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Pharmacology: Clarithromycin is an antibiotic of the macrolide family. Clarithromycin exerts its antibacterial activity by inhibiting synthesis of proteins, by means of a link with the 50S sub-unit of the cellular ribosome. Clarithromycin has demonstrated excellent in-vitro activity against both standard strains of bacteria and clinical isolates. It is highly potent against a wide variety of aerobic and anaerobic gram-positive and gram-negative organisms. The in-vitro antibacterial spectrum of clarithromycin is as follows: Usually Sensitive Bacteria: Streptococcus agalactiae, Streptococcus pyogenes, Streptococcus viridans, Streptococcus pneumoniae, Heamophilus influenzae, Haemophilus parainfluenzae, Neisseria gonorrheae, Listeria monocytogenes, Legionella pneumophila, Pasteurella multocida, Mycoplasma pneumoniae, Helicobacter (Campylobacter) pylori, Campylobacter jejuni, Chlamydia trachomatis, Chlamydia pneumoniae (TWAR), Moraxella (Branhamella) catarrhalis, Bordetella pertussis, Borrelia burgdorferi, Staphylococcus aureus, Clostridium perfringens, Peptococcus niger, Propionibacterium acnes, Bacteroides melaninogenicus, Mycobacterium avium, Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum and Mycobacterium intracellulare.
Non-Sensitive Bacteria: Enterobacteriaceae, Pseudomonas spp.
Pharmacokinetics: The principal metabolite of clarithromycin in man and other primates is a microbiologically-active metabolite, 14-OH-clarithromycin. This metabolite is as active or 1- to 2-fold less active than the parent compound for most organisms, except for H. influenzae against which it is twice as active. The parent compound and the 14-OH metabolite exert either an additive or synergistic effect on H. influenzae in vitro and in vivo, depending on bacterial strains.
Clarithromycin is rapidly absorbed from the gastrointestinal tract after oral administration. The absolute bioavailability of 250 mg clarithromycin was approximately 50%. Food slightly delays both the onset of clarithromycin absorption and the formation of the antimicrobially active metabolite, 14-OH clarithromycin, but does not affect the extent of bioavailability. Therefore, Clarithromycin tablets may be given without regard to food.
In fasting healthy human subjects, peak serum concentrations were attained within 2 hours after oral dosing. Steady state peak serum clarithromycin concentrations were attained in 2 to 3 days and were approximately 1 μg/mL with a 250 mg dose administered every 12 hours, 2 to 3 μg/mL with a 500 mg dose administered every 12 hours and 3 to 4 μg/mL with a 500 mg dose administered every 8 hours. The elimination half-life of clarithromycin was about 3 to 4 hours with 250 mg administered every 12 hours but increased to 5 to 7 hours with 500 mg administered every 8 to 12 hours.
The nonlinearity of clarithromycin pharmacokinetics is slight at the recommended doses of 250 and 500 mg administered every 8 to 12 hours. With a 250 mg every 12 hours dosing, the principal metabolite, 14-OH clarithromycin, attains a peak steady-state concentration of about 0.6 μg/mL and has an elimination half life of 5 to 6 hours. With a 500 mg every 8 to 12 hours dosing, the peak steady-state concentration of 14-OH clarithromycin is slightly higher (up to 1 μg/mL), and its elimination half-life is about 7 to 9 hours. With any of these dosing regimens, the steady-state concentration of the metabolite is generally attained within 2 to 3 days.
After a 250-mg tab every 12 hrs, approximately 20% of the dose is excreted in the urine as clarithromycin while after a 500-mg tab every 12 hrs, the urinary excretion of clarithromycin is somewhat greater, approximately 30%. In comparison, after an oral dose of 250 mg (125 mg/5 mL) suspension every 12 hrs, approximately 40% is excreted in urine as clarithromycin. The renal clearance of clarithromycin is however, relatively independent of the dose size and approximates the normal glomerular filtration rate. The major metabolite found in urine is 14-OH clarithromycin, which accounts for an additional 10-15% of the dose with either a 250- or 500-mg tab administered every 12 hrs.
Steady-state concentrations of clarithromycin and 14-OH clarithromycin observed following administration of 500-mg doses of clarithromycin every 12 hrs to adult patients with HIV infection were similar to those observed in healthy volunteers. In adult HIV-infected patients taking 500- or 1000-mg doses of clarithromycin every 12 hrs, steady-state clarithromycin Cmax values ranged from 2-4 mg/mL and 5-10 mg/mL, respectively.
The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those in normal subjects; however, the 14-OH clarithromycin concentrations were lower in the hepatically impaired subjects. The decreased formation of 14-OH clarithromycin was at least partially offset by an increase in renal clearance of clarithromycin in the subjects with impaired hepatic function when compared to healthy subjects.
The pharmacokinetics of clarithromycin was also altered in subjects with impaired renal function. Clarithromycin and the 14-OH clarithromycin metabolite distribute readily into body tissues and fluids. There are no data available on cerebrospinal fluid penetration. Because of high intracellular concentrations, tissues concentrations are higher than serum concentrations.
