Claritrox Mechanism of Action

Pharmacotherapeutic group: Antibacterial for systemic use, macrolide. ATC Code: J01FA09.
Pharmacology: Pharmacodynamics: Film-coated tablet: Clarithromycin is a semisynthetic macrolide antibiotic.
Mechanism of actions: Clarithromycin binds to the 50S ribosomal subunit of the 70S ribosome of susceptible organisms, thereby inhibiting bacterial RNA-dependent protein synthesis.
Granules for oral suspension: Clinical studies: Clinical Experience in Patients with Non-Mycobacterial Infections: In clinical studies, clarithromycin at a dose of 7.5 mg/kg b.i.d. was demonstrated to be safe and effective in the treatment of pediatric patients with infections requiring oral antibiotic treatment. It has been evaluated in over 1200 children, ages six months to 12 years, with otitis media, pharyngitis, skin infections and lower respiratory tract infections.
In these studies, clarithromycin at a dose of 7.5 mg/kg b.i.d. showed comparable clinical and bacteriological efficacy to the reference agents which included penicillin V, amoxicillin, amoxicillin/clavulanate, erythromycin ethylsuccinate, cefaclor and cefadroxil.
Clinical Experience in Patients with Mycobacterial Infections: A preliminary study in pediatric patients (some were HIV positive) with mycobacterial infections demonstrated that clarithromycin was a safe and effective treatment when given alone and in combination with zidovudine or dideoxyinosine. Clarithromycin Pediatric Suspension was administered as 7.5, 15 or 30 mg/kg/day in two divided doses.
Some statistically significant effects on pharmacokinetic parameters were observed when clarithromycin was administered with antiretroviral compounds; however, these changes were minor and not likely to be of clinical significance. Clarithromycin at doses of up to 30 mg/kg/day was well tolerated.
Clarithromycin was effective in the treatment of disseminated M. avium complex infections in pediatric patients with AIDS, with some patients demonstrating continued efficacy after more than one year of therapy.
Pharmacokinetics: Film-coated tablet: Absorption: Well absorbed from the gastrointestinal tract; stable in gastric acid; food delays the rate, but not the extent, of absorption; bioavailability is approximately 55% in healthy volunteers.
Distribution and Elimination: Widely distributed into tissue and fluids, high concentrations are found in nasal mucosa, tonsils, and lungs; concentrations in tissue are higher than those in serum because of high intracellular concentrations.
Binding to Plasma Proteins: 65 to 75%.
Biotransformation: Hepatically metabolised.
Half-life: Normal renal function: 250 mg every 12 hours: 3 to 4 hours.
500 mg every 12 hours: 5 to 7 hours.
Renal function impairment (creatinine clearance of <30 ml per minute): Approximately 22 hours.
Peak serum concentration: Clarithromycin: Steady-state: 250 mg every 12 hours: Approximately 1 mcg/mL.
500 mg every 12 hours: 2 to 3 mcg/mL.
14-Hydroxyclarithromycin: Steady-state: 250 mg every 12 hours: Approximately 0.6 mcg/mL.
500 mg every 12 hours: Up to 1 mcg/mL.
Elimination: Renal: Approximately 20 and 30%, respectively, of the dose of 250- and 500-mg tablets given twice a day is excreted in the urine as unchanged drug. Faecal: Approximately 4% of a 250-mg dose is excreted in the faeces.
Granules for oral suspension: Absorption: The pharmacokinetic data of the clarithromycin tablet formulations, indicated that drug is rapidly absorbed from the gastrointestinal tract and the absolute bioavailability of a clarithromycin 250 mg tablet was approximately 50%. Both the onset of absorption and the formation of the antimicrobially-active metabolite, 14OH-clarithromycin, was slightly delayed by food, but the extent of bioavailability was not affected by administration of drug in the nonfasting state.
Distribution, Biotransformation and Elimination: In vitro: In vitro studies showed that protein binding of clarithromycin in human plasma averaged about 70% at clinically relevant concentrations of 0.45 to 4.5 μg/mL.
Normal Subjects: The bioavailability and pharmacokinetics of Clarithromycin Pediatric Suspension were investigated in adult subjects and in pediatric patients. A single dose study in adult subjects found the overall bioavailability of the pediatric formulation to be equivalent to or slightly greater than that of the tablet (dosage with each was 250 mg). As with the tablet, administration of the pediatric formulation with food leads to a slight delay in the onset of absorption, but does not affect the overall bioavailability of clarithromycin. The comparative clarithromycin Cmax, AUC, and T¹/₂ for the pediatric formulation (non fasted state) were 0.95μg/mL, 6.5μg hr/mL, and 3.7 hours, respectively, and for the 250mg tablet (fasted state) were 1.10μg/mL, 6.3μg hr/mL, and 3.3 hours, respectively.
In a multiple dose study in which adult subjects were administered 250 mg of the Clarithromycin Pediatric Suspension every 12 hours, steady-state blood levels were nearly reached by time of the fifth dose. Pharmacokinetic parameters after the fifth dose for Clarithromycin Pediatric Suspension were: Cmax 1.98 μg/mL, AUC 11.5 μg hr/mL, Tmax 2.8 hours and T¹/₂ 3.2 hours for clarithromycin, and 0.67, 5.33, 2.9 and 4.9, respectively, for 14-OH-clarithromycin. In fasting healthy human subjects, peak serum concentrations were attained within two hours after oral dosing. With b.i.d. dosing using a 250 mg tablet every 12 hours, steady-state peak serum concentrations of clarithromycin were attained in two to three days and were approximately 1 μg/mL. Corresponding peak serum concentrations were 2 to 3 μg/mL with a 500 mg dose administered every 12 hours.
The elimination half-life of clarithromycin was about three to four hours with a 250 mg tablet administered every 12 hours but increased to five to seven hours with 500 mg administered every 12 hours. 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 five to six hours after a dose of 250 mg every 12 hours. With a dose of 500 mg every 12 hours, the peak steady-state concentrations of 14-OH-clarithromycin are slightly higher (up to 1 μg/mL), and its elimination half-life is about seven hours. With either dose, the steady-state concentration of this metabolite is generally attained within two to three days Elimination half-life was estimated to be approximately 2.2 hr and 4.3 hr for the parent compound and metabolite, respectively.
Approximately 20% of a 250 mg oral dose given every 12 hours is excreted in the urine as unchanged clarithromycin. After a dose of 500 mg every 12 hours, urinary excretion of unchanged parent drug is approximately 30%. 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% to 15% of either a 250 mg or 500 mg dose administered every 12 hours.
Patients: Clarithromycin and its 14-OH metabolite distribute readily into body tissues and fluids. Concentrations in tissues are usually several fold higher than serum concentrations. Examples from tissue and serum concentrations are presented as follows: (See Table 1.)

Click on icon to see table/diagram/image

In pediatric patients requiring oral antibiotic treatment, clarithromycin demonstrated good bioavailability with a pharmacokinetic profile consistent with previous results from adult subjects using the same suspension formulation. The results indicated rapid and extensive drug absorption in children and, except for a slight delay in onset of absorption, food seemed to have no significant effect on drug bioavailability or pharmacokinetic profiles. Steady-state pharmacokinetic parameters obtained after the ninth dose on treatment day five were as follows for the parent drug: Cmax 4.60 mcg/mL, AUC 15.7 μg/hr/mL and Tmax 2.8 hr; the corresponding values for the 14-OH metabolite were: 1.64 μg/mL, 6.69 μg/hr/mL, and 2.7 hr, respectively.
Elimination half-life was estimated to be approximately 2.2 hr and 4.3 hr for the parent compound and metabolite, respectively.
In another study, information was obtained regarding the penetration of clarithromycin in middle ear fluid in patients with otitis media. Approximately 2.5 hours after receiving the fifth dose (dosage was 7.5 mg/kg b.i.d.), the mean concentration of clarithromycin was 2.53 mcg/g fluid in the middle ear and for the 14-OH metabolite was 1.27 μg/g. The concentrations of parent drug and 14-OH metabolite were generally twice as high as the corresponding concentrations in serum.
Hepatic Impairment: The steady-state concentrations of clarithromycin in subjects with impaired hepatic function did not differ from those of 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.
Renal Impairment: The pharmacokinetics of clarithromycin were also altered in subjects with impaired renal function who received multiple 500 mg oral doses. The plasma levels, half-life, Cmax and Cmin for both clarithromycin and its 14-OH metabolite were higher and the AUC was larger in subjects with renal impairment than in normal subjects. The extent to which these parameters differed was correlated with the degree of renal impairment; the more severe the renal impairment, the more significant the difference (see Dosage & Administration).
Elderly Subjects: In a comparative study of healthy, young adults and healthy, elderly subjects given multiple 500 mg oral doses of clarithromycin, the circulating plasma levels were higher and elimination was slower in the elderly group compared to the younger group. However, there was no difference between the two groups when renal clearance of clarithromycin was correlated with creatinine clearance. It was concluded from these results that any effect on the handling of clarithromycin is related to renal function and not to subject age.
Patients with Mycobacterial Infections: Steady-state concentrations of clarithromycin and 14-OH-clarithromycin observed following administration of usual doses to patients with HIV infections (tablets for adults; granular suspension for children) were similar to those observed in normal subjects. However, at the higher doses which may be required to treat mycobacterial infections, Clarithromycin concentrations can be much higher than those observed at usual doses.
In children with HIV infection taking 15 to 30 mg/kg/day of clarithromycin in two divided doses, steady-state Cmax values generally ranged from 8 to 20 mcg/mL. However, Cmax values as high as 23 mcg/mL have been observed in HIV-infected pediatric patients taking 30 mg/kg/day in two divided doses as Clarithromycin Pediatric Suspension. Elimination half-lives appeared to be lengthened at these higher doses as compared to that observed with usual doses in normal subjects. The higher plasma concentrations and longer elimination half-lives observed at these doses are consistent with the known nonlinearity in clarithromycin pharmacokinetics.
Microbiology: Film-coated tablet: Clarithromycin is active in vitro against a variety of aerobic and anaerobic gram-positive and gram-negative microorganisms.
Additionally, the 14-OH clarithromycin metabolite also has clinically significant antimicrobial activity. The 14-OH clarithromycin is twice as active against Haemophilus influenzae microorganisms as the parent compound.
Clarithromycin has been shown to be active against most strains of the following microorganisms both in-vitro and in clinical infections.
Aerobic Gram-positive microorganisms: Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes.
Aerobic Gram-negative microorganisms: Haemophilus influenzae and Moraxella catarrhalis.
Other microorganisms: Mycoplasma pneumoniae and Chlamydia pneumoniae (TWAR).
Mycobacteria: Mycobacterium avium complex (MAC) consisting of: Mycobacterium avium, Mycobacterium intracellulare and Helicobacter pylori.
Clarithromycin has been shown to be active against most strains of Helicobacter pylori in-vitro and in clinical infections when combined with omeprazole, lansoprazole and amoxycillin, or ranitidine bismuth citrate.
The following in-vitro data are available, but their clinical significance is unknown.
Aerobic Gram-positive microorganisms: Streptococcus agalactiae, Streptococci (Groups C,F,G), Viridans group streptococci.
Aerobic Gram-negative microorganisms: Bordetella pertussis, Legionella pneumophila and Pasteurella multocida.
Anaerobic Gram-positive microorganisms: Clostridium perfringens, Peptococcus niger and Propionibacterium acnes.
Anaerobic Gram-negative microorganisms: Prevotella melaninogenica (formerly Bacteroides melaninogenicus).
Granules for oral suspension: Clarithromycin exerts its antibacterial action by binding to the 50S ribosomal subunits of susceptible bacteria and suppresses protein synthesis.
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 minimum inhibitory concentrations (MICs) of clarithromycin are generally one log2 dilution more potent than the MICs of erythromycin.
In vitro data also indicate clarithromycin has excellent activity Legionella pneumophilia, Mycoplasma pneumoniae, and Helicobacter pylori (Campylobacter). In vitro and in vivo data show that this antibiotic has activity against clinically significant mycobacterial species. The in vitro data indicate Enterobacteriaceae, pseudomonas species and other non-lactose fermenting gram-negative bacilli are not susceptible to clarithromycin.
Clarithromycin has been shown to be active against most strains of the following microorganisms both in vitro and in clinical infections as described in the Indications: Aerobic Gram-Positive microorganisms: Staphylococcus aureus, Streptococcus pneumonia, Streptococcus pyogenes, Listeria monocytogenes.
Aerobic Gram-negative microorganisms: Haemophilus influenza, Haemophilus parainfluenzae, Moraxella catarrhalis, Neisseria gonorrhoeae, Legionella pneumophila.
Other microorganisms: Mycoplasma pneumonia, Chlamydia pneumonia (TWAR).
Mycobacteria: Mycobacterium leprae, Mycobacterium kansasii, Mycobacterium chelonae, Mycobacterium fortuitum, Mycobacterium avium complex (MAC) consisting of: Mycobacterium avium, Mycobacterium Intracellulare.
Beta-lactamase production should have no effect on clarithromycin activity.
NOTE: Most strains of methicillin-resistant and oxacillin-resistant staphylococci are resistant to clarithromycin.
The following in vitro data are available, but their clinical significance is unknown.
Clarithromycin exhibits in vitro activity against most strains of the following microorganisms; however, the safety and effectiveness of clarithromycin in treating clinical infections due to these microorganisms have not been established in adequate and well-controlled clinical trials.
Aerobic Gram-positive microorganisms: Streptococcus agalactiae Streptococci (Group C, F, G), Viridans group streptococci.
Aerobic Gram-negative microorganisms: Bordetella pertussis, Pasteurella multocida.
Anaerobic Gram-positive microorganisms: Clostridium perfringens, Peptococcus niger, Propionibacterium acnes.
Anaerobic Gram-negative microorganisms: Bacteroides melaninogenicus.
Spirochetes: Borrelia burgdorferi, Treponema pallidum.
Campylobacter: Campylobacter jejuni: 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 was found to be two to ten times more active than erythromycin in several experimental animal infection models. It was shown, for example, to be more effective than erythromycin in mouse systemic infection, mouse subcutaneous abscess, and mouse respiratory tract infections caused by S. pneumonia, S. aureus, S. pyogenes, and H. influenza. In guinea pigs with Legionella infection, this effect was more pronounced; an intraperitoneal dose of 1.6 mg/kg/day of clarithromycin was more effective than 50mg/kg/day of erythromycin.
Susceptibility Tests: Quantitative methods that require measurement of zone diameters give the most precise estimates of antibiotic susceptibility of bacteria to antimicrobial agents. One recommended procedure uses discs impregnated with 15 μg of clarithromycin for testing susceptibility; (Kirby-Bauer diffusion test); interpretations correlate zone diameters of this disc test with MIC values for clarithromycin. The MICs are determined by the broth or agar dilution method. With this procedure, a report from the laboratory of "susceptible" indicates that the infecting organism is likely to respond to therapy. A report of "resistant" indicates that the infective organism is not likely to respond to therapy. A report of "intermediate susceptibility" suggests that the therapeutic effect of the drug may be equivocal or that the organism would be susceptible if higher doses were used. (Intermediate susceptibility is also referred to as moderately susceptible.)