Macrolides

·        Chemistry.

·        Erythromycin.

·        Clarithromycin.

Chemistry

1.       Produced by Streptomyces erythreus.

2.       Large lactone ring to which are attached one or more sugar residues.

3.       Classification:

a.       Natural: erythromycin, spiramycin.

b.       Semisynthetic: clarithromycin, azithromycin.

4.       Mechanism of action:

a.       Inhibits protein synthesis by binding to 50S ribosomal subunits of bacteria.

b.       Exerts its effects only against multiplying organisms.

Erythromycin

1.       Preparations:

a.       Erythromycin base is available as enteric coated tablets as it is destroyed by gastric acid.

b.       Esters of erythromycin: stearate, estolate, ethylsuccinate.

2.       Pharmacokinetics:

a.    Oral bioavailability of enteric coated base: 35%.

b.       Widely distributed in most tissues except the CSF and the brain where penetration is poor.

c.    Half-life: 2h.

d.       Mainly concentrated in the liver and excreted in the bile in the active form.

e.       There is some reabsorption of the drug from the intestine, forming the enterohepatic circulation.

f.     Only 2 – 5% of oral dose and 12 – 15% of intravenous dose are excreted in the active form in the urine.

3.       Adverse reactions:

a.       Gastrointestinal disturbances: epigastric distress, nausea, vomiting and diarrhea.

b.       Thrombophlebitis: i.v. infusion; i.m injections cause severe muscular pain and should not be used.

c.       Hypersensitivity reactions: fever, eosinophilia, rash.

4.       Reduce hepatic metabolism of:

a.       Carbamazepine.

b.       Cyclosporine.

c.       Phenytoin.

d.       Lovastatin.

e.       Warfarin.

f.       Theophylline.

g.       Midazolam.

5.       Spectrum of antimicrobial activity:

6.       Enterobacteriaeae are resistant to erythromycin.

7.       Therapeutic indications:

a.    Mild to moderate infections of the respiratory tract, skin and soft tissue caused by Streptococcus pyogenes and Streptococcus pneumoniae.

b.       Pharyngitis and tonsilitis caused by Streptococcus pyogenes: oral erythromycin.

c.       Alternative to penicillin for prevention of recurrent attacks of rheumatic fever: oral erythromycin.

d.       Alternative to parenteral penicillin G or ampicillin for intrapartum chemoprophylaxis of group B streptococcal disease: parenteral erythromycin.

e.       Respiratory infections caused by Haemophilus influenzae: erythromycin + sulfonamide.

f.       Chancroid caused by Haemophilus ducreyi: oral erythromycin.

g.       Alternative to penicillin G for treatment of primary or secondary syphilis: oral erythromycin.

h.       Chlamydial infections and nongonococcal urethritis: erythromycin or azithromycin.

i.       Primary atypical pneumonia caused by Mycoplasma pneumoniae: erythromycin, clarithromycin or azithromycin.

j.       Prophylaxis and treatment of Bordetella pertussis infection: erythromycin.

k.       Prophylaxis and treatment of Corynebacterium diphtheria infection: erythromycin.

l.       Others: infections caused by Legionella, Campylobacter and Borrelia burgdoferi.

Clarithromycin

1.       Pharmacokinetics:

a.    Half-life: 4h.

b.       Rapidly and completely absorbed from GI tract.

c.    60% of dose inactivated by metabolism which is saturable and the remainder is eliminated in the urine.

2.       Causes fewer gastrointestinal adverse effects than erythromycin.

3.       Therapeutic indications:

a.       Respiratory tract infections, skin and skin structure infectionis and otitis media caused by susceptible organisms.

b.       Treatment and prevention of disseminated infections caused by Mycobacterium avium complex.

c.       Treatment of Helicobacter pylori infection and duodenal ulcer disease: clarithromycin + amoxicilin + lansoprazole.

d.       Pharyngitis and tonsillitis caused by Streptococcus pyogenes.

e.       Acute bacterial sinusitis caused by Haemophilus influenzae, Branhamella catarrhalis, or Streptococcus pneumoniae.

Azithromycin

1.       Azithromycin is active against a number of Gram-negative organisms including haemophilus influenzae and Neisseria gonorrhoea and Chlamydiae, but less effective against Gram-positive organisms than erythromycin.

2.       Pharmacokinetics:

a.    Long half-life: 50h.

b.       Rapidly absorbed from GI tract but incomplete with greater bioavailability than erythromycin.

c.       Remains largely unmetabolized.

d.       Excreted in the bile and faeces.

3.       Gastrointestinal effects are les than erythromycin but diarrhoea, nausea and abdominal pain occur.

4.    In view of its high hepatic excretion, use in patients with liver disease should be avoided.

5.       Therapeutic indications:

a.       Treatment of mild to moderate respiratory tract infections and uncomplicated skin and skin structure infections caused by susceptible organisms.

b.       Urethritis or cervicitis caused by Chlamydia trachomatis or Neisseria gonorrhoea: oral erythromycin.

c.       Chancroid caused by Haemophilus ducreyi: oral erythromycin.

d.       Prevention of disseminated infections caused by Mycobacterium avium complex in patients with advanced HIV infection.

e.    Used orally in children for the treatment of acute otitis media, community-acquired pneumonia and pharyngitis or tonsillitis caused by susceptible organisms.