Seasonal influenza in nonpregnant adults: Treatment

INTRODUCTION — Seasonal influenza is an acute respiratory illness caused by influenza A or B viruses [1-3]. Influenza occurs in outbreaks and epidemics worldwide, mainly during the winter season in temperate climates. Influenza is usually a self-limited infection; however, it is associated with increased morbidity and mortality in certain high-risk patient groups.

The United States Centers for Disease Control and Prevention (CDC) has issued recommendations for the use of antivirals for influenza [1]. The Infectious Diseases Society of America (IDSA) published updated influenza guidelines in 2018 [2]. Our recommendations are generally in keeping with those of the CDC and IDSA.

Issues related to treatment of seasonal influenza will be reviewed here. Issues related to use of antiviral agents for prevention of seasonal influenza are discussed separately, as are the pharmacologic characteristics of the antiviral drugs and issues related to antiviral drug resistance. (See "Seasonal influenza in adults: Role of antiviral prophylaxis for prevention" and "Antiviral drugs for influenza: Pharmacology and resistance".)

Management of pregnant patients with seasonal influenza is discussed separately. (See "Seasonal influenza and pregnancy", section on 'Management'.)

Issues related to avian influenza are discussed separately. (See "Avian influenza: Epidemiology and transmission" and "Avian influenza: Clinical manifestations and diagnosis" and "Avian influenza: Treatment and prevention".)

GENERAL PRINCIPLES

Site of care — Hospitalization is warranted for patients with significant dehydration and for severely ill patients, especially those with respiratory distress, hypoxemia, impaired cardiopulmonary function, or altered mental status. In the absence of these findings, admission for observation may be warranted for patients with increased risk for complications (table 1) and uncertain clinical trajectory.

Symptom management — Hydration should be maintained. Acetaminophen or nonsteroidal anti-inflammatory drugs may be used for management of fever, headache, and myalgia.

HOSPITALIZED PATIENTS — Criteria for hospitalization are discussed above. (See 'Site of care' above.)

The clinical approach for management of hospitalized patients includes antiviral treatment as well as evaluation and treatment for concomitant infection.

Antiviral therapy

Timing of treatment

●Clinical approach − For patients hospitalized with known or suspected influenza, we administer antiviral treatment promptly, regardless of symptom duration.

Initiation of antiviral treatment should not be delayed while awaiting the results of diagnostic testing [1]. In addition, treatment should not be withheld from patients with high clinical suspicion for influenza but negative rapid antigen test results, given inadequate diagnostic sensitivity. For hospitalized patients with negative molecular diagnostic testing and persistent clinical suspicion for influenza, empiric antiviral treatment should be continued while additional diagnostic specimens are obtained. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

●Supporting evidence − Some observational data suggest decreased mortality risk associated with antiviral treatment [4-6]. There are no available assessments of mortality from randomized trials because such trials have been conducted among healthy individuals (with low influenza mortality rate).

•In one meta-analysis including 78 observational studies and 29,234 hospitalized patients with influenza during the 2009-2010 influenza A H1N1 pandemic, treatment with a neuraminidase inhibitor treatment (irrespective of timing) was associated with a reduction in mortality risk (adjusted odds ratio 0.81, 95% CI 0.70-0.93). In addition, treatment within two days of symptom onset was associated with a reduction in mortality risk (adjusted OR 0.48, 95% CI 0.41-0.56) [4].

•In a cohort study including 1330 patients with influenza requiring intensive care, early treatment with oseltamivir (within 48 hours of symptoms) was associated with lower mortality (relative risk 0.69, 95% CI 0.49 to 0.94) [5].

In addition, early initiation of antiviral treatment among hospitalized patients has been associated with reduced length of stay [7,8].

Antiviral selection

●Preferred regimen − Oseltamivir is the preferred antiviral agent for treatment of influenza; dosing is summarized in the table (table 2).

There is no role for increasing the oseltamivir dose, given lack of benefit [9,10].

Based on available data, there is no role for routine use of combination antiviral therapy for treatment of influenza [2,11-13]. In one trial including more than 360 hospitalized patients with severe influenza treated with a neuraminidase inhibitor and randomly assigned to treatment with or without baloxavir, no difference in clinical outcomes (including time to clinical improvement) was observed [12].

●Alternative regimens − Alternative antiviral agents for treatment of severe influenza include peramivir or zanamivir (both administered parenterally):

•Peramivir may be used for patients who cannot tolerate oral therapy; while peramivir has been approved by the US Food and Drug Administration for treatment of uncomplicated influenza [1,2], we think its use is reasonable for patients with severe influenza who cannot tolerate oral agents. In such cases we favor administration of 600 mg intravenously once daily for five days (rather than a single dose) [14]. In some cases, an extended treatment course may be warranted; this is discussed further below.

•In regions where parenteral zanamivir is available (eg, the United Kingdom and the European Union), this agent may be used if other antiviral agents cannot be used. The usual duration of treatment for parenteral zanamivir is 5 to 10 days [15]. Inhaled zanamivir should not be used for treatment of severe influenza given limited data.

Baloxavir should not be used for treatment of severe influenza given limited efficacy data.

Efficacy data and adverse effects of antiviral agents are discussed below. (See 'Antiviral efficacy and adverse effects' below.)

Antiviral duration — In general, we administer antiviral treatment to hospitalized patients for five days.

For patients with ongoing symptoms of severe lower respiratory tract disease (particularly in the setting of immunosuppression), an extended duration of antiviral treatment (up to 10 days) may be reasonable, particularly in those who continue to have detectable viral RNA from a respiratory specimen after 5 days of antiviral treatment [2,16,17]. (See 'Antiviral resistance' below.)

Concomitant infection — Patients who present with respiratory failure and/or hemodynamic instability warrant further diagnostic evaluation. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Additional diagnostic evaluation'.)

Empiric treatment for concomitant bacterial infection is warranted for patients with influenza in the following circumstances [2]:

●Patients presenting with respiratory failure and/or hemodynamic instability

●Patients who fail to improve or clinically deteriorate after three to five days of antiviral therapy and supportive care

The diagnostic evaluation for concomitant infection is discussed separately. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis", section on 'Additional diagnostic evaluation'.)

For patients in the above circumstances, administration of empiric antibacterial treatment for pneumonia is reasonable (in addition to antiviral treatment for influenza) [2].

Antibiotic selection should be guided by Gram stain and culture of sputum, if available. If the etiology of the pneumonia is uncertain, empiric antibiotics effective against the organisms commonly implicated in secondary bacterial pneumonia among patients with influenza (Streptococcus pneumoniae, Streptococcus pyogenes, and Staphylococcus aureus) should be used.

Agents with activity against S. pneumoniae and S. pyogenes include a third-generation cephalosporin (such as ceftriaxone) or a respiratory fluoroquinolone (eg, levofloxacin or moxifloxacin). Empiric treatment for methicillin-resistant S. aureus infection with vancomycin or linezolid should be initiated in patients with severe or necrotizing pneumonia [2,18]. (See "Treatment of community-acquired pneumonia in adults in the outpatient setting" and "Treatment of community-acquired pneumonia in adults who require hospitalization".)

Infection control — Infection control measures for prevention of seasonal influenza are discussed separately. (See "Infection control measures for prevention of seasonal influenza".)

OUTPATIENTS

Clinical approach — The approach to clinical decision-making regarding outpatient antiviral therapy is summarized in the algorithm (algorithm 1).

Patients at risk for complications or severe illness

●Clinical approach – For the following outpatients with known or suspected influenza A or B (regardless of symptom duration), we suggest antiviral treatment [2]:

•Patients at increased risk for complications (table 1)

•Patients with progressive illness who do not require hospitalization

In such cases, antiviral treatment may reduce the duration of illness and reduce the risk of respiratory tract complications; it may or may not reduce the risk of hospitalization.

●Supporting evidence − For outpatients with increased risk for complications, the impact of antiviral treatment on the risk of hospitalization is uncertain:

•In a 2024 systematic review and meta-analysis including 15 randomized trials and 6166 adult outpatients with influenza infection (median age 45 years; 54 percent treated with oseltamivir), oseltamivir was not associated with reduced risk of hospitalization (relative risk 0.79; 95% confidence interval [CI] 0.48-1.29; risk difference -0.17 percent; 95% CI -0.23 to 0.48 percent) [19]. Oseltamivir was also not associated with reduced hospitalization among patients age ≥65 years (relative risk 1.01; 95% CI 0.21-4.90)

•In contrast to the above findings, in a 2015 meta-analysis including 4328 adult outpatients (of whom approximately 70 percent were older patients with comorbidities) in 9 randomized trials comparing oseltamivir treatment (within 36 hours) with placebo, those treated with oseltamivir had shorter median time to symptom resolution (97.5 versus 122.7 hours; difference -25.2, 95% CI -36.2 to -16.0), fewer lower respiratory tract complications requiring antibiotic treatment (4.9 versus 8.7 percent; risk ratio 0.56, 95% CI 0.42-0.75), and a modest difference in hospitalization rate (0.6 versus 1.7 percent; risk difference -1.1 percent, 95% CI -1.4 to 0.3) [20]. Adverse effects included nausea and vomiting.

Patients who may transmit infection

●Clinical approach − For outpatients with known or suspected influenza A or B (regardless of symptom duration) who have exposure to individuals at increased risk for influenza complications (table 1), such as household contacts and health care workers, we suggest antiviral treatment [1,2]. In such cases, antiviral treatment may reduce the likelihood of transmission to vulnerable individuals.

Patients who are not at high risk for complications or transmission

●Clinical approach − For outpatients with uncomplicated illness who are not at increased risk for complications (table 1), treatment should be guided by duration of symptoms:

•Symptoms <48 hours – For patients within 48 hours of symptom onset, whether to administer antiviral treatment should be guided by shared clinical decision-making; treatment may be associated with a modest reduction in duration of illness (by approximately 24 hours).

•Symptoms ≥48 hours – For patients beyond 48 hours of symptom onset, we suggest not administering antiviral treatment, given lack of proven benefit.

●Supporting evidence  

•Symptoms <48 hours: For outpatients with uncomplicated influenza, early antiviral treatment (within 48 hours of symptom onset) may be associated with a modest reduction in duration of illness (by approximately 24 hours) [20-24]:

-Neuraminidase inhibitors – In a review including 20 oseltamivir trials and 46 zanamivir trials among healthy individuals, oseltamivir reduced the time to first alleviation of symptoms among adults by 16.8 hours (95% CI 8.4-25.1 hours) and zanamivir reduced the time to first alleviation of symptoms among adults by 14.4 hours (0.60 days; 95% CI 0.39-0.81 days) [21].

-Baloxavir – In a randomized trial including 2184 outpatients ≥12 years with uncomplicated influenza treated with baloxavir or placebo, baloxavir treatment was associated with a reduction in the median time to symptom improvement by 29 hours (95% CI 14.6-42.8) [23].

•Symptoms ≥48 hours: In a randomized trial including 496 patients with influenza in Bangladesh enrolled ≥48 after illness onset (of whom 40 were ≥18 years of age), the median duration of symptoms was similar in both groups (oseltamivir 3 days [interquartile range 2 to 5], placebo 3 days [1 to 5]) [25].

Antiviral selection — Oseltamivir is the preferred antiviral agent for treatment of influenza; it is the agent with the most established efficacy and safety. Dosing is summarized in the table (table 2).

Alternative antiviral agents for treatment of uncomplicated influenza include baloxavir (oral single dose), zanamivir (inhaled regimen twice daily for five days), or peramivir (parenteral single dose) (table 2). Clinical considerations for selection among these agents include:

●Baloxavir should not be used for treatment of immunocompromised hosts; its use has been associated with emergence of resistance [22,23].

●Zanamivir is contraindicated in patients with asthma or chronic obstructive pulmonary disease because of the risk of bronchospasm.

●Peramivir should be reserved for patients who cannot tolerate oral or inhaled agents.

Efficacy data and adverse effects of antiviral agents are discussed below. (See 'Antiviral efficacy and adverse effects' below.)

Antiviral duration — For patients with uncomplicated influenza, the treatment duration for oseltamivir or zanamivir is five days; the treatment duration for peramivir or baloxavir consists of a single dose (table 2).

Infection control and returning to work/school — Use of face masks and hand hygiene may reduce household transmission. Individuals with influenza should remain home from work, school, and other public places until at least 24 hours after resolution of fever (without use of antipyretics) and improvement in symptoms.

Infection control measures for prevention of seasonal influenza are discussed further separately. (See "Infection control measures for prevention of seasonal influenza".)

PATIENTS WITH PERSISTENT SYMPTOMS

Evaluation and treatment for bacterial infection — The approach to diagnostic evaluation for and empiric treatment of bacterial infection for patients with influenza is described above. (See 'Concomitant infection' above.)

Antiviral resistance

●Epidemiology − Factors associated with the emergence of antiviral drug resistance include the administration of postexposure prophylaxis with a neuraminidase inhibitor (particularly if underdosed), immunosuppression, and prolonged antiviral treatment [26,27].

Clinicians should remain informed about current surveillance data on the frequency and geographic distribution of neuraminidase inhibitor-resistant influenza viruses during influenza season [2].

In general, oseltamivir resistance (and peramivir cross-resistance) is rare; since 2009, 99 percent of influenza virus isolates tested in the United States have been susceptible to neuraminidase inhibitors [1,28]. (See "Antiviral drugs for influenza: Pharmacology and resistance", section on 'Drug resistance'.)

Baloxavir resistance may occur more commonly than resistance to neuraminidase inhibitors; in one randomized trial including more than 1000 patients with influenza treated with baloxavir, oseltamivir, or placebo, emergence of viral escape mutants with reduced drug susceptibility was observed in 10 percent of patients treated with baloxavir [22].

●When to suspect drug resistance − Evaluation for antiviral resistance should be pursued for patients in the following circumstances [2]:

•Patients who develop influenza infection while receiving or immediately following receipt of antiviral prophylaxis with a neuraminidase inhibitor.

•Immunocompromised patients and patients with severe influenza who remain ill despite treatment with a neuraminidase inhibitor, with evidence of persistent influenza virus replication (demonstrated by persistently positive reverse-transcriptase polymerase chain reaction or viral culture results after 7 to 10 days of antiviral therapy).

•Patients with persistent symptoms of influenza who were treated with subtherapeutic dosing of a neuraminidase inhibitor or baloxavir.

In such cases, a respiratory sample should be sent to the state laboratory for resistance testing, where phenotypic and/or genotypic assays are performed.

●Management – If oseltamivir resistance is suspected, neither oseltamivir nor peramivir should be used. Zanamivir is the preferred treatment, as such resistance usually does not extend to zanamivir [2]. If inhaled zanamivir cannot be used, oral baloxavir is an option. Intravenous zanamivir is available in the European Union and the United Kingdom, but not in the United States. (See "Antiviral drugs for influenza: Pharmacology and resistance", section on 'Drug resistance'.)

In one study including 68 patients with resistant H1N1 virus infection during the 2008-2009 influenza season treated with oral oseltamivir or inhaled zanamivir, the duration of fever after the first dose was longer among patients treated with oseltamivir (49 versus 28 hours), confirming correlation between in vitro susceptibility and clinical effectiveness [29].

Thus far, baloxavir has not been adequately studied for treatment of oseltamivir-resistant influenza. Emergence of resistance after a single dose of baloxavir raises concerns about the long-term utility of this drug as monotherapy [22].

ANTIVIRAL AGENTS

Antiviral drug classes — Classes of antiviral drugs for treatment of influenza include (table 2) [1-3]:

●Neuraminidase inhibitors – Neuraminidase inhibitors include oseltamivir, zanamivir, and peramivir (active against influenza A and B). Neuraminidase inhibitors interfere with release of progeny influenza virus from infected cells, thereby preventing new rounds of infection.

●Endonuclease inhibitor − Baloxavir is a selective inhibitor of influenza cap-dependent endonuclease (active against influenza A and B).

●Adamantanes – Adamantanes include amantadine and rimantadine (active against influenza A). These drugs target the M2 protein of influenza A, which forms a proton channel in the viral membrane that is essential for viral replication.

Due to emergence of high rates of adamantane resistance among influenza A viruses, the United States Centers for Disease Control and Prevention recommends that adamantanes not be used for the treatment of influenza in the United States [1].

Antiviral efficacy and adverse effects

Oseltamivir

●Efficacy − Treatment with oseltamivir may shorten the duration of influenza symptoms by approximately one day [20,24,25,30,31] and reduce the duration of viral shedding [25,32]. Some studies have also shown that oseltamivir reduces illness severity and complication rates [20,33], hospital admission rates [20,34], and length of hospital stay [35,36].

Most of the evidence supporting use of antiviral therapy for treatment of influenza is based on data from trials evaluating the efficacy of oseltamivir. These data are summarized above. (See 'Timing of treatment' above and 'Clinical approach' above.)

Some data suggest lower efficacy of oseltamivir for reducing symptoms in the setting of infection due to influenza B. In a study in Japan including 1818 patients with influenza A and 1485 patients with influenza B treated with oseltamivir, the duration to resolution of fever was longer for patients with influenza B (mean duration 65 versus 48 hours) [37].

●Adverse effects − Oseltamivir can cause nausea and vomiting [20], but these adverse effects do not generally result in drug discontinuation. There have been reports of delirium in patients (primarily children) receiving oseltamivir for treatment of influenza. Most of these reports came from Japan, where the drug is used more commonly than in the United States [38]. However, subsequent studies have not demonstrated a causal association between oseltamivir and neuropsychiatric events [39,40]. (See "Seasonal influenza in children: Management", section on 'Efficacy'.)

Zanamivir — Zanamivir is administered by inhalation. An intravenous formulation is available in some regions (United Kingdom and the European Union) but is not available in the United States.

●Efficacy – Treatment with zanamivir may shorten the duration of influenza symptoms. In a 2014 meta-analysis including 26 randomized trials of healthy adults and children with influenza (obtained from the manufacturer of zanamivir and the European Medicines Agency), treatment with zanamivir was associated with shortened median time to symptom resolution by 14.4 hours (95% CI 9.4-19.4 hours) [41]. A reduction in the risk of pneumonia, hospital admission, or mortality was not observed.

The efficacy of parenteral zanamivir appears comparable with that of oral oseltamivir; in a trial including 626 hospitalized patients randomly assigned to treatment with parenteral zanamivir or oral oseltamivir, the median time to clinical response was comparable between the groups [42].

●Adverse effects – Zanamivir (inhaled) can cause bronchospasm in patients with asthma and other chronic respiratory disorders; therefore, this agent is contraindicated in these patient groups.

Zanamivir inhalation powder is not recommended for use in nebulizers or mechanical ventilators since the carrier can clog ventilator tubing [43,44].

Peramivir — Peramivir is administered parenterally; it is approved by the US Food and Drug Administration (FDA) for treatment of uncomplicated influenza infection in adults who have been ill for ≤2 days.

●Efficacy − Among outpatients, the efficacy of peramivir appears to be comparable with that of oseltamivir. In a randomized trial including 1091 adults with uncomplicated influenza infection randomly assigned to receive peramivir (600 mg intravenous [IV] single dose) or oseltamivir, symptom duration was comparable between the groups [45].

Among hospitalized patients, the benefit of peramivir remains uncertain due to limited data. In one randomized trial including 121 hospitalized patients treated with peramivir (600 mg IV once daily for five days) or placebo, a benefit of peramivir was not observed [14]. In another randomized trial including 40 hospitalized patients treated with peramivir (300 IV once daily for 5 days) or oseltamivir, symptom duration was comparable between the groups [46].

●Adverse effects − Diarrhea is a common adverse effect reported in patients receiving peramivir. Rare but serious adverse effects associated with peramivir include skin or hypersensitivity reactions such as Stevens-Johnson syndrome and erythema multiforme. In addition, there have been postmarketing reports of neuropsychiatric events from Japan [47].

Baloxavir — Baloxavir is administered orally; it is approved by the FDA for treatment of uncomplicated influenza in adults who have been ill for ≤2 days. Emergence of resistance after a single dose has raised concerns about the long-term utility of baloxavir monotherapy [22,23]; issues related to antiviral resistance are discussed further separately. (See "Antiviral drugs for influenza: Pharmacology and resistance".)

●Efficacy − Treatment with baloxavir may shorten the duration of influenza symptoms by approximately one day [22].

In a randomized trial (CAPSTONE-1) including more than 1000 otherwise healthy outpatients with uncomplicated influenza randomly assigned to treatment with baloxavir, oseltamivir, or placebo, the median time to resolution of symptoms was 53.7 hours with baloxavir versus 80.2 hours with placebo [22]. The time to resolution of symptoms was similar with baloxavir and oseltamivir.

In a subsequent trial (CAPSTONE-2) including more than 1000 outpatients at high risk of influenza complications (table 1) randomly assigned to treatment with baloxavir, oseltamivir, or placebo, the efficacy of baloxavir and oseltamivir were similar (median time to resolution of symptoms was 73 hours and 81 hours, respectively) and superior to placebo (median time to resolution of symptoms was 102 hours), respectively [23].

●Adverse effects − Adverse effects include diarrhea (1.8 percent of baloxavir recipients compared with 1.3 percent of placebo recipients and 1.4 percent of oseltamivir recipients) [22]. Hypersensitivity reactions (eg, anaphylaxis, urticaria, angioedema, erythema multiforme) have been reported in postmarketing surveillance [48].

Investigational approaches — Investigational approaches for treatment of influenza include parenteral and/or long-acting formulations of neuraminidase inhibitors [49] and antiviral agents with novel mechanisms of action [50,51]. Based on available data, there is no role for routine use of combination antiviral therapy for treatment of influenza; this is discussed above. (See 'Antiviral selection' above.)

A number of adjunctive therapies have been proposed for the management of patients with influenza, thus far, none has sufficient evidence to support its use:

●Statins – It has been hypothesized that the anti-inflammatory effects of statins could reduce the severity of illness associated with influenza infection; randomized trials are needed. (See "Mechanisms of benefit of lipid-lowering drugs in patients with coronary heart disease", section on 'Reduced inflammation'.)

●Glucocorticoids – There has been interest in the potential for glucocorticoids to improve outcomes in patients with influenza infection by reducing inflammation. However, in a meta-analysis of observational studies, glucocorticoid use was associated with an increased mortality risk (odds ratio 3.90, 95% CI 2.31-6.60) [52]. Given the possibility of harm, glucocorticoids should not be used as adjunctive therapy for treatment of patients with influenza in the absence of a separate indication for their use [2,53].

●Intravenous immunoglobulin, convalescent plasma, and hyperimmune globulin – There has been interest in use of these agents as adjunctive therapy for severe influenza infection [54]; further study is needed [2].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Treatment and prevention of seasonal influenza with antivirals".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Flu (The Basics)")

●Beyond the Basics topic (see "Patient education: Influenza symptoms and treatment (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●General principles

•Site of care − Hospitalization is warranted for patients with significant dehydration and for severely ill patients, especially those with respiratory distress, hypoxemia, impaired cardiopulmonary function, or altered mental status. In the absence of these findings, admission for observation may be warranted for patients with increased risk for complications (table 1) and uncertain clinical trajectory. (See 'Site of care' above.)

•Symptom management − Hydration should be maintained. Acetaminophen or nonsteroidal anti-inflammatory drugs may be used for management of fever, headache, and myalgia. (See 'Symptom management' above.)

●Hospitalized patients

•Antiviral treatment

-Timing − For hospitalized patients with known or suspected influenza presenting <48 hours after symptom onset, we recommend antiviral treatment (Grade 1C); for those presenting ≥48 hours after symptom onset, we suggest antiviral treatment (Grade 2C). (See 'Timing of treatment' above.)

-Antiviral selection − We suggest treatment with oseltamivir (Grade 2C). Alternative agents include peramivir or zanamivir (administered parenterally). Dosing is summarized in the table (table 2). (See 'Antiviral selection' above.)

Zanamivir (inhaled) is contraindicated in patients with asthma or chronic obstructive pulmonary disease, and it should not be used for treatment of severe influenza (given limited data). Peramivir (parenteral) should be reserved for patients who cannot tolerate oral or inhaled agents. Baloxavir should not be used for treatment of severe influenza (given limited data) or immunocompromised hosts (given concern for emergence of resistance).

•Concomitant infection − For patients in the following circumstances, we suggest administration of empiric antibacterial treatment for pneumonia (in addition to antiviral treatment for influenza) (Grade 2C) (see 'Concomitant infection' above):

-Patients with respiratory failure and/or hemodynamic instability

-Patients who fail to improve after three to five days of antiviral therapy and supportive care

-Patients who develop fever after defervescence

Patients should be treated with an agent active against Streptococcus pneumoniae and Streptococcus pyogenes (such as ceftriaxone, levofloxacin, or moxifloxacin). In addition, for patients with severe or necrotizing pneumonia, empiric treatment for methicillin-resistant Staphylococcus aureus infection (with vancomycin or linezolid) should be administered.

●Outpatients – The approach to decision-making regarding outpatient antiviral therapy is summarized in the algorithm (algorithm 1).

•Outpatients at risk for complications or severe illness – For the following outpatients with known or suspected influenza A or B (regardless of symptom duration), we suggest antiviral treatment (algorithm 1) (Grade 2C):

-Patients at increased risk for complications (table 1)

-Patients with progressive illness who do not require hospitalization

In such cases, antiviral treatment may reduce the duration of illness and reduce the risk of respiratory tract complications and hospitalization. (See 'Patients at risk for complications or severe illness' above.)

•Outpatients who may transmit infection to high-risk contacts − For outpatients with known or suspected influenza A or B (regardless of symptom duration) who have exposure to individuals at increased risk for influenza complications (table 1), such as household contacts and health care workers, we suggest antiviral treatment (algorithm 1) (Grade 2C). In such cases, antiviral treatment may reduce the likelihood of transmission to vulnerable individuals. (See 'Patients who may transmit infection' above.)

•Outpatients who are not at high risk for complications or transmission − For outpatients with uncomplicated illness who are not at increased risk for complications (table 1), treatment should be guided by duration of symptoms (algorithm 1) (see 'Patients who are not at high risk for complications or transmission' above):

-Symptoms <48 hours − For patients within 48 hours of symptom onset, whether to administer antiviral treatment should be guided by individual patient circumstances; treatment may be associated with a modest reduction in duration of illness (by approximately 24 hours).

-Symptoms ≥48 hours − For patients beyond 48 hours of symptom onset, we suggest not administering antiviral treatment (Grade 2C), given lack of benefit.

•Antiviral selection − For outpatients with influenza, we suggest treatment with oseltamivir (Grade 2C); it is the agent with the most established efficacy and safety data. Alternative agents include inhaled zanamivir and oral baloxavir. Dosing is summarized in the table (table 2). (See 'Antiviral selection' above.)

•Infection control and returning to work/school − Use of face masks and hand hygiene may reduce household transmission. Individuals with influenza should remain home from work, school, and other public places until at least 24 hours after resolution of fever (without use of antipyretics) and improvement in symptoms. (See 'Infection control and returning to work/school' above.)

●Antiviral resistance − Antiviral resistance is rare; risk factors include administration of postexposure prophylaxis, prolonged antiviral treatment, and immunosuppression. For patients with suspected or known infection due to oseltamivir-resistant influenza virus, we suggest treatment with zanamivir (Grade 2C). (See 'Antiviral resistance' above.)