Clarithromycin

Structural formula
General
Non-proprietary name	Clarithromycin
other names	6- O -Methylerythromycin ( IUPAC ) Clarithromycinum ( Latin )
Molecular formula	C 38 H 69 NO 13
Brief description	white to almost white, crystalline powder
External identifiers / databases
CAS number 81103-11-9 EC number 617-200-4 ECHA InfoCard 100.119.644 PubChem 84029 DrugBank DB01211 Wikidata Q118551
Drug information
ATC code	J01 FA09
Drug class	Macrolide antibiotics
Mechanism of action	Inhibition of the translocase and thus protein biosynthesis in bacteria
properties
Molar mass	747.95 g · mol -1
Physical state	firmly
Melting point	225.7 ° C
pK s value	8.99 (25 ° C)
solubility	Water : 0.342 mg l −1 (25 ° C) Soluble in acetone and dichloromethane , sparingly soluble in methanol
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed GHS labeling of hazardous substances Caution H and P phrases H: 302 P: no P-phrases
Toxicological data	1270 mg kg −1 ( LD 50 ,  rat ,  oral ) 850 mg kg −1 ( LD 50 ,  mouse ,  ip )
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Clarithromycin is a drug from the group of macrolide antibiotics . It acts on the 50S subunit of the bacterial ribosomes , where it inhibits translocation and thus disrupts protein synthesis . This makes it bacteriostatically effective. Like all macrolides, the agent belongs to the broad-spectrum antibiotics and also has an intracellular effect.

Clinical information

Application areas (indications)

Clarithromycin is used to treat bacterial infections of the respiratory tract (e.g. bronchitis or pneumonia ), ear, nose and throat (e.g. tonsillitis / tonsillitis or sinusitis / sinusitis ) or the skin (e.g. pusus) / Impetigo or rose / erysipelas ). Among others, streptococci (including pneumococci ), legionella , chlamydia , bacteria without cell walls such as mycoplasma and also atypical mycobacteria related to the tuberculosis pathogens such as Bordetella pertussis are among the target germs. The clinical efficacy of all macrolides against Haemophilus influenzae is now considered to be insufficient. Clarithromycin is also used in the eradication of Helicobacter pylori colonization of the gastric mucosa ( gastritis ).

Contraindications (contraindications)

Clarithromycin must not be used if there is an existing hypersensitivity to other drugs of the group of macrolide antibiotics ( e.g. erythromycin ). A joint use with the active ingredients cisapride , pimozide , terfenadine or astemizole is also prohibited, as otherwise life-threatening cardiac arrhythmias can occur. Clarithromycin must also not be taken together with the ergot alkaloids dihydroergotamine and ergotamine . Because of the predominant excretion via metabolism in the liver, patients with severe hepatic impairment should not be treated with clarithromycin.

Drug interactions

The concentrations of the active substances cisapride , pimozide , terfenadine and astemizole in the blood ( plasma level ) are increased by clarithromycin. This increases the risk of cardiac arrhythmias (see contraindications). A corresponding increase in the plasma level of ergot alkaloids can lead to symptoms of intoxication with spasmodic narrowing of the blood vessels ( vasospasm ) and the resulting circulatory disorders (see contraindications).

Since clarithromycin inhibits the activity of the cytochrome P450 isoenzyme CYP3A4, numerous other drugs whose breakdown is determined by this enzyme can increase in concentration and have a stronger effect. These include among others, the antiarrhythmic drugs quinidine and disopyramide , the anticonvulsant carbamazepine , the gout agent colchicine , digoxin , the HMG-CoA reductase inhibitors (statins), anticoagulants (oral anticoagulants ), the PDE5 inhibitor Sildenafil , Tadalafil and Vardenafil , the asthma drug theophylline , tolterodine , a subgroup of benzodiazepines (the triazolobenzodiazepines, e.g. midazolam , triazolam , alprazolam ), the antiviral drug zidovudine and the proton pump blocker omeprazole . Also, calcium channel blockers are metabolized by the same system, it is why with clarithromycin in patients affected again and again to hypotensive crises come. With all of these drugs, the concentration in the blood should be monitored or the dose adjusted when treatment with clarithromycin is taken at the same time.

Besides clarithromycin, atazanavir , itraconazole or saquinavir also inhibit the enzyme CYP3A. If used at the same time, there may be bilateral interactions. Patients should be monitored accordingly for increased or prolonged effects.

Conversely, the simultaneous use of the antifungal drug fluconazole and the virostat ritonavir may increase the concentration of clarithromycin. However, due to the wide therapeutic range, that is, the large difference between the effective and toxic amount, no dose adjustment is necessary. Drugs that induce another enzyme system, the cytochrome P-450 system, such as nevirapine , rifampicin , rifabutin , rifapentine or efavirenz , can lead to an increased breakdown of clarithromycin. If used at the same time, it must be checked whether the success of the treatment may be jeopardized.

Use during pregnancy and breastfeeding

There is insufficient experience with the use of clarithromycin during pregnancy and breastfeeding. In any case, it passes into breast milk. When used during pregnancy - especially in the first three months - and breastfeeding, the potential benefits and risks should therefore be carefully weighed.

Special patient groups

Careful control of transaminases and bilirubin is required in patients with or suspected of having hepatic impairment . In the case of impaired renal function with a creatinine clearance below 30 ml / min, halving the standard dose is recommended. The application should then only take place under close medical supervision.

Adverse effects (side effects)

The gastrointestinal tract can often cause nausea, vomiting, a feeling of pressure in the upper abdomen, occasionally of a cramp-like nature, cramps, soft or dark stools or diarrhea. If the diarrhea is severe or persistent, pseudomembranous colitis should also be considered. Another common side effect is the impairment of the sense of smell or taste. Occasionally, hypersensitivity reactions with non-itchy skin reddening occur, but very rarely also with Stevens-Johnson syndrome , ringing in the ears ( tinnitus ) and hearing loss and seizures .

Rare side effects are mostly temporary liver dysfunction with biliary blockage ( cholestasis ) and jaundice ( jaundice ). However, fatal courses have also been described in seriously ill patients or the simultaneous use of other drugs. Changes in the excitability of the heart muscle, which are expressed in the ECG as a prolongation of the QT time and can lead to an acceleration of the heartbeat ( ventricular tachycardia ) and even tachycardiac arrhythmias, have also rarely been reported. In particular, caution should be exercised with previously exposed persons.

Impairments to the central nervous system , which manifest themselves in dizziness , confusion, anxiety, insomnia , nightmares , hallucinations and psychoses , as well as headaches, also occur "rarely". Inflammation and discoloration of the tongue, inflammation of the gums or the oral mucosa, fungal infections of the mucous membranes or discoloration of the teeth have also been observed rarely. The latter can usually be removed with a dental cleaning. After all, very rarely one has to deal with an acute inflammation of the pancreas ( pancreatitis ), an increased creatinine value possibly due to a kidney inflammation ( interstitial nephritis ), or a decrease in white blood cells ( leukopenia ) - then inflammation values ​​in the blood may no longer be meaningful - or the Calculate blood platelets ( thrombopenia ).

Pharmacological properties

Mechanism of action (pharmacodynamics)

Clarithromycin acts as a macrolide antibiotic by inhibiting protein formation ( protein biosynthesis ) in bacteria by binding to the 50s subunits of the bacterial ribosomes . This prevents activated amino acids from being transferred to the peptide chains . Thus, in contrast to the β-lactam antibiotics , which are derived from penicillin , it also works against wallless bacteria.

Bioavailability

After oral administration, there is unchanged migration through the stomach and rapid and even absorption in the small intestine. At the usual dosage, the plasma half-life in adults is between three and four hours. At average plasma concentrations, protein binding is 72%. It decreases with increasing concentrations. In all tissues except the central nervous tissue, concentrations are many times higher than in the blood.

metabolism

The enzyme CYP3A causes a strong conversion in the form of N- demethylation and oxidation . The most important metabolic product is the 14-hydroxy ( R ) - epimer of clarithromycin, which is also antibacterial. At higher doses, the metabolism decreases relatively, which indicates a saturation of the process. About three quarters of the total amount is excreted with the stool via the liver and bile. The remainder passes unchanged into the urine via the kidneys.

toxicology

In mice and rats, the LD _{50 was} 700 times the dose that is used therapeutically for humans. Symptoms of overdose were liver dysfunction in all species studied, which regressed after clarithromycin was discontinued.

Trade names

Monopreparations

Biaxin (D), Clamycin (CH), Claromycin (CH), Klacid (D, A, CH), Klaciped (CH), Mavid (D), Clarithrocin (CH), Clarilind (D), numerous generics (D, A , CH)

Combination preparations

ZacPac (D) (combination of pantoprazole , amoxicillin and clarithromycin)

Individual evidence

1. ↑ ^{a b} European Pharmacopoeia Commission (ed.): EUROPEAN PHARMACOPOE 5TH EDITION . tape 5.0-5.8 , 2006.
2. ↑ Agafonova, EV; Moshchenskiy, YV; Tkachenko, ML: DSC study and calculation of metronidazole and clarithromycin thermodynamic melting parameters for individual substances and for eutectic mixture in Thermochim. Acta 580 (2014) 1–6, doi: 10.1016 / j.tca.2014.01.018 .
3. ↑ ^{a b c d} Entry on clarithromycin in the ChemIDplus database of the United States National Library of Medicine (NLM) .
4. ↑ ^{a b} sheet clarithromycin at Sigma-Aldrich , accessed on 23 March 2011 ( PDF ).
5. ↑ Henrik Holtmann: Basics of medical microbiology, virology and hygiene / Henrik Holtmann; Monika Bobkowski , 1st ed., Elsevier, Urban & Fischer, Munich 2008, ISBN 978-3-437-42416-8 .
6. ↑ Bodmann, Grabein, Paul Ehrlich Society for Chemotherapy eV: Recommendations for calculated parenteral initial therapy for bacterial diseases - Update 2010, ISBN 978-3-00-031623-4 , p. 9.
7. ↑ Sonja Gandhi, Jamie L. Fleet, David G. Bailey, Eric McArthur, Ron Wald, Faisal Rehman, Amit X. Garg: Calcium-Channel Blocker – Clarithromycin Drug Interactions and Acute Kidney Injury. In: JAMA. , S., doi: 10.1001 / jama.2013.282426 .
8. ^ Lutz Hein: Pharmazeutische Zeitung online: Long QT syndrome: When the heart gets out of step . Retrieved February 14, 2012.
9. ^ Arizona Cert, Center for Education and Research on Therapeutics: http://qtdrugs.org/ . Retrieved February 14, 2012.
10. ↑ Red List online, as of October 2009.
11. ↑ AM comp. d. Switzerland, as of October 2009.
12. ↑ AGES-PharmMed, as of October 2009.

This article is about a health issue. It is not used for self-diagnosis and does not replace a diagnosis by a doctor. Please note the information on health issues !