PHARMACOLOGY OF

ANTIMICROBIAL DRUGS

DR.DATTEN BANGUN,MSC,SPFK
DEPT.FARMAKOLOGI &TERAPEUTIK
FAKULTAS KEDOKTERAN
UHN

Bacteria
Unicellular, prokaryotes
DNA and RNA
Binary fission
No mitochondria
Rigid cell wall containing peptidoglycan

Eubacteria
Classified according to:
size & shape
cell wall (Gram stain)
aerotolerance

Gram stain reaction

positive - purple
negative - pink

Shape
coccus - round (chains? clusters?)
bacillus - rod

Chemotherapy

The use of drugs to treat a

disease
Antimicrobial drugs Interfere with the growth of
microbes within a host
Antibiotic

Substance produced by a
microbe that, in small amount
inhibits another microbe

Selective toxicity

A drug that kills harmful

microbes without damaging
the host.

Features of Antimicrobial
Drugs

Antimicrobial action

Drugs may kill or inhibit bacterial growth

Inhibit = bacteriostatic
Kill = bacteriocidal

drugs rely on host immunity to

Bacteriostatic
eliminate pathogen
drugs are useful in situations
Bacteriocidal
when host defenses cannot be relied upon
to control pathogen

Features of Antimicrobial Drugs

distribution, metabolism and
Tissue
excretion
differ in how they are distributed,
Drugs
metabolized and excreted

Important factor for consideration when prescribing

Time it takes for the body to eliminate one half the

original dose in serum

Half-life dictates frequency of dosage

of elimination of drug from body

Rate
expressed in half-life

with liver or kidney damage tend to

Patients
excrete drugs more slowly

Features of Antimicrobial Drugs

of combinations of
Effects
antimicrobial drugs

some times used to treat

Combination
infections
action of one drug enhances
When
another, effect is synergistic
action of one drug interferes with
When
another, effect is antagonistic
effect of combination is neither
When
synergistic or antagonistic, effect said to
be additive

Features of Antimicrobial Drugs

Adverse effects

Allergic reactions
Allergies to penicillin
Toxic effects
Aplastic anemia--Chloramphenicol
Body cannot make RBC or WBC
Suppression of normal flora
Antibiotic associated colitis,diarrhea
Antimicrobial resistance

Principles / Definitions
Spectrum of Activity:
1.Narrow spectrum :
= drug is effective against a limited number of
species

2.Broad spectrum
= drug is effective against a wide variety of species
- Gram negative agent
- Gram positive agent
- Anti-anaerobic activity

 1928
Fleming
discovered
penicillin,
produced by
Penicillium.
1940
Howard Florey
and Ernst
Chain
performed first
clinical trials of
penicillin.

Figure 20.1

The Action of Antimicrobial

Drugs

Figure 20.2

MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
Mechanism of action
include:
1.Inhibition of cell wall
synthesis
2.Inhibition of protein
synthesis
3.Inhibition of nucleic acid
synthesis
4.Inhibition of metabolic
pathways
5.Interference with cell
membrane integrity

The Action of Antimicrobial

Drugs

Figure 20.4

The Action of Antimicrobial

Drugs

Figure 20.4

1. Inhibition of Cell wall synthesis

Bacteria cell wall unique in construction
Contains peptidoglycan
Antimicrobials that interfere with the synthesis of
cell wall do not interfere with eukaryotic cell
Due to the lack of cell wall in animal cells and
differences in cell wall in plant cells
These drugs have very high therapeutic index
Low toxicity with high effectiveness
Antimicrobials of this class include
lactam drugs
Vancomycin
Bacitracin

1.Cell Wall synthesis Inhibitor

The weakness in the cell wall causes the cell to
lyze.

1.Cell Wall synthesis Inhibitor

Beta-lactams group:
Penicillins and cephalosporins
Part of group of drugs called lactams
Have shared chemical structure called -lactam
ring
Competitively inhibits function of penicillinbinding proteins
Inhibits peptide bridge formation between
glycan molecules
This causes the cell wall to develop weak
points at the growth sites and become fragile.

1.Cell Wall synthesis Inhibitor

The cephalosporins
Chemical structures make them resistant to
inactivation by certain -lactamases
Tend to have low affinity to penicillin-binding
proteins of Gram + bacteria, therefore, are
most effective against Gram bacteria.
Chemically modified to produce family of
related compounds
First, second, third and fourth generation
cephalosporins

Cephalosporins
1st generation- mainly gram pos, some gram neg
(cefazolin)
2nd generation- weaker gram pos, better gram neg
(cefuroxime)
3rd generation - excellent gram neg, some gram pos
(ceftriaxone)
4th generation - excellent gram neg, good gram pos
(cefepime)

First-Generation Cephalosporins: What

do they cover?
Cefazolin (Kefzol) and cephalexin (Keflex)
Activity includes:
Methicillin susceptible staphylococci
Streptococci excluding enterococci
E. coli, Klebsiella sp., and P. mirabilis
Many anaerobes excluding B. fragilis

Features of Antimicrobial Drugs

Spectrum of activity

vary with respect to range of

Antimicrobials
organisms controlled

Narrow spectrum

Work on narrow range of organisms

Gram positive only OR Gram negative only

Broad spectrum

Work on broad range of organisms

Gram positive AND Gram negative

Disadvantage of broad spectrum is disruption of normal flora

Where do you think they should be

used?
Simple mixed aerobic infections.
In penicillin allergic (not immediate)
patients.
Surgical prophylaxis.
Convenience drug for S. aureus and
streptococci?

What about second generation

cephalosporins?
Cefuroxime

Cefoxitin/cefotetan
Think Haemophilus in
1st generation plusaddition to 1st
anaerobes
generation specturm
A mixed, non-serious
A respiratory drug
infection surgeon drug
Think cefazolin/metro
which is what we
would use

Third-Generation Cephalosporins
Cefotaxime, ceftriaxone (IV)
Enhanced activity against Enterobacteriaceae
Enhanced activity against streptococci, including penicillin resistant
S. pneumoniae.
Long half life favors ceftriaxone
Less diarrhea favors cefotaxime
Ceftazidime (IV)
Active against P. aeruginosa.
Decreased activity against gram positive cocci.

1.Cell Wall synthesis Inhibitor

Vancomycin
Inhibits formation of glycan chains
Inhibits formation of peptidoglycans and cell wall construction
Does not cross lipid membrane of Gram Gram - organisms innately resistant

Important in treating infections caused by penicillin

resistant Gram + organisms
Must be given intravenously due to poor absorption
from intestinal tract
Acquired resistance most often due to alterations in
side chain of NAM molecule
Prevents binding of vancomycin to NAM component of glycan

Bacitracin
Interferes with transport of peptidoglycan precursors across
cytoplasmic membrane
Toxicity limits use to topical applications
Common ingredient in non-prescription first-aid ointments

2.Protein Synthesis Inhibitor

Structure of prokaryotic ribosome acts as target
for many antimicrobials of this class
Differences in prokaryotic and eukaryotic
ribosomes responsible for selective toxicity
Drugs of this class include
Aminoglycosides
Tetracyclins
Macrolids
Chloramphenicol

2.Protein Synthesis Inhibitor

Aminoglycosides
Irreversibly binds to 30S ribosomal subunit
Causes distortion and malfunction of ribosome
Blocks initiation translation
Causes misreading of mRNA
Not effective against anaerobes, enterococci and
streptococci
Often used in synergistic combination with -lactam
drugs
Allows aminoglycosides to enter cells that are often
resistant

2.Protein Synthesis Inhibitor

Examples of aminoglycosides include
Gentamicin, streptomycin and tobramycin
Side effects with extended use include
Oto toxicity
Nephrotoxicity

2.Protein Synthesis Inhibitor

Tetracyclins
Reversibly bind 30S ribosomal subunit
Blocks attachment of tRNA to ribosome
Prevents continuation of protein synthesis
Effective against certain Gram + and Gram Newer tetracyclines such as doxycycline have
longer half-life
Allows for less frequent dosing
Resistance due to decreased accumulation by
bacterial cells
Can cause discoloration of teeth if taken as young
child ,hepatotoxic in pregnant woman
Oral absorption is inhibited by divalent cation like
Calcium,ferrum,etc.

Complexation or chelation;
EX1., Tetracycline interacts with iron preparations

or
Milk (Ca2+ )

Unabsorpable complex

Ex2., Antacid (aluminum or magnesium) hydroxide

Decrease absorption of
ciprofloxacin by 85%
due to chelation

2.Inhibitors of protein synthesis

Ribosomes are the site of protein synthesis
many classes of antibiotics inhibit protein
synthesis by binding to the ribosome
binding may be reversible or irreversible
Macrolides, ketolides, lincosamides,
streptogramins
Tetracyclines
Aminoglycosides

2.Inhibitors of protein synthesis

Macrolides (erythromycin, clarithromycin, azithromycin)
- primarily gram positive, mycoplasma, chlamydia
- bacteriostatic, time dependent killing
Lincosamides (clindamycin)
- gram positive, anaerobic activity
Resistance (acquisition of a gene)
- M phenotype: macrolides only
efflux
- MLSB phenotype:
macrolides, lincosamides, streptogramins
target site modification
constitutive, inducible

2.Inhibitors of protein synthesis

Aminoglycosides: gentamicin, tobramycin,
amikacin
- excellent gram negative, moderate gram
positive
- bactericidal, concentration dependent
Resistance
Primarily due to aminoglycoside modifying
enzymes

2.Protein Synthesis Inhibitor

Macrolids
Reversibly binds to 50S ribosome
Prevents continuation of protein synthesis

Effective against variety of Gram + organisms and

those responsible for atypical pneumonia
Often drug of choice for patients allergic to penicillin
Macrolids include
Erythromycin, clarithromycin and azithromycin

Resistance can occur via modification of RNA target

Other mechanisms of resistance include
production
of enzyme that chemically modifies drug as well as
alterations that result in decreased uptake of drug

2.Protein Synthesis Inhibitor

Chloramphenicol
Binds to 50S ribosomal subunit
Prevents peptide bonds from forming and
blocking proteins synthesis

Effective against a wide variety of

organisms
Generally used as drug of last resort for
life-threatening infections
Rare but lethal side effect is aplastic
anemia

2.Protein Synthesis Inhibitor

3.Nucleic Acid Synthesis Inhibitor

These include
Fluoroquinolones
Rifamycins

Fluoroquinolones
Inhibit action of topoisomerase DNA gyrase
(Topoisomerase maintains supercoiling of DNA)
Effective against Gram + and Gram
Examples include:
= Ciprofloxacin and
= Oloxacin
Resistance due to alteration of DNA gyrase

3.Nucleic Acid Synthesis Inhibitor

Rifamycins
Block prokaryotic RNA polymerase
Block initiation of transcription

Rifampin; most widely used rifamycins

Effective against many Gram + and some Gram as well as members of genus Mycobacterium
Primarily used to treat tuberculosis and Hansens
disease as well as preventing meningitis after
exposure to N. meningitidis
Resistance due to mutation coding RNA
polymerase
Resistance develops rapidly

4.Metabolic Pathways Inhibitor

Relatively few
Most useful are folate inhibitors
Mode of actions to inhibit the production of folic
acid
Antimicrobials in this class include
Sulfonamides
Trimethoprim

4.Metabolic Pathways Inhibitor

Sulfonamides
Group of related compounds
Collectively called sulfa drugs
Inhibit growth of Gram + and Gram - organisms
Through competitive inhibition of enzyme that aids
in production of folic acid
Structurally similar to para-aminobenzoic acid
Substrate in folic acid pathway
Human cells lack specific enzyme in folic acid pathway
Basis for selective toxicity
Resistance due to plasmid
Plasmid codes for enzyme that has lower affinity to
drug

Mechanism of action of
TMP-SMX

4.Metabolic Pathways Inhibitor

Trimethoprim
Inhibits folic acid production
Interferes with activity of enzyme following
enzyme inhibited by sulfonamides
Often used synergistically with sulfonamide
Most common mechanism of resistance is
plasmid encoded alternative enzyme
Genes encoding resistant to sulfonamide and
trimethoprim are often carried on same plasmid

Side-effects:- rarely:
- Steven-Johnsons Syndrome

5.Interference with cell membrane

integrity
1. Damage cell membrane
Polymixn B most common
Common ingredient in first-aid skin ointments
2. Binds membrane of Gram - cells
Alters permeability
Leads to leakage of cell and cell death
Also bind eukaryotic cells but to lesser extent
Limits use to topical application

Antimicrobial resistance
Resistance: the inability to kill or inhibit the
organism with clinically achievable drug
concentrations
Resistance may be innate (naturally resistant)
Resistance may be acquired
- mutation
- acquisition of foreign DNA

Antibiotic Resistance
A condition where the antimicroba does not
produce its effect anymore

Mechanisms of antibiotic resistance

1. Drug inactivating enzymes
2. Alteration of target molecule
3. Decreased uptake of the drug
4. Increased elimination of the drug
A variety of mutations can lead to antibiotic resistance.
Resistance genes are often on plasmids or transposons
that can be transferred between bacteria.

RESISTANCE TO ANTIMICROBIAL
DRUGS
Mechanisms of resistance
1. Drug inactivating enzymes
Some organisms produce enzymes that chemically
modify drug
Penicillinase breaks -lactam ring of penicillin
antibiotics
2. Alteration of target molecule
Minor structural changes in antibiotic target can
prevent binding
Changes in ribosomal RNA prevent macrolids
from binding to ribosomal subunits

RESISTANCE TO ANTIMICROBIAL
DRUGS
Mechanisms of resistance
3. Decreased uptake of the
drug
Alterations in porin
proteins decrease
permeability of cells
Prevents certain
drugs from entering

RESISTANCE TO ANTIMICROBIAL
DRUGS
Mechanisms of resistance
4. Increased elimination of
the drug
Some organisms produce
efflux pumps
Increases overall
capacity of organism to
eliminate drug
Enables organism to
resist higher
concentrations of
drug
Tetracycline
resistance

Antibiotic Resistance,
WHY?
Misuse of antibiotics selects for resistant
mutants.
Misuse includes:
Using outdated, weakened antibiotics
Using antibiotics for the common cold and
other inappropriate conditions
Use of antibiotics in animal feed
Failure to complete the prescribed regimen
Using someone else's leftover prescription

Antimicrobial resistance
Factors which may accelerate the
development of resistance
- inadequate levels of antibiotics at the
site of infection
- duration of treatment too short
- overwhelming numbers of organisms
- overuse / misuse of antibiotics

ANTIMICROBIAL
SUSCEPTIBILITY TESTING
Probably the most
widely used testing
method is the diskdiffusion method, also
known as the KirbyBauer test.

EFFECTS OF COMBINATIONS
OF DRUGS

Combinations of antimicrobial drugs

should be used only for:
1. To take advantage of the synergistic effect.
2. To lessen the toxicity of individual drugs.
3 To prevent the emergence of resistance
4 To treat polymicrobial infections
5 Initial empiric therapy

Effects of Drug Combinations

Synergism: occurs when the effect of two
drugs together is greater than the effect of
either alone.

Antagonism: occurs when the effect of two

drugs together is less than the effect of either
alone.

What is the ideal antibiotic

Have rapid and extensive tissue distribution
Have a relatively long half-life.
Be free of interactions with other drugs.
Be convenient for administration.
Be relatively inexpensive

Principles / Definitions
Treatment vs prophylaxis
= Prophylaxis - antimicrobial agents are administered to
prevent infection
= Treatment - antimicrobial agents are administered to
cure existing or suspected infection