Background Information about Azithromycin

Clinical Questions

What are the pharmacology, side effects, and interactions of azithromycin?

Key Findings

  • Azithromycin is approved for multiple indications and has a favorable safety profile compared to other macrolide antibiotics.
  • Azithromycin is associated with multiple potential side effects, most notably QT prolongation, and its use should be limited in patients with known cardiac problems and/or in conjunction with other QT prolonging agents.

Summary of Information

Azithromycin Indications and Safety:

Azithromycin was first approved for clinical use in 1988.[1] It is currently FDA approved for use in mild to moderate bacterial infections including sinusitis, community acquired pneumonia, urethritis/cervicitis, pharyngitis, and acute bacterial exacerbations of COPD.[2] Common side effects associated with both oral and IV administration include nausea and vomiting likely due to increased gastric motility.1 Severe side effects include prolongation of the QT interval and torsades de pointes, pseudomembranous colitis, exacerbation of myasthenia gravis, and the drug reactions Steven-Johnson Syndrome/TEN and DRESS.[2],[3] Irreversible ototoxicity has also been observed at high dose IV administration.[4] In addition, there is an increased rate of cancer relapse for hematopoietic stem cell transplant patients with ALL, AML, or bronchiolitis obliterans who received long term azithromycin therapy (greater than two years).[5] However, patients taking azithromycin for short periods have a negligible risk of this complication. Azithromycin crosses the placenta and is found in low concentrations in breast milk, but is considered safe to use in pregnancy.[6] There is some evidence showing increased incidence of hypertrophic pyloric stenosis in breastfed infants whose mothers took azithromycin during the first 13 days postpartum.[7] Infants should be monitored for adverse effects such as vomiting, diarrhea, and candidiasis.

Azithromycin Pharmacology:

Azithromycin is the first of the azalide class of antimicrobials and has been shown to have a completely different pharmacokinetic profile and much improved adverse effect profile than that of macrolides such as erythromycin. It does not undergo significant metabolism and does not complex with or induce CYPs, therefore decreasing the potential for drug interactions.[8],[9] Azithromycin has also been found to have a long terminal half-life of 50 hours with 500 mg IV dosing and 79 hours with 500 mg oral dosing, making once a day or single dose treatments possible.[10],[11] It is also known to have a large volume of distribution and is able to achieve extensive tissue penetration compared to macrolides.[8],[12] Azithromycin has also been shown to achieve high intracellular concentrations in polymorphonuclear leukocytes (PMNLs), monocytes, lymphocytes and alveolar macrophage.[13] The co-administration of meals along with azithromycin in the form of tablets, sachets or suspensions showed no impact on bioavailability, hence azithromycin oral dosing can be given without regard to food intake.[14]

Azithromycin Interactions:

Azithromycin has the potential to increase QT interval and thus concurrent azithromycin administration is not recommended with high risk QT-prolonging agents, such as fexinidazole and pimozide, to minimize risk of torsades de pointes. Other QT prolonging agents such as antipsychotics or class IC antiarrhythmics should be used with caution with monitoring of QTc interval. In addition, azithromycin as a p-glycoprotein inhibitor should be avoided in concurrent use of colchicine, topotecan, rimegepant, pazopanib, or vincristine as it may increase the serum concentration of these drugs.[15] There is conflicting evidence on the effect of azithromycin on warfarin drug metabolism. In general, it appears that there is a modest decrease in warfarin clearance and thus a possible increase in anticoagulant effect.[16],[17] Patients should continue to have INR monitored on azithromycin therapy. There is potential risk of increased rhabdomyolysis with concurrent use of statins, and patients should be monitored on such therapy.[18]

Author Information

Authors: Ritika Prasad MS4, Soumya Kurnool MS4, and Phoebe Stark MS2, UC San Diego School of Medicine
Completed on: March 21, 2020
Last revised on: Not yet revised

Reviewed by: Sara Baird MD
Reviewed on: April 14, 2020

This summary was written as part of the CoRESPOND Earth 2.0 COVID-19 Rapid Response at UC San Diego. For more information about the project, please visit http://earth2-covid.ucsd.edu

References

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  4. Bizjak ED, Haug MT, Schilz RJ, et al. Intravenous azithromycin-induced ototoxicity. Pharmacotherapy. 1999;19(2):245-8.  [PMID:10030778]
  5. Patel B, Sheshadri A, Saliba RM, et al. Azithromycin Exposure Following Hematopoietic Stem Cell Transplantation Is Associated with an Increased Risk of Cancer Relapse in Acute Leukemia. Biol Blood Marrow Transplant. 2019;25(3):S231-S232. doi:10.1016/j.bbmt.2018.12.222
  6. Ramsey PS, Vaules MB, Vasdev GM, et al. Maternal and transplacental pharmacokinetics of azithromycin. Am J Obstet Gynecol. 2003;188(3):714-8.  [PMID:12634646]
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  10. Ballow CH, Amsden GW, Highet VS, et al. Pharmacokinetics of Oral Azithromycin in Serum, Urine, Polymorphonuclear Leucocytes and Inflammatory vs Non-Inflammatory Skin Blisters in Healthy Volunteers. Clin Drug Investig. 1998;15(2):159-67.  [PMID:18370479]
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  12. Amsden GW. Advanced-generation macrolides: tissue-directed antibiotics. Int J Antimicrob Agents. 2001;18 Suppl 1:S11-5.  [PMID:11574189]
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  14. Foulds G, Luke DR, Teng R, Willavize SA, Friedman H, Curatolo WJ. The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension. J Antimicrob Chemother. 1996;37 Suppl C:37-44. doi:10.1093/jac/37.suppl_c.37
  15. Lexicomp Online. Lexicomp Drug Interactions.
  16. Bachmann K, Schwartz JI, Forney R, et al. The effect of erythromycin on the disposition kinetics of warfarin. Pharmacology. 1984;28(3):171-6.  [PMID:6718483]
  17. Woldtvedt BR, Cahoon CL, Bradley LA, et al. Possible increased anticoagulation effect of warfarin induced by azithromycin. Ann Pharmacother. 1998;32(2):269-70.  [PMID:9496419]
  18. Strandell J, Bate A, Hägg S, et al. Rhabdomyolysis a result of azithromycin and statins: an unrecognized interaction. Br J Clin Pharmacol. 2009;68(3):427-34.  [PMID:19740401]
  19. Foulds G, Luke DR, Teng R, Willavize SA, Friedman H, Curatolo WJ. The absence of an effect of food on the bioavailability of azithromycin administered as tablets, sachet or suspension. J Antimicrob Chemother. 1996;37 Suppl C:37-44. doi:10.1093/jac/37.suppl_c.37