Importantly, we found that amantadine and oseltamivir contributed to the synergy of the TCAD regimen against amantadine-resistant and oseltamivir-resistant viruses. The contributions from both drugs to the synergy of the TCAD regimen were significant at clinically achievable concentrations where they had little or no antiviral activity as a single agent. For instance, a comparison of the synergy volume of the TCAD regimen at 0.32 mg/mL amantadine to the synergy volume of the ribavirin/ oseltamivir carboxylate double combination (no amantadine) revealed that amantadine contributed 39%, 24%, and 44% to the total synergy of the TCAD regimen against CA04, CA05, and CA10, respectively. Similarly, against the oseltamivir-resistant viruses, oseltamivir carboxylate at 0.32 mg/mL contributed 76% and 83% to the total synergy of the TCAD regimen against MS H274Y and HI H274Y, respectively. Thus, all three drugs contributed to the synergy and activity of the TCAD regimen against amantadine-and oseltamivir-resistant viruses, and the activities of amantadine and oseltamivir were restored in the context of the TCAD regimen against influenza strains that were resistant to these drugs, thereby maximizing the clinical utility of these drugs. The mechanism(s) by which amantadine and oseltamivir carboxylate contribute to the synergy of the TCAD regimen against resistant strains is unclear. The interactions between M2, HA, and NA on the surface of the influenza particle are complex and not well understood, and a number of studies have demonstrated that HA-M2 and HA-NA interactions can affect the susceptibility to amantadine and oseltamivir, respectively [32, 33] . Furthermore, amantadine has been demonstrated to exert antiviral activity via interactions with HA at higher concentrations [34, 35] . It is conceivable that, as the result of protein-protein interactions between M2, HA, and NA, the binding of a drug at one site may affect the conformation and therefore affinity for another drug at another site. The mechanism by which ribavirin contributes to the synergy of the TCAD regimen is also unclear. Ribavirin has been documented to act through multiple mechanisms affecting both virus replication and host immune response [36] [37] [38] , and it remains to be elucidated which of these mechanisms are responsible for the synergy with amantadine and oseltamivir.