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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

2. Prostatitis – included in treatment of prostatitis caused by atypical pathogens

 Azithromycin and not fluoroquinolones – DOC for prostatitis caused by C. trachomatis
and GPB.
 has good penetration into prostate → eradication rates of around 80%
 enters prostatic fluid, and may be effective in achieving bacteriological cure of
chronic bacterial prostatitis due to gram-negative organisms

3. Sexually transmitted infections (STIs) - treatment of certain sexually transmitted

infections, such as chlamydia, when other antibiotics like doxycycline are not suitable

4. Genital ulcer disease (Chancroid)

 Treatment of genital ulcer disease in men due to Haemophilus ducreyi (chancroid)
 azithromycin is commonly used in a single large dose (1 g)

5. Pelvic inflammatory disease - due to Chlamydia trachomatis, Neisseria gonorrhoeae, or

Mycoplasma hominis – erythromycin or azithromycin

6. Treatment of Mycobacterium avium-intracellulare which may cause infection in

immuno-compromised patients
7. Treatment of community-acquired pneumonia
8. It is active against Toxoplasma gondii
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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.

 Current evidence suggests that macrolides, in general, do not appear to be associated

with an increased risk of major birth defects when used during pregnancy
 Breastfeedding:
 generally considered compatible with breastfeeding. They are often prescribed to
nursing mothers, and the benefits of treating the mother's infection usually
outweigh the potential risks to the infant

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

 an antibiotic that belongs to the lincosamide class

 Mechanism of action
 It inhibits bacterial protein synthesis by binding to the 50S ribosomal subunit of the
bacterial ribosome.
 This action interferes with the synthesis of bacterial proteins, leading to inhibition of
bacterial growth

Spectrum of activity
 has a broad spectrum of activity, primarily against

 Gram-positive bacteria - Staphylococcus and Streptococcus species

 anaerobic bacteria: some strains of Bacteroides and Clostridium species

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