Clarithromycin

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Clarithromycin
Clarithromycin structure.svg
Clarithromycin ball-and-stick.png
Systematic (IUPAC) name
(3R,4S,5S,6R,7R,9R,11S,12R,13S,14S)-6-{[(2S,3R,4S,6R) -4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy} -14-ethyl-12,13-dihydroxy-4-{[(2R,4S,5S,6S)-5-hydroxy -4-methoxy-4,6-dimethyloxan-2-yl]oxy}-7 -methoxy-3,5,7,9,11,13-hexamethyl -1-oxacyclotetradecane-2,10-dione
Clinical data
Trade names Biaxin
AHFS/Drugs.com monograph
MedlinePlus a692005
Pregnancy cat. C (USA)
B3 (Aus)
Legal status prescription only
Routes oral, intravenous
Pharmacokinetic data
Bioavailability 50%
Protein binding low binding
Metabolism hepatic
Half-life 3-4 h
Identifiers
CAS number 81103-11-9 YesY
ATC code J01FA09
PubChem CID 5284534
DrugBank DB01211
ChemSpider 21112273 N
UNII H1250JIK0A YesY
KEGG D00276 YesY
ChEMBL CHEMBL1741 N
Chemical data
Formula C38H69NO13 
Mol. mass 747.953 g/mol
 N (what is this?)  (verify)

Clarithromycin (6-O-methyl erythromycin) is a macrolide antibiotic used to treat bacterial infections, particularly respiratory infections (pharyngitis, tonsillitis, sinusitis, acute exacerbation of chronic obstructive pulmonary disease, pneumonia[1] ), skin infections and lyme disease.[2] In addition, it is used to treat Helicobacter pylori, a cause of gastritis,[3]

Recently there has been research towards whether Clarithromycin can be used to effectively treat idiopathic hypersomnia.[4]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[5]

Side effects[edit]

The most common (>1%) side effects are gastrointestinal: diarrhea, nausea, abdominal pain and vomiting. It also can cause headaches, insomnia, and abnormal liver function tests. Allergic reactions include rashes and anaphylaxis. Less common side effects include extreme irritability, hallucinations (auditory and visual), dizziness/motion sickness, alteration in senses of smell and taste, including a metallic taste. Dry mouth, panic attacks and nightmares have also been reported, albeit less frequently.

Full list of known side effects: http://www.drugs.com/sfx/clarithromycin-side-effects.html

Clarithromycin may cause positive results on urine drug screens for cocaine.[citation needed]

Cardiac[edit]

Clarithromycin can lead to a prolonged QT interval. In patients with long QT syndrome, cardiac disease, or patients taking other QT prolonging medications, this can increase risk for life threatening arrhythmias.[6]

Liver and kidney[edit]

Clarithromycin has been known to cause jaundice, cirrhosis, and kidney problems, including renal failure.

Central nervous system[edit]

Common (>1%) Adverse effects of clarithromycin in the central nervous system include dizziness, headaches. Rarely, it can cause ototoxicity, delirium and mania.

Infection[edit]

A risk of oral candidiasis, due to the elimination of the yeast's natural bacterial competitors by the antibiotic is also incurred.

Pregnancy[edit]

Clarithromycin has been shown to induce miscarriage in animals and a recent study found an increased risk of miscarriage in women exposed to Clarithromycin in early pregnancy.[7]

In the CLARICOR Trial, the use of short-term clarithromycin treatment correlated with an increased incidence of deaths classified as sudden cardiac deaths in stable coronary heart disease patients not using statins.[8] Some case reports suspect it of causing liver disease.[9]

Interactions[edit]

Clarithromycin inhibits an important enzyme, CYP3A4. This enzyme is involved in the metabolism of many other commonly prescribed drugs. Taking clarithromycin with these other drugs may lead to unexpected increases or decreases in drug levels. Complete list of drugs metabolized through CYP3A4 available here:

Statins

When taken along with some certain statins (a class of drugs used to reduce blood serum cholesterol levels), there is an increased risk of side effects from the statins including muscle aches and rhabdomyolysis.[10]

Calcium Channel blockers<

Patients on a calcium channel blocker who were also given clarithromycin have a higher risk of critically low blood pressure, kidney failure and death, compared to pairing calcium channel blockers with azithromycin, a drug similar to clarithromycin but without CYP3A4 inhibition.[11]

Ergotamines When these migraine medications are taken with Clarithromycin, there is increased risk of acute ergot toxicity including vasospasm and ischemia of the extremities.[12]

Carbamazepine Clarithromycin almost doubles the level of carbamazepine in body by reducing its clearance, inducing toxic symptoms of carbamazepine, including diplopia and nausea, as well as hyponatremia (reduced level of sodium in serum).

HIV medications Depending on the combination of medications, Clarithromycin therapy could be contraindicated, require changing doses of some medications, or be acceptable without dose adjustments.[13]

Buspirone It can also cause serotonin syndrome symptoms when taken in conjunction with buspirone.

Contraindications[edit]

Clarithromycin should be used with caution if the patient has liver or kidney disease, certain heart problems or takes drugs that might cause certain heart problems (e.g., QT prolongation or bradycardia), or an electrolyte imbalance (e.g., low potassium or sodium levels).

Spectrum of resistance and susceptibility[edit]

Clarithromycin covers gram positive bacteria and atypical bacteria. It has been effective in treating bacterial infections including tonsillitis, sinusitis, pneumonia, and others. The following represents susceptibility data for a few medically significant microorganisms.

  • Haemophilus influenzae: 0.008 μg/mL - >256 μg/mL
  • Streptococcus pneumoniae: 0.001 μg/mL - >256 μg/mL
  • Streptococcus pyogenes: 0.001 μg/mL - >128 μg/mL

[14]

Many Gram-positive microbes quickly develop resistance to clarithromycin after standard courses of treatment, most frequently via acquisition of the erm(B) gene, which confers high-level resistance to all macrolides.[15]

Its antibacterial spectrum is the same as erythromycin, but it is also active against Mycobacterium avium complex MAV, M. leprae and atypical mycobacteria.

Mechanism of action[edit]

Clarithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the subunit 50S of the bacterial ribosome and thus inhibits the translation of peptides.

Pharmacokinetics[edit]

Unlike erythromycin, clarithromycin is acid-stable, so can be taken orally without being protected from gastric acids. It is readily absorbed, and diffused into most tissues and phagocytes. Due to the high concentration in phagocytes, clarithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of clarithromycin are released; its concentration in the tissues can be over 10 times higher than in plasma. Highest concentrations were found in liver, lung tissue and stool.

Metabolism[edit]

Clarithromycin has a fairly rapid first-pass metabolism in the liver. Its major metabolites include an inactive metabolite, N-desmethylclarithromycin and an active metabolite, 14-(R)-hydroxyclarithromycin. Compared to clarithromycin, 14-(R)-hydroxyclarithromycin is less potent against Mycobacterial tuberculosis and Mycobacterial avium complex. Clarithromycin (20%-40%) and its active metabolite (10%-15%) are excreted in urine. Of all the drugs in its class, clarithromycin has the best bioavailability at 50%, which makes it amenable to oral administration. The elimination half-life of Clarithromycin is 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. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days.[16]

History[edit]

Clarithromycin was invented by researchers at the Japanese drug company Taisho Pharmaceutical in the 1970s. The product emerged through efforts to develop a version of the antibiotic erythromycin that did not experience acid instability in the digestive tract, causing side effects, such as nausea and stomach ache. Taisho filed for patent protection for the drug around 1980 and subsequently introduced a branded version of its drug, called Clarith, to the Japanese market in 1991. In 1985, Taisho partnered with the American company Abbott Laboratories for the international rights, and Abbott also gained FDA approval for Biaxin in October 1991. The drug went generic in Europe in 2004 and in the US in mid-2005.

Brand names[edit]

In Pakistan it is available under the brand name Claritek™, and is manufactured and marketed by Getz Pharmaceuticals. Its use is approved for upper and lower RTI, H. pylori, and, skin and soft tissue infections. In Bangladesh, it is available as Claricin, produced by the Acme Laboratories Ltd. In the United States, generic clarithromycin is available from Andrx, Genpharm, Ivax, Ranbaxy Laboratories, Roxane, Sandoz, Teva and Wockhardt. It is also used as part of a combination therapy to treat Helicobacter pylori. In the Middle East, it is available as Claridar, produced by Dar Al Dawa. In India, Acnesol-CL gel, containing 1% clarithromycin, marketed by Systopic, is used to treat acne vulgaris.

Clarithromycin is available under several brand names, for example Binoclar, Bioclar, Biaxin, Crixan, Clarihexal, Clacid, Claritt, Clacee, Clarac, Clariwin, Claripen, Clarem, Claridar, Fromilid, Infex, Klaricid, Klacid, Klaram, Klabax, Monoclar, Resclar, Ranbaxy, Truclar, Vikrol.

References[edit]

  1. ^ 1. American Thoracic Society, “Guidelines for the Initial Management of Adults With Community-Acquired Pneumonia: Diagnosis, Assessment of Severity, and Initial Antimicrobial Therapy,” Am Rev Respir Dis, 1993, 148(5):1418-26. [PubMed 8239186]
  2. ^ 40. Wormser GP, Dattwyler RJ, Shapiro ED, et al. The Clinical Assessment, Treatment, and Prevention of Lyme Disease, Human Granulocytic Anaplasmosis, and Babesiosis: Clinical Practice Guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2006;43(9):1089-134; published erratum appears in Clin Infect Dis, 2007;45(7):941. [PubMed 17029130] Rev Respir Dis, 1993, 148(5):1418-26. [PubMed 8239186]
  3. ^ Chey WD and Wong B, “American College of Gastroenterology Guideline on the Management of Helicobacter pylori Infection,” Am J Gastroenterol, 2007 102(8):1808-25. [PubMed 17608775]
  4. ^ Lynn Marie Trotti, MD (June 15, 2010). "Clarithromycin for the Treatment of Primary Hypersomnia". Emory University - Georgia Research Alliance. ClinicalTrials.gov. 
  5. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  6. ^ Yamaguchi S, Kaneko Y, Yamagishi T, et al. [Clarithromycin-induced torsades de pointes]. Nippon Naika Gakkai Zasshi. 2003;92(1):143-5.
  7. ^ Andersen JT, Petersen M, Jimenez-Solem E, Broedbaek K, Andersen NL, et al. (2013) Clarithromycin in Early Pregnancy and the Risk of Miscarriage and Malformation: A Register Based Nationwide Cohort Study. PLoS ONE 8(1): e53327. doi:10.1371/journal.pone.0053327
  8. ^ Winkel, P.; Hilden, J. R.; Fischer Hansen, J. R.; Hildebrandt, P.; Kastrup, J.; Kolmos, H. J. R.; Kjøller, E.; Jespersen, C. M.; Gluud, C.; Jensen, G. B.; Claricor Trial, G. (2011). "Excess Sudden Cardiac Deaths after Short-Term Clarithromycin Administration in the CLARICOR Trial: Why is This So, and Why Are Statins Protective". Cardiology 118 (1): 63–67. doi:10.1159/000324533. PMID 21447948.  edit
  9. ^ Tietz, A.; Heim, M. H.; Eriksson, U.; Marsch, S.; Terracciano, L.; Krähenbühl, S. (2003). "Fulminant liver failure associated with clarithromycin". The Annals of Pharmacotherapy 37 (1): 57–60. PMID 12503933.  edit
  10. ^ Patel AM, Shariff S, Bailey DG, et al. Statin toxicity from macrolide antibiotic coprescription: a population-based cohort study. Ann Intern Med. 2013;158(12):869-76.
  11. ^ [1]
  12. ^ Demir S, Akin S, Tercan F, Ariboğan A, Oğuzkurt L. Ergotamine-induced lower extremity arterial vasospasm presenting as acute limb ischemia. Diagn Interv Radiol. 2010;16(2):165-7.
  13. ^ Sekar VJ, Spinosa-guzman S, De paepe E, et al. Darunavir/ritonavir pharmacokinetics following coadministration with clarithromycin in healthy volunteers. J Clin Pharmacol. 2008;48(1):60-5.
  14. ^ http://www.toku-e.com/Assets/MIC/Clarithromycin%20USP.pdf
  15. ^ Malhotra-Kumar, S.; Lammens, C.; Coenen, S.; Van Herck, K.; Goossens, H. (2007). "Effect of azithromycin and clarithromycin therapy on pharyngeal carriage of macrolide-resistant streptococci in healthy volunteers: A randomised, double-blind, placebo-controlled study". The Lancet 369 (9560): 482–490. doi:10.1016/S0140-6736(07)60235-9. PMID 17292768.  edit
  16. ^ Ferrero JL, Bopp BA, Marsh KC, et al. Metabolism and Disposition of Clarithromycin in Man. Drug Metab Dispos. 1990;18(4):441-446. [PubMed 1976065]

External links[edit]