Macrolides

Dr. Salman August 2004

Protein Synthesis Inhibitors “Macrolides”

Classification:
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Erythromycin Clarithromycin Azithromycin Ketolides

Telithromycin (newer drugs)

Antibacterial Activity (Erythromycin)
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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.

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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
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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
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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
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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)
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Spectrum: Similar to erythromycin EXCEPT it is more active
against mycobacterium avium. M. leprae

Absorption:
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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.
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.

Distribution:

Elimination:
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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

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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
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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:
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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 Erythromycin is more effective 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. Treatment and prophylaxis of toxoplasmosis encephalitis and diarrhea due to Cryptosporidium.

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Diphtheria:

Mycobacterial Infections:

Other infections:

Adverse Effects Of Macrolides.

GIT Effects:

Anorexia, nausea, vomiting and diarrhea – oral administration Erythromycin particularly can produce acute cholestatic hepatitis (fever, jaundice, impaired liver functions) probably as a hypersensitivity reaction. Fever, eosinophilia and skin eruptions.

Liver Toxicity:

Other Hypersensitivity reactions:

Cardiac involvement:

Erythromycin has been reported to cause cardiac arrhythmias, including QT prolongation. (esp. in patients with underlying cardiac disease) Potential complication of treatment with erythromycin followed by I/V administration.

Transient auditory Impairment:

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 distributed in tissues and intracellular penetration is good. Metabolized in the liver and eliminated by combination of biliary and urinary routes.

Distribution:

Elimination:

Dose: 800mg single daily dose.

Indications:

Respiratory tract infections including community-acquired bacterial pneumonia, acute-on-chronic bronchitis, sinusitis, streptococcal pharyngitis. Cardiac effects more pronounced like erythromycin

Adverse effects:

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 P450mediated metabolism of these drugs.

Clarithromycin:

Being structurally closely related to erythromycin has same interaction profile 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.

Azythromycin