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 Azyth, Zithromax, Azithrocin, Azin, Zeto
AHFS/Drugs.com monograph
MedlinePlus a697037
Licence data US FDA:link
Pregnancy cat. B1 (AU) B (US)
Legal status -only (US)
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 (Azyth, Zithromax, Azithrocin, Zmax, Azin, Zedd, Azocam, Penalox, Azi-Once, Zeto)[1] is an azalide, a subclass of macrolide antibiotics. It is derived from erythromycin, with a methyl-substituted nitrogen atom incorporated into the lactone ring, thus making the lactone ring 15-membered.

Azithromycin prevents bacteria from growing by interfering with their protein synthesis. It binds to the 50S subunit of the bacterial ribosome, and thus inhibits translation of mRNA.

Azithromycin is used to treat or prevent certain bacterial infections, most often those causing middle ear infections, strep throat, pneumonia, typhoid, gastroenteritis, bronchitis and sinusitis. In recent years, it has been used primarily to prevent bacterial infections in infants and those with weaker immune systems. It is also effective against certain sexually transmitted infections, such as nongonococcal urethritis, chlamydia, and cervicitis. Some studies have indicated it also to be effective against late-onset asthma, but these findings are controversial and not widely accepted.[2][3]

It is on the World Health Organization's List of Essential Medicines, a list of the most important medication needed in a basic health system.[4]

Medical uses[edit]

Azithromycin is used to treat many different infections, including acute otitis media, nonstreptococcal bacterial pharyngitis, gastrointestinal infections such as traveler's diarrhea, respiratory tract infections such as pneumonia, cellulitis, babesiosis, Bartonella infection, chancroid, cholera, donovanosis, leptospirosis, Lyme disease, malaria, Mycobacterium avium complex disease, Neisseria meningitis, pelvic inflammatory disease, pertussis, scrub typhus, toxoplasmosis, and salmonellosis.[5] It is used to prevent bacterial endocarditis and some sexually transmitted infections.[5] It is also effective against localized dental infections, uncomplicated skin and skin structure infections, urethritis and cervicitis and also genital ulcer disease.[6] Azithromycin is used as a second line treatment for strep throat and for those allergic to penicillin.[7] It has a similar antimicrobial spectrum to erythromycin, but is more effective against certain Gram-negative bacteria, in particular, Haemophilus influenzae (although it would not be the first choice of treatment in this infection).[8] Azithromycin resistance has been described[9] and is endemic in many areas. Long-term use in treating Staphylococcus aureus infections with azithromycin may increase bacterial resistance to this and other macrolide antibiotics.[10]

Azithromycin has been shown to be effective against malaria when used in combination with artesunate or quinine; the optimal dose for this is not yet known.[11]

Spectrum of bacterial susceptibility[edit]

Chlamydia pneumoniae, Chlamydia trachomatis, Eikenella corrodens, Escherichia coli, Haemophilus influenzae, Moraxella catarrhalis, Mycobacterium chelonae, Mycoplasma fermentans, Neisseria gonorrhoeae and Ureaplasma urealyticum are generally susceptible to azithromycin dihydrate, while Pseudomonas aeruginosa, and Staphylococcus aureus are resistant to azithromycin dihydrate. In general, Streptococcus pyogenes is susceptible.[12] Some Brevibacterium spp., Corynebacterium amycolatum, Haemophilus influenzae and Mycobacterium abscessus have developed resistance to azithromycin dihydrate to varying degrees.[13]

The following represents azithromycin susceptibility data on medically significant organisms.

  • Haemophilus influenzae - 0.001 μg/mL - >256 μg/mL
  • Streptococcus pneumoniae - 0.004 μg/mL - >512 μg/mL
  • Streptococcus pyogenes - 0.001 μg/mL - >256 μg/mL

[14]

Adverse effects[edit]

Most common side-effects are gastrointestinal: 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, new research shows that antibiotics, with the exception of rifampin and rifabutin, do not affect the effectiveness of hormonal contraceptives, such as the pill, patch or vaginal ring.[15] This change in advice comes because to date there is no evidence that conclusively demonstrates that 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, i.e., 2–5 years, who may spit it out.[16]

Occasionally, patients have developed cholestatic hepatitis or delirium. Accidental intravenous overdosage in an infant caused severe heart block, resulting in residual encephalopathy.[17][18]

In 2013, the FDA issued a warning saying 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 released by the New England Journal of Medicine 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 that people with preexistent 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, or arrhythmias.[19][20][21][22][23]

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, and thus inhibits translation of mRNA. Nucleic acid synthesis is not affected.[24]

Pharmacokinetics[edit]

Unlike erythromycin, azithromycin is acid-stable, so it can be taken orally with no need of protection from gastric acids. It is readily absorbed, but its absorption is greater on an empty stomach. Time to peak concentration in adults is 2.1 to 3.2 hours for oral dosage forms and one to two hours after a dose. 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]

According to Davis' Drug Guide for Nurses, following a single dose of 500 mg, the half-life of azithromycin is 11–14 h. The longer half-life of 68 h is achieved only when multiple doses are consumed. Biliary excretion of azithromycin, predominantly unchanged, is a major route of elimination. Over the course of a week, approximately 6% of the administered dose appears as unchanged drug in urine.

Etymology[edit]

The name Azithromycin is derived from the azane-substituent and erythromycin.

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 of Sumamed in 1988. Pfizer launched azithromycin under Pliva's license in other markets under the brand name Zithromax in 1991.[25] 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 (FDA) 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.[26]

In 2010 azithromycin was the most prescribed antibiotic in outpatients in the US,[27] whereas in Sweden where outpatient antibiotic usage is a third macrolides are only on 4% of prescriptions.[28]

Available forms[edit]

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

Azithromycin is commonly administered in tablet or oral suspension (a one-dose version was made available in 2005). It is also available for intravenous injection and in a 1% ophthalmic solution. Tablets come in doses of 250 mg and 500 mg. Oral suspension comes in strengths of 100 mg/5 ml and 200 mg/5 ml. The 250-mg tablets are often dispensed in packages of six and commonly referred to as a "Z-Pak," whereas the 500-mg tablets are commonly available commercially in a pack of three tablets, or "Tri-Pak," intended as a three-day treatment. A common dose of oral azithromycin therapy consists of a "double dose" of medication on the first day of treatment and subsequent treatment for four or five additional days. With the "Z-Pak", this means two 250-mg tablets (a total of 500 mg) on the first day and one 250-mg tablet once daily for the next four days.

Pfizer brand name, i.e. Zithromax, azithromycin tablets are mottled pink, unscored, film-coated, modified oval-shaped tablets containing azithromycin monohydrate and the following inactive ingredients: butylated hydroxytoluene, calcium phosphate, carmine, colloidal silicon dioxide, FD&C red # 40 lake, FD&C yellow # 6 lake, hypromellose (2910, 15cP), lactose monohydrate, magnesium stearate, pregelatinized starch, sodium lauryl sulfate, talc, titanium dioxide, and triacetin. In Colombia (South America), it is marketed under the name Zaret from Laboratorios Bussié. In Bangladesh, it is marketed under the name Azithin from Chemist Laboratories Ltd. and Penalox from Rephco Pharmaceuticals Limited. In Canada azithromycin is marketed by Sandoz.

Azi-Once™ (6 x 250 mg capsules) is manufactured by Jamjoom Pharmaceuticals in Jeddah, Kingdom of Saudi Arabia

References[edit]

  1. ^ American Society of Health-System Pharmacists (October 15, 2012). "Azithromycin". MedlinePlus. United States National Library of Medicine. Retrieved September 19, 2013. 
  2. ^ Hahn, DL (1995). "Treatment of Chlamydia pneumoniae infection in adult asthma: A before-after trial". The Journal of family practice 41 (4): 345–51. PMID 7561707. 
  3. ^ Klausner, Jeffrey D.; Passaro, Douglas; Rosenberg, Jon; Thacker, W. Lanier; Talkington, Deborah F.; Werner, S. Benson; Vugia, Duc J. (1998). "Enhanced Control of an Outbreak of Mycoplasma pneumoniaePneumonia with Azithromycin Prophylaxis". The Journal of Infectious Diseases 177 (1): 161–6. doi:10.1086/513818. PMID 9419183. 
  4. ^ "WHO Model List of EssentialMedicines". World Health Organization. October 2013. Retrieved 22 April 2014. 
  5. ^ a b monograph
  6. ^ "Azithromycin - Indications and Usage". drugs.com. 
  7. ^ Dajani, Adnan; Taubert, Kathryn; Ferrieri, Patricia; Peter, Georges; Shulman, Stanford (1995). "Treatment of Acute Streptococcal Pharyngitis and Prevention of Rheumatic Fever: A Statement for Health Professionals". Pediatrics 96 (4): 758–64. PMID 7567345. 
  8. ^ Auwaerter, Paul (November 17,2011). "Haemophilus species". Johns Hopkins ABX Guide. Retrieved September 19, 2013. 
  9. ^ Chisholm, S. A.; Neal, T. J.; Alawattegama, A. B.; Birley, H. D. L.; Howe, R. A.; Ison, C. A. (2009). "Emergence of high-level azithromycin resistance in Neisseria gonorrhoeae in England and Wales". Journal of Antimicrobial Chemotherapy 64 (2): 353–8. doi:10.1093/jac/dkp188. PMID 19468025. 
  10. ^ Hansen, C.R.; Pressler, T.; Hoiby, N.; Johansen, H.K. (2009). "Long-term, low-dose azithromycin treatment reduces the incidence but increases macrolide resistance in Staphylococcus aureus in Danish CF patients". Journal of Cystic Fibrosis 8 (1): 58–62. doi:10.1016/j.jcf.2008.09.001. PMID 18849202. 
  11. ^ Noedl, H.; Krudsood, S.; Chalermratana, K.; Silachamroon, U.; Leowattana, W.; Tangpukdee, N.; Looareesuwan, S.; Miller, R. S.; Fukuda, M.; Jongsakul, K.; Sriwichai, S.; Rowan, J.; Bhattacharyya, H.; Ohrt, C.; Knirsch, C. (2006). "Azithromycin Combination Therapy with Artesunate or Quinine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Adults: A Randomized, Phase 2 Clinical Trial in Thailand". Clinical Infectious Diseases 43 (10): 1264–71. doi:10.1086/508175. PMID 17051490. 
  12. ^ Van Asselt, G. J.; Sloos, J. H.; Mouton, R. P.; Van Boven, C. P. A.; Van De Klundert, J. A. M. (1995). "Susceptibility of Streptococcus pyogenes to azithromycin, clarithromycin, erythromycin and roxithromycin in vitro". Journal of Medical Microbiology 43 (5): 386–91. doi:10.1099/00222615-43-5-386. PMID 7563004. 
  13. ^ "Azithromycin Dihydrate – Product Data Sheet". TOKU-E. December 1, 2010. 
  14. ^ http://www.toku-e.com/Assets/MIC/Azithromycin%20dihydrate.pdf
  15. ^ 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. 
  16. ^ Zmuida, China. "How to Give a Child Azithromycin". Retrieved 2013-01-06. [unreliable medical source?][self-published source?]
  17. ^ 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. 
  18. ^ Baselt, R. (2008). Disposition of Toxic Drugs and Chemicals in Man (8th ed.). Foster City, CA: Biomedical Publications. pp. 132–133. 
  19. ^ Denise Grady (May 16, 2012). "Popular Antibiotic May Raise Risk of Sudden Death". The New York Times. Retrieved May 18, 2012. 
  20. ^ 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. 
  21. ^ FDA Statement regarding azithromycin (Zithromax, Azithrocin) and the risk of cardiovascular death
  22. ^ Zithromax (azithromycin): FDA Statement on risk of cardiovascular death
  23. ^ FDA Drug Safety Communication: Azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms
  24. ^ "azithromycin (Zithromax, Zmax, Z-Pak) - Side Effects, Drug Interactions". MedicineNet. Retrieved 2013-01-06. 
  25. ^ Banić Tomišić, Z. (2011). "The Story of Azithromycin". Kemija u industriji 60 (12): 603–617. ISSN 0022-9830. 
  26. ^ "Merck Completes Acquisition of Inspire Pharmaceuticals, Inc." (Press release). Merck. 
  27. ^ 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. 
  28. ^ 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]