Macrolides

Dr. Salman
August 2004
 Protein Synthesis Inhibitors
“Macrolides”
 Classification:
 Erythromycin
 Clarithromycin
 Azithromycin
 Ketolides
 Telithromycin (newer drugs)
Antibacterial Activity (Erythromycin)
 These drugs are usually bacteriostatic but may be
bactericidal on high concentration against very
susceptible organisms.
 They are effective against aerobic gram positive bacilli
and cocci
 S. pyogenes
 Streptococcus viridans
 Clostridium perfringens
 Cornybacterium diphtheria
 Listeria monocytogenes
 Less activity against gram negative including H.
influenzae, N. meningitidis.
 Good against N. gonorrhoeae
 Pasteurella multocida, borrelia
 Bordetella pertussis
 Compylobacter jejuni
 M. pneumoniae, legionella pneumophila
 C. Trachomatis
 Atypical mycobacteria including M.
scrofulaceum.
 M. kansassi and M. avium-intracellulare vary in
sensitivity.
Mechanism Of Action
 It is bacteriostatic sometimes bactericidal
 Protein synthesis is inhibited by binding
reversibly to 50S ribosomal sub-unit
 It is believed that they do not inhibit peptide bond
formation directly but rather inhibit the
translocation step wherein a newly synthesized
peptidyl tRNA molecule moves from the acceptor
site on the ribosome to the peptidyl (donor site).
They can inhibit elongation of the protein by
blocking the translocation of the ribosome to the
next codon on the mRNA.
Mechanism Of Action.
Mechanism of development of resistance
 There are four mechanisms through which
different bacteria develop resistance against
macrolides
 Efflux of the drug by an active pump mechanism
 Methylase enzyme leads to ribosomal modification
and inability to bind the drugs to the site
 Hydrolysis of macrolides by estrase produced by
Enterobacteriaceae
 Alteration of 50S ribosomal proteins by
chromosomal mutation – Bacillus sutilis,
Compylobacter and gram positive cocci
Pharmacokinetics:
 Erythromycin:
 Absorption:
 Incompletely but adequately absorbed from upper
part of small intestine, inactivated by gastric acids
therefore prepared as enteric coated tabs.
 Food increases GI acidity -- slows absorption.
 High plasma concentrations can be obtained if
given in injectable form.
 Distribution:
 Diffuses readily into intracellular fluids, activity
can be achieved at essentially all sites EXCEPT
brain and CSF
 Elimination:
 The drug is excreted in active from only
2%-5% in urine
 It is mainly accumulated in Liver and
excreted in active form in bile.
 Dose needs not be adjusted in renal patients.
Therapeutic Uses of Erythromycin
 Dose ranges from 1 – 2g /d in divided doses every 6 hrs.
may be increased to 8 g in case of severity of infection.
 Mycoplasma pneumoniae infections
 Ligionnaires’ disease.
 Drug of choice in pneumonia caused by ligionella sp.
 Chlamydial infections
 Diphtheria
 Pertussis (drug of choice)
 Streptococcal infections
 Staphylococcal infections
 Compylobacter infections
 Tetanus
 Prophylactic use:
 It may be used prophylactically in recurrence
of rheumatic fever in patients, or during
dental procedures, in patients with sensitivity
to Benzyl Penicillin which is drug of choice
for that conditions.
Clarithromycin
 It is derived from erythromycin by adding
a methyl group and has improved acid
stability and oral absorption compared with
erythromycin.
Clarithromycin (continued)
 Spectrum: Similar to erythromycin EXCEPT it is more active
against mycobacterium avium. M. leprae
 Absorption:
 It is absorbed rapidly from GIT
 Bioavailibility reduces to 50%-55% due to its rapid first-pass
metabolism.
 The standard formulation may be given with or without food
 Extended-release form of this drug which is given 1g once daily
should be given with food which improves bioavailibility.
 Distribution:
 After absorption it undergoes rapid first-pass metabolism to its active
metabolite 14-hydroxyclarithromycin. Both of these agents are
distributed widely throughout the body and achieve high intracellular
concentrations. Tissue concentrations usually exceed serum conc.
 Elimination:
 Eliminated by renal and non-renal mechanisms.
 It is metabolized in the liver into several metabolites, the active
14-hydroxy being most significant.
 Large amount is excreted in urine in changes and unchanged
form, still the dose needs not to be altered in several renal
conditions.
Therapeutic uses of Clarithromycin
 The advantages of clarithromycin compared with erythromycin are lower
frequency of gastrointestinal intolerance and less frequent dosing. Except for
the micro-organisms notified above the two drugs are therapeutically similar
 Helicobacter pylori infections
 Mycobacterial infections ( first line therapy)
 Tetanus
 Syphilis
 Compylobacter infections
 Streptococcal infections: Pharyngitis, scarlet fever etc
 Staphylococcal infections, but can not be relied upon.
 Legionella infections
 Mycoplasma infections
 Prophylactic uses as described in erythromycin
 DOSE: 250 – 500mg twice daily depending upon age and severity of
infection.
Azithromycin
 SPECTRUM
 Similar to erythromycin with more activity against H.
influenzae and campylobacter, very active against M.
catarrhalis, P. multocida, Chlamydia, M. Pneumoniae, L.
pneumophila, B. burgdorferi, Fusobacterium and N.
gonorrhoeae.
 Enhanced activity against M. avium-intracellulare as well
as some protozoa e,g., Toxoplasma gondii,
Cryptosporidium, and plasmodium.
Pharmacokinetics (Azithromycin)
 Absorption:
 Azithromycin administered orally is well absorbed
from GIT and distributed widely throughout the body
EXCEPT to cerebrospinal fluid.
 Administration with antacids esp. aluminum and
magnesium hydroxide will interfere with absorption (
not bioavailability)
 Dose : 250 – 500mg once daily
 Distribution:
 Its unique pharmacokinetic properties include
extensive tissue distribution and high drug
concentrations within cells (including phagocytes),
resulting in much greater tissue or secretion drug
concentrations compared to simultaneous serum
concentrations.
 Tissue fibroblasts act as natural reservoirs of drug,
and transfer of drug to phagocytes is easily achieved.
 Protein binding is low.
 Elimination:
 Still being elucidated
 Undergoes some hepatic metabolism to inactive
metabolites, biliary excretion is the major route of
elimination.
 Only 12% of the drug is excreted unchanged in urine.
 Therapeutic uses:
 Chlamydial infections:
 Azithromycin is specifically recommended as an alternative to
doxycycline in patients with uncomplicated urethral, endocervical,
rectal, or epididymal infections.
 Pneumonia caused by Chlamydial pneumoniae
 Diphtheria:
 Erythromycin is more effective
 Mycobacterial Infections:
 Azithromycin or Clarithromycin are first line of therapy against
prophylaxis and treatment of disseminated infections caused by M.
avium-intracellulare in AIDS pts. And treatment of pulmonary
disease in non-HIV-infected patients.
 Other infections:
 Treatment and prophylaxis of toxoplasmosis encephalitis and
diarrhea due to Cryptosporidium.
Adverse Effects Of Macrolides.
 GIT Effects:
 Anorexia, nausea, vomiting and diarrhea – oral
administration
 Liver Toxicity:
 Erythromycin particularly can produce acute
cholestatic hepatitis (fever, jaundice, impaired liver
functions) probably as a hypersensitivity reaction.
 Other Hypersensitivity reactions:
 Fever, eosinophilia and skin eruptions.
 Cardiac involvement:
 Erythromycin has been reported to cause cardiac
arrhythmias, including QT prolongation. (esp. in
patients with underlying cardiac disease)
 Transient auditory Impairment:
 Potential complication of treatment with
erythromycin followed by I/V administration.
Ketolides: ( Telithromycin)
 These are semisynthetic 14-membered-ring
macrolides.
 They differ from erythromycin by
substitution of a 3-keto group for neutral
sugar L-cladinose
 Spectrum:
 Including the spectrum of erythromycin they are
active against:
 S. pyogenes, S. pneumoniae, S. aureus, H.
influenzae, Moraxella catarrhalis, mycoplasma,
legionella, chlamydia, H. Pylori, N. gonorrhoeae,
bacteroides fragilis, T. gondii and non-tuberculous
mycobacteria.
 Many macrolide-resistat strains are
vulnerable due to structural modification
which renders ability to resist efflux-pump
 Pharmacokinetics:
 Absorption:
 Absorbed from GIT
 Distribution:
 distributed in tissues and intracellular penetration
is good.
 Elimination:
 Metabolized in the liver and eliminated by
combination of biliary and urinary routes.
 Dose: 800mg single daily dose.
 Indications:
 Respiratory tract infections including
community-acquired bacterial pneumonia,
acute-on-chronic bronchitis, sinusitis,
streptococcal pharyngitis.
 Adverse effects:
 Cardiac effects more pronounced like
erythromycin
Drug Interactions
Erythromycin and Clarithromycin cause clinically significant drug interactions
 Erythromycin:
 Potentiates the effects of estemizole, carbamazapine,, corticosteroids,
cyclosporine,, digoxin, ergot alkaloids, terfenadine, theophylline, triazolam,
Valproate, and Warfarin, probably by interacting with cytochrome P450-
mediated metabolism of these drugs.
 Clarithromycin:
 Being structurally closely related to erythromycin has same
interaction profile
 Azythromycin
 Different structure (15-membered lactone ring structure) appears
to be free of these interactions. Caution is advised, nevertheless,
when using azithromycin in conjugation with the drugs known to
interact with erythromycin.