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Antimicrobial Agents and Chemotherapy, September 2008, p. 3284-3292, Vol. 52, No. 9
0066-4804/08/$08.00+0     doi:10.1128/AAC.00555-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Surveillance for Neuraminidase Inhibitor Resistance among Human Influenza A and B Viruses Circulating Worldwide from 2004 to 2008

Tiffany G. Sheu, Varough M. Deyde, Margaret Okomo-Adhiambo, Rebecca J. Garten, Xiyan Xu, Rick A. Bright, Eboneé N. Butler, Teresa R. Wallis, Alexander I. Klimov, and Larisa V. Gubareva^*

Influenza Division, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333

Received 29 April 2008/ Returned for modification 23 May 2008/ Accepted 3 July 2008

The surveillance of seasonal influenza virus susceptibility to neuraminidase (NA) inhibitors was conducted using an NA inhibition assay. The 50% inhibitory concentration values (IC₅₀s) of 4,570 viruses collected globally from October 2004 to March 2008 were determined. Based on mean IC₅₀s, A(H3N2) viruses (0.44 nM) were more sensitive to oseltamivir than A(H1N1) viruses (0.91 nM). The opposite trend was observed with zanamivir: 1.06 nM for A(H1N1) and 2.54 nM for A(H3N2). Influenza B viruses exhibited the least susceptibility to oseltamivir (3.42 nM) and to zanamivir (3.87 nM). To identify potentially resistant viruses (outliers), a threshold of a mean IC₅₀ value + 3 standard deviations was defined for type/subtype and drug. Sequence analysis of outliers was performed to identify NA changes that might be associated with reduced susceptibility. Molecular markers of oseltamivir resistance were found in six A(H1N1) viruses (H274Y) and one A(H3N2) virus (E119V) collected between 2004 and 2007. Some outliers contained previously reported mutations (e.g., I222T in the B viruses), while other mutations [e.g., R371K and H274Y in B viruses and H274N in A(H3N2) viruses) were novel. The R371K B virus outlier exhibited high levels of resistance to both inhibitors (>100 nM). A substantial variance at residue D151 was observed among A(H3N2) zanamivir-resistant outliers. The clinical relevance of newly identified NA mutations is unknown. A rise in the incidence of oseltamivir resistance in A(H1N1) viruses carrying the H274Y mutation was detected in the United States and in other countries in the ongoing 2007 to 2008 season. As of March 2008, the frequency of resistance among A(H1N1) viruses in the United States was 8.6% (50/579 isolates). The recent increase in oseltamivir resistance among A(H1N1) viruses isolated from untreated patients raises public health concerns and necessitates close monitoring of resistance to NA inhibitors.

Published ahead of print on 14 July 2008.

Present address: PATH, 1800 K Street NW, Suite 800, Washington, DC 20006.

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