Summary

IDSA living guideline on pharmacologic treatment and prevention of COVID-19, updated through October 2025. Covers antiviral selection for mild-to-moderate disease (nirmatrelvir/ritonavir preferred, then remdesivir, then molnupiravir), immunomodulator selection for severe/critical hospitalized disease (corticosteroids plus baricitinib or tocilizumab; abatacept or infliximab as alternatives), and pre-exposure prophylaxis with pemivibart in immunocompromised hosts. Recommendations against hydroxychloroquine, lopinavir/ritonavir, ivermectin, colchicine, famotidine, and routine convalescent plasma in immunocompetent hospitalized patients.

Key Recommendations

For ambulatory adults with mild-to-moderate COVID-19 at high risk of progression, strongly recommend nirmatrelvir/ritonavir over no antiviral treatment within 5 days of symptom onset.
When nirmatrelvir/ritonavir is precluded by drug interactions, use IV remdesivir (3-day course) as the preferred alternative in high-risk outpatients.
Reserve molnupiravir for high-risk outpatients with no other treatment option; recommend against in patients without risk factors and avoid in pregnancy and patients <18 years.
In ambulatory patients without risk factors for progression, suggest against routine antiviral treatment (nirmatrelvir/ritonavir, remdesivir, or molnupiravir).
Strongly recommend dexamethasone in hospitalized critically ill COVID-19 patients; suggest dexamethasone in hospitalized severe (hypoxemic) but non-critical patients; suggest against in non-hypoxemic patients.
In hospitalized adults on systemic glucocorticoids with rapidly progressing severe or critical COVID-19, add either baricitinib or tocilizumab as an additional immunomodulator.
When baricitinib and tocilizumab are unavailable, suggest abatacept or infliximab as alternative immunomodulators added to corticosteroids in severe/critical COVID-19.
Suggest pemivibart pre-exposure prophylaxis (4,500 mg IV every 3 months) in moderately/severely immunocompromised patients ≥12 years when circulating variants remain susceptible.
Recommend against hydroxychloroquine (alone or with azithromycin), lopinavir/ritonavir, ivermectin (ambulatory), and colchicine (hospitalized) for treatment of COVID-19.
Recommend against convalescent plasma in immunocompetent hospitalized patients; suggest against routine use in hospitalized immunocompromised patients; high-titer plasma may be used in high-risk ambulatory patients with no other options.
Suggest against remdesivir in critically ill COVID-19 patients on invasive mechanical ventilation or ECMO; use 5-day course in hospitalized patients on supplemental oxygen not on mechanical ventilation.
Screen patients’ medications for serious drug-drug interactions with nirmatrelvir/ritonavir, particularly clopidogrel, statins, calcineurin inhibitors, and strong CYP3A inducers.

Thresholds & Doses

Nirmatrelvir/ritonavir, eGFR >60 mL/min: 300 mg/100 mg PO every 12 hours × 5 days, started within 5 days of symptom onset.
Nirmatrelvir/ritonavir, eGFR 30–<60 mL/min: 150 mg/100 mg PO every 12 hours × 5 days.
Nirmatrelvir/ritonavir, eGFR <30 mL/min (including hemodialysis): 300 mg/100 mg on day 1, then 150 mg/100 mg once daily on days 2–5.
Remdesivir for outpatients: 200 mg IV day 1, then 100 mg IV days 2 and 3 (3-day course); no renal dose adjustment.
Remdesivir for hospitalized severe COVID-19 (SpO2 ≤94% on room air): 5-day course preferred over 10-day course in patients not on mechanical ventilation.
Molnupiravir: 800 mg PO every 12 hours × 5 days; not authorized for patients <18 years or in pregnancy; use contraception during and 3 months after.
Dexamethasone: 6 mg IV or PO daily × 10 days or until discharge; up to 20 mg/day acceptable in critical illness; alternatives methylprednisolone 32 mg or prednisone 40 mg daily, or hydrocortisone 50 mg IV q6h.
Baricitinib: 4 mg PO daily (renally adjusted) × 14 days or until hospital discharge.
Tocilizumab: 8 mg/kg IV (max 800 mg) as single infusion; may repeat once after ≥8 hours; CRP threshold ≥75 mg/L used in RECOVERY trial.
Sarilumab and tofacitinib: suitable alternatives if tocilizumab/baricitinib unavailable; tofacitinib 10 mg PO every 12 hours up to 14 days.
Abatacept: 10 mg/kg IV (max 1000 mg) single dose plus standard of care.
Infliximab: 5 mg/kg IV single dose plus standard of care.
Pemivibart pre-exposure prophylaxis: 4,500 mg IV every 3 months; administer ≥2 weeks after COVID-19 vaccination; anaphylaxis risk 0.6%.
Vilobelimab: 800 mg IV (up to 6 doses) — recommended only in clinical trial setting.
Severity definitions: severe = SpO2 ≤94% on room air; critical = mechanical ventilation, ECMO, high-flow nasal cannula, or non-invasive ventilation.
Convalescent plasma (ambulatory): FDA-qualified high-titer plasma within 8 days of symptom onset in high-risk patients without other options.

Citations

How to Approach a Patient with Mild to Moderate COVID-19 — antiviral selection algorithm and risk stratification (Tables 1 and 2).
Recommendation: Nirmatrelvir/Ritonavir (updated 10/14/2025) — strong recommendation for high-risk outpatients; renal dosing; drug interactions (Figures 3-4).
Remdesivir for Mild or Moderate COVID-19 (updated 10/14/2025) — 3-day IV course in high-risk outpatients.
Remdesivir for Severe or Critical COVID-19 — 5-day course preferred; against use in patients on invasive ventilation/ECMO.
Recommendation: Glucocorticoids — dexamethasone 6 mg × 10 days in critical and severe hospitalized patients (RECOVERY trial).
Recommendation: Baricitinib vs. Tocilizumab (10/14/2025) — either may be added to corticosteroids in rapidly progressing severe or critical COVID-19.
Recommendation: Abatacept and Infliximab (5/30/2025) — alternative immunomodulators when baricitinib/tocilizumab unavailable.
Recommendation: Neutralizing Antibodies for Prophylaxis (Pemivibart, 8/12/2024) — PrEP in immunocompromised patients ≥12 years; 4,500 mg IV q3 months.