Rifampin Reduces Early Mortality in ExperimentalStreptococcus pneumoniaeMeningitis

Abstract

Compared with beta-lactam antibiotics, rifampin releases smaller quantities of proinflammatory cell wall products from Streptococcus pneumoniae in vitro. Mice infected intracerebrally with S. pneumoniae were treated subcutaneously with 2-mg doses of rifampin or ceftriaxone (n=43 each) every 12 h for 3 days and then observed for another 3 days. Rifampin reduced overall mortality from 49% to 26% (P=.04). Kaplan-Meyer analysis revealed a substantial reduction of mortality during the first 24 h in mice receiving rifampin (difference in survival time: P=.007). Eight h after receiving a single 2-mg dose of rifampin or ceftriaxone, rifampin-treated mice had lower serum and cerebrospinal fluid concentrations of lipoteichoic and teichoic acids than did ceftriaxone-treated mice (median serum level: <0.5 vs. 27.0 ng/mL, P=.02; median cerebrospinal fluid level of pooled specimens: 97.5 vs. 206.0 ng/mL). Thus, the use of rifampin appears promising for reducing the release of proinflammatory bacterial components and decreasing early mortality in bacterial meningitis.

Animal Models ofStreptococcus pneumoniaeDisease

“…Inbred mouse strains, including BALB/c, C57BL/6, DBA, and CBA mice, have largely been exploited for the analysis of pneumococcal pneumonia (12,113,131,176,186,201,234), sepsis (15,42,43,163,186), meningitis (86,95,136,173,230), and otitis media (162,164). Experimental sepsis has also been induced in immunodeficient mice, such as the CBA/N strain, which carries the Xid-linked immune deficiency (38,43).…”

“…Meningitis was studied by performing bacterial counts for different organs, histology of the brain, clinical score calculations, and behavioral tests. This model has been employed to study the efficacy of rifampin against meningitis (173) and has also been used for analyzing host and pneumococcal factors involved in disease pathogenesis (35,76,198,255). In another work by the same research group, mice surviving pneumococcal meningitis presented with clear deficits in motor skills, spatial memory, and learning when subjected to behavioral tests (e.g., Morris water maze test, tightrope test) (254).…”

Group B Streptococci Exposed to Rifampin or Clindamycin (versus Ampicillin or Cefotaxime) Stimulate Reduced Production of Inflammatory Mediators by Murine Macrophages

“…Beta-lactam treatment of certain Gram-positive bacteria, including Streptococcus pneumoniae and Staphylococcus aureus, has also been reported to trigger a more marked release of bacterial components and a more pronounced host inflammatory response (14,18). These findings may have clinical relevance: in one study, treatment of pneumococcal meningitis in a mouse model with rifampin (versus ceftriaxone) was associated with reductions in the concentrations of bacterial components (lipoteichoic acid and teichoic acid) in the serum and CSF of these animals and with decreased early mortality (19).…”

Lipoproteins and Diseases of the Brain

“…Bacterial lipoproteins still remain in the tissue even after the degradation of bacteria by antibiotic therapies [33,34]. As a result, many studies suggest that minimizing the production of bacterial proteins or inhibiting bacterial protein synthesis is more effective at preventing neural injury from bacterial infections in animal models or patients [35,36] than simply using antibiotics to kill bacteria. Bacterial lipoproteins in the brain trigger microglia activation via the toll-like receptors (TLRs) to produce inflammatory mediators (e.g., cytokines and reactive oxygen species) [37][38][39] and induce migration of immune cells across the BBB [40,41].…”