Curr Infect Dis Rep (2012) 14:275–283 through the kidneys, and dose reduction is recommended for patients with an estimated creatinine clearance of less than 30 mL/min. Approximately 15 % of inhaled zanamivir reaches the bronchi and lungs. Excretion is primarily renal, but given its limited systemic bioavailability, there is no need to modify the dose in patients with renal insufficiency. The pulmonary half-life is 2.8 h. The most common toxicities reported with NI have been nausea and vomiting (approximately 15 % of patients). These side effects are usually mild and limited to the first days of treatment, although more serious side effects have been described. Oseltamivir has been linked to self- injury and delirium in pediatric populations, although no causal association could be demonstrated [42, 43]. The use of inhaled zanamivir has been associated with bronchospasm, sometimes severe or fatal, particularly in patients with under- lying airways disease such as chronic obstructive pulmonary disease (COPD) or asthma [44]. Amantadine and rimantadine target the M2 protein of influenza A, which forms a proton channel in the viral membrane that is essential for viral replication. Amantadine is primarily excreted unchanged in the urine. In patients older than 65 years and in those with an estimated creatinine clearance of less than 50 mL/min, the daily dose should be reduced. Rimantadine is extensively metabolized in the liver, and dose reduction is recommended for patients with severe hepatic dysfunction, renal failure (creatinine clear- ance <10 mL/min), and the elderly. Central nervous system (CNS) side effects are well described with amantadine, particularly in elderly patients. In comparison, rimantadine is associated with a considerably reduced rate of CNS side effects [45]. Clinical Outcomes In mild to moderate uncomplicated disease, the reported benefits of early treatment (< 48 h of symptom onset) with NI have been a shorter duration and severity of flu-like symptoms, and a reduced duration of viral shedding [46–49]. More importantly, several trials and a few system- atic reviews have shown that treatment with NI may reduce illness severity and the rate of lower respiratory tract com- plications [47, 50–52]. In a meta-analysis of 10 randomized- controlled trials, Kaiser et al. found that therapy with osel- tamivir was effective in reducing the incidence of influenza- related lower respiratory tract complications that required antibiotic use (4.6 % for oseltamivir vs. 10.3 % for placebo, P < 0.001), independent of the presence of risk factors for complications [51]. More recently, Hernán et al. conducted another meta-analysis of 11 controlled trials, most of which were included in the previous meta-analysis by Kaiser et al. They found that treatment with oseltamivir significantly re- duced influenza-related lower respiratory tract complications 279 by 37 % (CI 95 % [18–52]) [52]. NI have also been reported to reduce the duration of hospitalization in severely-ill cases [53], and also to reduce influenza-related mortality [54]. Dur- ing the 2009 H1N1 Influenza A pandemic, several observa- tional studies of hospitalized and critically-ill patients reported that treatment with oseltamivir reduced disease severity, com- plications and mortality [55–57]. In a Chinese study of 1291 patients with confirmed H1N1 influenza A infection, oselta- mivir reduced the risk of developing pneumonia, even when administered after the first 48 h of symptom onset (OR 0.12, 95 % CI [0.08–0.18]) [58]. In another retrospective study of 304 hematopoietic stem cell transplant recipients with influ- enza infection, 161 patients had H1N1 influenza A confirmed infection, and both early and delayed administration of anti- viral therapy was shown to be beneficial in terms of decreased risk of lower respiratory tract compromise (OR0 0.04, 95 % CI [0–0.2] vs. OR0 0.14, 95 % CI [0–0.7]) [59]. An intrave- nous form of zanamivir is under development, and was made available during the 2009 H1N1 influenza A pandemic for severely ill patients with highly suspected or confirmed oseltamivir-resistant infection that could not tolerate inhaled zanamivir. Several studies reported favorable outcomes with the use of IV zanamivir [60–63]. During the 2009 swine influenza pandemic, the FDA briefly authorized the emergency use of peramivir, an investigational NI that is administered intravenously [64]. In one study, a single dose of 300 mg or 600 mg of IV peramivir significantly reduced the time to alleviation of symptoms compared with placebo (HR 0.68 and 0.67 for the 300 mg and 600 mg doses respectively) [65]. Laninamivir octanoate, another long acting NI in development, was non-inferior to a five-day course of oral oseltamivir in adults with seasonal influenza in one study [66]. Experience with avian influenza H5N1, which has caused sporadic cases since 2004 with an elevated mortality rate, is much more limited and recommendations for its treatment are in most cases extrapolated from trials of seasonal influenza. There are, however, reports that suggest reduced severity and mortality with the administration of oseltamivir in patients with avian influenza [67–69]. In patients with pneumonia or with clinical failure to standard regime with oseltamivir, a higher dose of 150 mg bid for 10 days should be considered [24, 67]. In regions with adamantine-susceptible strains, combination therapy with a NI and an adamantine may also be considered with pneumonia or clinical worsening [24]. Therapy with osel- tamivir should be administered even in the late course of influenza A (H5N1) infection since viral replication is more prolonged than with seasonal influenza [24]. Indications for Treatment The United States Advisory Committee on Immunization Practices (ACIP) and the CDC have recently published