Table 3.

Antiviral agents for community-acquired respiratory viral infections (RVIs) and relevance to critically ill patients

	Mechanism of action	Target Virus	Resistance	Formulation	Applicability to critically ill patients
Amantadine	M2 ion channel blockers	Influenza A	High levels of resistance	Oral	Not recommended
Rimantadine	M2 ion channel blockers	Influenza A	High levels of resistance	Oral	Not recommended
Oseltamivir	Neuraminidase inhibitor(NAI)	Influenza A and B	Uncommon (1-3% of circulating isolates) but higher for treatment-emergent in critically ill and immunocompromised	Oral	Needs dose adjustment in patients with renal impairment No dose adjustment is necessary in patients with mild to moderate hepatic impairment Extemporaneous formulation possible or gastric delivery in intubated patients
Zanamivir	NAI	Influenza A and B	Rare	Intravenous; nebulized solution (investigational); inhaled dry powder (commercial formulation)	Inhibitory for most strains resistant to oseltamivir Nebulized formulation (investigational) with limited use in severely ill patients Limited systemic absorption and distribution to extrapulmonary sites of inhaled commercial product Lactose-containing powder commercial preparation with lactose carrier should not be given nebulized as it may cause ventilator circuit obstruction Intravenous formulation similar in efficacy to oseltamivir in hospitalized patients. Intravenous zanamivir is approved by the European Medicines Agency (EMA)
Peramivir	NAI	Influenza A and B	Uncommon (see oseltamivir above)	Intravenous	Intravenous formulation (multiple doses) similar in efficacy to oseltamivir in hospitalized patients Peramivir is approved by the FDA and EMA for uncomplicated influenza
Laninamivir	NAI	Influenza A and B	Rare	Inhaled, single dose, long acting	Not suitable for mechanically ventilated patients. Approved in Japan only
Favipiravir	Polymerase inhibitor (PB1 transcriptase), viral mutagen	Influenza A, B and other RNA viruses	Not seen in clinical strains	Oral	Under study in hospitalized patients in combination with NAIs Teratogenicity risk PK altered in critically ill with reduced drug exposure– appropriate dose regimen uncertain Approved only for stockpiling in Japan
Baloxavir	Polymerase inhibitor (PA cap-dependent endonuclease)	Influenza A, B	Treatment-emergence resistance common with monotherapy	Oral	Under study (multiple-dose) in combination with NAIs in hospitalized patients Not studied and PK uncertain in critically ill patients Inhibitory for strains resistant to M2Is and/or NAIs At present, baloxavir is approved in the US, Japan, and over eight other countries
Nitazoxanide	Host-directed and influenza HA	Influenza and other RVIs	Not seen in clinical strains	Oral	Not effective in hospitalized SARI patients. Not recommended.
Ribavirin	Host-directed effects, transcriptase inhibitor, viral mutagen	RSV, influenza, measles other RVIs	Not seen in clinical strains	Aerosolized, oral, intravenous (investigational)	Aerosol formulation approved in RSV-infected children but of uncertain value. All 3 formulations have been used in treating RSV-infected HSCT and SOT patients Anecdotal use of systemic ribavirin in severe measles and other paramyxovirus infections Not recommended in combination with interferons for MERS Teratogenicity risk Aerosol delivery presents risk of healthcare worker exposure
Cidofovir	DNA polymerase inhibitor	Adenovirus		Intravenous	Anecdotal use in severe adenovirus infections and in immunocompromised patients
Acyclovir	DNA polymerase inhibitor	VZV, HSV	Uncommon except in immunocompromised	Intravenous, oral	Intravenous recommended in VZV pneumonia; addition of systemic corticosteroids recommended by some experts

Please refer to the online supplement for references

SARI severe acute respiratory infection, RSV respiratory syncytial virus, HSCT hematopoietic stem-cell transplantation, SOT solid-organ transplantation, MERS Middle East Respiratory Syndrome, VZV varicella-zoster virus, HSV herpes simplex virus, NAI neuraminidase inhibitors, EMA European Medicines Agency, FDA Food and Drug Agency