We examined the cerebrospinal fluid penetration of daptomycin after the addition of dexamethasone and its bactericidal efficacy with and without ceftriaxone in an experimental rabbit model of pneumococcal meningitis. The combination of daptomycin with ceftriaxone was the most efficacious regimen for pneumococcal meningitis. The previous addition of dexamethasone affected the antibacterial activity of daptomycin only marginally, either as monotherapy or combined with ceftriaxone, although the penetration of daptomycin into inflamed meninges was significantly reduced from 6 to 2%. Daptomycin with ceftriaxone might be a potential candidate for the empirical therapy of bacterial meningitis, although the activity of this regimen against Listeria monocytogenes remains to be demonstrated.The worldwide continuous spread of penicillin-resistant pneumococci represents one of the major challenges for clinicians and infectiologists. The epidemiological situation in Europe varies considerably with a global tendency of increasing penicillin resistance rates from 6% in 1997 to 22% in 1999 (8). In the United States and Canada, the combined rate of penicillin intermediate plus resistant strains varied between 24% and 67% as reported in the multinational SENTRY antimicrobial resistance surveillance program (5). Based on a recent study, the rates of highly resistant strains were 14.7%, 12.7%, and 15.9% for Europe, Latin America, and North America, respectively (9). In adults, pneumococci are the most frequent pathogens causing meningitis (1, 11). In meningitis due to highly resistant strains, high-dose vancomycin has been recommended, either alone or in combination with third-generation cephalosporins (1,14). In adults, the addition of steroids, now established as standard adjunctive therapy, reduces the penetration of vancomycin into the cerebrospinal fluid (CSF) by 29% (10, 12).We have previously shown that daptomycin, a cyclic lipopeptide, was very efficacious in experimental pneumococcal meningitis due to a penicillin-resistant strain and managed to sterilize the CSF samples of all rabbits at the end of the experimental period. Little is known about the effect of dexamethasone, as standard adjunctive treatment in bacterial meningitis, on the meningeal penetration and efficacy of daptomycin. The aim of this study was first to test the effect of dexamethasone on the penetration of daptomycin into inflamed meninges and second to compare the activity of the different regimens after the addition of dexamethasone in pneumococcal meningitis due to a penicillin-resistant strain. The comparator regimen was ceftriaxone combined with vancomycin, which is the standard empirical regimen. MATERIALS AND METHODSPneumococcal strain. The pneumococcal strain Streptococcus pneumoniae WB4 was isolated from a patient at the Inselspital in Bern, Switzerland, and has been routinely used in this experimental model. The MICs for this strain were as follows: 4 mg/liter for penicillin, 0.5 mg/liter for ceftriaxone, 0.12 to 0.25 mg/liter for vancomycin, a...