Can I prescribe Paxlovid (nirmatrelvir/ritonavir), oseltamivir (Tamiflu), and azithromycin for a patient with COVID‑19 and influenza?

Can You Prescribe Paxlovid, Tamiflu, and Azithromycin Together?

Yes, you can prescribe Paxlovid (nirmatrelvir/ritonavir) with oseltamivir (Tamiflu) for a patient with confirmed COVID-19 and influenza co-infection, but azithromycin should NOT be routinely added unless there is documented bacterial superinfection.

Drug Interaction Assessment

Paxlovid and Oseltamivir Compatibility

• There are no significant drug-drug interactions between nirmatrelvir/ritonavir and oseltamivir, as oseltamivir is not metabolized via CYP3A4 pathways that ritonavir inhibits 1, 2.
• Before prescribing Paxlovid with any medications, systematically check the Liverpool COVID-19 Drug Interaction Tool to verify compatibility, as ritonavir is a potent CYP3A4 inhibitor causing potentially life-threatening interactions 1, 3.

Azithromycin: Not Recommended for Routine Use

• Azithromycin should NOT be routinely prescribed for COVID-19, as multiple randomized trials demonstrate no mortality benefit, no reduction in hospital length of stay, and no improvement in clinical status (OR 1.02,95% CI 0.69–1.49) 4.
• The European Respiratory Society explicitly recommends against routine azithromycin use in hospitalized COVID-19 patients, citing concerns about antimicrobial resistance from widespread unnecessary use 4.
• Macrolides like azithromycin should be avoided in COVID-19 patients because of cardiac side effects (QT prolongation), particularly when other QT-prolonging agents may be used 4.

When to Use Each Agent

Paxlovid Indications

• Prescribe Paxlovid for patients with confirmed mild-to-moderate COVID-19 who are at high risk for progression to severe disease, within 5 days of symptom onset 1, 3.
• High-risk criteria include: age ≥65 years, immunocompromised status, unvaccinated or vaccine non-responders, and chronic medical conditions 1, 3.
• Standard dosing is nirmatrelvir 300 mg with ritonavir 100 mg orally twice daily for 5 days 1, 3.

Oseltamivir (Tamiflu) Indications

• Prescribe oseltamivir 75 mg twice daily for 5 days for patients with confirmed influenza who present within 48 hours of symptom onset 4, 2.
• Oseltamivir reduces duration of symptomatic illness by up to 1.5 days and severity by up to 38% when initiated within 36 hours of symptom onset 2.
• For patients unable to mount adequate febrile response (immunocompromised, elderly), oseltamivir may still be beneficial despite lack of documented fever 4.

Azithromycin: Only for Documented Bacterial Infection

• Only prescribe azithromycin if there is confirmed or strongly suspected bacterial co-infection, not routinely for viral respiratory infections 4.
• Bacterial co-infection in COVID-19 is uncommon (<10% of patients isolate a bacterial pathogen) 4.
• If bacterial coverage is needed, beta-lactams providing coverage for Streptococcus pneumoniae and methicillin-susceptible Staphylococcus aureus (e.g., amoxicillin-clavulanate or third-generation cephalosporins) should be first-line, not macrolides 4.

Clinical Decision Algorithm

For a patient with confirmed COVID-19 AND influenza:

1. Assess COVID-19 severity and risk factors – If high-risk and within 5 days of symptom onset, prescribe Paxlovid 1, 3.

2. Assess influenza timing – If within 48 hours of symptom onset, prescribe oseltamivir 4, 2.

3. Screen for drug interactions – Use Liverpool COVID-19 Drug Interaction Tool before prescribing Paxlovid; review all medications for CYP3A4-dependent drugs 1, 3.

4. Evaluate for bacterial superinfection – Only add antibiotics if clinical evidence suggests bacterial pneumonia (e.g., focal consolidation, elevated procalcitonin, purulent sputum) 4.

5. If antibiotics needed, choose beta-lactam over macrolide – Amoxicillin-clavulanate or ceftriaxone preferred over azithromycin to avoid QT prolongation and antimicrobial resistance 4.

Critical Safety Considerations

Paxlovid-Specific Precautions

• Ritonavir causes drug interactions during the 5-day treatment course and for several days after completion; medications may require temporary discontinuation, dose adjustment, or additional monitoring 1.
• For moderate renal impairment (eGFR 30–60 mL/min), reduce nirmatrelvir to 150 mg with ritonavir 100 mg twice daily 1.
• Paxlovid is contraindicated in severe hepatic impairment (Child-Pugh class C) 1.

Cardiac Monitoring

• Both ritonavir and azithromycin can prolong QT interval; if azithromycin must be used, obtain baseline ECG and monitor for arrhythmias 4.
• Avoid combining multiple QT-prolonging agents when possible 4.

Common Pitfalls to Avoid

• Do not prescribe azithromycin "just in case" for viral respiratory infections – this promotes antimicrobial resistance without clinical benefit 4.
• Do not assume all respiratory infections require antibiotics – bacterial co-infection rates are low in COVID-19 4.
• Do not delay Paxlovid beyond 5 days of symptom onset – efficacy diminishes significantly after this window 1, 3.
• Do not forget to check drug interactions before prescribing Paxlovid – ritonavir interactions can be life-threatening 1, 3.
• Do not use hydroxychloroquine with azithromycin – this combination has no benefit and increases adverse events 4.