In patients without neutropenia and without major immunodeficiency, fluconazole and amphotericin B are not significantly different in their effectiveness in treating candidemia.

No bacterial disease has undergone a more dramatic change in epidemiology during the past decade than acute bacterial meningitis. This review describes the changing epidemiology and considers some important recent observations that contribute to our understanding of the pathogenesis and pathophysiology of meningitis. The major focus is on the mechanisms of neuronal injury and the pathophysiologic concepts responsible for death and neurologic sequelae. In recent years, experimental studies have amplified our understanding of the substantial body of evidence that now implicates cytokines and chemokines, proteolytic enzymes, and oxidants in the inflammatory cascade leading to tissue destruction in bacterial meningitis. The molecular mechanisms responsible for oxidant-induced neuronal injury in meningitis are explored in some depth. Genetic targeting and/or pharmacologic blockade of the implicated pathways may be a future strategy for therapeutic adjunctive measures to improve outcome and may hold substantial promise, in concert with antimicrobial agents, in humans with acute bacterial meningitis.

The diversity of infectious agents capable of inducing meningitis and blood-brain barrier (BBB) injury suggests the potential for a common host mediator. The inflammatory polypeptides, IL-1 and TNF, were tested in an experimental rat model as candidate mediators for induction of meningitis and BBB injury. Intracisternal challenge ofrII-l-into rats induced neutrophil emigration into cerebrospinal fluid (CSF) and significantly increased BBB permeability to systemically administered 12511 BSA as early as 3 h later (P < 0.05). This injury was reversible, dose dependent and significantly inhibited by prior induction of systemic neutropenia (via intraperitoneal cyclophosphamide) or preincubation of the rIL-1,6 inoculum (50 U) with an IgG monoclonal antibody to rIL-1#,. Similar kinetics and reversibility of CSF inflammation and BSA permeability were observed using equivalent dose inocula of rIL-1 alpha. rTNF-a was less effective as an independent inducer of meningitis or BBB injury over an inoculum range of 10' U (0.0016 ,ug/kg)-10' U (160 ag/kg) when injected intracisternally, but inoculum combinations of low concentrations of rTNFa (103 U) and rIL-1l (0.0005-5.0 U) were synergistic in inducing both meningitis and BBB permeability to systemic 125I-BSA. These data suggest that in situ generation of interleukin-1 within CSF (with or without TNF) is capable of mediating both meningeal inflammation and BBB injury seen in various central nervous system infections. (J. Clin.

A B S T R A C T The role of' dextrani in the pathogeniesis of' bacterial endocarditis was investigated by studying the adhereniee of' dextran producing oral streptococci to the constituenits of' nonl)acterial thrombotic endocarditis (NBTE) in vitro and in vivo. The adherence of' Streptococcus saniguis to fibrin and platelets was determinedl in an in vitro assay system simulating non-I)acterial thrombotic endocarditis. Adherence was increased when the organismiis were grown in sucrosesuipplemented media (adherence ratio x 104, 177+6 in 5% suicrose vs. 140±7 in 0.5% sucrose, P < 0.001), and decreased by incubating the organisms in dextranase (adherence ratio x 104, 117+ 16, P < 0.001), an effect which was nullified by heat inactivating this enzyme (adherence ratio x 104, 192+7, P < 0.001). The amount of dextran produced in broth by three different oral streptococci correlated directly with the adherence observed to fibrin and a fibrin-platelet matrix in vitro (P < 0.001). These organisms adhered more readily to a fibrin-platelet matrix than to fibrin alone (adherence ratio x 104, 455±30 vs. 177±6, respectively, P < 0.001).The role of dextran formation was also examined in vivo in rabbits with preexisting NBTE. After injection of 107 S. sangguis, 12 of 17 animals developed endocarditis. In contrast, when the organisms were pretreated with dextranase (an enzyme that removes dextran from the bacterial cell surface), the same inoculum resulted in endocarditis in only 5 of' 19 animals (P < 0.05). In addition, a fresh strain of' S. sanguis that produiced high levels of dextran (1,220+50 ,Ag/ml) and adhered avidly to fibrin (adherence ratio x 104, 220 ±11) prodtuced endocarditis in 12 of' 18 rabbits after injection of 107 organisms. Another isolate of the same

The factors responsible for blood-brain barrier (BBB) injury during bacterial meningitis are incompletely defined. We evaluated the role of Haemophilus influenzae type b (Hib) lipopolysaccharide (LPS) in the alteration of blood-brain barrier permeability (BBBP) in an adult, normal and leukopenic, rat model of meningitis. Intracisternal inoculation of Hib LPS resulted in (a) dose-dependent increases in BBBP from 2 pg to 20 ng, with significant attenuation in the peak response after challenge with 500 ng and 1 ,ug, (b) time-dependent increases in BBBP, with a delayed onset of at least 2 h, maximum alteration at 4 h, and complete reversal at 18 h; (c) greater BBBP than after challenge with the live parent strain; (d) and a close correlation (r = 0.86) between CSF pleocytosis and BBBP at 4 h. The LPS effect was significantly inhibited by preincubation with Polymyxin B and neutrophil acyloxyacyl hydrolase, however two different oligosaccharide-specific monoclonal antibodies did not inhibit activity. No change in BBBP after inoculation with Hib LPS occurred in leukopenic rats. Hib LPS, in the setting of an intact leukocyte response, exerts profound effects on BBBP.