Azithromycin
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| Clinical data | |
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| Other names | 9-deoxy-9a-aza-9a-methyl-9a-homoerythromycin A |
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| Routes of administration | Oral (capsule or suspension), intravenous, ophthalmic |
| ATC code | |
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| Pharmacokinetic data | |
| Bioavailability | 38% for 250 mg capsules |
| Metabolism | Hepatic |
| Elimination half-life | 68 hours |
| Excretion | Biliary, renal (4.5%) |
| Identifiers | |
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| CAS Number | |
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| CompTox Dashboard (EPA) | |
| ECHA InfoCard | 100.126.551 |
| Chemical and physical data | |
| Formula | C38H72N2O12 |
| Molar mass | 748.984 g·mol−1 g·mol−1 |
| 3D model (JSmol) | |
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Azithromycin is an azalide, a subclass of macrolide antibiotics.
Azithromycin is one of the world's best-selling antibiotics,[2] and is derived from erythromycin; however, it differs chemically from erythromycin in that a methyl-substituted nitrogen atom is incorporated into the lactone ring, thus making the lactone ring 15-membered.
Azithromycin is used to treat or prevent certain bacterial infections, most often those causing middle ear infections, tonsillitis, throat infections, laryngitis, bronchitis, pneumonia, Typhoid, and sinusitis. In recent years it has primarily been used to prevent bacterial infections in infants and those with weaker immune systems. It is also effective against certain urinary tract infections and venereal diseases, such as non-gonococcal urethritis, chlamydia, gonorrhea and cervicitis. Recent studies have also indicated it to be effective against late-onset asthma, but these findings are controversial and not widely accepted.[3][4]
Patriots Rock
Azithromycin's name is derived from the azane-substituent and erythromycin. Its formal chemical name is
(2R,3S,4R,5R,8R,10R,11R,12S,13S,14S)-11-((2S,3R,4S,6R)- 4-(dimethylamino)-3-hydroxy-6-methyltetrahydro-2H-pyran-2-yloxy)- 2-ethyl-3,4,10-trihydroxy-13-((2S,4R,5S)-5-hydroxy- 4-methoxy-4-methyltetrahydro-2H-pyran-2-yloxy)- 3,5,6,8,10,12,14-heptamethyl-1-oxa-6-azacyclopentadecan-15-one
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, and was later found by Pfizer's scientists while going through patent documents. 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 brought their azithromycin on the market in Central and Eastern Europe under the brand name of Sumamed in 1988, Pfizer Zithromax in 1991, and Zentiva Azitrox. 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 currently marketed in the US by Inspire Pharmaceuticals.
Available forms
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 250 mg and 500 mg doses. Oral suspension comes in 100 mg/teaspoon and 200 mg/teaspoon strengths. 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 (e.g., Zithromax) azithromycin tablets are mottled pink, unscored, film-coated, modified-oval-shaped tablets containing azithromycin monohydrate equivalent to 250 mg or 500 mg azithromycin 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. The 250 mg tablets have the following appearance: They are mottled pink, of a modified-oval-shape, and have "Pfizer" engraved into one side with "306" engraved into the other. The 500 mg tablet is similar in appearance with the exception of its relative size and "ZTM500" engraved onto one side with "Pfizer" on the reverse. As with all medications, generic azithromycin tablets produced by companies other than Pfizer without the Zithromax brand name may have different appearances. For instance, the generic azithromycin sold under the Greenstone brand is pink, with the hexagonal "G" Greenstone, Ltd. logo engraved on one side and the numerals 3060 on the other. Greenstone, Ltd. is a subsidiary of Pfizer. The Novartis subsidiary Sandoz ships azithromycin as white oval tablets stamped with "GGD6" (250 mg) or "GGD8" (500 mg). A generic azithromycin made by Wockhardt is made as white oval tablets stamped with "W961" (250 mg).
Brand names
Azithromycin is sold under brand names APO-Azithromycin in Canada; Zithromax in Finland, Italy, The United Kingdom, The United States, Australia, Portugal, South Africa, Canada, Thailand and Belgium; Hemomicin in Serbia; Zithromac in Japan; Vinzam/Zitromax in Spain; Zmax; Sumamed in Croatia, Slovakia and Czech Republic; ATM, Aztrin, Azigard, Zitrocin, Azibiot, Azifine, AziCip, Azi Sandoz, Aziswift, AZORTA & AZEE, Azithral in India;[5] Azocam and Bactizith in Pakistan.
Mechanism of action
Azithromycin prevents bacteria from growing by interfering with their protein synthesis. Azithromycin binds to the 50S subunit of the bacterial ribosome, and thus inhibits translation of mRNA. Nucleic acid synthesis is not affected.
Microbiology
Azithromycin has a similar antimicrobial spectrum as erythromycin, but is more effective against certain gram-negative bacteria, particularly Haemophilus influenzae. Azithromycin resistance has been described and is endemic in many areas.
Azithromycin has been proven to be most effective against isolates of the following microorganisms:
- Staphylococcus aureus
- Streptococcus agalactiae
- Streptococcus pneumoniae
- Streptococcus pyogenes
- Haemophilus ducreyi
- Haemophilus influenzae
- Moraxella catarrhalis
- Neisseria gonorrhoeae
- Chlamydia pneumoniae
- Chlamydia trachomatis
- Mycoplasma pneumoniae
- Helicobacter pylori
- Salmonella typhi
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.[6]
Pharmacokinetics
Unlike erythromycin, azithromycin is acid-stable and can therefore 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 1 to 2 hours for intravenous (IV) forms. Due to the high concentration in phagocytes, azithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of azithromycin are released. The concentration of azithromycin in the tissues can be over 50 times higher than in plasma. This is due to ion trapping and the high lipid solubility.
Azithromycin's half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days. The new extended-release formulation of azithromycin "Zmax" is a liquid oral suspension that releases the drug in a single 2-g dose. With the macrolide technology of Zmax, this allows the drug to bypass the stomach, reducing gastrointestinal side effects of high-dose azithromycin.
Metabolism
Following a single 500 mg dose, plasma concentrations of azithromycin declined in a polyphasic pattern with a mean apparent plasma clearance of 630 mL/min and a terminal elimination half-life of 68 hours. The prolonged terminal half-life is thought to be due to extensive uptake and subsequent release of drug from tissues.
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.
Side effects
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. Serious allergic reactions, nervousness, dermatologic reactions, and fatalities have been reported. As with all antimicrobial agents, pseudomembranous colitis can occur during and up to several weeks after azithromycin therapy. This drug may interfere with the effectiveness of birth control pills; other forms of contraception may be required during the treatment period.
Azithromycin suspension tastes bad, which can make it difficult to administer to young children (e.g. 2 - 5 years) who may spit it out.
Allergic reaction
Patients who suffer from an allergic reaction to Azithromycin can experience blood in the stool 4–10 days after ingestion, although cases of this have been recorded as early as after the first day of ingestion. These allergies are usually non-severe if the treatment is immediately stopped. A severe reaction includes a severe rash, hives, breathing difficulties, or dizziness.
References
- ^ "FDA-sourced list of all drugs with black box warnings (Use Download Full Results and View Query links.)". nctr-crs.fda.gov. FDA. Retrieved 22 Oct 2023.
- ^ [1]
- ^ Hahn,D.L. (1995). "Treatment of chlamydia pneumoniae infection in adult asthma: A before -after trial". J Fam Pract. 41: 345–351.
- ^ JD Klausner, D Passaro, J Rosenberg, WL Thacker, DF Talkington, SB Werner, DJ Vugia (1998). "Enhanced control of an outbreak of Mycoplasma pneumoniae pneumonia with azithromycin prophylaxis". Journal of Infectious Diseases. 177: 161–166. doi:10.1086/513818.
{{cite journal}}: CS1 maint: multiple names: authors list (link) - ^ [2]
- ^ Noedl H, Krudsood S, Chalermratana K; et al. (2006). "Azithromycin combination therapy with artesunate or quinine for the treatment of uncomplicated Plasmodium falciparum malaria in adults: a randomised, phase 2 clinical trial in Thailand". 43 (10): 1264–71. PMID 17051490.
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