Evaluation of combined ceftriaxone and dexamethasone therapy in experimental cephalosporin-resistant pneumococcal meningitis

The treatment of meningitis caused by strains of Streptococcus pneumoniae with decreased susceptibility to third-generation cephalosporins is an increasingly frequent and difficult problem. In this study a rabbit model of meningitis was used to determine the efficacy of ceftriaxone at different dosages, and to establish the effect of the addition of dexamethasone to the chemotherapeutic regimen. Groups of eight rabbits were inoculated with 10(6) cfu/mL of a cephalosporin-resistant strain of S. pneumoniae (MIC of cefotaxime/ceftriaxone 2 mg/L). Eighteen hours after inoculation, ceftriaxone (50 or 100 mg/kg/day) with or without dexamethasone (0.25 mg/kg/ day) was administered for a period of 48 h. The ceftriaxone dose of 50 mg/kg/day was not fully effective in this model (therapeutic failure rate 28%). With a dose of 100 mg/kg/day there were no therapeutic failures and all CSF cultures were below the level of detection at 48 h. CSF ceftriaxone concentrations, area under the time-concentration curve and time above the MIC were not significantly different with or without dexamethasone. However, concomitant use of dexamethasone resulted in higher CSF bacterial counts and a higher number of therapeutic failures (57% with the 50 mg/kg/day dose and 28% with the 100 mg/kg/day dose). Increasing doses of ceftriaxone might be an effective mode of therapy for meningitis caused by S. pneumoniae with MIC less than or equal to 2 mg/L. However, in contrast to cephalosporin-sensitive cases, in cases caused by ceftriaxone-resistent strains, concomitant use of dexamethasone was associated with a higher failure rate even when a higher dosage of ceftriaxone was used.