Klacid Mechanism of Action

Pharmacotherapeutic group: Antibacterial for systemic use, macrolide. ATC Code: J01FA09.
Pharmacology: Pharmacodynamics: Film-coated tablet and Granules for oral suspension: Mechanism/Mode of action: Clarithromycin is an antibiotic belonging to the macrolide antibiotic group. It exerts its antibacterial action by selectively binding to the 50s ribosomal sub-unit of susceptible bacteria preventing translocation of activated amino acids. It inhibits the intracellular protein synthesis of susceptible bacteria.
The 14-hydroxy metabolite of clarithromycin, a product of parent drug metabolism also has antimicrobial activity. The metabolite is less active than the parent compound for most organisms, including Mycobacterium spp. An exception is Haemophilus influenza where the 14-hydroxy metabolite is two-fold more active than the parent compound.
Clarithromycin is also bactericidal against several bacterial strains.
Clarithromycin is usually active against the following organisms in vitro: Gram-positive Bacteria: Staphylococcus aureus (methicillin susceptible); Streptococcus pyogenes (Group A beta-hemolytic streptococci); alpha-hemolytic streptococci (viridans group); Streptococcus (Diplococcus) pneumoniae; Streptococcus agalactiae; Listeria monocytogenes.
Gram-negative Bacteria: Haemophilus influenzae; Haemophilus parainfluenzae; Moraxella (Branhamella) catarrhalis; Neisseria gonorrhoeae; Legionella pneumophila; Bordetella pertussis; Helicobacter pylori; Campylobacter jejuni.
Mycoplasma: Mycoplasma pneumoniae; Ureaplasma urealyticum.
Other Organisms: Chlamydia trachomatis; Mycobacterium avium; Mycobacterium leprae, Chlamydia pneumoniae (Granules for oral suspension).
Anaerobes: Macrolide-susceptible Bacteroides fragilis; Clostridium perfringens; Peptococcus species; Peptostreptococcus species; Propionibacterium acnes.
Clarithromycin also 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 species.
Breakpoints: The following breakpoints have been established by the European Committee for Antimicrobial Susceptibility Testing (EUCAST). (See Table 1.)

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Modified-release tablet: Mode of action: The mechanism of action of clarithromycin is based on the inhibition of protein biosynthesis by binging to the 50S subunit of the bacterial ribosome. Clarithromycin has a relevant bactericidal effect. This is very well documented in particular for respiratory tract pathogens.
The 14(R)-hydroxy metabolite of clarithromycin, a product of the metabolisation of the parent substance which is found in humans, also has an antibacterial effect. The MICs of this metabolite are one or two-fold more active against Haemophilus influenza than the parent compound. Depending on the nature of the assay strain investigated, clarithromycin and its metabolite show an additive or synergistic effect in vitro and in vivo.
Pharmacokinetic/pharmacodynamic relationship: In recent in-vitro and in-vivo studies, it could be demonstrated that the bactericidal activity of clarithromycin is predominantly concentration-dependent. Clarithromycin is actively enriched with high concentrations of phagocytes. In vivo, the post-antibiotic effect is 2-3 times stronger than in erythromycin
Clarithromycin and the 14(R)-hydroxy clarithromycin metabolite are extremely well distributed in the body tissues and fluids. A tissue penetration study with extended-release clarithromycin confirmed that therapeutic levels of clarithromycin and its active metabolites were evident in the tissues up to 24 hours after the administration of a single daily dose of 1000 mg, essentially in the case of lower respiratory tract infections.
Following the administration of extended-release clarithromycin, at a single daily dose of 1000 mg, a higher steady state of clarithromycin concentrations were detected in the epithelial fluid (4 to 25 times higher on average) and alveolar macrophages (150-250 times higher on average) compared with plasma concentrations measured at the same time, in the 24-hour period following administration. Furthermore, 14(R)-hydroxy clarithromycin reached higher steady-state concentrations (40-80 times higher on average) in the alveolar macrophages compared to plasma concentrations.
Concentrations of the extended-release clarithromycin formulation following daily administration of 500 mg or 1000 mg reached levels in the plasma and lung tissue that exceeded the MICs of the most common pathogens in respiratory tract, skin and soft tissue infections. These concentrations were similar to the values recorded for the rapid-release pharmaceutical form.
Mechanism of resistance: Resistance to clarithromycin can be based on the following mechanisms: Efflux: resistance can be caused as a result of an increase in the number of efflux pumps in the cytoplasmic membrane, by which only 14- and 15- membered macrolides are affected (so-called M phenotype).
Change in the target structure: as a result of the methylation of the 23S rRNS, the affinity for the ribosomal binding sites is reduced, resulting in resistance to macrolides (M), lincosamides (L) and group B streptogramins (S_B) (so-called MLS_B phenotype).
The enzymatic inactivation of macrolides is only of subordinate clinical importance.
In the M phenotype, there is complete cross-resistance of clarithromycin with azithromycin, erythromycin and roxithromycin. In the MLS_B phenotype, there is additionally cross-resistance with clindamycin and streptogramin B. There is partial cross-resistance with the 16-membered macrolide spiramycin.
Breakpoints: Clarithromycin is tested using the usual serial dilution. The following minimal inhibitory concentrations are established for susceptible and resistant micro-organisms: EUCAST (European Committee on Antimicrobial Susceptibility Testing): See Table 2.

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Prevalence of acquired resistance in Germany: The prevalence of acquired resistance of individual species can vary from place to place and over time. Therefore, particularly for adequate treatment of severe infections, local information on the resistance situation is required. If, because of the local resistance situations, the efficacy of clarithromycin is called into question, a therapy consultation by experts should be sought. Particularly in serious infections or in the case of failed therapy, a microbiological diagnosis with detection of the microorganisms and their susceptibility to clarithromycin should be sought. However, it has not been definitively proven that in vitro resistance leads to clinical inefficacy in the case of mild to moderately severe community-acquired respiratory tract infections.
Prevalence of acquired resistance in Germany on the basis of the data of the last 5 years from national resistance-monitoring projects and studies (status: February 2018): See Table 3.

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Pharmacokinetics: Film-coated tablet: 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 gastritis 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.
Modified-release tablet: Absorption: Clarithromycin is less sensitive to gastric acid than erythromycin due to its structure as 6-O-methyl erythromycin.
Extended-release clarithromycin tablets facilitate the absorption of clarithromycin via the gastrointestinal tract over 12 to 14 hours after oral administration. Compared to an equivalent dose of fast-releasing clarithromycin tablets, the extended-release tablets reach lower and later maximum steady-state plasma concentrations but an equivalent 24-hour AUC for clarithromycin and its microbiologically active metabolites, 14(R)-hydroxy clarithromycin. The AUC values at time zero (prior to administration) up to 3 hours post-dose (AUC_0-3) were higher for rapid-release clarithromycin, taken twice daily, than for the same single daily dose of extended-release clarithromycin. This shows that there is no risk of a rapid decrease in plasma levels with the extended-release pharmaceutical form.
The pharmacokinetic profile of orally administered rapid-release clarithromycin has been studied extensively in numerous studies in humans and animals. These studies show that clarithromycin is absorbed effectively and rapidly with an absolute bioavailability of almost 50%. Small or no unexpected accumulations were found.
Bioequivalence studies comparing rapid and extended-release pharmaceutical forms highlighted a relative bioavailability of almost 96% for clarithromycin and 100% for 14(R)-hydroxy clarithromycin.
Whereas the extent of 14(R)-hydroxy clarithromycin formulation is not affected by food intake following administration of Klacid MR tablets (1000 mg once daily). Administration on an empty stomach compared to administration with food is linked to an approximately 30% lower AUC for clarithromycin. Therefore, Klacid MR should be taken with food.
Pharmacokinetic study data: The absorption of clarithromycin in the gastrointestinal tract following oral administration is delayed with Klacid MR Tablets. Compared to an equivalent daily dose with rapid-release clarithromycin tablets, the extended-release tablets lead to lower, later maximum steady state plasma concentrations but an equivalent 24-hour AUC for clarithromycin and its microbiologically active metabolites, 14(R)-hydroxy clarithromycin.
Summary of the pharmacokinetic results recorded for clarithromycin and 14(R)-hydroxy clarithromycin: See Table 4.

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In a repeated dose study, the uniform mean half-life for extended-release clarithromycin (5.6; 5.7 hours) compared to rapid-release clarithromycin (5.3 hours) was slightly increased but the differences were not statistically significant. The established half-life is initially determined by the intrinsic elimination half-life of the substance, clarithromycin. This is anticipated, regardless of pharmaceutical form.
Distribution: Clarithromycin and the 14(R)-hydroxy clarithromycin metabolite are very well distributed in the body tissues and body fluids. The distribution volume is approximately 2 to 4 l/kg (see Pharmacodynamics as previously mentioned). In-vitro studies with clarithromycin revealed average plasma protein binding of 70% with concentrations of 0.45 to 4.5 μg/ml.
Macrolides penetrate the phagocytes (polynuclear neutrophils, monocytes, peritoneal and alveolar macrophages) where they accumulate. The intraphagocytic concentrations in humans can be high. These properties account for the efficacy of clarithromycin against intracellular bacteria.
One study with Klacid MR administered at a single daily dose of 2 x 500 mg for 5 days showed that the concentration of clarithromycin and its active metabolites was higher in the epithelial fluid (4 to 25 times higher on average) and the alveolar macrophages (150 to 250 times higher on average) than in the plasma.
Metabolism: The data currently available show that clarithromycin is primarily metabolized at cytochrome-P450 3A (CYP3A) in the liver. Clarithromycin is extensively metabolized essentially via N-demethylation or oxidation in position 14 of the molecule. Hydroxylation at position C-14 is stereospecific. Clarithromycin is biologically converted into three metabolites, namely N-demethyl-clarithromycin, descladinosyl-clarithromycin and 14-OH-clarithromycin.
The most important metabolite in humans and other primates is the microbiologically active metabolite, 14-OH-clarithromycin. This metabolite is as active as or 1 to 2 times less active than the parent compound against most organisms, except for H. influenza, against which it is 1 to 2 times more active. Depending on the strain, the mother compound and the 14-OH metabolite have an additive or synergistic effect on H. influenza both in vitro and in vivo.
Non-linearity: The non-linear pharmacokinetic profile of clarithromycin, combined with the relative decrease in 14-hydroxylation and N-demethylation at higher doses, shows that the metabolism of clarithromycin reaches saturation at high doses. Non-linearity is slight with a clinically relevant daily dose of 1000 mg or less.
Elimination: Clarithromycin is eliminated via the liver and kidneys. Measurements recorded with radio-labelled substance in humans following single oral dose administration of 250 mg or 1200 mg rapid-release clarithromycin showed that the amount excreted via the urine accounted for 37.9% of the lower dose and 46% of the higher dose. The parent compound (18.4% and 29.4%) and the 14-(R)-hydroxy clarithromycin metabolite (13.7% and 9.9%) account for the majority eliminated in radioactive urine following the administration of 250 mg and 1200 mg, respectively.
As regards elimination in the stools, 40.2% (250 mg dose) and 29.1% (1200 mg dose) were detected. The parent compound accounted for 4.4% and 10.6%, respectively, equivalent to the low and high doses. A comparison of the metabolite profile in the stools and urine showed that the second metabolisation products are mainly eliminated in the stools.
Hepatic Impairment: No changes in the pharmacokinetic data of clarithromycin and the 14-(R)-hydroxy metabolite were observed in patients with mild, alcohol-induced liver damage. No studies have been carried out in subjects with severe hepatic impairment.
Renal Impairment: A study involving healthy subjects presenting with impaired renal function was carried out in order to assess and compare the pharmacokinetic profile of multiple dosing with 500 mg rapid-release clarithromycin. The plasma levels, half-life, C_max and C_min for clarithromycin and its 14-(R)-hydroxy metabolite were higher and the AUC was greater in subjects with impaired renal function. The elimination constant (K_elim) and elimination via the urine were lower.
Most pharmacokinetic parameters show a clear correlation with creatinine clearance. When creatinine clearance is less than 30 ml/minute, the elimination half-life is tripled for clarithromycin and quadrupled for 14-OH-clarithromycin, which indicates significantly higher accumulation. After 5 days of treatment, a C_max of 8.3 μg/ml was recorded in patients with severe renal failure (creatinine clearance of 10 to 29 ml/min). Similar changes were observed in the kinetic profile of the 14-(R)-hydroxy clarithromycin metabolite.
Elderly patients: A study involving elderly male and female subjects (age >65) and young male subjects (21-29 years) was carried out in order to assess and compare multiple dosing safety and the pharmacokinetic profile of 500 mg rapid-release clarithromycin. Higher plasma levels and slower elimination were recorded with the parent compound and 14-(R)-hydroxy clarithromycin metabolite in the elderly test group than in the younger test group. The differences could be linked to the physiological decrease in kidney function in older patients.
No difference was, however, observed between the groups when a correlation was established between renal clearance and creatinine clearance. These results indicate that the onset of metabolisation effects with clarithromycin is linked to renal function as opposed to age.
Granules for oral suspension: Clarithromycin is rapidly and well absorbed from the gastro-intestinal tract after oral administration. The microbiologically active 14(R)-hydroxyclarithromycin is formed by first pass metabolism. Clarithromycin, may be given without regard to meals as food does not affect the extent of bioavailability. Food does slightly delay the onset of absorption of clarithromycin and formation of the 14-hydroxy metabolite. Although the pharmacokinetics of clarithromycin are non linear, steady state is attained within 2 days of dosing. 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.
Clarithromycin provides tissue concentrations that are several times higher than circulating drug level. Increased levels of clarithromycin have been found in both tonsillar and lung tissue. Clarithromycin penetrates into the middle ear fluid at concentrations greater than in the serum. Clarithromycin is 80% bound to plasma proteins at therapeutic levels.
Klacid granules for oral susp 125 mg/5 ml does not contain tartrazine or other azo dyes, lactose or gluten.
Toxicology: Preclinical safety data: Film-coated tablet and Granules for oral suspension: Fertility, Reproduction and Teratogenicity: Studies performed in rats at oral doses up to 500 mg/kg/day (highest dose associated with overt renal toxicity) demonstrated no evidence for clarithromycin-related adverse effects on male fertility. This dose corresponds to a human equivalent dose (HED) of approximately 5 times the maximum recommended human dose (MRHD) on a mg/m² basis for a 60-kg individual.
Fertility and reproduction studies in female rats have shown that a daily dosage of 150 mg/kg/day (highest dose tested) caused no adverse effects on the oestrus cycle, fertility, parturition and number and viability of offspring. Oral teratogenicity studies in rats (Wistar and Sprague-Dawley), rabbits (New Zealand White) and cynomolgous monkeys failed to demonstrate any teratogenicity from clarithromycin at the highest doses tested up to 1.5, 2.4 and 1.5 times the MRHD on a mg/m² basis in the respective species. However, a 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 at ~5 times the MRHD on a mg/m² basis for a 60-kg individual. Embryonic loss was seen in monkeys but only at dose levels which were clearly toxic to the mothers.
Film-coated tablet: In acute mouse and rat studies, the median lethal dose was greater than the highest feasible dose for administration (5 g/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 400 mg/kg/day, some dogs and monkeys developed corneal opacities and/or oedema.
Modified-release tablet: Animal studies showed that the toxicity of clarithromycin depends on the dose and duration of the treatment. In all species, the liver was the target organ of toxic effects; in dogs and monkeys, lesions were detectable in the liver after a 14-day treatment. However, the toxic doses in animals were clearly higher than the recommended therapeutic doses in humans. In rats treated with 150 mg/kg/day of clarithromycin, cardiovascular deformities were evident.
In-vitro and in-vivo studies on the mutagenic potential were negative.
Reproductive toxicity studies showed that clarithromycin in maternally-toxic doses in rabbits and monkeys leads to increased miscarriage. In studies on rats, no embryotoxicity or teratogenicity was established. In mice, at 70 times the clinical dose cleft palate occurred (frequency 3 to 30%).
Granules for oral suspension: The acute oral LD₅₀ values for a clarithromycin suspension administered to 3-day old mice were 1290 mg/kg for males and 1230 mg/kg for females. The LD₅₀ values in 3-day old rats were 1330 mg/kg for males and 1270 mg/kg for females. For comparison, the LD₅₀ of orally-administered clarithromycin is about 2700 mg/kg for adult mice and about 3000 mg/kg for adult rats. These results are consistent with other antibiotics of the penicillin group, cephalosporin group and macrolide group in that the LD₅₀ is generally lower in juvenile animals than in adults.
In both mice and rats, body weight was reduced or its increase suppressed and suckling behaviour and spontaneous movements were depressed for the first few days following drug administration. Necropsy of animals that died disclosed dark-reddish lungs in mice and about 25% of the rats; rats treated with 2197 mg/kg or more of a clarithromycin suspension were also noted to have a reddish - black substance in the intestines, probably because of bleeding. Deaths of these animals were considered due to debilitation resulting from depressed suckling behaviour or bleeding from the intestines.
Pre-weaning rats (5 days old) were administered a clarithromycin suspension formulation for two weeks at doses of 0, 15, 55 and 200 mg/kg/day. Animals from the 200 mg/kg/day group had decreased body-weight gains, decreased mean haemoglobin and haematocrit values, and increased mean relative kidney weights compared to animals from the control group. Treatment-related minimal to mild multifocal vacuolar degeneration of the intrahepatic bile duct epithelium and an increased incidence of nephritic lesions were also observed in animals from this treatment group. The "no-toxic effect" dosage for this study was 55 mg/kg/day.
An oral toxicity study was conducted in which immature rats were administered a clarithromycin suspension (granules for suspension) for 6 weeks at daily dosages of 0, 15, 50 and 150 mg base/kg/day. No deaths occurred and the only clinical sign observed was excessive salivation for some of the animals at the highest dosage from 1 to 2 hours after administration during the last 3 weeks of treatment. Rats from the 150 mg/kg dose group had lower mean body weights during the first three weeks, and were observed to have decreased mean serum albumin values and increased mean relative liver weight compared to the controls. No treatment-related gross or microscopic histopathological changes were found. A dosage of 150 mg/kg/day produced slight toxicity in the treated rats and the "no effect dosage" was considered to be 50 mg/kg/day.
Juvenile beagle dogs, 3 weeks of age, were treated orally daily for four weeks with 0, 30, 100, or 300 mg/kg of clarithromycin, followed by a 4-week recovery period. No deaths occurred and no changed in the general condition of the animals were observed. Necropsy revealed no abnormalities. Upon histological examination, fatty deposition of centrilobular hepatocytes and cell infiltration of portal areas were observed by light microscopy and an increase in hepatocellular fat droplets was noted by electron microscopy in the 300 mg/kg dose group. The toxic dose in juvenile beagle dogs was considered to be greater than 300 mg/kg and the "no effect dose" 100 mg/kg.