Modulation of Inflammation and Cachectin Activity in Relation to Treatment of Experimental Hemophilus influenzae Type b Meningitis

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Abstract
By use of an experimental lapin model, the effect of ceftriaxone therapy on inflammation during Hemophilus inf/uenzae type b (Hib) meningitis was evaluated. Meningitis was induced by intracisternal inoculation of 2 × 104 to 2 × lO5 colony-forming units of Hib. Administration of ceftriaxone 6 h after infection provoked rapid bacterial lysis associated with greatly increased concentrations of bacteria-free endotoxin (lipooligosaccharide) and tumor necrosis factor a (TNF) in the cerebrospinal fluid (CSF). CSF TNF activity peaked 2 h after initiation of antibiotic therapy (24.4 ± 2 ng/ml), was significantly higher than that in untreated controls (1.4 ± 1.1 ng/ml; P <.05), and was associated with a substantially increased inflammatory response as reflected by higher CSF white blood cell count (24,500 ± 8,151 vs. 1,920 ± 644 in untreated controls; P < .05), lower glucose, and higher protein and lactate concentrations. Simultaneous administration of dexamethasone with antibiotic therapy resulted in a significant reduction in CSF TNF activity that was associated with a substantial reduction in CSF white blood cell count. These data suggest that initiation of ceftriaxone therapy in experimental Hib meningitis exacerbates the meningeal inflammatory response, which can be modulated by concurrent dexamethasone administration.

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