Against the 2009 H1N1 strains, the interactions of oseltamivir carboxylate, peramivir, and zanamivir in double combinations ranged from additive to moderately antagonistic, indicative that the activity of these drugs was not enhanced in combination compared to their activity as single agents. These results suggest that double combinations of NAIs may not provide any added benefit over the drugs as single agents. Given that all NAIs bind in the same substrate binding pocket in NA, the use of these drugs in combination in the absence of enhanced activity raises the risk of selecting for a single mutation that could confer resistance to both neuraminidase inhibitors simultaneously. Indeed, cross-resistance to oseltamivir and zanamivir resulting from a single amino acid change has been documented for seasonal influenza A and B viruses [30] . If this were to occur in the 2009 H1N1 background, the resulting virus would be resistant to all approved anti-influenza drugs.