Rifampin (RIF) releases smaller quantities of lipoteichoic acids (LTAs) fromStreptococcus 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 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 -lactam may be a strategy to decrease neuronal injury in bacterial meningitis.Neuronal injury in bacterial meningitis is a consequence of leukocyte invasion into central nervous system compartments, stimulation of microglia and resident macrophages, and the direct toxicity of bacterial components on the cerebral endothelium and neuronal cells. Pneumococcal cell wall components attract leukocytes into the central nervous system and stimulate the release of proinflammatory cytokines (9, 25). Teichoic acids and lipoteichoic acids (LTAs) are the most potent proinflammatory constituents of the membrane and cell wall of Streptococcus pneumoniae. When injected into the subarachnoid space, LTAs cause profound meningeal inflammation (25).In the initial phase of treatment with -lactam antibiotics, a brisk increase in the level of meningeal inflammation occurs (13). Several bactericidal antibiotics without a primary influence upon cell wall synthesis (trovafloxacin, rifampin [RIF], rifabutin, and quinupristin-dalfopristin) delayed and/or decreased the release of LTAs in comparison with the time of release after treatment with ceftriaxone (CRO) (15,22,26). In this respect, bacterial protein synthesis inhibitors were more effective than quinolones (22,23). In humans, adverse outcomes after S. pneumoniae meningitis correlated with the LTA concentration in cerebrospinal fluid (CSF) upon hospital admission (20). Consequently, in a mouse model of S. pneumoniae meningitis, RIF reduced the concen...