Journal
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
Volume 49, Issue 11, Pages 4515-4520Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.49.11.4515-4520.2005
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- NIAID NIH HHS [R01 AI045782-05, R01 AI045782, AI-45782] Funding Source: Medline
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The susceptibilities of five zanamivir-resistant and six oseltamivir-resistant influenza viruses were assessed against four neuraminidase (NA) inhibitors, including peramivir and A-315675, by a fluorometric NA activity inhibition assay. The enzyme activity of a majority of the variants was effectively inhibited by either A-315675 or both peramivir and A-315675 (50% inhibitory concentration, < 10 nM). A novel oseltamivir-resistant influenza virus B variant carrying substitution at residue 198 (Asp -> Asn) (N2 numbering) retained susceptibility to peramivir and A-315675. In vivo, the Asn198 variant showed no apparent fitness impairment as judged by its recovery on day 5 from the nasal washes of ferrets coinfected with equal doses of the wild-type virus and the Asn198 variant. Based on the sequence analysis of the virus in the nasal washes, oseltamivir treatment (5 mg/kg twice daily for 5 days) did not provide growth advantage to the Asn198 variant. Nevertheless, treatment with A-315675 (prodrug A-322278) reduced the number of the animals (two of seven) shedding the Asn198 variant. These studies indicate that different patterns of susceptibility and cross-resistance between NA inhibitors may prove important if antiviral resistance to zanamivir and oseltamivir were to emerge.
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