Drugs

Azithromycin

Other Names: Zithromax, azithromycin dihydrate Drug Class: Opportunistic Infections and Coinfections

Chemical Image:

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azithromycin dihydrate

azithromycin dihydrate

Molecular Weight: 785.0184

Drug Description


Azithromycin is a semisynthetic azalide antibiotic, a subclass of macrolide antibiotics. Azalides are distinguished from other macrolides by the addition of nitrogen at position 9a of the lactone ring. Azithromycin differs structurally from erythromycin by a methyl-substituted nitrogen atom incorporated into the macrolide ring. [1] Azithromycin has a broader spectrum of activity than that of erythromycins or clarithromycin. [2]


References

[1] AHFS Drug Information 2007; p. 246

[2] AHFS Drug Information 2007; p. 232

HIV/AIDS-Related Uses


Azithromycin was approved by the FDA on June 14, 1996, for the prevention of disseminated Mycobacterium avium complex (MAC) disease in patients with advanced HIV infection. Azithromycin may be an effective treatment for symptomatic Cryptosporidiosis in HIV infected patients; however, it is not effective in eradicting cryptosporidial infection. [1]


References

[1] USP DI 2005; p. 484

Dosing Information


Mode of Delivery

Oral. [1]

Intravenous. [2]

Dosage Form

Film-coated tablets containing anhydrous azithromycin 250, 500, or 600 mg. [3]

Oral suspension containing 100 or 200 mg of anhydrous azithromycin per 5 ml, or 1 g anhydrous azithromycin per single dose packet. [4]

Lyophilized azithromycin in vacuum 10 ml vials containing the equivalent of 500 mg azithromycin. [5]

Storage

Tablets should be stored below 30 C (86 F). Dry powder for reconstitution into azithromycin oral suspension should be stored below 30 C (86 F). [6]


References

[1] USP DI 2005; pp. 486-7

[2] USP DI 2005; pp. 486-7

[3] AHFS Drug Information 2007; p. 246

[4] AHFS Drug Information 2007; p. 246

[5] Pfizer Zithromax for Injection Prescribing Information, October 2003, p. 19. Available at: http://www.pfizer.com/download/uspi_zithromaxIV.pdf. Accessed 2/14/07.

[6] FDA Zithromax for Injection Prescribing Information, October 2003, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050733s023lbl.pdf. Accessed 2/14/07.

Pharmacology


Like other macrolides, azithromycin binds the 50S ribosomal subunit of the 70S ribosome of susceptible organisms, inhibiting RNA-dependent protein synthesis. Azithromycin is bactericidal for Streptococcus pyogenes, Streptococcus pneumoniae, and Haemophilus influenzae; it is bacteriostatic for staphylococci and most aerobic gram-negative species. [1] Azithromycin concentrates in phagocytes; penetration of the drug into phagocytic cells is necessary for activity against intracellular pathogens (e.g., Staphylococcus aureus). The site of action appears to be the same as that of the macrolides, clindamycin, lincomycin, and chloramphenicol. [2]

Azithromycin has an expanded spectrum of activity compared with erythromycin and clarithromycin. Azithromycin generally is more active in vitro against gram-negative organisms than erythromycin or clarithromycin and has activity comparable to erythromycin against most gram-positive organisms. Azithromycin is not inactivated by the beta-lactamases produced by Haemophilus influenzae or Moraxella catarrhalis. [3]

Azithromycin is rapidly absorbed from the gastrointestinal (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% to 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 azithromycin results from incomplete GI absorption rather than acid degradation of the drug or extensive first-pass metabolism. [4] Time to peak concentration in adults is 2.1 to 3.2 hours for oral dosage forms and 1 to 2 hours for intravenous (IV) forms. For oral dosage forms, after a 500 mg loading dose on Day 1, then 250 mg once a day for Days 2 to 5, peak plasma concentrations in healthy adults were approximately 0.41 to 0.38 mcg/ml on Day 1 and 0.24 to 0.26 mcg/ml on Day 5. For IV forms, peak plasma concentrations were approximately 1.1 mcg/ml after a 3-hour IV infusion of 500 mg at a concentration of 1 mg/ml and approximately 3.6 mcg/ml after a 1-hour IV infusion of 500 mg at a concentration of 2 mg/ml. [5] Presence of food in the GI tract may affect the extent of absorption of oral azithromycin; however, the effect of food on absorption depends on the dosage form administered. [6]

Azithromycin is rapidly and widely distributed throughout the body. Azithromycin concentrates intracellularly, resulting in tissue concentrations 10 to 100 times higher than those found in plasma or serum. Azithromycin is highly concentrated in fibroblasts and phagocytic cells. [7] In addition to direct tissue uptake, it has been suggested that uptake and release of azithromycin by phagocytic cells contribute to the distribution of the drug into inflamed and infected tissues. Only very low concentrations of azithromycin have been detected in cerebrospinal fluid in patients with noninflamed meninges. [8]

Azithromycin is in FDA Pregnancy Category B. Adequate and well-controlled studies have not been done in pregnant women. Reproduction studies done in rats and mice given azithromycin at doses of up to moderately maternally toxic levels (i.e., 200 mg/kg per day) have found no evidence of harm to the fetus. On a mg/m2 basis, these doses are estimated to be four and two times the human daily dose of 500 mg in rats and mice, respectively. [9] Azithromycin has been detected in human milk. Physicians should exercise caution when administering azithromycin to nursing women. [10]

Protein binding to azithromycin varies with concentration but is generally very low to moderate, with approximately 7% binding at 1 mcg/ml, to 50% at 0.02 to 0.05 mcg/ml. [11] Plasma azithromycin concentrations following a single 500 mg oral or IV dose decline in a polyphasic manner, with a terminal elimination half-life average of 68 hours. [12] More than 50% of azithromycin is eliminated through biliary secretion as unchanged drug. [13] Azithromycin is excreted in feces primarily as unchanged drug. The primary route of biotransformation involves N-demethylation of the desoamine sugar or at the 9a position on the macrolide ring. While short-term administration of azithromycin produces hepatic accumulation of the drug and increases azithromycin demethylase activity, current evidence indicates that hepatic cytochrome P-450 induction or inactivation via cytochrome-metabolite complex formation does not occur. [14] Approximately 4.5% of a dose is eliminated in urine as unchanged drug within 72 hours. Approximately 11% to 14% of an IV dose is eliminated in urine as unchanged drug within 24 hours. [15]

Resistance to macrolide antibiotics may be natural or acquired. In studies evaluating prevention of disseminated MAC disease, drug-resistant isolates were detected in 29% to 58% of individuals in whom disease developed while receiving clarithromycin and in 11% of those receiving azithromycin. MAC isolates resistant to azithromycin are resistant to clarithromycin. Erythromycin-resistant staphylococci and streptococci are also resistant to clarithromycin and azithromycin. [16]


References

[1] USP DI 2005; p. 484

[2] AHFS Drug Information 2007; p. 247

[3] AHFS Drug Information 2007; p. 243

[4] AHFS Drug Information 2007; p. 244

[5] USP DI 2005; p. 484

[6] AHFS Drug Information 2007; p. 244

[7] USP DI 2005; p. 484

[8] AHFS Drug Information 2007; p. 245

[9] USP DI 2005; p. 485

[10] AHFS Drug Information 2007; p. 241

[11] USP DI 2005; p. 484

[12] AHFS Drug Information 2007; p. 245

[13] USP DI 2005; p. 484

[14] AHFS Drug Information 2007; p. 245

[15] USP DI 2005; p. 484

[16] AHFS Drug Information 2007; p. 244

Adverse Events/Toxicity


The most frequently reported adverse effect seen with azithromycin use is thrombophlebitis; this effect occurs with the injection form only. Other adverse effects of all dosage forms include acute interstitial nephritis, allergic reactions, pseudomembranous colitis, GI disturbances, dizziness, and headache. [1]


References

[1] USP DI 2005; p. 485

Drug and Food Interactions


When azithromycin is administered in capsule form, food decreases maximum concentration (Cmax) values by approximately 52% and area under the plasma concentration-time curve (AUC) values by approximately 43%. In tablet form, food increases Cmax values by 23% and 34% for the 250 mg and 600 mg tablets, respectively, and has no effect on AUC values. In oral suspension form, food increases the Cmax values by approximately 56% but has no effect on AUC values. [1]

Concurrent use of aluminum- and magnesium-containing antacids decreases the Cmax of azithromycin by approximately 24%, but has no effect on AUC. Oral azithromycin should be administered at least 1 hour before or 2 hours after aluminum- and magnesium-containing antacids. [2]


References

[1] USP DI 2005; p. 484

[2] USP DI 2005; p. 485

Contraindications


Azithromycin is contraindicated in patients with known hypersensitivity to azithromycin, erythromycin, or any macrolide antibiotics. [1]

Azithromycin should be administered to patients with hepatic function impairment with caution because biliary excretion is the major route of elimination for azithromycin. [2]


References

[1] FDA Zithromax for Injection Prescribing Information, October 2003, p. 3. Available at: Zithromax Prescribing Information, p. 15. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050730s021,050693s014lbl.pdf. Accessed 02/14/07.

[2] USP DI 2005; p. 485

Clinical Trials


Click here to search ClinicalTrials.gov for trials that use Azitromicina.


Chemistry


CAS Name

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)-, [1]

CAS Number

83905-01-5 [2]

Elemental Composition

C60.94%, H9.69%, N3.74%, O25.63%

Molecular Weight

748.98

Melting Point

113 to 115 C

Physical Description

White, crystalline powder (dihydrate form). [3]

Stability

After reconstitution with sterile water, azithromycin solution for injection is stable for 24 hours when stored below 30 C (86 F) or for 7 days if stored under refrigeration at 5 C (41 F). [4]


References

[1] USPD 2003; p. 89

[2] ChemIDplus Available at: http://chem.sis.nlm.nih.gov/chemidplus/. Accessed 02/14/07.

[3] FDA Zithromax for Injection Prescribing Information, October 2003, p. 3. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050733s023lbl.pdf. Accessed 2/14/07.

[4] FDA Zithromax for Injection Prescribing Information, October 2003, p. 19. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/050733s023lbl.pdf. Accessed 2/14/07.

Further Reading



Zithromax Prescribing Information from the FDA Web site
[PDF]. A more current version may be available on the manufacturer's Web site.
Zithromax for IV Infusion Prescribing Information from the FDA Web site [PDF]. A more current version may be available on the manufacturer's Web site.
Kadappu KK, Nagaraja MV, Rao PV, Shastry BA. Azithromycin as treatment for cryptosporidiosis in human immunodeficiency virus disease. J Postgrad Med 2002 Jul-Sep;48(3):179-81.
Phillips P, Chan K, Hogg R, Bessuille E, Black W, Talbot J, O'Shaughnessy M, Montaner J. Azithromycin prophylaxis for Mycobacterium avium complex during the era of highly active antiretroviral therapy: evaluation of a provincial program. Clin Infect Dis 2002 Feb 1;34(3):371-8.
Pozniak A. Mycobacterial diseases and HIV. J HIV Ther 2002 Feb;7(1):13-6.
Shafran SD, Mashinter LD, Phillips P, Lalonde RG, Gill MJ, Walmsley SL, Toma E, Conway B, Fong IW, Rachlis AR, Williams KE, Garber GE, Schlech WF, Smaill F, Pradier C. Successful discontinuation of therapy for disseminated Mycobacterium avium complex infection after effective antiretroviral therapy. Ann Intern Med 2002 Nov 5;137(9):734-7.