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 μg/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 β-lactam may be a strategy to decrease neuronal injury in bacterial meningitis.