Tamiflu
Detection and control of influenza outbreaks in well-vaccinated nursing home populations.

Monto AS, Rotthoff J, Teich E, Herlocher ML, Truscon R, Yen HL, Elias S, Ohmit SE.

Department of Epidemiology, University of Michigan School of Public Health, Ann Arbor, MI 48109-2029, USA. asmonto umich.edu

BACKGROUND: Influenza outbreaks continue to occur in nursing homes despite high vaccination coverage among residents. Recommendations for outbreak control in institutions such as nursing homes advises use of antiviral drugs to reduce influenza transmission. METHODS: Influenza surveillance was performed among elderly residents of nursing homes in Michigan during 2 influenza seasons. The antiviral drug oseltamivir was used for outbreak control at the discretion of nursing home staff once influenza transmission was confirmed by virus isolation or rapid antigen detection. RESULTS: During 2000-2001, influenza was not confirmed in any of the 28 participating homes, despite transmission of types A (H1N1) and B in the community. During 2001-2002, influenza type A (H3N2) transmission was confirmed in 8 (26%) of 31 participating homes; influenza vaccine coverage among residents was 57%- 98% in outbreak-associated homes. Oseltamivir was used in all homes with influenza transmission; outbreak control varied according to the rapidity of outbreak recognition and the extent of antiviral use. Reported adverse events were primarily gastrointestinal reactions and rashes. Analysis of the usefulness of rapid antigen detection tests for outbreak recognition indicated a sensitivity of only 77% (specificity, 92%). CONCLUSIONS: Oseltamivir was reasonably well tolerated, and its use, along with continued promotion of vaccination coverage among nursing home residents and staff, should be a valuable addition to institutional outbreak-control strategies.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15356805&dopt=Abstract oseltamivir Tamiflu



Tamiflu
In vitro generation and characterisation of an influenza B variant with reduced sensitivity to neuraminidase inhibitors.

Cheam AL, Barr IG, Hampson AW, Mosse J, Hurt AC.

World Health Organisation Collaborating Centre for Reference and Research on Influenza, 45 Poplar Road, Parkville, Victoria 3052, Australia.

A contemporary influenza type B virus was passaged in vitro in the presence of increasing concentrations of the neuraminidase inhibitors, zanamivir and oseltamivir carboxylate (0.1-1000 microM over nine passages). After the fifth passage in the presence of zanamivir (10 microM), the virus acquired a Glu 119 Asp neuraminidase mutation (influenza A N2 subtype numbering) in the enzyme active site. After a further three passages, in which growth occurred in 100 microM of zanamivir, a Gln 218 Lys mutation (A (H3) numbering) in the HA1 domain of the haemagglutinin was found. In a fluorescence-based neuraminidase inhibition assay, viruses with the Glu 119 Asp NA mutation had a 32,000-fold reduction in sensitivity to the NA inhibitor zanamivir compared to the wild-type virus, while the mutation resulted in a 105-fold reduction in sensitivity to oseltamivir carboxylate. Viruses grown in the presence of 1000 microM oseltamivir carboxylate did not acquire any neuraminidase mutations but did have a His 103 Gln substitution (A (H3) numbering) in the HA1 region of the haemagglutinin which was demonstrated to significantly reduce receptor binding strength in vitro. Tissue culture assays demonstrated that the HA mutation caused a seven-fold reduction in sensitivity to oseltamivir carboxylate, and a 90-fold reduction in sensitivity to zanamivir.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15451185&dopt=Abstract oseltamivir Tamiflu



Tamiflu
A reverse genetics study of resistance to neuraminidase inhibitors in an influenza A/H1N1 virus.

Abed Y, Goyette N, Boivin G.

Research Center in Infectious Diseases of the CHUQ-CHUL, Quebec City, Canada.

A system of reverse genetics was used to generate influenza A/H1N1 viruses harbouring neuraminidase (NA) mutations previously associated with resistance to NA inhibitors in various viral subtypes. The His274Tyr and Glu119Gln mutants were rescued whereas the Arg292Lys and Glu1l9 --> Gly, Val, Ala or Asp mutants could not be generated. In NA inhibition assays, the His274Tyr mutant was resistant to oseltamivir (430-fold over wild-type) and BCX-1812 (50-fold) but was sensitive to zanamivir. A similar trend was seen when the mutant was evaluated by plaque reduction assay (PRA). The Glu119Gln mutant expressed a low level of resistance to oseltamivir (nine-fold) and zanamivir (fourfold) in NA inhibition assay but was only marginally resistant to oseltamivir (fourfold) in PRA. The replication capacity of both mutants, in particular that of the His274Tyr virus, was impaired when compared with the wild-type virus in vitro.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15456089&dopt=Abstract oseltamivir Tamiflu



Tamiflu
Influenza viruses resistant to the antiviral drug oseltamivir: transmission studies in ferrets.

Herlocher ML, Truscon R, Elias S, Yen HL, Roberts NA, Ohmit SE, Monto AS.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, Michigan 48109, USA.

Three type A influenza viruses, each of which has a distinct neuraminidase-gene mutation and is resistant to the neuraminidase inhibitor oseltamivir, have been isolated. Previously, in the ferret model, an R292K mutant of a type A (H3N2) virus was not transmitted under conditions in which the wild-type virus was transmitted. This model was used to investigate whether the E119V mutant of a type A (H3N2) virus and the H274Y mutant of a type A (H1N1) virus would be transmitted under similar circumstances. Both mutant viruses were transmitted, although the H274Y mutant required a 100-fold-higher dose for infection of donor ferrets and was transmitted more slowly than was the wild type. Both the mutant and the wild-type viruses retained their genotypic characteristics.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15478068&dopt=Abstract oseltamivir Tamiflu



Tamiflu
Influenza infections after hematopoietic stem cell transplantation: risk factors, mortality, and the effect of antiviral therapy.

Nichols WG, Guthrie KA, Corey L, Boeckh M.

Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109-4417, USA. wgnick2000 yahoo.com

BACKGROUND: Community-acquired respiratory viruses, such as influenza virus, are thought to be major causes of morbidity and mortality in patients who had undergone hematopoietic stem cell transplantation (HSCT). Risk factors for acquisition, progression to pneumonia, and the effect of antiviral therapy are unknown. METHODS: We reviewed records from patients with documented influenza over 12 consecutive respiratory-virus infection seasons at a single transplantation center. RESULTS: From 1 September 1989 through 31 March 2002, influenza virus was isolated from 62 of 4797 persons undergoing HSCT (1.3%); 44 patients had upper respiratory tract infections (URIs) alone, and 18 developed pneumonia. Among patients with influenza virus infection, pneumonia developed more commonly among those infected earlier after transplantation (median, 36 vs. 61 days, P=.04) and those with concurrent lymphopenia. Of the 51 cases that were initially diagnosed as URIs, 17 were treated with antivirals, and 34 were not treated. Six untreated patients (18%) developed pneumonia, whereas 1 (13%) of 8 patients treated with rimantadine and 0 of 9 treated with oseltamivir developed pneumonia. The duration of influenza virus shedding was longer in patients treated with steroid doses of >1 mg/kg than among those treated with doses of <1 mg/kg (mean, 15 vs. 9 days); there was a trend towards decreased shedding with oseltamivir therapy (but not rimantadine therapy) after controlling for steroid use (P<.08). The 30-day mortality rate was highest among patients who had progression to pneumonia (5 [28%] of 18 patients); pulmonary copathogens (such as Aspergillus fumigatus) were commonly isolated. CONCLUSIONS: Influenza virus infection is an important cause of mortality early after HSCT. Our nonrandomized data suggest that early antiviral therapy with neuraminidase inhibitors may prevent progression to pneumonia and decrease viral shedding, which may prevent both influenza-related death in index patients and nosocomial transmission to others.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15494906&dopt=Abstract oseltamivir Tamiflu