BACTERIAL MENINGITIS

CENTRAL NERVOUS SYSTEM INFECTIONS

0733-8619/99 $8.00

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BACTERIAL MENINGITIS David H. Spach, MD, and Lisa A. Jackson, MD, MPH

In the past decade, significant advances have occurred in the field of bacterial meningitis. Work from many investigators has greatly enhanced our fundamental understanding of the pathogenesis of bacterial meningitis,particularly with regard to the cascade of biological events that cause excessive inflammation within the central nervous system.81Without question, the most important event in the field of bacterial meningitis in the past decade is the drastic decline in the incidence of Huemophilus influenzue meningitis in children as a result of the widespread use of ~ , ~ ~the significant decline in H. the conjugated H . influenzue type b v a c ~ i n e . " With influenzue type b meningitis, Streptococcus pneumoniue has moved to the forefront as the most important bacterial cause of meningiti~.~~ Recently, the steady increase in the level of penicillin-resistant S. pneumoniue3O has reached proportions that, in many areas, has altered the choice of empiric antibiotic therapy for meningitis. In this article, we focus on new information in several specific areas related to central nervous system pyogenic infections, specificallynew advances in the understanding of pathogenesis, new epidemiologic trends, up-to-date pathogen-specificinformation, and current recommendationsfor the management of bacterial meningitis. Issues related to the laboratory diagnosis of meningitis, nonbacterial pathogens, and chronic meningitis are covered in other articles in this issue. PATHOGENESIS OF BACTERIAL MENINGITIS

Bacteria pass through four major steps before they cause meningitis: (1) attachment to and colonization of the host nasopharyngeal mucosal epithelium, (2) invasion of the adjacent intravascular space and survival of the host's initial complement-mediated defense against bacteremia, (3) translocation across the blood-brain barrier and entrance into the cerebrospinalfluid, and (4) survival and replication within the milieu of the cerebrospinalf l ~ i d . ~ ~During , ' O ~ the early steps,

From the Division of Infectious Diseases, University of Washington School of Medicine (DHS); and the Department of Epidemiology, School of Public Health and Community Medicine, University of Washington (LAJ), Seattle, Washington NEUROLOGIC CLINICS VOLUME 17 * NUMBER 4 * NOVEMBER 1999

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bacteria use specific tactics to overcome host barriers and defenses; namely, they disarm the host plasma cell-mediated mucosal IgA by secreting IgA proteases, and they evade circulating serum complement activity with their capsular polysaccharide. Most bacterial strains that cause meningitis have a capsular polysaccharide and thus are referred to as encapsulated bacteria.Io3The outer adhesive bacterial pili play an instrumental role in the attachment of the bacteria to the nasopharyngeai mucosa and to the vascular endothelium of meningeal vessels.81 Once the bacteria reach the cerebrospinal fluid, they have an excellent chance of surviving, mainly because the initial host response generates minimal immunoglobulin and complement-mediated localized humoral defenses. Indeed, investigators in Switzerland found undetectable cerebrospinalopsonic activity in 50% of persons who have bacterial m e n i n g i t i ~ . ~ ~ Eventually, the host generates an immune response to the bacteria in the cerebrospinal fluid. Although the host response may effectively kill bacteria, the killing process may cause inflammation,brain edema, localized neurologic injury, and even death. Animal models have been used for more accurate determination of the critical bacterial factors that lead to meningeal inflammationand subsequent poor outcomes. Available data suggest the subcapsular surface components, such as the bacterial cell wall and lipopolysaccharide (and not the outermost capsular polysaccharides), serve as the critical components in stimulating host-mediated meningeal inflammation;both of the major cell-wall components, teichoic acid and peptidoglycan, play a major role in this inflammatory activity.Io4Animal studies with H. influenzae have shown that intracisternal inoculation of either H . influenzae type b polysaccharide or H. influenzae outer membrane vesicles induces meningeal Exinflammation and increases the permeability of the blood-brain barrier.69,114 actly how the cell-wall components generate meningeal inflammation remains incompletely defined but most likely relates to release of host endogenous inflammatory mediators, namely, interleukin-1 (IL-l), IL-6, tumor necrosis factor (TNF), and possibly prostaglandins; directly inoculating IL-1 and TNF into the cerebrospinal fluid of either rats or rabbits induces meningeal inflammation similar to the inflammatory responses observed with l i p o p o l y s a ~ c h a r i d e . ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ The migration of neutrophils into the cerebrospinalfluid is a complicated and important event in the pathogenesis of bacterial meningitis. Quagliarello and Schelds' have proposed a three-phase model that explains neutrophil migration into the cerebrospinal fluid and the resultant breakdown of the blood-brain barrier. The first phase, which lasts for 1 to 2 hours, begins with release of inflammatory cytokines, such as IL-1 and TNF, within the cerebrospinalfluid in response to bacterial replication or lysis. These inflammatory cytokines interact with the surface membranes of endothelial cells and generate local production of thrombin, leading to rapid and transient membrane surface expression of selectin molecules (CD62 and endothelial leukocyte-adhesionmolecule-1 [ELAM-I]).These selectin molecules significantly enhance neutrophil endothelial binding. The binding process is further strengthened by leukocyte-adhesion molecule-1 (LAM-I), a third selectin molecule present on the surface of unstimulated neutrophils. In the second phase, the prolonged inflammatory cytokine stimulation causes the vascular endothelium to release IL-8, and this event causes the initial selectin-mediatedneutrophil binding to be replaced with a 8-2 integrin-mediated neutrophil binding to endothelial intercellular adhesion molecules (ICAMs), leading to neutrophil diapedesis and entry into the cerebrospinal fluid. In the third phase, the cytokines within the cerebrospinal fluid activate neutrophils, causing them to degranulate and release vasoactive lipid autacoids (platelet-activatingfactor, leukotrienes, and prostaglandins)as well as toxic oxygen intermediates; these substances impair the

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blood-brain barrier by both enhancing uptake of circulating albumin by the endothelial cells and by allowing leakage of albumin into the cerebrospinal fluid through open intercellular venule junctions. The migration of the neutrophils into the cerebrospinal fluid and subsequent neutrophil degranulation serve as critical factors that cause increased permeability in the blood-brain barrier and resultant vasogenic brain edema. In addition, several studies have shown that increased nitric oxide concentrationsin cerebrospinal fluid can cause cerebral edema.27,n From an anatomic perspective, the fixed space of the skull and the spine limits brain expansion and thus serves as a critical determinant for intracranial pressure. Accordingly, the intracranial pressure directly depends on the collective volume of cerebrospinal fluid, brain tissue, and cerebral venous and arterial blood. Multiple factors contribute to the brain edema and increased cerebrospinal fluid volume associated with bacterial meningitis: (1)increased permeability in the blood brain barrier leads to a major increase in volume of fluid within the cerebrospinal fluid; (2) toxins released by bacteria or neutrophils within the central nervous system alter brain cell membranes, leading to increased intracellularwater content; and (3) increased resistance to cerebrospinal outflow impedes reabsorption of cerebrospinal fluid and thus increases cerebrospinal fluid v o l ~ m e .Several ~ ~ , ~me~ diators play a major role in meningitis-associated changes in cerebrovascular blood flow and in volume of blood within the cranial cavity. Fassbender and coll e a g u e have ~ ~ ~shown that patients who have meningitis who have increased levels of IL-1 and IL-6 have high cerebral blood flow velocities. Recent work in animals has suggested that induction of nitric oxide synthase occurs within meningeal vessels and within cells of the cerebrospinal fluid; the production of nitric oxide appears to reduce cerebral ischemia.60 In addition, loss of cerebrovascular autoregulation-as a result of the generation of oxygen intermediates in the microvasculature-causes cerebral blood flow to correspond directly with mean arterial blood pressure, an event that can cause hyperperfusion or hypoperfusion of the brain.lo6

RECENT TRENDS IN EPIDEMIOLOGY

In 1986, before the use of the conjugated H . influenzae vaccine, Wenger and colleagues113 studied the incidence of bacterial meningitis in the United States and found H. influenzae caused 44% of cases of bacterial meningitis, S. pneumoniae 18%, Neisseria meningitidis 14%,Streptococcus agalactiae (group B streptococcus)6%,Listeria monocytogenes 3%,and other organisms combined 15%(Fig. l).II3 The overall rates per million persons per year were H. influenzae 29, S. pneumoniae 11, N. meningitidis 9, group B streptococcus 4, L. monocytogenes 2, and other bacteria More than 70% of cases of meningitis in children younger than 5 years of age . ~ ~ ~ authors estimated that before resulted from infection with H. i n f l ~ e n z a eOther the use of the conjugated H. influenzae vaccine nearly 1 in 200 children younger . ~1994 ~ and 1995, approxthan the age of 5 developed H . influenzae m e n i n g i t i ~In imately 5 years after the licensure of the conjugated H . influenzae vaccine, Schuchat and colleagues94analyzed 248 cases of bacterial meningitis from population-based surveillance in four states (Maryland, Georgia, Tennessee, and California).These investigators found S. pneumoniae was the most common pathogen causing bacterial meningitis (Fig. 2) and determined pathogen-specific rates per million persons per year: S. pneumoniae 11, N . meningitidis 6, group B streptococcus 3, L. monocytogenes 2, and H. influenzae 2. Based on their data, Schuchat and co-workers

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Figure 1. Distribution of bacterial meningitis pathogens in the United States in 1986. (Dafa from Wenger JD, HightowerAW, Facklam RR, et al: Bacterial meningitis in the UnitedStates, 1986: Report of a multistate surveillance study. The Bacterial Meningitis Study Group. J Infect Dis 162:1316, 1990.)

Figure 2. Distribution of bacterial meningitis pathogens in the United States in 1995. (Data from Schuchat A, Robinson K, Wenger JD, et al: Bacterial meningitis in the United States in 1995. N Engl J Med 337:970, 1997.)

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estimated these 5 pathogens caused 5755 cases of bacterial meningitis in 1995, compared with an estimated 12,920 cases caused by these same pathogens in 1986. The median age of bacterial meningitis in 1995 was 25 years compared with 15 months of age in 1986. The overall decrease in number of cases and significant increase in median age predominantly resulted from a 94% decrease in H. influenzae meningitis. In addition, cases of N.meningitidis declined 33% and group B streptococcus declined 25% (Fig. 3). From 1962 through 1988, Durand and co-workerss3reviewed 493 episodes of acute bacterial meningitis diagnosed in adults at the Massachusetts General Hospital and found that 40% of cases were nosocomial. Among the 296 episodes of community-acquired meningitis, S. pneumoniae (37%),N.meningitidis (13%),and L. monocytogenes (10%)were the most frequently isolated pathogens. Gram-negative bacilli (not H. influenme) caused 33% of the nosocomial episodes but only 3% of the community-acquired episodes. The investigators identified age older than 59 years, obtunded mental state on admission, and seizures within the first 24 hours as major risk factors for death among those with community-acquiredmeningitis. The mortality rate was 25% for community-acquired meningitis and 35% for nosocomial meningitis.

Figure 3.Change in incidence of bacterial meningitis pathogens in the United States in 1995 compared with 1986. (Data from Schuchat A, Robinson K, Wenger JD, et al: Bacterial meningitis in the United States in 1995. N Engl J Med 337:970, 1997;and Wenger JD, Hightower AW, Facklam RR, et al: Bacterial meningitis in the United States, 1986; Report of a multistate surveillance study. The Bacterial Meningitis Study Group. J Infect Dis 162:1316,1990.)

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PATHOGEN-SPECIFICINFORMATION Streptococcus pneumoniae Microbiology and Epidemiology

S . pneurnoniae is a gram-positivecoccus that appears as pairs and chains when viewed in clinical Gram-stained samples. This organism contains C-polysaccharide, a unique teichoic acid component linked to peptidoglycan on the outermost surface of the cell wall. Almost all pneumococcal isolates have an external capsule; the capsule consists of repeating oligosaccharides and protects the organism from .~~~ of S. pneumoniue host polymorphonuclear-generated p h a g o ~ y t o s i sSerotyping is based on antigenic differences of the capsular polysaccharides. The American serotyping system numbers the specific serotypes by the order the isolates were identified, with more than 80 known serotypes having been identified. The Danish system groups several serotypes within one number if the isolates have similar antigenic properties; for example, the American serotypes 19, 57, 58, and 59 correspond with the Danish serotypes of 19F, 19A, 19B, and 19C. Most laboratories do not routinely perform serotyping on pneumococcal clinical isolates, but serotyping does play a role in epidemiologic surveys and with vaccine d e ~ e l o p m e n t . ~ ~ The nasopharynx serves as the primary site of pneumococcal colonization and persons may carry up to four distinct pneumococcal serotypes at one time.Io5 Colonization studies have shown that 5% to 10% of healthy adults and 20% to 40% of healthy children carry at least one strain of S. pneumoniue, with a higher colonizationrate in winter months.%Pneumococcalcolonizationtypically persists for weeks to months. The organism is spread from person-to-person by way of respiratory droplets, with increased chance of spread in crowded conditions, such as in daycare centers, military barracks, and prisons.ffiMany experts believe that day care centers serve as a major source of pneumococcal spread as shown by one study that documented extensive spread of a specific penicillin-resistant pneumococcal serotype (23F)within a daycare center.87Children who become colonized with S. pneumoniae in the daycare setting often introduce this organism into their household, followed by subsequent spread to others within the household.47Reports have documented nosocomial spread of pneumococcus, although this probably plays a minor role in the overall epidemiology of pneumococcal transmission.86 In the United States, the incidence of S. pneumoniae meningitis is approximately 11 cases per million persons per ~ e a r . 9Infants ~ younger than 1 month of age have the highest age-specific rate of meningitis caused by S. pneumoniae, with a rate of 157 cases per million persons per year.94Pneumococcal meningitis is the most common cause of bacterial meningitis in multiple different age groups, namely, age groups 1 to 23 months, 19 to 59 years, and older than 59.94Pneumococcal meningitis is associated with an overall case-fatality rate of 21%, a rate significantly higher than rates seen with invasive pneumococcalpneumonia (13%).94 Invasive pneumococcal disease occurs with increased frequency among persons with primary or secondary causes of defective antibody production, as well as in those who have defective clearance of bacteria. In children, the disease often results from local extension from a sinus or middle-ear infection, leading to transient bacteremia with hematogenous seeding of the choroid plexus. In adults, the major identified risk factors for developing invasive pneumococcal disease include splenectomy, diabetes mellitus, liver disease, alcohol use, and human immunodeficiency virus (HIV) infection. The clinical presentation of persons who have pneumococcal meningitis is similar to that of other types of pyogenic meningitis, with the exception that patients who have pneumococcal meningitis often have

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concomitant pneumococcal pneumonia. Several retrospective studies have shown that individuals infected with penicillin-susceptible pneumococcal strains have a similar clinical presentation and outcome as those infected with nonsusceptible strain^.^,^^,^^'

Therapy and Prevention

In recent years, treatment of pneumococcal meningitis has become increasingly complicated as a result of widespread penicillin-resistant S. pneumoniae.Penicillin-resistant clones have emerged in certain areas of the world, with some strains undergoing subsequent global dissemination. Penicillin resistance results from changes in the high-molecular-weight penicillin-binding proteins, with increasing resistance occurring with greater changes in these proteins. Penicillinbinding proteins normally function as enzymes that play a critical role in the synthesis and modification of bacterial cell wall^.^^^^^ Penicillin susceptibilitytesting in the microbiology laboratory classifies s. pneurnoniae isolates as either susceptible (minimum inhibitory concentration [MIC] <0.1 pg/mL), intermediate resistant (MIC 0.1 to 1.0 pg/mL), or highly resistant (MIC >2.0 ~ g / m L )Because .~~ all p-lactam antibiotics interact with penicillin-binding proteins, alterations in these proteins usually lead to some degree of cross resistance among penicillins, Cephalosporin-susceptibilitytesting classifies cephalosporins,and ~arbapenems.~~ S. pneumoniae isolates as susceptible MIC C0.25 pg/mL, intermediate resistant 0.5 . ~ ~development of S. pneumoniae to 1.0pg/mL, or highly resistant >2.0 p ~ g / m LThe resistance to vancomycin does not correlate with penicillin re~istance.~~ Several studies have shown an alarming level of penicillin-resistant S. pneumoniae. In a 1993and 1994 study of antimicrobial-susceptibility testing of 740 pneumococcal isolates recovered from normally sterile body sites of patients at 12 hospitals in 11 states, 14.1%of the isolates had intermediate-level resistance to penicillin and 3.2%had high-level penicillin resistance.= In 1994 and 1995, Doern and colleagues30tested 1527 clinically significant outpatient isolates of S. pneumoniae collected in 30 different United States medical centers and found 14.1%of the strains had intermediate-level resistance to penicillin and 9.5% had high-level penicillin resistance; of 31 cerebrospinal fluid isolates, 7.7% had intermediate-level resistance to penicillin and 9.7%with high-level resistance. In 1995, Schuchat and co-workers9*tested 84 cerebrospinal fluid isolates and found 18 (21%)with intermediate-level resistance to penicillin and 12 (14%) with high-level resistance to peni~illin.~~ In 1996 and 1997, Thornsberry and co-workersloZ tested more than 4000 respiratory isolates and found 22% had intermediate-level resistance to penicillin and 13%had high-level resistance. These studies, taken together, have also shown significant levels of resistance to cephalosporins,with the exception that generally more than 90% of S. pneumoniae isolates have remained susceptible to third-generation cephalosporins such as cefotaxime or ceftriaxone. If, however, one specifically looks at penicillin-resistant strains, significantlyless than 90%of these resistant isolates remain susceptible to third-generation cephalosporins. The frequency of resistance to the newer fluoroquinolones, such as levofloxacin, sparfloxacin, grepafloxacin, and trovafloxacin, has been poorly characterized but appears to be very low. Fortunately, investigators have not documented clinically significant resistance to vancomycin in S. p n e ~ m o n i a e . ~ ~ Penicillin-susceptible pneumococcus responds to typical meningitis doses of either penicillin, ampicillin, cefotaxime, or ceftriaxone. Treatment of penicillinnonsusceptible pneumococcus is complex, mainly because concentrationsof penicillins and cephalosporins in the cerebrospinal fluid are usually inadequate to

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achieve prompt eradication of some intermediately resistant and most highly resistant pneumococcal s t r a i n ~ ? Because ~ , ~ ~ no prospective trials of treatment for penicillin-nonsusceptible pneumococcus have been performed, most recommendations for treatment are based on a combination of in vitro data, animal model data, and retrospective analysis of human cases. Penicillin or ampicillin should not be used to treat penicillin-nonsusceptible pneumococcus.lllStrains of penicillin-resistant pneumococci that remain susceptible to cephalosporins should continue to respond to cephalosporins.18For those strains showing intermediate-level cephalosporin resistance, case reports have documented delayed sterilization of cerebrospinal fluid as well as treatment failure.10,40 Multiple reports have documented cephalosporin treatment failures in strains with high-level cephalosporin resistance.lO,11,17.58,98

For those strains with intermediate-levelor high-level resistance to both penicillins and cephalosporins, most experts would recommend adding vancomycin to either ceftriaxone or c e f o t a ~ i m e . ~ Although ~,~~,~~ prospective ,~~~ comparative clinical data do not exist to support this recommendation, in vitro data as well as animal studies of penicillin- and cephalosporin-resistant meningitis suggest the combination of vancomycin plus ceftriaxone has greater activity than either drug used alone.4O Vancomycin as a single agent is not recommended, mainly because of its poor penetration into the cerebrospinal fluid."O Moreover, Viladrich and coworkers110described 4 of 11 adults who had penicillin-resistant pneumococcal meningitis who had clinical failure when treated with vancomycin alone."O In contrast, one study of children who had acute meningitis found that vancomycin penetrated reliably into the cerebrospinal To complicate matters further, animal studies of pneumococcal meningitis have shown concomitant administration of dexamethasone decreases the penetration of vancomycin into the cerebrospinal f l ~ i d . ~ ~ , ~ ~ , ~ ~ Some experts have suggested that rifampin plus a third-generation cephalosporin serves as an excellent combination regimen in patients who have penicillinresistant and cephalosporin-resistant pneumococcus.18~39 Animal models have shown excellent activity of rifampin combined with ceftriaxone when used for penicillin-resistant, rifampin-sensitive pneumococcal m e n i n g i t i ~ .In ~ ~vitro , ~ ~ testing of penicillin-resistant pneumococcus, however, suggested rifampin, when combined with ceftriaxone, imipenem, or vancomycin, decreased the bactericidal activity of these agents.32Dexamethasone does not appear to alter cerebrospinal fluid rifampin levels." Some experts have recommended using rifampin plus ceftriaxone in adults who have penicillin- and cephalosporin-resistant pneumococcus if the person receives adjunctive dexamethasone;n,82one might also consider adding vancomycin to this regimen. Treatment of penicillin-resistant pneumococcal meningitis with chloramphenicol has uniformly shown very disappointing results and thus should not be Meropenem, a carbapenem-class antibiotic recently received Food and Drug Administration (FDA) approval for use as a treatment of meningitis, has very good activity against penicillin-susceptible pneumococci, but a recent study tested 59 isolates with either intermediate-level or high-level resistance to penicillin and found 49% also had resistance to r n e r ~ p e n e mAccordingly, .~~ meropenem should not be used to treat meningitis caused by intermediate-level or high-level resistant pneumococci. Trovafloxacin, a fluoroquinolone with enhanced activity against S. pneumoniae, has good activity against penicillin-nonsusceptible S. pneumoniae. In a rabbit model, trovafloxacin showed strong bactericidal activity in the treatment of meningitis caused by a highly penicillin-resistant strain of S. pneum o n i ~ eInsufficient .~~ clinical data exist with the use of trovafloxacin for the treatment of meningitis, and recently documented hepatotoxicity with this drug will

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likely prohibit its use in this setting. Encouraging results in animals have been reported with the investigational fluoroquinolones gatifloxacin and moxifloxacin for the treatment of drug-resistant S. pneurnor~iae.~~,~~ Most intermediate- and high-level penicillin-resistant pneumococcal strains (serotypes) are included in the current 23-valent capsular polysaccharide pneumococcal vaccine; this vaccine, however, does not generate good immune responses in young children and thus is not effective in preventing invasive pneumococcal infections in this age group.Z2Several companies have developed new 7- to 9-valent conjugated vaccines; these investigational vaccines contain most of the critical drug-susceptible and drug-resistant pneumococcal strains that currently predominate in the United States.z1,22 In a randomized, double-blinded, placebo-controlled trial, 37,000 infants and children in Northern California received either 7-valent conjugated pneumococcal vaccine (given at 2, 4, 6, and 12 to 15 months) or placebo given at that same dosing ~chedu1e.l~ Preliminary results have shown the vaccine was 100%effective in preventing invasive disease of the serotypes contained in the vaccine and very few cases of invasive disease occurred with serotypes not contained in the vaccine.I5In a separate and much smaller double-blinded, placebo-controlled trial in 264 children aged 12 to 17 months, the children received either a 9-valent-conjugated pneumococcal vaccine (2 doses given 2 to 3 months apart) or placebo.26The children who received vaccine had a significant decrease in their nasopharyngeal carriage rates of specific pneumococcal serotypes contained in the vaccine, but they had a concomitant increase in the carriage rates of pneumococcal serotypes not contained in the vaccine.26At the time of this writing, no conjugated pneumococcal vaccine has received FDA approval for use in the United States.

Haemophilus influenzae Microbiology and Epidemiology

H . influenzae is a small (1 to 3 pm), gram-negative, coccobacillus. Most H . influenzae strains do not have an outer capsule and are referred to as nonencapsulated, serologically nontypeable strains. But, among the isolates of H. influenzae that cause meningitis in children, almost all express capsular surface antigens and are referred to as encapsulated strains. Based on capsular differences,investigators have defined six antigenically distinct encapsulated serotypes, designated a to f.80 The serotype b produces a capsular polysaccharide composed of repeating units of polyribosyl-ribitol phosphate (PRP). Laboratories can determine specific relatedness of either encapsulated or nonencapsulated strains by analyzing 4 to 6 outer membrane proteins to generate a so-called outer-membrane p r ~ f i l e . ' Neverthe~,~~ less, some strains have identical outer-membrane profiles but show clear genetic differences; multilocus enzyme genotyping (using an analysis of 17 cytoplasmic proteins) can distinguish these closely related strains.50 For H . influenzae, no natural host exists other than humans. Person-to-person transmission of H. influenzae occurs via the respiratory route, either by airborne respiratory droplets or via direct contact with respiratory secretions.Children have a greater risk of developing invasive H. influenzae with exposure to a sibling with invasive H . influenzae than with exposure to a child at a daycare center who has invasive H . i n f l u e n ~ a e .Humans ~ ~ , ~ ~ frequently become colonized with H. influenzae in the upper respiratory tract, particularly the nonencapsulated, nontypeable strains. Among the strains of H. influenzae that cause meningitis in children, how-

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ever, almost all are encapsulated and more than 95% are type b strains. Acquiring anticapsular antibody increases with age, and nonencapsulated strains of H. influenzue cause up to 50% of H. influenzue meningitis cases in a d ~ l t ~ Immunity . ~ ~ , ~ ~ ~ , to nonencapsulated strains remains poorly understood. Risk factors identified for adults developing H. influenzue meningitis include recent or remote head trauma, previous neurosurgery, paranasal sinusitis, otitis media, and cerebrospinal fluid leak. Before the widespread use of conjugated H. influenme vaccine in the United States, approximately 1 in 200 children younger than 5 years of age developed invasive H. influenzue disease, and the peak incidence of H. influenzue type b meningitis ranged from 6 to 15 months. In approximately 20% to 30% of these cases, permanent neurologic damage was sustained, and H. influenzae meningitis previously was the leading cause of acquired mental r e t a r d a t i ~ n . ~After ~,~~ the , ~wide~' spread use of conjugated type b vaccine in the early 1990s, the incidence of H. influenzae meningitis has drastically declined, decreasing more than 90% for persons younger than 5 years of age4,8,68,94; for persons 5 years or older, however, the Data from 1995 rate of H. influenzae meningitis has not significantly shows that children aged 1 to 23 months have the highest incidence of H. influenzue meningitis, with an estimated 7 cases per million persons per year.94Data from 1996 to 1997 shows that rates of invasive disease in children younger than 5 years of age varies with differences in race or ethnicity, with cases per 1 million persons per year reported as 5 in whites, 6 in Asians/Pacific Islanders, 7 in blacks, 7 in Hispanics, and 124 in American Indians/Alaskan native^.^ The higher attack rates among American Indians and Alaskan Natives may result from (1) lower natural antibody levels when compared with whites, (2) decreased responsiveness to immunization, and (3) adverse social and economic factors that lead to lower nutritional status and increased transmission of infectious pathogens secondary to greater crowding.88Persons who have H . influenzue meningitis have a clinical presentation similar to persons who have other types of bacterial meningitis and some may have a fulminant course. The case fatality rates for modern-day H. influenzue meningitis is estimated at 6%.94Adults generally have higher case fatality rates compared with children, predominantly because many of the adults who have H. influenzae meningitis have underlying disease.

Therapy and Prevention

The treatment of H. influenzae has been influenced by the steady increase in p-lactamase-producing strains, generally strains that produce either TEM-1 or ROB-1 p-lactarna~e.~~ Results from a national multicenter surveillance study involving 1537 clinical isolates obtained from 30 United States medical center laboratories between November 1994 and May 1995 found that 36% of the isolates produced p-lactamase and 39% were resistant to a m ~ i c i l l i nThis . ~ ~ study also described some strains that did not produce b-lactamase, yet were resistant to ampicillin, presumably because of alterations in penicillin-binding proteins. This study, however, contained predominantly respiratory tract isolates and overall less than 2% were type b isolates. Available data suggest that H. influenzue resistance to either ceftriaxone or cefotaxime rarely occurs and thus either of these antibiotics are considered the drug of choice to treat H. influenzue meningitis. Chemoprophylaxis to prevent spread of secondary cases of invasive H.influenzue consists of giving rifampin 20 mg/kg (maximum 600 mg) daily as a single dose for 4 days (for adults, 600 mg daily as a single dose for 4 days); chemoprophylaxis is not recommended for those individuals fully vaccinated against H. i n f l u e n z ~ e .The ~~~~*~

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conjugated H. influenzae vaccine is recommended for all children, with the first dose given at age 2 months (not earlier than 6 weeks)?

Lisferia monocytogenes Microbiology and Epidemiology

L. monocytogenes is a p-hemolytic, facultatively anaerobic, Gram-positive rod. Investigators have identified 12 distinct serotypes of L. monocytogenes based on differences in flagellar and carbohydrate-containing antigens. More than 90% of human cases result from infection with one of three serotypes: 4b, 1/2a, 1/2b. L. monocytogenes is an intracellular pathogen with a unique life cycle. After phagocytosis, the organism lyses the phagolysosome and escapes into the cell cytoplasm where it proliferates. The bacteria then use the host cell's contractile system to migrate to the periphery of the cytoplasm and to form protrusions that are then ingested by adjacent cells, thus starting the cell cycle again.99The organisms may enter the bloodstream either in leukocytes or as free organisms after cell lysis. The annual incidence of meningitis due to L. monocytogenes, as estimated from 1995 Center for Disease Control (CDC) data, is 2 cases per million persons.94The highest age-specific rate of meningitis caused by L. monocytogenes is among neonates younger than 1 month of age and is estimated at 392 cases per million persons per year. Second to the neonatal period, persons 60 years of age or older have the highest rate (6 cases per million persons per year), accounting for approximately 20% of all cases of bacterial meningitis in this age group. Among adults, risk factors for disease include pregnancy, advanced age, and immunosuppressive conditions. Listeriu meningitis is associated with an overall case-fatality rate of 15%.94 Although investigators have identified multiple outbreaks of listeriosis, most cases in the United States occur sporadically. For both outbreak-associated and sporadic cases, the foodborne route serves as the primary mode of transmission. The organism was first recognized as a foodborne pathogen in the 1980s, when several outbreaks of listeriosis provided the opportunity for epidemiologicstudies that identified co1eslaw:l pasteurized milk (presumably contaminated after paste~rization),3~ and Mexican-style soft cheese62as sources of infection. Since that time, several studies have implicated ready-to-eat foods, such as foods purchased from store delicatessen counters and uncooked hot dogs, as sources of sporadic and outbreak-associated listeri~sis.~~ Other foods, such as raw beef and poultry, but less frequently cause clinical are often contaminated with L. monocyt~genes~~ infection, probably because consumers routinely cook these products. Two major forms of invasive clinical infection occur in neonates: early onset and late onset. Early-onset infection develops in utero, presumably after maternal bacteremia, with infection manifesting in the infant at birth, or within a few days after birth. Sepsis is the most common clinical syndrome. In contrast to early-onset disease, late-onset neonatal listeriosis becomes apparent several days to several weeks after birth. Meningitis occurs more frequently with late-onset disease than with early-onset disease. Pregnant women are at increased risk of developing invasive listeriosis, particularly during the third trimester. Most often, pregnant women who have invasive listeriosis present with bacteremia, but meningitis can occur. Disease in nonpregnant adults occurs primarily in persons who are immunocompromised, such as individuals who have malignancy, renal failure, HIV infection, organ transplantation, advanced age, as well as those who receive corticosteroid treatment or chemotherapy.

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Compared with patients who have other types of bacterial meningitis, patients who have listeria meningitis less frequently have meningeal signs and cerebrospinal fluid studies usually show a lower white blood cell count, less neutrophilic predominance, and a lower protein c o n c e n t r a t i ~ n .Most ~ ~ , ~cases do not have a positive cerebrospinal fluid Gram’s stain.16,48,70,99 Because of its unique life cycle, L. rnonocytogenes can directly invade the cerebral cortex, a process that may account for the higher rate of seizures among patients who have listeria mening i t i ~ .Listeriu ~ ~ , ~meningoencephalitis is often associated with cranial-nerveabnormalities and other focal d i ~ t u r b a n c e s . ~ O ~ ~ ~ ~ Therapy and Prevention

Most experts recommend ampicillin or penicillin as the treatment of choice for listeria meningitis, with prolonged treatment, generally for 3 to 4 weeks, particularly in immunosuppressed patient^.^^,^^ Experimental animal models suggest gentamicin when combined with either ampicillin or penicillin generates enhanced bactericidal a ~ t i v i t y .Thus, ~ ~ , ~many ~ ~ experts recommend adding an aminoglycoside to penicillin or ampicillin, but sparse clinical data exist to support or to refute this practice. Trimethoprim-sulfamethoxazole has bactericidal activity against L. rnonocytogenes in vitro and is generally considered as the preferred alternative for patients who have documented penicillin allergy. Chloramphenicol or vancomycin are not recommended for patients who have systemic listeria infection. Because listeriosis results from foodborne transmission, basic foodhandling precautions can reduce the risk of infection.6These precautions include thoroughly cooking meat, keeping uncooked meat separate from other foods, washing raw vegetables thoroughly before eating, avoiding unpasteurized milk, avoiding foods made with unpasteurized milk, and washing hands, knives, and cutting boards after preparing uncooked foods. Certain high-risk groups, namely, those who are pregnant, elderly, or immunocompromised, should follow additional recommendations: avoiding soft cheeses, such as Mexican-style, feta, Brie, Camembert, and blue-veined cheese; ensuring that leftover or ready-to-eat foods are reheated until steaming hot before eating; and, possibly, avoiding foods from delicatessen counters. Enhanced efforts to reduce the contamination of processed foods by L. monocytogenes and the dietary recommendations noted above for persons at risk may have contributed to a recent decrease in disease caused by L. monocytogenes.lOO

Group B Streptococcus (Streptococcusagalactiae)

Microbiology and Epidemiology

Group B streptococcus (S. uguluctiue) is a major cause of neonatal sepsis and meningitis and is an important cause of invasive bacterial infection in adults. The following serotypes of group B streptococcusare recognized: Ia, Ib, Ia/c, 11,111, IV, V, and VI. The overall incidence of group B streptococcal meningitis is 3 cases per million persons per year, with a case fatality rate of 7%. Group B streptococcus occurs most frequently among neonates younger than 1 month of age (1250 cases per million persons per year), accounting for nearly 70% of cases of bacterial meningitis in this age gr0up.9~Adults develop group B streptococcal meningitis infrequently, with an incidence of approximately 1 case per million persons per year. Among adults, group B streptococcus causes less than 5% of cases of bacterial meningitis.

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723

Most neonatal group B streptococcal infections occur in the first days of life and are termed early-onset infections. Newborns who have early-onset group B streptococcal disease acquire the organism by means of intrapartum transmission from mothers who are colonized with group B streptococcus in the genital tract. Risk factors for early-onset group B streptococcal disease include premature birth, low birth weight, prolonged rupture of membranes, intraparturn fever, and maternal group B streptococcus bacteruria during pregnancy. Late-onset disease occurs between 1 week and 3 months of age and may reflect either acquisition of the organism during passage through the birth canal or transmission from an external source in the hospital or community. Among neonates who have either early-onset or late-onset invasive group B streptococcal disease, meningitis develops in approximately 10% of cases.92 In adults, pregnancy-associated group B streptococcal disease most often manifests during labor, starting as an amniotic infection that can progress to maternal sepsis. Meningitis is an infrequent complication of pregnancy-associated infection. Among nonpregnant adults, risk factors for invasive group B streptococcal disease, including both bacteremia and meningitis, consist of advanced age, diabetes, cirrhosis, and systemic m a l i g n a n ~ y . ~ Adults ~ , ~ ~ , ~acquire 5 a substantial proportion of group B streptococcal infections nosocomially. In one study, nosocomial infection accounted for 22%of all cases of invasive disease in nonpregnant

Therapy and Prevention

Group B streptococcus isolates have remained highly susceptible to penicillin and ampicillin and thus either of these antibiotics are considered the drug of choice for treatment of group B streptococcal meningitis. Some experts recommend using a combination of ampicillin and gentamicin for treatment of neonatal meningitis, based on data from animal studies that have shown synergy with these drugs.28,8z To prevent early-onset neonatal group B streptococcal infection, maternal intrapartum antimicrobial prophylaxis is recommended, using either a screening-based approach or a risk-based a p p r ~ a c hThe . ~ screening-based approach provides intrapartum antibiotics to all women who have group B streptococcus vaginorectal colonization identified by late-gestation (35 to 37 week) cultures and to those who do not have culture results and who deliver at less than 37 weeks gestation. The risk-based approach provides intrapartum antibiotics to women delivering either at less than 37 weeks gestation, after an interval of 18 hours or more of ruptured membranes or with an intrapartum temperature of 38°C (100.4"F) or higher. Both strategies provide intrapartum antibiotics to women who have group B streptococcus bacteruria identified during the pregnancy, as well as to women who previously delivered an infant who had group B streptococcal disease. Some hospitals have used DNA hybridization assays to identify group B streptococcus colonization during labor. In one study, a modified DNA hybridization assay with a 3-hour culture enrichment protocol yielded a sensitivity of 73% and a specificity of 99%.57 Despite several decades of effort to develop a group B streptococcal vaccine, none is currently licensed. Early vaccines incorporated group B streptococcalpolysaccharide antigens, but more recently developed vaccines have attempted to improve immunogenicity by the use of protein-conjugated polysa~charides.~~ The primary goal of the vaccine is to reduce invasive neonatal disease. Accordingly, women of childbearing age would serve as the target group for vaccination prior to becoming pregnant; ideally these women would receive the vaccine as a routine

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adolescent vaccine. In addition, adults who have an increased risk of infection, such as those who are advanced in age or who have diabetes, cirrhosis, or systemic malignancy, may also be targeted for vaccination.

Neisseria meningitidis (Meningococcus)

Microbiologyand Epidemiology

N. meningitidis (meningococcus) is an encapsulated, gram-negative bacteria that typically appears as pairs on Gram's stain. The organism is classified into serogroups based on the composition of the capsular polysaccharide. Although more than 13 serogroups can cause human disease, three serogroups (A, B, and C) account for 90% of cases of meningococcal disease worldwide. Serogroup A very rarely causes disease in the United States, but it plays an important role globallyby causing widespread epidemics in Asia and Africa. In the United States, most cases have resulted from infection with either serogroup B or C; more recently, however, serogroup Y has been identified as a cause of an increasing proportion of cases in several regions.@N. meningitidis commonly colonizes the nasopharynx without causing symptoms and transmission occurs by person-toperson spread of respiratory secretions. Overall, in the United States, meningococcal meningitis occurs at a rate of 6 cases per million persons per year. The orgaiizin accounts for 25% of all cases of bacterial meningitis and is associated with a case-fatality rate of 3%.94Unlike listeriosis and group B streptococcal infection, maternal to fetal transmission via the genital tract or bloodstream does not occur. Therefore, newborns rarely develop invasive meningococcal infection. Children 1to 23 months of age, however, have the highest rate of meningococcal meningitis (45 cases per million persons per year); among this age group, N. meningitidis accounts for approximatelyone-third of cases of bacterial meningitis. Moreover, N. meningitidisis also the most common cause of bacterial meningitis among persons 2 to.18 years of age, accounting for approximately60%of cases; this proportion declines to 20% among persons 19 to 59 years of age and to less than 5% among persons 60 years of age and older." Meningococcal infection has a seasonal pattern, with peak rates in the late winter and the early spring. Although most cases in the United States occur sporadically, outbreaks have been caused by meningococcal serogroups B5I and C.53 Persons who have component deficiencies in the terminal common complement pathway (C3, C5-C9) and asplenic individuals have an increased risk of developing meningococcal disease. Meningococcal meningitis usually presents with the typical symptoms of fever, headache, and meningismus. The course of disease varies, but it can progress to fulminant disease and death within hours. Patients often have a petechial rash, most frequently on the trunk and lower body. The petechial lesions can coalesce and form larger ecchymotic lesions. Purpura fulminansis a severe manifestation of meningococcalsepsis in which disseminated intravascular coagulopathy leads to widespread purpura and, in some instances, progresses to cause distal extremity necrosis. Purpura fulminans is associated with a high case-fatality rate. Complications of meningococcal meningitis include cutaneous scars, amputations, hearing loss, and renal injury? Markers of increased risk of death among patients who have meningococcal bacteremia and meningitis include the presence of a hemorrhagic diathesis, focal neurologic signs at the time of admission to the hospital, and age of 60 years or older. Receipt of adequate

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725

antibiotic therapy before admission to the hospital reduces the likelihood of death.I3

Therapy and Prevention

Most experts consider penicillin or ampicillin as the drug of choice for meningococcal meningitis. Ceftriaxone or cefotaxime also have excellent activity in vitro and achieve high cerebrospinal fluid concentrations. Outside of the United States, several reports have documented rare P-lactamase-producing strains that show high-level penicillin resi~tance;~ but within the United States no strains with high-level penicillin resistance have been identified.Strains with altered penicillinbinding proteins and intermediate resistance to penicillin have been identified within the United S t a t e ~ , 5 ~ and , ~ 'these ~ strains accounted for an estimated 4% of clinical meningococcal isolates in 1991.= One report described induction of intermediate resistance to ampicillin and penicillin in a patient treated with 7 days of high-dose ampicillin (2 g every 4 hours)." The clinical significance of infection with strains with intermediate levels of resistance is uncertain. One study of children in Spain found no difference in outcome between patients infected with intermediate-level resistant or susceptible strains, all of whom received penicillin therapy.'08 Moreover, others have shown that standard meningitis doses of penicillin produce cerebrospinal fluid penicillin concentrations that exceed the MIC of In recent years, work in Vietintermediate-level resistant meningococcal nam and France has documented meningococcalisolates with high-level resistance to chl~ramphenicol.~~ Although most clinicians in the United States do not routinely use chloramphenicol, primarily because of the risk of bone marrow toxicity, in many developing countries intramuscular chloramphenicol is the standard treatment for suspected meningococcal meningitis. Close contacts of patients who have meningococcal disease have a significantly increased risk of developing invasive meningococcal infection in the several-week period after exposure to an index case. The estimated attack rate for household contacts is 4 cases per 1000 persons exposed, a risk 500 to 800 times greater than in the general population not exposed to persons who have meningococcal infection.' Accordingly, experts recommend antimicrobial chemoprophylaxis for close contacts, including household members, daycare center contacts, and anyone directly exposed to the patient's oral secretions. Because most cases of secondary disease occur within several days of exposure to the primary patient, the exposed individual should receive chemoprophylaxis, ideally within 24 hours after the exposure. Although the goal of chemoprophylaxisis to eradicate N. meningitidis pharyngeal carriage, obtaining pharyngeal cultures of contacts is not recommended, mainly because they do not help to identify persons to target for chemoprophylaxis and waiting for culture results may unnecessarily delay starting chemoprophylaxis. Rifampin is the drug of choice for chemoprophylaxis and is administered twice daily for 2 days (600 mg every 12 hours for adults, 10 mg/kg of body weight every 12 hours for children older than or equal to 1 month of age, and 5 mg/kg every 12 hours for infants younger than 1 month of age).zRifampin, however, is contraindicated during pregnancy, it can change the color of urine and other body fluids to reddish orange, it may cause soft contact lenses to become permanently discolored, and it can affect the reliability of oral contraceptives. Ciprofloxacin is also highly effective in eradicating nasopharyngeal carriage of N. meningitidis and a single 500-mg oral dose may be given as an alternative to rifampin. Ciprofloxacin

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is not generally recommended for persons younger than 18 years of age or for pregnant or lactating women, mainly because studies in juvenile laboratory animals have shown that ciprofloxacin can damage cartilage in weight-bearing joints. One study showed that a single 500-mg oral dose of azithromycin is also highly effective in eradicating nasopharyngeal carriage of N. meningitidis.42For pregnant women, ceftriaxone administered in a single intramuscular dose of 250 mg is an alternative to the agents described above. Treatment of meningococcal meningitis with agents other than ceftriaxone or other third-generation cephalosporins may not reliably eradicate nasopharyngeal carriage. Therefore, if the patient receives treatment with other agents, such as penicillin or ampicillin, they also need to receive chemoprophylaxis before hospital discharge. The currently available meningococcal vaccine contains polysaccharides to serogroups A, C, Y, and W-135. In the United States, the vaccine is not recommended for routine use because it is weakly immunogenic in children younger than 2 years of age (the group with the greatest risk of sporadic disease), and it induces protection of relatively short duration (3 to 5 years). The vaccine, however, does have some use in controlling meningococcal outbreaks caused by one of the four serogroups included in the vaccine. In addition, routine meningococcal vaccination is recommended for persons in certain high-risk groups, namely, those who have terminal complement component deficiencies, those who have anatomic or functional asplenia, and military recruits, because since they have a high risk of acquiring group C meningococcal disease. Vaccinating travelers to areas in which group A epidemics occur, such as sub-Saharan Africa, may also be considered, especially if the traveler expects prolonged contact with local persons. Serogroup A and C meningococcal conjugate vaccines that generate enhanced immunogenicity in young children are now undergoing clinical trials.6I One study showed conjugated type C meningococcal vaccine induces high titers of anticapsular and bactericidal antibodies in healthy children aged 15 to 23 months, as well as inducing excellent immunologic memory." Unfortunately, the poor immunogenicity of the B capsular polysaccharide has hampered efforts to develop a vaccine effective against this serogroup. Although some strategies have focused primarily on the use of noncapsular antigens,I4 a serogroup B vaccine is not yet available. EMPlRlC AND PATHOGEN-SPECIFICTHERAPY

At the time a patient undergoes initial evaluation for presumed bacterial meningitis, the clinician does not have information regarding the specific causative pathogen and its susceptibility to antibiotics. Although a cerebrospinal fluid Gram's stain may strongly suggest a specific pathogen, it does not give definitive information. Accordingly, at the initial encounter, the clinician must choose appropriate empiric therapy (Table 1).This initial antibiotic choice depends on the age of the person who has meningitis, the regional antibiotic resistance profiles of common meningitis pathogens, and whether the person with meningitis has underlying immune deficiency. As a result of the recent significant increase in penicillin-resistant S. pneumoniue in the United States, many protocols for initial therapy have included the use of vancomycin, especially when the initial cerebrospinal fluid Gram's stain suggests a diagnosis of S. pneumoniue. Once the specific bacteria has been isolated and susceptibility testing has been performed, pathogen-directed therapy can, if necessary, replace empiric therapy (Table 2). Specific doses of drugs commonly used for treating bacterial meningitis are given in Table 3.

U tJ . U

gram-negative bacilli

Ampicillin plus Fluoroquinolone (Ciprofloxacin, Levofloxacin, or Trovafloxacin)

Ampicillin plus Ceftriaxone (or Cefotaxime)

Streptococcus pneumoniae, Listeria rnonocytogenes,

50 years and older

monocytogenes

Add Vancomycin in areas with greater than 2% incidence of highly drug resistant Streptococcus pneumoniae;for patients who have major penicillin allergy, TMP-SMX can substitute for ampicillin to treat Listeria

coccus pneumoniae

Add Vancomycin in areas with greater than 2% incidence of highly drug resistant Strepto-

coccus pneumoniae

Add Vancomycin in areas with greater than 2% incidence of highly drug resistant Strepto-

Meropenem or Chloramphenicol Meropenem or Chloramphenicol

Cerebrospinal fluid levels not reliable in low-birth-weight infants and should be monitored

Comment

Chloramphenicol plus Gentamicin

Alternative Regimens

Ceftriaxone (or Cefotaxime)

Ceftriaxone (or Cefotaxime)

Ampicillin plus Ceftriaxone (or Cefotaxime)

Antibiotic Regimen

Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae

Listeria rnonocytogenes, E. coli, Streptococcus pneumoniae Neisseria meningitidis, Streptococcuspneumoniae, Haemophilus influenzae

Group B Streptococcus,

Major Pathogens

18 to 50 years

3 months to 18 years

Less than 3 months

Age

Table 1. RECOMMENDED EMPlRlC ANTIMICROBIALTHERAPY FOR BACTERIAL MENINGITIS BASED ON AGE

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SPACH &JACKSON

Table 2. PATHOGEN-SPECIFICTHERAPY FOR PATIENTS WHO HAVE BACTERIAL MENINGITIS Organism

Group B Streptococcus

Haemophilus influenzae Listeria monocytogenes Neisseria meningitidis Streptococcus pneumoniae (MIC < 0.1) Streptococcus pneumoniae (MIC 2 0.1)

Preferred Regimen

Penicillin G (or Ampicillin) Ceftriaxone (or Cefotaxime) Ampicillin plus Gentamicin Penicillin G (or Ampicillin) Ceftriaxone (or Cefotaxime) Vancomycin plus Ceftriaxone (or Cefotaxime)

*Alternative Choices

Duration (Days)

Vancomycin

14-21 days

Chloramphenicol

7-10 days

Trimethoprimsulfamethoxazole Ceftriaxone (or Cefotaxime) Chloramphenicol Penicillin; meropenem

14-21 days

Substitute rifampin for vancomycin; use vancomycin monotherapy if highly allergic to cephalosporins

7-10 days 10-14 days 10-14 days

*Recommended choice for patient who has severe allergy to preferred medication.

The issue of whether to use corticosteroids in bacterial meningitis has stimulated extensive discussion and this issue remains controversial. The theoretical goal of corticosteroid use in meningitis is to minimize meningeal inflammation and thus to decrease the incidence and severity of brain injury. McIntyre and colleagues%analyzed data from 11 randomized, controlled trials of dexamethasone therapy in childhood bacterial meningitis, which were published from 1988

Table 3. RECOMMENDED INTRAVENOUS DOSES OF ANTIMICROBIALS USED TO TREAT BACTERIAL MENINGITIS Antimicrobial

Dose in Children

Dose in Adult

Ampicillin Cefotaxime Ceftriaxone Ceftazidime Chloramphenicol Gentamicin

75 mg/kg q6h 50-75 mg/kg q6h 50-75 mg/kg q12h 75 mg/kg q8h 25 mg/kg q6h t2.5 mg/kg q8h

Levofloxacin Meropenem Penicillin G Rifampin Trimethoprimsulfamethoxazole Vancomycin

Not indicated for use 40 mg/kg q8h 50,000 U/kg q4h 10 mg/kg q24h (max 600 mg) *10.0 mg/kg q12h

2.0 g q4h 2.0 g q6h 2.0 g q12h 2.0 g q8h 1.0 g q6h t2.0 mg/kg load, then 1.7 mg/kg q8h 0.5 g q24h 1.0 g q8h 4.0 million U q4h 600 mg q24h *10.0 mg/kg q12h

t15 mg/kg q6h

t l . O g q12h

*Based on Trimethoprim component. tMonitor blood levels and adjust accordingly; maximum 2 g per day for Vancomycin in children.

BACTERIAL MENINGITIS

729

to November 1996. Using random-effects meta-analysis models, they generated organism-specific summary estimates. For studies involving H. influenzae meningitis, dexamethasone significantly reduced severe hearing loss, even when they stratified studies by whether dexamethasone was given before or after antibiotics. In studies involving patients who have pneumococcal meningitis, dexamethasone significantly reduced severe hearing loss only if given before or with the first dose of antibiotics.For all organisms combined, there was no clear-cut benefit for dexamethasone in protecting against neurologic deficits other than hearing loss; this analysis, however, is complicated by the lack of uniform criteria used for evaluating neurologic deficits other than hearing loss. Adverse effects were not significantly increased with dexamethasone, except for an increase in secondary fever and an increased incidence of gastrointestinal bleeding in persons who received more than 2 days of dexamethasone. Three factors complicate the decision of whether to use corticosteroids: (1)sparse data exist on the use of corticosteroidsfor bacterial meningitis in adults, ( 2 ) H. influenzae was the predominant pathogen in most of the studies, and (3) most studies were performed before the widespread problem of penicillinresistant s. pneumoniae. Moreover, some experts have expressed concern that use of corticosteroids may decrease the cerebrospinal fluid penetration of some antimicrobials, such as vancomycin. Nevertheless, most experts favor the use of intravenous dexamethasone at a dose of 0.15 mg/kg every 6 hours for 4 days or 0.4 mg/kg every 12 hours for 2 days in children older than 2 months of age who have bacterial meningitis.66,82,116 If corticosteroids are given, they should be given before or with the first dose of antibiotic. For adults, some have recommended limiting the use of dexamethasone to those instances in which a patient has a positive cerebrospinal fluid Gram’s stain and an increased intracranial pressure.82 Further contemporary studies are needed to clarify the use of steroids in bacterial meningitis.

FUTURE DIRECTIONS

Despite the tremendous advances in the field of bacterial meningitis, significant morbidity and mortality continues to occur as a result of these infections. Future efforts will likely focus on the development of effective vaccines against S. pneumoniae, L. monocytogenes, and group B streptococcus.The need for an effective S. pneumoniae vaccine has taken on extreme importance for two reasons: (1) S. pneumoniae has become the most important bacterial meningitis pathogen, and ( 2 ) the alarming increase in drug-resistant S. pneumoniae has significantly complicated antibiotic therapy for bacterial meningitis. Clearly, a major advance in the area of preventing S. pneumoniae infections is greatly needed. The promising preliminary data with the new conjugated S. pneumoniae vaccineI5has generated enthusiasm that such a vaccine could have a drastic effect on the incidenceof invasive pneumococcal infections, including meningitis. The recently published conjugated N. meningitidis data also is very encouraging, but further work is needed to develop an excellent meningococcal conjugated vaccine that incorporates capsular B polysaccharide.HIn the near future, we may see the conjugated S. pneumoniae and N. meningitidis vaccines incorporated into routine childhood immunizations. Vaccine successes with regard to H. influenzae and S. pneumoniae will likely lead to enhanced efforts to develop effective L. monocytogenes and group B streptococcal vaccines. Effective vaccines will reduce but not eradicate bacterial meningitis;

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therefore, discovering and developing novel specific inhibitors of the inflammatory cascade will remain an important priority. The recent advances in the understanding of the pathogenesis of bacterial meningitis may make such an advance a reality in the future.

References 1. Analysis of endemic meningococcal disease by serogroup and evaluation of chemoprophylaxis. J Infect Dis 134:201, 1976 2. Control and prevention of meningococcal disease: Recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR 461, 1997 3. Prevention of perinatal group B streptococcal disease: A public health perspective. Centers for Disease Control and Prevention. MMWR 45:1, 1996 4. Progress toward eliminating Huemophilus influenzae type b disease among infants and children-United States, 1987-1997. MMWR 47993, 1998 5. Recommendations for use of Haemophilus b conjugate vaccines and a combined diphtheria, tetanus, pertussis, and Haemophilus b vaccine. Recommendations of the advisory Committee on Immunization Practices (ACIP).MMWR 42:1,1993 6. Update: Foodborne listeriosis-United States, 1988-1990. MMWR 41:251, 1992 7. Update: Prevention of Huemophilus influenzue type b disease. MMWR 35:170,1986 8. Adams WG, Deaver KA, Cochi SL, et al: Decline of childhood Huemophilus influenme type b (Hib) disease in the Hib vaccine era. JAMA 269:221, 1993 9. Arditi M, Mason EO Jr, Bradley JS, et al: Three-year multicenter surveillance of pneumococcal meningitis in children: Clinical characteristics, and outcome related to penicillin susceptibility and dexamethasone use. Pediatrics 102:1087, 1998 10. Asensi F, Otero MC, Perez-Tamarit D, et al: Risk/benefit in the treatment of children with imipenem-cilastatin for meningitis caused by penicillin-resistant pneumococcus. J Chemother 5:133,1993 11. Asensi F, Perez-Tamarit D, Otero MC, et a1 Imipenem-cilastatin therapy in a child with meningitis caused by a multiply resistant pneumococcus [letter]. Pediatr Infect Dis J 8: 895,1989 12. Barenkamp SJ, Munson RS Jr, Granoff DM: Subtyping isolates of Huemophilus influenzue type b by outer-membrane protein profiles. J Infect Dis 143:668, 1981 13. Barquet N, Domingo P, Cayla JA, et al: Prognostic factors in meningococcal disease. Development of a bedside predictive model and scoring system. Barcelona Meningococcal Disease Surveillance Group. JAMA 278:491,1997 14. Bjune G, Hoiby EA, Gronnesby JK, et al: Effect of outer membrane vesicle vaccine against group B meningococcal disease in Norway. Lancet 338:1093,1991 15. Black S, Shinefield H, Ray P, et a1 Efficacy of heptavalent conjugate pneumococcal vaccine in 37,000 infants and children: Results of the Northern California Kaiser Permanente Efficacy Trial. [Abstract LB-91. In 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, CA September 24-27,1998 16. Bouvet E, Suter F, Gibert C, et a1 Severe meningitis due to Listeriu monocytogenes. A review of 40 cases in adults. Scand J Infect Dis 14267, 1982 17. Bradley JS, Connor JD: Ceftriaxone failure in meningitis caused by Streptococcus pneumoniue with reduced susceptibility to beta-lactam antibiotics. Pediatr Infect Dis J 10:871, 1991 18. Bradley JS, Scheld WM: The challenge of penicillin-resistant Streptococcus pneumoniue meningitis: Current antibiotic therapy in the 1990s. Clin Infect Dis 24(suppl 2):S213, 1997 19. Broome CV, Facklam RIC Epidemiology of clinically significant isolates of Streptococcus pneumoniue in the United States. Rev Infect Dis 3:277, 1981 20. Broome CV, Mortimer EA, Katz SL, et a 1 Use of chemoprophylaxis to prevent the spread of Hemophilus influenzue B in day-care facilities. N Engl J Med 316:1226, 1987 21. Butler JC: Epidemiology of pneumococcal serotypes and conjugate vaccine formulations. Microb Drug Resist 3:125, 1997 22. Butler JC, Hofmann J, Cetron MS, et al: The continued emergence of drug-resistant Streptococcus pneumoniue in the United States: An update from the Centers for Disease

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Control and Prevention's Pneumococcal Sentinel Surveillance System. J Infect Dis 174: 986,1996 23. Cabellos C, Martinez-Lacasa J, Martos A, et al: Influence of dexamethasone on efficacy of ceftriaxone and vancomycin therapy in experimental pneumococcal meningitis. Antimicrob Agents Chemother 39:2158,1995 24. Caputo GM, Appelbaum PC, Liu H H Infections due to penicillin-resistant pneumococci. Clinical, epidemiologic, and microbiologic features. Arch Intern Med 153:1301, 1993 25. Cochi SL, Broome CV, Hightower AW Immunization of US children with Hemophilus influenzae type b polysaccharide vaccine. A cost-effectiveness model of strategy assessment. JAMA 253:521, 1985 26. Dagan R, Givon N, Yagupsky P, et al: Effect of a 9-valent pneumococcal vaccine conjugated to CRM-{l97} (PncCRM9) on nasopharyngeal (NP) carriage of vaccine type and non-vaccine type S. pneumoniue (Pnc) strains among day care center (DCC) attendees [Abstract G-521. In 38th Interscience Conference of Antimicrobial Agents and Chemotherapy, San Diego, CA September 24-27,1998 27. Destache CJ, Pakiz CB, Dash AK, et al: Nitric oxide concentrations and cerebrospinal fluid parameters in an experimental animal model of Streptococcus pneumoniue meningitis. Pharmacotherapy 18:612,1998 28. Deveikis A, Schauf V, Mizen M, et al: Antimicrobial therapy of experimental group B streptococcal infection in mice. Antimicrob Agents Chemother 11:817, 1977 29. Dillon JR, Pauze M, Yeung KH: Spread of penicillinase-producing and transfer plasmids from the gonococcus to Neisseriu meningitidis. Lancet 1:779, 1983 30. Doern GV, Brueggemann A, Holley HP Jr, et al: Antimicrobial resistance of Streptococcus pneumoniue recovered from outpatients in the United States during the winter months of 1994 to 1995: Results of a 30-center national surveillance study. Antimicrob Agents Chemother 40:1208,1996 31. Doern GV, Brueggemann AB, Pierce G, et al: Antibiotic resistance among clinicalisolates of Huemophilus influenzue in the United States in 1994 and 1995 and detection of betalactamase- positive strains resistant to amoxicillin-clavulanate: Results of a national multicenter surveillance study. Antimicrob Agents Chemother 41 32. Doit CP, Bonacorsi SP, Fremaux AJ, et al: In vitro killing activ clinically achievable concentrations in cerebrospinal fluid against penicillin-resistant Streptococcus pneumoniue isolated from children with meningitis. Antimicrob Agents Chemother 38:2655,1994 33. Durand ML, Calderwood SB, Weber DJ, et al: Acute bacterial meningitis in adults. A review of 493 episodes [see comments]. N Engl J Med 328:21, 1993 34. Erickson L, De Wals P: Complications and sequelae of meningococcal disease in Quebec, Canada, 1990-1994. Clin Infect Dis 26:1159,1998 35. Farley MM, Harvey RC, Stull T, et al: A population-based assessment of invasive disease due to group B Streptococcus in nonpregnant adults. N Engl J Med 328:1807, 1993 36. Fassbender K, Ries S, Schminke U, et al: Inflammatory cytokines in CSF in bacterial meningitis: Association with altered blood flow velocities in basal cerebral arteries. J Neurol Neurosurg Psychiatry 61:57,1996 37. Fleming DW, Cochi SL, MacDonald KL, et al: Pasteurized milk as a vehicle of infection in an outbreak of listeriosis. N Engl J Med 312:404, 1985 38. Friedland IR, Klugman KP: Failure of chloramphenicol therapy in penicillin-resistant pneumococcal meningitis. Lancet 339:405, 1992 39. Friedland IR, McCracken GH Jr: Management of infections caused by antibiotic-resistant Streptococcuspneumoniae. N Engl J Med 331:377,1994 40. Friedland IR, Paris M, Ehrett S, et al: Evaluation of antimicrobial regimens for treatment of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis. Antimicrob Agents Chemother 371630,1993 41. GalimandYM, Gerbaud G, Guibourdenche M, et al: High-level chloramphenicol resistance in Neisseriu meningitidis. N Engl J Med 339:868, 1998 42. Girgis N, Sultan Y, Frenck RW Jr, et a1 Azithromycin compared with rifampin for eradication of nasopharyngeal colonization by Neisseriu meningitidis. Pediatr Infect Dis J 17816,1998

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Address request reprints to David H. Spach, MD Harborview Medical Center 2 West Clinic, 359930 325 Ninth Avenue Seattle, WA 98104-2499 e-mail: [email protected]