Tumor necrosis factor alpha (TNF-␣) and TNF-␤ are key mediators in bacterial inflammation. We therefore examined the role of TNF-␣ and its two receptors in murine pneumococcal central nervous system infection. TNF-␣ knockout mice and age-and sex-matched controls and TNF receptor (p55 and p75)-deficient mice and heterozygous littermates were infected intracerebrally with a Streptococcus pneumoniae type 3 strain. Mice were monitored until death or were killed 36 h after infection. Bacterial titers in blood, spleen, and brain homogenates were determined. Leukocyte infiltration and neuronal damage were assessed by histological scores. TNF-␣-deficient mice died earlier than the controls after intracerebral infection although overall survival was similar. TNF-␣ deficiency did not inhibit leukocyte recruitment into the subarachnoid space and did not lead to an increased density of bacteria in brain homogenates. However, it caused a substantial rise of the concentration of S. pneumoniae cells in blood and spleen. Spleen bacterial titers were also increased in p55-and p75-deficient mice. TNF receptor-deficient mice showed decreased meningeal inflammation. Neuronal damage was not affected by either TNF-␣ or TNF receptor deficiency. In a murine model of pneumococcal peritonitis, 10 2 CFU of S. pneumoniae produced fatal peritonitis in TNF-␣-deficient, but not wild-type, mice. Early leukocyte influx into the peritoneum was impaired in TNF-␣-deficient mice. The lack of TNF-␣ or its receptors renders mice more susceptible to S. pneumoniae infections.

In a rabbit model of Streptococcus pneumoniae meningitis single doses of 10 and 2.5 mg of the glycopeptide LY333328 per kg of body weight reduced bacterial titers in cerebrospinal fluid (CSF) almost as rapidly as ceftriaxone at 10 mg/kg/h (changes in log CFU, ؊0.29 ؎ 0.21 and ؊0.26 ؎ 0.22 versus ؊0.34 ؎ 0.15/ml/h). A dose of 1 mg/kg was bacteriostatic (change in log CFU, 0.01 ؎ 0.11/ml/h). In two animals receiving LY333328 at a dose of 40 mg/kg the bacterial titers were reduced by 0.54 and 0.51 log CFU/ml/h. The penetration of CSF by LY333328 was 1 to 5%. The concentrations of lipoteichoic and teichoic acids in CSF and neuronal damage were similar in ceftriaxone-and LY333328-treated animals.Since the first description of a penicillin-resistant pneumococcal strain in 1967 in Australia (6), penicillin-resistant pneumococci have spread worldwide (1). Furthermore, reduced sensitivity of Streptococcus pneumoniae isolates to cephalosporins and other ␤-lactam antibiotics (7) resulting in clinical failures of cefotaxime and ceftriaxone in the treatment of meningitis has increased in frequency (2, 4).Vancomycin is active against penicillin-resistant pneumococci. Although bactericidal concentrations of vancomycin were achieved in cerebrospinal fluid (CSF) in children with bacterial meningitis (9), clinical failures in adults have been reported probably because of a diminished blood-brain barrier penetration during adjunctive steroid therapy (19). This emphasizes the need for compounds either with a higher activity or with an improved CSF penetration compared to vancomycin for treatment of bacterial meningitis. LY333328 diphosphate is a semisynthetic glycopeptide inhibiting the synthesis of peptidoglycan in gram-positive bacteria. It is highly active against many resistant organisms, including methicillin-and teicoplanin-resistant staphylococci, vancomycin-resistant enterococci, and penicillin-resistant and multiresistant pneumococci (3,5,13). In a search for new therapeutic agents, we investigated its activity and its influence on the release of proinflammatory bacterial compounds and on neuronal damage in the rabbit model of S. pneumoniae meningitis with a strain susceptible to penicillin.In vitro antimicrobial activity. S. pneumoniae type 3 (MIC and minimal bactericidal concentration [MBC] of LY333328, 0.015 and 0.03 g/ml, respectively; MIC and MBC of ceftriaxone, 0.03 and 0.06 g/ml, respectively; MIC and MBC of penicillin, Ͻ0.1 g/ml) (gift of M. G. Täuber, Department of Medical Microbiology, University of Bern, Bern, Switzerland) was grown, centrifuged, and resuspended in fresh tryptic soy broth to a final concentration of 6.83 Ϯ 0.16 log CFU/ml (n ϭ 5). Control cultures were grown after resuspension without antibiotics. Ceftriaxone and LY333328 (final concentration, 10 g/ml) were added to 15-ml aliquots, and bacterial counts were determined at 0, 1, 3, 6, 9, and 12 h. Rabbit model. Meningitis was induced by intracisternal injection of approximately 106 CFU of S. pneumoniae. Blood (3 ml) and CSF (300 l) were drawn befo...