Drug vignettes: Azithromycin

May 13, 2020

Robin E Ferner*, Jeffrey K Aronson

On behalf of the Oxford COVID-19 Evidence Service Team
Centre for Evidence-Based Medicine, Nuffield Department of Primary Care Health Sciences
University of Oxford
*University of Birmingham

Correspondence to r.e.ferner@bham.ac.uk

Description of the drug, including regulatory status
Azithromycin is a macrolide antibacterial drug, derived from erythromycin, licensed in the USA and in the UK, and used to treat bacterial infections.

It has been used in combination with hydroxychloroquine in the treatment of COVID-19. However, there is an adverse drug–drug interaction between the two, which contraindicates their combined use. 

Mechanism of action
Azithromycin exerts its antibacterial action by binding to the RNA of susceptible organisms and impeding the assembly of the 50S ribosomal subunit. This prevents RNA-dependent protein synthesis.

Some macrolides, including azithromycin, may reduce interleukin-6 (IL-6) production in vitro, and azithromycin accumulates in lung fluid. Since IL-6 contributes to the cytokine storm associated with influenza and other viral infections, azithromycin has been proposed as a potential modifier of severe viral infections.

It was reported in a brief abstract from Wuhan in 2012 that azithromycin, independently of its anti-inflammatory action, inhibited replication of hepatitis C virus (HCV) in cultured human hepatocytes, by disrupting autophagy, which is required for release of the virus in cells after endocytosis, after which viral replication can begin.

Investigations of the tropism of Zika virus (ZIKV) for different cell types identified azithromycin as a possible anti-ZIKV drug in glial cells in vitro. The effect is linked to azithromycin’s ability to block the candidate entry (“docking”) factor for ZIKV on host cell membranes, labelled AXL. Azithromycin “dramatically reduced ZIKV infection of U87 cells at an EC50 of 2–3 μM at multiplicities of infection (MOIs) of 0.01 to 0.1.”

During the early phase of influenza (H1N1) virus infection, azithromycin blocked influenza virus internalization into host cells. Furthermore, in cell culture it targeted progeny virions newly budded from the host cells and inactivated their endocytic activity, but only if administered at or before introduction of H1N1. In a murine model, repeated intranasal azithromycin injection, starting 7 hours after inoculation of the virus, reduced viral replication at day 2 after inoculation.

Proposed mechanism of action in COVID-19
“…the mechanism of azithromycin against SARS-CoV-2 is unclear at present.” However, the mechanisms outlined above might be relevant. Nevertheless, they are weak mechanisms, which would not be expected a priori to have large effects.

Indications of licensed formulations
In the UK:

– acute bacterial sinusitis (adequately diagnosed);

– acute bacterial otitis media (adequately diagnosed);

– pharyngitis, tonsillitis;

– acute exacerbation of chronic bronchitis (adequately diagnosed);

– mild to moderately severe community acquired pneumonia;

– skin and soft tissue infections;

– uncomplicated Chlamydia trachomatis urethritis and cervicitis;

Note: all of these indications are for bacterial infections.

Practical use in licensed indications
There are 14 entries in the electronic medicines compendium from eight different pharmaceutical companies describing formulations of azithromycin. Six are for tablets or capsules containing 250 mg, four for 500 mg tablets, two for powder for oral suspension 200 mg per 5 mL, one for 500 mg of powder for solution for intravenous infusion, and one for eye drops, 15 mg/g.

Azithromycin is given once a day either 1 hour before or at least 2 hours after food.

A typical adult oral dosage regimen is 500 mg/day for 3 days. For some infections 1000 mg or 2000 mg can be given as a single dose.

A typical adult intravenous dosage regimen is 500 mg/day for at least two consecutive days, followed by 500 mg/day orally for up to 7–10 days..

After oral administration azithromycin is slowly and poorly (about 37%) absorbed, and absorption is variable. Peak plasma concentrations are reached after 2–3 hours. It has a long half-life (2–4 days) because of extensive tissue distribution.

Biliary excretion of unchanged azithromycin is a major route of elimination. About 12% is excreted unchanged in the urine, mostly in the first 24 hours. Its metabolites are microbiologically inactive.

Known contraindications and cautions
Hypersensitivity reactions can occur.

The clearance of azithromycin is reduced in patients with severe renal impairment.

Known and potential adverse effects
The Summary of Product Characteristics and the US Drug Label list many adverse drug reactions. Common or very common adverse reactions include diarrhoea, nausea, vomiting, headache, and fatigue. Uncommon or rare adverse effects and adverse reactions include gastritis, dyspnoea, reduced white cell count, abnormal liver function tests, anxiety and agitation, rashes, and arthralgia. The reaction frequencies are defined according to the following convention: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1,000 to < 1/100); rare (≥ 1/10,000 to < 1/1,000); very rare (< 1/10,000).

QTc  interval prolongation
Azithromycin prolongs the QTc interval and therefore increases the risk of the ventricular arrhythmia known as torsade de pointes; this can be fatal. See also Drug–drug interactions below.

Drug–drug interactions
Azithromycin inhibits the enzyme CYP3A4, although less so than some other macrolides. This can lead to interactions with medicines that are metabolized by CYP3A4.

Macrolides increase exposure to digoxin, probably by inhibiting its presystemic metabolism by Eubacterium lentum in the gut.

Azithromycin should not be combined with other drugs that prolong the QTc interval; these include chloroquine and hydroxychloroquine.

  • In a report of 84 adults treated with hydroxychloroquine + azithromycin, the QTc interval increased by more than 40 milliseconds in nearly one-third of patients, and to more than 500 milliseconds in more than one in ten.
  • In a series of 40 patients with COVID-19, the QTc interval was prolonged by 500 milliseconds or more in 6/18 (33%) patients treated with hydroxychloroquine + azithromycin, and in  1/22 (5%) of those treated with hydroxychloroquine alone (P = 0.03).
  • A review of 90 patients reported that the median QTc increased by 23 [interquartile range 10–40] milliseconds in the 37 patients treated with hydroxychloroquine + azithromycin, compared with 5.5 [-14–31] milliseconds in the 53 patients given hydroxychloroquine alone. One patient who had hydroxychloroquine and azithromycin discontinued because of QTc prolongation (499 milliseconds) developed torsade de pointes 3 days later.

Experience in other viral infections
In a retrospective study of 349 critically ill patients with MERS, azithromycin and other macrolide antibacterial drugs had no effect on 90-day mortality or improvement in MERS-CoV RNA clearance; patients who received macrolides were more likely to be admitted with community-acquired MERS.

A protocol for a trial in Ebola of antiviral drugs, which included azithromycin, was registered in 2015, but no results are available.

In a randomized, double-blind, placebo-controlled trial in 184 infants with bronchiolitis azithromycin did not improve major clinical outcomes, even when restricting the findings to those with proven respiratory syncytial virus infection.

Experience in COVID-19
Evidence from trials in COVID-19 is beginning to appear, but often in pre-print form or without detailed peer review. This means that caution is needed before accepting the findings from these uncontrolled or poorly controlled unmasked studies.

A French study examined the value of hydroxychloroquine in COVID-19 in 26 volunteer patients, six of whom dropped out; their outcomes were compared with those who declined to take part, or who were treated in other hospitals. Six experimental subjects were treated with azithromycin in addition to hydroxychloroquine, although the choice of subjects “depending on their clinical presentation” was not further explained. The outcome measures reported were viral titres by RT-PCR, and not those specified in the trial protocol. The six patients who received both hydroxychloroquine and azithromycin had negative viral tests on day 5.

After publication this trial was extensively criticized, and major discrepancies were noted. A comparison of the trial protocol with the published results also showed major discrepancies. Subsequently, the President of the International Society of Antimicrobial Chemotherapy (ISAC), which publishes the journal in which the results had been published within a day of receipt, the International Journal of Antimicrobial Agents, posted a statement noting that ISAC “shares the concerns regarding the above article [and] believes the article does not meet the Society’s expected standard, especially relating to the lack of better explanations of the inclusion criteria and the triage of patients to ensure patient safety.”

The same research group subsequently published preliminary results in 80 patients and, more recently, in a draft manuscript describing the outcome in 1061 patients with COVID-19 treated for at least 3 days with hydroxychloroquine + azithromycin. In the larger study, 31 patients were in hospital for 10 days or more, another 10 were transferred to intensive care units, and 8 elderly patients died. There was no control group. The authors nevertheless claimed that the drug combination avoided disease progression and prevented viral persistence.

Another research group reported the results in 11 COVID-19 patients treated with  hydroxychloroquine + azithromycin; quantitative PCR remained positive in 8 of the 10 patients in whom they were repeated after five or six days of treatment. 

There have been no reports of the results of well-designed clinical trials of the use of azithromycin in COVID-19. It is more likely to reduce the risk of secondary bacterial infection than to have a direct antiviral effect, but other antibacterial agents are preferable for this purpose. It should not be used in combination with hydroxychloroquine. Until the results of adequately powered, double-masked, randomized controlled trials appear, if any, it should not be used to treat COVID-19 except as part of such trials.

Disclaimer: This article has not been peer-reviewed; it should not replace individual clinical judgement and the sources cited should be checked. The views expressed in this commentary represent the views of the authors and not necessarily those of the host institution, the NHS, the NIHR, or the Department of Health and Social Care. The views are not a substitute for professional medical advice.