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Clarithromycin

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Clarithromycin
Clinical data
Trade namesBiaxin, others
Other names6-O-methylerythromycin A
AHFS/Drugs.comMonograph
MedlinePlusa692005
License data
Pregnancy
category
  • AU: B3
Routes of
administration		By mouth, intravenous
Drug classMacrolides
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • US: WARNING[1]Rx-only
  • EU: Rx-only[2]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability50%
Protein bindinglow binding
MetabolismLiver
Elimination half-life3–4 h
Identifiers
  • (3R,4S,5S,6R,7R,9R,11S,12R,13S,14R)-6-{[(2S,3R,4S,6R) -4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy} -14-ethyl-12,13-dihydroxy-4-{[(2R,4R,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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.119.644 Edit this at Wikidata
Chemical and physical data
FormulaC38H69NO13
Molar mass747.964 g·mol−1
3D model (JSmol)
  • CC[C@@H]1[C@@]([C@@H]([C@H](C(=O)[C@@H](C[C@@]([C@@H]([C@H]([C@@H]([C@H](C(=O)O1)C)O[C@H]2C[C@@]([C@H]([C@@H](O2)C)O)(C)OC)C)O[C@H]3[C@@H]([C@H](C[C@H](O3)C)N(C)C)O)(C)OC)C)C)O)(C)O
  • InChI=1S/C38H69NO13/c1-15-26-38(10,45)31(42)21(4)28(40)19(2)17-37(9,47-14)33(52-35-29(41)25(39(11)12)16-20(3)48-35)22(5)30(23(6)34(44)50-26)51-27-18-36(8,46-13)32(43)24(7)49-27/h19-27,29-33,35,41-43,45H,15-18H2,1-14H3/t19-,20-,21+,22+,23-,24+,25+,26-,27+,29-,30+,31-,32+,33-,35+,36-,37-,38-/m1/s1 ☒N
  • Key:AGOYDEPGAOXOCK-KCBOHYOISA-N ☒N
 ☒NcheckY (what is this?)  (verify)

Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections.[3] This includes strep throat, pneumonia, skin infections, H. pylori infection, and Lyme disease, among others.[3] Clarithromycin can be taken by mouth as a tablet or liquid or can be infused intravenously.[3]

Common side effects include nausea, vomiting, headaches, and diarrhea.[3] Severe allergic reactions are rare.[3] Liver problems have been reported.[3] It may cause harm if taken during pregnancy.[3] It is in the macrolide class and works by slowing down bacterial protein synthesis.[3] Clarithromycin resistance is already a major challenge to healthcare systems and such resistance is spreading, leading to recommendations to test the susceptibility of pathogenic organisms to the antibiotic before commencing clarithromycin therapy.[4]

Clarithromycin was developed in 1980 and approved for medical use in 1990.[5][6] It is on the World Health Organization's List of Essential Medicines.[7] Clarithromycin is available as a generic medication.[3] It is made from erythromycin and is chemically known as 6-O-methylerythromycin.[8]

Medical uses

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Antibiotic

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Clarithromycin is primarily used to treat a number of bacterial infections including pneumonia, Helicobacter pylori, and as an alternative to penicillin in strep throat.[3] Other uses include cat scratch disease and other infections due to Bartonella, cryptosporidiosis, as a second line agent in Lyme disease and toxoplasmosis.[3] It may also be used to prevent bacterial endocarditis in those who cannot take penicillin.[3] It is effective against upper and lower respiratory tract infections, skin and soft tissue infections and helicobacter pylori infections associated with duodenal ulcers.[citation needed]

Spectrum of bacterial susceptibility

[edit]

Aerobic Gram-positive bacteria

Aerobic Gram-negative bacteria

Helicobacter

Mycobacteria

Mycobacterium avium complex consisting of:

Other bacteria

Safety and effectiveness of clarithromycin in treating clinical infections due to the following bacteria have not been established in adequate and well-controlled clinical trials:[9]

Aerobic Gram-positive bacteria

Aerobic Gram-negative bacteria

Anaerobic Gram-positive bacteria

Anaerobic Gram-negative bacteria

Idopathic hypersomnia

[edit]

Clarithromycin has been researched as a potential treatment for idiopathic hypersomnia (IH) in adults, but the evidence is limited. A 2021 Cochrane study determined that the evidence is inadequate to definitively determine the efficacy of clarithromycin in the management of idiopathic hypersomnia.[10] The American Academy of Sleep Medicine's 2021 clinical practice guidelines conditionally suggested its use, especially for those who don't respond to other therapies.[11][12]

Contraindications

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Side effects

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The most common side effects are gastrointestinal: diarrhea (3%), nausea (3%), abdominal pain (3%), and vomiting (6%). It also can cause headaches, insomnia, and abnormal liver function tests. Allergic reactions include rashes and anaphylaxis. Less common side effects (<1%) include extreme irritability, hallucinations (auditory and visual), dizziness/motion sickness, and alteration in senses of smell and taste, including a metallic taste. Dry mouth, panic attacks, and nightmares have also been reported, albeit less frequently.[13]

Cardiac

[edit]

In February 2018, the US Food and Drug Administration (FDA) issued a safety communication warning with respect to an increased risk for heart problems or death with the use of clarithromycin, and has recommended that alternative antibiotics be considered in those with heart disease.[14]

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.[15]

In one trial, the use of short-term clarithromycin treatment was correlated with an increased incidence of deaths classified as sudden cardiac deaths in stable coronary heart disease patients not using statins.[16]

Liver and kidney

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Clarithromycin has been known to cause jaundice, cirrhosis, and kidney problems, including kidney failure.[citation needed] Some case reports suspect it of causing liver disease.[17]

Central nervous system

[edit]

Common adverse effects of clarithromycin in the central nervous system include dizziness, headaches. Rarely, it can cause ototoxicity, delirium and mania.[citation needed]

Infection

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A risk of oral candidiasis and vaginal candidiasis, due to the elimination of the yeast's natural bacterial competitors by the antibiotic, has also been noted.[citation needed]

Pregnancy and breastfeeding

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Clarithromycin should not be used in pregnant women except in situations where no alternative therapy is appropriate.[9] Clarithromycin can cause potential hazard to the fetus hence should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.[9] For lactating mothers it is not known whether clarithromycin is excreted in human milk.[9]

Interactions

[edit]

Clarithromycin inhibits a liver enzyme, CYP3A4, involved in the metabolism of many other commonly prescribed drugs. Taking clarithromycin with other medications that are metabolized by CYP3A4 may lead to unexpected increases or decreases in drug levels.[18][19]

A few of the common interactions are listed below.

Colchicine

[edit]

Clarithromycin has been observed to have a dangerous interaction with colchicine as the result of inhibition of CYP3A4 metabolism and P-glycoprotein transport. Combining these two drugs may lead to fatal colchicine toxicity, particularly in people with chronic kidney disease.[9]

Statins

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Taking clarithromycin concurrently with certain statins (a class of drugs used to reduce blood serum cholesterol levels) increases the risk of side effects, such as muscle aches and muscle break down (rhabdomyolysis).[20]

Calcium channel blockers

[edit]

Concurrent therapy with calcium channel blocker may increase risk of low blood pressure, kidney failure, and death, compared to pairing calcium channel blockers with azithromycin, a drug similar to clarithromycin but without CYP3A4 inhibition.[21] Administration of clarithromycin in combination with verapamil have been observed to cause low blood pressure, low heart rate, and lactic acidosis.[9]

Carbamazepine

[edit]

Clarithromycin may double the level of carbamazepine in the body by reducing its clearance, which may lead to toxic symptoms of carbamazepine, such as double vision, loss of voluntary body movement, and nausea, as well as hyponatremia.[22]

HIV medications

[edit]

Depending on the combination of medications, clarithromycin therapy could be contraindicated, require changing doses of some medications, or be acceptable without dose adjustments.[23] For example, clarithromycin may lead to decreased zidovudine concentrations.[24]

Mechanism of action

[edit]

Clarithromycin prevents bacteria from multiplying by acting as a protein synthesis inhibitor. It binds to 23S rRNA, a component of the 50S subunit of the bacterial ribosome, thus inhibiting the translation of peptides.[citation needed]

Pharmacokinetics

[edit]

Unlike erythromycin, clarithromycin is acid-stable, so can be taken orally without having to be protected from gastric acids. It is readily absorbed, and diffuses 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 are 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 the Mycobacterium 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. Its elimination half-life is about 3 to 4 hours with 250 mg administered every 12 h, but increased to 5 to 7 h with 500 mg administered every 8 to 12 h. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days.[25]

History

[edit]

Clarithromycin was invented by researchers at the Japanese drug company Taisho Pharmaceutical in 1980.[5] 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 stomachache. 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.[26]

Society and culture

[edit]
A pack of clarithromycin tablets manufactured by Taisho Pharmaceutical

Available forms

[edit]

Clarithromycin is available as a generic medication.[3] In the United States, clarithromycin is available as immediate-release tablets, extended-release tablets, and granules for oral suspension.[3]

Brand names

[edit]

Clarithromycin is available under several brand names in many different countries, including Biaxin, Crixan, Claritron, Clarihexal, Clacid, Claritt, Clacee, Clarac, Clariwin, Claripen, Clarem, Claridar, Cloff, Fromilid, Infex, Kalixocin, Karicin, Klaricid, Klaridex, Klacid, Klaram, Klabax, Klerimed, MegaKlar, Monoclar, Resclar, Rithmo, Truclar, Vikrol and Zeclar.[citation needed]

Manufacturers

[edit]

In the UK the drug product is manufactured in generic form by a number of manufacturers including Somex Pharma, Ranbaxy, Aptil and Sandoz.

References

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  1. ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 October 2023.
  2. ^ "Active substance: clarithromycin" (PDF). List of nationally authorised medicinal products. European Medicines Agency. 10 December 2020.
  3. ^ a b c d e f g h i j k l m n "Clarithromycin". The American Society of Health-System Pharmacists. Archived from the original on 3 September 2015. Retrieved 4 September 2015.
  4. ^ Mommersteeg MC, Nieuwenburg SA, Wolters LM, Roovers BH, van Vuuren HA, Verhaar AP, et al. (November 2023). "The use of non-invasive stool tests for verification of Helicobacter pylori eradication and clarithromycin resistance". United European Gastroenterol J. 11 (9): e894-903. doi:10.1002/ueg2.12473. PMC 10637120. PMID 37854002.
  5. ^ a b Greenwood D (2008). Antimicrobial drugs : chronicle of a twentieth century medical triumph (1 ed.). Oxford: Oxford University Press. p. 239. ISBN 978-0-19-953484-5. Archived from the original on 5 March 2016.
  6. ^ Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 498. ISBN 978-3-527-60749-5.
  7. ^ World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  8. ^ Kirst HA (2012). Macrolide Antibiotics (2 ed.). Basel: Birkhäuser Basel. p. 53. ISBN 978-3-0348-8105-0. Archived from the original on 5 March 2016.
  9. ^ a b c d e f g h i j k l "Biaxin Filmtab (clarithromycin tablets, USP) Biaxin XL Filmtab (clarithromycin extended-release tablets) Biaxin Granules (clarithromycin for oral suspension, USP)" (PDF). 2 November 2015. Archived (PDF) from the original on 24 August 2015. Retrieved 2 November 2015.
  10. ^ Trotti LM, Becker LA, Friederich Murray C, Hoque R (May 2021). "Medications for daytime sleepiness in individuals with idiopathic hypersomnia". The Cochrane Database of Systematic Reviews. 2021 (5): CD012714. doi:10.1002/14651858.CD012714.pub2. PMC 8144933. PMID 34031871. There is insufficient evidence to conclude whether clarithromycin is effective for the treatment of idiopathic hypersomnia.
  11. ^ Maski K, Trotti LM, Kotagal S, Robert Auger R, Rowley JA, Hashmi SD, et al. (September 2021). "Treatment of central disorders of hypersomnolence: an American Academy of Sleep Medicine clinical practice guideline". Journal of Clinical Sleep Medicine. 17 (9): 1881–1893. doi:10.5664/jcsm.9328. PMC 8636351. PMID 34743789. Recommendation 9: We suggest that clinicians use clarithromycin (vs no treatment) for the treatment of idiopathic hypersomnia in adults. (CONDITIONAL)
  12. ^ "Treatment of Central Disorders of Hypersomnolence: An American Academy of Sleep Medicine Clinical Practice Guideline - Guidelines at a Glance" (PDF). American Academy of Sleep Medicine. 2021. Archived (PDF) from the original on 25 February 2024. Retrieved 25 February 2024.
  13. ^ "Clarithromycin Side Effects in Detail". Drugs.com. Archived from the original on 19 August 2017. Retrieved 18 August 2017.
  14. ^ "Safety Alerts for Human Medical Products - Clarithromycin (Biaxin): Drug Safety Communication - Potential Increased Risk of Heart Problems or Death in Patients With Heart Disease". U.S. Food and Drug Administration (FDA). Archived from the original on 24 April 2018. Retrieved 24 February 2018.
  15. ^ Yamaguchi S, Kaneko Y, Yamagishi T, et al. [Clarithromycin-induced torsades de pointes]. Nippon Naika Gakkai Zasshi. 2003;92(1):143–5.
  16. ^ Winkel P, Hilden J, Fischer Hansen J, Hildebrandt P, Kastrup J, Kolmos HJ, et al. (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): 63–7. doi:10.1159/000324533. PMID 21447948. S2CID 11873791.
  17. ^ Tietz A, Heim MH, Eriksson U, Marsch S, Terracciano L, Krähenbühl S (January 2003). "Fulminant liver failure associated with clarithromycin". The Annals of Pharmacotherapy. 37 (1): 57–60. doi:10.1345/1542-6270(2003)037<0057:flfawc>2.0.co;2. PMID 12503933.
  18. ^ Hougaard Christensen MM, Bruun Haastrup M, Øhlenschlaeger T, Esbech P, Arnspang Pedersen S, Bach Dunvald AC, et al. (April 2020). "Interaction potential between clarithromycin and individual statins-A systematic review". Basic Clin Pharmacol Toxicol. 126 (4): 307–317. doi:10.1111/bcpt.13343. PMID 31628882.
  19. ^ Herdegen T, Cascorbi I (December 2023). "Drug Interactions of Tetrahydrocannabinol and Cannabidiol in Cannabinoid Drugs: Recommendations for Clinical Practice". Dtsch Arztebl Int. 120 (49): 833–840. doi:10.3238/arztebl.m2023.0223. PMC 10824494. PMID 37874128. S2CID 264438050.
  20. ^ Patel AM, Shariff S, Bailey DG, Juurlink DN, Gandhi S, Mamdani M, et al. (June 2013). "Statin toxicity from macrolide antibiotic coprescription: a population-based cohort study". Annals of Internal Medicine. 158 (12): 869–76. doi:10.7326/0003-4819-158-12-201306180-00004. PMID 23778904. S2CID 21222679.
  21. ^ Gandhi S, Fleet JL, Bailey DG, McArthur E, Wald R, Rehman F, et al. (December 2013). "Calcium-channel blocker-clarithromycin drug interactions and acute kidney injury". JAMA. 310 (23): 2544–53. doi:10.1001/jama.2013.282426. PMID 24346990.
  22. ^ Gélisse P, Hillaire-Buys D, Halaili E, Jean-Pastor MJ, Vespignan H, Coubes P, et al. (November 2007). "[Carbamazepine and clarithromycin: a clinically relevant drug interaction]". Revue Neurologique. 163 (11): 1096–9. doi:10.1016/s0035-3787(07)74183-8. PMID 18033049.
  23. ^ Sekar VJ, Spinosa-Guzman S, De Paepe E, De Pauw M, Vangeneugden T, Lefebvre E, et al. (January 2008). "Darunavir/ritonavir pharmacokinetics following coadministration with clarithromycin in healthy volunteers". Journal of Clinical Pharmacology. 48 (1): 60–5. doi:10.1177/0091270007309706. PMID 18094220. S2CID 38368595.
  24. ^ Polis MA, Piscitelli SC, Vogel S, Witebsky FG, Conville PS, Petty B, et al. (August 1997). "Clarithromycin lowers plasma zidovudine levels in persons with human immunodeficiency virus infection". Antimicrobial Agents and Chemotherapy. 41 (8): 1709–14. doi:10.1128/AAC.41.8.1709. PMC 163990. PMID 9257746.
  25. ^ Ferrero JL, Bopp BA, Marsh KC, Quigley SC, Johnson MJ, Anderson DJ, et al. (1990). "Metabolism and disposition of clarithromycin in man". Drug Metabolism and Disposition. 18 (4): 441–6. PMID 1976065.
  26. ^ Vieweg WV, Hancox JC, Hasnain M, Koneru JN, Gysel M, Baranchuk A (August 2013). "Clarithromycin, QTc interval prolongation and torsades de pointes: the need to study case reports". Therapeutic Advances in Infectious Disease. 1 (4): 121–138. doi:10.1177/2049936113497203. PMC 4040724. PMID 25165548.
[edit]
  • US patent 4331803, Watanabe Y, Morimoto S, Omura S, "Novel erythromycin compounds", issued 1981-05-19, assigned to Taisho Pharmaceutical 
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