Azithromycin

Pharmaceuticals -> Antibiotics

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Used in Switzerland

Pharmaceutical

Pharmaceuticals -> Antibiotics (Macrolides)

log Kow = 4.02

4.02

0.9

soluble in ethanol and DSMO, minimally soluble in water

5.14e-01 g/L

Breast Feeding; Lactation; Milk, Human; Anti-Bacterial Agents; Anti-Infective Agents; Macrolides

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

Ophthalmological preparations > Anti-infective agents

113-115 °C

White crystalline powder. mp: 126 °C. Optical rotation: -41.4 deg at 26 °C/D (c = 1 in CHCl3) /Azithromycin dihydrate/

113 - 115 °C

Positive

5.24

2.7

Agilent XCT

Electrospray ionization

formic acid (5.3nM)

8.5

pKa = 8.74

263.5 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

263.3 Ų [M+H]+ [CCS Type: TW; Method: calibrated with polyalanine and drug standards]

273.75 Ų [M+Na]+

Danger

H317 (97.5%): May cause an allergic skin reaction [Warning Sensitization, Skin]

P233, P260, P261, P264, P270, P271, P272, P273, P280, P284, P302+P352, P304+P340, P319, P321, P333+P317, P342+P316, P362+P364, P391, P403, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 122 reports by companies from 8 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Status: Active Update: 30-05-2014 https://echa.europa.eu/registration-dossier/-/registered-dossier/6141

1-Oxa-6-azacyclopentadecan-15-one, 13-[(2,6-dideoxy-3-C-methyl-3-O-methyl-.alpha.-L-ribo-hexopyranosyl)oxy]-2-ethyl-3,4,10-trihydroxy-3,5,6,8,10,12,14-heptamethyl-11-[[3,4,6-trideoxy-3-(dimethylamino)-.beta.-D-xylo-hexopyranosyl]oxy]-, (2R,3S,4R,5R,8R,10R,11R,12S,13S,14R)-: Does not have an individual approval but may be used as a component in a product covered by a group standard. It is not approved for use as a chemical in its own right.

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl azithromycin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

As with all fires, evacuate personnel to a safe area. Firefighters should use self-contained breathing equipment and protective clothing.

Water spray, dry chemical, carbon dioxide or foam as appropriate for surrounding fire and materials.

Store in tight container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity.

Store in tight, light-resistant container as defined in the USP-NF. This material should be handled and stored per label instructions to ensure product integrity. Store in a freezer.

Commercially available azithromycin 250- or 500-mg tablets should be stored at 15-30 °C.

Azithromycin powder in single-dose packets for oral suspension should be stored at 5-30 °C. Following reconstitution, the entire contents of the single-dose packet should be ingested immediately.10 Azithromycin powder for extended-release oral suspension should be stored at 30 °C or lower. Following reconstitution, azithromycin single-dose extended-release oral suspension should be stored in the original bottle at 25 °C but may be exposed to 15-30 °C. The reconstituted suspension should be consumed within 12 hours.

For more Storage Conditions (Complete) data for AZITHROMYCIN (6 total), please visit the HSDB record page.

Wear approved respiratory protection, chemically compatible gloves and protective clothing. Wipe up spillage or collect spillage using a high efficiency vacuum cleaner. Avoid breathing dust. Place spillage in appropriately labelled container for disposal. Wash spill site.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

SRP: Wastewater from contaminant suppression, cleaning of protective clothing/equipment, or contaminated sites should be contained and evaluated for subject chemical or decomposition product concentrations. Concentrations shall be lower than applicable environmental discharge or disposal criteria. Alternatively, pretreatment and/or discharge to a permitted wastewater treatment facility is acceptable only after review by the governing authority and assurance that "pass through" violations will not occur. Due consideration shall be given to remediation worker exposure (inhalation, dermal and ingestion) as well as fate during treatment, transfer and disposal. If it is not practicable to manage the chemical in this fashion, it must be evaluated in accordance with EPA 40 CFR Part 261, specifically Subpart B, in order to determine the appropriate local, state and federal requirements for disposal.

As a general rule, when handling USP Reference Standards avoid all contact and inhalation of dust, mists, and/or vapors associated with the material. Wash thoroughly after handling.

As with all dry powders it is advisable to ground mechanical equipment in contact with dry material to dissipate the potential buildup of static electricity.

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

SRP: Contaminated protective clothing should be segregated in such a manner so that there is no direct personal contact by personnel who handle, dispose, or clean the clothing. The completeness of the cleaning procedures should be considered before the decontaminated protective clothing is returned for reuse by the workers. Contaminated clothing should not be taken home at the end of shift, but should remain at employee's place of work for cleaning.

Respiratory Protection: Where respirators are deemed necessary to reduce or control occupational exposures, use NIOSH-approved respiratory protection and have an effective respirator program in place. Gloves: Chemically compatible. For handling solutions, ensure that the glove material is protective against the solvent being used. Use handling practices that minimize direct hand contact. Employees who are sensitive to natural rubber (latex) should use nitrile or other synthetic nonlatex gloves. Use of powdered latex gloves should be avoided due to the risk of latex allergy. Eye Protection: Safety glasses with sideshields are recommended. Face shields or goggles may be required if splash potential exists or if corrosive materials are present. Approved eye protection (e.g., bearing the ANSI Z87 or CSA stamp) is preferred. Maintain eyewash facilities in the work area. Protective clothing: For handling of laboratory scale quantities, a cloth lab coat is recommended. Where significant quantities are handled, work clothing may be necessary to prevent take-home contamination.

Engineering controls such as exhaust ventilation are recommended.

Because concomitant use of pimozide and other macrolides (e.g., clarithromycin) has increased pimozide concentrations and is associated with a risk of prolonged QT interval and serious cardiovascular effects, the manufacturer of pimozide states that concomitant use of pimozide and macrolides (including azithromycin) is contraindicated.

Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased phenytoin concentrations. Therefore, the patient should be carefully monitored if azithromycin and phenytoin are used concomitantly.

Although the single-dose extended-release oral suspension of azithromycin may be taken without regard to antacids containing magnesium hydroxide and/or aluminum hydroxide, conventional oral azithromycin preparations (tablets or oral suspension) should not be administered simultaneously with aluminum- or magnesium-containing antacids. A study using azithromycin capsules (no longer commercially available) indicate that administration of oral azithromycin 500 mg with an aluminum- and magnesium hydroxide-containing antacid resulted in a decreased rate of absorption of azithromycin as evidenced by 24% reduction in peak serum azithromycin concentrations; however, the extent of azithromycin absorption (AUC) was unaffected.

Although specific drug interaction studies have not been performed with azithromycin, concomitant use with other macrolides has resulted in increased concentrations of ergot alkaloids (ergotamine, dihydroergotamine). Therefore, the patient should be carefully monitored if azithromycin and ergot alkaloids are used concomitantly.

For more Interactions (Complete) data for AZITHROMYCIN (14 total), please visit the HSDB record page.

Like other macrolide antibiotics, azithromycin has been linked to a low rate of acute, transient and asymptomatic elevation in serum aminotransferases which occurs in 1% to 2% of patients treated for short periods, and a somewhat higher proportion of patients given azithromycin long term.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 3100(SRC), determined from a log Kow of 4.02(2) and a regression-derived equation(3), indicates that azithromycin is expected to have slight mobility in soil(SRC). The pKa of azithromycin is 8.74(2), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as an cation and cations do not volatilize. Azithromycin is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 2.6X10-24 mm Hg at 25 °C(SRC), determined from a fragment constant method(5). Biodegradation data in soil were not available(SRC, 2012).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 3100(SRC), determined from a log Kow of 4.02(2) and a regression-derived equation(3), indicates that azithromycin is expected to adsorb to suspended solids and sediment(SRC). A pKa of 8.74(2) indicates azithromycin will exist almost entirely in the cation form at pH values of 5 to 9 and therefore volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 200(SRC), from its log Kow(2) and a regression-derived equation(3), suggests the potential for bioconcentration in aquatic organisms is high, provided the compound is not metabolized by the organism(SRC). Azithromycin photodegradation followed first-order reaction kinetics in environmental waters under simulated solar radiation; in artificial freshwater (pH 6.8) the half-life was 7 hours(5). Biodegradation data in water were not available(SRC, 2012).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), azithromycin, which has an estimated vapor pressure of 2.6X10-24 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase azithromycin may be removed from the air by wet or dry deposition(SRC).

Azithromycin is considered a safe antimicrobial agent, and only a few patients discontinue it due to adverse effects. This medication is also associated with fewer adverse cardiac effects than other macrolides (eg, erythromycin, clarithromycin).

Median concentrations of azithromycin were 170 ng/L in raw influents and 160 ng/L in tertiary effluents of conventional wastewater treatment employed in Zurich, Switzerland(1). The compound exhibited a 60% frequency of detection in the Ebro River Basin, Spain, input being traced to wastewater treatment plant effluents. Average concentrations found in June 2005 and November 2005 in river waters downstream from 7 wastewater treatment plants were reported as 68, 16, 9, 2, 23, 17, and 14 ng/L; the method detection limit = 1 ng/L(2). Azithromycin concentrations in sewage water effluents of the Netherlands in 2002 ranged from approximately 170 to 500 ng/L(3). Mean concentrations in effluent from a tertiary wastewater treatment facility located in the Los Angeles, CA metropolitan area were 124, 337, and 304 ng/L in July 2008, May 2009, and October 2009, respectively; reporting limit = 10 ng/L(4). Azithromycin was detected in 5 of 5 influent samples at a concentrations of (ng/L; date): 17, 8/9/02; 6, 9/22/06; 37, 12/18/06; 53, 2/9/07; and detected, not quantified, 3/8/07. The limit of detection was 1 ng/L. Concentrations in effluent samples were (ng/L; date): 6, 8/9/02; 12, 9/22/06; 35, 12/18/06; 30, 2/9/07; and detected, not quantified; 3/8/07. Sampling took place at a wastewater treatment plant in Kentucky serving a local community of approximately 15,000 with an additional influx of approximately 10,000 students, academic year 2006-2007(5).

The Koc of azithromycin is estimated as 3100(SRC), using a log Kow of 4.02(1) and a regression-derived equation(2). According to a classification scheme(3), this estimated Koc value suggests that azithromycin is expected to have slight mobility in soil. The pKa of azithromycin is 8.74(1), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4).

Using a 2.4 meter soil column, treated effluent was applied to the top of the column over 23 days, simulating a recharge condition similar to those in arid or semiarid climates. The soil used was a Mohall-Laveen sandy loam from an area northwest of Phoenix, AZ with no known history of cultivation or irrigation. Secondarily treated effluent from a 17.5 million gallon/day municipal waste water treatment plant serving 120,000-150,000 residents near Phoenix, AZ was employed. Azithromycin was not detected in the outflow of the column; reporting limit not determined(1). The compound was shown to absorb to suspended solids and sludge during waste water treatment plant processes; Kd values in activated sludge were 460 and 352 for October 2003 and February 2004, respectively, at municipal treatment facilities in Switzerland (a KD of 376 was reported for an unspecified field study)(2).

/SIGNS AND SYMPTOMS/ Serious hypersensitivity reactions, including angioedema, anaphylaxis, and dermatologic reactions, have occurred rarely in patients receiving azithromycin. Fatalities have been reported.

/CASE REPORTS/ /The investigators/ report the case of a 25-year-old female patient with severe aggravation of myasthenia gravis due to azithromycin which was prescribed for an influenza syndrome. One hour after the intake of 500 mg azithromycin the patient developed weakness of the legs and respiratory distress due to respiratory muscle failure. She was hospitalized in a comatose state and required intubation and mechanical ventilation for six days. Acute worsening of myasthenia gravis was observed in this patient in 1986 after parenteral administration of erythromycin. Erythromycin causing aggravation of myasthenia gravis by interfering with neuromuscular transmission is reported in the literature. The close temporal relationship between the intake of azithromycin and severe worsening of myasthenia gravis in our patient suggests that azithromycin, a new azalid-antibiotic of the macrolid group, can exacerbate myasthenia gravis. /The investigators/ conclude that azithromycin should be added to the list of drugs to be used with caution in patients with myasthenia gravis.

/CASE REPORTS/ Vanishing bile duct syndrome is a severe cholestatic disease associated with toxic effects of medications. Stevens-Johnson syndrome is a hypersensitivity disorder that may also be caused by medications. We present a case of a 62-year-old male patient who developed vanishing bile duct syndrome a month after Stevens-Johnson syndrome. These adverse drug reactions were associated with the use of azithromycin (500 mg daily for 3 days). The patient was initially treated for Stevens-Johnson syndrome with steroids, antihistamines and proton pump inhibitors and fully recovered. However, a month after the beginning of Stevens-Johnson syndrome, he developed vanishing bile duct syndrome and was treated with steroids, ursodeoxycholic acid, antihistamines and tacrolimus. Unfortunately, the treatment was unsuccessful and he was listed for liver transplantation which was performed 7 months after the beginning of jaundice. ...

/CASE REPORTS/ ... A case of an elderly patient with idiopathic dilated cardiomyopathy who developed a significative prolongation of the QT interval after two days of treatment with azithromycin for a community-acquired pneumonia /is reported/. QT prolongation is associated with a high risk of serious ventricular tachyarrhythmias. Three days after discontinuation of azithromycin, QT interval returned to the normal value.

For more Human Toxicity Excerpts (Complete) data for AZITHROMYCIN (6 total), please visit the HSDB record page.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Azithromycin

vLess-DILI-concern

7

Adverse reactions

DOI:10.1016/j.drudis.2016.02.015

An estimated BCF of 200 was calculated in fish for azithromycin(SRC), using a log Kow of 4.02(1) and a regression-derived equation(2). According to a classification scheme(3), this BCF suggests the potential for bioconcentration in aquatic organisms is high(SRC), provided the compound is not metabolized by the organism(SRC).

The Approved Drug Products with Therapeutic Equivalence Evaluations List identifies currently marketed prescription drug products, incl azithromycin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.

J01FA10

J - Antiinfectives for systemic use

S - Sensory organs

QS - Sensory organs

QJ - Antiinfectives for systemic use

J01FA10; S01AA26

Macrolides stop bacterial growth by inhibiting protein synthesis and translation, treating bacterial infections. Azithromycin has additional immunomodulatory effects and has been used in chronic respiratory inflammatory diseases for this purpose.

In order to replicate, bacteria require a specific process of protein synthesis, enabled by ribosomal proteins. Azithromycin binds to the 23S rRNA of the bacterial 50S ribosomal subunit. It stops bacterial protein synthesis by inhibiting the transpeptidation/translocation step of protein synthesis and by inhibiting the assembly of the 50S ribosomal subunit,. This results in the control of various bacterial infections,. The strong affinity of macrolides, including azithromycin, for bacterial ribosomes, is consistent with their broad‐spectrum antibacterial activities. Azithromycin is highly stable at a low pH, giving it a longer serum half-life and increasing its concentrations in tissues compared to erythromycin.

Azithromycin usually is bacteriostatic, although the drug may be bactericidal in high concentrations against selected organisms. Bactericidal activity has been observed in vitro against Streptococcus pyogenes, S. pneumoniae, and Haemophilus influenzae. Azithromycin inhibits protein synthesis in susceptible organisms by penetrating the cell wall and binding to 50S ribosomal subunits, thereby inhibiting translocation of aminoacyl transfer-RNA and inhibiting polypeptide synthesis. The site of action of azithromycin appears to be the same as that of the macrolides (i.e., erythromycin, clarithromycin), clindamycin, lincomycin, and chloramphenicol. The antimicrobial activity of azithromycin is reduced at low pH. Azithromycin concentrates in phagocytes, including polymorphonuclear leukocytes, monocytes, macrophages, and fibroblasts. Penetration of the drug into phagocytic cells is necessary for activity against intracellular pathogens (e.g., Staphylococcus aureus, Legionella pneumophila, Chlamydia trachomatis, Salmonella typhi).

Terminal elimination half-life: 68 hours

An elimination half-life of 54.5 hours has been reported in children 4 months to 15 years of age receiving single or multiple oral doses of azithromycin.

Plasma azithromycin concentrations following a single 500-mg oral or IV dose decline in a polyphasic manner with a terminal elimination half-life averaging 68 hours. The high values for apparent steady-state volume of distribution (31.3-33.3 L/kg) and plasma clearance (630 mL/minute, 10.18 mL/minute per kg) of azithromycin suggest that the prolonged half-life is related to extensive uptake and subsequent release of the drug from tissues. The average tissue half-life of azithromycin is estimated to be 1-4 days. The half-life of the drug in peripheral leukocytes ranges from 34-57 hours.

In vitro and in vivo studies to assess the metabolism of azithromycin have not been performed, however, this drug is eliminated by the liver,.

The principal route of biotransformation involves N-demethylation of the desosamine sugar or at the 9a position on the macrolide ring. Other metabolic pathways include O-demethylation and hydrolysis and/or hydroxylation of the cladinose and desosamine sugar moieties and the macrolide ring. Up to 10 metabolites of azithromycin have been identified, and all are microbiologically inactive. While short-term administration of azithromycin produces hepatic accumulation of the drug and increases azithromycin demethylase activity, current evidence indicates that hepatic cytochrome p450 induction of inactivation via cytochrome-metabolite complex formation does not occur. In contrast to erythromycin, azithromycin does not inhibit its own metabolism via this pathway.

F94OW58Y8V

AZITHROMYCIN

Established Pharmacologic Class [EPC] - Macrolide Antimicrobial

Chemical/Ingredient structural concept [Chemical/Ingredient] - Macrolides

Azithromycin is a Macrolide Antimicrobial. The chemical classification of azithromycin is Macrolides.

J2KLZ20U1M

Bioavailability of azithromycin is 37% following oral administration. Absorption is not affected by food. Macrolide absorption in the intestines is believed to be mediated by P-glycoprotein (ABCB1) efflux transporters, which are known to be encoded by the _ABCB1_ gene.

Biliary excretion of azithromycin, primarily as unchanged drug, is a major route of elimination. Over a 1 week period, approximately 6% of the administered dose is found as unchanged drug in urine.

After oral administration, azithromycin is widely distributed in tissues with an apparent steady-state volume of distribution of 31.1 L/kg. Significantly greater azithromycin concentrations have been measured in the tissues rather than in plasma or serum,. The lung, tonsils and prostate are organs have shown a particularly high rate of azithromycin uptake. This drug is concentrated within macrophages and polymorphonucleocytes, allowing for effective activity against Chlamydia trachomatis. In addition, azithromycin is found to be concentrated in phagocytes and fibroblasts, shown by in vitro incubation techniques. In vivo studies demonstrate that concentration in phagocytes may contribute to azithromycin distribution to inflamed tissues.

Mean apparent plasma cl=630 mL/min (following single 500 mg oral and i.v. dose)

Biliary excretion of azithromycin, predominantly as unchanged drug is a major route of elimination following oral administration.

Azithromycin is rapidly absorbed from the GI tract after oral administration; absorption of the drug is incomplete but exceeds that of erythromycin. The absolute oral bioavailability of azithromycin is reported to be approximately 34-52% with single doses of 500 mg to 1.2 g administered as various oral dosage forms. Limited evidence indicates that the low bioavailability of zithromycin results from incomplete GI absorption rather acid degradation of the drug or extensive first-pss metabolism.

MEDICATION

Use (kg) in Switzerland (2009): >250

Preparation: BE 892357; G. Kobrehel, S. Djokic, US 4517359 (1982, 1985 both to Sour Pliva); D.J.M. Allen, K.M. Nepveux, EP 298650; eidem, US 6268489 (1989, 2001 both to Pfizer)

Antibiotics are fermentation products and are isolated either as unfinished products or as intermediates, generally solid substances of limited stability. They are purified by methods normally employed in organic chemistry, which include chromatography, crystallization, and precipitation. /Antibiotics/