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Antimicrobial Agents and Chemotherapy, May 2007, p. 1741-1752, Vol. 51, No. 5
0066-4804/07/$08.00+0     doi:10.1128/AAC.01459-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Roxithromycin Favorably Modifies the Initial Phase of Resistance against Infection with Macrolide-Resistant Streptococcus pneumoniae in a Murine Pneumonia Model

Department of Bacteriology,¹ Center for Infectious Diseases, Nara Medical University School of Medicine, Kashihara, Nara 634-8521, Japan²

Received 20 November 2006/ Returned for modification 22 December 2006/ Accepted 5 March 2007

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 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.

Published ahead of print on 12 March 2007.