Metabolic profiling to evaluate the impact of amantadine and rimantadine on the secondary metabolism of a model organism.

Metabolic profiling offers huge potential to highlight markers and mechanisms in support of toxicology and pathology investigations during drug development. The main objective was to modify therapy with adamantane derivatives: amantadine and rimantadine, to increase their bioavailability and evaluate the influence of such therapy on drug metabolism using Saccharomyces cerevisiae as the model organism. In this study, the profile of endogenous metabolites of a model organism was measured and interpreted to provide an opportunity to investigate changes induced by treatment with amantadine and rimantadine. It was found that resveratrol supplementation synergistically enhanced the effects of amantadine treatment and increased rimantadine metabolism, potentially reducing side effects. The fingerprinting strategy was used as an efficient technique for qualitatively evaluating and monitoring changes in the profiles of endogenous components and their contents in a model organism. Chemometric tools were employed to find marker compounds that can be defined as characteristic indicators of a pharmacological response to a therapeutic intervention. An improved understanding of the mechanisms involved in drug effect and an increased ability to predict individual variations in the drug response of organisms will improve the treatment process and the development of new therapies.

[Adamantan derivatives capable of inhibiting the reproduction of a Rimantadine resistant strain of influenza A(H1N1)pdm09 virus (Influenza A virus, Alphainfluenzavirus, Orthomyxoviridae).]

INTRODUCTION: Adamantanthane-type drugs such as rimantadine and amantadine have long been used to treat diseases caused by influenza A virus. However, as a result of the mutations, influenza viruses have become resistant to aminoadamantans. The target for these drugs was the protein channel M2. Influenza A virus M2 viroporin in the protein shell forms fairly specific ion channels with a diameter of about 11 Å, specializing in transporting protons inside the viral particle (virion). Restoration of the antiviral properties of adamantanthane-type drugs consists in the selection of advanced functional groups bound by the carbocycle to find new sites of binding to the protein target M2. The purpose of the study is to identify the antiviral properties of new adamantanum derivatives to the pandemic strain of influenza A virus in vitro. MATERIAL AND METHODS: Compounds of aminoadamantans with amino acids and other organic molecules were obtained by classical peptide synthesis methods. The structure of the compound was tested by means of physical and chemical methods. Antiviral properties of synthetic compounds were studied in vitro on monolayer MDCK cells infected with pandemic strain of influenza A/California/07/2009 virus in two schemes of administration of investigated compounds and virus. RESULTS: The reference strain of the influenza virus A/California/07/2009(H1N1) was sensitive to the compounds under test in varying degrees. The antiviral activity of the compounds was expressed in a 50% inhibitory concentration (IС50) ranging from 0.5 to 2.5 мкM, which is generally a good indicator for the Rimantadine/Amantadine resistant strain. DISCUSSION: The values of the IС50 for compounds introduced two hours before contact with the virus were slightly higher than those for single-moment introduction of the substance and virus. The effect of increasing the inhibitory concentration in the prophylactic scheme of compounds was valid for all compounds of the experiment. CONCLUSION: The presented synthetic compounds are active against the variant of influenza A virus resistant to Rimantadine and Amantadine preparations. The obtained compounds can be used as model structures for creation of a new drug of direct action against advanced strains of influenza A virus.

Amantadine and rimantadine for influenza A in children and the elderly.

BACKGROUND: Influenza is an acute respiratory illness caused by influenza A and B viruses. Complications may occur, especially among children and the elderly. OBJECTIVES: To assess the effectiveness and safety of amantadine and rimantadine in preventing, treating and shortening the duration of influenza A in children and the elderly. SEARCH METHODS: We searched CENTRAL (2014, Issue 9), MEDLINE (1966 to September week 4, 2014) and EMBASE (1980 to October 2014). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing amantadine and/or rimantadine with no intervention, placebo, other antivirals or different doses or schedules of amantadine or rimantadine in children and the elderly with influenza A. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results. We extracted and analysed data using the standard Cochrane methodology. MAIN RESULTS: We identified 12 studies (2494 participants: 1586 children and 908 elderly) comparing amantadine and rimantadine with placebo, paracetamol (one trial: 69 children) or zanamivir (two trials: 545 elderly) to treat influenza A.Amantadine was effective in preventing influenza A in children (773 participants, risk ratio (RR) 0.11; 95% confidence interval (CI) 0.04 to 0.30). The assumed risk of influenza A in the control group was 10 per 100. The corresponding risk in the rimantadine group was one per 100 (95% CI 0 to 3). Nevertheless, the quality of the evidence was low and the safety of the drug was not well established.For treatment, rimantadine was beneficial in abating fever on day three of treatment in children: one selected study with low risk of bias, moderate evidence quality and 69 participants (RR 0.36; 95% CI 0.14 to 0.91). The assumed risk was 38 per 100. The corresponding risk in the rimantadine group was 14 per 100 (95% CI 5 to 34).Rimantadine did not show any prophylactic effect in the elderly. The quality of evidence was very low: 103 participants (RR 0.45; 95% CI 0.14 to 1.41). The assumed risk was 17 per 100. The corresponding risk in the rimantadine group was 7 per 100 (95% CI 2 to 23).There was no evidence of adverse effects caused by treatment with amantadine or rimantadine.We found no studies assessing amantadine in the elderly. AUTHORS' CONCLUSIONS: The quality of the evidence combined with a lack of knowledge about the safety of amantadine and the limited benefits of rimantadine, do not indicate that amantadine and rimantadine compared to control (placebo or paracetamol) could be useful in preventing, treating and shortening the duration of influenza A in children and the elderly.

Antivirals for treatment of influenza: a systematic review and meta-analysis of observational studies.

BACKGROUND: Systematic reviews of randomized, controlled trials in patients with influenza suggest a lack of evidence about the effects of antiviral therapy on several patient-important outcomes of influenza. PURPOSE: To systematically review observational studies for benefits and harms of oseltamivir, zanamivir, amantadine, or rimantadine in the treatment of influenza. DATA SOURCES: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, CINAHL, SIGLE, the Chinese Biomedical Literature Database, Panteleimon, and LILACS up to November 2010; contact with pharmaceutical companies; and reference lists. STUDY SELECTION: Observational studies in any language that compared single antiviral therapy with no therapy or other antiviral therapy, or that had no comparator, for influenza or influenza-like illness. DATA EXTRACTION: Two independent investigators extracted data. Confidence in the estimates of the obtained effects (quality of evidence) was assessed by using the Grading of Recommendations Assessment, Development, and Evaluation approach. DATA SYNTHESIS: 74 studies fulfilled the inclusion criteria. Meta-analyses of the few studies providing effects with adjustment for confounders suggest that, in high-risk populations, oral oseltamivir may reduce mortality (odds ratio, 0.23 [95% CI, 0.13 to 0.43]; low-quality evidence), hospitalization (odds ratio, 0.75 [CI, 0.66 to 0.89]; low-quality evidence), and duration of symptoms (33 hours [CI, 21 to 45 hours]; very low-quality evidence) compared with no treatment. Earlier treatment with oseltamivir was generally associated with better outcomes. Inhaled zanamivir may lead to shorter symptom duration (23 hours [CI, 17 to 28 hours]; moderate-quality evidence) and fewer hospitalizations (odds ratio, 0.66 [CI, 0.37 to 1.18]) but more complications than no treatment. Direct comparison of oral oseltamivir and inhaled zanamivir suggests no important differences in key outcomes. Data from 1 study suggest that oral amantadine may reduce mortality and pneumonia associated with influenza A. No included study evaluated rimantadine. LIMITATIONS: Mortality was assessed in high-risk patients, and generalizability is limited. The overall body of evidence is limited by risk for confounding and selection, reporting, and publication bias. CONCLUSION: Therapy with oral oseltamivir and inhaled zanamivir may provide a net benefit over no treatment of influenza. However, as with the randomized trials, the confidence in the estimates of the effects for decision making is low to very low. PRIMARY FUNDING SOURCES: World Health Organization and McMaster University.

Amantadine and rimantadine for influenza A in children and the elderly.

BACKGROUND: The effectiveness and safety of amantadine (AMT) and rimantadine (RMT) for preventing and treating influenza A in adults has been systematically reviewed. However, little is known about these treatments in children and the elderly. OBJECTIVES: To systematically review the effectiveness and safety of AMT and RMT in preventing and treating influenza A in children and the elderly. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 2) which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (1966 to June week 3, 2011) and EMBASE (1980 to June 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing AMT and/or RMT with placebo, control, other antivirals or different doses or schedules of AMT or RMT, or both, or no intervention, in children and the elderly. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and assessed methodological quality. We resolved disagreements by consensus. In all comparisons except for one, we separately analysed the trials in children and the elderly using Review Manager software. MAIN RESULTS: A total of 12 studies involving 2494 participants (1586 children and adolescents and 908 elderly) compared AMT and RMT with placebo, paracetamol (one trial; 69 children) or zanamivir (two trials; 545 seniors). All studies were RCTs but most were still susceptible to bias. Two trials in the elderly had a high risk of bias because of incomplete outcome data. In one of those trials there was also a lack of outcome assessment blinding. Risk of bias was unclear in 10 studies due to unclear random sequence generation and allocation concealment. Only two trials in children were considered to have a low risk of bias.AMT was effective in preventing influenza A in children. A total of 773 participants were included in this outcome (risk ratio (RR) 0.11; 95% confidence interval (CI) 0.04 to 0.30). The assumed risk of influenza in the control group was 10 per 100 and the corresponding risk in the RMT group was one per 100 (95% CI 0 to 3). The quality of the evidence was considered low. For treatment purposes, RMT was beneficial for abating fever on day three of treatment. For this purpose one study was selected with low risk of bias and included 69 children (RR 0.36; 95% CI 0.14 to 0.91). The assumed risk was 38 per 100 and the corresponding risk in the RMT group was 14 per 100, 95% CI 5 to 34. The quality of the evidence was moderate.RMT did not show a prophylactic effect against influenza in the elderly, but the quality of evidence was considered very low. There were 103 participants (RR 0.45; 95% CI 0.14 to 1.41, for an assumed risk of 17 per 100 and a corresponding risk in the RMT group of 7 per 100, 95% CI 2 to 23). We did not identify any AMT trials in the elderly that met our inclusion criteria.There was no evidence of adverse effects of AMT and RMT in children or an adverse effect of RMT in the elderly. We did not identify any AMT trials in the elderly that met our inclusion criteria. AUTHORS' CONCLUSIONS: AMT is effective in preventing influenza A in children but the NNTB is high (NNTB: 12 (95% CI 9 to 17). RMT probably helps the abatement of fever on day three of treatment, but the quality of the evidence is poor. Due to the small number of available studies, we could not reach a definitive conclusion on the safety of AMT or the effectiveness of RMT in preventing influenza in children and the elderly.

Pharmacokinetics and safety of coadministered oseltamivir and rimantadine in healthy volunteers: an open-label, multiple-dose, randomized, crossover study.

Preclinical data suggest increased antiviral activity and less viral resistance when neuraminidase inhibitors and adamantanes are used in combination to harness the complementary effects of their different mechanisms of action. Healthy volunteers were randomized to 5-day oral treatment with oseltamivir 75 mg or rimantadine 100 mg twice daily as monotherapy or to combination treatment. Each participant received all 3 regimens in 1 of 6 treatment sequences, with a minimum of 7 days' washout between periods. Final follow-up was 10 to 14 days after the final dose. Drug exposure, elimination, safety, and tolerability were assessed. There were no clinically relevant differences in 12-hour areas under the concentration-time curves of drug in plasma or peak plasma drug concentrations with combination versus monotherapy. Elimination half-life was unaffected by coadministration. There were no safety/tolerability concerns. One case of vomiting and 1 of paresthesia were considered remotely related to combination treatment, and 1 episode of toothache and 1 of acne were considered unrelated. There were no serious adverse events and no deaths. Combination therapy with oseltamivir and rimantadine at recommended dosages in adults had no discernible effect on the pharmacokinetics of either drug and raised no tolerability issues.

Maternal and neonatal outcomes after antepartum treatment of influenza with antiviral medications.

OBJECTIVE: To review the maternal and neonatal outcomes after antepartum exposure to M2 ion channel inhibitors or oseltamivir to provide some guidance on the risk, if any, of antiviral medication during pregnancy. METHODS: This was a retrospective cohort study examining maternal and neonatal outcomes after antepartum exposure to antiviral therapy for influenza. We evaluated maternal characteristics, pregnancy outcomes, and fetal outcomes and compared them with our overall obstetric population. RESULTS: Exposure to antiviral therapies (M2 ion channel inhibitors [n=104] compared with oseltamivir [n=135] compared with the control group [n=82,097]) during pregnancy was not associated with increased rates of preterm birth (7% compared with 10% compared with 6%, P=.190), premature rupture of membranes (23% compared with 16% compared with 22%, P=.154), gestational diabetes (4% compared with 8% compared with 6%, P=.388), or preeclampsia (6% compared with 1% compared with 4%, P=.209). Exposure was not associated with increased duration of hospital stay for mother or neonate. There were no differences in the incidence of minor malformations (19% compared with 15% compared with 22%, P=.101). Liveborn singletons without major malformations did not have differences in fetal weight (3,238+/-586 g compared with 3,281+/-642 g compared with 3,336+/-571 g, P=.186), need for intubation (2% compared with 0.8% compared with 1%, P=.552), intensive care nursery admission (3% compared with 3% compared with 2%, P=.418), or hyperbilirubinemia (12% compared with 9% compared with 8%, P=.282). Liveborn singletons had no grade 3 or 4 intraventricular hemorrhages, seizures, or neonatal deaths. Two preterm neonates exposed to different classes of medications had necrotizing enterocolitis (1.0% compared with 0.8% compared with 0.02%, P<.001). CONCLUSION: We found no evidence of an association between antepartum antiviral exposure and adverse outcomes. LEVEL OF EVIDENCE: II.

Safety of oseltamivir compared with the adamantanes in children less than 12 months of age.

BACKGROUND: When oseltamivir is administered in extremely high doses (500-1000 mg/kg) to young juvenile rats, central nervous system toxicity and death occurred in some animals. Mortality was not observed in older juvenile rats, suggesting a possible relationship between neurotoxicity and an immature blood-brain barrier. To assess potential neurologic adverse effects of oseltamivir use in infants, a retrospective chart review was performed in infants less than 12 months of age who received oseltamivir, amantadine, or rimantadine. METHODS: The primary objective was to describe the frequency of neurologic adverse events among children less than 12 months of age who received oseltamivir compared with those receiving adamantanes. Medical record databases, emergency department databases, and/or pharmacy records at 15 medical centers were searched to identify patients. RESULTS: Of the 180 infants identified as having received antiviral therapy, 115 (64%) received oseltamivir, 37 (20%) received amantadine, and 28 (16%) received rimantadine. The median dose of oseltamivir was 2.0 mg/kg/dose in 3- to 5-month-old and 2.2 mg/kg/dose in 9- to 12-month-old infants. The maximum dose administered was 7.0 mg/kg/dose. There were no statistically significant differences in the occurrence of adverse neurologic events during therapy among subjects treated with oseltamivir versus those treated with the adamantanes (P = 0.13). CONCLUSIONS: This is the largest report to date of oseltamivir use in children less than 12 months of age. Neurologic events were not more common with use of oseltamivir compared with that of the adamantanes. Dosing of oseltamivir was variable, illustrating the need for pharmacokinetic data in this younger population.

Amantadine and rimantadine for influenza A in children and the elderly.

BACKGROUND: Although amantadine (AMT) and rimantadine (RMT) are used to relieve or treat influenza A symptoms in healthy adults, little is known about the effectiveness and safety of these antivirals in preventing and treating influenza A in children and the elderly. OBJECTIVES: The aim of this review was to systematically consider evidence on the effectiveness and safety of AMT and RMT in preventing and treating influenza A in children and the elderly. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2007, issue 3); MEDLINE (1966 to July 2007) and EMBASE (1980 to July 2007). SELECTION CRITERIA: Randomised or quasi-randomised trials comparing AMT and/or RMT in children and the elderly with placebo, control, other antivirals or comparing different doses or schedules of AMT and/or RMT or no intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and assessed methodological quality. Disagreements were resolved by consensus. In all comparisons except for one, the trials in children and in the elderly were analysed separately. Data were analysed and reported using Cochrane Review Manager 4.2. software. MAIN RESULTS: In children, RMT was effective in the abatement of fever on day three of treatment. AMT showed a prophylactic effect against influenza A infection. AMT and RMT were not related to an increase in the occurrence of adverse effects. RMT also was considered to be well tolerated by the elderly, but showed no prophylactic effect. Different doses were comparable in the prophylaxis of influenza in the elderly, as well as in reporting adverse effects. Zanamivir prevented influenza A more effectively than RMT in the elderly. AUTHORS' CONCLUSIONS: AMT was effective in the prophylaxis of influenza A in children. As confounding matters might have affected our findings, caution should be taken when considering which patients should to be given this prophylactic. Our conclusions about effectiveness of both antivirals for the treatment of influenza A in children were limited to a proven benefit of RMT in the abatement of fever on day three of treatment. Due to the small number of available studies we could not reach a definitive conclusion on the safety of AMT or the effectiveness of RMT in preventing influenza in children and the elderly.

Drug-induced linear immunoglobulin A bullous dermatosis mimicking Stevens-Johnson syndrome: a case report.

Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare autoimmune disorder characterized by vesiculobullous mucocutaneous eruptions. LABD also has been reported as a drug-induced reaction. Idiopathic LABD and drug-induced LABD are clinically indistinguishable and can resemble bullous pemphigoid, dermatitis herpetiformis, or bullous erythema multiforme. LABD is diagnosed with direct immunofluorescence (DIF), and idiopathic LABD can be distinguished from drug-induced LABD with a careful medication history. We present the case of a 54-year-old man with drug-induced LABD after ingestion of rimantadine, zanamivir, and azithromycin for presumed influenza. The patient's bullous eruption resolved with discontinuation of the offending medications and treatment with prednisone and pentoxifylline.

Antiviral therapy and prophylaxis for influenza in children.

Antiviral agents are available that are safe and effective for the treatment and prophylaxis of influenza virus infections in children. The neuraminidase inhibitors (oseltamivir [Tamiflu] and zanamivir [Relenza]) are preferred agents because of current widespread resistance to the adamantanes (amantadine [Symmetrel] and rimantadine [Flumadine]). Therapy should be provided to children with influenza infection who are at high risk of severe infection and to children with moderate-to-severe influenza infection who may benefit from a decrease in the duration of symptoms. Prophylaxis should be provided (1) to high-risk children who have not yet received immunization and during the 2 weeks after immunization, (2) to unimmunized family members and health care professionals with close contact with high-risk unimmunized children or infants who are younger than 6 months, and (3) for control of influenza outbreaks in unimmunized staff and children in an institutional setting. Testing of current H5N1 avian influenza virus isolates, the potential agents of pandemic influenza, suggests susceptibility to oseltamivir and zanamivir. Because no prospective data exist on the efficacy of these agents in humans for H5N1 strains, the dosage and duration of therapy in adults and children may differ from those documented to be effective for epidemic influenza strains.

Amantadine and rimantadine for influenza A in adults.

BACKGROUND: Amantadine hydrochloride and rimantadine hydrochloride have antiviral properties, but they are not widely used due to a lack of knowledge of their potential value and concerns about possible adverse effects. OBJECTIVES: The objective of this review was to assess the efficacy, effectiveness and safety ("effects") of amantadine and rimantadine in healthy adults. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2005), MEDLINE (2003 to August Week 4, 2005), EMBASE (October 2003 to July 2005) and reference lists of articles. SELECTION CRITERIA: Randomised and quasi-randomised studies comparing amantadine and/or rimantadine with placebo, control medication or no intervention, or comparing doses or schedules of amantadine and/or rimantadine in healthy adults. DATA COLLECTION AND ANALYSIS: For prophylaxis (prevention) trials the numbers of participants with clinical influenza (influenza-like-illness or ILI) or with confirmed influenza A and adverse effects were analysed. Analysis for treatment trials was of the mean duration of fever, length of hospital stay and adverse effects. MAIN RESULTS: Amantadine prevented 25% of ILI cases (95% confidence interval (CI) 13% to 36%), and 61% of influenza A cases (95% CI 35% to 76%). Amantadine reduced duration of fever by one day (95% CI 0.7 to 1.2). Rimantadine demonstrated comparable effectiveness, but there were fewer trials and the results for prophylaxis were not statistically significant. Both amantadine and rimantadine induced significant gastrointestinal adverse effects. Adverse effects of the central nervous system and study withdrawals were significantly more common with amantadine than rimantadine. Neither drug affected the rate of viral shedding from the nose and the course of asymptomatic influenza. AUTHORS' CONCLUSIONS: Amantadine and rimantadine have comparable efficacy and effectiveness in relieving or treating symptoms of influenza A in healthy adults, although rimantadine induces fewer adverse effects than amantadine. The effectiveness of both drugs in interrupting transmission is probably low. Routine use of both drugs should be discouraged and both drugs should only be used when all other measures fail.

Inhaled zanamivir versus rimantadine for the control of influenza in a highly vaccinated long-term care population.

BACKGROUND: Despite vaccination, influenza commonly causes morbidity and mortality in institutional settings. Influenza control with rimantadine and amantadine is limited by emergence and transmission of drug-resistant influenza A variants, ineffectiveness against influenza B, and toxicity. This study evaluated the efficacy and tolerability of zanamivir versus rimantadine for influenza outbreak control in long-term care facilities. METHODS: This double-blind, randomized, controlled study prospectively enrolled nursing home residents for 3 influenza seasons (1997 to 2000). Vaccine was offered to all subjects. Following influenza outbreak declaration, subjects were randomized to inhaled zanamivir 10 mg or standard of care (rimantadine 100 mg for influenza A or placebo for influenza B) once daily for 14 days. The proportion of randomized subjects developing symptomatic, laboratory-confirmed influenza during prophylaxis was the primary endpoint. RESULTS: Of 482 randomizations (238 zanamivir, 231 rimantadine, 13 placebo), 96% of subjects were elderly or had high-risk conditions; over 90% were vaccinated. Symptomatic, laboratory-confirmed influenza occurred in 3% of zanamivir subjects and 8% of rimantadine subjects during chemoprophylaxis (P = .038; additional protective efficacy for zanamivir over rimantadine = 61%). Since only 25 subjects were randomized during 2 influenza B outbreaks and none developed influenza, the influenza B data were excluded from further analysis. Zanamivir was well tolerated and unassociated with emergence of resistant virus; rimantadine-resistant variants were common. CONCLUSIONS: This is the first prospective, controlled study demonstrating effectiveness of chemoprophylaxis for influenza outbreak control. Zanamivir prevents symptomatic, laboratory-confirmed influenza more effectively than rimantadine, is unassociated with resistant virus, and has a favorable safety profile. Zanamivir is an appropriate alternative for influenza outbreak control among institutionalized vaccinated elderly.

Safety and efficacy of nebulized zanamivir in hospitalized patients with serious influenza.

Influenza is an important cause of hospitalization due to lower respiratory tract involvement for which there is no specific antiviral treatment with proven efficacy. We conducted a double-blind, randomized, placebo-controlled trial to assess the tolerability and efficacy of nebulized zanamivir (16 mg four times a day) in combination with rimantadine compared to rimantadine with nebulized saline for treating influenza in adults hospitalized with influenza. Twenty patients tolerated the inhaled zanamivir (ZNV) plus rimantadine without decline in peak expiratory flow rates compared to the 21 who received inhaled saline. The study was terminated early because the approval of ZNV made further enrollment untenable. No significant differences were observed in the proportion of patients shedding virus by treatment day 3 (57% ZNV plus rimantadine, 67% placebo plus rimantadine), or in the durations of hospitalization and supplemental oxygen use. More ZNV plus rimantadine recipients exhibited no or mild cough on day 3 of treatment (94 vs 55%, P=0.01). Two rimantadine-resistant viruses emerged during rimantadine monotherapy; no ZNV resistance was observed. Nebulized ZNV appears to be well tolerated in this hospitalized population but further studies are needed to assess its efficacy.