Is there evidence to support treating influenza or Covid-19 with antiviral medications plus Zithromax (azithromycin) to prevent secondary bacterial infections in the lungs?

No Evidence Supports Routine Azithromycin Use to Prevent Secondary Bacterial Infections in Influenza or COVID-19

The highest quality evidence demonstrates that empirical azithromycin should NOT be routinely prescribed with antivirals for influenza or COVID-19 to prevent secondary bacterial infections, as bacterial co-infection rates are low (3.5% at admission) and indiscriminate antibiotic use increases antimicrobial resistance without proven benefit. 1

Bacterial Co-infection Rates Are Lower Than Expected

The actual incidence of bacterial co-infection contradicts the rationale for prophylactic antibiotics:

• Only 3.5% of COVID-19 patients have bacterial co-infection upon hospital admission 1, 2
• Secondary bacterial infections during hospitalization occur in up to 15% of cases, primarily in critically ill patients requiring prolonged ventilation 1, 3
• The vast majority of patients with viral respiratory infections do not develop bacterial superinfection requiring antibiotics 2

Current Guidelines Recommend Restrictive Antibiotic Use

The Dutch Working Party on Antibiotic Policy (SWAB) and European Society of Clinical Microbiology and Infectious Diseases published evidence-based guidelines in 2021 explicitly recommending against routine antibiotic use in COVID-19 patients: 1

• Restrictive antibiotic use is recommended from an antibiotic stewardship perspective, especially upon admission 1
• Broad-spectrum antibiotics should be avoided in patients with mild or no symptoms 1
• Universal antibiotic prescriptions can lead to steep increases in antimicrobial resistance rates during a pandemic 1

When to Actually Consider Antibiotics

Antibiotics should only be initiated when specific clinical criteria suggest bacterial superinfection, not prophylactically: 4

Clinical indicators warranting antibiotics:

• Fever with purulent sputum production 2
• Clinical deterioration after initial improvement 2
• Focal consolidation on physical exam, hypoxemia, or infiltrate on chest imaging 2
• Procalcitonin level >0.5 ng/mL 2, 4
• Elevated white blood cell count and C-reactive protein 4

Diagnostic approach before starting antibiotics:

• Obtain sputum and blood cultures before initiating empirical therapy 1, 2, 4
• Perform pneumococcal urinary antigen testing 1, 4
• Stop antibiotics after 48 hours if cultures are negative and the patient is improving 1, 4

Azithromycin Specifically Shows No Benefit

The RECOVERY trial added over 8,000 patients to the azithromycin analysis and demonstrated no beneficial evidence for azithromycin use in COVID-19 management: 1

• Azithromycin will not be updated in future European Respiratory Society guidelines due to lack of efficacy 1
• Azithromycin carries cardiac risks, particularly QT prolongation, especially when combined with other medications like hydroxychloroquine 1, 5
• Macrolides and quinolones should be avoided due to cardiac side effects if patients are on other QT-prolonging medications 4

The Contradictory 2020 Opinion

One early 2020 opinion piece suggested empirical antibiotics for COVID-19 patients, arguing that bacterial superinfection is "hard to detect" and symptoms overlap: 1

However, this recommendation was:

• Published before high-quality evidence emerged
• Based on speculation rather than controlled trials 1
• Explicitly contradicted by subsequent 2021 evidence-based guidelines showing bacterial co-infection rates are actually quite low 1

Appropriate Antibiotic Selection When Indicated

If bacterial superinfection is confirmed or highly suspected based on the criteria above, follow community-acquired pneumonia guidelines: 4

For non-ICU patients:

• Beta-lactam such as amoxicillin-clavulanate or third-generation cephalosporin 4
• If atypical coverage needed, consider doxycycline instead of azithromycin to avoid cardiac risks 4

For ICU/critically ill patients:

• Double antipseudomonal coverage may be necessary based on local epidemiology 4
• Consider anti-MRSA coverage in selected patients 4

Common Pitfalls to Avoid

• Overuse of antibiotics without evidence of bacterial co-infection increases antimicrobial resistance 4
• Not all radiographic abnormalities indicate bacterial co-infection; they may be due to viral infection alone 4
• Serum biomarkers alone should not determine when to start antibiotics, especially in non-critically ill patients 4
• The FDA label for azithromycin does not include prophylaxis for secondary bacterial infections in viral respiratory illness 6