Basic Principles and Rational Use

of Antibiotics

Dr.Novita carolia, M.Sc

Dept. Pharmacology and Pharmacy, Medical Faculty, Lampung
University
 Overview

Selective toxicity of antimicrobial (AM)

ability to kill invading m.o without harming host’s cells

Effective treatment in infectious disease

BUT it requires an appropriate concentration to attack

the m.o while tolerabled by the host
Terms
Chemotheraphy:
• Drugs with selective toxicity against invading
parasites (virus, bacteria, protozoa, fungi and
helminth)

Antibiotics:
• Substances produced by some microorganism
(or by pharmaceutical chemists) that kill/inhibit
the growth of other microorganism (m.o)
• = antimicrobial
 IDEAL ANTIBIOTICS
CRITERIA

1. Most selective, most effective to

infectied microorganisms
2. More bactericidal effect in the site of
action
3. Antibacterial effect is not interfered
by body fluid, exudate, plasma
protein or enzymes and persist for a
long duration in the blood
4. Minimal toxicity
5. Resistance develops slowly
6. Given by any route
7. Reachable cost
 SPECTRUM OF AB
EFFECTS
1. Narrow spectrum antibiotics (NSAB)
Main effect : sensitive for gram (+)
bacteria and bacil
Pen. G, Pen. resistent penicillinase
bacitracin, macrolides, lincomycin, vancomycin

2. Broad Spectrum Antibiotics (BSAB)

Main effect : sensitive for gram (+) and
(-) bacteriae
Pen. (ampi and amoxycillin), cefalosporins,
tetracyclins, chloramphenicol, trimetroprim and
sulfonamides
 Molecular basis of chemotherapy

• chemotherapeutic drugs should be toxic for invading

m.o in the host
• Selective toxicity depends on biochemical differences
between parasite – host
• Biochemical reaction as potential targets :
• Class I: glucose & other carbon source
• Class II: energy and class I compound to make amino acid,
nucleotides, etc
• Class III: small molecules are built into larger molecules,
e.g. proteins, nucleic acid, peptidoglycan
 Biochemical reactions as potential
targets
Class I: poor targets

Class II: better targets

• Folate synthesis – inhibited by sulfonamides
• Folate utilisation – inhibited by folate antagonist
• Pyrimidine & purine analogues – produce fraudulent
nucleotides

Class III: important targets

• Peptidoglycan synthesis – B-lactam
• Protein synthesis – work though tRNA (T-S); mRNA (AMG)
• Nucleic acid synthesis – work though DNA (quinolon,
rifampicin)
 Resistance to AB

If with max dose

• a. Nature of m.o (exp: gr (-) m.o are
of AM (tolerated
resistant to vancomycin)
by the host)  • b. Acquired resistance
the growth of • Spontaneous mutation
m.o is not • Selection
halted.

Why it’s happen? •  inappropriate use of the drugs

 Resistance to AB

Plasmid:
Transposons:
Can be spread extrachromosomal
stretches of DNA
genetic element
• From person – • Can replicate • can be
person (by independently, transported from
bacteria) • Can carry genes palsmid - another
• From bacteria – coding for • Also from plasmid
bacteria (by resistance to AB to chromosom &
plasmid) v.v
• From plasmid –
plasmid (by
transposons)
 Resistance to AB: mechanism?

Genetic alterations  DR
Spontaneous mutation of DNA DNA transfer of DR (through plasmid)

Altered expression of proteins in DR-organism

Modification of target sites Decreased accumulation Enzymatic inactivation
• MRSA, quinolon resistance • Decrease permeability OR • B-lactamase
increase Efflux system that pump
out the drug
 Multidrug Resistance (MDR)

Resistance to commonly used AB

MDR- TB (resistant to >2 anti-TB drugs)
Some strains of Staph. &enterococc. (resistant to most all AB)

Lead to serious untreatable infection

 How to select AM?
Identity of m.o
and it’s
sensitivity to AM

What about cost Where is site of

of th/? infection?

We need information about:

Any patient’s How is the

factors? safety of AM
Availability? we’ll use?
 RATIONAL USE OF
AB

Define the patient problems

Specify the therapeutic objectives
Verify the suitable of your personal
treatment
Start the treatment
PROCEDURES Give information, instruction and warning
Monitoring and stop treatment

Clinical diagnosis
Identification, sensitivity test of
bacteria
Pharmacodynamics
Pharmacokinetics
STEPS TO PROCEDURES
Host factors
However…
Critically ill patient (C.I.P) need immediate AM
Empiric therapy

cover infections by both gr (+), (-), &/ anaerob

To prevent worsening the condition

To prevent the death

 I. Empiric therapy..

When • For C.I. P  pts can’t wait the result of

m.o identification [gram (+) / (-)] and
DST
? • Immunocompromised patients

• Take the specimen for lab first!!

How?
• choose broad spectrum
• administration: iv
 Empiric therapy
Empiric therapy Receive culture report
Coverage by a combination of
Coverage
antibiotics suchby
as,aclindamycin
combinationplusof with sensitivities
antibiotics such
gentamicin, as, clindamycin
effective plus
against gr (+),
gentamicin,
gr effective or
(-) and anaerobes, against gr (+),
a single
gr (-)
broad and anaerobes,
spectrum orsuch
antibiotic, a single
as
broadimipenem
spectrumcilastatin
antibiotic, such as
imipenem cilastatin If mixed
If mixed
If Gram
If Gram
positive
positive
only
only If Gram Continue therapy
Cont. gr (+) coverage. If Gram
negative only as initiated
negative only
discontinue gram (-) &
anaerobic coverage If anaerobic only
If anaerobic only
Cont. gr (-) coverage
Cont. anaerobic coverage
Discontinue gr (+) and
anaerobic coverage Discontinue gr (+) & (-)
coverage

Strategic for empiric therapy

II. Pay attention to specific cond related to PK

• For AM excreted
through kidney 
Renal  toxicity  adjust
the dosage
dysfunction • or…change the
drugs

• Don’t give drugs

Liver concentrated/elimi
nated by the liver
dysfunction (macrolides, sulfa)
  toxicity
 Pay attention to specific cond related to PK

Pregnancy
Poor
and Age
perfusion
lactation
Some AM cross Newborn:
placenta & excreted in immaturation of
the breast milk  organs’ function
teratogenic or rise
Exp: diabetic problems (toxicity)
Children: deal
foot with PAD with growth
 difficult to process
treat infection Exp: pyrimetamin
(for toxomplasma), Geriatric pts :
AMG alteration organs
function
Pay attention to specific cond related to PK
Pay attention to specific cond related to PK
 III. Safety and Cost-benefit

• Both drugs and patients’ factors

• B-lactam is least toxic compared to
Safety other AM
• Pt’s factors: age, co-morbidity

• Consider the efficacy AND the cost

Cost- • In EMG case: efficacy is the most
benefit important!
• Feasibility !
 IV. Bacteriostatic vs. Bactericidal AM

Bacteriostatic:
Only stop growth & So, it limits the spread of Wait for immune system
replication of m.o infection to solve the rest

Bactericidal:
kills the m.o  decreases the amount of m.o

BUT, some AM is -statics for certain m.o while it’s -cidal to

another m.o (chloramphenicol)
V. Spectrum of AM
• single/limited group of
m.o
narrow
• exp. INH – only for
m.TB

• Gram (+), (-)

extended
• exp; ampicillin

• Not only to gr (+), (-)

• But also to other m.o
broad
• Exp. TS,
chloramphenicol
 VI. Combination of AM
Select if possible only single AM
It prevents:
• Superinfections
•  emerge of drug resistance
• Minimize toxicity
•  the cost

BUT sometimes wee need drug combination

• Synergism  more effective (B-lactam + AMG)
• Wider coverage
 VII. Complication of AM Therapy

1. Hypersensitivity
• Ag-Ab complex reaction
• Mild (urticaria) – severe (anaphylaxtic reaction)
• Exp: penicillin

2. Direct toxicity
• Toxic directly to the cellular
• Related to the plasma conc.
• Exp: AMG (nepfro & oto-toxicity)

3. Superinfection
• Broad spectrum AM  alter Normal flora  OI
 VIII. Classification of AM
a. Chemical structure

• B-lactams AM (B-lactam ring): 1st, 2nd, 3rd, 4th generation

• AMG : AMK, KNM, STREPT

b. Activity against certain m.o

• Anti viral
• Antifungal
• Antibacterial  !!!

c. Mechanism of action

• Inhibitors of metabolism
• Inhibitors of cell wall synthesis
• Inhibitors of protein synthesis
• Inhibitors of nucleic acid fct/synthesis