The adamantane drugs, amantadine and rimantadine, block a viral ion channel protein required for cell entry and traditionally have been effective for treatment and prophylaxis of seasonal type A influenza. However, more than 90% of seasonal H3N2 viruses in the US are now resistant to the adamantanes, and in January 2006, the Centers for Disease Control and Prevention (CDC) recommended against the use of the adamantane class of antivirals for the treatment and prophylaxis of influenza in the United States until susceptibility to adamantanes has been reestablished among circulating influenza A isolates [50]. Avian H5N1 influenza strains currently circulating are frequently resistant to these agents [51, 52]. This resistance has been shown to develop during therapy for both seasonal influenza as well as avian influenza, and it has been noted de novo in clinical and field isolates of H5N1 influenza [51, 52]. These drugs reportedly have been widely used in poultry flocks and it is hypothesized that this has selected for resistant isolates in the field. The resistance appears to be stable in the current H5N1 strains and it is unlikely that these drugs will have a role either in prophylaxis or treatment of avian influenza.

Neuraminidase inhibitors include oseltamivir and zanamavir; these agents inhibit the release of new viruses from infected cells and limit spread of infection from cell to cell. These drugs can reduce the severity and duration of illness caused by seasonal influenza, but are most effective when administered early in the course of illness, preferably within 48 h after symptom onset. Most strains of the H5N1 virus tested have been susceptible to the neuraminidase inhibitors, although resistance to oseltamivir has been reported [53, 54]. There are no good clinical data to support the efficacy of these drugs against H5N1 influenza, but they are generally safe and well tolerated. The reported case series from Thailand showed a nonsignificant trend towards better outcome with earlier oseltamivir treatment [41]. The major limitations to the use of neuraminidase inhibitors is likely to be unavailability due to limited production capacity, and prohibitive price for under-resourced countries. The manufacturing process for oseltamivir is complex and time consuming. Although the manufacturing capacity of osel-tamivir has recently quadrupled, it will take a decade to produce enough oseltamivir to treat 20% of the world's population.

The majority of H5N1-related human deaths have been due to severe pneumonia, multiorgan system dysfunction and shock resulting directly from the virus, and thus cannot be prevented with antibiotics. However, influenza is often complicated by secondary bacterial pneumonia, and antibiotics could be life saving in the case of late-onset pneumonia. The mainstay of therapy is likely to be early detection and aggressive supportive care.

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