Macrolides
Content
Macrolide antibiotics
• Mechanism
of action
• Mechanism
of resistance
• Pharmacokinetics
• Adverse
effects
• Clinical
uses
Objectives
At the end of this session, students will be able to:
• List
various macrolide antibiotics
• Describe
the mechanism of action of macrolide antibiotics
• Outline
the pharmacokinetics of macrolides
• Explain
the clinical uses of macrolides
Macrolides
• Multimembered
lactone ring structure
• One
or more deoxysugar molecules are attached
• Prototype
– Erthromycin – 14 membrane lactone ring attached with deoxysugar moiety
• Derived from Streptomyces erythreus
• Roxithromycin,
clarithromycin and azithromycin – semisynthetic derivatives of erythromycin
• Erythromycin
• Roxithromycin
• Clarithromycin
• Spiramycin
• Azithromycin
• Oleandomycin
• Troleandomycin
Mechanism of action
• Inhibits
protein synthesis
• Broad
spectrum antibiotics but more active against gram positive
• Low
concentration – Bacteriostatic
• High
concentration – Bactericidal
• Binds
to 50s ribosomal subunit
• Inhibit
translocation of peptide chain
• Enter
organism by active transport
• Entry
is favored at alkaline pH
• Remain
unionised at alkaline pH
• Penetration
is 100 times more at alkaline pH
• Inhibits
the action of action of chloramphenicol
• No
affinity to mammalian ribosomes
Mechanism of resistance
• Presence
of efflux pumps
• Ribosomal
protection by enzyme – methylase
• Drug
hydrolyis by esterase
• Chromosomal
mutations altering 50s subunit
Antimicrobial spectrum
• Similar
to that of β– lactam
antibiotics
• Used
as substitute for penicillins
• Gram
positive organisms
– Streptococcus
pneumoniae
– Streptococcus
pyogenes
– Cornybacterium
diptheriae
– Clostridium
tetanii
• Gram
negative organism
– Nesseria
gonorrhea
– N.
meningitis
– H.
influenzae
– H.
pylori
Adverse effects
• Available
as Erthromycin base, Erythromycin estolate, Erythromycin ethyl succinate and
Stearate
• Oral
– large dose – GI probles
• Erythromycin
estolate – Cholestatic jaundice
• i.v-
high dose – transient auditory impairment
• Infants
– hypertonic pyloric stenosis
• Other
microlides causes minor GIT upsets
Pharmacokinetics – Erythromycin
• Available
as base and ester
• Ester
used in oral formulations
• Parenteral – Erythromycin gluceptate and lactobionate
• i.m
– pain
• Absorbed
from upper part of small intestine
• Food
interferes with absorption
• Incomplete
absorption
Distribution
• Good
but not in CSF
• Therapeutic
concentration attained in tonsils, middle ear fluid, lungs, prostrate fluid
Metabolism –
liver
Excretion
• Major
– bile
• Small
amount – Urine
• Plasma
half-life – 1.5 h
Pharmacokinetics
Roxithromycin
•
Long acting
•
Half-life 12h; acid stable
•
Better absorbed and good tissue penetration
Azithromycin
•
Acid stable
•
High concentration attained in prostrate, lungs,
stomach and inflammatory cells
Clarothromycin
•
Long acting; acid stable
•
Wide distribution
•
60-70%
protein bound
Clinical uses
Clinical uses
Erythromycin
• Streptococcal
and pneumococcal infections
• Respiratory,
neonatal and genital infection caused by clamydia
• Alternate
drug for syphillis and gonorrhea
• Prophylactic
for recurrence of rheumatic fever
Roxithromycin
• Substitute
of erythromycin in pharyngitis, tonsilitis, sinusitis, acute bronchitis &
pneumonia
Azithromycin
• Respiratory
tract infection
• Urogenital
infection
Clarithromycin
• Upper
and lower respiratory tract infection
Summary
• Macrolides
are multimembered lactone ring structure containing one or more deoxysugar
molecules
• Major
prototype includes erthromycin that has a 14 membrane lactone ring attached
with deoxysugar moiety
• Erythromycin is derived from Streptomyces
erythreus
• Roxithromycin,
clarithromycin and azithromycin – semisynthetic derivatives of erythromycin
• Inhibits
protein synthesis after binding to 50s ribosomal subunit
• Effective
against both gram positive and gram
negative organisms
