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Modulation of inflammation and cachectin activity in relation to treatment of experimental Hemophilus influenzae type
M M Mustafa1, O Ramilo, J Mertsola
1Department of Pediatrics, Howard Hughes Medical Institute. Dallas, TX.
Abstract:
By use of an experimental lapin model, the effect of ceftriaxone therapy on inflammation during Hemophilus influenzae type b (Hib) meningitis was evaluated. Meningitis was induced by intracisternal inoculation of 2 x 10(4) to 2 x 10(5) 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 alpha (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 less than .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 less than .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.
Insights
Ceftriaxone therapy for Hemophilus influenzae type b (Hib) meningitis in rabbits increased inflammation. Dexamethasone given with ceftriaxone reduced this inflammatory response, suggesting a way to modulate meningitis treatment.
Area of Science:
- * Microbiology and Immunology
- * Pharmacology and Therapeutics
- * Neurology and Infectious Diseases
Background:
- * Bacterial meningitis, particularly Hemophilus influenzae type b (Hib), remains a significant health concern.
- * Antibiotic therapy is crucial, but the inflammatory response during treatment can impact patient outcomes.
Purpose of the Study:
- * To evaluate the impact of ceftriaxone on inflammation in an experimental model of Hib meningitis.
- * To assess the potential of dexamethasone to modulate this inflammatory response.
Main Methods:
- * An experimental rabbit model was used to induce Hemophilus influenzae type b meningitis.
- * Ceftriaxone was administered 6 hours post-infection, with some groups receiving concurrent dexamethasone.
- * Cerebrospinal fluid (CSF) analysis included measurements of endotoxin, tumor necrosis factor alpha (TNF), white blood cell count, glucose, protein, and lactate.
Main Results:
- * Ceftriaxone treatment led to rapid bacterial lysis and significantly increased CSF concentrations of endotoxin and TNF.
- * Antibiotic therapy was associated with heightened inflammatory markers: elevated CSF white blood cells, lower glucose, and higher protein and lactate.
- * Simultaneous dexamethasone administration significantly reduced CSF TNF activity and white blood cell counts.
Conclusions:
- * Initiating ceftriaxone therapy in experimental Hib meningitis can exacerbate the meningeal inflammatory response.
- * Concurrent administration of dexamethasone can effectively modulate this exacerbated inflammation.
- * These findings suggest a potential therapeutic strategy for managing inflammation during Hib meningitis treatment.