Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2011 Publisher: Abbott Laboratories Limited Abbott House Vanwall Business Park Vanwall Road Maidenhead Berkshire SL6 4XE UK
Pharmacotherapeutic group: Anti-infectious
ATC code: J01FA09
Clarithromycin is a semi-synthetic derivative of erythromycin A. It exerts its antibacterial action by binding to the 50s ribosomal sub-unit of susceptible bacteria and suppresses protein synthesis. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The minimum inhibitory concentrations (MICs) of clarithromycin are generally two-fold lower than the MICs of erythromycin.
The 14-hydroxy metabolite of clarithromycin also has antimicrobial activity. The MICs of this metabolite are equal or two-fold higher than the MICs of the parent compound, except for H. influenzae where the 14-hydroxy metabolite is two-fold more active than the parent compound.
Clarithromycin has bactericidal activity against several bacterial strains. The organisms include Haemophilus influenzae, Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, Moraxella (Branhamella) catarrhalis, Neisseria gonorrhoeae, H. pylori and Campylobacter spp.
The activity of clarithromycin against H. pylori is greater at neutral pH than at acid pH.
Clarithromycin is extensively distributed in body tissues and fluids. Because of high tissue penetration, intracellular concentrations are higher than serum concentrations.
Clarithromycin concentrations in tonsil and whole lung tissue are 2- to 6-fold higher than those observed in the serum. Tissue and serum concentrations observed in Abbott studies with immediate-release (IR) tablets are presented below.
| Mean Clarithromycin Concentration [250mg BID] | ||
|---|---|---|
| Tissue Type | Tissue | Serum |
| Tonsil | 1.6 μg/g | 0.8 μg/ml |
| Lung | 8.8 μg/g | 1.7 μg/ml |
Acquired macrolide resistance in S. pneumoniae, S. pyogenes, and S. aureus is mediated primarily by the presence of one of two mechanisms (i.e. erm and mef or msr).
Ribosomal binding of the antimicrobial is prevented through methylation of the ribosome by an enzyme (erm). Alternatively an efflux mechanism (mef or msr) can prevent the antimicrobial from reaching its ribosomal target by pumping the antimicrobial out of the cell. No acquired resistance mechanisms have been identified in Moraxella or Haemophilus spp. Macrolide resistance mechanisms are equally effective against 14- and 15-membered macrolides including erythromycin, clarithromycin, roxithromycin, and azithromycin. The mechanisms for penicillin resistance and macrolide resistance are unrelated.
Attention should be paid to the erm-mediated cross-resistance between macrolides such as clarithromycin and lincosamides such as lincomycin and clindamycin.
Clarithromycin antagonises the bacterial effects of beta-lactam antibiotics. Also the effects of lincomycin and clindamycin are antagonised, at least in vitro.
H. pylori is associated with acid peptic disease including duodenal ulcer and gastric ulcer in which about 95% and 80% of patients respectively are infected with the agent. H. pylori is also implicated as a major contribution factor in the development of gastric and ulcer recurrence in such patients.
Clarithromycin has been used in small numbers of patients in other treatment regimens. Possible kinetic interactions have not been fully investigated.
These regimens include:
Clarithromycin plus tinidazole and omeprazole; clarithromycin plus tetracycline, bismuth subsalicylate and ranitidine; clarithromycin plus ranitidine alone.
Clinical studies using various different H. pylori eradication regimens have shown that eradication of H. pylori prevents ulcer recurrence.
Clarithromycin is rapidly and well absorbed from the gastro-intestinal tract after oral administration of Clarithromycin tablets. The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first pass metabolism. Clarithromycin may be given without regard to meals as food does not affect the extent of bioavailability of Clarithromycin tablets. Food does slightly delay the onset of absorption of clarithromycin and formation of the 14-hydroxymetabolite. The pharmacokinetics of clarithromycin are non linear; however, steady-state is attained within 2 days of dosing. At 250 mg b.i.d. 15-20% of unchanged drug is excreted in the urine. With 500 mg b.i.d. daily dosing urinary excretion is greater (approximately 36%). The 14-hydroxyclarithromycin is the major urinary metabolite and accounts for 10-15% of the dose. Most of the remainder of the dose is eliminated in the faeces, primarily via the bile. 5-10% of the parent drug is recovered from the faeces.
When clarithromycin 500 mg is given three times daily, the clarithromycin plasma concentrations are increased with respect to the 500 mg twice daily dosage.
Clarithromycin provides tissue concentrations that are several times higher than the circulating drug levels. Increased levels have been found in both tonsillar and lung tissue. Clarithromycin is 80% bound to plasma proteins at therapeutic levels.
Clarithromycin also penetrates the gastric mucus. Levels of clarithromycin in gastric mucus and gastric tissue are higher when clarithromycin is co-administered with omeprazole than when clarithromycin is administered alone.
In acute mouse and rat studies, the median lethal dose was greater than the highest feasible dose for administration (5g/kg).
In repeated dose studies, toxicity was related to dose, duration of treatment and species. Dogs were more sensitive than primates or rats. The major clinical signs at toxic doses included emesis, weakness, reduced food consumption and weight gain, salivation, dehydration and hyperactivity. In all species the liver was the primary target organ at toxic doses. Hepatotoxicity was detectable by early elevations of liver function tests. Discontinuation of the drug generally resulted in a return to or toward normal results. Other tissues less commonly affected included the stomach, thymus and other lymphoid tissues and the kidneys. At near therapeutic doses, conjunctival injection and lacrimation occurred only in dogs. At a massive dose of 400mg/kg/day, some dogs and monkeys developed corneal opacities and/or oedema.
Fertility and reproduction studies in rats have shown no adverse effects. Teratogenicity studies in rats (Wistar (p.o.) and Spraque-Dawley (p.o. and i.v.)), New Zealand White rabbits and cynomolgous monkeys failed to demonstrate any teratogenicity from clarithromycin. However, a further similar study in Sprague-Dawley rats indicated a low (6%) incidence of cardiovascular abnormalities which appeared to be due to spontaneous expression of genetic changes. Two mouse studies revealed a variable incidence (3-30%) of cleft palate and embryonic loss was seen in monkeys but only at dose levels which were clearly toxic to the mothers.
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