Antibacterial Drugs

B.K. SATRIYASA
Learning Objective
1. Describe the mechanism of antibacterial action

2. Identify the prototype drugs in each class.

3. Clinical use of antibacterial

4. List The major adverse effects

TERM
 BACTERICIDAL, kills bacteria
 BACTERIOSTATICS, inhibits bacterial
growth, requires host defense mechanism to
eradicate the infection.
 MINIMAL INHIBITORY
CONCENTRATION ( MIC)
 SELECTIVE TOXICITY
Antibacterial agent
 Antibacterail agent: Chemical
that kills or inhibits the growth
of bacterial
 MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
 Mechanism of action include:
 Inhibition of cell wall synthesis
 Inhibition of protein synthesis
 Inhibition of nucleic acid
synthesis
 Inhibition of metabolic
pathways
 Interference with cell
membrane integrity
MECHANISMS OF ACTION OF
ANTIBACTERIAL DRUGS
 Inhibition of Cell wall synthesis
 Bacteria cell wall unique in construction
 Contains peptidoglycan

 These drugs have very high therapeutic index

 Low toxicity with high effectiveness

 Antimicrobials of this class include

 β lactam drugs

 Vancomycin

 Bacitracin
MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
 Inhibition of protein synthesis
 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
MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
 Interference with cell membrane integrity
 Few damage cell membrane
 Polymixn B most common
 Common ingredient in first-aid skin ointments
 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
PENICILLINS &
CEPHALOSPORINS
 Penicillins and cephalosporins
 Part of group of drugs called β –lactams
 Have shared chemical structure called β-lactam ring
 Competitively inhibits function of penicillin-binding proteins
 Inhibits peptide bridge formation between glycan molecules
 This causes the cell wall to develop weak points at the growth sites
and become fragile.
Penicillins

 Penicillins contain a b-lactam ring which

inhibits the formation of peptidoglycan
crosslinks in bacterial cell walls
(especially in Gram-positive organisms)
 Penicillins are bactericidal but can act
only on dividing cells
 They are not toxic to animal cells which
have no cell wall
 Penicillins (cont.)
Clinical Pharmacokinetics
 Penicillins are poorly lipid soluble and do not
cross the blood-brain barrier in appreciable
concentrations unless it is inflammed (so
they are effective in meningitis)
 They are actively excreted unchanged by
the kidney, so the dose should be reduced
in severe renal failure
 This tubular secretion can be blocked by
probenecid to potentiate penicillins`s action
 Penicillins (cont.)
 This is the result of production of b-
lactamase in the bacteria which destroys
the b-lactam ring
 It occurs in e.g. Staphylococcus aureus,
Haemophilus influenzae and Neisseria
gonorrhoea
 Penicillins (cont.)
Adverse effects
 Allergy (in 0.7% to 1.0% patients). Patient
should be always asked about a history of
previous exposure and adverse effects
 Superinfections(e.g.caused by Candida )
 Diarrhoea : especially with ampicillin, less
common with amoxycillin
 Rare: haemolysis, nephritis
Cephalosporins
 They also owe their activity to b-lactam ring
and are bactericidal.
 They are broad-spectrum antibiotics.
 They are relatively expensive but good
alternatives to penicillins when a broad
-spectrum drug is required, should not be
used as first choice unless the organism is
known to be sensitive
 Cephalosporins
Examples and pharmacokinetics
 Cephradine and cephalexin are well absorbed
orally
 Cephradine can be also given parenterally.
 They cover mostly Gram-positive organism,
such as Streptococcus pyogenes, S.
pneumoniae and Staphylococcus aureus, as
well as some Gram-negative bacteria
 alhough they are less effective in this than
later cephalosporins
 They are excreted by the kidney (reduce
dose in renal failure)
Cephalosporins (cont.)
Examples and pharmacokinetics
 Cefuroxime can be given parenterally or as an
oral prodrug.
 It has a broader spectrum, including many
Gram-negative bacilli.
 Cefotaxime is given parenterally.
 It has an even broader spectrum, including
many Enterobacter, E.coli, Proteus strains.
 Cephalosporins (cont.)
Adverse effects
 Allergy (10-20% of patients wit penicillin
allergy are also allergic to cephalosporins)
 Nephritis and acute renal failure
 Superinfections
 Gastrointestinal upsets when given orally
 Aminoglycosides
 They cause misreading of mRNA by the
ribosome, leading to abnormal protein
production.
 They are bactericidal.
 To enter the bacterium, they need to be
actively transported across the cell
membrane.
 Anaerobic organisms are resistant.
 Aminoglycosides
Clinical pharmacokinetics
 These are poorly lipid soluble and, therefore,
not absorbed orally
 Parenteral administration is required for
systemic effect.
 They do not enter the CNS even when the
meninges are inflamed.
 They are not metabolized.
 Aminoglycosides (cont.)
Clinical pharmacokinetics
 They are excreted unchanged by the kidney
(where high concentration may occur, perhaps
causing toxic tubular dmage) by glomerular
filtration (no active secretion).
 Their clearance is markedly reduced in renal
impairment and toxic concentrations are more
likely.
 Aminoglycosides (cont.)
Adverse effects
 The main adverse effects are:
Nephrotoxicity, Toxic to the 8th cranial
nerve (ototoxic), especially the vestibular
division.
 Other adverse effects are not dose-related,
and are relatively rare, e.g. allergies,
eosinophilia.
MACROLIDES

 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
ERYTHROMYCIN
 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
 Macrolides (cont.)
Examples and clinical
pharmacokinetics
 Erythromycin is acid labile but is given as an
enterically coated tablet
 Absorption is erratic and poor.
 It is excreted unchanged in bile and is
reabsorbed lower down the gastrointestinal
tract (enterohepatic circulation).
 It may be given orally or parenterally
 Macrolides (cont.)
Examples and clinical
pharmacokinetics
 Newer macrolides such as clarithromycin and
azithromycin may have fewer adverse
effects. They have immunomodulatory effects
which improves the clinical outcome.
 Clindamycin
 Clindamycin, although chemically distinct, is
similar to erythromycin in mode of action and
spectrum.
 It is rapidly absorbed and penetrates most
tissues well, except CNS.
 It is particularly useful systematically for S.
aureus (e.g.osteomyelitis as it penetrates
bone well) and anaerobic infections.
 Clindamycin
Adverse effects
 Diarrhoea is common.
 Superinfection with a strain of Clostridium
difficile which causes serious inflammation of
the large bowel (Pseudomembranous colitis)
AMINOGLYCOSIDES
 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 β-lactam drugs
 Allows aminoglycosides to enter cells that are often resistant
AMINOGLYCOSIDES

 Examples of aminoglycosides
include
 Gentamicin, streptomycin and

tobramycin
 Side effects with extended use
include
 Otto toxicity

 Nephrotoxicity
TETRACYCLINS
 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
TETRACYCLINES
CHLORAMPHENICOL
 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
CLORAMPHENICOL
 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
MECHANISMS OF ACTION
OF ANTIBACTERIAL DRUGS
 Inhibition of nucleic acid synthesis
 These include
 Fluoroquinolones
 Rifamycins
FLUOROQUINOLONES
 Fluoroquinolones
 Inhibit action of topoisomerase DNA
gyrase
 Topoisomerase maintains supercoiling

of DNA
 Effective against Gram + and Gram -
 Examples include
 Ciprofloxacin and ofloxacin

 Resistance due to alteration of DNA

gyrase
RIFAMYCINS
 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 Hansen’s
disease as well as preventing meningitis after exposure
to N. meningitidis
 Resistance due to mutation coding RNA polymerase
 Resistance develops rapidly
SULFONAMIDES
 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
TRIMETHOPRIM
 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
SEHAT DENGAN FITNES
RESISTANCE TO
ANTIMICROBIAL DRUGS
 Mechanisms of resistance
 Drug inactivating enzymes
 Some organisms produce
enzymes that chemically modify
drug
 Penicillinase breaks β-lactam ring
of penicillin antibiotics
 Alteration of target molecule
 Minor structural changes in
antibiotic target can prevent
binding
 Changes in ribosomal RNA prevent
macrolids from binding to
ribosomal subunits
SUSCEPTIBILITY OF BACTERIAL
TO ANTIMICROBIAL DRUG
 Mechanisms of resistance
 Decreased uptake of the drug
 Alterations in porin proteins
decrease permeability of cells
 Prevents certain drugs from
entering
 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
Rational ATB therapy
 Precise diagnosis (clinical./microbiology)
 Regional sensitivity/resistance patterns
 ATB centre / Narional reference lab
 Clinical state (renal, liver functions)
 PK / PD relations
 To reach the effectice concentration in
the infection site
 Pk/PD of antibiotics

conc. in the site Antimicrobial

of infection effect

Conc. in the
dose blood

conc. in other
tissues other effects
ADME

PHARMACOKINETICS PHARMACODYNAMICS
EFFECTS OF COMBINATIONS
OF DRUGS
Combinations of antimicrobial drugs should be
used only for:
1.To prevent or minimize the
emergence of resistant strains.
2.To take advantage of the synergistic
effect.
3.To lessen the toxicity of individual
drugs.
4. Mixed Infections
5. To Achieve synergistic effects
EFFECTS OF COMBINATIONS
OF DRUGS
Sometimes the chemotherapeutic effects of
two drugs given simultaneously is greater than
the effect of either given alone.
 This is called synergism. For example,
penicillin and streptomycin in the treatment
of bacterial endocarditis. Damage to
bacterial cell walls by penicillin makes it
easier for streptomycin to enter.
EFFECTS OF COMBINATIONS
OF DRUGS
 Other combinations of drugs can be
antagonistic.
 For example, the simultaneous use of
penicillin and tetracycline is often less
effective than when wither drugs is
used alone. By stopping the growth
of the bacteria, the bacteriostatic
drug tetracycline interferes with the
action of penicillin, which requires
bacterial growth.
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