Clarithromycin is an acid stable macrolide antibiotic indicated for use in the
treatment of skin, urinary and respiratory tract infections. Compared to erythromycin,
clarithromycin exhibits the same in vitro activity against conventional pathogens, but
is better tolerated by generating less gastrointestinal problems.
Clarithromycin is a polyketide synthase-derived semisynthetic macrolide antibiotic. It is active against methicillin-susceptible, but not methicillin-resistant, S. aureus (MIC50s = 0.06 and >128 μg/ml), S. pyogenes, L. monocytogenes, and B. pertussis (MIC50 = 0.015, 0.25, and ≤0.008 μg/ml, respectively), among others. Clarithromycin (25 mg/kg) decreases the number of colony-forming units (CFUs) in the spleen in a mouse model of M. avium infection. Formulations containing clarithromycin have been used in the treatment of bacterial infections and, when used in combination with other antibiotics, in the treatment of H. pylori.
Colourless Crystalline Needles
A macrolide antibiotic and protein synthesis inhibitor
Labeled Clarithromycin, intended for use as an internal standard for the quantification of Clarithromycin by GC- or LC-mass spectrometry.
Clarithromycin is a semi-synthetic macrolide antibiotic. Clarithromycin is a derivative of Erythromycin (E650000).
A semi-synthetic macrolide antibiotic. A derivative of erythromycin
Clarithromycin (6-methoxyerythromycin) is a macrolide antibiotic active against a broad range of Gram positive bacteria. Clarithromycin was designed to enhance acid stability and improve oral bioavailability compared with erythromycin which is highly unstable to acidic conditions, undergoing a series of internal ketalisations between the 9-keto moiety and alcohols at C6 and C11. Omura and colleagues found that protection of the labile 6-OH group by methylation provided a simple but elegant solution.
ChEBI: The 6-O-methyl ether of erythromycin A, clarithromycin is a macrolide antibiotic used in the treatment of respiratory-tract, skin and soft-tissue infections. It is also used to eradicate Helicobacter pylori in the treatment
f peptic ulcer disease. It prevents bacteria from growing by interfering with their protein synthesis.
In a mixture of 50 ml of dry dimethylsulfoxide and 100 ml of dry
tetrahydrofuran were dissolved 30 g of O,N-dibenzyloxycarbonyl-des-Nmethylerythromycin A and 18 ml of methyl iodide. The solution was stirred
under cooling at -12-10°C in a nitrogen stream and 2.4 g of 55-65% sodium
hydride oily dispersion were added thereto in small portions. The mixture was
stirred for a further one hour. After completion of the reaction, 50 ml of
triethylamine were poured into the reaction mixture with stirring under icecooling, and the precipitates were filtered off. The obtained solid product was
washed thoroughly with ethyl acetate, and the washings and the mother
liquor were combined. The combined liquor was washed with a saturated
aqueous sodium chloride solution and dried over anhydrous magnesium
sulfate. The solvent was evaporated in vacuo and the crude product was
applied onto a silica gel dry column (E. Merck Darmstadt; silica gel 60 for
column chromatography, 70-230 mesh). The mixture was eluted with of ethyl
acetate/n-hexane (1:1).
15 ml each of fraction was collected and analyzed by silica gel thin layer
chromatography, developing in a mixture of ethyl acetate and n-hexane (1:1).
The fractions having Rf value 0.16 were combined (c.f., Rf value of starting
compound 0.07) and the solvent was evaporated in vacuo, affording 12.2 g of
a colorless froth.
In a mixture of 1.32 g of sodium acetate, 0.8 ml of sodium acetate, 40 ml of
water and 200 ml of ethanol were dissolved 10 g of the colorless froth
obtained, and 1.0 g of palladium black was added to the above solution.
Catalytic reduction was performed for 5 hours at room temperature under
atmospheric pressure in a gentle hydrogen stream. 32 ml of 37% aqueous
formaldehyde solution were poured into the reaction mixture and the catalytic
reduction was continued for a further 7 hours. After completion of the
reaction, the catalyst was filtered off and the filtrate was concentrated under
reduced pressure approximately to a quarter volume. To the concentrate were
added 100 ml of water, and the mixture was adjusted to about pH 10 with an
aqueous sodium carbonate solution. The mixture was extracted thoroughly
with chloroform and the extract was washed with water and dried. After
evaporation of the solvent in vacuo, the residue was recrystallized from a
mixture of chloroform and diethyl ether, giving 6 g of crystals.
The crystals were stirred for 5 hours in 500 ml of diethyl ether and filtered off.
The filtrate was concentrated to dryness and the residual substance was
recrystallized from a mixture of chloroform and diethyl ether, giving 4.5 g of
6-O-methylerythromycin A (Clarithromycin) in the form of colorless needles;
m.p. 217-220°C (with decomposition).
Activity against susceptible common pathogens is two to four times greater than that of erythromycin A . Most respiratory pathogens, with the exception of H. influenzae, are inhibited at a concentration of ≤0.25 mg/L. It inhibits Mycoplasma pneumoniae at 0.004 mg/L and Mor. catarrhalis at 0.06 mg/L. It is eight times more active than erythromycin A against Legionella spp., C. trachomatis and Ch. pneumoniae. Against anaerobic species, activity is similar to that of erythromycin A. Against H. influenzae the 14-hydroxy metabolite is twice as active as the parent compound.
Some of the microbiological properties of clarithromycin appear to be superior to those of erythromycin. It exhibitsgreater potency against M. pneumoniae, Legionellaspp., Chlamydia pneumoniae, H. influenzae, and M. catarrhalisthan does erythromycin. Clarithromycin also hasactivity against unusual pathogens such as Borrelia burgdorferi(the cause of Lyme disease) and the Mycobacteriumavium complex (MAC). Clarithromycin is significantly moreactive than erythromycin against group A streptococci, S.pneumoniae, and the viridans group of streptococci in vivobecause of its superior oral bioavailability. Clarithromycin is,however, more expensive than erythromycin, which must beweighed against its potentially greater effectiveness.
Adverse reactions to clarithromycin are rare. The mostcommon complaints relate to GI symptoms, but these seldomrequire discontinuance of therapy. Clarithromycin,like erythromycin, inhibits cytochrome P450 oxidases and,thus, can potentiate the actions of drugs metabolized bythese enzymes.
Clarithromycin occurs as a white crystalline solid that ispractically insoluble in water, sparingly soluble in alcohol,and freely soluble in acetone. It is provided as 250- and 500-mg oral tablets and as granules for the preparation of aqueousoral suspensions containing 25 or 50 mg/mL.
Moderately toxic by ingestion. Human sys-temic effects.
Pharmaceutical Applications
A semisynthetic erythromycin A derivative (6-O- methyl erythromycin A) formulated for oral and intravenous use.
Macrolides, such as clarithromycin, prevent protein synthesis in bacteria, by binding to 50S ribosomal subunit. It also binds to other ribosomal proteins, and prevents the translocation of pepti-dyl-tRNA. In patients with refractory asthma, it is capable of regulating the levels of interleukin-8 (IL-8), and neutrophil accumulation and activation in lungs. Thus, it might be used as an additional therapy in asthma to reduce noneosinophilic airway inflammation.
Oral absorption： 55%
Cmax 50 mg oral： 0.75 mg/L after 1.7 h
500 mg oral： 1.65 mg/L after 2 h
Terminal half-life： 2.7–3.5 h
Volume of distribution ：250 L
Plasma protein binding 80%
absorption and distribution
It is more stable to gastric acid than erythromycin, but internal ketalization between the 9-keto group and the C-12 hydroxyl group has been described resulting in an inactive product: pseudo clarithromycin. It is rapidly absorbed orally and absorption is not affected by food. Concentrations in tonsil and lung tissues exceed the simultaneous plasma level by a factor of two and four, respectively.
Metabolism and excretion
The primary metabolic pathway is N-demethylation of the d-desosamine and stereospecific hydroxylation at the 14- position of the erythronolide A ring. Metabolism to the 14-hydroxy derivative is saturable above 800 mg. Around 20&ndash：40% of the administered dose is eliminated in urine. The apparent elimination half-life of the 14-hydroxy metabolite is around 7 h. The parent compound and its principal metabolite are retained in renal impairment, resulting in long apparent elimination half-lives, exceeding 30 and 45 h, respectively, in patients whose creatinine clearance is less than 30 mL/min.
Antibacterial agent:
Also adjunct in treatment of duodenal ulcers by
eradication of H pylori
Clarithromycin is well tolerated, producing little gastrointestinal disturbance and only transient changes in some liver function tests.
Clarithromycin, (2R,3S,4S, 5R,6R,8R,10R,11R,12S,13R)-3-(2,6-dideoxy-
3-C-3-O-dimethyl-α-L-ribo-hexopyranosyloxy)-6-methoxy-9-oxo-11,12-dihydroxy-
2,4,6,8,10,12-hexamethyl-5-(3,4,6-trideoxy-3-dimethylamino-β-D-xylo-hexopyranosyloxy)
cyclopentadecan-13-olide (32.2.2), is a semisynthetic analog of erythromycin A, in which
the hydroxyl group at C6 is replaced with a methoxyl group.
Veterinary Drugs and Treatments
In small animal medicine, clarithromycin is primarily of interest
in treating atypical mycobacterial infections or treatment of
Helicobacter spp. infections in cats and ferrets. In equine medicine,
clarithromycin may be useful in treating Rhodococcus equi infections
in foals.
Potentially hazardous interactions with other drugs
Anti-arrhythmics: possibly increased disopyramide
concentration; increased risk of ventricular
arrhythmias with dronedarone - avoid.
Antibacterials: increased rifabutin concentration -
reduce rifabutin dose; concentration of bedaquiline
possibly increased - avoid if for more than
14 days; possibly increased risk of ventricular
arrhythmias with delamanid; avoid with fidaxomicin;
clarithromycin concentration reduced by rifamycins.
Anticoagulants: avoid with apixaban; effect of
coumarins enhanced; increased risk of bleeding with
dabigatran.
Antidepressants: avoid with reboxetine;
concentration of trazodone possibly enhanced.
Antiepileptics: increased carbamazepine, phenytoin
and fosphenytoin concentration.
Antifungals: avoid combination with ketoconazole
in severe renal impairment; concentration of
itraconazole increased.
Antihistamines: metabolism of mizolastine inhibited
- avoid.
Antimalarials: avoid concomitant administration
with artemether/lumefantrine; increased risk of
ventricular arrhythmias with piperaquine with
artenimol - avoid.
Antimuscarinics: reduce dose of fesoterodine; avoid
with tolterodine.
Antipsychotics: increased risk of ventricular
arrhythmias with droperidol and pimozide - avoid;
possibly increased lurasidone and quetiapine
concentration - avoid.
Antivirals: concentration of both drugs increased with atazanavir and telaprevir; concentration of
daclatasvir increased - reduce dose of daclatasvir;
avoid with dasabuvir and paritaprevir; concentration
of clarithromycin reduced by efavirenz and
active metabolites of clarithromycin increased;
concentration of etravirine increased and
clarithromycin concentration reduced; concentration
of maraviroc possibly increased - consider reducing
maraviroc dose; concentration reduced by nevirapine
but active metabolite increased also nevirapine
concentration increased; concentration of rilpivirine
possibly increased - avoid; increased risk of
ventricular arrhythmias with saquinavir - avoid;
avoid with simeprevir; oral clarithromycin reduces
absorption of zidovudine; concentration increased
by ritonavir and tipranavir, also concentration of tipranavir increased - reduce dose of clarithromycin
in renal impairment.
Anxiolytics: metabolism of midazolam inhibited.
Avanafil: concentration of avanafil possibly increased
- avoid.
Calcium-channel blockers: possibly inhibits
metabolism of calcium channel blockers.
Ciclosporin: increased ciclosporin concentration
(although may take ~ 5 days after starting
clarithromycin before increase in ciclosporin levels is
seen).
Cilostazol: concentration of cilostazol possibly
increased, reduce cilostazol to 50 mg bd.
Colchicine: treatment with both agents has been
shown in a study to increase the risk of fatal
colchicine toxicity, especially in patients with renal
impairment - avoid.1 Cytotoxics: concentration of axitinib increased -
reduce axitinib dose; concentration of bosutinib
possibly increased - avoid or reduce dose of
bosutinib; concentration of cabozantinib, dasatinib,
ibrutinib, pazopanib and ponatinib possibly
increased - avoid with dasatinib, reduce dose
of ibrutinib and pazopanib and initial dose of
ponatinib; concentration of docetaxel possibly
increased - avoid or reduce dose; possible increased
risk of ventricular arrhythmias with ceritinib
and panobinostat - avoid with panobinostat;
concentration of crizotinib and everolimus
possibly increased - avoid; avoid with cabazitaxel,
nilotinib and pazopanib; possibly increases olaparib
concentration - reduce olaparib dose or avoid; reduce
dose of ruxolitinib; increased risk of neutropenia
with vinorelbine.
Diuretics: increased eplerenone concentration - avoid.
Domperidone: increased risk of ventricular
arrhythmias - avoid.
Ergot alkaloids: increase risk of ergotism - avoid.
Guanfacine: concentration of guanfacine possibly
increased - halve guanfacine dose.
5 HT1
agonists: increased eletriptan concentration
- avoid.
Ivabradine: increased ivabradine concentration - avoid.
Ivacaftor: concentration of ivacaftor possibly increased.
Lenalidomide: possibly increased lenalidomide
concentration.
Lipid-lowering drugs: avoid with lomitapide;
concentration of pravastatin increased; increased risk
of myopathy with atorvastatin and simvastatin, avoid
with simvastatin and max dose of atorvastatin 20 mg.2
Lumacaftor: concentration possibly reduced by
lumacaftor - reduce dose of lumacaftor.
Naloxegol: possibly increases naloxegol concentration Ranolazine: concentration of ranolazine possibly
increased - avoid.
Sildenafil: concentration of sildenafil increased -
consider reducing initial dose for ED or reduce dose
for PAH.
Sirolimus: possibly increased sirolimus concentration
- avoid.
Tacrolimus: increased tacrolimus levels.
Theophylline and aminophylline: possibly increased
theophylline and aminophylline concentration.
Ticagrelor: concentration of ticagrelor possibly
increased - avoid.
The microbiologically active metabolite
14-hydroxyclarithromycin is formed by first pass
metabolism. The pharmacokinetics of clarithromycin are non
linear. At 250 mg bd, 15-20% of unchanged drug is excreted
in the urine. With 500 mg bd dosing urinary excretion is
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.
a population-based analysis of the risk of drug interaction between clarithromycin and statins for hospitalisation or death. lipids health dis. 2015 oct 24;14:131.
