INTRODUCTION — Seasonal influenza is an acute respiratory illness caused by influenza A or B viruses. Influenza occurs in outbreaks and epidemics worldwide, mainly during the winter season. Although acutely debilitating, influenza is usually a self-limited infection. However, it is associated with increased morbidity and mortality in certain high-risk populations.

Three classes of antiviral drugs are available for the treatment of influenza [1-6]:

●The neuraminidase inhibitors, zanamivir, oseltamivir, and peramivir, which are active against both influenza A and B.

●The selective inhibitor of influenza cap-dependent endonuclease, baloxavir, which is active against influenza A and B.

●The adamantanes, amantadine and rimantadine, which are only active against influenza A. Due to a marked increase in resistant isolates, the United States Centers for Disease Control and Prevention (CDC) recommends that adamantanes not be used in the United States for the treatment of influenza, except in selected circumstances [1]. (See 'Choice of antiviral drug' below.)

The role of these drugs in the treatment of seasonal influenza will be reviewed here. Their role in the prevention of seasonal influenza, treatment and prevention of avian influenza, and treatment and prevention of influenza in children are discussed separately; the pharmacologic characteristics of the antiviral drugs used for influenza are also presented elsewhere. (See "Prevention of seasonal influenza with antiviral drugs in adults" and "Avian influenza A H5N1: Treatment and prevention" and "Seasonal influenza in children: Management" and "Avian influenza A H7N9: Treatment and prevention", section on 'Postexposure prophylaxis' and "Pharmacology of antiviral drugs for influenza" and "Seasonal influenza in children: Prevention with antiviral drugs".)

BENEFITS OF THERAPY — When initiated promptly, antiviral therapy with a neuraminidase inhibitor or baloxavir can shorten the duration of influenza symptoms by approximately one half to three days; in most studies, the benefit has been greatest when given within the first 24 to 30 hours and in patients with fever at presentation [7-15]. Most trials of oseltamivir in ambulatory patients have been limited to patients presenting within 48 hours of symptom onset [16]. The prevailing impression has been that there is little or no benefit when treatment is initiated two days or more after the onset of uncomplicated influenza. However, a patient survey found that only 13 percent of patients called their clinician within 48 hours of the onset of influenza-like symptoms [17].

Some studies have suggested that antiviral therapy reduces the severity and incidence of complications of influenza [10,13,18-23], the need for hospitalization [24], the length of stay in those hospitalized for influenza including older adults [25-27], and influenza-associated mortality [28-30]. However, other studies of immunocompetent patients have not shown a reduction in complications of influenza among patients who received antiviral therapy [11,12]. The efficacy and safety of antiviral agents for seasonal influenza are discussed in greater detail below. (See 'Neuraminidase inhibitors' below and 'Adamantanes' below.)

There is evidence that antiviral therapy is underutilized in patients at high risk for complications of influenza. In a study encompassing five influenza seasons, 15,972 outpatients with an acute respiratory illness and at increased risk for influenza complications were identified; 3196 (20 percent) had laboratory-confirmed influenza, and, of these, 1292 (40 percent) presented to care within two days of symptom onset [31]. Of these 1292 patients, only 472 (37 percent) were prescribed an antiviral agent. Earlier presentation was associated with antiviral treatment (odds ratio [OR] 4.1, 95% CI 3.5-4.8), as was fever (OR 3.2, 95% CI 2.7-3.8), although 25 percent of high-risk outpatients with influenza infection were afebrile. Empiric treatment of four high-risk outpatients with acute respiratory illness was needed to treat one patient with influenza infection.

ANTIVIRAL THERAPY — 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 [5]. Our recommendations are generally in keeping with those of the CDC and IDSA. Refer to the CDC website for updated recommendations. Clinicians in other countries should consult with their ministries of health and/or the World Health Organization for specific recommendations.

In 2014, the authors of some meta-analyses of oseltamivir and zanamivir questioned recommendations for the use of these agents [11,12]. However, based upon all available data, including a 2015 meta-analysis that used individual patient data and demonstrated the benefit of oseltamivir [13], we continue to recommend antiviral therapy with a neuraminidase inhibitor for patients with any of the indications for treatment discussed below. Our position is consistent with that of the IDSA and the CDC; both groups released statements addressing the concerns raised by authors of the meta-analyses [32,33].

Target populations for treatment — Individuals with severe disease (requiring hospitalization or evidence of lower respiratory tract infection) or at high risk for complications should receive antiviral therapy. Antiviral therapy, when indicated, should be initiated as promptly as possible.

Definition of high risk — Adults at high risk for complications for influenza are summarized in the table (table 1) [1]. Adults at high risk include [15,34-37]:

●Those ≥65 years of age

●Women who are pregnant or postpartum (within two weeks after delivery)

●Residents of long-term care facilities

●Native Americans including Alaska Natives

●Those with extreme obesity (body mass index [BMI] ≥40)

●Individuals with certain chronic medical conditions (eg, immunocompromising condition, chronic lung disease, chronic heart disease, chronic kidney disease)

●Those receiving glucocorticoids or other immunosuppressive medications

Of the groups described above, those at highest risk for influenza complications may be those with underlying lung disease and/or severe immunosuppression (eg, lung transplant recipients, individuals with advanced HIV infection [CD4 <200 cells/microL]).

Antiviral treatment should be considered in asplenic patients with influenza. Although there are no data regarding the risk for severe or complicated influenza among asplenic individuals, influenza is a risk factor for secondary bacterial infections that can cause severe disease among such patients [38].

Indications for treatment — In accordance with the Advisory Committee on Immunization Practices' and IDSA's guidelines, we recommend prompt initiation of antiviral therapy for individuals with suspected or confirmed influenza infection and any of the following features, irrespective of influenza vaccination status [1,5]:

●Patients hospitalized with influenza, regardless of illness duration prior to hospitalization

●Outpatients with severe or progressive illness, regardless of illness duration

●Outpatients who are at high risk of influenza complications, as defined above and in the table (table 1), regardless of illness duration (see 'Definition of high risk' above)

The IDSA states that antiviral therapy can be considered for patients with suspected or confirmed influenza who are not at high risk for influenza complications, irrespective of influenza vaccination history, if they meet any of the following criteria [5]; we generally suggest antiviral therapy for these groups:

●Outpatients with illness onset ≤48 hours before presentation in order to reduce the duration of illness; those who present >48 hours after illness onset should not be treated with antivirals since most studies suggest they are unlikely to benefit [1,5].

●Symptomatic outpatients who are household contacts of persons at high risk for influenza complications, particularly those who are severely immunocompromised (table 1).

●Symptomatic health care providers who routinely care for patients at high risk for influenza complications, particularly those who are severely immunocompromised (table 1).

Patients who are recovering from influenza generally do not require antiviral therapy [39]. The decision of whether to initiate antiviral therapy for each patient should be based upon what is known about the potential benefits of therapy for seasonal influenza versus the potential risks. The risk of promoting antiviral drug resistance should be considered when deciding which patients to treat. Overuse of antiviral drugs for influenza may promote further development of resistance that could lead to these agents becoming ineffective.

Timing of antiviral initiation — When indicated, treatment should be started as soon as possible since antiviral therapy is most likely to provide benefit when initiated within the first 48 hours of illness [1,5,40]. Treatment should not be delayed while awaiting the results of diagnostic testing, nor should it be withheld in patients with indications for therapy who present >48 hours after the onset of symptoms, particularly among patients requiring hospitalization. Furthermore, patients who have a negative rapid antigen test for influenza but in whom the clinical suspicion for influenza infection is high should be treated with antivirals since the sensitivity of these tests is generally low. Even with the reverse-transcriptase polymerase chain reaction (RT-PCR), which is more sensitive than the rapid antigen tests, false-negative results can occur due to improper or poor clinical specimen collection or from poor handling of a specimen after collection and before testing [41]. For hospitalized patients, especially for patients with lower respiratory tract disease, if no other etiology is identified and influenza is still suspected, additional specimens should be tested, and antiviral treatment should be initiated or continued. (See "Seasonal influenza in adults: Clinical manifestations and diagnosis".)

Most studies suggest that the benefit of treatment is greatest with early administration. In one study of patients with mild uncomplicated influenza infection who did not have risk factors for severe or complicated illness, antiviral therapy initiated within 48 hours of symptom onset reduced symptom duration compared with placebo, but therapy initiated after 48 hours of symptoms did not [42]. Observational data also suggest that treatment within 48 hours is associated with a mortality benefit among critically ill patients. (See 'Mortality' below.)

However, some individual benefit to treatment may remain after the initial 48 hours of symptoms, even among outpatients, particularly in those with more severe symptoms and/or at high risk for complications. In a large, randomized, open-label trial across several primary care centers in Europe, adding oseltamivir to usual care reduced symptom duration among outpatients with influenza-like illness compared with placebo, even among those with symptom duration >48 hours; for adults ≥65 years old with comorbidities and moderate to severe symptoms, oseltamivir was estimated to reduce symptoms by 2.3 to 3.2 days if started 48 to 72 hours after symptom onset [43].

Choice of antiviral drug — It is important to assess the risk of oseltamivir-resistant influenza before choosing therapy for patients with influenza. Clinicians should review local or state influenza surveillance data to determine which types of influenza (A or B) and subtypes of influenza A (H1N1 or H3N2) are circulating. (See 'Influenza activity' below and 'Oseltamivir resistance' below.)

Antiviral agents for treatment of influenza include neuraminidase inhibitors (oseltamivir, zanamivir, and peramivir) and an inhibitor of influenza cap-dependent endonuclease (baloxavir) (table 2) [1,5]:

●For treatment of patients with uncomplicated influenza (suspected or confirmed), a neuraminidase inhibitor (oseltamivir, zanamivir, or peramivir) or baloxavir can be used. Of these, we favor oseltamivir.  

●For treatment of patients with severe influenza, oseltamivir is the preferred agent; peramivir may be used for patients who cannot tolerate oral therapy. Data on the efficacy of baloxavir in patients with severe influenza are limited. In regions where intravenous (IV) zanamivir is available (United Kingdom and the European Union), it is recommended when other antiviral agents cannot be used.

The US Food and Drug Administration has approved IV peramivir only for patients with uncomplicated influenza [1,5]; however, we think it is reasonable to use peramivir for patients with severe influenza who cannot receive oseltamivir (eg, who cannot tolerate oral agents).

Oseltamivir or peramivir should only be used if oseltamivir-resistant influenza is not suspected. Resistance to oseltamivir is rare; when present, it confers cross-resistance to peramivir but usually not to zanamivir.

The adamantanes, amantadine and rimantadine, are active only against influenza A viruses. High resistance rates to adamantanes have developed among influenza A viruses, and these drugs are not indicated. (See 'Adamantanes' below.)

The management of pregnant women with influenza is discussed in greater detail separately. (See "Seasonal influenza and pregnancy", section on 'Treatment'.)

Dosing — The usual oseltamivir dosing for the treatment of influenza is 75 mg orally twice daily; for zanamivir, the dose is 10 mg (two inhalations) twice daily (table 2). The usual recommended dose of peramivir is 600 mg IV as a single dose (ie, for uncomplicated influenza). Although the optimal dosing of peramivir in patients with severe influenza is unknown, if it is used in this setting (eg, in a severely ill patient who cannot receive enteral oseltamivir), we favor giving a dose of 600 mg IV once daily (rather than a single dose); in a clinical trial, this dosing regimen appeared to be safe [5,44]. Dosing of oseltamivir and peramivir must be modified for renal insufficiency.

Doubling the dose of oseltamivir to 150 mg orally twice daily has been suggested for some severely ill patients with H5N1 avian influenza and was also suggested for certain severely ill patients (eg, immunocompromised hosts) during the 2009 to 2010 H1N1 influenza pandemic [45,46]. However, there is no evidence that IV zanamivir (available in the United Kingdom and Europe but not in the United States) or double-dose oseltamivir is more effective than the usual dose in hospitalized patients with or without severe illness [47-49]. We therefore do not give a double dose of oseltamivir for seasonal influenza. The CDC and IDSA also do not recommend higher than usual doses of oseltamivir [1,5].

In a randomized trial of hospitalized patients with severe influenza, mortality was similar in patients who received double-dose or standard-dose oseltamivir (7.3 versus 5.6 percent) [47]. No differences were observed for clearance of virus by RT-PCR on day 5 of treatment or median days of supplemental oxygen, intensive care, or mechanical ventilation. In a prospective study of adults hospitalized with influenza between 2010 and 2012 in Hong Kong who were treated with a single or double dose of oseltamivir twice daily, there were no differences between the groups in influenza RNA or culture negativity at day 5, RNA decline rate, or duration of fever, oxygen supplementation, or hospitalization [48]. In contrast with the trial discussed above, the majority of patients in this study were not critically ill. In an international multicenter trial, patients with severe influenza were randomly assigned to zanamivir 600 mg IV twice daily, zanamivir 300 mg IV twice daily, or oseltamivir 75 mg orally twice daily for 5 to 10 days [49]. The time to clinical response (a composite of vital sign stabilization and hospital discharge) was similar in all three groups (high-dose zanamivir: 5.14 days, standard-dose zanamivir: 5.87 days, and standard-dose oseltamivir: 5.63 days).

The use of a double dose of oseltamivir for H5N1 avian influenza is discussed separately. (See "Avian influenza A H5N1: Treatment and prevention", section on 'Treatment'.)

For individuals weighing 40 to <80 kg, the dose of baloxavir is 40 mg as a single oral dose; for individuals weighing ≥80 kg, the dose is 80 mg as a single oral dose [6]. Coadministration of baloxavir with dairy products, calcium-fortified beverages, polyvalent cation-containing laxatives, antacids, or oral supplements (eg, calcium, iron, magnesium, selenium, zinc) should be avoided.

Duration — The usual recommended duration of antiviral therapy with oseltamivir and zanamivir is five days [1,5]. Peramivir and baloxavir are typically given as a single dose. However, as noted above, peramivir should probably be given daily to those with severe disease, though data to support this practice are lacking. A longer duration of oseltamivir or peramivir merits consideration in patients with severe lower respiratory tract disease (especially pneumonia or acute respiratory distress syndrome) or immunocompromised individuals, particularly in those who continue to have a positive influenza RT-PCR result from a respiratory specimen, although published data to guide such practice are not available [1,5].

Special circumstances

Pregnancy — Aggressive treatment of influenza is important in pregnant women as they are at increased risk of complications of influenza. During the 2009 H1N1 influenza pandemic, pregnant women had a more severe clinical course and higher mortality compared with nonpregnant women. This is discussed in greater detail separately. (See "Seasonal influenza and pregnancy", section on 'Maternal effects' and "Seasonal influenza and pregnancy", section on 'Treatment'.)

Hematopoietic cell transplantation — The use of antivirals in hematopoietic cell transplant (HCT) recipients has not been studied in randomized trials. A retrospective review of laboratory-confirmed influenza cases in HCT recipients found that 62 of 4797 patients (1.3 percent) were diagnosed with influenza within 120 days of undergoing HCT [50]. Of the 51 patients who were initially diagnosed with upper respiratory tract involvement and no signs or symptoms suggesting pneumonia, 6 of 34 untreated patients developed pneumonia, whereas none of nine patients treated with oseltamivir and one of eight patients treated with rimantadine developed pneumonia.

HCT recipients should be treated for influenza according to the recommendations for patients at high risk for influenza complications described above. (See 'Indications for treatment' above.)

Oseltamivir resistance — Oseltamivir-resistant seasonal H1N1 influenza A viruses emerged in 2007 and were present at high rates worldwide during the 2008 to 2009 influenza season, prior to the onset of the 2009 H1N1 influenza A ("swine influenza") pandemic. The pandemic strain of H1N1 influenza A was generally susceptible to oseltamivir, except for sporadic cases. Since September 2009, 99 percent of influenza virus isolates tested in the United States have been susceptible to neuraminidase inhibitors [1,51]. (See "Antiviral drug resistance among seasonal influenza viruses", section on 'Oseltamivir resistance'.)

Indications for testing for and management of infection with an antiviral-resistant influenza virus are presented separately. (See "Antiviral drug resistance among seasonal influenza viruses", section on 'When to suspect resistance to neuraminidase inhibitors' and "Antiviral drug resistance among seasonal influenza viruses", section on 'Treatment'.)

NEURAMINIDASE INHIBITORS — Zanamivir (inhaled), oseltamivir, and peramivir are moderately effective for the treatment of infections with susceptible viruses, reducing the duration and severity of symptoms particularly when treatment is initiated early after onset of symptoms. The neuraminidase inhibitors also reduce the duration of shedding and viral titer [52]. These agents have been approved by the US Food and Drug Administration for the treatment of acute uncomplicated influenza in patients who have been symptomatic for ≤48 hours [53-55].

Investigational neuraminidase inhibitors are discussed below. (See 'Investigational approaches' below.)

Efficacy of oseltamivir

Symptoms and complications — Oseltamivir has been demonstrated to shorten the duration of influenza symptoms by approximately one day [7,8,11,13,19,42,43,56-60] and to reduce the duration of viral shedding [42,52]. Some studies have also shown that oseltamivir reduces illness severity and complication rates [13,19,20], hospital admissions [13,61], and the length of hospitalization [25,26].

Meta-analyses have provided contradictory results regarding the impact of oseltamivir on influenza-related lower respiratory tract complications in healthy adults. One reason for this is that some trials evaluated patients with influenza-like illness, whereas others limited their analysis to those with laboratory-confirmed influenza infection. Including all patients with influenza-like illness leads to an underestimate of benefit since oseltamivir does not have activity against viruses other than influenza. As an example, a 2011 meta-analysis that analyzed the results from 11 randomized trials concluded that oseltamivir treatment reduced the risk of lower respiratory tract complications by 28 percent overall (95% CI 11-42 percent) and by 37 percent among patients with confirmed influenza infections (95% CI 18-52 percent) [21].

A 2015 meta-analysis evaluated all published and unpublished randomized trials of oseltamivir for the treatment of influenza in adults that were sponsored by the manufacturer of oseltamivir [13]. This meta-analysis was funded by the manufacturer of oseltamivir but was performed by an independent research group. Individual patient data from nine trials of 4328 adults were included. In the intention-to-treat population of patients with laboratory-confirmed influenza infection, there was a significant reduction in time to alleviation of all symptoms for oseltamivir compared with placebo (time ratio 0.79, 95% CI 0.74-0.85; median times to alleviation of symptoms 97.5 versus 122.7 hours). Oseltamivir conferred no benefit in patients without confirmed influenza infection. In the intention-to-treat influenza-infected population, among those who were assigned to oseltamivir, there were fewer lower respiratory tract complications requiring antibiotics more than 48 hours after randomization (risk ratio [RR] 0.56, 95% CI 0.42-0.75; events in 65 of 1544 patients in the oseltamivir group versus 110 of 1263 patients in the placebo group [4.9 versus 8.7 percent]) and fewer hospital admissions for any cause (RR 0.37, 95% CI 0.17-0.81; events in 9 of 1329 patients in the oseltamivir group versus 22 of 1045 patients in the placebo group [0.6 versus 1.7 percent]). It should be noted that the difference in hospital admissions was modest (a 1.1 percent reduction in those assigned to oseltamivir versus placebo).

Another group has published a series of meta-analyses since 2009 questioning the benefit of oseltamivir. In 2014, this group published a meta-analysis of unpublished clinical study reports from 15 randomized trials of treatment with oseltamivir (11 in adults, 4 in children) obtained from the European Medicines Agency and the manufacturer of oseltamivir [11]. In this meta-analysis, treatment with oseltamivir reduced the duration of symptoms by 16.8 hours in immunocompetent adults and children with influenza-like illness. There was no difference in hospital admissions in adults who received oseltamivir and those who received placebo. When studies were included in which the diagnosis of pneumonia could not be verified by the meta-analysts, oseltamivir appeared to reduce the risk of pneumonia (RR 0.55, 95% CI 0.33-0.90; risk difference 1 percent, 95% CI 0.22-1.49 percent). However, the effect was not statistically significant in the five trials that used a more detailed diagnosis form for pneumonia. No trials reported laboratory or diagnostic confirmation of pneumonia. There was no significant reduction in the risk of unverified bronchitis, otitis media, sinusitis, or any complication classified as serious or that led to study withdrawal. The authors noted that the evidence of clinically significant effects on complications was limited because these events were rare and because of problems with study design.

The methodologies of the 2014 and 2015 studies differed in that the 2014 systematic review used aggregate study results [11], while 2015 meta-analysis used individual patient data [13]. Pooling individual patient data is considered by many experts to be the most rigorous form of meta-analysis [62]. (See "Systematic review and meta-analysis", section on 'Individual patient data'.)

Analysis of patients with influenza-like illness (rather than laboratory-confirmed influenza) is likely to result in an underestimate of the benefits of oseltamivir [63]. The 2014 meta-analysis evaluated patients with influenza-like illness [11], while the 2015 meta-analysis did separate assessments of patients with influenza-like illness, those with laboratory-confirmed influenza infection, and those without confirmed influenza infection [13].

A subsequent randomized, but underpowered and unblinded, trial suggested that oseltamivir treatment did not reduce clinical failures in hospitalized patients who presented with influenza-associated lower respiratory tract infections late in the course of their illness (median of five days after symptom onset) [64].

A randomized, double-blinded, placebo-controlled trial of oseltamivir in adults with influenza, and at low risk for complications, demonstrated a modest decrease in viral RNA shedding on day 3 of treatment (45 percent with oseltamivir, 57 percent with placebo) [65]. However, there was no significant difference in time to alleviation of symptoms. Of note, the proportion of patients with influenza B was relatively high at 28 percent, and some studies have found oseltamivir to be less effective for influenza B than for influenza A (see below).

Mortality — Some observational studies have found an association between oseltamivir use and mortality reduction in patients with influenza [28-30,66,67]. No randomized trials have assessed mortality because all such trials have been conducted in healthy individuals in whom the mortality rate from influenza is very low.

In a cohort study conducted over eight influenza seasons of 1330 critically ill patients treated with oseltamivir for influenza infection, 622 (47 percent) died in the intensive care unit [67]. Among patients with influenza A H3N2, early treatment (≤48 hours from symptom onset) was associated with lower mortality (relative risk 0.69, 95% credible interval 0.49-0.94) than late treatment. No effect on mortality was observed among patients with influenza A H1N1 or influenza B infection.

Influenza B — Some studies, but not others, have shown that oseltamivir may be less effective in reducing clinical symptoms related to influenza B. In a prospective multicenter study conducted in Japan, influenza A was documented in 1818 patients and influenza B in 1485 patients [56]. The duration from treatment initiation to resolution of fever was significantly longer for patients with influenza B than for influenza A (mean duration 65 versus 48 hours, respectively). In addition, after four to six days of oseltamivir therapy, the reisolation rate was higher for influenza B than for influenza A (52 versus 16 percent) in a subset of 75 patients in whom viral isolation was performed.

In contrast, in a study of 64 children with influenza infections treated with oseltamivir (34 with influenza A subtype H3N2, 11 with influenza A subtype H1N1, 19 with influenza B), there were no differences in the reduction of viral shedding or time to clearance of virus among viral subtypes [68]. Another study, comparing oseltamivir and inhaled zanamivir in children, found the two drugs to be comparably effective, in terms of resolution of fever, for both influenza A (H3N2 or H1N1) and B [69].

Efficacy of zanamivir — Zanamivir is administered by oral inhalation. Inhaled zanamivir is contraindicated in patients with underlying asthma or other chronic respiratory conditions. (See 'Adverse effects' below.)

An intravenous formulation of zanamivir was evaluated in clinical trials [70-72] but is not available. (See 'Neuraminidase inhibitors' below.)

Inhaled zanamivir has been demonstrated in randomized trials to shorten the duration of influenza symptoms by one to three days [9,10,73]. In a 2003 meta-analysis of randomized trials, inhaled zanamivir reduced the median duration of symptoms of laboratory-confirmed influenza by 1.3 days in otherwise healthy adults ≤65 years of age and by 2 days in adults ≥65 years of age or patients with comorbidities [7]. Subsequent meta-analyses have shown similar benefits [60,74].

In a 2014 meta-analysis of unpublished clinical study reports from 26 randomized trials that included previously healthy adults and children obtained from the European Medicines Agency and the manufacturer of zanamivir, zanamivir reduced the average time to first alleviation of symptoms of influenza-like illness by 14.4 hours [12]. Zanamivir did not reduce the risk of self-reported investigator-mediated pneumonia or radiologically confirmed pneumonia in adults. There was no reduction in otitis media or sinusitis, but there was a small reduction in bronchitis (RR 0.75, 95% CI 0.61-0.91; risk difference 1.8 percent, 95% CI 0.65-2.80). There were no data to evaluate the effect on hospital admission. Evaluating patients with influenza-like illness (rather than laboratory-confirmed influenza) is likely to result in an underestimate of the benefits of zanamivir [63].

Efficacy of peramivir — Peramivir was approved by the US Food and Drug Administration in 2014 for treating uncomplicated influenza infection in adults who have been ill for ≤2 days [55]. Peramivir is administered as a single intravenous dose of 600 mg because it has strong and prolonged affinity for influenza virus neuraminidase [55,75].

The efficacy of peramivir was demonstrated in a trial that included 297 patients with laboratory-confirmed influenza infection who were randomly assigned to receive a single dose of either placebo or peramivir at a dose of 300 or 600 mg [55]. Individuals who received peramivir 600 mg had their influenza symptoms alleviated an average of 21 hours sooner and became afebrile approximately 12 hours sooner than those who received placebo. Results for the group that received the 300 mg dose were not reported. Efficacy could not be established in patients with influenza requiring hospitalization.

Peramivir has also been compared with oseltamivir. In a multinational trial, 1091 adults with influenza infection were randomly assigned to receive either a single intravenous infusion of peramivir (300 or 600 mg) or oral administration of oseltamivir (75 mg twice a day for five days) [76]. The median duration of influenza symptoms was 78, 81, and 82 hours in the groups treated with 300 mg of peramivir, 600 mg of peramivir, or oseltamivir, respectively. Both doses of peramivir were considered to be noninferior to oseltamivir. Although this trial suggested that 300 mg of peramivir is as effective as 600 mg of peramivir, in a trial by the same group that compared different doses of peramivir (600 mg or 300 mg IV daily of peramivir for one to five days) in 37 high-risk patients (with immunocompromise, chronic respiratory disease, or diabetes) with influenza infection, the duration of illness was shorter among those who received the 600 mg dosing compared with the 300 mg dosing (median duration of 42 versus 114 hours; hazard ratio 0.50, 95% CI 0.25-0.98) [77].

In a trial, 121 patients hospitalized with laboratory-confirmed influenza were randomly assigned to treatment with peramivir (600 mg IV once daily for five days) or placebo [44]. The median time to clinical resolution was 42.5 hours (95% CI 34.0-57.9 hours) for peramivir versus 49.5 hours (95% CI 40.0-61.9 hours) for placebo, a difference that was not statistically significant. A larger treatment effect was observed in patients with symptoms for <48 hours before enrollment or admitted to an intensive care unit. Although greater reductions in viral shedding were observed in patients who received peramivir, these differences were not statistically significant. Another randomized trial [78] compared peramivir (300 once daily for 5 days) with oseltamivir (75 mg twice daily for 5 days) in 40 patients hospitalized with severe influenza A and viral pneumonia. Outcomes were similar between the two groups, with slightly more rapid resolution of fever in the peramivir group (12 versus 24 hours).

Adverse effects — Adverse effects of neuraminidase inhibitors are typically mild, although more serious side effects have been described. Zanamivir can cause bronchospasm and a decline in respiratory function in patients with asthma and other chronic respiratory disorders. As a result, the manufacturer has issued a warning advising particular caution in patients with asthma or chronic obstructive pulmonary disease [79].

Zanamivir inhalation powder is not recommended for use in nebulizers or mechanical ventilators since the lactose carrier can clog ventilator tubing [53,80]. (See "Pharmacology of antiviral drugs for influenza", section on 'Adverse effects'.)

There have been postmarketing reports of self-injury and 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 [54]. However, subsequent studies have not demonstrated a causal association between neuraminidase inhibitors and abnormal behavior [81,82] . (See "Seasonal influenza in children: Management", section on 'Efficacy'.)

Oseltamivir can also cause nausea and vomiting [13], but these side effects have not generally resulted in discontinuation of therapy. (See "Pharmacology of antiviral drugs for influenza", section on 'Adverse effects'.)

Diarrhea is a common adverse effect reported in patients receiving peramivir. Rare but serious adverse effects associated with peramivir include serious skin or hypersensitivity reactions such as Stevens-Johnson syndrome and erythema multiforme. As with oseltamivir, there have been postmarketing reports from Japan of delirium and abnormal behavior leading to injury in patients with influenza who were receiving peramivir.

BALOXAVIR — Baloxavir marboxil is a novel oral selective inhibitor of influenza cap-dependent endonuclease that blocks influenza proliferation by inhibiting the initiation of mRNA synthesis [83,84]. It is approved in the United States for the treatment of acute uncomplicated influenza in adults and children ≥12 years of age (including individuals at high risk of complications) who have been symptomatic for ≤48 hours [4,6]. No data are available regarding its safety or efficacy in persons weighing less than 40 kg or in individuals with immunocompromise or severe influenza.

Efficacy — Baloxavir reduces the time to alleviation of influenza symptoms by approximately one day compared with placebo [6,14].

Baloxavir was evaluated in a phase III trial of otherwise healthy outpatients aged 12 to 64 years with uncomplicated influenza (CAPSTONE-1) in which patients received a single weight-based dose of baloxavir (40 mg for patients <80 kg; 80 mg for patients ≥80 kg), oseltamivir 75 mg orally twice daily for five days, or placebo [14]. The median time to alleviation of symptoms (the primary endpoint) in the 1064 patients in the intention-to-treat infected population was 53.7 hours with baloxavir versus 80.2 hours with placebo. The time to alleviation of symptoms was similar with baloxavir and oseltamivir. Baloxavir was associated with more rapid declines in infectious viral load than placebo or oseltamivir; by one day after initiation of the trial regimen, the median reductions in viral load from baseline were 4.8, 2.8, and 1.3 log₁₀ TCID₅₀/mL in the baloxavir, oseltamivir, and placebo groups, respectively. The median duration of infectious virus detection was shorter in the baloxavir group (24 hours) than in the oseltamivir group (72 hours) and the placebo group (96 hours). The emergence of polymerase acidic protein variants with I38T/M/F substitutions conferring reduced susceptibility to baloxavir occurred in 9.7 percent of baloxavir recipients and in 2.2 percent of baloxavir recipients in a phase II trial performed by the same investigators [14].

In another phase III trial that included 1158 high-risk adolescents and adults with laboratory-confirmed influenza infection, the median time to resolution of symptoms was 73 hours (95% CI 67-85 hours) with baloxavir, 81 hours with oseltamivir, and 102 hours (95% CI 93-113 hours) with placebo [6,23]. The majority of patients had underlying asthma, chronic lung disease, diabetes mellitus, heart disease, obesity, or were ≥65 years of age.

Unanswered questions include whether combination therapy with oseltamivir and baloxavir provides greater clinical benefit than monotherapy with either agent in hospitalized and/or severely immunocompromised patients, and whether baloxavir can successfully treat patients with neuraminidase inhibitor-resistant influenza infections [85]. The emergence of resistance after a single dose raises concerns about the long-term utility of this drug as monotherapy, particularly if it is used widely.

Adverse effects — In the phase III CAPSTONE-1 trial of baloxavir described above, of the adverse events that were considered to be related to the trial regimen, the most common was diarrhea, occurring in 1.8 percent of baloxavir recipients compared with 1.3 percent of placebo recipients and 1.4 percent of oseltamivir recipients [14]. Hypersensitivity reactions (eg, anaphylaxis, urticaria, angioedema, erythema multiforme) have been reported in postmarketing surveillance [6].

ADAMANTANES — The adamantanes, amantadine and rimantadine, are active only against influenza A viruses, but high rates of resistance have developed among influenza A viruses, and these drugs are infrequently indicated. These drugs prevent viral replication by blocking the viral M2 protein ion channel, which prevents fusion of the virus and host-cell membranes [86]. (See "Antiviral drug resistance among seasonal influenza viruses" and "Pharmacology of antiviral drugs for influenza", section on 'Mechanism of action'.)

The Advisory Committee on Immunization Practices recommends that adamantanes (M2 inhibitors) not be used for the treatment of influenza in the United States [39]. (See 'Neuraminidase inhibitors' above and 'Choice of antiviral drug' above.)

Efficacy — In a 2006 meta-analysis that included trials of the adamantanes from the 1960s through the 1980s, prior to the emergence of substantial rates of resistance, both amantadine and rimantadine reduced the duration of symptoms of influenza by about one day and reduced the severity of fever and other symptoms in patients with uncomplicated influenza A infections [18]. In recent years, high levels of resistance to these agents have emerged, initially in Asia and more recently in North America. (See "Antiviral drug resistance among seasonal influenza viruses", section on 'Adamantane resistance'.)

Adverse effects — Studies in young adults have reported a discontinuation rate of 13 to 17 percent with amantadine, largely attributable to central nervous system toxicity [87,88]. Rimantadine causes fewer central nervous system side effects than amantadine (13 versus 6 percent) [87] and has a discontinuation rate due to adverse effects that is similar to placebo [87,88]. (See "Pharmacology of antiviral drugs for influenza", section on 'Adverse effects'.)

INVESTIGATIONAL APPROACHES — There are several investigational approaches for the treatment of influenza. These approaches include parenteral and/or long-acting formulations of neuraminidase inhibitors, combination antiviral therapy with more than one agent, and antiviral agents with novel mechanisms of action. Some experts have called for the use of primary virologic endpoints in the evaluation of new influenza therapies, particularly in patients with severe influenza infection and/or in those at high risk of severe disease [89].

Neuraminidase inhibitors — Parenteral formulations of zanamivir and oseltamivir have been developed but are considered investigational [70-72,90]. During the 2009 H1N1 influenza A pandemic, the US Food and Drug Administration (FDA) issued an emergency use authorization for the use of peramivir, and intravenous (IV) zanamivir was made available for compassionate use from its manufacturer through an emergency investigational new drug application. Peramivir was approved by the FDA in 2014, but IV zanamivir is no longer available [1]. (See 'Efficacy of peramivir' above.)

Long-acting neuraminidase inhibitors, which could allow a single dose to replace a five-day course, are being developed [90-92]. In a randomized trial, a single inhalation of a long-acting neuraminidase inhibitor, laninamivir octanoate, was noninferior to a five-day course of oral oseltamivir in adults with seasonal influenza [92]. The median time to alleviation of illness was 73 hours among those who received 40 mg of laninamivir compared with 86 hours among those who received 20 mg of laninamivir and 74 hours among those who received oseltamivir. The proportion of patients shedding influenza virus at day 3 was significantly lower among those who received 40 mg of laninamivir compared with oseltamivir.

Another long-acting neuraminidase inhibitor that can be given as a single IV dose is peramivir. (See 'Efficacy of peramivir' above.)

Combination antiviral therapy — There has been interest in evaluating combination antiviral therapy for influenza, but we do not recommend this approach based on available data, as there is inadequate evidence of benefit [5].

In a double-blind multicenter trial, patients with influenza who were at increased risk of influenza complications were randomly assigned to receive five days of either combination therapy with oseltamivir, amantadine, and ribavirin or oseltamivir alone [93]. The percentage of patients with virus detectable by nasopharyngeal swab polymerase chain reaction at day 3 was lower in the combination therapy group (40 versus 50 percent; mean difference 10.0, 95% CI 0.2-19.8), but there were no clinical endpoint improvements in this group, including median duration of symptoms and duration of fever.

Other agents — Agents that have shown promise in animal models and/or humans include conjugated sialidase, hemagglutinin inhibitors, small interfering RNA, polymerase inhibitors, protease inhibitors, monoclonal antibodies, and a sphingosine analog [70,90,94-104].

Pimodivir is an oral inhibitor of polymerase basic protein 2 that was found in a phase IIb trial to significantly reduce the area under the curve of the virus load, determined by quantitative reverse-transcriptase polymerase chain reaction from nasopharyngeal swab specimens, from baseline to day 8 compared with placebo [105]. The trial was stopped early because this criterion (the primary endpoint) was met and was most favorable in patients who received pimodivir 600 mg twice daily plus oseltamivir 75 mg twice daily, followed by those who received pimodivir 600 mg twice daily, and those who received pimodivir 300 mg twice daily. However, the time to resolution of influenza symptoms showed only a nonsignificant trend toward a faster time to symptom resolution in those who received pimodivir 600 mg twice daily plus oseltamivir 75 mg twice daily or pimodivir 600 mg alone.

Nitazoxanide is an antiparasitic agent that also has activity against influenza viruses; it blocks maturation of viral hemagglutinin at the post-translational level [106]. In a phase IIb/III trial of patients with uncomplicated influenza, nitazoxanide at a dose of 600 mg twice daily (but not at a dose of 300 twice daily) was associated with a shorter duration of symptoms than placebo [106]. However, in a subsequent phase II randomized trial, nitazoxanide did not reduce the duration of hospitalization in patients with severe influenza-like illness [107].

Ribavirin is a nucleoside analog that has in vitro activity against both influenza A and B viruses. However, clinical data regarding its efficacy have been inconclusive; thus, it is not recommended for the treatment of influenza infection [108].

Adjunctive therapies — Several adjunctive therapies have been proposed for the management of patients with influenza, but 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, although this has not been established. In a surveillance study of 3043 hospitalized patients with laboratory-confirmed seasonal influenza infection in the United States, the 1013 patients who were receiving a statin had a lower likelihood of dying than those who were not (adjusted odds ratio 0.59, CI 0.38-0.92) [109], although confounding factors may have been present. Randomized trials are necessary to determine whether statins result in a survival benefit in patients with influenza infection. (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 risk of mortality (odds ratio 3.90, 95% CI 2.31-6.60) [110]. One randomized trial of adjunctive glucocorticoids in patients with community-acquired pneumonia was found but excluded from the meta-analysis as the number of patients with influenza was too small to draw conclusions regarding the effect of glucocorticoids. Given the suggestion of harm, glucocorticoids should not be used as adjunctive therapy in patients with influenza infection unless there is a separate clear indication for their use [5,111].

●Clarithromycin and naproxen – In an open-label trial, adults hospitalized with H3N2 influenza and pneumonia were randomly assigned to a two-day combination regimen of oseltamivir, clarithromycin, and naproxen, followed by three days of oseltamivir alone; the control group received five days of oseltamivir [112]. All patients also received oral amoxicillin-clavulanate for community-acquired bacterial pneumonia. Combination therapy was associated with lower 30-day mortality (0.9 versus 8.2 percent), lower 90-day mortality (1.9 versus 10.0 percent), less frequent high dependency unit admission, and shorter hospital stay. The virus titer, pneumonia severity index, and nasopharyngeal aspirate specimens with ≥5 percent neuraminidase inhibitor-resistant virus quasispecies were lower in the combination therapy group. A cause of atypical pneumonia was not diagnosed from any patients in either group. Possible explanations for the improved outcomes in the combination therapy group include immunomodulatory and/or direct antiviral effects of clarithromycin and/or naproxen and better treatment of bacterial pneumonia. Further investigation of this strategy is warranted, preferably in randomized clinical trials evaluating the role of each component.

●Intravenous immunoglobulin, convalescent plasma, and hyperimmune globulin – There is also interest in using intravenous immunoglobulin, convalescent plasma, or hyperimmune globulin as adjunctive therapy for severe influenza infections [113-118]. However, further study is necessary before these preparations can be recommended for influenza [5].

MANAGEMENT OF ARDS — Patients who develop acute respiratory distress syndrome (ARDS) in the setting of influenza infection should receive standard of care with a lung protective ventilation strategy of low tidal volume and applied positive end-expiratory pressure [119]. In patients who continue to have severe hypoxemia despite implementation of these measures, certain "rescue" strategies can be used, including extracorporeal membrane oxygenation or prone positioning. (See "Ventilator management strategies for adults with acute respiratory distress syndrome" and "Acute respiratory distress syndrome: Supportive care and oxygenation in adults", section on 'Management of hypoxemia' and "Extracorporeal membrane oxygenation (ECMO) in adults".)

SYMPTOM MANAGEMENT — Acetaminophen or nonsteroidal anti-inflammatory drugs can be used to treat fever, headache, and myalgia associated with influenza. Salicylates should be avoided, particularly in children and adolescents below 18 years of age because of the association between salicylate use and Reye syndrome in those with influenza. (See "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome'.)

Cough suppressants can be used in those bothered by cough, although the cough associated with influenza is self-limited in most cases. Patients should be advised to maintain hydration. Activity may need to be modified based on patient symptoms but can be resumed as tolerated.

ANTIBIOTICS FOR SECONDARY BACTERIAL PNEUMONIA — In patients with suspected or confirmed influenza who present with severe disease (extensive pneumonia, respiratory failure, hypotension, and fever), clinicians should evaluate for and empirically treat possible bacterial coinfection in addition to giving an antiviral agent for influenza [5]. Clinicians should also evaluate for and empirically treat possible bacterial coinfection in patients who deteriorate after initial improvement, particularly in those treated with an antiviral agent. Clinicians should consider evaluating for bacterial coinfection in patients who fail to improve after three to five days of antiviral therapy.

The choice of antibiotics for pneumonia should be guided by Gram stain and culture of sputum, when available. If the etiology of the pneumonia is not clear from the sputum examination, empiric antibiotics effective against the most common bacterial pathogens following influenza (ie, Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus) should be used. Agents that can be used to empirically treat S. pneumoniae and S. pyogenes include a third-generation cephalosporin (eg, ceftriaxone) or a respiratory fluoroquinolone (eg, levofloxacin or moxifloxacin). If methicillin-resistant S. aureus is suspected or if the patient is critically ill, an agent with activity against this pathogen (eg, vancomycin or linezolid) should be used as part of the empiric regimen [5]. (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 — Individuals with influenza who are managed as outpatients should remain home from work, school, and other populated environments until at least 24 hours after they no longer have a fever without the use of antipyretics [120]. Infection control measures at home may be beneficial.

A randomized trial found that the combination of hand hygiene and face masks, when implemented within 36 hours of symptom onset in the index patient, prevents the household transmission of seasonal influenza (adjusted odds ratio 0.33, 95% CI 0.13-0.87) [121].

In a community-based trial, individuals were randomly assigned to receive either access or no access to an automated web-based handwashing intervention that maximized handwashing intention, monitored handwashing behavior, provided tailored feedback, reinforced helpful attitudes and norms, and addressed negative beliefs [122]. After 16 weeks, fewer individuals in the intervention group reported one or more episodes of respiratory tract infection than in the control group (51 versus 59 percent; multivariate risk ratio [RR] 0.86, 95% CI 0.83-0.89). The intervention also reduced transmission of respiratory tract infections (reported within one week of another household member) both to and from the index person.

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

INFLUENZA ACTIVITY — The United States Centers for Disease Control and Prevention (CDC), in collaboration with the World Health Organization (WHO) and its reporting network, tracks influenza virus isolates throughout the world to monitor disease activity and antiviral resistance patterns and to predict the appropriate components for the annual influenza vaccine. Surveillance information, which is updated weekly during influenza season, is available via the CDC through its website. In addition, FluNet, a database for global influenza virus surveillance, is available via the WHO website. The typical trends of influenza activity in the United States are shown in the following figure (figure 1).

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

Target groups for therapy

●The risk of promoting antiviral drug resistance should be considered when deciding which patients to treat. Individuals with severe disease (requiring hospitalization or with evidence of lower respiratory tract infection) or at high risk for complications should receive antiviral therapy. (See 'Target populations for treatment' above.)

●When indicated, antiviral therapy should be initiated as soon as possible since antiviral therapy is most likely to provide benefit when initiated within the first 48 hours of illness. Treatment should not be delayed while awaiting the results of diagnostic testing, nor should it be withheld in patients with indications for therapy who present >48 hours after the onset of symptoms, particularly among patients requiring hospitalization. Furthermore, patients who have a negative rapid antigen test for influenza but in whom the clinical suspicion for influenza infection is high should be treated with antivirals since the sensitivity of these tests may be low. (See 'Timing of antiviral initiation' above.)

●We recommend oseltamivir for individuals with confirmed or suspected influenza virus infection who are severely ill, such as those requiring hospitalization for lower respiratory tract infection, and those who are showing signs of rapid clinical deterioration (Grade 1C). (See 'Indications for treatment' above.)

●We recommend antiviral therapy for outpatients who present within 48 hours of symptom onset with confirmed or suspected influenza infection and who are at increased risk for complications (Grade 1B). We suggest antiviral therapy for outpatients who present >48 hours after symptom onset with confirmed or suspected influenza infection and who are at increased risk for complications provided that they are not yet improving (Grade 2C). Despite the limited evidence, we have a low threshold for giving antiviral therapy to such patients given the possibility of benefit and the favorable adverse effect profile of influenza antivirals. (See 'Indications for treatment' above.)

●We suggest antiviral therapy for patients who present within 48 hours of symptom onset with mild illness and who are not at increased risk for complications (Grade 2C). There is high-quality evidence for benefit to the individual patient; however, there is only low-quality evidence regarding the magnitude of the risk of promoting resistance, which remains a major concern. (See 'Indications for treatment' above.)

●We recommend that patients with uncomplicated influenza who have had more than 48 hours of influenza signs and symptoms not be treated with antivirals (Grade 1B). (See 'Indications for treatment' above.)

●We suggest antiviral therapy for symptomatic outpatients with uncomplicated influenza who are not at high risk for influenza complications but who are household contacts of persons at high risk for influenza complications, particularly those who are severely immunocompromised (Grade 2C). We also suggest antiviral therapy for symptomatic health care providers with uncomplicated influenza who are not at high risk for influenza complications but who routinely care for patients at high risk for influenza complications, particularly those who are severely immunocompromised (Grade 2C). (See 'Indications for treatment' above.)

●Management of pregnant women is discussed separately. (See "Seasonal influenza and pregnancy", section on 'Treatment'.)

Choice of antiviral agent

●Clinicians should review local or state influenza surveillance data during influenza season to determine which types of influenza (A or B) and subtypes of influenza A (H1N1 or H3N2) are circulating, as well as antiviral resistance patterns. (See 'Choice of antiviral drug' above and 'Influenza activity' above.)

●Antiviral agents for treatment of influenza include neuraminidase inhibitors (oseltamivir, zanamivir, or peramivir) and the inhibitor of influenza cap-dependent endonuclease (baloxavir) (table 2) (see 'Choice of antiviral drug' above):

•For treatment of patients with uncomplicated influenza infection, a neuraminidase inhibitor (oseltamivir, zanamivir, or peramivir) or baloxavir can be used. Of these, we favor oseltamivir, with baloxavir and inhaled zanamivir as alternatives. Peramivir should be reserved for those who cannot tolerate oral or inhaled agents. Oseltamivir and peramivir should be used only if oseltamivir-resistant influenza is not suspected.

•For treatment of patients with severe influenza, oseltamivir is the preferred agent; peramivir may be used for patients who cannot tolerate oral or inhaled agents.

●A neuraminidase inhibitor (oseltamivir, zanamivir, or peramivir) or the inhibitor of influenza cap-dependent endonuclease (baloxavir) can be used for the treatment of patients with uncomplicated influenza infection (table 2). Of these, we favor an oral (oseltamivir, baloxavir) or inhaled (zanamivir) drug over intravenous peramivir. Oseltamivir and peramivir should only be used if oseltamivir-resistant influenza is not suspected. As noted above, oseltamivir is the preferred drug for severe influenza, but it is reasonable to use peramivir for patients with severe influenza who cannot receive oseltamivir (eg, those who cannot tolerate enteral agents). (See 'Choice of antiviral drug' above.)

●The dosing of antiviral agents for influenza is summarized in the following table (table 2). The usual duration of therapy for zanamivir or oseltamivir is five days. Peramivir and baloxavir are typically given as a single dose. However, peramivir should probably be given daily to those with severe disease. A longer duration of oseltamivir or peramivir can be used in patients with severe lower respiratory tract disease (especially pneumonia or acute respiratory distress syndrome) or immunocompromised individuals, particularly in those who continue to have a positive influenza reverse-transcriptase polymerase chain reaction result from a respiratory specimen. (See 'Choice of antiviral drug' above and 'Duration' above.)

●Because of the high rates of influenza isolates resistant to adamantanes, amantadine and rimantadine are not recommended for the treatment of influenza. (See 'Choice of antiviral drug' above.)