BACKGROUND: The use of neuraminidase inhibitors (oseltamivir and zanamivir) for the treatment of ill individuals has been an important intervention during the 2009 H1N1 pandemic. However, the emergence and spread of drug resistance remains a major concern and, therefore, optimizing antiviral strategies is crucial to retain the long-term effectiveness of these pharmaceutical interventions.METHODS: A dynamic model of disease transmission was developed to investigate optimal scenarios for the use of a secondary drug (eg, zanamivir). Considering both small and large stockpiles, attack rates were projected by simulating the model to identify ‘tipping points’ for switching to zanamivir as resistance to oseltamivir develops.RESULTS: The use of a limited stockpile of zanamivir can substantially reduce the overall attack rate during pandemic outbreaks. For a reasonably large stockpile of zanamivir, it is optimal to delay the use of this drug for a certain amount of time during which oseltamivir is used as the primary drug. For smaller stockpiles, however, earlier use of zanamivir will be most effective in reducing the overall attack rate. Given a limited stockpile of zanamivir (1.8% in the Canadian plan) without replenishment, and assuming that the fraction of ill individuals being treated is maintained below 60%, the results suggest that zanamivir should be dispensed as the primary drug for thresholds of the cumulative number of oseltamivir resistance below 20%.INTERPRETATION: Strategic use of a secondary drug becomes crucial for pandemic mitigation if vaccination and other interventions fail to sufficiently reduce disease transmission in the community. These findings highlight the importance of enhanced surveillance and clinical monitoring for rapid identification of resistance emergence and its population incidence, so that optimal timing for adaptation to the use of drugs can be achieved.