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

Abstract

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.Streptococcus pneumoniae is the most prevalent pathogen associated with community-acquired pneumonia, and the emergence of antibiotic resistance among pneumococcal isolates linked to community-acquired pneumonia has been of great concern. Especially, the incidence of macrolide-resistant S. pneumoniae is rapidly increasing (11,22). Nevertheless, macrolide compounds have been empirically among the firstline drugs for the treatment of outpatients with communityacquired pneumonia. Such empirical therapy is likely to involve the risk of exacerbating the disease in cases of infection with macrolide-resistant S. pneumoniae (31, 32). However, despite the appreciable level of macrolide resistance, concordance between in vitro macrolide susceptibility and clinical outcomes among patients with community-acquired pneumonia is lacking (5, 34); the exact clinical relevance of in vitro findings has yet to be determined. A recent report (12) has shown that the ability of macrolides to reduce pneumococcal virulence factors may account for the discordance between the in vitro resistance of pneumococci and the conservative clinical effects of macrolides. In addition to the su...

Microbial exposure early in life regulates airway inflammation in mice after infection with Streptococcus pneumoniae with enhancement of local resistance

“…Pneumococcal pneumonia was induced by intratracheal inoculation of type 3 S. pneumoniae strain NMU112 in a 20-l volume (5 ϫ 10 4 cfu, equivalent to 100 LD50) as previously described (62). The exact inoculated dose was verified by plating out 500ϳ1,000-fold dilutions onto blood agar plates.…”

Macrolides and β-Lactam Antibiotics Enhance C3b Deposition on the Surface of Multidrug-Resistant Streptococcus pneumoniae Strains by a LytA Autolysin-Dependent Mechanism

“…All macrolide antibiotics impair bacterial protein synthesis by acting on the 50S bacterial ribosomal subunit. Macrolides at subinhibitory concentrations, but not other groups of antibiotics, inhibit the production of pneumolysin, which is an important virulence factor of S. pneumoniae involved in evasion of C3b (1,10,24,25). In addition, it has been shown that macrolide compounds, such as ERY, AZM, and clarithromycin, but not roxithromycin, significantly inhibited pneumolysin and PspA.…”

Treatment with anti‐inflammatory drugs in community‐acquired pneumonia

“…Despite a reduction in the number of PMNs, bacterial counts were lower in treated mice. This was attributed to an increase in mononuclear cells that exhibit enhanced phagocytic bactericidal activity targeted against pneumococci and cause less damage to surrounding lung tissue [57]. In addition to the effect on cytokines and inflammatory cells, effects of macrolides on structural cells of the respiratory tract have also been reported.…”