Antibiotic Therapy, Endotoxin Concentration in Cerebrospinal Fluid, and Brain Edema in Experimental Escherichia coli Meningitis in Rabbits

Abstract

We investigated the effect of cefotaxime and chloramphenicol on endotoxin concentrations in cerebrospinal fluid (CSF) and on the development of brain edema in rabbits with Escherichia coli meningitis. Both antibiotics were similarly effective in reducing bacterial titers. Cefotaxime, but not chloramphenicol, induced a marked increase of endotoxin in CSF, from log., 1.5 ± 0.8 to log., 2.8 ± 0.7 ng/ml (P < .01). This result was associated with an increase in brain water content (405 ± 12 g of water/loo g of dry weight compared with 389 ± 8 g in untreated controls; P < .01), whereas in animals treated with chloramphenicol, brain water content was identical to controls. The cefotaxime-induced increase in endotoxin concentration and brain edema were both neutralized by polymyxin B, which binds to the lipid A moiety of endotoxin, or by a monoclonal antibody to lipid A. These results indicate that treating gram-negative bacillary meningitis with selected antibiotics induces increased endotoxin concentrations in CSF that are associated with brain edema.

Influence of Granulocytes on Brain Edema, Intracranial Pressure, and Cerebrospinal Fluid Concentrations of Lactate and Protein in Experimental Meningitis

“…[16,43]. Brain edema was examined because of its association with brain injury due to various causes [44].…”

“…Brain edema was examined because of its association with brain injury due to various causes [44]. In experimental meningitis the development of brain edema, albeit not massive, has been documented [16,43,45], and clinical evidence exists of severe brain edema in fatal cases of meningitis [8,46]. According to Fishman et al [23] and Fishman [44], brain edema during meningitis ("granulocytic edema") comprises all three types of brain edema, i.e., vasogenic edema, cytotoxic edema, and interstitial edema.…”

Steroid Therapy for Bacterial Meningitis

“…Schaad and Kaplan, the efficacy of dexamethasone therapy in humans has only been proven for H. influenzae meningitis. In several studies of experimental pneumococcal meningitis, dexamethasone was effective in modulating meningeal inflammation, including cerebral edema and intracranial pressure [1,4 In the two clinical trials of pneumococcal meningitis mentioned previously [ 10,16], there was evidence suggesting that steroid therapy improved outcome. There is no information on the efficacy of dexamethasone in treating meningococcal meningitis; because sequelae occur in <10% of these patients, a very large number of patients would need to be studied to establish its efficacy.…”

“…There is convincing in vitro and in vivo evidence that this steroid decreases the liberation of various cytokines [4][5][6]. Other effects of dexamethasone, some of which may be independent of its effect on cytokine release, include reduction of brain edema, intracranial pressure, blood-brain barrier permeability, and CSF lactate concentrations.…”

“…Results from animal studies strongly indicate that the optimal time for adjunctive dexamethasone therapy is just before administration of the first dose of parenteral antibiotics [4][5][6]. Exacerbation of inflammation that occurred during the initial antibiotic therapy in pediatric patients with Haemophilus influenzae meningitis was shown by documentation of a substantial increase in cytokine concentrations in the CSF 2-6 hours after the first dose of ceftriaxone was administered [13].…”