Linezolid Decreases Susceptibility to Secondary Bacterial Pneumonia Postinfluenza Infection in Mice Through its Effects on IFN-γ

Influenza infection predisposes patients to secondary bacterial pneumonia that contributes significantly to morbidity and mortality. Although this association is well documented, the mechanisms that govern this synergism are poorly understood. A window of hyporesponsiveness following influenza infection has been associated with a substantial increase in local and systemic IFN-gamma concentrations. Recent data suggest that the oxazolidinone antibiotic linezolid decreases IFN-gamma and TNF-alpha production in vitro from stimulated PBMCs. We therefore sought to determine whether linezolid would reverse immune hyporesponsiveness after influenza infection in mice through its effects on IFN-gamma. In vivo dose-response studies demonstrated that oral linezolid administration sufficiently decreased bronchoalveolar lavage fluid levels of IFN-gamma at day 7 postinfluenza infection in a dose-dependent manner. The drug also decreased morbidity as measured by weight loss compared with vehicle-treated controls. When mice were challenged intranasally with Streptococcus pneumoniae 7 d postinfection with influenza, linezolid pretreatment led to decreased IFN-gamma and TNF-alpha production, decreased weight loss, and lower bacterial burdens at 24 h postbacterial infection in comparison with vehicle-treated controls. To determine whether these effects were due to suppression of IFN-gamma, linezolid-treated animals were given intranasal instillations of rIFN-gamma before challenge with S. pneumoniae. This partially reversed the protective effects observed in the linezolid-treated mice, suggesting that the modulatory effects of linezolid are mediated partially by its ability to blunt IFN-gamma production. These results suggest that IFN-gamma, and potentially TNF-alpha, may be useful drug targets for prophylaxis against secondary bacterial pneumonia following influenza infection.