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, Azithrocin, others[1]
AHFS/Drugs.com Monograph
MedlinePlus a697037
License data
Pregnancy
category
  • AU: B1
  • US: B (No risk in non-human studies)
Routes of
administration
Oral (capsule, tablet or suspension), intravenous, ophthalmic
Legal status
Legal status
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 Number 83905-01-5 YesY
ATC code J01FA10 (WHO) S01AA26 (WHO)
PubChem CID 55185
IUPHAR/BPS 6510
DrugBank DB00207 YesY
ChemSpider 10482163 YesY
UNII J2KLZ20U1M YesY
KEGG D07486 YesY
ChEBI CHEBI:2955 YesY
ChEMBL CHEMBL529 YesY
NIAID ChemDB 007311
Synonyms 9-deoxy-9α-aza-9α-methyl-9α-homoerythromycin A
Chemical data
Formula C38H72N2O12
Molar mass 748.984 g·mol−1
  (verify)

Azithromycin is an antibiotic useful for the treatment of a number of bacterial infections.[2] This includes middle ear infections, strep throat, pneumonia, traveler's diarrhea, and certain other intestinal infections. It may also be used for a number of sexually transmitted infections including chlamydia and gonorrhea infections. Along with other medications, it may also be used for malaria. It can be taken by mouth or intravenously with doses once per day.[2]

Common side effects include nausea, vomiting, diarrhea and upset stomach. An allergic reaction or a type of diarrhea caused by Clostridium difficile is possible. No harm has been found with use during pregnancy.[2] Its safety during breastfeeding is not confirmed, but it is likely safe.[3] Azithromycin is an azalide, a type of macrolide antibiotic. It works by decreasing the production of protein, thus stopping bacterial growth.[2]

Azithromycin was first made in 1980.[4] It is on the World Health Organization's List of Essential Medicines, the most important medications needed in a basic health system.[5] It is available as a generic medication[6] and is sold under many trade names worldwide.[1] The wholesale cost in the developing world is about 0.18 to 2.98 USD per dose.[7] In the United States it is about 33 USD for a course of treatment.[2]

Medical uses[edit]

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 patient-by-patient basis against the risk of cardiovascular and other adverse effects.[8]
  • Acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae. Other agents, such as amoxicillin/clavulanate are generally preferred, however.[9][10]
  • Community-acquired pneumonia' due to C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae[11]
  • 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.[12]
  • Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy[13]
  • 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.[14]

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.

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

Aerobic and facultative Gram-positive microorganisms

Aerobic and facultative Gram-negative microorganisms

Anaerobic microorganisms

Other microorganisms

Pregnancy and breastfeeding[edit]

No harm has been found with use during pregnancy.[2] However, there are no adequate well-controlled studies in pregnant women.[17]

Safety of the medication during breastfeeding is unclear. It has been reported that because only low levels are found in breastmilk and the medication has also been used in young children, it is unlikely that breastfed infants would suffer adverse effects.[3] Nevertheless, it is recommended that the drug be used with caution during breastfeeding.[2]

Adverse effects[edit]

Most common side effects are diarrhea (5%), nausea (3%), abdominal pain (3%), and vomiting. Fewer than 1% of people stop taking the drug due to side effects. Nervousness, dermatologic reactions, and anaphylaxis have been reported.[18] 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.[19] This change in advice comes because to date, no evidence conclusively demonstrates antibiotics (other than rifampicin or rifabutin) affect these contraceptives.[citation needed]

Occasionally, patients have developed cholestatic hepatitis or delirium. Accidental intravenous overdose in an infant caused severe heart block, resulting in residual encephalopathy.[20][21] Clostridium difficile has been reported with use of azithromycin.[2]

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 certain drugs to treat abnormal heart rhythms.[22][23][24][25][26]

Pharmacology[edit]

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.[27]

Pharmacokinetics[edit]

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.[citation needed] Azithromycin's half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.[28]

Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours.[28] 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.[29] 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.[30]

Society and culture[edit]

Names[edit]

It is sold under many trade names worldwide.[1]

Cost[edit]

It is available as a generic medication.[6] The wholesale cost is about 0.18 to 2.98 USD per dose.[7] In the United States it is about 33 USD for a course of treatment.[2]

Available forms[edit]

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

Usage[edit]

In 2010, azithromycin was the most prescribed antibiotic for outpatients in the US,[31] whereas in Sweden where outpatient antibiotic use is a third as prevalent, macrolides are only on 3% of prescriptions.[32]

References[edit]

  1. ^ a b c Drugs.com International trade names for Azithromycin Page accessed Jan 14, 2015
  2. ^ a b c d e f g h i "Azithromycin". The American Society of Health-System Pharmacists. Retrieved Aug 1, 2015. 
  3. ^ a b "Azithromycin use while Breastfeeding". Retrieved 4 September 2015. 
  4. ^ Greenwood, David (2008). Antimicrobial drugs : chronicle of a twentieth century medical triumph (1. publ. ed.). Oxford: Oxford University Press. p. 239. ISBN 9780199534845. 
  5. ^ "WHO Model List of EssentialMedicines" (PDF). World Health Organization. October 2013. Retrieved 22 April 2014. 
  6. ^ a b Hamilton, Richart (2015). Tarascon Pocket Pharmacopoeia 2015 Deluxe Lab-Coat Edition. Jones & Bartlett Learning. ISBN 9781284057560. 
  7. ^ a b "Azithromycin". International Drug Price Indicator Guide. Retrieved 4 September 2015. 
  8. ^ Taylor SP, Sellers E, Taylor BT (2015). "Azithromycin for the Prevention of COPD Exacerbations: The Good, Bad, and Ugly". Am. J. Med. doi:10.1016/j.amjmed.2015.07.032. PMID 26291905. 
  9. ^ 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. doi:10.1177/0194599815572097. PMID 25832968. 
  10. ^ 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. PMID 24784128. 
  11. ^ 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. doi:10.1086/511159. PMID 17278083. 
  12. ^ Neff MJ (2004). "AAP, AAFP release guideline on diagnosis and management of acute otitis media". Am Fam Physician. 69 (11): 2713–5. PMID 15202704. 
  13. ^ Randel A (2013). "IDSA Updates Guideline for Managing Group A Streptococcal Pharyngitis". Am Fam Physician. 88 (5): 338–40. PMID 24010402. 
  14. ^ "Gonococcal Infections - 2015 STD Treatment Guidelines". 
  15. ^ The Guardian newspaper: 'Super-gonorrhoea' outbreak in Leeds, 18 September 2015
  16. ^ "Gonococcal Infections - 2015 STD Treatment Guidelines". 
  17. ^ http://labeling.pfizer.com/ShowLabeling.aspx?id=511#section-1
  18. ^ Mori F, Pecorari L, Pantano S, Rossi M, Pucci N, De Martino M, Novembre E (2014). "Azithromycin anaphylaxis in children.". Int J Immunopathol Pharmacol. 27 (1): 121–6. doi:10.1177/039463201402700116. PMID 24674687. Retrieved 19 February 2016. 
  19. ^ 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 3326585free to read. PMID 21477683. 
  20. ^ 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. 
  21. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 132–133. 
  22. ^ Denise Grady (May 16, 2012). "Popular Antibiotic May Raise Risk of Sudden Death". The New York Times. Retrieved May 18, 2012. 
  23. ^ 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 3374857free to read. PMID 22591294. 
  24. ^ FDA Statement regarding azithromycin (Zithromax, Azithrocin) and the risk of cardiovascular death
  25. ^ Zithromax (azithromycin): FDA Statement on risk of cardiovascular death
  26. ^ FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms
  27. ^ "azithromycin (Zithromax, Zmax, Z-Pak) - Side Effects, Drug Interactions". MedicineNet. Retrieved 2013-01-06. 
  28. ^ a b http://www.drugs.com/pro/zithromax.html
  29. ^ Banić Tomišić, Z. (2011). "The Story of Azithromycin". Kemija u industriji. 60 (12): 603–617. ISSN 0022-9830. 
  30. ^ "Merck Completes Acquisition of Inspire Pharmaceuticals, Inc." (Press release). Merck. 
  31. ^ 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. 
  32. ^ 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]