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Azithromycin

 

Azithromycin

Azithromycin
Systematic (IUPAC) name
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-15-oxo- 11-{[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy}-1-oxa-6-azacyclopentadec-13-yl 2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranoside
Clinical data
Trade names Zithromax, Azithrocin, others
AHFS/Drugs.com
MedlinePlus
Licence data US FDA:
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration
Oral (capsule, tablet or suspension), intravenous, ophthalmic
Pharmacokinetic data
Bioavailability 38% for 250 mg capsules
Metabolism Hepatic
Biological half-life

11–14 h (single dose)

68 h (multiple dosing)
Excretion Biliary, renal (4.5%)
Identifiers
CAS Registry Number  Y
ATC code J01 S01
PubChem CID:
IUPHAR/BPS
DrugBank  Y
ChemSpider  Y
UNII  Y
KEGG  Y
ChEBI  Y
ChEMBL  Y
NIAID ChemDB
Synonyms 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A
Chemical data
Formula C38H72N2O12
Molecular mass 748.984 g·mol−1
 Y   

Azithromycin is an health system.[4] It is available as a generic medication.[5] The wholesale cost is about 0.18 to 2.98 USD per dose.[6] In the United States it is about 33 USD for a course of treatment.[1]

Contents

  • Medical uses 1
    • Spectrum of bacterial susceptibility 1.1
  • Adverse effects 2
  • Mechanism of action 3
  • Pharmacokinetics 4
  • Metabolism 5
  • History 6
  • Society and culture 7
    • Names 7.1
    • Cost 7.2
    • Available forms 7.3
    • Usage 7.4
  • References 8
  • External links 9

Medical uses

Azithromycin is used to treat many different infections, including:

  • Prevention and treatment of acute bacterial exacerbations of chronic obstructive pulmonary disease due to H. influenzae, M. catarrhalis, or S. pneumoniae. The benefits of long-term prophylaxis must be weighed on a patent-by-patient basis against the risk of cardiovascular and other adverse effects.[7]
  • Acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae. Other agents, such as amoxicillin/clavulanate are generally preferred, however.[8][9]
  • Community-acquired pneumonia' due to C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae[10]
  • Acute otitis media caused by H. influenzae, M. catarrhalis or S. pneumoniae. Azithromycin is not, however, a first-line agent for this condition. Amoxicillin or another beta lactam antibiotic is generally preferred.[11]
  • Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy[12]
  • Uncomplicated skin and skin structure infections due to S. aureus, S. pyogenes, or S. agalactiae
  • Urethritis and cervicitis due to C. trachomatis or N. gonorrhoeae
  • Genital ulcer disease (chancroid) in men due to H. ducreyi
  • In combination with ceftriaxone, azithromycin is part of the United States Centers for Disease Control-recommended regimen for the treatment of gonorrhea. Azithromycin is active as monotherapy in most cases, but the combination with ceftriaxone is recommended based on the relatively low barrier to resistance development in gonococci.[13]

Spectrum of bacterial susceptibility

Azithromycin has relatively broad but shallow antibacterial activity. It inhibits some Gram-positive bacteria, some Gram-negative bacteria, and many atypical bacteria.

A strain of gonnorhea reported to be highly resistant to azithromycin was found in the population in 2015. Neisseria gonorrhoeae is normally susceptible[14] but is not widely used as monotherapy due to a low barrier to resistance development.[15][16]

Aerobic and facultative Gram-positive microorganisms

Aerobic and facultative Gram-negative microorganisms

Anaerobic microorganisms

Other microorganisms

Adverse effects

Most common side effects are diarrhea (5%), nausea (3%), abdominal pain (3%), and vomiting. Fewer than 1% of patients stop taking the drug due to side effects. Nervousness, dermatologic reactions, and anaphylaxis have been reported. As with all antimicrobial agents, pseudomembranous colitis can occur during and up to several weeks after azithromycin therapy. In the past, physicians cautioned women that antibiotics can reduce the effectiveness of oral contraceptives. However, antibiotics, with the exception of rifampin and rifabutin, do not affect the effectiveness of hormonal contraceptives.[17] This change in advice comes because to date, no evidence conclusively demonstrates antibiotics (other than rifampicin or rifabutin) affect these contraceptives.

Occasionally, patients have developed cholestatic hepatitis or delirium. Accidental intravenous overdose in an infant caused severe heart block, resulting in residual encephalopathy.[18][19] Clostridium difficile has been reported with use of azithromycin.[1]

In 2013, the FDA issued a warning that azithromycin, "can cause abnormal changes in the electrical activity of the heart that may lead to a potentially fatal irregular heart rhythm." The FDA noted in the warning a 2012 study that found the drug may increase the risk of death, especially in those with heart problems, compared with those on other antibiotics such as amoxicillin or no antibiotic. The warning indicated people with preexisting conditions are at particular risk, such as those with QT interval prolongation, low blood levels of potassium or magnesium, a slower than normal heart rate, or those who use of certain drugs used to treat abnormal heart rhythms.[20][21][22][23][24]

Mechanism of action

Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, thus inhibiting translation of mRNA. Nucleic acid synthesis is not affected.[25]

Pharmacokinetics

Azithromycin is an acid-stable antibiotic, so it can be taken orally with no need of protection from gastric acids. It is readily absorbed, but absorption is greater on an empty stomach. Time to peak concentration (Tmax) in adults is 2.1 to 3.2 hours for oral dosage forms. Due to its high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma, due to ion trapping and its high lipid solubility (volume of distribution is too high).

Azithromycin's half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.

Metabolism

Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours.[26] Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, about 6% of the administered dose appears as unchanged drug in urine.

History

A team of researchers at the Croatian pharmaceutical company Pliva—Gabrijela Kobrehel, Gorjana Radobolja-Lazarevski, and Zrinka Tamburašev, led by Dr. Slobodan Đokić—discovered azithromycin in 1980. It was patented in 1981. In 1986, Pliva and Pfizer signed a licensing agreement, which gave Pfizer exclusive rights for the sale of azithromycin in Western Europe and the United States. Pliva put its azithromycin on the market in Central and Eastern Europe under the brand name Sumamed in 1988. Pfizer launched azithromycin under Pliva's license in other markets under the brand name Zithromax in 1991.[27] Pfizer's exclusive rights have since lapsed and Pliva-manufactured azithromycin is also marketed in the United States by generic drug maker Teva Pharmaceuticals (which now owns Pliva).

After several years, the U.S. Food and Drug Administration approved AzaSite, an ophthalmic formulation of azithromycin, for the treatment of eye infections. AzaSite is marketed in the U.S. and Canada by Inspire Pharmaceuticals, a wholly owned subsidiary of Merck.[28]

Society and culture

Azithromycin 250-mg capsules ("Z-Pak") from Ukraine
Sumamed - azithromycin tablets from Croatia

Names

Brand names include Zithromax, Azithrocin, Azyth, Azin, Zeto and Azithral,AZIF-500

Cost

It is available as a generic medication.[5] The wholesale cost is about 0.18 to 2.98 USD per dose.[6] In the United States it is about 33 USD for a course of treatment.[1]

Available forms

Azithromycin is commonly administered in film-coated tablet, capsule, oral suspension, intravenous injection, granules for suspension in sachet (1 g), and ophthalmic solution.

Usage

In 2010, azithromycin was the most prescribed antibiotic for outpatients in the US,[29] whereas in Sweden where outpatient antibiotic use is a third as prevalent, macrolides are only on 3% of prescriptions.[30]

References

  1. ^ a b c d e f g "Azithromycin". The American Society of Health-System Pharmacists. Retrieved Aug 1, 2015. 
  2. ^ "Azithromycin use while Breastfeeding". Retrieved 4 September 2015. 
  3. ^ Greenwood, David (2008). Antimicrobial drugs : chronicle of a twentieth century medical triumph (1. publ. ed.). Oxford: Oxford University Press. p. 239.  
  4. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  5. ^ a b Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning.  
  6. ^ a b "Azithromycin". International Drug Price Indicator Guide. Retrieved 4 September 2015. 
  7. ^ Taylor SP, Sellers E, Taylor BT (2015). "Azithromycin for the Prevention of COPD Exacerbations: The Good, Bad, and Ugly". Am. J. Med.  
  8. ^ Rosenfeld RM, Piccirillo JF, Chandrasekhar SS, Brook I, Ashok Kumar K, Kramper M, Orlandi RR, Palmer JN, Patel ZM, Peters A, Walsh SA, Corrigan MD (2015). "Clinical practice guideline (update): adult sinusitis". Otolaryngol Head Neck Surg 152 (2 Suppl): S1–S39.  
  9. ^ Hauk L (2014). "AAP releases guideline on diagnosis and management of acute bacterial sinusitis in children one to 18 years of age". Am Fam Physician 89 (8): 676–81.  
  10. ^ Mandell LA, Wunderink RG, Anzueto A, Bartlett JG, Campbell GD, Dean NC, Dowell SF, File TM, Musher DM, Niederman MS, Torres A, Whitney CG (2007). "Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults". Clin. Infect. Dis. 44 Suppl 2: S27–72.  
  11. ^ Neff MJ (2004). "AAP, AAFP release guideline on diagnosis and management of acute otitis media". Am Fam Physician 69 (11): 2713–5.  
  12. ^ Randel A (2013). "IDSA Updates Guideline for Managing Group A Streptococcal Pharyngitis". Am Fam Physician 88 (5): 338–40.  
  13. ^ "Gonococcal Infections - 2015 STD Treatment Guidelines". 
  14. ^ The Guardian newspaper: 'Super-gonorrhoea' outbreak in Leeds, 18 September 2015
  15. ^ "Gonococcal Infections - 2015 STD Treatment Guidelines". 
  16. ^ "Gonococcal Infections - 2015 STD Treatment Guidelines". 
  17. ^ Toh, Sengwee; Mitchell, Allen A.; Anderka, Marlene; de Jong-Van den Berg, Lolkje T.W.; Hernández-Díaz, Sonia; National Birth Defects Prevention Study (2011). "Antibiotics and oral contraceptive failure — a case-crossover study". Contraception 83 (5): 418–25.  
  18. ^ Tilelli, John A.; Smith, Kathleen M.; Pettignano, Robert (2006). "Life-Threatening Bradyarrhythmia After Massive Azithromycin Overdose". Pharmacotherapy 26 (1): 147–50.  
  19. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 132–133. 
  20. ^ Denise Grady (May 16, 2012). "Popular Antibiotic May Raise Risk of Sudden Death".  
  21. ^ Ray, Wayne A.; Murray, Katherine T.; Hall, Kathi; Arbogast, Patrick G.; Stein, C. Michael (2012). "Azithromycin and the Risk of Cardiovascular Death". New England Journal of Medicine 366 (20): 1881–90.  
  22. ^ ) and the risk of cardiovascular deathAzithrocinFDA Statement regarding azithromycin (Zithromax,
  23. ^ Zithromax (azithromycin): FDA Statement on risk of cardiovascular death
  24. ^ FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms
  25. ^ "azithromycin (Zithromax, Zmax, Z-Pak) - Side Effects, Drug Interactions". MedicineNet. Retrieved 2013-01-06. 
  26. ^ http://www.drugs.com/pro/zithromax.html
  27. ^ Banić Tomišić, Z. (2011). "The Story of Azithromycin". Kemija u industriji 60 (12): 603–617.  
  28. ^ "Merck Completes Acquisition of Inspire Pharmaceuticals, Inc." (Press release). Merck. 
  29. ^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (Apr 11, 2013). "U.S. outpatient antibiotic prescribing, 2010.". The New England Journal of Medicine 368 (15): 1461–1462.  
  30. ^ Hicks, LA; Taylor TH, Jr; Hunkler, RJ (Sep 19, 2013). "More on U.S. outpatient antibiotic prescribing, 2010.". The New England Journal of Medicine 369 (12): 1175–1176.  

External links

  • "azithromycin" at medicinenet.com
  • "Azithromycin". Drug Information Portal.  
  • Azithromycin PubMed Health
  • Azithromycin Dosage on Drugs.com
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