REVIEW

Bacterial Meningitis: Recent Advances in Pathophysiology and Treatment Allan R. Tunkel, MD, PhD; Brian Wispelwey, MD; and W. Michael Scheld, MD

Purpose: To review recent advances in the understanding of pathogenic and pathophysiologic mechanisms underlying bacterial meningitis that may lead to the development of adjunctive strategies for treating this disorder. Data Identification: Studies published from 1975 to 1989 were identified using Index Medicus and by reviewing the bibliographies of identified articles. Study Selection: We reviewed the experimental and human studies evaluating pathogenesis, pathophysiology, and antimicrobial treatment of bacterial meningitis, as well as those reviews that have contributed to our understanding of meningitis. Data Extraction: We evaluated the data on the pathogenesis, pathophysiology, and treatment of bacterial meningitis and considered in depth the information from animal models that may have potentially important applications in the treatment of human disease. Results of Data Synthesis: Penicillin and ampicillin remain the drugs of choice for meningitis caused by Streptococcus pneumoniae and Neisseria meningitidis. The third-generation cephalosporins have revolutionized the treatment of gram-negative bacillary meningitis; one such agent, ceftazidime, is also useful for treating Pseudomonas aeruginosa meningitis. Modification of subarachnoid space inflammation by anti-inflammatory agents may lessen many of the pathophysiologic consequences of bacterial meningitis. A recent study of adjunctive dexamethasone therapy in infants and children with bacterial meningitis showed that the incidence of long-term neurologic sequelae was lower in the corticosteroid group. Conclusion: Future therapy for bacterial meningitis will use recent developments in the understanding of pathogenic and pathophysiologic mechanisms underlying this disease. Additional studies using monoclonal antibodies against specific virulence factors and investigations into the production of inflammatory cytokines in response to bacterial cell products may lead to additional treatments that decrease the high morbidity and mortality in patients with bacterial meningitis.

Annals of Internal Medicine. 1990;112:610-623. From the University of Virginia School of Medicine, Charlottesville, Virginia. For current author addresses, see end of text. 610

Oacterial meningitis continues to be an important cause of morbidity and mortality despite the availability of effective bactericidal antibiotics. Mortality rates associated with the three commonest causative agents of bacterial meningitis, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae, were 6.0%, 10.3%, and 26.3%, respectively, in the United States from 1978 to 1981 (1). Mortality rates have not changed during the last 30 years, and in children and adults who survive bacterial meningitis there is a high incidence of neurologic sequelae (2, 3). Recently, studies in new areas have increased our understanding of the pathogenic and pathophysiologic mechanisms underlying bacterial meningitis and have paved the way for new developments in the treatment of this disorder. In this review, we focus on recent advances in the understanding of the pathogenesis and pathophysiology of bacterial meningitis; such advances may eventually help in decreasing the refractory mortality and unacceptable morbidity from this disease. Studies of bacterial meningitis published from 1975 to 1989 were identified in Index Medicus and by reviewing bibliographies of identified articles. Experimental and human studies evaluating the pathogenesis, pathophysiology, and treatment of bacterial meningitis were analyzed by three independent observers. Data were then evaluated and applications of information gained from animal models are discussed in relation to the treatment of human disease.

Pathogenesis and Pathophysiology Most recent studies of the pathogenic and pathophysiologic mechanisms underlying bacterial meningitis have used animal models. In the infant rat model of experimental meningitis, animals developed meningitis after intranasal challenge with a sufficient inoculum of H. influenzae type b (4). This model most closely simulates the presumed pathogenesis of H. influenzae meningitis, with an initial nasopharyngeal focus leading to hematogenous dissemination and an age-dependent susceptibility to bacterial meningitis. This infant rat model has been particularly useful in delineating the early pathogenic sequences in H. influenzae meningitis, including the determinants of nasopharyngeal colonization, translocation into the bloodstream, intravascular survival, and the factors responsible for meningeal invasion. The experimental models of meningitis in adult animals must rely on the direct intracisternal inoculation of bacteria for the initiation of infection (5, 6) because adult animals will not develop meningitis after either intranasal or intravenous challenge with live organisms.

© 1990 American College of Physicians

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

Figure 1. Pathogenic steps leading to the initiation of bacterial meningitis.

Using adult rabbits or rats, these models can reliably produce lethal infections with a predictable time course, but because they bypass the natural dissemination of bacteria from the blood to cerebrospinal fluid (CSF), the pathogenesis is artificial. These models, however, have proven extremely useful for the study of the pathophysiologic consequences of bacterial meningitis once organisms have reached the subarachnoid space and for evaluating the relative efficacy of the antimicrobial therapies for bacterial meningitis (7). Figure 1 is a simplified schematic showing the most important pathogenic steps required for the initiation of bacterial meningitis. The hypothetical scheme shown in Figure 2 depicts the pathophysiologic mechanisms once invasion of the subarachnoid space has occurred. The following sections review the available evidence supporting each step shown in the two figures. The relevance of these observations to the optimal therapy for bacterial meningitis is considered in the last section of the review.

for invasive H. influenzae disease. Elegant experiments using laboratory transformants have shown that although all encapsulated strains (types a through f) of H. influenzae have the potential for systemic invasion after intraperitoneal inoculation of rats, type b strains are the most virulent and unencapsulated strains are not invasive (13, 14). In addition, only H. influenzae type b strains are invasive after intranasal inoculation of these animals, indicating that type b strains have unique virulence characteristics that correlate with a propensity for invasive disease in humans. Indeed, bactericidal antibodies directed against the capsule of type b isolates usually protect against invasive disease caused by these organisms (15). Antibodies against other surface properties (for example, lipopolysaccharide and various outer membrane proteins) of H. influenzae will also confer protection upon repeated challenge with the organism in experimental animal models (16-19). However, the precise roles of the bacterial capsule, lipopolysaccharide, and outer membrane proteins in mucosal translocation and bloodstream invasion by meningeal pathogens remain incompletely defined. Pathogens such as Neisseria meningitidis possess specialized protein surface appendages called fimbriae, or pili, which have been found in 80% of primary meningococcal isolates from nasopharyngeal carriers and from the CSF of patients with meningococcal meningitis (20). The meningococcus binds, using its fimbriae, to cell-surface receptors in the nasopharynx (21) and is then transported across specialized nasopharyngeal cells within a phagocytic vacuole (22, 23); this series of events appears to be essential for invasive meningococcal disease.

Mucosal Colonization, Systemic Invasion, and Bacteremia A critical step in the initiation of meningitis is the host acquisition of a new organism by nasopharyngeal colonization. Mucosal attachment is mediated by certain microbial virulence factors; specifically, specialized bacterial cell-surface components. Among the 84 known serotypes of pneumococci, 18 are responsible for 82% of the cases of bacteremic pneumococcal pneumonia (8, 9), with a close correlation between bacteremic subtypes and those implicated in meningitis (10-12). The presence of capsule is also the prime virulence factor

Figure 2. Hypothetical scheme of the pathophysiologic consequences of subarachnoid space inflammation from Haemophilus influenzae lipopolysaccharide (LPS). IL-1 = interleukin-1; TNF = tumor necrosis factor; PGE2 = prostaglandin E2; BBB = blood-brain barrier.

15 April 1990 • Annals of Internal Medicine • Volume 112 • Number 8 Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

611

Once the mucosal barrier is crossed, the bacteria have access to the bloodstream and must overcome additional host defenses to survive and invade the meninges. The most important bacterial virulence factor in this regard is encapsulation, which, by effectively inhibiting neutrophil phagocytosis and resisting classical complement pathway bactericidal activity, enhances bloodstream survival and intravascular bacterial replication. The common meningeal pathogens are all encapsulated. For example, over 84% of cases of neonatal meningitis caused by Escherichia coli are caused by strains bearing the Kl capsular antigen, and, in the absence of Kl-specific host antibody, these organisms are profoundly resistant to phagocytosis (24). The ability of this antigen to enhance the invasion of the central nervous system by bacteremic E. coli strains is poorly understood. Fortunately, there are host defense mechanisms to counteract the antiphagocytic capacity of bacterial capsule. The alternative complement pathway is directly activated by the capsular polysaccharide of S. pneumoniae; thus, cleaving of C3 occurs, with attachment of C3b to the bacterial surface, which facilitates opsonization, phagocytosis, and the intravascular clearance of the organism (25). This pathway is also activated by pneumococcal cell walls, resulting in the generation of C5a which leads to leukocyte margination and chemotaxis (26), and by H. influenzae type b (27). Impairment of the alternative complement pathway in patients with sickle cell anemia (28) may predispose these patients to invasive disease. The terminal complement components (C5, C6, C7, C8, and perhaps C9) are especially important in host defense against meningococcal infections, and congenital or acquired deficiencies in any of these terminal components may predispose patients to recurrent or chronic infections with N. meningitidis (29). Finally, it is important to emphasize that bacterial meningitis is a dynamic process and the local suppurative process in the central nervous system may lead to continued bacteremia and a nearly constant reseeding of the CSF. After the intracisternal inoculation of pneumococci in dogs, the transport of bacteria from CSF to blood has been found to occur only after active bacterial multiplication within the CSF and before the height of the febrile response or CSF pleocytosis (30); presumably, transport occurs through the arachnoid villi, which contain "pores" large enough to accommodate bacteria. Blood-Brain Barrier Invasion and Survival in the Subarachnoid Space The mechanism underlying bacterial traversal across a presumably intact blood-brain barrier is largely unknown. Previous studies (4, 31) in experimental animals suggested that the route of invasion of H. influenzae type b into the CSF from the bloodstream was through the dural venous sinus system (4) or that a nonspecific, sterile, focal inflammation above the cribiform plate facilitated central nervous system invasion at this site (31). Additional experiments on the pathogenesis of blood-brain barrier penetration of H. influenzae in infant primates have suggested that the choroid plexus is the first site of central nervous system inflammation 612

(32). Cells in the choroid plexus and cerebral capillaries may possess specific receptors for adhesion of bacteria, thus allowing transport of bacteria into CSF. The adhesion of certain bacteria to epithelial or endothelial cell surfaces may be mediated by fimbriae or other cellsurface components (33). The S fimbriae of E. coli have been shown to mediate adhesion of this organism to the luminal surfaces of the cerebrovascular endothelium and to the epithelium lining the choroid plexus and brain ventricles in infant rats (34). This binding is almost totally inhibited by the trisaccharide receptor analogue of S fimbriae and by neuraminidase treatment of the tissue which removes sialic-acid-containing residues. Fimbrial phase variation, to the nonfimbriated form, may then be necessary for the bacteria to pass through the vascular endothelium (35); this concept requires further study. Other microbial virulence factors may also be important for central riervous system invasion by bacteria. These include the polysaccharide capsule of H. influenzae type b (13) and the lipopolysaccharides of H. influenzae and N. meningitidis (36). The role of outer membrane proteins is less clear, although it has recently been suggested that H. influenzae strains with outer membrane protein subtype lc caused more episodes of meningitis and fewer cases of epiglottitis than did strains with subtype 1 (37), possibly as a result of the ability of each subtype to release lipopolysaccharide in vivo under appropriate conditions. The precise roles of bacterial encapsulation, lipopolysaccharide phenotype, and outer membrane protein subtypes in central nervous system invasion are unclear and deserve further intensive study. Once bacteria enter the subarachnoid space, host defense mechanisms are inadequate to control the infection. Assays for complement components in normal CSF are usually negative or show only minimal concentrations (38-40). Meningeal inflammation leads to increased (although low) concentrations of various complement components in CSF. This relative complement deficiency may be of critical importance because specific antibody and complement are essential for opsonization of the encapsulated meningeal pathogens and efficient phagocytosis (41, 42). An analysis of CSF samples from 18 patients with various forms of meningitis showed absent or barely detectable opsonic and bactericidal activity (39). Many factors may be responsible for the low complement concentrations in purulent CSF, including insufficient traversal across the bloodbrain barrier, variable subarachnoid space inflammation, enhanced clearance or removal from the subarachnoid space, low production rates in the central nervous system, or degradation at the site of infection. Leukocyte proteases released into the CSF during bacterial meningitis may degrade complement components at the site of infection. In the rabbit model of experimental pneumococcal meningitis, intracisternal inoculation of a nonspecific protease inhibitor, phenyl-methyl-suphonylfluoride, led to a decline in CSF pneumococcal concentrations (43), presumably by inhibiting neutrophilic protease-mediated complement destruction. The immunoglobulin concentrations in normal CSF are also low (blood to CSF ratio of immunoglobulin G is

15 April 1990 • Annals of Internal Medicine • Volume 112 • Number 8

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

800:1). This relative lack of CSF antibody, combined with the local complement deficiency, contributes to the regional host immunodeficiency in CSF during bacterial meningitis. However, local antibody synthesis in the CSF does occur in some forms of infectious meningitis and encephalitis and in patients infected with the human immunodeficiency virus (HIV) (44-46), although immunoglobulin concentrations remain low when compared with simultaneous serum concentrations (47, 48). One of the major hallmarks of subarachnoid space inflammation during meningitis is a CSF neutrophilic pleocytosis. The mechanism of leukocyte traversal across the blood-brain barrier is unknown, but infected CSF is chemotactic for leukocytes (49, 50). Experimental models of pneumococcal meningitis have shown C5a as one chemotactic factor present in CSF (51, 52), and C5a may enhance neutrophil adhesion to endothelial cells (53). Neutrophil adherence to vascular endothelial cells is also enhanced by pretreatment of the endothelial cells with lipopolysaccharide (54, 55) and inflammatory cytokines such as interleukin-1 or tumor necrosis factor (54, 56, 57) through induction of several cell-surface glycoprotein molecules, including endothelial leukocyte adhesion molecule-1 (58). The above studies were conducted in vascular endothelial cells from tissues other than brain (59), and it remains to be determined whether similar mechanisms underly the adhesion between neutrophils and cerebral vascular endothelium. Along these lines, a recent study (60) using a monoclonal antibody directed against the epitopes of the adhesion receptors of leukocytes (CD 18 family) has suggested that these receptors are necessary for the movement of leukocytes across the blood-brain barrier in response to microbial products inoculated directly into CSF (60). The relative contribution of the neutrophil to host defenses in purulent CSF remains unclear because inflammation in the subarachnoid space may have both beneficial and detrimental effects. Low CSF leukocyte concentrations are associated with a high mortality from bacterial meningitis in both experimental animal models (61, 62) and in humans (63-65); however, other studies do not support these observations. The mean survival in leukopenic dogs after intracisternal inoculation of pneumococci was actually longer when compared with controls that had a normal peripheral leukocyte concentration, although the small number of animals studied precluded statistical analysis (66). When rabbits rendered leukopenic by the intravenous injection of nitrogen mustard before pneumococcal challenge were compared with normal rabbits, no differences were seen in the bacterial growth rate; final bacterial concentrations in CSF; and CSF protein, glucose, and lactate concentrations (67). The magnitude of the resultant bacteremia, however, was approximately 100-fold greater in the leukopenic animals, suggesting that neutrophils either retard traversal from CSF to blood or enhance elimination from the bloodstream at extraneural sites. Therefore, bacterial eradication from the CSF during the early stages of meningitis may be leukocyte-independent, supporting the concept of a regional host immunodeficiency in this disease.

Subarachnoid Space Inflammation Although the bacterial strains that most commonly produce meningitis are all encapsulated, capsular polysaccharides are remarkably noninflammatory. Using the bacterial cell-surface components of S. pneumoniae, investigators induced CSF inflammatory changes in rabbits by the intracisternal inoculation of both encapsulated and unencapsulated S. pneumoniae, heat-killed unencapsulated pneumococci, and pneumococcal cell walls; however, no inflammatory changes were seen after the intracisternal injection of heat-killed encapsulated strains or isolated pneumococcal capsular polysaccharides (68). The inflammation was also induced by the intracisternal inoculation of the major components of the pneumococcal cell wall, peptidoglycan and ribitolphosphate teichoic acid (69), indicating that the generation of free pneumococcal cell wall components in the CSF during treatment with antibiotics that are bacteriolytic as well as bactericidal may contribute to increased inflammation in the subarachnoid space. Meningeal inflammation has also been induced in rabbits and rats by intracisternal inoculation of H. influenzae type b lipopolysaccharide (70, 71). The inflammation is blocked by polymyxin B, a cationic antibiotic that neutralizes the bioactivities of lipopolysaccharide by binding to the lipid A region of the molecule, and by neutrophil acyloxyacyl hydrolase, which causes partial deacylation of the lipopolysaccharide. Preincubation of the lipopolysaccharide with a monoclonal antibody directed against epitopes in the oligosaccharide region of the lipopolysaccharide did not reduce the inflammatory potential of this molecule after intracisternal inoculation. Similar results were seen after intracisternal inoculation of H. influenzae outer membrane vesicles (72, 73), which may represent a relevant nonreplicating vehicle in which H. influenzae lipopolysaccharide is released into CSF. The mechanism by which pneumococcal cell walls or H. influenzae lipopolysaccharide elicit inflammation in CSF has not yet been defined, although evidence is accumulating that these bacterial cell components stimulate the release of inflammatory cytokines, such as interleukin-1, tumor necrosis factor (74-77), or prostaglandins (78, 79), into the central nervous system. In rabbits, the intracisternal inoculation of living pneumococci or pneumococcal cell walls increases CSF prostaglandin E2 concentrations, an increase that correlates with the number of leukocytes in CSF (80). Several other studies (81-83), presented in abstract form, have shown that pneumococcal cell wall components induce interleukin-1 production by human monocytes (81) and that the intracisternal inoculation of rats with H. influenzae lipopolysaccharide produces elevated CSF concentrations of both interleukin-1 and tumor necrosis factor (82). Elevated CSF concentrations of tumor necrosis factor have also been seen in rabbits after the intracisternal inoculation of H. influenzae lipopolysaccharide (83). The presence of tumor necrosis factor in CSF may be specific for bacterial meningitis. A recent study (84) detected increased CSF concentrations of tumor necrosis factor in both mice and human subjects with bacterial, but not viral, meningitis. The source of

15 April 1990 • Annals of Internal Medicine • Volume 112 • Number 8

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

613

these inflammatory cytokines is unclear, but vascular endothelial cells can produce interleukin-1 in response to stimulation with either lipopolysaccharide or tumor necrosis factor (85-87). A hypothetical scheme depicting the pathophysiologic consequences of subarachnoid space inflammation due to H. influenzae lipopolysaccharide is shown in Figure 2. A similar scheme of events may be possible after the intracisternal inoculation of pneumococcal cell walls. Alterations in the Blood-Brain Barrier Bacterial meningitis increases the permeability of the blood-brain barrier to various substances, including proteins, hexoses, and ions. The barrier separates the CSF and the brain from the intravascular compartment and acts as a regulatory interface, with functions including active transport, facilitated diffusion, aqueous secretion forming CSF, and, most importantly, maintenance of homeostasis within the central nervous system (88-90). The major sites of the blood-brain barrier are the arachnoid membrane, choroid plexus epithelium, and the endothelial cells of the cerebral micro vasculature. Previous morphologic studies (91) have shown an intact arachnoid membrane in animals with experimental meningitis. Therefore, the increased permeability observed in patients with bacterial meningitis occurs at the level of the choroid plexus epithelium or the cerebral microvascular endothelium, or both. Our laboratory has used an adult rat model to study functional and morphologic alterations in the blood-brain barrier during meningitis after the intracisternal inoculation of encapsulated S. pneumoniae, H. influenzae, or E. coli (6). Increased permeability to radiolabeled albumin was seen with each pathogen tested and correlated with an early and sustained increase in pinocytotic vesicle formation as well as with a progressive increase in separation of intercellular tight junctions in the cerebral microvascular endothelium. The effect of leukocytes on the increased blood-brain barrier permeability was assessed in animals rendered leukopenic after the intraperitoneal injection of cyclophosphamide (92). Both normal and leukopenic rats had increased blood-brain barrier permeability after the intracisternal inoculation of either encapsulated or unencapsulated strains of H. influenzae, although permeability was greater after challenge with the encapsulated strain and the presence of CSF leukocytes augmented changes in permeability late in the disease course. We concluded that bacterial surface encapsulation is not essential for blood-brain barrier injury but facilitates its progression by allowing organisms to escape local host clearance mechanisms. Given the relatively innocuous nature of capsular polysaccharide in the induction of CSF pleocytosis and alterations in the blood-brain barrier, we next examined blood-brain barrier injury after challenge with purified H. influenzae lipopolysaccharide (71). The intracisternal inoculation of lipopolysaccharide led to increased blood-brain barrier permeability, and this effect was significantly inhibited by preincubation with either polymyxin B or neutrophil acyloxyacyl hydrolase but not by monoclonal antibodies to the oligosaccharide portion of the molecule. No change in blood-brain barrier perme614

ability occurred after lipopolysaccharide inoculation of leukopenic rats. Equivalent changes in blood-brain barrier permeability were obtained after the intracisternal inoculation of H. influenzae outer membrane vesicles (73), which may act as vehicles for delivery of lipopolysaccharide to central nervous system sites of action. Specific inflammatory cytokines may also produce blood-brain barrier alterations. The intracisternal inoculation of rats with human recombinant interleukin-1 led to increased blood-brain barrier permeability (93), and this response was significantly inhibited by preincubation of the interleukin-1 with a monoclonal antibody to interleukin-1 but was unaffected by preincubation of interleukin-1 with polymyxin B. The intracisternal inoculation of human recombinant tumor necrosis factor alone produced no significant changes in permeability. It appears, however, that interleukin-1 and tumor necrosis factor may act synergistically in the central nervous system because the inoculation of submaximal doses of interleukin-1 combined with tumor necrosis factor (at concentrations that do not independently increase CSF traversal of albumin) enhanced blood-brain barrier permeability (Quagliarello VJ, Wispelwey B, Long WJ, Scheld WM. Unpublished observations). Increased Intracranial Pressure and Alterations in Cerebral Blood Flow The increased intracranial pressure often seen in patients with bacterial meningitis most probably results from a constellation of factors and may eventually result in life-threatening cerebral herniation (94). The cerebral edema that occurs during meningitis may be vasogenic, cytotoxic, or interstitial in origin. Vasogenic cerebral edema is a consequence of increased bloodbrain barrier permeability. Cytotoxic cerebral edema is a form of brain swelling that may occur secondary to the release of toxic factors from neutrophils and possibly bacteria. Membranes of brain cells are altered (particularly by arachidonic acid metabolites), promoting increased intracellular water content, potassium leakage, glucose use, and lactate production (95, 96). In addition, the secretion of antidiuretic hormone contributes to the pathogenesis of cytotoxic edema by producing hypotonicity of brain parenchymal extracellular fluid and increasing the permeability of the brain to water (97). Cerebrospinal fluid concentrations of antidiuretic hormone are increased in children with bacterial meningitis (98). Finally, interstitial edema occurs from the obstruction of CSF flow, as in hydrocephalus (99). Bacterial meningitis exerts profound effects on blood vessels that course through the subarachnoid space, producing a vasculitis that results in luminal narrowing and thrombus formation with the potential for ischemia or infarction of brain (100). Vasculitis in subarachnoid space vessels can nearly always be shown angiographically in children with bacterial meningitis early in the disease course and usually resolves with appropriate antimicrobial therapy. With involvement of large arteries at the base of the brain, however, neurologic complications, including hemiparesis and quadriparesis, are usually severe and permanent, appearing 3 to 5 days after the onset of illness (101). Cerebral vasospasm may

15 April 1990 • Annals of Internal Medicine • Volume 112 • Number 8

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

also occur, secondary to the elaboration of humoral factors within the CSF or blood vessel wall (102). Septic cortical thrombophlebitis of the major draining veins or dural sinuses often leads to thrombosis, secondary brain infarction, focal neurological deficits, and seizure activity. The CSF outflow resistance, determined by factors inhibiting traversal of CSF from the subarachnoid space to the major dural sinuses, is markedly elevated during bacterial meningitis (103). Despite rapid sterilization of the CSF after 8 hours of penicillin therapy in rabbits with pneumococcal meningitis, CSF outflow resistance remained elevated for up to 2 weeks. These experimental results likely correlate with the slow rate of resolution of clinical symptoms during meningitis, the development of hydrocephalus, and, potentially, alterations in intracranial pressure and the development of interstitial cerebral edema. Recent studies in animal models have examined these concepts in greater detail. The brain water content (indicative of cerebral edema if elevated), CSF lactate concentration, and CSF pressure were determined in rabbits with experimental pneumococcal meningitis (104). All three variables were increased in infected animals. Treatment with ampicillin sterilized the CSF rapidly and normalized the intracranial pressure and brain water content, but the CSF lactate concentration remained elevated. The bacterial cell components responsible for producing brain edema were studied in an experimental model of E. coli meningitis (105) in which infected animals were treated with antimicrobial agents. Cefotaxime, but not chloramphenicol, induced a marked rise in CSF endotoxin concentrations associated with an increase in brain water content. These effects were neutralized by either polymyxin B or a monoclonal antibody against lipid A, indicating that increased endotoxin concentrations in CSF may be associated with brain edema. The role of the leukocyte in these processes was recently examined in an experimental model of pneumococcal meningitis (106) in which it appeared that leukocytes may not be the only factor essential for the development of brain edema, increased intracranial pressure, or changes in CSF concentrations of lactate or protein during the first 24 hours after infection. This area is controversial, however, and additional studies will be required to precisely define the role of CSF leukocytes in cerebral edema and the increased intracranial pressure seen in the advanced stages of meningitis. Alterations in cerebral blood flow have been shown in bacterial meningitis. Cerebral blood flow was measured in infant rhesus monkeys with severe H. influenzae meningitis (32). It was found that certain areas of the cortex (postcentral, temporal, and occipital areas) were hypoperfused relative to the hypothalamus and midbrain, but that the brain stem was hyperperfused. Decreases in cerebral blood flow were also positively associated with diminished blood pressure in the rabbit model of experimental pneumococcal meningitis (107). In eight human infants with bacterial meningitis who were less than 1 year old, the four older infants (3 to 10 months old) had reduced cerebral blood flow velocity when the intracranial pressure was at its peak, and, as

intracranial pressure decreased with therapy, the cerebral blood flow velocity increased (108). In the four neonates (5 to 30 days old), no changes in cerebral blood flow velocity were seen during bacterial meningitis. This diminished cerebral blood flow may result in persistent, and perhaps irreversible, damage to the central nervous system. Treatment Principles of Antimicrobial Therapy The choice of an antimicrobial agent to treat patients with bacterial meningitis depends on many factors. We have recently reviewed in detail the basic therapeutic principles in the treatment of bacterial meningitis (7), and only certain aspects are discussed here. One factor is antibiotic "penetration" into CSF. All beta-lactam antibiotics penetrate into CSF poorly (about 0.5% to 2% of peak serum concentrations) when the blood-brain barrier is normal (109), but penetration is enhanced in the presence of meningeal inflammation. Penetration is also enhanced by a high lipid solubility (110), a low degree of protein binding in serum (111), a low molecular weight (109), and a low degree of ionization at physiologic pH. A second major factor is the bactericidal efficacy of the antibiotic in purulent CSF. For example, the acidic pH of purulent CSF inhibits the bactericidal activity of the aminoglycosides (112). Other drugs may also influence antibiotic activity in purulent CSF. Chloramphenicol has been shown to inhibit the early bactericidal effect of penicillin against pneumococci in vitro and in experimental canine meningitis in vivo (113). Antagonism was most apparent when the administration of chloramphenicol preceded that of penicillin. In addition, chloramphenicol is bacteriostatic in vitro against most gram-negative aerobic bacilli and neutralized the bactericidal activity of gentamicin alone in a study (112) of experimental Proteus mirabilis meningitis in rabbits. This antagonism has been observed in clinical studies of patients with meningitis caused by organisms in the Enterobacteriaceae family; in these studies, the case fatality rate was highest (83%) when chloramphenicol (usually given with an aminoglycoside) was included in the therapeutic regimen (114). Ample evidence, both from experimental models and clinical trials in humans, reaffirms that effective therapy for bacterial meningitis depends on achieving optimum bactericidal activity in CSF. Thus, rapid killing of bacteria is seen only when CSF concentrations of beta-lactams or aminoglycosides exceed the minimal bactericidal concentration of the isolated strain by about 10- to 20-fold (115-117). A third factor is the mode of antibiotic administration. Both intermittent bolus and continuous administration of penicillin G were equally efficacious in a rabbit model of experimental pneumococcal meningitis (118). Serum concentrations achieved by either method were similar to those achieved in humans receiving standard parenteral regimens, but CSF penicillin concentrations after bolus administration were higher. When intermittent doses of ampicillin that achieved CSF concentrations below the minimal bactericidal concentration

15 April 1990 • Annals of Internal Medicine • Volume 112 • Number 8

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

615

Table 1. Antimicrobial

Therapy

for Bacterial

Organism Neisseria

Alternative Therapies

Standard Therapy meningitidis

Streptococcus

penicillin G or ampicillin

pneumoniae

penicillin G or ampicillin

Haemophilus influenzae (betalactamase-negative) H. influenzae (beta-lactamasepositive) Enterobacteriaceae Pseudomonas

aeruginosa

Streptococcus

agalactiae

Listeria

Meningitis

monocytogenes

Staphylococcus aureus (methicillin-sensitive) Staphylococcus aureus (methicillin-resistant) Staphylococcus epidermidis

ampicillin Third-generation cephalosporin* Third-generation cephalosporin* ceftazidime (plus an aminoglycoside) penicillin G or ampicillin (plus an aminoglycoside) ampicillin or penicillin G (plus an aminoglycoside) nafcillin or oxacillin

Third-generation cephalosporin*; cefuroxime; chloramphenicol Third-generation cephalosporin*; cefuroxime; chloramphenicol Third-generation cephalosporin*; cefuroxime; chloramphenicol chloramphenicol; cefuroxime Extended spectrum penicillin t plus an aminoglycoside; aztreonam %\ quinolonest Extended spectrum penicillint plus an aminoglycoside; aztreonam %\ imipenem %\ quinolonest Third-generation cephalosporin*; chloramphenicol trimethoprim-sulfamethoxazole vancomycin

vancomycin

trimethoprim-sulfamethoxazole; quinolonest

vancomycin (plus rifampin)

teicoplanin %\ daptomycin X

* Cefotaxime, ceftizoxime, or ceftriaxone have received the most scrutiny and are recommended. Cefoperazone or moxalactam are not indicated. Ceftazidime should be reserved for suspected or proven Pseudomonas aeruginosa meningitis. t Piperacillin or azlocillin. t The effectiveness of these antibiotics in bacterial meningitis has not been clearly documented.

were administered, a significant ''post-antibiotic'' effect was seen in vivo, characterized by a continued decline or stabilization of pneumococcal concentrations in CSF; this effect may contribute to the successful therapeutic results obtained with intermittent antibiotic administration. Specific Antimicrobial Agents The choice of antimicrobial regimens for specific forms of bacterial meningitis depends on the clinical recognition that meningitis is present, analysis of the cerebrospinal fluid, severity of illness, and the underlying disease status of the patient. Our recommendations for standard regimens to be used against specific pathogens are shown in Table 1. In patients with presumed bacterial meningitis and a negative CSF Gram stain or when there may be a delay in CSF examination, empiric antibiotic therapy should be started promptly based on the patient's age, probable infecting organisms, and underlying disease status (Table 2). Recommended dosages of antimicrobial agents are shown in Table 3. Table 2. Empiric

Therapy

Age 0 to 4 weeks 4 to 12 weeks 3 months to 18 years 18 to 50 years Older than 50 years

for Purulent

For bacterial meningitis caused by S. pneumoniae, penicillin G and ampicillin are equally efficacious. In the past, pneumococci were uniformly susceptible to penicillin in vitro with minimal inhibitory concentrations less than or equal to 0.06 ^g/mL. Reports (119-122) from several centers have now documented relatively resistant pneumococci (penicillin minimal inhibitory concentrations of 0.1 to 1.0 /ig/mL) as well as highly resistant strains (minimal inhibitory concentrations > 2 /xg/mL). The mechanism underlying penicillin resistance in pneumococci involves alterations in the structure and molecular size of penicillin-binding proteins (123). A surprising degree of variation exists in the number and molecular size of the penicillin-binding proteins in these strains, and, in addition, the penicillin-binding protein patterns are genetically stable, which allows these proteins to be used to identify particular isolates for epidemiologic purposes (124). The patient with bacterial meningitis caused by penicillin-resistant pneumococci presents a problem because sufficient CSF concentrations of penicillin are difficult to achieve with current

Meningitis*

Common Microorganisms

Therapy

Escherichia coli, group B streptococci, Listeria monocytogenes E. coli, group B streptococci, L. monocytogenes, Haemophilus influenzae, Streptococcus pneumoniae H. influenzae, Neisseria meningitidis, S. pneumoniae S. pneumoniae, N. meningitidis S. pneumoniae, N. meningitidis, L. monocytogenes, gram-negative bacilli

ampicillin plus a third-generation cephalosporint; or ampicillin plus an aminoglycoside ampicillin plus a third-generation cephalosporin Third-generation cephalosporin; or ampicillin plus chloramphenicol penicillin G or ampicillin ampicillin plus a third-generation cephalosporin

* Patients without underlying illness. t Cefotaxime, ceftizoxime, or ceftriaxone (most studies have evaluated only cefotaxime or ceftriaxone). 616

15 April 1990 • Annals of Internal Medicine • Volume 112 • Number 8

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

regimens. In view of recent trends in the resistance of S. pneumoniae to penicillin, we recommend susceptibility testing of all CSF isolates. If the organism is relatively resistant to penicillin, then a third-generation cephalosporin (for example, cefotaxime or ceftriaxone) should be used. When highly resistant strains (minimal inhibitory concentration > 2 /xg/mL) are isolated, vancomycin is the antimicrobial agent of choice. For empiric treatment of presumed bacterial meningitis, choice of an antibiotic should be guided by the prevalence of local resistance patterns of pneumococci, and a thirdgeneration cephalosporin should be used if relative resistance is suspected, proven, or likely (125). Penicillin or ampicillin is also effective therapy for meningitis caused by N. meningitidis. However, modification of this recommendation may become necessary. Rare beta-lactamase-producing strains of meningococci have been reported (126), and these strains are absolutely resistant to penicillin (minimal inhibitory concentration > 250 /xg/mL). In addition, meningococcal strains that are relatively resistant to penicillin (minimal inhibitory concentration range, 0.1 to 0.7 fjug/mL) have been increasingly reported from several areas, particularly Spain (127, 128). Most of these strains are in serogroup B (11 of 16) or serogroup C (4 of 16), as defined in one Spanish study (127). These strains do not produce beta-lactamase and the relative resistance appears to be mediated by a reduced affinity for penicillinbinding protein 3 (129). Similar trends have been reported from the United Kingdom (130) and other areas. However, because most patients harboring these strains have recovered with standard penicillin therapy, the clinical significance of this resistance is unclear. The therapy of H. influenzae type b meningitis has been complicated by the increasing prevalence of betalactamase-producing strains, first detected in 1974 and now accounting for approximately 25% of isolates overall in the United States in 1981 (1, 131), although geographic variability does exist. Based on this resistance pattern, the recommendation for empiric antimicrobial treatment of patients with suspected H. influenzae meningitis was changed more than a decade ago from ampicillin alone to ampicillin plus chloramphenicol. Chloramphenicol resistance is rare (< 1%) in the United States (132); however, greater than 50% of isolates from Spain are chloramphenicol resistant (133, 134), a finding which led the investigators to recommend cefotaxime as the initial drug of choice for suspected or proven H. influenzae meningitis. Cefotaxime or ceftriaxone has been shown to be as efficacious as ampicillin plus chloramphenicol in the treatment of H. influenzae meningitis (135, 136), and the American Academy of Pediatrics has now endorsed the use of these "new cephalosporins'' as the initial empiric therapy for children with bacterial meningitis (137). Although cefuroxime, a second-generation cephalosporin, initially appeared to be as efficacious as ampicillin plus chloramphenicol for the treatment of H. influenzae meningitis, recent reports (138) of a delay in sterilization of CSF and the development of epiglottitis while on therapy suggest caution. We prefer a third-generation agent to cefuroxime for empiric treatment of H. influenzae meningitis regardless of the age group.

Table 3. Recommended Doses of Antibiotics for Bacterial Meningitis in Adults with Normal Renal Function Antibiotic penicillin G ampicillin nafcillin, oxacillin chloramphenicol cefotaxime ceftizoxime ceftriaxone ceftazidime vancomycin gentamicin, tobramycin amikacin

Daily Dose (per 24 hours)

Dosing Interval, h

20 to 24 million units 12 grams 9-12 grams 4 to 6 grams* 12 grams 6 to 9 gramst 4 to 6 gramst 6 to 12 grams§ 2 grams 3 to 5 mg/kg body weight 15 mg/kg body weight

4 4 4 6 4 8 12 8 12 8 8

* Higher dose recommended if used for pneumococcal meningitis. t Limited data exist; higher dose recommended pending further study. X Actual dose studied was 50 mg/kg body weight every 12 hours. § Not enough patients studied to make firm recommendations.

The treatment of gram-negative bacillary meningitis in adults has been revolutionized by the development of the third-generation cephalosporins. Cure rates of 78% to 94% have been achieved with these new agents (139, 140), as compared with mortality rates of 40% to 90% seen with previous standard therapy, usually an aminoglycoside with or without chloramphenicol (114). Meningitis caused by Pseudomonas aeruginosa represents a special situation because reported mortality rates are approximately 84% (114). A new third-generation cephalosporin, ceftazidime, displays potent antipseudomonal activity in vitro and penetrates well into CSF in the presence of meningeal inflammation (141, 142). Although clinical experience is scant, 19 of 24 patients treated with ceftazidime alone or in combination with a parenteral aminoglycoside were cured (143). Proof that this regimen is superior in efficacy to the combination of an antipseudomonal penicillin (for example, piperacillin or azlocillin) plus an aminoglycoside is lacking. However, because of the rarity of P. aeruginosa meningitis, a prospective, controlled trial is not feasible, and, therefore, we currently recommend ceftazidime and an aminoglycoside as the therapy of choice for P. aeruginosa meningitis. Intrathecal or intraventricular aminoglycoside therapy should be considered if there is no response to systemic therapy. These modes of drug administration, however, are rarely needed for treating gram-negative bacillary meningitis at the present time. Finally, ciprofloxacin was found to be as efficacious as the combination of ceftazidime and tobramycin in the rabbit model of experimental P. aeruginosa meningitis (144). Although the penetration of the quinolones into CSF during meningitis in experimental animals or humans is good (approximately 20% to 50% of concurrent serum concentrations), clinical experience with these agents is limited (less than 20 case reports). At present, the quinolones should be considered only for patients with bacterial meningitis caused by multidrug-resistant, gram-negative bacilli who fail therapy with conventional beta-lactam plus aminoglycoside. Despite the broad spectrum of the third-generation cephalosporins, these agents are inactive against men-

15 April 1990 • Annals of Internal Medicine • Volume 112 • Number 8

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

617

ingitis caused by Listeria monocytogenes. Ampicillin or penicillin should be used for treating L. monocytogenes meningitis, and the addition of an aminoglycoside, because of documented in-vitro synergy, should be considered in cases of proven infection (145, 146), but whether or not this combination has superior efficacy is unknown. An alternative choice is trimethoprim-sulfamethoxazole, which is the only non-beta-lactam agent that is bactericidal against L. monocytogenes in vitro (147); however, chloramphenicol shows varying activity against L. monocytogenes in vitro, and its use has been associated with an unacceptably high failure rate in L. monocytogenes meningitis (114). In certain categories of illness, patients have an increased risk for infection with L. monocytogenes. These include the elderly, cancer patients, transplant recipients, persons with diabetes, and alcoholic persons, although 30% of adults and 54% of children and young adults with documented L. monocytogenes meningitis have no apparent immunocompromising condition (148). Therefore, certain subsets of patients should receive empiric antibiotic therapy for infection with L. monocytogenes when they present with purulent meningitis of unknown cause (for example, the addition of ampicillin to a thirdgeneration cephalosporin). Patients with Staphylococcus aureus meningitis, usually encountered after trauma or neurosurgical procedures, should be treated with high doses of nafcillin or oxacillin. Vancomycin is reserved for patients who are either allergic to penicillin or have methicillin-resistant organisms as the cause of the meningitis (149, 150). Coagulase-negative staphylococci are the commonest causative agents of CSF shunt infections. Initial therapy in this situation should consist of vancomycin with close monitoring of CSF concentrations during therapy. If the patient fails to improve, the addition of rifampin may be warranted (151, 152). Removal of the shunt is often essential for optimal therapy (149). Two other issues deserve comment. The first is the duration of antimicrobial therapy that is largely empiric and based on tradition. The treatment of acute bacterial meningitis caused by any of the three major meningeal pathogens is usually continued for 10 to 14 days and often longer (about 3 weeks) for gram-negative bacillary meningitis. Shorter courses of therapy may be equally efficacious for certain subsets of patients. Penicillin therapy for 7 days appears to be adequate for treatment of meningococcal meningitis, although some investigators (153) have even suggested that shorter courses (for example, 4 days) are sufficient. However, the adequacy of this shorter course requires confirmation because only 50 patients were studied and no control group was included. We currently favor a 1-week duration for the treatment of meningococcal meningitis in the United States. Other studies (138, 154, 155) have compared 7 with 10 days of treatment for bacterial meningitis in infants and children. Seven days of therapy was found to be effective and safe in this age group in which infections were largely caused by H. influenzae. However, therapy must be individualized, and some patients may require longer periods of treatment. Because of the high relapse rates reported with shorter courses, we still favor full parenteral dosages of appropriate agents for 3 618

weeks in adults with proven gram-negative bacillary meningitis. The second issue concerns the dosage interval and relates to the availability of ceftriaxone, a third-generation cephalosporin with a long half-life (8 hours). Several studies (156-159) in pediatric patients have documented that once-daily ceftriaxone is safe and efficacious for the treatment of bacterial meningitis. Although these results are impressive, we are cautious and do not currently favor once-daily ceftriaxone (as opposed to every 12 hours) as standard therapy for pediatric meningitis. Once-daily ceftriaxone therapy is currently under evaluation in adult patients and, pending results, cannot be recommended once-daily for the treatment of adult meningitis. Adjunctive Therapy Because of the greater understanding of the pathophysiologic mechanisms underlying bacterial meningitis, several innovative approaches are currently being examined to improve the prognosis of this disorder. Subarachnoid space inflammation is a major factor contributing to the morbidity and mortality in patients with meningitis. As stated earlier, the generation of pneumococcal cell wall components in CSF after treatment with bacteriolytic antibiotics, as seen in the rabbit model of meningitis, may contribute to the increased inflammation in the subarachnoid space (69), and this inflammation has been associated with increased CSF concentrations of prostaglandin E2 (80). This inflammatory response in CSF is reduced by inhibiting the cyclooxygenase pathway of arachidonic acid metabolism. Experimentally, methylprednisolone and oxindanac were particularly effective inhibitors of CSF pleocytosis, whereas indomethacin and diclofenac sodium were less potent (80). Inhibition of the cyclooxygenase pathway reduced both the CSF concentrations of prostaglandin E2 and leukocytes. An inhibitor of the lipooxygenase pathway (nordihydroguaiaretic acid) was ineffective in preventing cell-wall-induced inflammation. When tested after the intracisternal inoculation of live pneumococci, administration of cyclooxygenase inhibitors in conjunction with beta-lactam antibiotics also markedly reduced inflammation, indicating that these agents have the potential for improving outcome in patients with bacterial meningitis. The nonsteroidal anti-inflammatory agent indomethacin also decreases both brain water content and prostaglandin-E2 concentrations in experimental lapine pneumococcal meningitis, although there was no reduction in intracranial pressure (107). In addition, antiinflammatory agents (dexamethasone or oxindanac) lessen the massive influx of serum albumin and certain proteins of high and low molecular mass into the CSF during the early phase of experimental pneumococcal meningitis (160). However, ampicillin alone or in combination with indomethacin was ineffective in preventing this influx, and the abnormal protein profile in the CSF persisted for up to 30 days after the initiation of the experimental infection. Several corticosteroid agents have been evaluated in experimental models of meningitis. Earlier studies (161) with methylprednisolone showed a significant reduction

15 April 1990 • Annals of Internal Medicine • Volume 112 • Number 8

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

in the mass of leukocytes within the meninges of rabbits with pneumococcal meningitis. Cerebrospinal fluid outflow resistance is also reduced with methylprednisolone and to a greater extent than in untreated or penicillintreated rabbits with pneumococcal meningitis (103). Additional studies (104) have examined the effects of methylprednisolone or dexamethasone on brain water content, cerebrospinal fluid pressure, and CSF lactate concentrations. Both agents completely reversed the development of brain edema, whereas only dexamethasone reduced the increase in CSF pressure and lactate in rabbits with experimental pneumococcal meningitis. However, neither agent was superior to ampicillin alone in reducing cerebral edema or intracranial pressure, and no comparison was made between ampicillin alone and ampicillin plus corticosteroids, a comparison that would be relevant to the potential clinical efficacy of corticosteroids in humans. In a subsequent study (162) of experimental lapine H. influenzae meningitis, dexamethasone plus ceftriaxone was compared with ceftriaxone alone. The combination consistently reduced brain water content, CSF pressure, and CSF lactate to a greater degree than ceftriaxone alone, although the differences were not statistically significant. Adjunctive dexamethasone therapy has recently been evaluated in a doubleblind, placebo-controlled trial (163) involving 200 infants and children with bacterial meningitis. Patients received cefuroxime or ceftriaxone with either dexamethasone or placebo. As compared with those who received placebo, the patients who received dexamethasone became afebrile sooner and were significantly less likely to acquire moderate to severe bilateral sensorineural hearing loss. In addition, examination of CSF 24 hours after the initiation of therapy showed a more rapid increase of glucose and a decrease in lactate and protein concentrations in the patients who received dexamethasone. Corticosteroid treatment did not significantly affect the median CSF bactericidal titers in that study (163), although a previous study (164) has shown that methylprednisolone can decrease the entry into CSF of ampicillin and gentamicin in an experimental model of meningitis. Another study (165) has also suggested the potential usefulness of dexamethasone in infants and children with bacterial meningitis, and it is likely that these agents will prove to be useful adjunctive therapy in this disorder. However, if corticosteroids are to be used, close monitoring of the hematocrit and stool examination for occult blood is mandatory because gastrointestinal hemorrhage has been described in association with such therapy, albeit infrequently. Controlled trials of adjunctive corticosteroid therapy for meningitis in adults have not been reported but are in progress. Dexamethasone is likely to be particularly beneficial in the subset of patients with suspected or proven cerebral edema and raised intracranial pressure or in those who experience profound alterations in consciousness. It seems clear, however, that if corticosteroids are to be used, they should be administrated in conjunction with or just before antimicrobial therapy to lessen the inflammatory response in the subarachnoid space. The mechanism of this beneficial effect is incompletely defined. The appearance of late neurologic sequelae in infants and children with bacterial meningitis appears to corre-

late with initial CSF interleukin-1 beta concentrations (> 500 pg/mL), and preliminary evidence suggests that the combination of dexamethasone and antibiotics decreases CSF tumor necrosis factor and interleukin-1 concentrations more rapidly than antibiotics alone (166). Finally, specific monoclonal antibodies may prove valuable as adjunctive therapy for bacterial meningitis. Indeed, cures of bacterial meningitis were achieved in the preantibiotic era by the direct CSF instillation of immune serum supplemented with complement (167, 168). Human monoclonal antibodies against N. meningitidis enhanced opsonophagocytic activity in vitro in the presence of human complement and neutrophils and were highly protective against infection when used prophylactically in three animal models (169). Monoclonal antibodies to meningococcal lipopolysaccharide are also highly protective against bacterial challenge with the homologous strain in infant rats (170). To examine the potential usefulness of monoclonal antibodies in central nervous system infections, the CSF penetration of a bactericidal monoclonal antibody directed against surface-exposed epitopes in the polyribosyl-ribitol phosphate capsule of H. influenzae type b was measured (171). After intravenous administration, the IgG monoclonal antibody crossed the blood-brain barrier poorly (< 5.5%) despite high serum antibody concentrations and the presence of meningeal inflammation, which suggests that direct CSF inoculation is needed for this therapeutic modality. The intracisternal inoculation of an IgM monoclonal antibody directed against the lipid A moiety of E. coli lipopolysaccharide reduced the cefotaxime-induced increase in CSF lipopolysaccharide concentration and brain water content during experimental E. coli meningitis, with the latter reaching values similar to those in uninfected controls (105). In addition, an IgG monoclonal antibody to human recombinant interleukin-1 significantly reduced the neutrophilic exudation and increased the blood-brain barrier permeability seen after intracisternal inoculation of interleukin-1 in the rat model of experimental meningitis (93), which suggests a possible role for monoclonal antibodies in the prevention of central nervous system inflammation mediated by host cytokines. Future studies using monoclonal antibodies are essential to evaluate the applications of this form of therapy to bacterial meningitis. Based on limited data, however, it is unlikely that systemic administration of these antibodies alone will significantly influence central nervous system inflammation. Monoclonal antibodies directed against host cytokines or leukocyte-endothelial receptor ligands appear particularly promising and deserve further study.

Conclusions Antimicrobial therapy for patients with bacterial meningitis has significantly reduced the mortality associated with this disease. Most recently, the introduction of the third-generation cephalosporins has greatly reduced the fatality rate from gram-negative bacillary meningitis, and many of these agents are also effective against pneumococci, meningococci, and H. influenzae (including beta-lactamase-producing strains). A more thorough

15 April 1990 • Annals of Internal Medicine • Volume 112 • Number 8

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

619

understanding of the pathogenic and pathophysiologic mechanisms underlying meningitis should lead to an even greater reduction in mortality and morbidity. Bacterial virulence factors (for example, lipopolysaccharide) produce subarachnoid space inflammation and increased blood-brain barrier permeability with resultant cerebral edema, increased intracranial pressure, and alterations in cerebral blood flow. Mediators of inflammation, specifically interleukin-1 and tumor necrosis factor, may play a major role in the initiation of these early pathophysiologic events. Early intervention with antiinflammatory agents or specific monoclonal antibodies in conjunction with appropriate bactericidal antimicrobial agents may reduce the incidence of neurologic sequelae and death in patients with bacterial meningitis. Further progress can be expected in this important area. Acknowledgments: The authors thank Maryanne D. Chidsey and Eve Lorraine Schwartz for secretarial assistance. Grant Support: Supported in part by a research grant (ROl-All7904) and a training grant (T32-AI07046) from the National Institute of Allergy and Infectious Diseases. Dr. Scheld is an established investigator of the American Heart Association. Requests for Reprints: W. Michael Scheld, MD, Box 385, Division of Infectious Diseases, University of Virginia School of Medicine, Charlottesville, VA 22908. Current Author Addresses: Drs. Tunkel, Wispelwey, and Scheld: Division of Infectious Diseases, University of Virginia School of Medicine, Charlottesville, VA 22908. References 1. Schlech WF 3d, Ward JI, Band JD, Hightower A, Fraser DW, Broome CV. Bacterial meningitis in the United States, 1978 through 1981. The National Bacterial Meningitis Surveillance Study. JAMA. 1985;253:1749-54. 2. Bohr V, Paulson OB, Rasmussen N. Pneumococcal meningitis. Late neurologic sequelae and features of prognostic impact. Arch Neurol. 1984;41:1045-9. 3. Dodge PR, Davis H, Feigin RD, et al. Prospective evaluation of hearing impairment as a sequela of acute bacterial meningitis. N Engl J Med. 1984;311:869-74. 4. Moxon ER, Smith AL, Averill DR, Smith DH. Haemophilus influenzae meningitis in infant rats after intranasal inoculation. J Infect Dis. 1974;129:154-62. 5. Dacey RG Jr, Sande MA. Effect of probenecid on cerebrospinal fluid concentrations of penicillin and cephalosporin derivatives. Antimicrob Agents Chemother. 1974;6:437-44. 6. Quagliarello VJ, Long WJ, Scheld WM. Morphologic alterations of the blood-brain barrier with experimental meningitis in the rat. Temporal sequence and role of encapsulation. / Clin Invest. 1986; 77:1084-95. 7. Tunkel AR, Scheld WM. Applications of therapy in animal models to bacterial infection in human disease. Infect Dis Clin North Am. 1989;3:441-59. 8. Austrian R, Gold J. Pneumococcal bacteremia with special reference to bacteremic pneumococcal pneumonia. Ann Intern Med. 1964;60:759-76. 9. Finland M. Excursions into epidemiology: selected studies during the past four decades at Boston City Hospital. J Infect Dis. 1973; 128:76-124. 10. Broome CV, Facklam RR, Allen JR, Fraser DW, Austrian R. Epidemiology of pneumococcal serotypes in the United States, 1978— 1979. J Infect Dis. 1980;141:119-23. 11. Fraser DW, Geil CC, Feldman RA. Bacterial meningitis in Bernalillo County, New Mexico: a comparison with three other American populations. Am J Epidemiol. 1974;100:29-34. 12. Gray BM, Converse GM 3d, Dillon HC Jr. Serotypes of Streptococcus pneumoniae causing disease. J Infect Dis. 1979;140:979-83. 13. Moxon ER, Vaughn KA. The type b capsular polysaccharide as a virulence determinant of Haemophilus influenzae: studies using clinical isolates and laboratory transformants. J Infect Dis. 1981; 143:517-24. 14. Roberts M, Stull TL, Smith AL. Comparative virulence of Haemophilus influenzae with a type b or type d capsule. Infect Immun. 1981;32:518-24. 15. Anderson P, Johnston RB Jr, Smith DH. Human serum activities against Haemophilus influenzae type b. J Clin Invest. 1972;51:31-8.

620

16. Anderson P, Flesher A, Shaw S, Harding AL, Smith DH. Phenotypic and genetic variation in the susceptibility of Haemophilus influenzae type b to antibodies to somatic antigens. J Clin Invest. 1980;65:885-91. 17. Gulig PA, McCracken GH Jr, Frisch CF, Johnston KH, Hansen EJ. Antibody response of infants to cell surface-exposed outer membrane proteins of Haemophilus influenzae type b after systemic Haemophilus disease. Infect Immun. 1982;37:82-8. 18. Hansen EJ, Frisch CF, McDade RL Jr, Johnston KH. Identification of immunogenic outer membrane proteins of Haemophilus influenzae type b in the infant rat model system. Infect Immun. 1982; 32:1084-92. 19. Lam JS, Granoff DM, Gilsdorf JR, Costerton JW. Immunogenicity of outer membrane derivatives of Haemophilus influenzae type b. Curr Microbiol. 1980;3:359-64. 20. Devoe IW, Gilchrist JE. Pili on meningococci from primary cultures of nasopharyngeal carriers and cerebrospinal fluid of patients with acute disease. J Exp Med. 1975;141:297-305. 21. Stephens DS, McGee ZA. Attachment of Neisseria meningitidis to human mucosal surfaces: influence of pili and type of receptor cell. / Infect Dis. 1981;143:525-32. 22. McGee ZA, Stephens DS, Hoffman LH, Schlech WF 3d, Horn RG. Mechanisms of mucosal invasion by pathogenic Neisseria. Rev Infect Dis. 1983;5(Suppl 4):S708-14. 23. Stephens DS, Hoffman LH, McGee ZA. Interaction of Neisseria meningitidis with human nasopharyngeal mucosa: attachment and entry into columnar epithelial cells. J Infect Dis. 1983;148:369-76. 24. Cross AS, Gemski P, Sadoff JC, Orskov F, Orskov I. The importance of the Kl capsule in invasive infections caused by Escherichia coli. J Infect Dis. 1984;149:184-93. 25. Fine DP. Pneumococcal type-associated variability in alternate complement pathway activation. Infect Immun. 1975;12:772-8. 26. Winkelstein JA, Tomasz A. Activation of the alternative pathway by pneumococcal cell walls. J Immunol. 1977;118:451-4. 27. Quinn PH, Crosson FJ Jr, Winkelstein JA, Moxon ER. Activation of the alternative complement pathway by Haemophilus influenzae type b. Infect Immun. 1977;16:400-2. 28. Pearson H. Sickle cell anemia and severe infections due to encapsulated bacteria. J Infect Dis. 1977;136:S25-30. 29. Ross SC, Densen P. Complement deficiency states and infection: epidemiology, pathogenesis and consequences of neisserial and other infections in an immune deficiency. Medicine (Baltimore). 1984;63:243-73. 30. Scheld WM, Park TS, Dacey RG, Winn HR, Jane JA, Sande MA. Clearance of bacteria from cerebrospinal fluid to blood in experimental meningitis. Infect Immun. 1980;24:102-5. 31. Ostrow PT, Moxon ER, Vernon N, Kapko R. Pathogenesis of bacterial meningitis. Studies on the route of meningeal invasion following Haemophilus influenzae inoculation of infant rats. Lab Invest. 1979;40:678-85. 32. Smith AL, Daum RS, Scheifele D, et al. Pathogenesis of Haemophilus influenzae meningitis: In: Sell SH, Wright PF, eds. Haemophilus influenzae: Epidemiology, Immunology, and Prevention of Disease. New York: Elsevier Science Publishing Co;1982:89-109. 33. Beachey EH. Bacterial adherence: adhesin-receptor interactions mediating the attachment of bacteria to mucosal surfaces. J Infect Dis. 1981;143:325-45. 34. Parkkinen J, Korhonen TK, Pere A, Hacker J, Soinila S. Binding sites in the rat brain for Escherichia coli S fimbriae associated with neonatal meningitis. J Clin Invest. 1988;81:860-5. 35. Saukkonen KM, Nowicki B, Leinonen M. Role of type 1 and S fimbriae in the pathogenesis of Escherichia coli 018:K1 bacteremia and meningitis in the infant rat. Infect Immun. 1988;56:892-7. 36. Andersen BM, Solberg O. Endotoxin liberation and invasivity of Neisseria meningitidis. Scand J Infect Dis. 1984;16:247-54. 37. Takala AK, van Alphen L, Eskola J, Palmgren J, Bol P, Makela PH. Haemophilus influenzae type b strains of outer membrane subtypes 1 and lc cause different types of invasive disease. Lancet. 1987;2:647-50. 38. Rahal JJ, Simberkoff MS. Host defense and antimicrobial therapy in adult gram-negative bacillary meningitis. Ann Intern Med. 1982; 96:468-74. 39. Simberkoff MS, Moldover HN, Rahal JJ Jr. Absence of detectable bactericidal and opsonic activities in normal and infected human cerebrospinal fluids. A regional host defense deficiency. J Lab Clin Med. 1980;95:362-72. 40. Tofte RW, Peterson PK, Kim Y, Quie PG. Opsonic activity of normal human cerebrospinal fluid for selected bacterial species. Infect Immun. 1979;26:1093-8. 41. Brown EJ, Hosea SW, Frank MM. The role of the spleen in experimental pneumococcal bacteremia. J Clin Invest. 1981 ;67: 975-82. 42. Brown EJ, Hosea SW, Hammer CH, Burch CG, Frank MM. A quantitative analysis of the interaction of antipneumococcal antibody and complement in experimental pneumococcal bacteremia. J Clin Invest. 1982;69:85-98.

15 April 1990 • Annals of Internal Medicine • Volume 112 • Number 8

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

43. Scheld WM, Keeley JM. Effect of cerebrospinal fluid antibodycomplement on the course of experimental pneumococcal meningitis [Abstract]. Clin Res. 1983;31:375A. 44. Griffin DE. Immunoglobulins in the cerebrospinal fluid: changes during acute viral encephalitis in mice. J Immunol. 1981;126:27-31. 45. Kinnman J, Link H, Fryden A. Characterization of antibody activity in oligoclonal immunoglobulin G synthesized within the central nervous system in a patient with tuberculous meningitis. J Clin Microbiol. 1981;13:30-5. 46. Resnik L, diMarzo-Veronese F, Schiipbach J, et al. Intra-bloodbrain- barrier synthesis of HTLV-III-specific IgG in patients with neurologic symptoms associated with AIDS or AIDS-related complex. N Engl J Med. 1985;313:1498-1504. 47. Smith H, Bannister B, O'Shea MJ. Cerebrospinal-fluid immunoglobulins in meningitis. Lancet. 1973;1:591-3. 48. Whittle HC, Greenwood BM. Cerebrospinal fluid immunoglobulins and complement in meningococcal meningitis. J Clin Pathol. 1977; 30:720-2. 49. Greenwood BM. Chemotactic activity of cerebrospinal fluid in pyogenic meningitis. J Clin Pathol. 1978;31:213-6. 50. Wyler DJ, Wasserman SI, Karchmer AW. Substances which modulate leukocyte migration are present in CSF during meningitis. Ann Neurol. 1979;5:322-6. 51. Ernst JD, Hartiala KT, Goldstein IM, Sande MA. Complement (C5)-derived chemotactic activity accounts for accumulation of polymorphonuclear leukocytes in cerebrospinal fluid of rabbits with pneumococcal meningitis. Infect Immun. 1984;46:81-6. 52. Nolan CM, Clark RA, Beaty HN. Experimental pneumococcal meningitis: III. Chemotactic activity in cerebrospinal fluid. Proc Soc Exp Biol Med. 1975;150:134-6. 53. Tonnesen MG, Smedly LA, Henson PM. Neutrophil-endothelial cell interactions. Modulation of neutrophil adhesiveness induced by complement fragments C5a and C5a des arg and formyl-methionylleucyl-phenylalanine in vitro. J Clin Invest. 1984;74:1581-92. 54. Schleimer RP, Rutledge BK. Cultured human vascular endothelial cells acquire adhesiveness for neutrophils after stimulation with interleukin 1, endotoxin, and tumor-promoting phorbol diesters. J Immunol. 1986;136:649-54. 55. Thomas PD, Hampson FW, Casale JM, Hunninghake GW. Neutrophil adherence to human endothelial cells. J Lab Clin Med. 1988; 111:286-92. 56. Bevilacqua MP, Pober JS, Wheeler ME, Cotran RS, Gimbrone MA Jr. Interleukin 1 acts on cultured human vascular endothelium to increase the adhesion of polymorphonuclear leukocytes, monocytes, and related leukocyte cell lines. J Clin Invest. 1985;76: 2003-11. 57. Varani J, Bendelow J, Sealey DE, et al. Tumor necrosis factor enhances susceptibility of vascular endothelial cells to neutrophilmediated killing. Lab Invest. 1988;59:292-5. 58. Bevilacqua MP, Stengelin S, Gimbrone MA Jr, Seed B. Endothelial leukocyte adhesion molecule 1: an inducible receptor for neutrophils related to complement regulatory proteins and lectins. Science. 1989;243:1160-5. 59. Beilke MA. Vascular endothelium in immunology and infectious disease. Rev Infect Dis. 1989;11:273-83. 60. Tuomanen E, Wright SD. Reduction of inflammation by monoclonal antibody against adhesion receptors of leukocytes [Abstract]. In: Program and Abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, DC: American Society for Microbiology; 1988:266. 61. Giampaolo C, Scheld WM, Boyd J, Savory J, Sande M, Wills M. Leukocyte and bacterial interrelationships in experimental meningitis. Ann Neurol. 1981;9:328-33. 62. Scheld WM, Giampaolo C, Boyd J, Savory J, Wills MR, Sande MA. Cerebrospinal fluid prognostic indices in experimental pneumococcal meningitis. J Lab Clin Med. 1982;100:218-29. 63. Feldman WE. Relation of concentrations of bacteria and bacterial antigens in cerebrospinal fluid to prognosis in patients with bacterial meningitis. N Engl J Med. 1977;296:433-5. 64. Hodges RD, Perkins RL. Acute bacterial meningitis: an analysis of factors influencing prognosis. Am J Med Sci. 1975;270:427-40. 65. Weiss W, Figueroa W, Shapiro WH, Flippen HF. Prognostic factors in pneumococcal meningitis. Arch Intern Med. 1967;120:174-8. 66. Petersdorf RG, Luttrell CN. Studies on the pathogenesis of meningitis. I. Intrathecal injection. J Clin Invest. 1962;41:311-9. 67. Ernst JD, Decazes JM, Sande MA. Experimental pneumococcal meningitis: role of leukocytes in pathogenesis. Infect Immun. 1983; 41:275-9. 68. Tuomanen E, Tomasz A, Henstler B, Zak O. The relative role of bacterial cell wall and capsule in the induction of inflammation in pneumococcal meningitis. J Infect Dis. 1985;151:535-40. 69. Tuomanen E, Liu H, Hengstler B, Zak O, Tomasz A. The induction of meningeal inflammation by components of the pneumococcal cell wall. J Infect Dis. 1985;151:859-68. 70. Syrogiannopoulos GA, Hansen EJ, Erwin AL, et al. Haemophilus

71.

72.

73.

74.

75. 76.

77.

78.

79.

80.

81.

82.

83.

84.

85.

86. 87.

88. 89. 90.

91.

92.

93.

94.

influenzae type b lipooligosaccharide induces meningeal inflammation. J Infect Dis. 1988;157:237-44. Wispelwey B, Lesse AJ, Hansen EJ, Scheld WM. Haemophilus influenzae lipopolysaccharide-induced blood brain barrier permeability during experimental meningitis in the rat. J Clin Invest. 1988;82:1339-46. Mustafa MM, Ramilo O, Syrogiannopoulos GA, Olsen KD, McCracken GH Jr, Hansen EJ. Induction of meningeal inflammation by outer membrane vesicles of Haemophilus influenzae type b. J Infect Dis. 1989;159:917-22. Wispelwey B, Hansen EJ, Scheld WM. Haemophilus influenzae outer membrane vesicle-induced blood-brain barrier permeability during experimental meningitis. Infect Immun. 1989;57:2559-62. Beutler B, Krochin N, Milsark IW, Leudke C, Cerami A. Control of cachectin (tumor necrosis factor) synthesis: mechanisms of endotoxin resistance. Science. 1986;232:977-80. Dinarello CA. An update on human interleukin-1: from molecular biology to clinical relevance. J Clin Immunol. 1985;5:287-97. Movat HZ. Tumor necrosis factor and interleukin-1: role in acute inflammation and microvascular injury. J Lab Clin Med. 1987; 110:668-81. Tracey KJ, Lowry SF, Cerami A. Cachectin: a hormone that triggers acute shock and chronic cachexia. J Infect Dis. 1988;157: 413-20. Meyrick B, Hoover R, Jones MR, Berry LC Jr, Brigham KL. In vitro effects of endotoxin on bovine and sheep lung microvascular endothelial cells. J Cell Physiol. 1989;138:165-74. Nichols FC, Garrison SW, Davis HW. Prostaglandin E 2 and thromboxane B 2 release from human monocytes treated with bacterial lipopolysaccharide. J Leukoc Biol. 1988;44:376-84. Tuomanen E, Hengstler B, Rich R, Bray MA, Zak O, Tomasz A. Nonsteroidal anti-inflammatory agents in the therapy for experimental pneumococcal meningitis. J Infect Dis. 1987;155:985-90. Riesenfeld-Orn I, Garcia-Bustos J, Hoffman M, Tuomanen E. Pneumococcal cell wall components induce interleukin-1 but not tumor necrosis factor production by human monocytes [Abstract]. In: Program and Abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, D.C.: American Society for Microbiology;1988:266. Wispelwey B, Long WJ, Castracane JM, Scheld WM. Cerebrospinal fluid interleukin-1 activity following intracisternal inoculation of Haemophilus influenzae lipopoly saccharide into rats [Abstract]. In: Program and Abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, D.C.: American Society for Microbiology; 1988:265. Mustafa M, Ramilo O, Beutler B, Hansen EJ, McCracken GH Jr. Measurement of CSF cachectin (TNFa) activity in experimental Haemophilus influenzae type b (Hib) meningitis [Abstract]. In: Program and Abstracts of the 28th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, D.C.: American Society for Microbiology; 1988:266. Leist TP, Frei K, Kam-Hansen S, Zinkernagel RM, Fontana A. Tumor necrosis factor alpha in cerebrospinal fluid during bacterial, but not viral, meningitis. Evaluation in murine model infections and in patients. J Exp Med. 1988;167:1743-8. Libby P, Ordovas JM, Auger KR, Robbins AH, Birinyi LK, Dinarello CA. Endotoxin and tumor necrosis factor induce interleukin-1 gene expression in adult human vascular endothelial cells. Am J Pathol. 1986;124:179-85. Miossec P, Cavender D, Ziff M. Production of interleukin 1 by human endothelial cells. / Immunol. 1986;136:2486-91. Nawroth PP, Bank I, Handley D, Cassimeris J, Chess L, Stern D. Tumor necrosis factor/cachectin interacts with endothelial cell receptors to induce release of interleukin 1. J Exp Med. 1986;163: 1363-75. Bradbury MW. The structure and function of the blood-brain barrier. Fed Proc. 1984;43:186-90. Goldstein GW, Betz AL. The blood-brain barrier. Sci Am. 1986; 255:74-83. Pardridge WM, Oldendorf WH, Cancilla P, Frank HJ. Blood-brain barrier: interface between internal medicine and the brain. Ann Intern Med. 1986;105:82-95. Waggener JD. The pathophysiology of bacterial meningitis and cerebral abscesses: an anatomical interpretation. Adv Neurol. 1974;6:1-17. Lesse AJ, Moxon ER, Zwahlen A, Scheld WM. Role of cerebrospinal fluid pleocytosis and Haemophilus influenzae type b capsule on blood brain barrier permeability during experimental meningitis in the rat. J Clin Invest. 1988;82:102-9. Quagliarello VJ, Long WJ, Scheld WM. Human interleukin-1 modulates blood-brain barrier injury in vivo [Abstract]. In: Program and Abstracts of the 27th Interscience Conference on Antimicrobial Agents and Chemotherapy. Washington, D.C.: American Society for Microbiology;1987:204. Horwitz SJ, Boxerbaum B, O'Bell J. Cerebral herniation in bacterial meningitis in childhood. Ann Neurol. 1980;7:524-8.

15 April 1990 • Annals of Internal Medicine • Volume 112 • Number 8

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

621

95. Chan PH, Fishman RA. Brain edema: induction in cortical slices by polyunsaturated fatty acids. Science. 1979;201:358-60. 96. Fishman RA, Sligar K, Hake RB. Effects of leukocytes on brain metabolism in granulocytic brain edema. Ann Neurol. 1977;2: 89-94. 97. Kaplan SL, Feigin RD. The syndrome of inappropriate secretion of antidiuretic hormone in children with bacterial meningitis. J Pediatr. 1978;92:758-61. 98. Garcia H, Kaplan SL, Feigin RD. Cerebrospinal fluid concentration of arginine vasopressin in children with bacterial meningitis. J Pediatr. 1981;98:67-70. 99. Fishman RA. Brain edema. N Engl J Med. 1975;293:706-11. 100. Raimondi AJ, DiRocco C. The physiopathogenetic basis for the angiographic diagnosis of bacterial infection of the brain and its coverings in children. I. Leptomeningitis. Childs Brain. 1979;5: 1-13. 101. Igarashi M, Gilmartin RC, Gerald B, Wilburn F, Jabbour JT. Cerebral arteritis and bacterial meningitis. Arch Neurol. 1984;41: 531-5. 102. Yamashima T, Kashihara K, Ikeda K, Kubota T, Yamamoto S. Three phases of cerebral arteriopathy in meningitis: vasospasm and vasodilation followed by organic stenosis. Neurosurgery. 1985; 16:546-53. 103. Scheld WM, Dacey RG, Winn HR, Welsh JE, Jane JA, Sande MA. Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis. Alterations with penicillin and methylprednisolone. J Clin Invest. 1980;66:243-53. 104. Timber MG, Khayam-Bashi H, Sande MA. Effects of ampicillin and corticosteroids on brain water content, cerebrospinal fluid pressure, and cerebrospinal fluid lactate levels in experimental pneumococcal meningitis. J Infect Dis. 1985;151:528-34. 105. Tauber MG, Shibl AM, Hackbarth CJ, Larrick JW, Sande MA. Antibiotic therapy, endotoxin concentration in cerebrospinal fluid, and brain edema in experimental Escherichia coli meningitis in rabbits. J Infect Dis. 1987;156:456-62. 106. Tauber MG, Borschberg U, Sande MA. Influence of granulocytes on brain edema, intracranial pressure, and cerebrospinal concentrations of lactate and protein in experimental meningitis. / Infect Dis. 1988;157:456-64. 107. Tureen JH, Stella FB, Clyman RI, Mauray F, Sande MA. Effect of indomethacin on brain water content, cerebrospinal fluid white blood cell response and prostaglandin E 2 levels in cerebrospinal fluid in experimental pneumococcal meningitis in rabbits. Pediatr Infect Dis J. 1987;6:1151-3. 108. McMenamin JB, Volpe JJ. Bacterial meningitis in infancy: effects on intracranial pressure and cerebral blood flow velocity. Neurology. 1984;34:500-4. 109. Norrby R. A review of the penetration of antibiotics into CSF and its clinical significance. Scand J Infect Dis Suppl. 1978;14:296-309. 110. Scheld WM. Theoretical and practical considerations of antibiotic therapy for bacterial meningitis. Pediatr Infect Dis. 1985;4:74-83. 111. Strausbaugh LJ, Murray TW, Sande MA. Comparative penetration of six antibiotics into the cerebrospinal fluid of rabbits with experimental staphylococcal meningitis. J Antimicrob Chemother. 1980; 6:363-71. 112. Strausbaugh LJ, Sande MA. Factors influencing the therapy of experimental Proteus mirabilis meningitis in rabbits. J Infect Dis. 1978;137:251-60. 113. Wallace JF, Smith RH, Garcia M, Petersdorf RG. Studies on the pathogenesis of meningitis. VI. Antagonism between penicillin and chloramphenicol in experimental pneumococcal meningitis. J Lab Clin Med. 1967;70:408-18. 114. Cherubin CE, Marr JS, Sierra MF, Becker S. Listeria and gramnegative bacillary meningitis in New York City, 1972-1979. Frequent causes of meningitis in adults. Am J Med. 1981;71:199-209. 115. Schaad UB, McCracken GH Jr, Loock CA, Thomas ML. Pharmacokinetics and bacteriological efficacy of moxalactam, cefotaxime, cefoperazone, and rocephin in experimental bacterial meningitis. J Infect Dis. 1981;143:156-63. 116. Scheld WM, Brown RS Jr, Sande MA. Comparison of netilmicin with gentamicin in the therapy of experimental Escherichia coli meningitis. Antimicrob Agents Chemother. 1978;13:899-904. 117. Scheld WM, Sande MA. Bactericidal versus bacteriostatic antibiotic therapy of experimental pneumococcal meningitis in rabbits. / Clin Invest. 1983;71:411-9. 118. Sande MA, Korzeniowski OM, Alliegro GM, Brennan RO, Zak O, Scheld WM. Intermittent or continuous therapy of experimental meningitis due to Streptococcus pneumoniae in rabbits: preliminary observations on the postantibiotic effect in vivo. Rev Infect Dis. 1981;3:98-109. 119. Ward J. Antibiotic-resistant Streptococcus pneumoniae: clinical and epidemiologic aspects. Rev Infect Dis. 1981;3:254-66. 120. Jackson MA, Shelton S, Nelson JD, McCracken GH Jr. Relatively penicillin-resistant pneumococcal infections in pediatric patients. Pediatr Infect Dis. 1984;3:129-32. 121. Simberkoff MS, Lukaszewski M, Cross A, et al. Antibiotic-resistant 622

15 April 1990 • Annals

of Internal

Medicine

122. 123.

124.

125.

126.

127.

128.

129.

130. 131. 132.

133.

134.

135.

136.

137. 138.

139.

140.

141.

142.

143.

144.

145.

146. 147. 148. 149.

isolates of Streptococcus pneumoniae from clinical specimens: a cluster of serotype 19A organisms in Brooklyn, New York. J Infect Dis. 1986;153:78-82. Appelbaum PC. World-wide development of antibiotic resistance in pneumococci. Eur J Clin Microbiol. 1987;6:367-77. Tomasz A. Biochemistry and genetics of penicillin resistance in pneumococci. In: Ferretti JJ, Curtiss R III, eds. Streptococcal Genetics. Washington, DC: American Society for Microbiology; 1987:87-92. Jabes D, Nachman S, Tomasz A. Penicillin-binding protein families: evidence for the clonal nature of penicillin resistance in clinical isolates of pneumococci. J Infect Dis. 1989;159:16-25. Viladrich PF, Gudiol F, Linares J, Run G, Ariza J, Pallares R. Characteristics and antibiotic therapy of adult meningitis due to penicillin-resistant pneumococci. Am J Med. 1988;84:839-46. Dillon JR, Pauze M, Yeung KH. Spread of penicillinase-producing and transfer plasmids from the gonococcus to Neisseria meningitidis. Lancet. 1983;1:779-81. Campos J, Mendelman PM, Sako MU, Chaffin DO, Smith AL, Saez-Nieto JA. Detection of relatively penicillin G-resistant Neisseria meningitidis by disk susceptibility testing. Antimicrob Agents Chemother. 1987;31:1478-82. Van Esso D, Fortanals D, Uriz S, et al. Neisseria meningitidis strains with decreased susceptibility to penicillin. Pediatr Infect Dis. 1987;6:438-9. Mendelman PM, Campos J, Chaffin DO, Serfass DA, Smith AL, Saez-Nieto JA. Relative penicillin G resistance in Neisseria meningitidis and reduced affinity of penicillin-binding protein 3. Antimicrob Agents Chemother. 1988;32:706-9. Sutcliffe EM, Jones DM, el-Sheikh S, Percival A. Penicillin-insensitive meningococci in the UK [Letter]. Lancet. 1988;1:657-8. Peter G. Treatment and prevention of Haemophilus influenzae type b meningitis. Pediatr Infect Dis J. 1987;6:787-90. Givner LB, Abramson JS, Wasilauskas B. Meningitis due to Haemophilus influenzae type b resistant to ampicillin and chloramphenicol. Rev Infect Dis. 1989;11:329-34. Campos J, Garcia-Tornel S, Sanfeliu I. Susceptibility studies of multiple resistant Haemophilus influenzae isolated from pediatric patients and contacts. Antimicrob Agents Chemother. 1984;25: 706-9. Campos J, Garcia-Tornel S, Gairi JM, Fabregues I. Multiply resistant Haemophilus influenzae type b causing meningitis: comparative clinical and laboratory study. J Pediatr. 1986;108:897-902. del Rio M, Chrane D, Shelton S, McCracken GH Jr, Nelson JD. Ceftriaxone versus ampicillin and chloramphenicol for treatment of bacterial meningitis in children. Lancet. 1983;1:1241-4. Jacobs RF, Wells TG, Steele RW, Yamauchi T. A prospective randomized comparison of cefotaxime vs ampicillin and chloramphenicol for bacterial meningitis in children. J Pediatr. 1985; 107: 129-33. American Academy of Pediatrics Committee on Infectious Diseases. Treatment of bacterial meningitis. Pediatrics. 1988;81:904-7. Marks WA, Stutman HR, Marks MI, et al. Cefuroxime versus ampicillin plus chloramphenicol in childhood bacterial meningitis: a multicenter randomized controlled trial. J Pediatr. 1986; 109: 123-30. Cherubin CE, Corrado ML, Nair SR, Gombert ME, Landesman SH, Humbert G. Treatment of gram-negative bacillary meningitis. Role of new cephalosporin antibiotics. Rev Infect Dis. 1982; 4(Suppl):S453-64. Landesman SH, Corrado ML, Shah PM, Armengaud M, Barza M, Cherubin CE. Past and current roles for cephalosporin antibiotics in treatment of meningitis. Emphasis on use in gram-negative bacillary meningitis. Am J Med. 1981;71:693-703. Modai J, Vittecoq D, Decazes JM, Wolff M, Meulemans A. Penetration of ceftazidime into cerebrospinal fluid of patients with bacterial meningitis. Antimicrob Agents Chemother. 1983;24:126-8. Fong IW, Tomkins KB. Penetration of ceftazidime into the cerebrospinal fluid of patients with and without evidence of meningeal inflammation. Antimicrob Agents Chemother. 1984;26:115-6. Fong IW, Tomkins KB. Review of Pseudomonas aeruginosa meningitis with special emphasis on treatment with ceftazidime. Rev Infect Dis. 1985;7:604-12. Hackbarth CJ, Chambers HF, Stella F, Shibl AM, Sande MA. Ciprofloxacin in experimental Pseudomonas aeruginosa meningitis in rabbits. J Antimicrob Chemother. 1986;18(Suppl D):65-9. Trautmann M, Wagner J, Chahin M, Weinke T. Listeria meningitis: report of ten recent cases and review of current therapeutic recommendations. J Infect. 1985;10:107-14. Hansen PB, Jensen TH, Lykkegaard S, Kristensen HS. Listeria monocytogenes meningitis in adults. Sixteen consecutive cases 1973-1982. Scand J Infect Dis. 1987;19:55-60. Levitz RE, Quintiliani R. Trimethoprim-sulfamethoxazole for bacterial meningitis. Ann Intern Med. 1984;100:881-90. Gellin BG, Broome CV. Listeriosis. JAMA. 1989;261:1313-20. Schlesinger LS, Ross SC, Schaberg DR. Staphylococcus aureus

• V o l u m e 112 • N u m b e r 8

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

150. 151.

152. 153.

154.

155.

156.

157.

158.

159.

160.

161.

meningitis: a broad-based epidemiologic study. Medicine (Baltimore) 1987;66:148-56. Brumfitt W, Hamilton-Miller J. Methicillin-resistant Staphylococcus aureus. N Engl J Med. 1989;320:1188-96. Gombert ME, Landesman SH, Corrado ML, Stein SC, Melvin ET, Cummings M. Vancomycin and rifampin therapy for Staphylococcus epidermidis meningitis associated with CSF shunts. J Neurosurg. 1981;55:633-6. Vichyanond P, Olson L. Staphylococcal CNS infections treated with vancomycin and rifampin. Arch Neurol. 1984;41:637-9. Viladrich PF, Pallares R, Ariza J, Rufi G, Gudiol F. Four days of penicillin therapy for meningococcal meningitis. Arch Intern Med. 1986;146:2380-2. Jadavji T, Biggar WD, Gold R, Prober CG. Sequelae of acute bacterial meningitis in children treated for seven days. Pediatrics. 1985;78:21-5. Lin TY, Chrane DF, Nelson JD, McCracken GH Jr. Seven days of ceftriaxone therapy is as effective as ten days' treatment for bacterial meningitis. JAMA. 1985;253:3559-63. Congeni BL, Bradley J, Hammerschlag MR. Safety and efficacy of once daily ceftriaxone for the treatment of bacterial meningitis. Pediatr Infect Dis. 1986;5:293-7. Yogev R, Shulman ST, Chadwick EG, Davis AT, Glogowski W. Once daily ceftriaxone for central nervous system infections and other serious pediatric infections. Pediatr Infect Dis. 1986;5:298303. Dankner WM, Connor JD, Sawyer M, Straube R, Spector SA. Treatment of bacterial meningitis with once daily ceftriaxone therapy. J Antimicrob Chemother. 1988;21:637-45. Tuncer AM, Gur I, Ertem U, et al. Once daily ceftriaxone for meningococcemia and meningococcal meningitis. Pediatr Infect Dis J. 1988;7:711-3. Kadurugamuwa JL, Hengstler B, Zak O. Cerebrospinal fluid protein profile in experimental pneumococcal meningitis and its alteration by ampicillin and anti-inflammatory agents. J Infect Dis. 1989;159:26-34. Nolan CM, McAllister CK, Walters E, Beaty HN. Experimental

162.

163.

164.

165.

166.

167.

168. 169.

170.

171.

15 April 1990 • Annals

Downloaded From: http://annals.org/ by a Duke Medical Library User on 08/06/2013

pneumococcal meningitis. IV. The effect of methylprednisolone on meningeal inflammation. J Lab Clin Med. 1978;91:979-88. Syrogiannopoulos GA, Olsen KD, Reisch JS, McCracken GH Jr. Dexamethasone in the treatment of experimental Haemophilus influenzae type b meningitis. J Infect Dis. 1987;155:213-9. Lebel MH, Freij BJ, Syrogiannopoulos GA, et al. Dexamethasone therapy for bacterial meningitis. Results of two double-blind, placebo-controlled trials. N Engl J Med. 1988;319:964-71. Scheld WM, Brodeur JP. Effect of methylprednisolone on entry of ampicillin and gentamicin into cerebrospinal fluid in experimental pneumococcal and Escherichia coli meningitis. Antimicrob Agents Chemother. 1983;23:108-12. Lebel MH, Hoyt J, Waagner DC, Rollins NK, Finitzo T, McCracken GH Jr. Magnetic resonance imaging and dexamethasone therapy for bacterial meningitis. Am J Dis Child. 1989;143:301-6. Mustafa MM, Lebel MH, Ramilo O, et al. Correlation of interleukin-1/3 and cachectin concentrations in cerebrospinal fluid and outcome from bacterial meningitis. J Pediatr. 1989;115:208-13. Finland M, Brown JW, Rauh AE. Treatment of pneumococcic meningitis. A study of ten cases treated with sulfanilamide alone or in various combinations with specific antipneumococci serum and complement, including six recoveries. N Engl J Med. 1938; 218:1033-44. Flexner S. The results of serum treatment in 1300 cases of epidemic meningitis. J Exp Med. 1913;17:553-76. Raff HV, Devereux D, Shuford W, Abbott-Brown D, Maloney G. Human monoclonal antibody with protective activity for Escherichia coli Kl and Neisseria meningitidis group B infections. J Infect Dis. 1988;157:118-26. Saukkonen K, Leinonen M, Kayhty H, Abdillahi H, Poolman JT. Monoclonal antibodies to the rough lipopolysaccharide of Neisseria meningitidis protect infant rats from meningococcal infection. J Infect Dis. 1988;158:209-12. Gigliotti F, Lee D, Insel RA, Scheld WM. IgG penetration into the cerebrospinal fluid in a rabbit model of meningitis. J Infect Dis. 1987;156:394-8.

of Internal

Medicine

• Volume 112 • N u m b e r 8

623

Bacterial meningitis: recent advances in pathophysiology and treatment.

To review recent advances in the understanding of pathogenic and pathophysiologic mechanisms underlying bacterial meningitis that may lead to the deve...
3MB Sizes 0 Downloads 0 Views