title: Rifabutin for experimental pneumococcal meningitis.
abstract: Rifabutin is a lipophilic antibacterial with high in vitro activity against many pathogens involved in bacterial meningitis including pneumococci. Resistance to beta-lactam antibiotics in pneumococci is not associated with a decreased sensitivity to rifabutin (30 strains from Germany 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 of 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 onset of treatment was 7.3 +/- 0.6 log CFU/ml (mean +/- SD). Rifabutin decreased bacterial CSF titers in a dose-dependent manner [delta log CFU/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 +/- 0.12 (n = 4), 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 therapy, CSF TNF-alpha activities were lower with rifabutin 5 mg/kg/h than 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 not result, however, in a decrease of indicators of neuronal damage. In conclusion, intravenous rifabutin was bactericidal in experimental pneumococcal meningitis. Provided that a well-tolerated i.v. formulation will be available it may qualify as a reserve antibiotic for pneumococcal meningitis, in particular when strains with a reduced sensitivity to beta-lactam antibiotics are the causative pathogens.
authors.affiliation: Department of Neurology, University of Göttingen, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Schmidt
authors.forename: G
authors.initials: G
authors.lastname: Zysk
authors.forename: R R
authors.initials: RR
authors.lastname: Reinert
authors.forename: W
authors.initials: W
authors.lastname: Brück
authors.forename: A
authors.initials: A
authors.lastname: Stringaris
authors.forename: V
authors.initials: V
authors.lastname: Chen
authors.forename: K
authors.initials: K
authors.lastname: Stuertz
authors.forename: F
authors.initials: F
authors.lastname: Fischer
authors.forename: R
authors.initials: R
authors.lastname: Bartels
authors.forename: K J
authors.initials: KJ
authors.lastname: Schaper
authors.forename: S
authors.initials: S
authors.lastname: Weinig
authors.forename: R
authors.initials: R
authors.lastname: Nau
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000627:therapeutic use*; D002443:Ceftriaxone / Q000627:therapeutic use; D004195:Disease Models, Animal; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy*; D008826:Microbial Sensitivity Tests; D011817:Rabbits; D017828:Rifabutin / Q000627:therapeutic use*; D013296:Streptococcus pneumoniae / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D017828:Rifabutin; D002443:Ceftriaxone