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Azithromycin in Combination with Hydroxychloroquine for COVID-19
Macrolide  antimicrobial  


(Updated March 31, 2020)

 

TOP FIVE THINGS TO KNOW ABOUT AZITHROMYCIN AND OLDER ADULTS WITH COVID-19
  1. Azithromycin remains off label use in combination with hydroxychloroquine for COVID-19
  2. Unlike clarithromycin and erythromycin, azithromycin does not inhibit CYP3A4
  3. Azithromycin inhibits P-glycoprotein drug transporter and may increase levels of P-glycoprotein substrates (e.g. digoxin)
  4. While azithromycin’s risk of QT interval prolongation is low, monitor patients with prolonged QT, or at risk of QT interval prolongation (age>65 years, female, hypoK, hypoMg, Hypo Ca, concomitant QT prolonging drugs including diuretics, or a cardiac history).
  5. Predominantly cleared through biliary excretion and requires no dose adjustments.

 

Mechanism of Action: Bacteriostatic activity through inhibition of dependent protein synthesis by reversibly binding to the 50S subunit of ribosomes; this blocks the transpeptidation/translocation step of protein synthesis.(1) Proposed immunomodulatory effects against Zika and Ebola virus. In vitro, azithromycin suppresses Zika virus by upregulating host type I and III interferons and downstream interferon-stimulated genes. Azithromycin upregulates expression of innate immune receptors, MDA5 and RIG-I, and upregulates phosphorylation of TBK1 and IRF3.(2) The 50% effective concentrations (EC50) of azithromycin in vitro for Ebola is 2.79M.(3) The EC50 of azithromycin in vitro for Zika virus ranges from 2.1-5.1M.(4) As of March 25 2020, no in vitro data is available for SARS-CoV-1 or SARS-CoV-2.

 

Small, open-label non-randomized study evaluated synergistic effect of azithromycin used in combination with hydroxychloroquine for SARS-CoV-2 measured virological clearance (negative nasopharyngeal PCR) at day 6 (not a clinical endpoint such as mortality or ICU admission). Six out of six patients (100%) treated with hydroxychloroquine and azithromycin were virologically cured compared with hydroxychloroquine monotherapy (57.1%) and control (12.5%) p<0.001.(5) Given the limited data with azithromycin in the treatment of COVID-19, more studies are needed to determine clinical effectiveness.

 

Experimental and off-label use in SARS-CoV-2 (COVID-19)

  • Azithromycin 500mg on day 1 followed by 250mg once daily on days 2-5 in combination with hydroxychloroquine

Dose Adjustment

  • Hepatic – no adjustment needed for mild-moderate disease, use caution in severe liver impairment as azithromycin is primarily eliminated via the liver.(6)
  • Renal – no adjustment needed for mild-moderate renal impairment (GFR 10-80mL/min). Use caution in severe renal impairment (mean AUC0-120 increased 35% in subjects with GFR <10 mL/min)(6)


Clinically Significant Drug Interactions
Pharmacokinetic:

  • No significant effect on CYP isoenzymes (as opposed to other macrolides).(7) Minor CYP3A4 substrate.(7)
  • Inhibits P-glycoprotein and may increase serum concentrations of P-glycoprotein substrates (colchicine, edoxaban, dabigatran, digoxin).(7)
    • Associated with increased risk of hospitalization due to digoxin toxicity(8)
    • Population based case-control study in older adults taking digoxin evaluated the risk of sudden death 14 days following exposure to macrolides vs cefuroxime, and found no increased risk of death with azithromycin compared to cefuroxime(9)
  • Lovastatin, Simvastatin: case reports of increased risk rhabdomyolysis(7)
  • Warfarin: potential for increased serum concentrations, monitor INR(7)

Pharmacodynamic:

  • Azithromycin has low risk of QT interval prolongation. Risk increased when used together with other agents known to prolong the QT interval (i.e hydroxychloroquine), and patient specific factors (bradyarrhythmias, electrolyte abnormalities, elderly, female, known QT prolongation)
    • Retrospective cohort study examining azithromycin use with 30- and 90-day all-cause mortality and cardiovascular events (arrhythmia, heart failure, MI, any cardiac event) in elderly patients (65+) hospitalised with pneumonia
      • Lower risk 90-day mortality (NNT 21)
      • No significant difference in cardiac arrhythmia
      • Slightly higher risk of MI (NNH 144) – unclear as to whether this is a result of the drug or infection requiring hospitalization.(10)

Adverse Effects: Loose stools, vomiting, diarrhea, nausea. Elevated LFTs less common. QT prolongation, hepatotoxicity, SJS/TENS, DRESS are rare(7)

Monitoring Parameters: Baseline EKG (QTc prolongation), liver function tests, CBC with differential(7)


Pharmacokinetics: Parameters were similar in healthy older adults (65 – 85 years) compared to young adults, although in older women, Cmax was increased by 30-50%. Significant accumulation was not observed(6)
Absorption: Oral bioavailability 37%, Tmax: 2-3 hours(7),(10)
Distribution: Vd: 31-33L/kg (lipophilic).(7) Extensive tissue, distributes well into skin, lungs, sputum, tonsils, and cervix, compared to significantly lower serum concentrations.(11) Poor penetration into CSF.(7) High and persistent concentrations in bronchial secretions.(11) Protein binding: 7-50% (concentration dependent).(11)
A small study of steady-state pulmonary disposition of azithromycin in older adults recorded average concentrations of 1.14M in extracellular tissue and 261.4M in intracellular tissue, over a 24-hr dosing interval.(14)
Metabolism: minimally metabolized by CYP3A4 (does not inhibit or induce)(7)
Elimination half-life: 

  • Adults 68-72 hours(7)
  • Therapeutic effect continues for ~5 days following 5-day treatment regimen(14)

Excretion: 6% -14% unchanged in urine, mostly excreted unchanged in the bile mainly by ABCB1 and MRP2 (encoded by the gene ABCC2)(11)

 

References:
  1. PHARMGKB. Macrolide Antibiotic Pathway, Pharmacokinetics/Pharmacodynamics [Internet]. 2017 [cited 2020 Mar 24]. Available from https://www.pharmgkb.org/pathway/PA166160731
  2. Li C, Zu S, YQ D, Li D, Parvatiyar K, Quanquin N, Shang J, Sun N, Su J, Liu Z, Wang M, Aliyari SR, Li XF, Wu A, Ma F, Shi Y, Nielsevn-Saines K, Jung JU, Qin FX, Qin CF, Cheng G. Azithromycin protects against Zika virus infection by upregulating virus-induced type I and III interferon responses. Antimicrob Agents Chemother. 2019;63(12) doi 10.1128/AAC.00394-19
  3. Bixler SL, Duplantier AJ, Bavari S. Discovering drugs for the treatment of Ebola Virus. Curr Treat Options Infect Dis. 2017; 9(3): 299–317.
  4. Da Silva S, Silva Martins DO, Gomes Jardim AC. A review of the ongoing research on zika virus treatment. Viruses. 2018; 10(5):255
  5. Gautret P, Lagier J, Parola P, Hoang V, Meddeb L, Mailhe M, et al. Hydroxychloroquine and azithromycin as a treatment of COVID-19: results of an open-label non-randomized clinical trial. International Journal of Antimicrobial Agents. In Press.
  6. Canadian Pharmacists Association. Zithromax drug monograph [Internet]. 2018 Sep [cited 2020 Mar 23]. Available from https://myrxtx.ca. Subscription needed to view.
  7. Lexicomp. Azithromycin (systemic) [Internet]. 2020 Mar [cited 2020 Mar 23]. Available from http://online.lexi.com. Subscription needed to view.
  8. Gomes T, Mamdani MM, Juurlink DN. Macrolide Induced Digoxin Toxicity: A Population Based Study. Clinical Pharmacology & Therapeutics. 2009 Oct;86(4):383-6.
  9. Quinn KL, Macdonald EM, Gomes T, Mamdani MM, Huang A, Juurlink DN. Macrolides, digoxin toxicity and the risk of sudden death: a population based study. Drug Saf. 2017;40(9):835-40
  10. Mortensen EM, Halm EA, Pugh MJ. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA. 2014;311(21):2199-2208
  11. Micromedex DRUGDEX System. Azithromycin [Internet]. [cited 2020 Mar 26]. Available from http://micromedexsolutions.com. Subscription needed to view.
  12. PHARMGKB. Macrolide Antibiotic Pathway, Pharmacokinetics/Pharmacodynamics [Internet]. 2017 [cited 2020 Mar 24]. Available from https://www.pharmgkb.org/pathway/PA166160731
  13. Capitano B, Mattoes HM, Shore E, O’Brien A, Braman S, Sutherland C, Nicolau DP. Steady-state intrapulmonary concentrations of moxifloxacin, levofloxacin, and azithromycin in older adults. CHEST. 2004;125(3):965-73.
  14. Rx Files. Antibiotics Oral & IV Antibiotics: Overview [Internet]. 2019 Nov [cited 2020 Mar 23]. Available from https://www.rxfiles.ca. Subscription needed to view.

 

Last updated: March. 31, 2020 - 12:06 PM                                                                                                                                                                    Back to COVID-19 Resources