Azithromycin

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.

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/