Sub-MIC levels of
macrolides down-regulate bacterial
virulence factors and suppress inflammatory processes. The ability of
macrolides to reduce the production of
pneumolysin has been shown to explain the discrepancy between in vitro resistance and outcomes with
macrolides against
macrolide-resistant Streptococcus pneumoniae. In this study, we determined whether the ability of
macrolides to regulate inflammatory processes is beneficial for innate resistance to
macrolide-resistant pneumococci in a murine
pneumonia model. Among the
macrolides tested, only
roxithromycin did not affect in vitro pneumococcal
virulence factors at sub-MIC levels.
Roxithromycin (1.25 to 10 mg/kg of
body weight/day) was administered to mice by oral gavage for 3 days before
infection with a resistant strain of S. pneumoniae. We evaluated the efficacy of the treatment by determining mouse survival curves and by measuring bacterial burdens and several inflammatory parameters in the airways.
Pneumolysin and PspA in infected lungs were examined by Western blot assay.
Roxithromycin at doses of > or =5 mg/kg/day increased the median survival time and retarded
bacteremia without suppressing the production of
pneumolysin and PspA in infected lungs. This treatment reduced
matrix metalloproteinase-7 expression and activation and keratinocyte-derived
chemokine production in the lungs, while it increased mononuclear cell responses in the lungs, with enhanced bacterial clearance. Concentrations of
roxithromycin in plasma and tissues were below the MICs for the inoculated strain during
infection. The treatment also reduced inflammatory responses to killed pneumococci in the lungs. These results suggest that the modification by
roxithromycin of airway inflammatory responses, including those of
matrix metalloproteinase-7 and phagocytes, is beneficial for initial resistance to
macrolide-resistant pneumococci.