Using a rabbit model of meningitis, we sought to determine whether concomitant use of dexamethasone affects the penetration and efficacy of ceftriaxone or vancomycin in cerebrospinal fluid. Rabbits were inoculated with a penicillin-sensitive strain of Streptococcus pneumoniae and treated with ceftriaxone or vancomycin with or without dexamethasone. In the ceftriaxone-treated groups, no statistically significant differences were seen between the group treated with dexamethasone and that without dexamethasone; however, in the vancomycintreated groups we found statistically significant lower cerebrospinal fluid vancomycin levels at 2 h in the dexamethasone-treated rabbits and differences in bacterial killing.Dexamethasone (DEX) has been shown to down modulate inflammatory activity in experimental bacterial meningitis, to reduce neurological sequelae in pediatric Haemophilus influenzae and pneumococcal meningitis, and to reduce mortality in adult pneumococcal meningitis (5,7,9,10,12,14). However, the routine use of DEX as adjunctive therapy in bacterial meningitis is not yet widely accepted because of (i) its potential adverse effects, especially the possibility of gastrointestinal bleeding; (ii) the difficulties in assessing adequately the clinical evolution of meningitis, since DEX is associated with a more rapid decrease in fever; (iii) the possibility of deleterious effects in cases of viral meningitis; and (iv) the concerns of some about the possibility of DEX interfering with an adequate penetration of antibiotics in cerebrospinal fluid (CSF) (1, 13).In 1988 we carried out a study using vancomycin (VAN) in the therapy of adult pneumococcal meningitis (15) in order to explore real alternatives in the therapy of such an infection. The study was discontinued after 11 patients had been treated because of four therapeutic failures, all of them following an initial improvement. VAN levels in CSF were erratic, and the concomitant use of DEX, which was used in all cases as an early adjunctive therapy, was invoked as a possible explanation.On the other hand, ceftriaxone (CRO) is being widely used as a therapy of bacterial meningitis because of its broad spectrum of activity, its safety, and its efficacy, so we wanted to study the possible influence of DEX when used with either antibiotic in the therapy of pneumococcal meningitis. Recently, Paris et al. (11) published a work in which the rabbit model of pneumococcal meningitis was used to study the problem of the penetration in CSF of antibiotics used in conjunction with DEX. The experiments covered 24 h of therapy and showed a decrease in VAN penetration in CSF.

The object of the study was to assess the efficacy of rifampicin and the combination of rifampicin plus vancomycin in a rabbit model of experimental penicillin-resistant pneumococcal meningitis. We also studied the effect of concomitant dexamethasone on the CSF antibiotic levels and inflammatory parameters. The rabbit model of pneumococcal meningitis was used. Groups of eight rabbits were inoculated with 106 cfu/mL of a cephalosporin-resistant pneumococcal strain (MIC of cefotaxime/ceftriaxone 2 mg/L). Eighteen hours later they were treated with rifampicin 15 mg/kg/day, vancomycin 30 mg/kg/day or both plus minus dexamethasone (0.25 mg/kg/day) for 48 h. Serial CSF samples were withdrawn to carry out bacterial counts, antibiotic concentration and inflammatory parameters. Rifampicin and vancomycin promoted a reduction of >3 log cfu/mL at 6 and 24 h, and cfu were below the level of detection at 48 h. Combination therapy with vancomycin plus rifampicin was not synergic but it had similar efficacy to either antibiotic alone and it was able to reduce bacterial concentration below the level of detection at 48 h. Concomitant use of dexamethasone decreased vancomycin levels when it was used alone (P< 0.05), but not when it was used in combination with rifampicin. Rifampicin alone at 15 mg/kg/day produced a rapid bactericidal effect in this model of penicillin-resistant pneumococcal meningitis. The combination of vancomycin and rifampicin, although not synergic, proved to be equally effective. Using this combination in the clinical setting may allow rifampicin administration without emergence of resistance, and possibly concomitant dexamethasone administration without significant interference with CSF vancomycin levels.

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