Is azithromycin (a macrolide antibiotic) effective for treating Coronavirus Disease 2019 (COVID-19)?

Azithromycin Should Not Be Used for COVID-19 Treatment

Azithromycin should not be offered to patients with COVID-19 in the absence of bacterial infection, as multiple high-quality clinical trials show no benefit for COVID-19 treatment while risking antimicrobial resistance. 1

Evidence Against Azithromycin Use in COVID-19

• The European Respiratory Society (ERS) provides a conditional recommendation against offering azithromycin to hospitalized patients with COVID-19 in the absence of bacterial infection, based on very low quality evidence 1
• Multiple randomized trials demonstrate no difference in mortality (OR 1.02,95% CI 0.69–1.49), length of hospital stay, clinical status, or disease deterioration when azithromycin is used for COVID-19 1
• The American College of Physicians (ACP) explicitly recommends against using azithromycin in combination with hydroxychloroquine for COVID-19 treatment or prophylaxis 1
• The RECOVERY trial results (one of the largest COVID-19 treatment trials) showed no benefit of azithromycin in COVID-19 patients 1
• A systematic review and meta-analysis of 7 randomized controlled trials with 8,822 patients found azithromycin was not associated with reduced mortality (OR = 0.96,95% CI 0.88-1.05), need for mechanical ventilation, or reduced length of stay 2

Potential Harms of Inappropriate Azithromycin Use

• Widespread use of azithromycin during the pandemic raises significant antimicrobial resistance concerns 1, 3
• Azithromycin can cause QT prolongation, especially when combined with other medications, potentially leading to cardiac complications 4
• Patients with hepatic or renal impairment may experience increased drug levels and associated risks 4
• Electrolyte abnormalities, particularly hypokalemia and hypomagnesemia, can exacerbate QT prolongation risks when using azithromycin 4

Limited Context for Appropriate Antibiotic Use in COVID-19

• Bacterial co-infection is reported infrequently in COVID-19 patients, with systematic reviews suggesting <10% of patients isolate a bacterial pathogen 1
• Antibiotics should be reserved only for patients with proven or strongly suspected bacterial co-infection 1
• The PRINCIPLE trial, a large UK-based primary care randomized trial, found no justification for routine use of azithromycin for reducing recovery time or hospitalization risk in community patients with suspected COVID-19 3

Clinical Decision Algorithm

1. For patients with confirmed COVID-19 without evidence of bacterial infection:

   • Do NOT prescribe azithromycin 1
   • Focus on supportive care and evidence-based COVID-19 treatments 1

2. For COVID-19 patients with suspected bacterial co-infection:

   • Obtain appropriate cultures when possible 1
   • Consider targeted antibiotic therapy based on local resistance patterns 1
   • Discontinue antibiotics if bacterial infection is ruled out 1

3. For research purposes:

   • Azithromycin should only be used for COVID-19 in the context of well-designed clinical trials 1, 5
   • Future research should focus on identifying the frequency of bacterial co-infection in COVID-19 patients using molecular techniques and biomarkers 1

Common Pitfalls to Avoid

• Prescribing azithromycin "just in case" without evidence of bacterial infection contributes to antimicrobial resistance 3, 2
• Combining azithromycin with hydroxychloroquine increases risk of adverse events (39.3% for combination vs. 22.6% for standard care) without clinical benefit 1
• Relying on early, small studies or anecdotal reports rather than large randomized controlled trials leads to inappropriate prescribing 6, 5
• Failing to recognize that in vitro antiviral or anti-inflammatory properties of azithromycin have not translated to clinical benefit in COVID-19 patients 6, 2