Macrolides are a large group of anti microbials derived from Streptomyces spp. With low toxicity exhibiting bacteriostatic and bactericidal(against some) effects through inhibition of bacterial RNA dependent protein synthesis by binding to 50S ribosomal subunit and some times manifesting cross resistance among them. The antimicrobial spectrum is similar to benzyl penicillin but in addition active against Mycoplasmae, Chlamydiae, Legionellae, gram positive anaerobes etc.. The newer agents like clarithromycin, Azithromycin, Dirithromycin are found to be effective against pathogens implicated in opportunistic infections associated with AIDS like MAC infection, Toxoplasmosis, Cryptosporidiosis etc., and also in the eradication of H.pylori infection and in Lyme disease caused by B.burgedorferi. Macrolides like Spiramycin, Kitasamycin, Josamycin and Medicamycin, Miocamycin and Rokitamycin are widely used in Japan & Europe. Erythromycin, Azithromycin and Spiramycin can safely be used in PREGNANCY. Among the Macrolides Azithromycin, Dirithromycin and Spiramycin does not interfere with CYP3A isoenzyme and therefore NO drug interactions as seen with clarithromycin.
Macrolides have additional pharmacological actions not connected with their antimicrobial actions on the following receptors:
Motility receptors in GIT, Which forms the basis for their use as prokinetic agents in diabetic gastroparesis. Efforts are underway to isolate a preparation without antimicrobial effect.
CYP Receptor in the liver - By this effect with the exception of Azithromycin, Dirithromycin and spiramycin other Macrolides inhibit CYP3A isoenzyme and therefore involved in many clinically significant drug interactions and adverse effects. Ex: Interactions with theophylline, Digoxin,Oral anticoagulants, Terfinadine, Azole antifungals, Cisapride etc.,
Auditory Receptors _ as evidenced by the production of reversible hearing loss in AIDS patients receiving high doses. IV Erythromycin has the potential for causing hearing impairment.
Agents like Rosamycin (micromonosporaspp), and Flurithomycin are under investigation appear promising.
Clarithromycin is a semi synthetic broad spectrum macrolide antimicrobial agent having not only bactericidal activity against some organisms by virtue of its synergism with its microbiologically active 14 OH metabolite but also by its Post Antibiotic Effect (PAE).
Current Review focuses antimicrobial activity, Clinical pharmacokinetics, efficacy, tolerability & safety profiles, and pharmacoeconomic considerations of clarithromycin. The concluding topic of “Choosing Macrolides” has been added for the benefit of readers.
Clarithromycin is one of the newer macrolide which possess better pharmacokinteic and antimicrobial profiles unlike older compounds like erythromycin. Clarithromycin exhibits even bactericidal activity against
Some of the pathogens and even Post Antibiotic Effect (PAE) which is not seen with others. It has Good activity against;
C.trachomatis C.pneumoniae M.catarhalis
H.influenzae H.parainfluenzae L.pneumophiliae Etc.,
It is very active against agents causing atypical pneumonia like C.pneumoniae, M.pneumoniae and markedly active against L.pneumophiliae.
Similar effects are also observed against S.aureus, S.pyogenes and all strains of S.pneumoniae and M.catarrhalis and with GOOD against gram positive anaerobes. With reference to H.influenzae clarithromycin has twice the activity of erythromycin ( c.f. Azithromycin has increased activity against gram negative organisms particularly H.influenzae, Enterobactericae, and unlike Erythromycin & Clarithromycin it has activity against Salmonellae, Sigellae and E.coli ).
Clarithromycin has very good activity against agents causing opportunistic infections in AIDS patients viz., MAC infection, Toxoplasmosis, Cryptosporidiosis.
Clarithromycin is one of the second line drug in M.leprae ( along with minocycline). Recent studies have shown that clarithromycin is an effective agent against M.chelonae which causes disseminated cutaneous lesion and along with Omeprazole (Better Lansoprazole) clarithromycin is effective in eradication of H.pylori in patients with peptic ulcer. Very recent investigations revealed the high efficacy of clarithromycin against B.burgedorferi causing Lyme disease. It is also effective against Toxoplasmosis, and Cryptosporidiosis (c.f Spiramycin)
None of the existing Macrolides are effective against MRSA and Enterococci. Both clarithromycin and its 14 OH metabolite exhibit synergistic activity and PAE (post antibiotic effect) and are bactericidal to H.influenzae, S.pneumoniae, M.catarrhalis, S.pyogenes, S.agalectica. Clinical experience had shown that Clarithromycin improves immune function via its modulatory effects on cytokine production normalizes and/or improves viscoelastic properties of mucus and sputum and reduces sputum volume in normal individuals too.
Clarithromycin is acid stable rapidly and completely absorbed per orally to the extent of 100% and absolute bioavailability is 55% and is unaffected by food.
Binding- 80% to Plasma alpha 1 acidic glycoprotein
Vd - 191 - 306 L
Plasma t ½ - 3-4 hrs (Max 9 hrs)
Salivary concentration = Plasma concentration
Prolonged high concentrations in - Lungs, Tonsils, nasal tissue, middle ear and WBC (twice that of plasma).
Hepatic metabolism & its 14 OH metabolite is pharmacologically active (synergistic activity renders it bactericidal).
Clarithromycin inhibits the isoenzyme of Cyt P 450 viz., CYP3A family and thereby increase the concentrations of several drugs administered concurrently resulting in serious clinically significant drug interactions. The hepatic metabolism of clarithromycin is reduced in older patients with hepatic impairment and necessary dose adjustments have to be made., however, in mild hepatic dysfunction no dose adjustments need be necessary. Hepatic elimination constitutes about 60% and renal elimination about 37%. No dose adjustments is necessary unless creatinine clearance is < 30 ml/Mt. i.e., 1.8L/hr. Clarithromycin concentrations achieved in tissue exceed the plasma by;
3.1 : 1 Bronchial secretion
8.82 : 1 Middle year fluid
5.17 : 1 Epithelial lining fluid
94.1 : 1 Alveolar macrophages
28.7 : 1 Lung tissue
331 : 1 Tonsillar tissue
27.5 : 1 Nasal mucosa.
Of particular note is the high concentration in the alveolar macrophages, Lung tissue and tonsillar tissue show high penetration of the drug into the respiratory tract cells, a feature that should enhance efficacy against typical and atypical pathogens which usually cause community acquired pneumonia ( CAP). Concentrations of both clarithromycin and its 14 OH metabolite (active) exceed MICs for most respiratory pathogens maintained longer in tissue than fluid and longer in fluid secretions than in plasma.
Significant quantities of clarithromycin and its metabolites are excreted in breast milk of nursing mothers.
A Modified Release (MR) formulation of clarithromycin has been developed to increase the patient compliance and the elimination t ½ of clarithromycin and its metabolite is not altered although the peak concentrations may be delayed.