Mechanism of Action

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 twofold 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.

Pharmacodynamic Properties

PK/PD relationship

Clarithromycin is extensively distributed into body tissues and fluids. Due to the high tissue penetration, intracellular concentrations higher than serum concentrations. The main pharmacodynamic parameters to predict macrolidenactiviteit are unconvincing established. The time above the MIC (T/MIC) is the best determinant for the efficacy of clarithromycin. Because the concentrations of clarithromycin in the lung tissues and epithelial tissue fluid reaches the plasma concentrations exceed, the use of plasma concentrations based parameters are insufficient to accurately predict response for respiratory infections.

Mechanisms of resistance

Resistance mechanisms against macrolide antibiotics include alteration of the target site of the antibiotic or are based on modification and/or the active efflux of the antibiotic. Resistance development can be mediated via chromosomes or plasmids, be induced or exist constitutively.

Macrolideresistant bacteria generate enzymes which lead to methylation of residual adenine at ribosomal RNA and consequently to inhibition of the antibiotic binding to the ribosome. Macrolide-resistant organisms are generally cross-resistant to lincosamides and streptogramine B based on methylation of the ribosomal binding site. Clarithromycin ranks among the strong inducers of this enzyme as well. Furthermore, macrolides have a bacteriostatic action by inhibiting the peptidyl transferase of ribosomes. A complete cross-resistance exists among clarithromycin, erythromycin and azithromycin. Methicillin-resistant staphylococci and penicillin-resistant Streptococcus pneumoniae are resistant to macrolides such as clarithromycin.

Susceptibility

The prevalence of resistance may vary geographically and with time for selected species and local information on resistance is desirable, particularly when treating severe infections. This information gives only an appropriate guidance on the probabilities whether micro-organisms will be susceptible to clarithromycin or not.

Other information

Susceptibility and resistance of Streptococcus pneumoniae and Streptococcus spp. to clarithromycin can be predicted by testing erythromycin.

The mechanisms of acquired resistance in macrolides are: efflux of drug by an active pump mechanism, inducible or constitutive production of a methylase enzyme that modifies the ribosomal target, hydrolysis of macrolides by esterases, chromosomal mutations that alter a 50 S ribosomal protein. Cross-resistance between clarithromycin and other macrolides and clindamycin and lincomycin may therefore occur. Methicillin-resistant and oxacillin-resistant staphylococci (MRSA) and penicillin-resistant Streptococcus pneumoniae are resistant to all currently available Beta-lactam antibiotics and macrolides such as clarithromycin

Pharmacokinetic Properties

Absorption

Oral administration

Clarithromycin is rapidly and well absorbed from the gastrointestinal tract – primarily in the jejunum – but undergoes extensive first-pass metabolism after oral administration. The absolute bioavailability of a 250-mg clarithromycin tablet is approximately 50%. Food slightly delays the absorption but does not affect the extent of bioavailability. Therefore, clarithromycin tablets may be given without regard to food. Due to its chemical structure (6-O-Methylerythromycin) clarithromycin is quite resistant to degradation by stomach acid. Peak plasma levels of 1–2 μg/ml clarithromycin were observed in adults after oral administration of 250 mg twice daily. After administration of 500 mg clarithromycin twice daily the peak plasma level was 2.8 μg/ml. After administration of 250 mg clarithromycin twice daily the microbiologically active 14-hydroxy metabolite attains peak plasma concentrations of 0.6 μg/ml. Steady state is attained within 2 days of dosing.

Distribution

Oral administration

Clarithromycin penetrates well into different compartments with an estimated volume of distribution of 200-400 l. Clarithromycin provides concentrations in some tissues that are several times higher than the circulating drug levels. Increased levels have been found in both tonsils and lung tissue. Clarithromycin also penetrates the gastric mucus.

Clarithromycin is approximately 70% bound to plasma proteins at therapeutic levels.

IV administration

Following IV administration, the blood levels of clarithromycin achieved are well in excess of the MIC 90s for the common pathogens and the levels of 14-hydroxyclarithromycin exceed the necessary concentrations for important pathogens, e.g. H. influenzae. The microbiologically active metabolite 14-hydroxyclarithromycin is formed by first pass metabolism as indicated by lower biovailability of the metabolite following IV administration.

Clarithromycin gives good penetration into different compartments. 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 also penetrates the gastric mucus.

Clarithromycin is 80% bound to plasma proteins at therapeutic levels.

Serum half-life

The serum half-life of the active 14-®-hydroxy metabolite ranges between 5 to 6 hours.

Biotransformation and elimination

Oral administration

Clarithromycin is rapidly and extensively metabolised in the liver. Metabolism is in the liver involving the P450 cytochrome system. Three metabolites are described: N-demethyl clarithromycin, decladinosyl clarithromycin and 14-hydroxy clarithromycin. The pharmacokinetics of clarithromycin is non-linear due to saturation of hepatic metabolism at high doses. Elimination half-life increased from 2-4 hours following administration of 250 mg clarithromycin twice daily to 5 hours following administration of 500 mg clarithromycin twice daily. The half-life of the active 14-hydroxy metabolite ranges between 5 to 6 hours following administration of 250 mg clarithromycin twice daily.

Approximately 20-40% of clarithromycin is excreted as the unchanged active substance in the urine. This proportion is increased when the dose is increased. An additional 10% to 15% is excreted in the urine as 14-hydroxy metabolite. The rest is excreted in the faeces.Renal insufficiency increases clarithromycin levels in plasma, if the dose is not decreased. Total plasma clearance has been estimated to approximately 700 mL/min (11,7 mL/s), with a renal clearance of approximately 170 mL/min (2,8 mL/s).

IV administration

Clarithromycin is rapidly and extensively metabolised in the liver. Metabolism involves mainly N-dealkylation, oxidation and stereospecific hydroxylation at position C 14.

Linearity

IV administration

The pharmacokinetics of clarithromycin and the 14-hydroxy metabolite are non-linear; steady state is achieved by day 3 of IV dosing. Following a single 500 mg IV dose over 60 minutes, about 33% clarithromycin and 11% 14-hydroxyclarithromycin is excreted in the urine at 24 hours.

Clarithromycin 500 mg powder for concentrate for solution for infusion does not contain tartrazine or other azo dyes, lactose or gluten.

Special populations

Renal impairment: Reduced renal insufficiency function results in increased plasma levels of clarithromycin and the active metabolite levels in plasma.

Preclinical Safety Data

In 4-week-studies in animals, toxicity of clarithromycin was found to be related to the dose and to the duration of the treatment. In all species, the first signs of toxicity were observed in the liver, in which lesions were seen within 14 days in dogs and monkeys. The systemic levels of exposure, related to this toxicity, are not known in detail, but toxic doses were clearly higher than the therapeutic doses recommended for humans. Other tissues affected included the stomach, thymus and other lymphoid tissues as well as the kidneys. At near therapeutic doses conjunctival injection and lacrimation occurred only in dogs. At a dose of 400 mg/kg/day some dogs and monkeys developed corneal opacities and/or oedema.

No mutagenic effects were found in in vitro- and in vivo-studies with clarithromycin.

Studies on reproduction toxicity showed that administration of clarithromycin at doses 2x the clinical dose in rabbit (i.v.) and x10 the clinical dose in monkey (p.o.) resulted in an increased incidence of spontaneous abortions. These doses were related to maternal toxicity. No embryotoxicity or teratogenicity was noted in rat studies. Cardiovascular malformations were observed in rats treated with doses of 150 mg/kg/d. In mouse at doses x70 the clinical dose cleft palate occurred at varying incidence (3-30%).

Clarithromycin has been found in the milk of lactating animals.

In 3-day old mice and rats, the LD50 values were approximately half those in adult animals. Juvenile animals presented similar toxicity profiles to mature animals although enhanced nephrotoxicity in neonatal rats has been reported in some studies. Slight reductions in erythrocytes, platelets and leukocytes have also been found in juvenile animals.

Clarithromycin has not been tested for carcinogenicity.

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