eMedicine Specialties > Pediatrics: General Medicine > Infectious Disease

Meningitis, Bacterial

Author: Martha L Muller, MD, Associate Professor of Pediatrics, Division of Infectious Diseases, University of New Mexico School of Medicine
Contributor Information and Disclosures

Updated: Nov 23, 2009

Introduction

Background

Bacterial meningitis is a life-threatening illness that results from bacterial infection of the meninges. Beyond the neonatal period, the 3 most common organisms that cause acute bacterial meningitis are Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae type b (Hib). Since the routine use of Hib, conjugate pneumococcal, and conjugate meningococcal vaccines in the United States, the incidence of meningitis has dramatically decreased.

Although S pneumoniae is now the leading cause of community-acquired bacterial meningitis in the United States (1.1 cases per 100,000 population overall), since the introduction of the conjugate pneumococcal vaccine in 2000, the rate of pneumococcal meningitis has declined 59%. The incidence of disease caused by S pneumoniae is highest in children aged 1-23 months and in adults older than 60 years. Predisposing factors include respiratory infection, otitis media, mastoiditis, head trauma, hemoglobinopathy, human immunodeficiency virus (HIV) infection, and other immune deficiency states.

The emergence of penicillin-resistant S pneumoniae has resulted in new challenges in the treatment of bacterial meningitis. Because bacterial meningitis in the neonatal period has its own unique epidemiologic and etiologic features, it is described separately in this article.

Pathophysiology

Bacteria reach the subarachnoid space by a hematogenous route and may directly reach the meninges in patients with a parameningeal focus of infection.

Once pathogens enter the subarachnoid space, an intense host inflammatory response is triggered by lipoteichoic acid and other bacterial cell wall products produced as a result of bacterial lysis. This response is mediated by the stimulation of macrophage-equivalent brain cells that produce cytokines and other inflammatory mediators. This resultant cytokine activation then initiates several processes that ultimately cause damage in the subarachnoid space, culminating in neuronal injury and apoptosis.

Interleukin 1 (IL-1), tumor necrosis factor-alpha (TNF-a), and enhanced nitric oxide production play critical roles in triggering inflammatory response and ensuing neurologic damage. Infection and inflammatory response later affect penetrating cortical vessels, resulting in swelling and proliferation of the endothelial cells of arterioles. A similar process can involve the veins, causing mural thrombi and obstruction of flow. The result is an increase in intracellular sodium and intracellular water.

The development of brain edema further compromises cerebral circulation, which can result in increased intracranial pressure and uncal herniation. Increased secretion of antidiuretic hormone resulting in the syndrome of inappropriate antidiuretic hormone secretion (SIADH) occurs in most patients with meningitis and causes further retention of free water. These factors contribute to the development of focal or generalized seizures.

Severe brain edema also results in a caudal shift of midline structures with their entrapment in the tentorial notch or foramen magnum. Caudal shifts produce herniation of the parahippocampal gyri, cerebellum, or both. These intracranial changes appear clinically as an alteration of consciousness and postural reflexes. Caudal displacement of the brainstem causes palsy of the third and sixth cranial nerves. If untreated, these changes result in decortication or decerebration and can progress rapidly to respiratory and cardiac arrest.

Pathogenesis of neonatal meningitis

Bacteria from the maternal genital tract colonize the neonate after rupture of membranes, and specific bacteria, such as group B streptococci (GBS), enteric gram-negative rods, and Listeria monocytogenes, can reach the fetus transplacentally and cause infection. Furthermore, newborns can also acquire bacterial pathogens from their surroundings, and several host factors facilitate a predisposition to bacterial sepsis and meningitis. Bacteria reach the meninges via the bloodstream and cause inflammation. After reaching the CNS, bacteria spread from the longitudinal and lateral sinuses to the meninges, the choroid plexus, and the ventricles.

IL-1 and TNF-a also mediate local inflammatory reactions by inducing phospholipase A₂ activity, initiating the production of platelet-activating factor and arachidonic acid pathway. This process results in production of prostaglandins, thromboxanes, and leukotrienes. By activating adhesion-promoting receptors on endothelial cells, these cytokines result in attraction of leukocytes, and then release of proteolytic enzymes from the leukocytes causes alteration of blood-brain permeability, activation of coagulation cascade, brain edema, and tissue damage.

Inflammation of the meninges and ventricles produces a polymorphonuclear response, an increase in cerebrospinal fluid (CSF) protein content, and utilization of glucose in CSF. Inflammatory changes and tissue destruction in the form of empyema and abscesses are more pronounced in gram-negative meningitis. Thick inflammatory exudate causes blockage of the aqueduct of Sylvius and other CSF pathways, resulting in both obstructive and communicating hydrocephalus.

Frequency

United States

Prior to the routine use of the pneumococcal conjugate vaccine, the incidence of bacterial meningitis in the United States was about 6000 cases per year; roughly half of these were in pediatric patients (³ 18 y). N meningitidis causes about 4 cases per 100,000 children (aged 1-23 mo). The rate of S pneumoniae meningitis was 6.5 cases per 100,000 children (aged 1-23 mo). This number has since declined given the routine use of conjugate pneumococcal vaccine in children. The recent introduction of conjugate meningococcal vaccine in the United States is expected to reduce the incidence of bacterial meningitis even further.

Incidence of neonatal bacterial meningitis is 0.25-1 case per 1000 live births. In addition, incidence is 0.15 case per 1000 full-term births and 2.5 cases per 1000 premature births. Approximately 30% of newborns with clinical sepsis have associated bacterial meningitis.

Since the initiation of intrapartum antibiotics in 1996, a decrease has occurred in the national incidence of early-onset GBS infection from approximately 1.8 cases per 1000 live births in 1990 to 0.32 case per 1000 live births in 2003.

Mortality/Morbidity

In general, mortality rates vary with age and pathogen, with the highest being for S pneumoniae. Despite effective antimicrobial and supportive therapy, mortality rates among neonates remain high, with significant long-term sequelae in survivors. Bacterial meningitis also causes long-term sequelae and results in significant morbidity beyond the neonatal period. Mortality rates are highest during the first year of life, decreasing in mid life and increasing again in elderly persons.

Despite advances in care for patients with bacterial meningitis, the overall case fatality remains steady at approximately 10-30%.

Race

Incidence rates are higher in black and Native American populations.

Sex

Male infants have a higher incidence of gram-negative neonatal meningitis. Female infants are more susceptible to L monocytogenes infection. Streptococcus agalactiae (group B streptococci) affects both sexes equally.

Clinical

History

• Symptoms of neonatal bacterial meningitis are nonspecific and include the following:
  • Poor feeding
  • Lethargy
  • Irritability
  • Apnea
  • Listlessness
  • Apathy
  • Fever
  • Hypothermia
  • Seizures
  • Jaundice
  • Bulging fontanelle
  • Pallor
  • Shock
  • Hypotonia
  • Shrill cry
  • Hypoglycemia
  • Intractable metabolic acidosis
• The following symptoms are readily recognized as associated with meningitis in infants and children:
  • Nuchal rigidity
  • Opisthotonos
  • Bulging fontanelle
  • Convulsions
  • Photophobia
  • Headache
  • Alterations of the sensorium
  • Irritability
  • Lethargy
  • Anorexia
  • Nausea
  • Vomiting
  • Coma
  • Fever (generally present, although some severely ill children present with hypothermia)

Physical

• Neonatal
  • A high index of suspicion and awareness of risk factors usually results in early diagnosis and prompt treatment.
  • Cardinal signs of meningitis (eg, fever, vomiting, stiff neck) are rarely present. For neonatal meningitis, these signs are the exception, rather than the rule.
• Infants and children
  • Kernig and Brudzinski signs are helpful indicators when present, but they may be absent (along with nuchal rigidity) in the very young, debilitated, or malnourished infants.
  • Skin findings range from a nonspecific blanching, erythematous, maculopapular rash to a petechial or purpuric rash, most characteristic of meningococcal meningitis.
  • Patients also may have other foci of infection. Presenting symptoms may point toward those foci, causing unnecessary delay in diagnosis of bacterial meningitis.
  • Approximately 15% of patients have focal neurologic signs upon diagnosis. The presence of focal neurologic signs predicts a complicated hospital course and significant long-term sequelae.
  • Generalized or focal seizures are observed in as many as 33% of patients. Seizures that occur during the first 3 days of illness usually have little prognostic significance. However, prolonged or difficult-to-control seizures, especially when observed beyond the fourth hospital day, are predictors of a complicated hospital course with serious sequelae.
  • In later stages of the disease, a few patients develop focal CNS symptoms and other systemic signs (eg, fever) indicating a significant collection of fluid in the subdural space. Incidence of subdural effusion is independent of the bacterial organism causing meningitis.
  • Approximately 6% of affected infants and children show signs of disseminated intravascular coagulopathy and endotoxic shock. These signs are indicative of a poor prognosis.

Causes

• Etiology of neonatal meningitis
  • Bacteria often are acquired from the maternal vaginal flora. Gram-negative enteric flora and group B streptococci are predominant pathogens. In premature newborns who receive multiple antibiotics, hyperalimentation, and who undergo various surgical procedures, Staphylococcus epidermidis and Candida species are uncommon etiologies but are reported in greater frequency in neonates. L monocytogenes is another well known but fairly uncommon etiologic pathogen.
  • Early-onset group B streptococcal meningitis occurs during the first 7 days of life, a consequence of maternal colonization and the absence of protective antibody in the neonate; it often is associated with obstetric complications. The disease is seen most often in premature or low birth weight babies. Pathogens are acquired before or during the birth process.
  • Late-onset meningitis is defined as disease occurring after 7 days of life. Etiologic agents include perinatally acquired and nosocomial pathogens. S agalactiae (group B streptococci) are classified into 5 distinct serotypes: Ia, Ib, Ic, II, and III. Although these serotypes occur with almost equal frequency in the early onset of disease, serotype III causes 90% of late-onset disease.
  • Use of respiratory equipment in the nursery increases the risk of infection caused by Serratia marcescens, Pseudomonas aeruginosa, and Proteus species. Invasive devices predispose infants to the infections caused by Staphylococcus epidermidis and Pseudomonas, Citrobacter, and Bacteroides species.
  • Infection with Citrobacter diversus, Citrobacter koseri, Salmonella species, and Proteus species though uncommon, carries a high mortality rate. These patients often develop brain abscesses, particularly Citrobacter where meningitis produces brain abscesses in 80-90% of cases.
• Etiology of meningitis in infants and children: In children older than 4 weeks, S pneumoniae and N meningitidis are the most common etiologic agents. H influenzae type b has essentially disappeared in countries where the conjugate vaccine is routinely used.
• S pneumoniae meningitis
  • S pneumoniae are lancet-shaped, gram-positive diplococci and are the leading cause of meningitis. Of the 84 serotypes, numbers 1, 3, 6, 7, 14, 19, and 23 are the ones most often associated with bacteremia and meningitis.
  • Children of any age may be affected, but incidence and severity are highest in very young and elderly persons.
  • In patients with recurrent meningitis, predisposing factors are anatomic defects, asplenia, and primary immune deficiency. Often history includes recent or remote head trauma.
  • This organism also has a predilection for causing meningitis in patients with sickle cell disease, other hemoglobinopathies, and functional asplenia. Immunity is type specific and long lasting.
  • S pneumoniae colonizes the upper respiratory tract of healthy individuals; however, disease often is caused by a recently acquired isolate. Transmission is person-to-person, usually by direct contact, and secondary cases are rare. The incubation period varies from 1-7 days, and infections are more prevalent during the winter when viral respiratory disease is prevalent. The disease often results in sensorineural hearing loss, hydrocephalus, and other CNS sequelae. Prolonged fever despite adequate therapy is common in patients with meningitis caused by this organism.
  • Effective antimicrobial therapy can eradicate the organism from nasopharyngeal secretions within 24 hours. Over the past decade, pneumococci have developed resistance to a variety of antibiotics. Although this development is seen worldwide, resistance rates to penicillin vary from 10-60%. Recent multicenter surveillance results of pneumococci isolated from the cerebrospinal fluid (CSF) show resistance rates of 20% and 7% to penicillin and ceftriaxone, respectively. Penicillin resistance in pneumococci is due to alterations in enzymes necessary for growth and repair of the penicillin-binding proteins; thus, beta-lactamase inhibitors offer no advantage. Penicillin-resistant pneumococci often demonstrate resistance to sulfamethoxazole/trimethoprim, tetracyclines, chloramphenicol, and macrolides. However, selected third-generation cephalosporins (eg, cefotaxime, ceftriaxone) do exhibit activity against most penicillin-resistant isolates.
  • To date, all isolates remain susceptible to vancomycin and various oxazolidinones. Several of the new fluoroquinolones (eg, levofloxacin), although contraindicated in children, have excellent activity against most pneumococci and achieve adequate CNS penetration.
  • Tolerance, a trait distinct from resistance, was first described in 1970 to characterize bacteria that stop growing in the presence of antibiotic, yet do not lyse and die. Pneumococci tolerant to penicillin and vancomycin have been previously described in literature and a subsequent link to recrudescence in meningitis described in one child. The overall incidence and clinical impact of such bacterial strains is unknown. However, this characteristic should be kept in mind in cases of recurrent pneumococcal meningitis.
• N meningitidis meningitis
  • N meningitidis are gram-negative, kidney bean–shaped organisms and frequently are found intracellularly. Organisms are grouped serologically on the basis of capsular polysaccharide; A, B, C, D, X, Y, Z, 29E, and W-135 are the pathogenic serotypes. In developed countries, serotypes B, C, Y, and W-135 account for most childhood cases. Group A strains are most prevalent in developing countries and have resulted in epidemics of meningococcal meningitis throughout the world and in outbreaks in military barracks. The upper respiratory tract frequently is colonized with meningococci, and transmission is person-to-person by direct contact through infected droplets of respiratory secretions, often from asymptomatic carriers. The incubation period generally is less than 4 days, with a range of 1-7 days.
  • Most cases occur in infants aged 6-12 months; a second lower peak occurs among adolescents. A petechial or purpuric rash frequently is seen. Mortality rates are significant in patients who have a rapidly progressive fulminant form of the disease. Normocellular CSF also has been reported in patients with meningococcal meningitis. Most deaths occur within 24 hours of hospital admission in patients who have features associated with poor prognosis (eg, hypotension, shock, neutropenia, extremes of ages, petechiae and purpura of <12 h duration, disseminated intravascular coagulopathy, acidosis, presence of organism in WBC on peripheral smear, low erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP], serogroup C disease).
  • Higher rates of fatality and physical sequelae such as scarring and amputation are reported in survivors of serogroup C disease. Long-term sequelae are rare in patients who have an uneventful hospital course.
• H influenzae type b meningitis
  • H influenzae type b is a pleomorphic gram-negative rod whose shape varies from a coccobacillary form to a long curved rod. H influenzae meningitis occurs primarily in children who have not been immunized with H influenzae type b vaccine, with 80-90% of the cases occurring in children aged 1 month to 3 years. By age 3 years, a significant number of nonimmunized children acquire antibodies against the capsular polyribophosphate of H influenzae type b, which are protective.
  • Mode of transmission is person-to-person by direct contact through infected droplets of respiratory secretions. The incubation period generally is less than 10 days.
  • Current mortality rates are less than 5%. Most fatalities occur during the first few days of the illness.
  • Plasmid-mediated resistance to ampicillin due to the production of beta-lactamase enzymes by bacterium is being reported increasingly, and now 30-35% of the isolates are ampicillin resistant. As many as 30% of cases may have subtle long-term sequelae. Administration of dexamethasone early in treatment reduces the morbidity and sequelae.
• L monocytogenes meningitis: L monocytogenes causes meningitis in newborns, immunocompromised children, and pregnant women. The disease also has been associated with the consumption of contaminated foods (eg, milk, cheese). Most cases are caused by serotypes Ia, Ib, and IVb. Signs and symptoms in patients with listerial meningitis tend to be subtle, and diagnosis often is delayed. In the laboratory, this pathogen can be misidentified as a diphtheroid or as hemolytic streptococci.
• Other causes
  • S epidermidis and other coagulase-negative staphylococci frequently cause meningitis and CSF shunt infection in patients with hydrocephalus or following neurosurgical procedures.
  • Immunocompromised children can develop meningitis caused by species of Pseudomonas, Serratia, Proteus, and diphtheroids.

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