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
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