Clarithromycin

Clarithromycin
Names
Trade namesBiaxin, others
IUPAC name
  • (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
Clinical data
Drug classMacrolide antibiotic[1]
Main usesStrep throat, pneumonia, skin infections, H. pylori infection, Lyme disease[2]
Side effectsNausea, vomiting, headaches, diarrhea[2]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • C (USA)
    B3 (Aus)
Routes of
use		By mouth, intravenous
Defined daily dose500 mg (by mouth)
1,000 mg (by injection)[3]
External links
AHFS/Drugs.comMonograph
MedlinePlusa692005
Legal
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetics
Bioavailability50%
Protein bindinglow binding
Metabolismliver
Elimination half-life3–4 h
Chemical and physical data
FormulaC38H69NO13
Molar mass747.964 g·mol−1
3D model (JSmol)
SMILES
  • 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
  • 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

Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections.[2] This includes strep throat, pneumonia, skin infections, H. pylori infection, and Lyme disease, among others.[2] Clarithromycin can be taken by mouth as a pill or liquid.[2]

Common side effects include nausea, vomiting, headaches, and diarrhea.[2] Severe allergic reactions are rare.[2] Liver problems have been reported.[2] It may cause harm if taken during pregnancy.[2] It is in the macrolide class and works by decreasing protein production of some bacteria.[2]

Clarithromycin was developed in 1980 and approved for medical use in 1990.[4][5] It is on the World Health Organization's List of Essential Medicines.[6] Clarithromycin is available as a generic medication.[2] The wholesale cost in the developing world is between US$0.13 and $0.79 per dose.[7] In the United States it is moderately expensive at $50–100 for a course of treatment.[8] It is made from erythromycin and is chemically known as 6-O-methylerythromycin.[9]

Medical uses

It is in the 'watch' group of the WHO AWaRe Classification.[10]

Clarithromycin is primarily used to treat a number of bacterial infections including pneumonia, Helicobacter pylori, and as an alternative to penicillin in strep throat.[2] Other uses include cat scratch disease and other infections due to bartonella, cryptosporidiosis, as a second line agent in Lyme disease and toxoplasmosis.[2] It may also be used to prevent bacterial endocarditis in those who cannot take penicillin.[2] It is effective against upper and lower respiratory tract infections, skin and soft tissue infections and helicobacter pylori infections associated with duodenal ulcers.

Spectrum of susceptibility

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:[11]

Aerobic Gram-positive bacteria

Aerobic Gram-negative bacteria

Anaerobic Gram-positive bacteria

Anaerobic Gram-negative bacteria

Dosage

The defined daily dose is 500 mg by mouth and 1,000 mg by injection.[3] The typical dose is 500 mg by mouth two times per day for 7 days.[1]

Contraindications

Side effects

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.[12]

Heart

In February 2018, the 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.[13]

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.[14]

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.[15] Some case reports suspect it of causing liver disease.[16]

Liver and kidney

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

Central nervous system

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

Infection

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.

Pregnancy and breastfeeding

Clarithromycin should not be used in pregnant women except in situations where no alternative therapy is appropriate.[11] 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.[11] For lactating mothers it is not known whether clarithromycin is excreted in human milk.[11]

Interactions

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.

A few of the common interactions are listed below.

Colchicine

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.[11]

Statins

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).[17]

Calcium channel blockers

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.[18] Administration of clarithromycin in combination with verapamil have been observed to cause low blood pressure, low heart rate, and lactic acidosis.[11]

Carbamazepine

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, nausea, as well as hyponatremia.[19]

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.[20] For example, clarithromycin may lead to decreased zidovudine concentrations.[21]

Mechanism of action

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.

Pharmacokinetics

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

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.[22]

History

Clarithromycin was invented by researchers at the Japanese drug company Taisho Pharmaceutical in 1980.[4] 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.

Society and culture

Cost

Clarithromycin is available as a generic medication.[2] The wholesale cost is between US$0.13 and $0.79 per dose.[7] In the United States it is moderately expensive at $50–100 for a course of treatment.[8]

  • Clarithromycin costs (US)
    Clarithromycin costs (US)
  • Clarithromycin prescriptions (US)
    Clarithromycin prescriptions (US)

Available forms

In the United States, clarithromycin is available as immediate release tablets, extended release tablets, and granules for oral suspension.[2]

Brand names

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

Manufacturers

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

References

  1. 1 2 "CLARITHROMYCIN oral - Essential drugs". medicalguidelines.msf.org. Archived from the original on 28 August 2021. Retrieved 17 August 2020.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 "Clarithromycin". The American Society of Health-System Pharmacists. Archived from the original on September 3, 2015. Retrieved September 4, 2015.
  3. 1 2 "WHOCC - ATC/DDD Index". www.whocc.no. Archived from the original on 17 September 2020. Retrieved 30 August 2020.
  4. 1 2 Greenwood, David (2008). Antimicrobial drugs : chronicle of a twentieth century medical triumph (1 ed.). Oxford: Oxford University Press. p. 239. ISBN 9780199534845. Archived from the original on 2016-03-05.
  5. ↑ Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 498. ISBN 9783527607495. Archived from the original on 2020-07-28. Retrieved 2019-03-02.
  6. ↑ 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.
  7. 1 2 "Clarithromycin". International Drug Price Indicator Guide. Archived from the original on 2 July 2018. Retrieved 7 September 2015.
  8. 1 2 Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. p. 92. ISBN 9781284057560.
  9. ↑ Kirst, Herbert A. (2012). Macrolide Antibiotics (2 ed.). Basel: Birkhäuser Basel. p. 53. ISBN 9783034881050. Archived from the original on 2016-03-05.
  10. ↑ Zanichelli, Veronica; Sharland, Michael; Cappello, Bernadette; Moja, Lorenzo; Getahun, Haileyesus; Pessoa-Silva, Carmem; Sati, Hatim; van Weezenbeek, Catharina; Balkhy, Hanan; Simão, Mariângela; Gandra, Sumanth; Huttner, Benedikt (1 April 2023). "The WHO AWaRe (Access, Watch, Reserve) antibiotic book and prevention of antimicrobial resistance". Bulletin of the World Health Organization. 101 (4): 290–296. doi:10.2471/BLT.22.288614. ISSN 0042-9686. Archived from the original on 7 May 2023. Retrieved 17 November 2023.
  11. 1 2 3 4 5 6 7 8 9 10 11 12 "BIAXIN® Filmtab® (clarithromycin tablets, USP) BIAXIN® XL Filmtab® (clarithromycin extended-release tablets) BIAXIN® Granules (clarithromycin for oral suspension, USP)" (PDF). November 2, 2015. Archived (PDF) from the original on August 24, 2015. Retrieved November 2, 2015.
  12. ↑ "Clarithromycin Side Effects in Detail - Drugs.com". Drugs.com. Archived from the original on 2017-08-19. Retrieved 2017-08-18.
  13. ↑ "Safety Alerts for Human Medical Products - Clarithromycin (Biaxin): Drug Safety Communication - Potential Increased Risk of Heart Problems or Death in Patients With Heart Disease". FDA. Archived from the original on 24 April 2018. Retrieved 24 February 2018.
  14. ↑ Yamaguchi S, Kaneko Y, Yamagishi T, et al. [Clarithromycin-induced torsades de pointes]. Nippon Naika Gakkai Zasshi. 2003;92(1):143–5.
  15. ↑ 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.
  16. ↑ 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.
  17. ↑ 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.
  18. ↑ Gandhi S, Fleet JL, Bailey DG, McArthur E, Wald R, Rehman F, Garg AX (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.
  19. ↑ Gélisse P, Hillaire-Buys D, Halaili E, Jean-Pastor MJ, Vespignan H, Coubes P, Crespel A (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.
  20. ↑ Sekar VJ, Spinosa-Guzman S, De Paepe E, De Pauw M, Vangeneugden T, Lefebvre E, Hoetelmans RM (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.
  21. ↑ 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.
  22. ↑ 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.
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