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Synonyms:A-56268, TE-031, 6-O-methylerythromycin, ATC:J01FA09Use:macrolide antibioticChemical name:6-O-methylerythromycinFormula:C38H69NO13
- MW:747.96 g/mol
klacid XL / Klaricid XL / Macladin / Naxy / Veclam / Zeclar
Jih-Hua Liu, David A. Riley, “Preparation of crystal form II of clarithromycin.” U.S. Patent US5844105, issued May, 1997. US5844105
NEW DRUG APPROVALS
ClarithromycinCAS Registry Number: 81103-11-9CAS Name: 6-O-MethylerythromycinManufacturers’ Codes: A-56268; TE-031Trademarks: Biaxin (Abbott); Clarosip (Grñenthal); Clathromycin (Taisho); Cyllind (Abbott); Klacid (Abbott); Klaricid (Abbott); Macladin (Guidotti); Naxy (Sanofi Winthrop); Veclam (Zambon); Zeclar (Abbott)Molecular Formula: C38H69NO13Molecular Weight: 747.95Percent Composition: C 61.02%, H 9.30%, N 1.87%, O 27.81%Literature References: Semisynthetic macrolide antibiotic; derivative of erythromycin, q.v. Prepn: Y. Watanabe et al.,EP41355; eidem,US4331803 (1981, 1982 both to Taisho); and in vitro antibacterial activity: S. Morimoto et al.,J. Antibiot.37, 187 (1984). In vitro and in vivo antibacterial activity: P. B. Fernandes et al.,Antimicrob. Agents Chemother.30, 865 (1986). Comparative antibacterial spectrum in vitro: C. Benson et al.,Eur. J. Clin. Microbiol.6, 173 (1987); H. M. Wexler, S. M. Finegold, ibid. 492. HPLC determn in biological fluids: D. Croteau et al.,J. Chromatogr.419, 205 (1987); in plasma: H. Amini, A. Ahmadiani, J. Chromatogr. B817, 193 (2005). Acute toxicity study: S. Abe et al.,Chemotherapy (Tokyo)36, Suppl. 3, 274 (1988). Symposium on pharmacology and comparative clinical studies: J. Antimicrob. Chemother.27, Suppl. A, 1-124 (1991). Comprehensive description: I. I. Salem, Anal. Profiles Drug Subs. Excip.24, 45-85, (1996).Properties: Colorless needles from chloroform + diisopropyl ether (1:2), mp 217-220° (dec). Also reported as crystals from ethanol, mp 222-225° (Morimoto). uv max (CHCl3): 288 nm (e 27.9). uv max (CHCl3): 240, 288 nm; (methanol): 211, 288 nm. [a]D24 -90.4° (c = 1 in CHCl3). Stable at acidic pH. LD50 in male, female mice, male, female rats (mg/kg): 2740, 2700, 3470, 2700 orally, 1030, 850, 669, 753 i.p., >5000 all s.c. (Abe).Melting point: mp 217-220° (dec); mp 222-225° (Morimoto)Optical Rotation: [a]D24 -90.4° (c = 1 in CHCl3)Absorption maximum: uv max (CHCl3): 288 nm (e 27.9). uv max (CHCl3): 240, 288 nmToxicity data: LD50 in male, female mice, male, female rats (mg/kg): 2740, 2700, 3470, 2700 orally, 1030, 850, 669, 753 i.p., >5000 all s.c. (Abe)Therap-Cat: Antibacterial.Keywords: Antibacterial (Antibiotics); Macrolides.
Clarithromycin, a semisynthetic macrolide antibiotic derived from erythromycin, inhibits bacterial protein synthesis by binding to the bacterial 50S ribosomal subunit. Binding inhibits peptidyl transferase activity and interferes with amino acid translocation during the translation and protein assembly process. Clarithromycin may be bacteriostatic or bactericidal depending on the organism and drug concentration.
Clarithromycin, sold under the brand name Biaxin among others, is an antibiotic used to treat various bacterial infections. This includes strep throat, pneumonia, skin infections, H. pylori infection, and Lyme disease, among others. Clarithromycin can be taken by mouth as a pill or liquid.
Common side effects include nausea, vomiting, headaches, and diarrhea. Severe allergic reactions are rare. Liver problems have been reported. It may cause harm if taken during pregnancy. It is in the macrolide class and works by decreasing protein production of some bacteria.
Clarithromycin was developed in 1980 and approved for medical use in 1990. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. Clarithromycin is available as a generic medication. It is made from erythromycin and is chemically known as 6-O-methylerythromycin.
Clarithromycin is primarily used to treat a number of bacterial infections including pneumonia, Helicobacter pylori, and as an alternative to penicillin in strep throat. Other uses include cat scratch disease and other infections due to bartonella, cryptosporidiosis, as a second line agent in Lyme disease and toxoplasmosis. It may also be used to prevent bacterial endocarditis in those who cannot take penicillin. It is effective against upper and lower respiratory tract infections, skin and soft tissue infections and helicobacter pylori infections associated with duodenal ulcers.
Spectrum of bacterial susceptibility
Staphylococcus aureusAerobic Gram-positive bacteria
Aerobic Gram-negative bacteria
- Haemophilus parainfluenzae
- Haemophilus influenzae
- Moraxella catarrhalis
Mycobacterium avium complex consisting of:
Safety and effectiveness of clarithromycin in treating clinical infections due to the following bacteria have not been established in adequate and well-controlled clinical trials:
Aerobic Gram-positive bacteria
- Streptococcus agalactiae
- Streptococcus (Groups C, F, G)
- Viridans group streptococci
Aerobic Gram-negative bacteria
Anaerobic Gram-positive bacteria
- Clostridium perfringens
- Peptococcus Niger
- Cutibacterium acnes
Anaerobic Gram-negative bacteria
- Prevotella melaninogenica (formerly Bacteroides melaninogenicus)
- Clarithromycin should not be taken by people who are allergic to other macrolides or inactive ingredients in the tablets, including microcrystalline cellulose, croscarmelose sodium, magnesium stearate, and povidone
- Clarithromycin should not be used by people with a history of cholestatic jaundice and/or liver dysfunction associated with prior clarithromycin use.
- Clarithromycin should not be used in the setting of hypokalaemia (low blood potassium)
- Use of clarithromycin with the following medications: cisapride, pimozide, astemizole, terfenadine, ergotamine, ticagrelor, ranolazine or dihydroergotamine is not recommended.
- It should not be used with colchicine in people with kidney or liver impairment.
- Concomitant use with cholesterol medications such as lovastatin or simvastatin.
- Hypersensitivity to clarithromycin or any component of the product, erythromycin, or any macrolide antibiotics.
- QT prolongation or ventricular cardiac arrhythmias, including torsade de pointes.
The most common side effects are gastrointestinal: diarrhea (3%), nausea (3%), abdominal pain (3%), and vomiting (6%). It also can cause headaches, insomnia, and abnormal liver function tests. Allergic reactions include rashes and anaphylaxis. Less common side effects (<1%) include extreme irritability, hallucinations (auditory and visual), dizziness/motion sickness, and alteration in senses of smell and taste, including a metallic taste. Dry mouth, panic attacks, and nightmares have also been reported, albeit less frequently.
In February 2018, the FDA issued a Safety Communication warning with respect to an increased risk for heart problems or death with the use of clarithromycin, and has recommended that alternative antibiotics be considered in those with heart disease.
Clarithromycin can lead to a prolonged QT interval. In patients with long QT syndrome, cardiac disease, or patients taking other QT-prolonging medications, this can increase risk for life-threatening arrhythmias.
In one trial, the use of short-term clarithromycin treatment was correlated with an increased incidence of deaths classified as sudden cardiac deaths in stable coronary heart disease patients not using statins. Some case reports suspect it of causing liver disease.
Liver and kidney
Clarithromycin has been known to cause jaundice, cirrhosis, and kidney problems, including kidney failure.
Central nervous system
Common adverse effects of clarithromycin in the central nervous system include dizziness, headaches. Rarely, it can cause ototoxicity, delirium and mania.
A risk of oral candidiasis and vaginal candidiasis, due to the elimination of the yeast’s natural bacterial competitors by the antibiotic, has also been noted.
Pregnancy and breastfeeding
Clarithromycin should not be used in pregnant women except in situations where no alternative therapy is appropriate. Clarithromycin can cause potential hazard to the fetus hence should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. For lactating mothers it is not known whether clarithromycin is excreted in human milk.
Clarithromycin inhibits a liver enzyme, CYP3A4, involved in the metabolism of many other commonly prescribed drugs. Taking clarithromycin with other medications that are metabolized by CYP3A4 may lead to unexpected increases or decreases in drug levels.
A few of the common interactions are listed below.
Clarithromycin has been observed to have a dangerous interaction with colchicine as the result of inhibition of CYP3A4 metabolism and P-glycoprotein transport. Combining these two drugs may lead to fatal colchicine toxicity, particularly in people with chronic kidney disease.
Taking clarithromycin concurrently with certain statins (a class of drugs used to reduce blood serum cholesterol levels) increases the risk of side effects, such as muscle aches and muscle break down (rhabdomyolysis).
Calcium channel blockers
Concurrent therapy with calcium channel blocker may increase risk of low blood pressure, kidney failure, and death, compared to pairing calcium channel blockers with azithromycin, a drug similar to clarithromycin but without CYP3A4 inhibition. Administration of clarithromycin in combination with verapamil have been observed to cause low blood pressure, low heart rate, and lactic acidosis.
Clarithromycin may double the level of carbamazepine in the body by reducing its clearance, which may lead to toxic symptoms of carbamazepine, such as double vision, loss of voluntary body movement, nausea, as well as hyponatremia.
Depending on the combination of medications, clarithromycin therapy could be contraindicated, require changing doses of some medications, or be acceptable without dose adjustments. For example, clarithromycin may lead to decreased zidovudine concentrations.
Mechanism of action
Clarithromycin prevents bacteria from multiplying by acting as a protein synthesis inhibitor. It binds to 23S rRNA, a component of the 50S subunit of the bacterial ribosome, thus inhibiting the translation of peptides.
MetabolismUnlike erythromycin, clarithromycin is acid-stable, so can be taken orally without having to be protected from gastric acids. It is readily absorbed, and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, clarithromycin is actively transported to the site of infection. During active phagocytosis, large concentrations of clarithromycin are released; its concentration in the tissues can be over 10 times higher than in plasma. Highest concentrations are found in liver, lung tissue, and stool.
Clarithromycin has a fairly rapid first-pass metabolism in the liver. Its major metabolites include an inactive metabolite, N-desmethylclarithromycin, and an active metabolite, 14-(R)-hydroxyclarithromycin. Compared to clarithromycin, 14-(R)-hydroxyclarithromycin is less potent against mycobacterial tuberculosis and the Mycobacterium avium complex. Clarithromycin (20%-40%) and its active metabolite (10%-15%) are excreted in urine. Of all the drugs in its class, clarithromycin has the best bioavailability at 50%, which makes it amenable to oral administration. Its elimination half-life is about 3 to 4 hours with 250 mg administered every 12 h, but increased to 5 to 7 h with 500 mg administered every 8 to 12 h. With any of these dosing regimens, the steady-state concentration of this metabolite is generally attained within 3 to 4 days.
Clarithromycin was invented by researchers at the Japanese drug company Taisho Pharmaceutical in 1980. The product emerged through efforts to develop a version of the antibiotic erythromycin that did not experience acid instability in the digestive tract, causing side effects, such as nausea and stomachache. Taisho filed for patent protection for the drug around 1980 and subsequently introduced a branded version of its drug, called Clarith, to the Japanese market in 1991. In 1985, Taisho partnered with the American company Abbott Laboratories for the international rights, and Abbott also gained FDA approval for Biaxin in October 1991. The drug went generic in Europe in 2004 and in the US in mid-2005.
Society and culture
A pack of Clarithromycin tablets manufactured by Taisho Pharmaceutical
Clarithromycin is available as a generic medication. In the United States, clarithromycin is available as immediate release tablets, extended release tablets, and granules for oral suspension.
Clarithromycin is available under several brand names in many different countries, for example Biaxin, Crixan, Claritron, Clarihexal, Clacid, Claritt, Clacee, Clarac, Clariwin, Claripen, Clarem, Claridar, Cloff, Fromilid, Infex, Kalixocin, Karicin, Klaricid, Klaridex, Klacid, Klaram, Klabax, MegaKlar, Monoclar, Resclar, Rithmo, Truclar, Vikrol and Zeclar.
In the UK the drug product is manufactured in generic form by a number of manufacturers including Somex Pharma, Ranbaxy, Aptil and Sandoz.
Indian Pat. Appl., 2014DE00731, 31 Aug 2016
Heterocycles, 31(12), 2121-4; 1990
https://patents.google.com/patent/WO2006064299A1/enErythromycin A is known to be a useful macrolide antibiotic having a strong activity against Gram-positive bacteria, this compound has an undesirable property that it loses rapidly the antibacterial activity by the acid in stomach when administered orally, where- upon its blood concentration remains at a low level. 6-0-Alkyl derivatives of Erythromycin- A are well known as an useful antibacterial agents. 6-O-Methyl-Erythromycin-A (Clarithromycin) and a pharmaceutically acceptable salt is a potent macrolide antibiotic as reported in US Patent No. 4,331 ,803. Clarithromycin is stable in acidic medium and also remarkable in vivo activity and has a strong antibacterial property against Gram-positive bacteria compared to Erythromycin- A. This compound shows excellent effect for the treatment of infections by oral administration.A number of synthetic processes have been reported for preparing 6-O-alkyl erythromycin. US Patent No. 4,331 ,803 discloses a method for the preparation of Clarithromycin by methylating 6-OH group of 2′-O-3′-N-benzyloxycarbonyl erythromycinFormula (III)
21,3′-O-Protected ErythromycinMethylation of 6-OH group of the 2′,3′-benzyloxycarbonyl erythromycin was carried out using methyl iodide in the presence of a suitable base in a solvent. Clarithromycin was obtained from the compound after removing benzyloxycarbonyl group by hydrogenolysis and then subjecting to the reductive methylation in the presence of excess amount of farmaldehyde. Clarithromycin can also be synthesized by the methylation of 6-OH position of Erythromycin-A-9-OximeFormula (II)
Erythromycin-9-OximeSynthesis of Clarithromycin using 9-oxime or its derivatives are well reported in US Patent Nos. 5,274,085; 4,680,386; 4,668,776; 4,670,549 and 4,672,109. In case of Erythromycin-9-Oxime derivatives, the oxime is protected before methylation step with 2- alkenyl group (US Patent Nos. 4,670,549; 4,668,776) or benzyl group (US Patent Nos. 4,680,386 and 4,670,549). However, it has been reported (Ref. Journal of Antibiotics 46, No. 6, Page No. 647, year 1993) that when the Erythromycin-A-9-Oxime is protected by trimethylsilyl group, which is very unstable under basic condition pose potential impurities formation during methylation. There are some methods reported in US Patent Nos., e.g. , 4,680,386; 4,670,549 and US Patent No. 4,311,803 for the synthesis of Clarithromycin by using chlorobenzyloxycarbonyl group for protection at 2′ and 3′ function of of Erythromycin-A-9-Oxime derivatives.For the protection of 2′-OH group (US Patent No. 4,311 ,803) requires large amounts of benzyl chloroformate which poses problems in handling because of its severe irritating and toxic properties. This protection step also leads to the formation of 3′ -N- demethylation, which requires an additional re-methylation step. The de-protection of chlorobenzyloxy carbonyl group leads to the formation of undesired side products. In earlier reported processes, e.g. , US Patent No. 4,990,602; EP 0,272,110 Al where the methylation has been done on Erythromycin-A-9-Oxime derivatives by the protection of 2′ and 4″ hydroxyl groups using DMSO and THF as a solvent at 0° to 50C or at room temperature, smooth methylation takes place with less side product formation. However, by using the above methylation processes the formation of 6, 11-O-dimethyl erythromycin- A (Compound- A) is always more than 1.0 % in Clarithromycin. Hence, there is a need for an efficient methylation process for the production of Clarithromycin with lesser amount of 6,11-O-dimethyl erythromycin-A than reported previously.
EXAMPLE 1Erythromycin-A-9-OximeTo a solution of 201 Ltr water in 561 Kg isopropyl alcohol is added 282 Kg (4057 mol) of hydroxyl amine hydrochloride under stirring and the reaction mixture is brought to 10 to 200C. Caustic flakes (162 Kg, 4050 mol) is added slowly to the reaction mixture by keeping temperature between 10° to 200C. After 15 minutes of completion of addition, pH of reaction mixture is adjusted to 6.5 to 7.0 by the slow addition of glacial acetic acid (96 Ltr, 100.8 Kg, 1678.6 mole). To the stirred reaction mass is added 300 Kg (408.8 mole) of Erythromycin-A base and reaction mixture is stirred at 55° C for 28 hours. After completion of the reaction, mixture is brought to ambient temperature and to it a mixture of ammonia solution (270 Kg) and water (600 Ltr) is added within 1 hour followed by 3000 Ltr of fresh water in next two hours and stirred the reaction mass for further 1 hour. White solid product obtained is centrifuged, wet cake is washed with water and dried at 6O0C for 12 hours to give 270 Kg of erythromycin-A Oxime. Melting point = 156° to 158°C.EXAMPLE 22′,4″-O-Bis(trimethylsilyl)-erythro?nycin-A-9[O-(l-methoxy-l-methyl ethyl)oximeTo a solution of 80 Kg (106.8 mole) of Erythromycin-A-9-Oxime in 400 Ltr of dichloromethane is added 38.50 Kg (534 mole) of 2-methoxy propene at 100C temperature 19.25 Kg (166.6 mole) of pyridine hydrochloride is added under stirring and the reaction mixture is stirred at 8 to 12° C for 6 hours then to it is added 19.30 Kg (119.5 mole) of HMDS and stirring is continued for 12 to 15 hours at 15° to 18°C temperature. After completion of reaction, 400 Ltr of saturated aqueous sodium carbonate solution is added and the mixture is stirred thoroughly at room temperature. Aqueous layer is further extracted with fresh DCM (100 Ltr). Both DCM extracts are mixed together and washed with water (200 Ltr) followed by brine solution (200 Ltr). The solvent is evaporated under reduced pressure. To the obtained crude solid mass is charged isopropyl alcohol (240 Ltr) and distilled out 80 Ltr of isopropyl alcohol. To the reaction mixture 160 Ltr of water is charged and stirring continued at room temperature for 1 hour. Solid crystalline product obtained is centrifuged and dried at 60° to 650C for 8 hours under vacuum to give 85 Kg of title compound. Melting point = 125° to 126°C. HPLC Purity = More than 90 % .EXAMPLE 3Clarithromycin-9- OximeTo a solution of 80 Kg (82.98 mole) of 2′,4″-O-bis(trimethylsilyl)-erythromycin-A- 9-[O-(l-methoxy methyl ethyl)Oxime] in 1200 Ltr of a mixture of dimethyl sulfoxide and diethylether (1 : 1) are added methyl iodide (20.62 Kg, 145.2 mole) and 6.48 Kg (98.35 mole) of 85 % potassium hydroxide powder and the reaction mixture is stirred for 90 minutes at room temperature. To the reaction mass is added 53 Kg of 40 % dimethylamine solution and stirring is continued for 1 hour diethylether layer is separated and DMSO layer is further extracted with fresh diethylether (200 Ltr). Combined ether layer is washed with water and concentrated in vacuum. To the obtained semi solid mass 330 Ltr of isopropyl alcohol is charged and then distilled out 165 Ltr of isopropyl alcohol. To the obtained slurry 165 Ltr of water and 21.71 Kg formic acid (99%) are added and the mixture is stirred at room temperature for 30 minutes. 622 Ltr of water is added to the reaction mixture and pH is adjusted between 10.5 and 11.5 with 25 % aqueous sodium hydroxide solution. Solid compound obtained is centrifuged and wet cake is kept as such for further reaction on the basis of moisture content. Wet weight = 95 Kg, Moisture Content = 33 %, Dried weight = 62 KgEXAMPLE 46-O-Methyl erythromycin- A (Clarithromycin)62 Kg of 6-O-Methyl erythromycin-9-Oxime is charged into a mixture of 434 Ltr of isopropyl alcohol and water (1: 1) and to it is added 38.80 Kg of sodium metabisulphite (203 mole) and then the mixture is heated to reflux for 6 to 8 hours. To the reaction mixture is charged water (620 Ltr) at ambient temperature and then the mixture is adjusted to pH about 10.5 to 11.5 by adding 25% aqueous sodium hydroxide solution and stirred for further 1 hour. White solid crude product is centrifuged, washed with water (300 Ltr), dried at 65° to 750C for 8 hours to give 40 Kg of crude Clarithromycin which on re- crystallization with chloroform isopropyl alcohol mixture provided 20 Kg of Clarithromycin (Form II).
SYNEP 0041355; US 4331803J Antibiot 1984,37(2),187-189
The methylation of 2′-O,N-bis(benzyloxycarbonyl)-N-demethylerythromycin A (I) with methyl iodide and KOH or NaHI in DMSO-dimethoxyethane gives the 6-O-methyl derivative (II), which is deprotected by hydrogenation with H2 over Pd/C in ethanol acetic acid affording 6-O-methyl-N-demethylerythromycin A (III). Finally, this compound is methylated with formaldehyde under reductive conditions (H2-Pd/C) in ethanol/acetic acid.
2 Clarithromycin. Initial attempts of making clarithromycin (2) from erythromycin (1) by methylation of 8 gave approximately equal amounts of 2 and 10 by methylation at O-6 and O-11, respectively (Scheme 2, route A).[28–30] This allowed 2 to be obtained in approximately 39% yield, but it contained a small impurity of di-O-methylated 9. To improve the yields and obtain 2 in pure form, other alternatives were explored. During methylation of analogues of 8 it was observed that the conformation of the macrocyclic core plays an important role for the regioselectivity of the O-methylation. As oximes are readilyhydrolysed and may have different conformations than ketone 8, oximes 11 and 13 were subjected to methylation. Interestingly, methylation of 13, but not of 11, proved to be highly selective for O-6 and provided 14 in 86% yield (Scheme2 route B); an observation which supports that 13 populates different conformations compared to 8 and 11 under the methylation conditions. Compound 14 was then hydrogenated with Pd/C to deprotect the two benzyloxycarbonyl groups and the 2-chlorobenzyl group. The N-methylamine was then methylated by reductive amination and the oxime was deprotected by hydrolysis to provide clarithromycin (2). This procedure was further modified for process-scale synthesis so that clarithromycin (2) could be obtained in 70% yield starting from oxime 11 without the isolation of any intermediate. M. Shigeo, T. Yoko, W. Yoshiaki, O. Sadafumi, J. Antibiot. 1984, 37, 187 – 189.  Y. Watanabe, T. Adachi, T. Asaka, M. Kashimura, S. Morimoto, Heterocycles 1990, 31, 2121 – 2124.  E. H. Flynn, H. W. Murphy, R. E. McMahon, J. Am. Chem. Soc. 1955, 77, 3104 – 3106.  Y. Watanabe, S. Morimoto, T. Adachi, M. Kashimura, T. Asaka, J. Antibiot. 1993, 46, 647 – 660.32] R. A. Dominguez, M. D. C. C. Rodriguez, L. . D. Tejo, R. N. Rib, J. S. Cebrin, J. I. B. Bilbao, 2003, US6642364B2.
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|Trade names||Biaxin, others|
|License data||EU EMA: by INNUS DailyMed: Clarithromycin|
|By mouth, intravenous|
|ATC code||J01FA09 (WHO)|
|Legal status||AU: S4 (Prescription only)US: ℞-onlyEU: Rx-only In general: ℞ (Prescription only)|
|Protein binding||low binding|
|Elimination half-life||3–4 h|
|CompTox Dashboard (EPA)||DTXSID3022829|
|Chemical and physical data|
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////////////////////CLARITHROMYCIN, Antibacterial, Antibiotics, Macrolides, A-56268, TE-031,
#CLARITHROMYCIN, #Antibacterial, #Antibiotics, #Macrolides, #A-56268, #TE-031,
- Molecular FormulaC37H67NO13
- Average mass733.927 Da
- эритромицин [Russian] [INN]إيريثروميسين [Arabic] [INN]红霉素 [Chinese] [INN]
Synthesis ReferenceTakehiro Amano, Masami Goi, Kazuto Sekiuchi, Tomomichi Yoshida, Masahiro Hasegawa, “Process for preparing erythromycin A oxime or a salt thereof.” U.S. Patent US5274085, issued October, 1966.
US5274085ErythromycinCAS Registry Number: 114-07-8Additional Names: E-Base; E-Mycin; Erythromycin ATrademarks: Aknemycin (Hermal); Aknin (Lichtenstein); Emgel (GSK); Ery-Derm (Abbott); Erymax (Merz); Ery-Tab (Abbott); Erythromid (Abbott); ERYC (Warner-Chilcott); Erycen (APS); Erycin (Nycomed); Erycinum (Cytochemia); Ermysin (Orion); Gallimycin (Bimeda); Ilotycin (Lilly); Inderm (Dermapharm); PCE (Abbott); Retcin (DDSA); Staticin (Westwood); Stiemycin (Stiefel)Molecular Formula: C37H67NO13Molecular Weight: 733.93Percent Composition: C 60.55%, H 9.20%, N 1.91%, O 28.34%Literature References: Antibiotic substance produced by a strain of Streptomyces erythreus (Waksman) Waksman & Henrici, found in a soil sample from the Philippine Archipelago. Isoln: McGuire et al.,Antibiot. Chemother.2, 281 (1952); Bunch, McGuire, US2653899 (1953 to Lilly); Clark, Jr., US2823203 (1958 to Abbott). Properties: Flynn et al.,J. Am. Chem. Soc.76, 3121 (1954). Solubility data: Weiss et al.,Antibiot. Chemother.7, 374 (1957). Structure: Wiley et al.,J. Am. Chem. Soc.79, 6062 (1957). Configuration: Hofheinz, Grisebach, Ber.96, 2867 (1963); Harris et al.,Tetrahedron Lett.1965, 679. There are three erythromycins produced during fermentation, designated A, B, and C; A is the major and most important component. Erythromycins A and B contain the same sugar moieties, desosamine, q.v., and cladinose (3-O-methylmycarose). They differ in position 12 of the aglycone, erythronolide, A having an hydroxyl substituent. Component C contains desosamine and the same aglycone present in A but differs by the presence of mycarose, q.v., instead of cladinose. Structure of B: P. F. Wiley et al.,J. Am. Chem. Soc.79, 6070 (1957); of C: eidem,ibid. 6074. Synthesis of the aglycone, erythronolide B: E. J. Corey et al.,ibid.100, 4618, 4620 (1978); of erythronolide A: eidem,ibid.101, 7131 (1979). Asymmetric total synthesis of erythromycin A: R. B. Woodward et al.,ibid.103, 3215 (1981). NMR spectrum of A: D. J. Ager, C. K. Sood, Magn. Reson. Chem.25, 948 (1987). HPLC determn in plasma: W. Xiao et al., J. Chromatogr. B817, 153 (2005). Biosynthesis: Martin, Goldstein, Prog. Antimicrob. Anticancer Chemother., Proc. 6th Int. Congr. Chemother.II, 1112 (1970); Martin et al.,Tetrahedron31, 1985 (1975). Cloning and expression of clustered biosynthetic genes: R. Stanzak et al.,Biotechnology4, 229 (1986). Reviews: T. J. Perun in Drug Action and Drug Resistance in Bacteria1, S. Mitsuhashi, Ed. (University Park Press, Baltimore, 1977) pp 123-152; Oleinick in Antibioticsvol. 3, J. W. Corcoran, F. E. Hahn, Eds. (Springer-Verlag, New York, 1975) pp 396-419; Infection10, Suppl. 2, S61-S118 (1982). Comprehensive description: W. L. Koch, Anal. Profiles Drug Subs.8, 159-177 (1979).Properties: Hydrated crystals from water, mp 135-140°, resolidifies with second mp 190-193°. Melting point taken after drying at 56° and 8 mm. [a]D25 -78° (c = 1.99 in ethanol). uv max (pH 6.3): 280 nm (e 50). pKa1 8.8. Basic reaction. Readily forms salts with acids. Soly in water: ~2 mg/ml. Freely sol in alcohols, acetone, chloroform, acetonitrile, ethyl acetate. Moderately sol in ether, ethylene dichloride, amyl acetate.Melting point: mp 135-140°, resolidifies with second mp 190-193°pKa: pKa1 8.8Optical Rotation: [a]D25 -78° (c = 1.99 in ethanol)Absorption maximum: uv max (pH 6.3): 280 nm (e 50) Derivative Type: EthylsuccinateCAS Registry Number: 41342-53-4Trademarks: Anamycin (Chephasaar); Arpimycin (Rosemont); E.E.S. (Abbott); Eritrocina (Abbott); Eryliquid (Linden); Eryped (Abbott); Erythroped (Abbott); Esinol (Toyama); Monomycin (Grñenthal); Paediathrocin (Abbott); Pediamycin (Abbott); Refkas (Maruko)Molecular Formula: C43H75NO16Molecular Weight: 862.05Percent Composition: C 59.91%, H 8.77%, N 1.62%, O 29.70%Literature References: Prepn: GB830846; R. K. Clark, US2967129 (1960, 1961 both to Abbott).Properties: Hydrated crystals from acetone + water, mp 109-110°. [a]D -42.5°.Melting point: mp 109-110°Optical Rotation: [a]D -42.5° Therap-Cat: Antibacterial.Therap-Cat-Vet: Antibacterial.Keywords: Antibacterial (Antibiotics); Macrolides.
NEW DRUG APPROVALS
Erythromycin is an antibiotic which belongs to the group of macrolide antibiotics. The pharmaceutically distributed product consists of three components: Erythromycin A, B, and C where Erythromycin A represents the main component. Naturally this antibiotic is synthesized by the grampositive bacteria Streptomyces erythreus (Saccharopolyspora erythrea).
In 1949 Erythromycin was found for the first time in a soil sample in the Philippine region Iloilo. A research team, led by J. M. McGuire, was able to isolate Erythromycin which was part of the soil sample. Under the brand name Ilosone the product was launched commercially in 1952. They named the brand after the region where the antibiotic was found. Analogically the first product name was Ilotycin. Furthermore, in 1953 the U.S. patent was granted. Since 1957 the structure of Erythromycin is known and in 1965 the X-ray structure analysis gave awareness of the absolute configuration. In 1981, almost 30 years after the detection of Erythromycin, Robert B. Woodward, the Nobel prize laureate of chemistry in 1965, and his coworkers posthumously reported the first synthesis of Erythromycin A
The structural characteristic of macrolides, to which Erythromycin affiliates, is a macrocyclic lactone ring of fourteen, fifteen or sixteen members. In case of Erythromycin the lactone ring consists of 14-members. Substituents on the mainchain are cladinose on C-3 and desosamine on C-5. Erythromycin is not a single compound but represents an alloy of structural very similar components. The main constituents are Erythromycin A, B and C. As shown in Table 1 and Figure 1 they only differ in two rests on the lactone ring or on the cladinose each case. In addition to the variants already mentioned, further variants, like Erythromycin D and E are known. They are pre- and post-stages in the biosynthesis and often do not have antibiotic effects
Chemical and Pharmacokinetic Properties Formula: C37H67NO13 CAS-Number: 114-07-8 Molar Mass: 733.93g/mol Half Hife 1.5 hours pkA: 8,6 – 8,8 Melting Point: 411K (hydrat) 463-466K (anhydrous)
Erythromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes respiratory tract infections, skin infections, chlamydia infections, pelvic inflammatory disease, and syphilis. It may also be used during pregnancy to prevent Group B streptococcal infection in the newborn, as well as to improve delayed stomach emptying. It can be given intravenously and by mouth. An eye ointment is routinely recommended after delivery to prevent eye infections in the newborn.
Common side effects include abdominal cramps, vomiting, and diarrhea. More serious side effects may include Clostridium difficile colitis, liver problems, prolonged QT, and allergic reactions. It is generally safe in those who are allergic to penicillin. Erythromycin also appears to be safe to use during pregnancy. While generally regarded as safe during breastfeeding, its use by the mother during the first two weeks of life may increase the risk of pyloric stenosis in the baby. This risk also applies if taken directly by the baby during this age. It is in the macrolide family of antibiotics and works by decreasing bacterial protein production.
Erythromycin was first isolated in 1952 from the bacteria Saccharopolyspora erythraea. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. The World Health Organization classifies it as critically important for human medicine. It is available as a generic medication. In 2017, it was the 215th most commonly prescribed medication in the United States, with more than two million prescriptions.
Table 4.2.1 Therapeutic indications for the macrolide antibiotics.
Erythromycin can be used to treat bacteria responsible for causing infections of the skin and upper respiratory tract, including Streptococcus, Staphylococcus, Haemophilus and Corynebacterium genera. The following represents MIC susceptibility data for a few medically significant bacteria:
- Haemophilus influenzae: 0.015 to 256 μg/ml
- Staphylococcus aureus: 0.023 to 1024 μg/ml
- Streptococcus pyogenes: 0.004 to 256 μg/ml
- Corynebacterium minutissimum: 0.015 to 64 μg/ml
It may be useful in treating gastroparesis due to this promotility effect. It has been shown to improve feeding intolerances in those who are critically ill. Intravenous erythromycin may also be used in endoscopy to help clear stomach contents.
Enteric-coated erythromycin capsule from Abbott Labs
Erythromycin is available in enteric-coated tablets, slow-release capsules, oral suspensions, ophthalmic solutions, ointments, gels, enteric-coated capsules, non enteric-coated tablets, non enteric-coated capsules, and injections. The following erythromycin combinations are available for oral dosage:
- erythromycin base (capsules, tablets)
- erythromycin estolate (capsules, oral suspension, tablets), contraindicated during pregnancy
- erythromycin ethylsuccinate (oral suspension, tablets)
- erythromycin stearate (oral suspension, tablets)
For injection, the available combinations are:
- erythromycin gluceptate
- erythromycin lactobionate
For ophthalmic use:
- erythromycin base (ointment)
Gastrointestinal disturbances, such as diarrhea, nausea, abdominal pain, and vomiting, are very common because erythromycin is a motilin agonist. Because of this, erythromycin tends not to be prescribed as a first-line drug.
More serious side effects include arrhythmia with prolonged QT intervals, including torsades de pointes, and reversible deafness. Allergic reactions range from urticaria to anaphylaxis. Cholestasis, Stevens–Johnson syndrome, and toxic epidermal necrolysis are some other rare side effects that may occur.
Studies have shown evidence both for and against the association of pyloric stenosis and exposure to erythromycin prenatally and postnatally. Exposure to erythromycin (especially long courses at antimicrobial doses, and also through breastfeeding) has been linked to an increased probability of pyloric stenosis in young infants. Erythromycin used for feeding intolerance in young infants has not been associated with hypertrophic pyloric stenosis.
Erythromycin estolate has been associated with reversible hepatotoxicity in pregnant women in the form of elevated serum glutamic-oxaloacetic transaminase and is not recommended during pregnancy. Some evidence suggests similar hepatotoxicity in other populations.
It can also affect the central nervous system, causing psychotic reactions, nightmares, and night sweats.
Erythromycin is metabolized by enzymes of the cytochrome P450 system, in particular, by isozymes of the CYP3A superfamily. The activity of the CYP3A enzymes can be induced or inhibited by certain drugs (e.g., dexamethasone), which can cause it to affect the metabolism of many different drugs, including erythromycin. If other CYP3A substrates — drugs that are broken down by CYP3A — such as simvastatin (Zocor), lovastatin (Mevacor), or atorvastatin (Lipitor)—are taken concomitantly with erythromycin, levels of the substrates increase, often causing adverse effects. A noted drug interaction involves erythromycin and simvastatin, resulting in increased simvastatin levels and the potential for rhabdomyolysis. Another group of CYP3A4 substrates are drugs used for migraine such as ergotamine and dihydroergotamine; their adverse effects may be more pronounced if erythromycin is associated. Earlier case reports on sudden death prompted a study on a large cohort that confirmed a link between erythromycin, ventricular tachycardia, and sudden cardiac death in patients also taking drugs that prolong the metabolism of erythromycin (like verapamil or diltiazem) by interfering with CYP3A4. Hence, erythromycin should not be administered to people using these drugs, or drugs that also prolong the QT interval. Other examples include terfenadine (Seldane, Seldane-D), astemizole (Hismanal), cisapride (Propulsid, withdrawn in many countries for prolonging the QT time) and pimozide (Orap). Theophylline, which is used mostly in asthma, is also contraindicated.
Erythromycin and doxycycline can have a synergistic effect when combined and kill bacteria (E. coli) with a higher potency than the sum of the two drugs together. This synergistic relationship is only temporary. After approximately 72 hours, the relationship shifts to become antagonistic, whereby a 50/50 combination of the two drugs kills less bacteria than if the two drugs were administered separately.
It may alter the effectiveness of combined oral contraceptive pills because of its effect on the gut flora. A review found that when erythromycin was given with certain oral contraceptives, there was an increase in the maximum serum concentrations and AUC of estradiol and dienogest.
Erythromycin is an inhibitor of the cytochrome P450 system, which means it can have a rapid effect on levels of other drugs metabolised by this system, e.g., warfarin.
Mechanism of action
Erythromycin displays bacteriostatic activity or inhibits growth of bacteria, especially at higher concentrations. By binding to the 50s subunit of the bacterial rRNA complex, protein synthesis and subsequent structure and function processes critical for life or replication are inhibited. Erythromycin interferes with aminoacyl translocation, preventing the transfer of the tRNA bound at the A site of the rRNA complex to the P site of the rRNA complex. Without this translocation, the A site remains occupied, thus the addition of an incoming tRNA and its attached amino acid to the nascent polypeptide chain is inhibited. This interferes with the production of functionally useful proteins, which is the basis of this antimicrobial action.
Erythromycin increases gut motility by binding to Motillin, thus it is a Motillin receptor agonist in addition to its antimicrobial properties.
Erythromycin is easily inactivated by gastric acid; therefore, all orally administered formulations are given as either enteric-coated or more-stable salts or esters, such as erythromycin ethylsuccinate. Erythromycin is very rapidly absorbed, and diffuses into most tissues and phagocytes. Due to the high concentration in phagocytes, erythromycin is actively transported to the site of infection, where, during active phagocytosis, large concentrations of erythromycin are released.
Most of erythromycin is metabolised by demethylation in the liver by the hepatic enzyme CYP3A4. Its main elimination route is in the bile with little renal excretion, 2%-15% unchanged drug. Erythromycin’s elimination half-life ranges between 1.5 and 2.0 hours and is between 5 and 6 hours in patients with end-stage renal disease. Erythromycin levels peak in the serum 4 hours after dosing; ethylsuccinate peaks 0.5-2.5 hours after dosing, but can be delayed if digested with food.
Erythromycin crosses the placenta and enters breast milk. The American Association of Pediatrics determined erythromycin is safe to take while breastfeeding. Absorption in pregnant patients has been shown to be variable, frequently resulting in levels lower than in nonpregnant patients.
Standard-grade erythromycin is primarily composed of four related compounds known as erythromycins A, B, C, and D. Each of these compounds can be present in varying amounts and can differ by lot. Erythromycin A has been found to have the most antibacterial activity, followed by erythromycin B. Erythromycins C and D are about half as active as erythromycin A. Some of these related compounds have been purified and can be studied and researched individually.
Over the three decades after the discovery of erythromycin A and its activity as an antimicrobial, many attempts were made to synthesize it in the laboratory. The presence of 10 stereogenic carbons and several points of distinct substitution has made the total synthesis of erythromycin A a formidable task. Complete syntheses of erythromycins’ related structures and precursors such as 6-deoxyerythronolide B have been accomplished, giving way to possible syntheses of different erythromycins and other macrolide antimicrobials. Woodward successfully completed the synthesis of erythromycin A.
Erythromycin related compounds
In 1949 Abelardo B. Aguilar, a Filipino scientist, sent some soil samples to his employer Eli Lilly. Eli Lilly’s research team, led by J. M. McGuire, managed to isolate erythromycin from the metabolic products of a strain of Streptomyces erythreus (designation changed to Saccharopolyspora erythraea) found in the samples.
Lilly filed for patent protection on the compound which was granted in 1953. The product was launched commercially in 1952 under the brand name Ilosone (after the Philippine region of Iloilo where it was originally collected). Erythromycin was formerly also called Ilotycin.
The antibiotic clarithromycin was invented by scientists at the Japanese drug company Taisho Pharmaceutical in the 1970s as a result of their efforts to overcome the acid instability of erythromycin.
Scientists at Chugai Pharmaceuticals discovered an erythromycin-derived motilin agonist called mitemcinal that is believed to have strong prokinetic properties (similar to erythromycin) but lacking antibiotic properties. Erythromycin is commonly used off-label for gastric motility indications such as gastroparesis. If mitemcinal can be shown to be an effective prokinetic agent, it would represent a significant advance in the gastrointestinal field, as treatment with this drug would not carry the risk of unintentional selection for antibiotic-resistant bacteria.
Society and culture
It is available as a generic medication.
In the United States in 2014 the price increased to seven dollars per tablet.
The price of Erythromycin rose three times between 2010 and 2015, from 24 cents per tablet in 2010 to $8.96 in 2015. In 2017, a Kaiser Health News study found that the per-unit cost of dozens of generics doubled or even tripled from 2015 to 2016, increasing spending by the Medicaid program. Due to price increases by drug manufacturers, Medicaid paid on average $2,685,330 more for Erythromycin in 2016 compared to 2015 (not including rebates). By 2018, generic drug prices had climbed another 5% on average.
Brand names include Robimycin, E-Mycin, E.E.S. Granules, E.E.S.-200, E.E.S.-400, E.E.S.-400 Filmtab, Erymax, Ery-Tab, Eryc, Ranbaxy, Erypar, EryPed, Eryped 200, Eryped 400, Erythrocin Stearate Filmtab, Erythrocot, E-Base, Erythroped, Ilosone, MY-E, Pediamycin, Zineryt, Abboticin, Abboticin-ES, Erycin, PCE Dispertab, Stiemycine, Acnasol, and Tiloryth.
Erythromycin/tretinoin, a combination of tretinoin and the antibiotic erythromycin
The total synthesis of the erythromycins (Figure 4.2.2) poses a supreme challenge and has attracted the attention of some of the world’s most eminent synthetic chemists, leading to many elegant examples of the total synthesis of complex natural products. The total synthesis of the erythronolide A aglycone (lacking the sugar units) was first reported by E. J. Corey (Nobel Prize in Chemistry in 1990) in a series of articles in the late 1970s (Scheme 4.2.2) (Corey et al., 1979 and references cited therein), and the total synthesis of erythromycin (known then as erythromycin A) by R. B. Woodward (Nobel Prize in Chemistry in 1965) in a series of articles in 1981, after his death (Scheme 4.2.3) (Woodward et al., 1981 and references cited therein). The Woodward synthesis is particularly elegant, as the dithiadecalin intermediate supplies both the C3-C8 and C9-C13 fragments (Scheme 4.2.3).
Figure 4.2.2 Erythromycins A and B and their aglycones, erythronolides A and B
Scheme 4.2.2 Corey’s total synthesis of erythronolide A (38 steps from the cyclohexadiene fragment; 0.04% overall yield)
Scheme 4.2.3 Woodward’s total synthesis of erythromycin (56 steps from 4-thianone; 0.01% overall yield)
Once again, erythromycin is such a complex antibiotic that its commercial production by total synthesis will never be feasible, and it is obtained from the submerged culture of free or immobilised Saccharopolyspora erythraea (El-Enshasy et al., 2008).
We have now seen a number of examples of how very complex semi-synthetic antibiotics can be prepared through the combination of fermentation (to give the complex natural product) and chemical modification, so you will no doubt already have spotted that both clarithromycin and roxithromycin are semi-synthetic macrolide antibiotics. Clarithromycin can be obtained in a five-step synthetic procedure, from erythromycin oxime (Brunet et al., 2007), while roxithromycin can also be prepared from this oxime (Massey et al., 1970) in a single step (Scheme 4.2.4) (Gouin d’Ambrieres et al., 1982). What is not so obvious is that azithromycin is also a semi-synthetic macrolide, having originally been produced by PLIVA Pharmaceuticals from erythromycin oxime via a sequence of reactions which included the well-known Beckmann rearrangement (Djoki et al., 1986). For more on the synthesis of the erythromycins, see Paterson and Mansuri (1985).
Scheme 4.2.4 Preparation of the semi-synthetic macrolide antibiotic roxithromycin
Erythromycin. Erythromycin (1) was discovered in 1952 during the investigation of soil samples from Iloilo, Philippines for antibiotic activity[18, 19] and its molecular structure was assigned in 1957. The microorganism that produced erythromycin was isolated and characterised as Streptomyces erythreus, strain NRRL 2338.[18, 19] Over the years, strain improvements and genetic engineering has allowed the yield of erythromycin to be increased so that 8–10 g L1 can now be produced from a tryptic soy broth.[21–25] Erythromycin forms anhydro-erythromycin 6 and 6:9, 9:12 spiroketal 7 under the acidic conditions in the stomach (Scheme 1), which results in the loss of its antibacterial activity and induction of abdominal pain.[26, 27] Generation of by-products 6 and 7 occurs through an acid-catalysed intramolecular reaction of the C-6 hydroxyl group with the C-9 keto moiety. To avoid this by-product formation several different semi-synthetic derivatives of erythromycin have been prepared in which either of these two functionalities are modified. They led to the discovery of clarithromycin (2) by O-6 methylation of erythromycin (Figure 3). Removal of the C-9 ketone by the formation of an oxime followed by Beckmann rearrangement and reduction led to azithromycin (3), which belongs to a new class of macrolides called “azalides”. Alternatively, conversion of the C-9 ketone to an amine, followed by reaction with an aldehyde, gave dirithromycin (4). Yet another approach involved the transformation of clarithromycin to the conformationally restricted telithromycin
Erythromycin, (3R,4S,5S,6R,7R,9R,11R,12R,13S,14R)-4-[(2,6-dideoxy-3-Cmethyl-3-O-methyl-α-L-ribo-hexopyranosyl)-oxy]-14-ethyl-7,12,13-trihydroxy- 3,5,7,9,11,13-hexamethyl-6-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy ]oxacyclotetradecan-2,10-dione (32.2.1), is more specifically called erythromycin A. It was first isolated in 1952 from the culture liquid of microorganisms of the type Streptomyces erytherus. Minor amounts of erythromycin B and C were also found in the culture fluid. Erythromycin B differs from A in that a hydrogen atom is located at position 12 in the place of a hydroxyl group, while erythromycin C differs from A in that the residue of a different carbohydrate, micarose (2-6-di-deoxy-3-C-methyl-L-ribohexose), is bound to the macrocycle in position 3 in the place of cladinose (4-methoxy-2,4-dimethyl-tetrahydropyran-3,6-diol).
Erythromycin A is produced only microbiologically using active strains of microorganisms of the type Saccharopolospora erythraea.
Erythromycin synthesis by modular polyketide synthases. The three genes EryAI-III encode three proteins of PKS: DEBS1 (the loading module, modules 1, 2) DEBS2 (modules 3, 4), DEBS3 (modules 5, 6, TE domain). Thus, PKS consists of the loading module, six extension modules, and TE domain. Each module includes from three to six domains: AT-acyl transferase, ACP-acyl carrier protein, KS-ketosynthase, KR-ketoreductase, DH-dehydratase, ERenoyl reductase.
The chemical synthesis of Erythromycin poses a huge challenge. The molecule contains ten stereogenic centers of which five are arranged consecutively. R. B. Woodward and his research team first succeeded in synthesizing Erythromycin A. The reaction sequence, however, is so complicated that the yield was only about 0,02 % and, thus, the synthesis is not utilizable comercially. This is the reason for the preferred use of the biosynthesis of Erythromycin via fermentation of Streptomyces erythreus. Other scientists and research teams dealt with the synthesis of Erythromycin as well and developed very similar approaches. Most methods for the Erythromycin synthesis are based on the construction of the aglycon from secoic acid via glycosylation. Indeed the process is also possible inversely: first, a glycosylation, then a lactonization occurs. The yield, however, is considerably less. While earlier scientist mainly dealt with the production of the different secoic acids, the lactonization process is the major problem today because there is no fully developed method for it yet. A lot of side reactions such as dimerization and polymerization appear, because a 14 membered ring is hard to enclose. Even if the chemical synthesis of Erythromycin has no importance for the comercial fabrication of the antibiotic, it is still important for the development and fabrication of its derivatives.
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- “Erythromycin”. Drug Information Portal. U.S. National Library of Medicine.
- U.S. Patent 2,653,899
|Trade names||Eryc, Erythrocin, others|
|License data||US DailyMed: Erythromycin|
|By mouth, intravenous (IV), intramuscular (IM), topical, eye drops|
|Drug class||Macrolide antibiotic|
|ATC code||D10AF02 (WHO) J01FA01 (WHO) S01AA17 (WHO) QJ51FA01 (WHO)|
|Legal status||AU: S4 (Prescription only)UK: POM (Prescription only)US: ℞-only|
|Bioavailability||Depends on the ester type between 30% – 65%|
|Metabolism||liver (under 5% excreted unchanged)|
|Elimination half-life||1.5 hours|
|PDB ligand||ERY (PDBe, RCSB PDB)|
|CompTox Dashboard (EPA)||DTXSID4022991|
|Chemical and physical data|
|Molar mass||733.937 g·mol−1|
//////////erythromycin, NSC-55929, NSC 55929, эритромицин , إيريثروميسين , 红霉素 , ANTIBACTERIAL, MACROLIDES, ANTIBIOTICS
#erythromycin, #NSC-55929, #NSC 55929, #эритромицин , #إيريثروميسين , #红霉素 , #ANTIBACTERIAL, #MACROLIDES, #ANTIBIOTICS
Azithromycin is an antibiotic used for the treatment of a number of bacterial infections. This includes middle ear infections, strep throat, pneumonia, traveler’s diarrhea, and certain other intestinal infections. It can 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.
Common side effects include nausea, vomiting, diarrhea and upset stomach. An allergic reaction, such as anaphylaxis, QT prolongation, or a type of diarrhea caused by Clostridium difficile is possible. No harm has been found with its use during pregnancy. Its safety during breastfeeding is not confirmed, but it is likely safe. Azithromycin is an azalide, a type of macrolide antibiotic. It works by decreasing the production of protein, thereby stopping bacterial growth.
Azithromycin was discovered 1980 by Pliva, and approved for medical use in 1988. It is on the World Health Organization’s List of Essential Medicines, the safest and most effective medicines needed in a health system. The World Health Organization classifies it as critically important for human medicine. It is available as a generic medication and is sold under many trade names worldwide. The wholesale cost in the developing world is about US$0.18 to US$2.98 per dose. In the United States, it is about US$4 for a course of treatment as of 2018. In 2016, it was the 49th most prescribed medication in the United States with more than 15 million prescriptions.
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.
- Community-acquired pneumonia due to C. pneumoniae, H. influenzae, M. pneumoniae, or S. pneumoniae
- Uncomplicated skin infections due to S. aureus, S. pyogenes, or S. agalactiae
- Urethritis and cervicitis due to C. trachomatis or N. gonorrhoeae. 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 and due to frequent co-infection with C. trachomatis and N. gonorrhoeae.
- Trachoma due to C. trachomatis
- Genital ulcer disease (chancroid) in men due to H. ducrey
- Acute bacterial sinusitis due to H. influenzae, M. catarrhalis, or S. pneumoniae. Other agents, such as amoxicillin/clavulanate are generally preferred, however.
- 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.
- Pharyngitis or tonsillitis caused by S. pyogenes as an alternative to first-line therapy in individuals who cannot use first-line therapy
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 gonorrhea reported to be highly resistant to azithromycin was found in the population in 2015. Neisseria gonorrhoeae is normally susceptible to azithromycin, but the drug is not widely used as monotherapy due to a low barrier to resistance development. Extensive use of azithromycin has resulted in growing Streptococcus pneumoniae resistance.
Aerobic and facultative Gram-positive microorganisms
- Staphylococcus aureus (Methicillin-sensitive only)
- Streptococcus agalactiae
- Streptococcus pneumoniae
- Streptococcus pyogenes
Aerobic and facultative Gram-negative microorganisms
- Haemophilus ducreyi
- Haemophilus influenzae
- Moraxella catarrhalis
- Neisseria gonorrhoeae
- Bordetella pertussis
- Legionella pneumophila
- Peptostreptococcus species
- Prevotella bivia
- Chlamydophila pneumoniae
- Chlamydia trachomatis
- Mycoplasma genitalium
- Mycoplasma pneumoniae
- Ureaplasma urealyticum
Pregnancy and breastfeeding
No harm has been found with use during pregnancy. However, there are no adequate well-controlled studies in pregnant women.
Safety of the medication during breastfeeding is unclear. It was reported that because only low levels are found in breast milk and the medication has also been used in young children, it is unlikely that breastfed infants would suffer adverse effects. Nevertheless, it is recommended that the drug be used with caution during breastfeeding.
Azithromycin appears to be effective in the treatment of COPD through its suppression of inflammatory processes. And potentially useful in asthma and sinusitis via this mechanism. Azithromycin is believed to produce its effects through suppressing certain immune responses that may contribute to inflammation of the airways.
Most common adverse 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, skin reactions, and anaphylaxis have been reported. Clostridium difficile infection has been reported with use of azithromycin. Azithromycin does not affect the efficacy of birth control unlike some other antibiotics such as rifampin. Hearing loss has been reported.
Occasionally, people have developed cholestatic hepatitis or delirium. Accidental intravenous overdose in an infant caused severe heart block, resulting in residual encephalopathy.
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.
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.
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. Azithromycin’s half-life allows a large single dose to be administered and yet maintain bacteriostatic levels in the infected tissue for several days.
Following a single dose of 500 mg, the apparent terminal elimination half-life of azithromycin is 68 hours. 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.
A team of researchers at the pharmaceutical company Pliva in Zagreb, SR Croatia, Yugoslavia, — 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. Patent protection ended in 2005.
Society and culture
It is available as a generic medication. The wholesale cost is about US$0.18 to US$2.98 per dose. In the United States it is about US$4 for a course of treatment as of 2018. In India, it is about US$1.70 for a course of treatment.
Azithromycin is commonly administered in film-coated tablet, capsule, oral suspension, intravenous injection, granules for suspension in sachet, and ophthalmic solution.
In 2010, azithromycin was the most prescribed antibiotic for outpatients in the US, whereas in Sweden, where outpatient antibiotic use is a third as prevalent, macrolides are only on 3% of prescriptions.
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Keywords: Antibacterial (Antibiotics); Macrolides.
- “Azithromycin”. Drug Information Portal. U.S. National Library of Medicine.
|Trade names||Zithromax, Azithrocin, others|
|Other names||9-deoxy-9α-aza-9α-methyl-9α-homoerythromycin A|
|By mouth (capsule, tablet or suspension), intravenous, eye drop|
|Drug class||Macrolide antibiotic|
|Bioavailability||38% for 250 mg capsules|
|Elimination half-life||11–14 h (single dose) 68 h (multiple dosing)|
|Excretion||Biliary, kidney (4.5%)|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||748.984 g·mol−1 g·mol−1|
|3D model (JSmol)|
/////////AZITHROMYCIN, Antibacterial, Antibiotics, Macrolides, CORONA VIRUS, COVID 19, アジスロマイシン ,
Substances Referenced in Synthesis Path
CAS-RN Formula Chemical Name CAS Index Name
76801-85-9 C37H70N2O12 2-deoxo-9a-aza-9a-homoerythromycin A 1-Oxa-6-azacyclopentadecan-15-one,
13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-α-L-ribo-hexopyranosyl)oxy]-2-eth- yl-3,4,10-trihydroxy-3,5,8,10,12,14-hexamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-β-D-xylo-hexopyranosyl]oxy]-, [2R-(2
90503-04-1 C37H70N2O14 [2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,
90503-05-2 C38H72N2O14 [2R-(2R*,3S*,4R*,5R*,8R*,10R*,11R*,12S*,
50-00-0 CH2O formaldehyde Formaldehyde
74-88-4 CH3I methyl iodide Methane, iodoTrade Names
Country Trade Name Vendor Annotation
D Ultreon Pfizer
Zithromax Pfizer Pharma/Gödecke/Parke-Davis
numerous generic preparations
F Azadose Pfizer
GB Zithromax Pfizer
I Azitrocin Bioindustria
Ribotrex Pierre Fabre
J Zithromac Pfizer
USA Azasite InSite Vision
Zithromax Pfizer as dihydrate
cps. 100 mg, 250 mg; Gran. 10%; susp. 200 mg (as dihydrate); tabl. 250 mg
Djokic, S. et al.: J. Antibiot. (JANTAJ) 40, 1006 (1987).
a DOS 3 140 449 (Pliva; appl. 12.10.1981; YU-prior. 6.3.1981).
US 4 517 359 (Pliva; 14.5.1985; appl. 22.9.1981; YU-prior. 6.3.1981).
b EP 101 186 (Pliva; appl. 14.7.1983; USA-prior. 19.7.1982, 15.11.1982).
US 4 474 768 (Pfizer; 2.10.1984; prior. 19.7.1982, 15.11.1982).
educt by ring expansion of erythromycin A oxime by Beckmann rearrangement:
Djokic, S. et al.: J. Chem. Soc., Perkin Trans. 1 (JCPRB4) 1986, 1881-1890.
Bright, G.M. et al.: J. Antibiot. (JANTAJ) 41, 1029 (1988). US 4 328 334 (Pliva; 4.5.1982; YU-prior. 2.4.1979).
stable, non-hygroscopic dihydrate: EP 298 650 (Pfizer; appl. 28.6.1988).
medical use for treatment of protozoal infections:
US 4 963 531 (Pfizer; 16.10.1990; prior. 16.8.1988, 10.9.1987).