. Rev Infect Dis
1987; 9 (Suppl 1) : S270 - S285.
9. Fourth Western Pacific Congress on Chemotherapy and Infectious Diseases.
Consensus statement on policies and strategies for promoting appropriate antibiotic
use. Manila, 1994.
8. Williams J D. Antibiotic policy. Scan J Infect Dis 1986; Supplement 49 : 175 -181
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Antibiotics Microbes