A synergistic interaction between influenza virus and bacteria contributes to excess mortality during influenza epidemics. Bacterial pneumonia after influenza infection typically presents at a more advanced stage, has complex features including multi-lobar involvement and bacteremia, and targets the frail and the elderly. For these reasons and because of the contribution of the virus itself to the pathogenesis, secondary bacterial pneumonia is more difficult to treat and the case fatality rate is higher. In addition, pre-clinical studies suggest that an over-exuberant host inflammatory response contributes to the severity of the illness and to treatment failures. The use of cell wall active antibiotics may be a contributing factor to these poor outcomes. The antibiotics most commonly used in clinical practice rapidly lyse organisms like Streptococcus pneumoniae and Staphylococcus aureus causing release of pathogen associated molecular patterns that act as triggers for inflammatory pathways, This problem may be exacerbated by the propensity of highly pathogenic influenza viruses such as the 1918 strain or the H5N1 strains currently infecting people in Asia and Europe to cause massive cytokine release. Since secondary bacterial infections account for a significant proportion of the deaths that occur during circulation of virulent strains, it is critical that we develop more effective treatment regimens before the next highly pathogenic influenza virus enters the population from avian sources or as a result of bioterrorism. We hypothesize that alternative treatment regimens, that do not lead to a robust host inflammatory response, will be more effective in the therapy of post-influenzal secondary bacterial pneumonia. This hypothesis will be tested in well described models of secondary pneumococcal and staphylococcal pneumonia. The goal of the proposed studies is to develop an effective treatment strategy for secondary bacterial pneumonia following influenza. The data generated by this work will provide a basis for educated treatment decisions in humans. PUBLIC HEALTH RELEVANCE: Secondary bacterial infections are a common cause of mortality during influenza epidemics, and are expected to be even more important during circulation of highly pathogenic influenza viruses such as pandemic strains or those released for the purposes of bioterrorism. Treatment of these infections is difficult and clinical failures are common for reasons that are at present unclear. The goal of the Proposed Studies is to generate information in a relevant pre-clinical model that will be immediately useful in planning for an influenza pandemic or bioterrorist event, as well as for annual influenza epidemics.