Influenza Antiviral Medications: Summary for Clinicians

Antiviral medications with activity against influenza viruses are an important adjunct to influenza vaccine in the control of influenza.

• Influenza antiviral prescription drugs can be used to treat influenza or to prevent influenza.
• Five licensed prescription influenza antiviral agents are available in the United States.
  • Three influenza antiviral medications approved by the U.S. Food and Drug Administration (FDA) are recommended for use in the United States during the 2016-2017 influenza season: oral oseltamivir (available as a generic version or under the trade name Tamiflu®), inhaled zanamivir (trade name Relenza®), and intravenous peramivir (trade name Rapivab®). These drugs are chemically related antiviral medications known as neuraminidase inhibitors that have activity against both influenza A and B viruses. Generic oseltamivir was approved by the FDA in August and became available in December of 2016.
  • Amantadine and rimantadine are antiviral drugs in a class of medications known as adamantanes. These medications are active against influenza A viruses, but not influenza B viruses. As in recent past seasons, there continues to be high levels of resistance (>99%) to adamantanes among influenza A (H3N2) and influenza A (H1N1) pdm09 (“2009 H1N1”) viruses. Therefore, amantadine and rimantadine are not recommended for antiviral treatment or chemoprophylaxis of currently circulating influenza A viruses.
• Antiviral resistance to oseltamivir, zanamivir, and peramivir among circulating influenza viruses is currently low, but this can change. Also, antiviral resistance can emerge during or after treatment in some patients (e.g., immunosuppressed).
  • For information about antiviral drug resistance to influenza viruses and guidance on the use of influenza antiviral medications when antiviral resistance is suspected or documented this season, see Antiviral Drug-Resistance among Influenza Viruses.
  • For weekly surveillance data on antiviral resistance this season, see the FluView U.S. Influenza Surveillance Report.

Table 1. Antiviral Medications Recommended for Treatment and Chemoprophylaxis of Influenza

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Summary of Influenza Antiviral Treatment Recommendations

• Clinical trials and observational data show that early antiviral treatment can shorten the duration of fever and illness symptoms, and may reduce the risk of complications from influenza (e.g., otitis media in young children, pneumonia, and respiratory failure).
• Early treatment of hospitalized patients can reduce death.
• In hospitalized children, early antiviral treatment has been shown to shorten the duration of hospitalization.
• Clinical benefit is greatest when antiviral treatment is administered early, especially within 48 hours of influenza illness onset.
• Antiviral treatment is recommended as early as possible for any patient with confirmed or suspected influenza who:
  • is hospitalized;
  • has severe, complicated, or progressive illness; or
  • is at higher risk for influenza complications.

• Clinical judgment, on the basis of the patient’s disease severity and progression, age, underlying medical conditions, likelihood of influenza, and time since onset of symptoms, is important when making antiviral treatment decisions for high-risk outpatients.
• When indicated, antiviral treatment should be started as soon as possible after illness onset, ideally within 48 hours of symptom onset. However, antiviral treatment might have some benefits in patients with severe, complicated or progressive illness, and in hospitalized patients when started after 48 hours of illness onset.
  • Observational studies in hospitalized patients with influenza have reported that clinical benefit is greatest when oseltamivir is started within 48 hours of illness onset (Hsu, 2012; Louie, 2013; Muthuri, 2013; Muthuri, 2014). However, some studies suggest that antiviral treatment might still be beneficial in hospitalized patients when started up to 4 or 5 days after illness onset (Louie, 2012; Yu, 2011). Antiviral treatment of pregnant women (of any trimester) with influenza A (2009 H1N1) virus infection has been shown to be most beneficial in preventing respiratory failure and death when started within less than 3 days of illness onset, but still provided benefit when started 3–4 days after onset compared to 5 or more days (Siston, 2010).
• Decisions about starting antiviral treatment should not wait for laboratory confirmation of influenza (see section on Diagnostic Testing for Influenza).
• While influenza vaccination is the first and best way to prevent influenza illness, a history of influenza vaccination does not rule out the possibility of influenza virus infection in an ill patient with clinical signs and symptoms compatible with influenza.
• Antiviral treatment also can be considered for any previously healthy, symptomatic outpatient not at high risk with confirmed or suspected influenza on the basis of clinical judgment, if treatment can be initiated within 48 hours of illness onset.
  • One randomized clinical trial in children with uncomplicated influenza demonstrated a modest reduction in duration of symptoms and virus shedding in patients initiating treatment after 48 hours; post hoc analysis suggested that treatment initiated 72 hours after illness onset reduced symptoms by one day compared with placebo (Fry, 2014).
• For outpatients with acute uncomplicated influenza, oral oseltamivir, inhaled zanamivir, or intravenous peramivir may be used for treatment.
  • The recommended treatment course for uncomplicated influenza is two doses per day of oral oseltamivir or inhaled zanamivir for 5 days, or one dose of intravenous peramivir for 1 day.
• Oral oseltamivir is preferred for treatment of pregnant women (Rasmussen, 2009; 2011). Pregnant women are recommended to receive the same antiviral dosing as non-pregnant persons. See Recommendations for Obstetric Health Care Providers Related to Use of Antiviral Medications in the Treatment and Prevention of Influenza for additional information.
• In a randomized controlled clinical trial, a single dose of intravenous peramivir shortened duration of influenza symptoms when used for treatment of outpatient adults with uncomplicated influenza by about 1 day (Kohno, 2010); similar benefit was shown in clinical trials when a single dose of peramivir was given by intramuscular injection for treatment of uncomplicated influenza in adults (Whitley, 2014).

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Treatment Considerations for Patients Hospitalized with Suspected or Confirmed Influenza

Treatment of patients with severe influenza (e.g., those requiring hospitalization) presents multiple challenges. The effect of specific antiviral strategies in serious or life-threatening influenza is not established from clinical trials conducted to support licensure of oral oseltamivir, inhaled zanamivir, or intravenous peramivir, as those studies were conducted primarily among previously healthy outpatients with uncomplicated illness. However, a number of observational studies have reported that oral oseltamivir treatment started 4 and 5 days after illness onset of patients hospitalized with suspected or confirmed influenza is associated with lower risk for severe outcomes (EH Lee, 2010; N Lee, 2008; N Lee, 2010; Louie, 2012; McGreer, 2007; Siston, 2010). For this reason, the following recommendations do not necessarily represent FDA-approved uses of antiviral products, but are based on published expert opinion and observational studies and are subject to change as the developmental status of investigational products and the epidemiologic and virologic features of influenza change over time.

• Initiation of antiviral treatment as early as possible is recommended for hospitalized patients. However, antiviral treatment might be effective in reducing morbidity and mortality in hospitalized patients even if treatment is not started until more than 48 hours after onset of illness.
• For hospitalized patients and patients with severe or complicated illness, treatment with oral or enterically administered oseltamivir is recommended. Inhaled zanamivir is not recommended because of the lack of data for use in patients with severe influenza disease. There is also insufficient data regarding efficacy of intravenous peramivir for hospitalized patients.
• The optimal duration and dosing are uncertain for severe or complicated influenza. Treatment regimens might need to be altered to fit the clinical circumstances. For example, clinical judgment should be the guide regarding the need to extend daily treatment regimens longer than 5 days for patients whose illness is prolonged. Critically ill patients with respiratory failure can have prolonged influenza viral replication in the lower respiratory tract
  • Clinical judgment and virologic testing of lower respiratory tract specimens by real-time reverse transcription-polymerase chain reaction (RT-PCR) should guide decisions to consider treatment regimens longer than 5 days for patients with severe and prolonged illness. For patients with lower respiratory tract disease, lower respiratory tract specimens, such as bronchoalveolar lavage fluid or endotracheal aspirates, are preferred; an oropharyngeal (throat) swab may be collected if lower respiratory specimens are not available. Testing of lower respiratory tract specimens may yield the diagnosis when testing of upper respiratory tract specimens is negative. Multiple respiratory tract specimens collected on different days should be tested if influenza virus infection is suspected but a definitive diagnosis has not been made.
  • Longer treatment regimens might be necessary in immunosuppressed persons who may have prolonged influenza viral replication. Such patients are at risk of developing antiviral-resistant virus.
  • A higher dose of oral or enterically administered oseltamivir has been recommended by some experts (e.g., 150 mg twice daily in adults with normal renal function) for treatment of influenza in immunocompromised patients and in severely ill hospitalized patients. However, oral or enterically administered oseltamivir has been reported to be adequately absorbed in critically ill adults, with standard doses producing therapeutic blood levels (Ariano, 2010), and limited data suggest that higher dosing may not provide additional clinical benefit (Abdel-Ghafar, 2008; Ariano, 2010; Kumar, 2010; Lee, 2013; South East Asia Infectious Disease Clinical Research Network, 2013). Studies indicate that the exposure to oseltamivir carboxylate (the active metabolite of oseltamivir) is similar between obese and non-obese subjects for both 75 mg and 150 mg doses given twice daily (Ariano, 2010; Jittamala, 2014; Pai, 2011; Thorne-Humphrey, 2011).
• Limited data suggest that oseltamivir administered orally or by oro/naso gastric tube is well absorbed in critically ill influenza patients, including those in the intensive care unit, on continuous renal replacement therapy, and/or on extracorporeal membrane oxygenation (Ariano, 2010; Eyler, 2012a; Eyler, 2012b; Giraud, 2011; Kromdijk, 2013; Lemaitre, 2012; Mulla, 2013; Taylor, 2008).
• However, for patients who cannot tolerate or absorb oral or enterically-administered oseltamivir because of suspected or known gastric stasis, malabsorption, or gastrointestinal bleeding, the use of intravenous peramivir or investigational intravenous zanamivir should be considered.
  • In a randomized trial of treatment of influenza in hospitalized patients aged >6 years, a significant clinical benefit was not demonstrated for intravenous peramivir at a dosage of 600 mg once daily (10 mg/kg once daily in children) for five days plus standard of care compared with placebo plus standard of care; however, peramivir was generally safe and well tolerated (de Jong, 2014).
  • Intravenous zanamivir is an investigational parenterally administered neuraminidase inhibitor product available only under an emergency investigational new drug (EIND) request to the manufacturer for compassionate use in hospitalized adult and pediatric patients with severe influenza. (See Intravenous Influenza Antiviral Medications and CDC Considerations Related to Investigational Use of Intravenous Zanamivir for 2016-2017 Influenza Season.)
• It is possible that some influenza viruses may become resistant to oseltamivir and peramivir during antiviral treatment with one of these agents and remain susceptible to zanamivir; this has been reported most often for influenza A H1N1 viruses (Graitcer, 2011; Lackenby, 2011; Memoli, 2010; Nguyen, 2010; Nguyen, 2012). Resistance of influenza viruses to antiviral drugs can also occur spontaneously, with no known exposure to antiviral medications (Hurt, 2011; Takashita, 2013; Takashita, 2014).
• If a hospitalized patient treated with oseltamivir and/or peramivir manifests progressive lower respiratory symptoms, resistant virus should be considered. In view of the limited alternatives, CDC recommends that investigational use of intravenous zanamivir should be considered for treatment of severely ill patients with oseltamivir-resistant virus infection (Dulek, 2010; Gaur, 2010; Committee of the WHO Consultation on Clinical Aspects of Pandemic (H1N1) 2009 Influenza, 2010). Oseltamivir or peramivir should not be stopped until intravenous zanamivir can be initiated. However, clinicians should note that failure to improve or clinical deterioration during oseltamivir or peramivir treatment is more likely to be related to the natural history of acute lung injury and inflammatory damage or onset of other complications (e.g., renal failure, septic shock, ventilator-associated pneumonia) than to emergence of oseltamivir or peramivir resistance. Severely immunosuppressed persons (e.g., hematopoietic stem cell transplant recipients) are at highest risk for emergence of oseltamivir- and peramivir-resistant influenza virus infection during or following oseltamivir and/or peramivir treatment (Hurt, 2012; Memoli, 2010). Molecular assays can detect genetic changes in influenza viruses associated with oseltamivir and peramivir resistance. The CDC Influenza Division is available for consultation as needed.
• Careful attention to ventilator and fluid management and to the prevention and treatment of secondary bacterial pneumonia (e.g., S. pneumoniae, S. pyogenes, and S. aureus, including MRSA) also is critical for severely ill patients (Bautista, 2010; Finelli, 2008; Hageman, 2006; Harper, 2009; Mandell, 2007; Mauad, 2010; Shieh, 2010).

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Diagnostic Testing for Influenza

• Rapid Influenza Diagnostic Tests (RIDTs) can be useful to identify influenza virus infection as a cause of respiratory outbreaks in any setting. RIDTs are antigen detection tests and produce results quickly, but the results may not be accurate. A recent meta-analysis evaluating 159 studies of 26 RIDTs compared with a reference standard of either RT-PCR or viral culture reported a pooled sensitivity of 62.3% (95% CI, 57.9% to 66.6%) and pooled specificity of 98.2% (CI, 97.5% to 98.7%), although sensitivities as low as 10% were reported in individual studies, depending on characteristics such as specimen type, age of patient, and virus detected (Chartrand, 2012).
  • o Sensitivities were generally lower in adults (53.9% [95% CI, 47.9% to 59.8%]) than in children (66.6% [95% CI, 61.6% to 71.7%]), and lower for influenza B (52.2% [95% CI, 45.0% to 59.3%]) than influenza A (64.6% [95% CI, 59.0% to 70.1%]) (Chartrand, 2012). Sensitivities were also lower when compared with RT-PCR as the reference standard (53.9% [95% CI, 48.2% to 59.6%]) versus viral culture (72.3% [95% CI, 66.8% to 77.9%]) (Chartrand, 2012).
  • In the meta-analysis, RIDTs did not perform markedly worse in the 35% of studies conducted during the 2009 H1N1 pandemic compared with performance during other influenza seasons (Chartrand, 2012). RIDT sensitivity of 58% was reported on respiratory specimens from 24 fatal cases of influenza A from the 2013-2014 season (Ayscue, 2014). Sensitivity in lower respiratory tract samples may be even lower than upper respiratory samples; in one study, RIDTs were positive in only five (25%) of 20 bronchoscopic samples in patients with severe 2009 H1N1 virus infection requiring mechanical ventilation (Blyth, 2009).
• False negative results occur more commonly than false positive results. In particular, false negative test results are common during influenza season. Additionally, other antigen detection tests (e.g. immunofluorescence assays) also lack sensitivity compared to RT-PCR. Clinicians should realize that a negative RIDT or immunofluorescence (e.g. direct florescent antibody staining – DFA) result does NOT exclude a diagnosis of influenza in a patient with suspected influenza. When there is clinical suspicion of influenza and antiviral treatment is indicated, antiviral treatment should be started as soon as possible without waiting for results of additional influenza testing.
• Other testing (i.e., RT-PCR, viral culture) is much more accurate, but can take longer. When influenza is suspected and antiviral treatment is indicated, antiviral treatment should begin as soon as possible and should not wait for the results of testing.
• Rapid molecular assays are a new type of molecular influenza diagnostic test. Currently, there are two rapid molecular assays that are FDA-approved for use in the United States. Additional rapid molecular assays may become available in the future. As with other molecular diagnostic tests, if influenza is suspected and treatment is clinically indicated, antiviral treatment should begin as soon as possible and should not wait for the results of testing.

To Minimize False RIDT Results

• Collect specimens as early in the illness as possible (ideally less than 4 days from illness onset).
• Follow manufacturer’s instructions, including acceptable specimens, and handling.
• Follow-up negative results with confirmatory tests (i.e., RT-PCR or viral culture) if a laboratory-confirmed influenza diagnosis is desired.

Information on Local Influenza Activity

• Clinicians should contact their local or state health department for information about current influenza activity. For more information about influenza activity in the United States during the influenza season, visit the Weekly U.S. Influenza Surveillance Report (FluView).
• For more information on influenza diagnostic testing, see Clinical Description & Lab Diagnosis of Influenza.

(Tables below Available as PDF [247 KB, 3 pages] )

Table 3. Recommended Dosage and Duration of Influenza Antiviral Medications for Treatment or Chemoprophylaxis

 

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Chemoprophylaxis

• Annual influenza vaccination is the best way to prevent influenza because vaccination can be given well before influenza virus exposures occur, and can provide safe and effective immunity throughout the influenza season.
• Antiviral medications are approximately 70% to 90% effective in preventing influenza and are useful adjuncts to influenza vaccination.
• CDC does not recommend widespread or routine use of antiviral medications for chemoprophylaxis so as to limit the possibilities that antiviral resistant viruses could emerge. Indiscriminate use of chemoprophylaxis might promote resistance to antiviral medications, or reduce antiviral medication availability for treatment of persons at higher risk for influenza complications or those who are severely ill.
• In general, CDC does not recommend seasonal or pre-exposure antiviral chemoprophylaxis, but antiviral medications can be considered for chemoprophylaxis in certain situations.
• The following are examples of situations where antiviral medications can be considered for chemoprophylaxis to prevent influenza
  • Prevention of influenza in persons at high risk of influenza complications during the first two weeks following vaccination after exposure to an infectious person.
  • Prevention for people with severe immune deficiencies or others who might not respond to influenza vaccination, such as persons receiving immunosuppressive medications, after exposure to an infectious person.
  • Prevention for people at high risk for complications from influenza who cannot receive influenza vaccine due to a contraindication after exposure to an infectious person.
  • Prevention of influenza among residents of institutions, such as long-term care facilities, during influenza outbreaks in the institution. For more information, see IDSA guidelines web site [259 KB, 30 pages].
• An emphasis on close monitoring and early initiation of antiviral treatment if fever and/or respiratory symptoms develop is an alternative to chemoprophylaxis after a suspected exposure for some persons.
• To be effective as chemoprophylaxis, an antiviral medication must be taken each day for the duration of potential exposure to a person with influenza and continued for 7 days after the last known exposure. For persons taking antiviral chemoprophylaxis after inactivated influenza vaccination, the recommended duration is until immunity after vaccination develops (antibody development after vaccination takes about two weeks in adults and can take longer in children depending on age and vaccination history).
• Antiviral chemoprophylaxis generally is not recommended if more than 48 hours have elapsed since the first exposure to an infectious person.
• Patients receiving antiviral chemoprophylaxis should be encouraged to seek medical evaluation as soon as they develop a febrile respiratory illness that might indicate influenza.

Special Considerations for Institutional Settings

Use of antiviral chemoprophylaxis to control outbreaks among high risk persons in institutional settings is recommended. An influenza outbreak is likely when at least two residents are ill within 72 hours, and at least one has laboratory confirmed influenza. When influenza viruses are circulating in the community, even one positive laboratory result in conjunction with other compatible illnesses on the unit indicates that an outbreak of influenza is occurring. When influenza is identified as a cause of a respiratory disease outbreak among nursing home residents, use of antiviral medications for chemoprophylaxis is recommended for residents (regardless of whether they have received influenza vaccination) and for unvaccinated health care personnel. For newly-vaccinated staff, antiviral chemoprophylaxis can be administered for up to two weeks (the time needed for antibody development) following influenza vaccination. Chemoprophylaxis may also be considered for all employees, regardless of their influenza vaccination status, if the outbreak is caused by a strain of influenza virus that is not well-matched by the vaccine. Antiviral chemoprophylaxis should be administered for a minimum of two weeks, and continue for at least seven days after the last known case was identified. For more information on the control of institutional outbreaks, please see CDC’s Interim Guidance for Influenza Outbreak Management in Long-Term Care Facilities and the IDSA guidelines web site [259 KB, 30 pages].

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Dosing in Adult Patients with Renal Impairment

Dose adjustment of oseltamivir is recommended for patients with creatinine clearance between 10 and 60 mL/min and patients with end-stage renal disease (ESRD) undergoing hemodialysis or continuous peritoneal dialysis receiving oseltamivir for the treatment or chemoprophylaxis of influenza. Oseltamivir is not recommended for patients with ESRD not undergoing dialysis. The recommended doses are detailed in Table 5; duration of treatment and chemoprophylaxis is the same as recommended for patients with normal renal function. No dose adjustment is recommended for inhaled zanamivir for a 5-day course of treatment for patients with renal impairment. The dose of intravenous peramivir should be reduced for patients with baseline creatinine clearance below 50 mL/min (see Table 5).

Adverse Events

• When considering use of influenza antiviral medications, clinicians must consider the patient’s age, weight and renal function; presence of other medical conditions; indications for use (i.e., chemoprophylaxis or therapy); and the potential for interaction with other medications.
• For more information on safety, effectiveness and dosing for oral oseltamivir, inhaled zanamivir, and intravenous peramivir, visit Antiviral Drugs or consult the package inserts.

For more information, visit the Seasonal Influenza (Flu) site, or call CDC at 800-CDC-INFO (English and Spanish) or 888-232-6348 (TTY).

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Selected References

• References noted in this summary are not complete. A more comprehensive list of influenza antiviral references can be found at Antiviral Guide References.

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Ariano RE, Sitar DS, Zelenitsky SA, et al. Enteric absorption and pharmacokinetics of oseltamivir in critically ill patients with pandemic (H1N1) influenza. CMAJ. 2010; 182(4): 357-63.

Ayscue P, Murray E, Uyeki T, et al. Influenza-associated intensive-care unit admissions and deaths – California, September 29, 2013-January 18, 2014. MMWR. 2014; 63(7): 143-7.

Bautista E, Chotpitayasunondh T, Gao Z, et al. Clinical aspects of pandemic 2009 influenza A (H1N1) virus infection. N Engl J Med. 2010; 362(18): 1708-19.

Blyth CC, Iredell JR, Dwyer DE. Rapid-test sensitivity for novel swine-origin influenza A (H1N1) virus in humans. N Engl J Med. 2009; 361(25): 2493.

Booy R, Lindley RI, Dwyer DE, et al. Treating and preventing influenza in aged care facilities: a cluster randomised controlled trial. PLoS One. 2012; 7(10): e46509.

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de Jong MD, Simmons CP, Thanh TT, et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med. 2006; 12(10): 1203-7.

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Earhart KC, Elsayed NM, Saad MD, et al. Oseltamivir resistance mutation N294S in human influenza A(H5N1) virus in Egypt. J Infect Public Health. 2009; 2(2): 74-80.

Eyler RF, Heung M, Pleva M, et al. Pharmacokinetics of oseltamivir and oseltamivir carboxylate in critically ill patients receiving continuous venovenous hemodialysis and/or extracorporeal membrane oxygenation. Pharmacotherapy. 2012 Dec; 32(12): 1061-9.

Eyler RF, Klein KC, Mueller BA. The pharmacokinetics of oseltamivir and oseltamivir carboxylate in a critically ill pediatric patient receiving extracorporeal membrane oxygenation and continuous venovenous hemodialysis. J Pediatr Pharmacol Ther. 2012 Apr; 17(2):173-6.

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Fiore AE, Fry A, Shay D, et al. Antiviral agents for the treatment and chemoprophylaxis of influenza — recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR. 2011; 60(1): 1-24.

Fry AM, Goswami D, Nahar K, et al. Efficacy of oseltamivir treatment started within 5 days of symptom onset to reduce influenza illness duration and virus shedding in an urban setting in Bangladesh: a randomised placebo-controlled trial. Lancet Infect Dis. 2014; 14(2): 109-18.

Gaur AH, Bagga B, Barman S, et al. Intravenous zanamivir for oseltamivir-resistant 2009 H1N1 influenza. N Engl J Med. 2010; 362(1): 88-9.

Giraud C, Manceau S, Oualha M, et al. High levels and safety of oseltamivir carboxylate plasma concentrations after nasogastric administration in critically ill children in a pediatric intensive care unit. Antimicrob Agents Chemother. 2011; 55(1): 433-5.

Graitcer SB, Gubareva L, Kamimoto L, et al. Characteristics of patients with oseltamivir-resistant pandemic (H1N1) 2009, United States. Emerging Infect Dis. 2011; 17(2): 255-7.

Hageman JC, Uyeki TM, Francis JS, et al. Severe community-acquired pneumonia due to Staphylococcus aureus, 2003-04 influenza season. Emerg Infect Dis. 2006; 12(6): 894-9.

Harper SA, Bradley JS, Englund JA, et al. Seasonal influenza in adults and children–diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2009; 48(8): 1003-32.

Hsu J, Santesso N, Mustafa R, et al. Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies. Ann Intern Med. 2012; 156(7): 512-24.

Hurt AC, Hardie K, Wilson NJ, et al. Community transmission of oseltamivir-resistant A(H1N1)pdm09 influenza. N Engl J Med. 2011; 365(26): 2541-2.

Hurt AC, Chotpitayasunondh T, Cox NJ, et al. Antiviral resistance during the 2009 influenza A H1N1 pandemic: public health, laboratory, and clinical perspectives. Lancet Infect Dis. 2012; 12(3): 240-8.

Ison MG, Fraiz J, Heller B, et al. Intravenous peramivir for treatment of influenza in hospitalized patients. Antivir Ther. 2014; 19(4):349-61.

Jefferson T, Jones MA, Doshi P, et al. Neuraminidase inhibitors for preventing and treating influenza in healthy adults and children. Cochrane Database Syst Rev. 2012; 1: CD008965.

Jittamala P, Pukrittayakamee S, Tarning J, et al. Pharmacokinetics of orally administered oseltamivir in healthy obese and non-obese Thai subjects. Antimicrob Agents Chemother. 2014; 58(3): 1615-21.

Kimberlin DW, Acosta EP, Prichard MN, et al. Oseltamivir pharmacokinetics, dosing, and resistance among children aged <2 years with influenza. J Infect Dis. 2013; 207(5): 709-20.

Kohno S, Kida H, Mizuguchi M, et al. Efficacy and safety of intravenous peramivir for treatment of seasonal influenza virus infection. Antimicrob Agents Chemother. 2010; 54(11)4568-74.

Komeda T, Ishii S, Itoh Y, et al. Post-marketing safety and effectiveness evaluation of the intravenous anti-influenza neuraminidase inhibitor peramivir (II): A pediatric drug use investigation. J Infect Chemother. 2014; doi: 10.1016/j.jiac.2014.11.009. [Epub ahead of print].

Kromdijk W, Sikma MA, van den Broek MP, et al. Pharmacokinetics of oseltamivir carboxylate in critically ill patients: each patient is unique. Intensive Care Med. 2013; 39(5): 977-8.

Kumar D, Morris MI, Kotton CN, et al. Guidance on novel influenza A/H1N1 in solid organ transplant recipients. Am J Transplant. 2010; 10(1): 18-25.

Lackenby A, Moran Gilad J, Pebody R, et al. Continued emergence and changing epidemiology of oseltamivir-resistant influenza A(H1N1)2009 virus, United Kingdom, winter 2010/11. Euro Surveill. 2011; 16(5).

Lee EH, Wu C, Lee EU, et al. Fatalities associated with the 2009 H1N1 influenza A virus in New York city. Clin Infect Dis. 2010; 50(11): 1498-504.

Lee N, Choi KW, Chan PKS, et al. Outcomes of adults hospitalised with severe influenza. Thorax. 2010; 65(6): 510-5.

Lee N, Cockram CS, Chan PK, et al. Antiviral treatment for patients hospitalized with severe influenza infection may affect clinical outcomes. Clin Infect Dis. 2008; 46(8): 1323-4.

Lee N, Hui DS, Zuo Z, et al. A prospective intervention study on higher-dose oseltamivir treatment in adults hospitalized with influenza a and B infections. Clin Infect Dis. 2013; 57(11): 1511-9.

Lemaitre F, Luyt CE, Roullet-Renoleau F, et al. Impact of extracorporeal membrane oxygenation and continuous venovenous hemodiafiltration on the pharmacokinetics of oseltamivir carboxylate in critically ill patients with pandemic (H1N1) influenza. Ther Drug Monit. 2012; 34(2): 171-5.

Lipsitch M, Hernán MA. Oseltamivir effect on antibiotic-treated lower respiratory tract complications in virologically positive randomized trial participants. Clin Infect Dis. 2013; 57(9): 1368-9.

Louie JK, Yang S, Acosta M, et al. Treatment with neuraminidase inhibitors for critically ill patients with influenza A (H1N1)pdm09. Clin Infect Dis. 2012; 55(9): 1198-204.

Louie JK, Yang S, Samuel MC, et al. Neuraminidase inhibitors for critically ill children with influenza. Pediatrics. 2013; 132(6): e1539-45.

Mandell LA, Wunderink RG, Anzueto A, et al. Infectious Diseases Society of America/American Thoracic Society consensus guidelines on the management of community-acquired pneumonia in adults. Clin Infect Dis. 2007; 44 Suppl 2: S27-72.

Mauad T, Hajjar LA, Callegari GD, et al. Lung Pathology in Fatal Novel Human Influenza A (H1N1) Infection. American Journal of Respiratory and Critical Care Medicine. 2010; 181(1): 72-9.

McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and outcomes of influenza requiring hospitalization in Ontario, Canada. Clin Infect Dis. 2007; 45(12): 1568-75.

Memoli MJ, Hrabal RJ, Hassantoufighi A, et al. Rapid selection of oseltamivir- and peramivir-resistant pandemic H1N1 virus during therapy in 2 immunocompromised hosts. Clin Infect Dis. 2010; 50(9):1252-5.

Mulla H, Peek GJ, Harvey C, et al. Oseltamivir pharmacokinetics in critically ill adults receiving extracorporeal membrane oxygenation support. Anaesth Intensive Care. 2013; 41(1): 66-73.

Muthuri SG, Myles PR, Venkatesan S, et al. Impact of neuraminidase inhibitor treatment on outcomes of public health importance during the 2009-10 influenza A(H1N1) pandemic: a systematic review and metaanalysis in hospitalized patients. J Infect Dis. 2013 Feb; 207(4): 553-63.

Nguyen HT, Sheu TG, Mishin VP, Klimov AI, Gubareva LV. Assessment of pandemic and seasonal influenza A (H1N1) virus susceptibility to neuraminidase inhibitors in three enzyme activity inhibition assays. Antimicrob Agents Chemother. 2010; 54(9):3671-7.

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