Azithromycin

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Azithromycin
Azithromycin structure.svg
Azithromycin 3d structure.png
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, Azyth, Azithrocin, Azin, Zeto
AHFS/Drugs.com monograph
MedlinePlus a697037
Licence data US FDA:link
Pregnancy cat.
Legal status
Routes Oral (capsule or suspension), intravenous, ophthalmic
Pharmacokinetic data
Bioavailability 38% for 250 mg capsules
Metabolism Hepatic
Half-life

11–14 h (single dose)

68 h (multiple dosing)
Excretion Biliary, renal (4.5%)
Identifiers
CAS number 83905-01-5 YesY
ATC code J01FA10 S01AA26
PubChem CID 55185
DrugBank DB00207
ChemSpider 10482163 YesY
UNII J2KLZ20U1M YesY
KEGG D07486 YesY
ChEBI CHEBI:2955 YesY
ChEMBL CHEMBL529 YesY
NIAID ChemDB 007311
Synonyms 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A
Chemical data
Formula C38H72N2O12 
Mol. mass 748.984 g·mol−1
 YesY (what is this?)  (verify)

Azithromycin (trade names Zithromax, Azyth, Sumamed) is an antibiotic useful for the treatment of bacterial infections. It is an azalide, a subclass of macrolide antibiotic. It is derived from erythromycin, with a methyl-substituted nitrogen atom incorporated into the lactone ring, thus making the lactone ring 15-membered. Azithromycin is somewhat more potent against certain bacterial species than erythromycin, but its widespread popularity arises primarily from its slow elimination from the body, which allows many infections to be treated with 3-5 days of once-daily administration, compared to 3-4 times a day for up to two weeks for erythromycin.[1]

Azithromycin inhibits the growth of bacteria by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, and thus inhibits translation of mRNA. This mechanism of action is typical of macrolide antibiotics.

This antibiotic is widely used alone or in combination with other drugs to treat[2] otitis media, pharyngitis, community-acquired respiratory infections (including pneumonia),[3] gastrointestinal infections[4] (such as those caused by eating contaminated food), and gonorrhea.[5]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medications needed in a basic health system.[6]

Spectrum of bacterial susceptibility[edit]

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

Aerobic and facultative Gram-positive microorganisms

Aerobic and facultative Gram-negative microorganisms

Anaerobic microorganisms

Other microorganisms

Medical uses[edit]

Azithromycin is used to treat many different infections, including:

  • Acute bacterial exacerbations of chronic obstructive pulmonary disease due to H. influenzae, M. catarrhalis, or S. pneumoniae
  • Acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae
  • Community-acquired pneumonia' due to C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae
  • Acute otitis media caused by H. influenzae, M. catarrhalis or S. pneumoniae
  • Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy
  • 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

A study comparing use of azithromycin, erythromycin, and cloxacillin gave results of eradicated baseline pathogen(s), mainly S. aureus, by 89, 78, and 59%, respectively. Azithromycin (total dose 1.5 g) given orally in five or six doses over five days, erythromycin and cloxacillin both given orally as 500 mg four times daily for seven days; the shortest treatment with azithromycin may improve patient compliance.[7]

Adverse effects[edit]

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.[8] This change in advice comes because to date, no evidence conclusively demonstrates antibiotics (other than rifampicin or rifabutin) affect these contraceptives.

Azithromycin suspension has an objectionable taste, so it can be difficult to administer to young children, who may spit it out.[9]

Occasionally, patients have developed cholestatic hepatitis or delirium. Accidental intravenous overdose in an infant caused severe heart block, resulting in residual encephalopathy.[10][11]

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.[12][13][14][15][16]

Mechanism of action[edit]

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.[17]

Pharmacokinetics[edit]

Azithromycin is 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,[citation needed] 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[edit]

Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours.[18] 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[edit]

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.[19] 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.[20]

In 2010, azithromycin was the most prescribed antibiotic for outpatients in the US,[21] whereas in Sweden where outpatient antibiotic use is a third as prevalent, macrolides are only on 3% of prescriptions.[22]

Available forms[edit]

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

Azithromycin is commonly administered in film coated tablet' (250 and 500 mg), capsule' (250 and 500 mg), oral suspension (100 mg/5 ml and 200 mg/5 ml), intravenous injection, 'granules for suspension in sachet (1 g), and ophthalmic solution ( 1%).

References[edit]

  1. ^ "Erythromycin Prescribing Information". Retrieved 2014-05-22. 
  2. ^ "FDA Drug Utilization Review: Azithromycin". Retrieved 2014-05-22. 
  3. ^ Shah PB, Giudice JC, Griesback R, Morley TF, Vasoya A (December 2004). "The newer guidelines for the management of community-acquired pneumonia". J Am Osteopath Assoc 104 (12): 521–6. PMID 15653779. 
  4. ^ DuPont HL (January 2012). "Approach to the patient with infectious colitis". Curr. Opin. Gastroenterol. 28 (1): 39–46. doi:10.1097/MOG.0b013e32834d3208. PMID 22080825. 
  5. ^ "Update to CDC's Sexually Transmitted Diseases Treatment Guidelines, 2010: Oral Cephalosporins No Longer a Recommended Treatment for Gonococcal Infections". 
  6. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  7. ^ Daniel R. "Azithromycin, erythromycin and cloxacillin in the treatment of infections of skin and associated soft tissues. European Azithromycin Study Group". Retrieved August 23, 2014. 
  8. ^ 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. doi:10.1016/j.contraception.2010.08.020. PMC 3326585. PMID 21477683. 
  9. ^ Zmuida, China. "How to Give a Child Azithromycin". Retrieved 2013-01-06. [unreliable medical source?][self-published source?]
  10. ^ Tilelli, John A.; Smith, Kathleen M.; Pettignano, Robert (2006). "Life-Threatening Bradyarrhythmia After Massive Azithromycin Overdose". Pharmacotherapy 26 (1): 147–50. doi:10.1592/phco.2006.26.1.147. PMID 16506357. 
  11. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 132–133. 
  12. ^ Denise Grady (May 16, 2012). "Popular Antibiotic May Raise Risk of Sudden Death". The New York Times. Retrieved May 18, 2012. 
  13. ^ 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. doi:10.1056/NEJMoa1003833. PMC 3374857. PMID 22591294. 
  14. ^ FDA Statement regarding azithromycin (Zithromax, Azithrocin) and the risk of cardiovascular death
  15. ^ Zithromax (azithromycin): FDA Statement on risk of cardiovascular death
  16. ^ FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms
  17. ^ "azithromycin (Zithromax, Zmax, Z-Pak) - Side Effects, Drug Interactions". MedicineNet. Retrieved 2013-01-06. 
  18. ^ http://www.drugs.com/pro/zithromax.html
  19. ^ Banić Tomišić, Z. (2011). "The Story of Azithromycin". Kemija u industriji 60 (12): 603–617. ISSN 0022-9830. 
  20. ^ "Merck Completes Acquisition of Inspire Pharmaceuticals, Inc." (Press release). Merck. 
  21. ^ 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. doi:10.1056/NEJMc1212055. PMID 23574140. 
  22. ^ 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. doi:10.1056/NEJMc1306863. PMID 24047077. 

External links[edit]