Azithromycin (Z-pack) Should NOT Be Used for COVID-19 Treatment
Do not prescribe azithromycin (Z-pack) for COVID-19 treatment, whether in hospitalized patients or outpatients, as it provides no benefit for mortality, clinical worsening, hospital admission, or symptom resolution, and contributes to antimicrobial resistance. 1, 2, 3
Evidence-Based Recommendation Against Routine Use
The European Respiratory Society provides a conditional recommendation against offering azithromycin to hospitalized COVID-19 patients in the absence of bacterial infection. 1, 2 This recommendation is supported by:
- No mortality benefit: Multiple randomized trials demonstrate no difference in 28-day mortality (OR 1.02,95% CI 0.69–1.49) when azithromycin is used for COVID-19. 1
- No clinical improvement: The landmark RECOVERY trial, which enrolled 7,763 patients, found that 22% died in both the azithromycin group (561/2582) and usual care group (1162/5181), with no difference in hospital stay duration or discharge rates. 3
- No benefit in outpatients: Azithromycin does not reduce hospital admission or death within 28 days (RR 0.94,95% CI 0.57 to 1.56) in outpatients with mild COVID-19. 4
The Only Appropriate Indication: Proven Bacterial Co-infection
Reserve azithromycin exclusively for COVID-19 patients with proven or strongly suspected bacterial co-infection. 1, 2
Bacterial co-infection occurs in less than 10% of COVID-19 patients according to systematic reviews. 1 When bacterial pneumonia is suspected:
- Obtain blood and sputum cultures before initiating antibiotics. 1
- Follow standard community-acquired pneumonia (CAP) guidelines for empirical coverage targeting Streptococcus pneumoniae, Haemophilus influenzae, Chlamydia pneumoniae, and Staphylococcus aureus. 1
- For low-risk inpatients: Use β-lactam (ampicillin-sulbactam, ceftriaxone, or cefotaxime) plus either azithromycin or doxycycline. 1
- Discontinue antibiotics within 48 hours if cultures are negative and the patient is improving. 1
Significant Harms of Inappropriate Use
Antimicrobial resistance: Widespread azithromycin use during the pandemic significantly contributes to antimicrobial resistance, a long-term public health threat. 1, 2
Cardiac complications: Azithromycin causes QT prolongation, particularly when combined with other medications like hydroxychloroquine, increasing risk of cardiac arrhythmias. 2 However, when used alone for COVID-19, cardiac arrhythmia rates were similar to usual care (RR 0.92,95% CI 0.73 to 1.15). 4
No benefit with hydroxychloroquine combination: The combination of hydroxychloroquine plus azithromycin showed increased adverse events (39.3%) compared to standard care (22.6%) without any clinical benefit. 1
Clinical Decision Algorithm
For COVID-19 patients WITHOUT evidence of bacterial infection:
- Do NOT prescribe azithromycin. 1, 2, 3
- Focus on supportive care and evidence-based COVID-19 treatments (such as corticosteroids for severe disease). 2
For COVID-19 patients WITH suspected bacterial co-infection:
- Obtain blood and sputum cultures when feasible. 1
- Initiate empirical antibiotic therapy based on CAP guidelines and local resistance patterns. 1
- Reassess at 48 hours and discontinue antibiotics if bacterial infection is ruled out. 1
- Consider procalcitonin testing to guide antibiotic discontinuation decisions. 1
Common Pitfalls to Avoid
Do not combine azithromycin with hydroxychloroquine: This combination increases adverse events without providing clinical benefit and should never be used. 1, 2
Do not prescribe "just in case": The low rate of bacterial co-infection (<10%) does not justify empirical azithromycin use in all COVID-19 patients. 1
Do not continue antibiotics without documented infection: If cultures are negative at 48 hours and the patient is improving, narrow or discontinue antibiotic therapy. 1
Avoid using outdated early pandemic protocols: Early enthusiasm for azithromycin was based on theoretical antiviral and anti-inflammatory properties that have been definitively disproven by high-quality randomized trials. 4, 3, 5