title: Rifampin followed by ceftriaxone for experimental meningitis decreases lipoteichoic acid concentrations in cerebrospinal fluid and reduces neuronal damage in comparison to ceftriaxone alone.
abstract: Rifampin (RIF) releases smaller quantities of lipoteichoic acids (LTAs) from Streptococcus pneumoniae than ceftriaxone (CRO). Due to the rapid development of resistance, RIF cannot be used as a single agent for therapy of bacterial meningitis. For this reason, we compared the effect of treatment with RIF followed by treatment with CRO (RIF-CRO) or the effect of treatment with clindamycin (CLI) followed by treatment with CRO (CLI-CRO) to that of CRO alone on the concentrations of LTAs and teichoic acids in vitro. The effects of RIF-CRO on LTA concentrations in cerebrospinal fluid (CSF) and on neuronal injury were investigated in a rabbit model of S. pneumoniae meningitis. In vitro, bacterial titers were effectively reduced by CRO, RIF-CRO, and CLI-CRO when each drug was used at 10 micro g/ml. The levels of release of LTAs after the initiation of therapy were lower in RIF-CRO- and CLI-CRO-treated cultures than in cultures treated with CRO alone (P < 0.05 from 3 to 12 h after initiation of treatment). Similarly, in rabbits, the increase in the amount of LTAs in CSF was lower in RIF-CRO-treated animals than in CRO-treated animals (P = 0.02). The density of dentate apoptotic granular cells was lower after RIF-CRO therapy than after CRO therapy (medians, 58.4 and 145.6/mm(2), respectively; 25th quartiles, 36.3 and 81.7/mm(2), respectively; 75th quartiles, 100.7 and 152.3/mm(2), respectively; P = 0.03). Therefore, initiation of therapy with a protein synthesis-inhibiting antibacterial and continuation of therapy with a combination that includes a beta-lactam may be a strategy to decrease neuronal injury in bacterial meningitis.
authors.affiliation: Department of Neurology, Georg-August University, Göttingen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Gerber
authors.forename: Karin
authors.initials: K
authors.lastname: Pohl
authors.forename: Valeska
authors.initials: V
authors.lastname: Sander
authors.forename: Stephanie
authors.initials: S
authors.lastname: Bunkowski
authors.forename: Roland
authors.initials: R
authors.lastname: Nau
mesh_terms: D000818:Animals; D002443:Ceftriaxone / Q000008:administration & dosage* / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D008070:Lipopolysaccharides / Q000134:cerebrospinal fluid*; D008586:Meningitis, Pneumococcal / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000473:pathology; D009474:Neurons / Q000473:pathology*; D011817:Rabbits; D012293:Rifampin / Q000008:administration & dosage*; D013682:Teichoic Acids / Q000134:cerebrospinal fluid*
chemical_list: D008070:Lipopolysaccharides; D013682:Teichoic Acids; C009900:lipoteichoic acid; D002443:Ceftriaxone; D012293:Rifampin