Attenuation of cerebrospinal fluid inflammation by the nonbacteriolytic antibiotic daptomycin versus that by ceftriaxone in experimental pneumococcal meningitis

Abstract

Antibiotic-induced bacteriolysis exacerbates inflammation and brain damage in bacterial meningitis. Here the quality and temporal kinetics of cerebrospinal fluid (CSF) inflammation were assessed in an infant rat pneumococcal meningitis model for the nonbacteriolytic antibiotic daptomycin versus ceftriaxone. Daptomycin led to lower CSF concentrations of interleukin 1beta (IL-1beta), IL-10, IL-18, monocyte chemoattractant protein 1 (MCP-1), and macrophage inflammatory protein 1 alpha (MIP-1alpha) (P < 0.05). In experimental pneumococcal meningitis, daptomycin treatment resulted in more rapid bacterial killing, lower CSF inflammation, and less brain damage than ceftriaxone treatment.

FIG. 1.

Profile of cyto-/chemokine concentration in the CSF for treatment with daptomycin versus that with ceftriaxone at different time points (2, 6, and 40 h) after initiation of therapy. The concentrations of IL-1β, IL-10, IL-18, MCP-1, and MIP-1α were significantly (P < 0.05, two-way ANOVA) lower in daptomycin-treated animals.

FIG. 2.

(A) CSF bacterial titers after antibiotic therapy. Sterilization of CSF was more rapid with therapy with daptomycin (DAP) than with therapy with ceftriaxone (CRO). Six hours after therapy, CSF was sterilized with daptomycin. At 2 and 4 h after therapy, bacterial titers differed significantly (P < 0.05, Mann-Whitney) between treatment groups. (B) Brain damage in experimental pneumococcal meningitis. The extent of cortical damage is significantly reduced (P = 0.02 Mann-Whitney) by daptomycin treatment versus that with ceftriaxone treatment. (C) Histopathology (overview). Cortical injury assessed by Nissl staining is characterized by wedge-shaped areas of decreased neuronal density (arrowheads), suggestive of ischemic necrosis (cresyl violet; original magnification, ×5; scale bar = 1 mm). (D) Histopathology. Focus of cortical neuronal loss (left side; arrowheads) containing neurons with morphological features of necrosis, including pyknotic nuclei, cell swelling, and fading of cytoarchitecture, is sharply demarcated from preserved brain tissue (right side; original magnification, ×200; scale bar, 50 μm; cresyl violet).