Experimental study of teicoplanin, alone and in combination, in the therapy of cephalosporin-resistant pneumococcal meningitis

Abstract

Objectives: The aim of the study was to determine the efficacy of teicoplanin, alone and in combination with ceftriaxone, in a rabbit model of cephalosporin-resistant pneumococcal meningitis, and to assess the effect of concomitant therapy with dexamethasone.

Methods: In vitro killing curves of teicoplanin, with and without ceftriaxone, were performed. Groups of eight animals per treatment were inoculated with a cephalosporin-resistant pneumococcal strain (penicillin MIC, 4 mg/L; ceftriaxone MIC, 2 mg/L; teicoplanin MIC, 0.03 mg/L) and treated over a 26 h period. Teicoplanin was administered at a dose of 15 mg/kg, alone and in combination with ceftriaxone at 100 mg/kg with or without dexamethasone at 0.25 mg/kg. CSF samples were collected at different time-points, and bacterial titres, white blood cell counts, lactate and protein concentrations and bacteriostatic/bactericidal titres were determined. Blood and CSF teicoplanin pharmacokinetic and pharmacodynamic parameters were determined.

Results: Teicoplanin alone promoted a decrease in bacterial counts at 6 h of -2.66 log cfu/mL and was bactericidal at 24 h, without therapeutic failures. Similar good results were obtained when dexamethasone was used simultaneously, in spite of the penetration of teicoplanin into the CSF being significantly reduced, from 2.31% to 0.71%. Teicoplanin and ceftriaxone combinations were synergic in vitro, but not in the meningitis model.

Conclusions: Teicoplanin alone was very effective in this model of cephalosporin-resistant pneumococcal meningitis. The use of concomitant dexamethasone resulted in lower CSF teicoplanin levels, but not in therapeutic failures. The combination of teicoplanin plus ceftriaxone and dexamethasone might be a good alternative for the empirical therapy of pneumococcal meningitis. Additional data should confirm our experiments, in advance of clinical trials to assess efficacy in humans.