RIFABUTIN FOR EXPERIMENTAL PNEUMOCOCCAL MENINGITIS

Rifabutin is a lipophilic antibacterial with high in vitro activity ag ainst many pathogens involved in bacterial meningitis including pneumo cocci. Resistance to p-lactam antibiotics in pneumococci is not associ ated with a decreased sensitivity to rifabutin (30 strains from German y with intermediate penicillin resistance: MIC range of penicillin: 0. 125-1 mg/l, MIC of rifabutin: <0.008-0.015 mg/l). Rifabutin at doses o f 0.625, 1.25, 2.5, 5 and 10 mg/kg/h i.v. was investigated in a rabbit model of meningitis using a Streptococcus pneumoniae type 3 (MIC/MBC of rifabutin: 0.015/ 0.06 mg/l). The bacterial density in CSF at the o nset of treatment was 7.3 +/- 0.6 log CFU/ml(mean +/- SD). Rifabutin d ecreased bacterial CSF titers in a dose-dependent manner [delta 10g CF U/ml/h (slope of the regression line log CFU/ml vs. time) at a dose of 0.625 mg/kg/h: -0.16 +/- 0.06 (n = 3), at 1.25 mg/kg/h: -0.20 +/- 0.1 2 (n = 3), at 2.5 mg/kg/h: -0.24 +/- 0.04 (n = 4), at 5 mg/kg/h: -0.31 +/- 0.10 (n = 8), and at 10 mg/kg/h: -0.29 +/- 0.10 (n = 5)]. At high doses rifabutin was as active as ceftriaxone at 10 mg/kg/h (delta log CFU/ml/h: -0.29 +/- 0.10, n = 10). Two and 5 h after initiation of th erapy, CSF TNF-alpha activities were lower with rifabutin 5 mg/kg/h th an with ceftriaxone (medians 2 vs, 141 U/ml, p = 0.005 at 2 h; median 51 vs. 120 U/ml 5 h after initiation of therapy, p = 0.04). This did n ot result, however, in a decrease of indicators of neuronal damage. In conclusion, intravenous rifabutin was bactericidal in experimental pn eumococcal meningitis. Provided that a well-tolerated i.v. formulation will be available it may qualify as a reserve antibiotic for pneumoco ccal meningitis, in particular when strains with a reduced sensitivity to beta-lactam antibiotics are the causative pathogens.