Professional Documents
Culture Documents
MACROLIDES
Azithromycin, Clarithromycin and Erythromycin
Mechanism of action
Binds to 50S subunit of bacterial ribosome and selectively inhibit synthesis of bacterial
protein by blocking the processes of transpeptidation and mRNA displacement
dissociation of peptidyl tRNA from ribosomes arrest of RNA-dependent protein
synthesis
Premature detachment of incomplete peptide chains
Suppression of RNA-dependent protein synthesis
Block enzymes that catalyze the transfer of new amino acid residue to the peptide
chain and chain elongation
Macrolides are gnerally bacteriostatic, but may be bactericidal when present at high
concentration against susceptible organisms
The binding occurs to the site of binding of clindamycin on 50 S ribosomal subunit and
so may interfere with actions of these drugs
Spectrum of activity
Similar to penicillins in their spectrum of activity
Effective against penicillin-resistant strains, most Gram-positive (MSSA,
streptococcus pneumoniae) and Gram-negative (H. influenza, Neisseria Spp.)
Anaerobes – against upper respiratory anaerobes
Atypical bacteria – all active against Mycoplasma, Chlamydia, Campylobacter and
Legionella
Resistant organism:
Penicillin-resistant Staphylococci
Enterobacteriaceae, other gram negative bacilli and B. fragilis
Pharmacokinetics
Oral and parenteral administration
After oral administration, they are absorbed from intestine if not inactivated by gastric
acid
Erythromycin base: destroyed by gastric acid (enteric coated tablets), erythromycin
ester salts: more acid stable and better absorption
Clarithromycin - acid stable, well absorbed
Azithromycin – acid stable, absorption is not significantly affected by food
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Widely distributed into most tissues, except brain and CSF and cross the placenta
accumulate within many cells and tissues, including macrophages (distribution to
inflamed tissues), fibroblasts and tend to concentrate in spleen, liver, kidneys, and
the lungs, in bile and milk
Erythromycin - metabolized CYP450 system in liver, excreted in bile
Azithromycin - minimal metabolism in liver and is primarily eliminated unchanged in
bile
Clarithromycin - undergoes extensive metabolism by CYP450 system in liver → active
metabolite, 14-hydroxy-clarithromycin, excreted in bile and urine, both drug and its
metabolite
Clarithromycin is only macrolide partially eliminated by kidney (18%), dose adjustment
when CrCl <30ml/min
Elimination t1/2:
azithromycin = 68 - 72 hrs - once-daily
erythromycin = 1.5 - 2 hrs – every 8 hrs
clarithromycin = 3-7 hrs – twice daily
Macrolides
Erythromycin has the problems of acid liability, poor GI intolerance, short elimination
half-life, narrow spectrum - active against GPB
Clarithromycin, azithromycin, roxithromycin:
Broader spectrum of activity – GPB, GNB
Improved pharmacokinetic properties – stable in stomach acid, better
bioavailability, better tissue penetration, prolonged half-life
Improved tolerability
Adverse effects
GIT – up to 33% (irritation)
Nausea, anorexia, vomiting, diarrhea
Most common with erythromycin, less with new agents
Acute cholestatic hepatitis – rare
fever, jaundice, impaired liver function – hypersensitivity reaction
Erythromycin estolate
Others: QTc prolongation
Allergy
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Drug interactions
Erythromycin and clarithromycin are inhibitors of cytochrome P450 system in liver,
may increase serum concentrations of:
Theophylline, cyclosporine, carbamazepine, phenytoin, warfarin and digoxin
Contraindications
Hepatic dysfunction
Hypersensitivity to macrolides
Pregnancy
Clarithromycin
Metabolized in liver to active metabolite with a half-life of 3-7 hrs
Dosage: 250-500 mg/BD/oral
Advantage over erythromycin:
Improved acid stability and oral absorption with higher blood concentrations
Lower frequency of GI intolerance
Less frequent dosing – t1/2 is about 3 times to that of erythromycin
Azithromycin
Rapidly absorbed from GIT, extensive tissue distribution except CSF, minimal metabolism
in liver, eliminated mainly by biliary route and only 6% is excreted unchanged in urine
Half-life is about 2-4 days as it is deposited in tissues and phagocytic cells from where it is
released slowly
given once daily and in some infections as a single dose (tissues
concentrations exceed serum concentrations by 10 – 100 fold)
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Azithromycin
Advantage over erythromycin:
Once daily dosing
No inhibition of CYP-450 and less drug interactions - because it has 15 member
(not 14 member like erythromycin and clarithromycin) lactone ring
Clinical uses
While macrolides are not typically the first choice for treating urological infections,
they can be used in specific situations
1. Atypical urogenital infections
Azitromycin - cervicitis and urethritis infections caused by Chlamydia
trachomatis and Mycoplasma genitalium and N. gonorrhoeae
Azithromycin is commonly used in a single, large dose (1 g)
Erythtomycin - 500 mg PO every 6hr for 7 day
Macrolides in pregnancy
The use of macrolide antibiotics during pregnancy is generally considered safe for certain
conditions
Azithromycin: Limited studies have suggested that it is generally considered safe during
pregnancy. It is often prescribed for respiratory tract infections and sexually transmitted
infections during pregnancy
Clarithromycin: limited data on use during pregnancy and generally reserved for
situations where the benefits outweigh potential risks.
ROXITHROMYCIN
Semisynthetic longer acting, acid stable macrolide and good oral absorption
Plasma t1/2 = 12 hrs
Antibacterial spectrum: similar to erythromycin
Better gastric tolerability
Lower affinity to CYP450
Used as an alternative to erythromycin for genital tract, respiratory, ENT, and skin and
soft tissue with similar efficacy
Dose :
150-300 mg BD 30 min before meals
Children: 2.5- 5.5 mg/kg BD
Telithromycin
Stable in acidic conditions with good activity against penicillin-resistant and
macrolide-resistant strains
The binding capacity to ribosomes is 10 times that of erythromycin and 6 times that of
clarithromycin
PKs: bioavailability of about 57% and a t1/2 of 10 hrs and is metabolized by CYP3A4 in liver
Disadvantages: potentially causes cardiovascular risk and hepatotoxicity, which
limits its use
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CLINDAMYCIN
Spectrum of activity
has a broad spectrum of activity, primarily against
Clinical uses
1. Anaerobic infections – in urogenital tract
2. Pelvic inflammatory disease (PID) – in combination
3. Complicated intra-abdominal infections – as an alternative in patients with a known
allergy to penicillin or cephalosporins
Other uses
Skin and soft tissue infections - caused by GPB such as Streptococci and staphylococci
and often effective against MRSA.
Anaerobic infections: especially with Bactroids fragilis - such as those involving the oral
cavity, skin, and soft tissues
Prevention of bacterial endocarditis in patients with cardiac valvular disease who are
allergic to penicillin and going for dental extraction or oropharyngeal procedures
Adverse effects
GIT – common, nausea, vomiting, abdominal pain, and diarrhea
skin rashes and, rarely, more severe allergic reactions
Hepatotoxicity - liver function especially in patients with pre-existing liver conditions
Pseudomembranous colitis