Using a rabbit model of
meningitis, we sought to determine the efficacy of
LY333328, a semisynthetic
glycopeptide, in the treatment of
cephalosporin-resistant
pneumococcal meningitis.
LY333328 was administered at a dose of 10 mg/kg of
body weight/day, alone and in combination with
ceftriaxone at 100 mg/kg/day with or without
dexamethasone at 0.25 mg/kg/day. The therapeutic groups were treated with
LY333328 with or without
dexamethasone and LY333328-ceftriaxone with or without
dexamethasone. Rabbits were inoculated with a
cephalosporin-resistant pneumococcal strain (
ceftriaxone MIC, 2 microg/ml;
penicillin MIC, 4 microg/ml;
LY333328 MIC, 0.008 microg/ml) and were treated over a 26-h period beginning 18 h after inoculation. The bacterial counts in cerebrospinal fluid (CSF), the white blood cell count, the
lactic acid concentration, the CSF
LY333328 concentration, and bactericidal and bacteriostatic activities were determined at different time points. In vitro,
LY333328 was highly bactericidal and its use in combination with
ceftriaxone at one-half the MIC was synergistic. In the rabbit model,
LY333328 alone was an excellent treatment for
cephalosporin-resistant
pneumococcal meningitis, with a rapid decrease in colony counts and no therapeutic failures. The use of
LY333328 in combination with
ceftriaxone improved the activity of
LY333328, but no synergistic effect was observed. The combination of
LY333328 with
dexamethasone was also rapidly bactericidal, but two therapeutic failures were observed. The combination of
LY333328 with
ceftriaxone and
dexamethasone was effective, without therapeutic failures.