Muller ML, dkk. Pediatric Bacterial Meningitis.

May 11
th
, 2011. Available from:
http://emedicine.medscape.com/article/961497-overview.


Signs and symptoms
The 3 classic symptoms (less likely in younger children):
Fever
Headache
Meningeal signs
Symptoms in neonates:
Poor feeding
Lethargy
Irritability
Apnea
Listlessness
Apathy
Fever
Hypothermia
Seizures
Jaundice
Bulging fontanelle
Pallor
Shock
Hypotonia
Shrill cry
Hypoglycemia
Intractable metabolic acidosis
Symptoms 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)
See Clinical Presentation for more specific information on the signs and symptoms of
pediatric bacterial meningitis.
Diagnosis
Definitive diagnosis is based on the following:
Bacteria isolated from the CSF obtained via lumbar puncture
Meningeal inflammation demonstrated by increased pleocytosis, elevated protein
level, and low glucose level in the CSF
Bacterial meningitis score
Components of the bacterial meningitis score
[1]
are as follows:
Positive CSF Gram stain
CSF absolute neutrophil count 1000/L or higher
CSF protein level 80 mg/dL or higher
Peripheral blood absolute neutrophil count 10,000/L or higher
History of seizure before or at the time of presentation
See Workup for more specific information on testing and imaging modalities for
pediatric bacterial meningitis.
Management
IV antibiotics are required; if cause is unknown, agents can be based on childs age,
as follows:
< 30 days, ampicillin and an aminoglycoside or a cephalosporin
30-60 days, ampicillin and a cephalosporin; because Streptococcus
pneumoniae may occur in this age range, consider vancomycin instead of
ampicillin
In older children, a cephalosporin or ampicillin plus chloramphenicol with
vancomycin (needs to be added secondary to the possibility of S pneumoniae)
Guidelines and recommendations
Infectious Diseases Society of America:
Vancomycin plus either ceftriaxone or cefotaxime
[2]

Duration of therapy:
o Neisseria meningitidis - 7 days
o Haemophilus influenzae - 7 days
o Streptococcus pneumoniae - 10-14 days
o S agalactiae (GBS) - 14-21 days
o Aerobic gram-negative bacilli - 21 days or 2 weeks beyond the first sterile culture
(whichever is longer)
o Listeria monocytogenes - 21 days or longer
American Academy of Pediatrics:
Duration of therapy should not be shorter than 5 days for meningococcus, 10 days
for H influenzae, and 14 days for S pneumoniae
[3]

Prevention
Preventive therapy has been shown to reduce mortality and morbidity and consists
of the following:
Chemoprophylaxis: Rifampin, ceftriaxone, ciprofloxacin; ciprofloxacin and
ceftriaxone are more effective against resistant strains of Neisseria meningitidis up
to 4 weeks after treatment
Haemophilus influenzae type b (Hib): Rifampin chemoprophylaxis for contacts of
index cases of invasive Hib disease; MenHibrix provides immunization against Hib
and meningococcal serogroups C and Y
Neisseria meningitidis: Quadrivalent (ie, A, C, Y, W-135) meningococcal conjugate
vaccine recommended for high-risk groups
See Treatment and Medication for more specific information on pharmacologic and
other therapies for pediatric bacterial meningitis.
Image library
Acute bacterial meningitis. This axial nonenhanced CT
scan shows mild ventriculomegaly and sulcal effacement.
Background
Pediatric bacterial meningitis is a life-threatening illness that results from bacterial
infection of the meninges. Because bacterial meningitis in the neonatal period has its
own unique epidemiologic and etiologic features, it will be discussed separately in
this article as necessary.
Beyond the neonatal period, the 3 most common organisms that cause acute
bacterial meningitis are Streptococcus pneumoniae, Neisseria
meningitidis, andHaemophilus 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), the rate of
pneumococcal meningitis is 59% lower than it was before the introduction of the
conjugate pneumococcal vaccine in 2000. 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.
Meningitis is a life-threatening illness and leaves some survivors with significant
sequelae. Therefore, meticulous attention must be paid to appropriate treatment and
monitoring of these patients. Patients require hospitalization for antibiotic therapy
and appropriate support. Adequate fluid administration is necessary to maintain
perfusion, especially cerebral perfusion. Fluid restrictions (to prevent cerebral
edema) may be more harmful because patients may be under resuscitated.
Antibiotics must be promptly administered.
The emergence of penicillin-resistant S pneumoniae has resulted in new challenges
in the treatment of bacterial meningitis.
Pathophysiology
Bacteria reach the subarachnoid space via 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 (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, and this
effect can result in increased intracranial pressure (ICP) and uncal herniation.
Increased secretion of antidiuretic hormone (ADH), 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 causes midline structures to shift caudally and become
entrapped 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.
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
arriving in the central nervous system (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
A
2
activity, initiating the production of platelet-activating factor and the arachidonic
acid pathway. This process results in production of prostaglandins, thromboxanes,
and leukotrienes. Activation of adhesion-promoting receptors on endothelial cells by
these cytokines attracts leukocytes, and the release of proteolytic enzymes from the
leukocytes results in altered blood-brain permeability, activation of the 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.
Etiology
Causes in different age groups
Neonates
Bacteria are often acquired from the maternal vaginal flora. Gram-negative enteric
flora and GBS are the dominant pathogens. In premature newborns who receive
multiple antibiotics, those on hyperalimentation, and those who undergo various
surgical procedures, Staphylococcus epidermidis and Candida species are
uncommon but are reported in greater frequency in neonates. L monocytogenes is
another well-known but fairly uncommon causative pathogen.
Early-onset GBS meningitis occurs during the first 7 days of life as a consequence of
maternal colonization and the absence of protective antibody in the neonate; it is
often 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. Causes
include perinatally acquired and nosocomial pathogens. Streptococcus
agalactiae(GBS) is 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 S
epidermidis andPseudomonas, Citrobacter, and Bacteroides species.
Infection with Citrobacter diversus, Citrobacter koseri, Salmonella species,
andProteus species, though uncommon, carries a high mortality. These patients
often develop brain abscesses, particularly those with Citrobacter, in whom
meningitis produces brain abscesses in 80-90% of cases.
Infants and children
In children older than 4 weeks, S pneumoniae and N meningitidis are the most
common etiologic agents. Hib has essentially disappeared in countries where the
conjugate vaccine is routinely used.
Causative organisms
Streptococcus pneumoniae
S pneumoniae is a gram-positive, lancet-shaped diplococcus that is 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 the 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, the 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 via direct contact; secondary cases are rare. The incubation period is
1-7 days, and infections are more common in winter, when viral respiratory disease
is prevalent. The disease often results in sensorineural hearing loss, hydrocephalus,
and other central nervous system (CNS) sequelae. Prolonged fever despite
adequate therapy is common with S pneumoniaemeningitis.
Effective antimicrobial therapy can eradicate the organism from nasopharyngeal
secretions within 24 hours. However, pneumococci have developed resistance to a
variety of antibiotics; this development is seen worldwide. Rates of resistance to
penicillin range from 10% to 60%. Multicenter surveillance of pneumococci isolated
from the cerebrospinal fluid (CSF) has found resistance rates of 20% to penicillin and
7% to ceftriaxone.
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 are often resistant to
trimethoprim-sulfamethoxazole, tetracyclines, chloramphenicol, and macrolides.
However, selected third-generation cephalosporins (eg, cefotaxime and ceftriaxone)
do exhibit activity against most penicillin-resistant pneumococcal isolates.
At present, all pneumococcal isolates remain susceptible to vancomycin and various
oxazolidinones. Several of the fluoroquinolones (eg, levofloxacin), though
contraindicated in children, have excellent activity against most pneumococci and
achieve adequate CNS penetration.
Tolerance, a trait distinct from resistance, is the term used to characterize bacteria
that stop growing in the presence of antibiotic yet do not lyse and die. Pneumococci
that are tolerant of penicillin and vancomycin have been described in literature, and a
subsequent link to recrudescent meningitis was described in 1 child. The overall
incidence and clinical impact of such bacterial strains are unknown. However, the
possibility of tolerance should be kept in mind in cases of recurrent pneumococcal
meningitis.
Neisseria meningitidis
N meningitidis is a gram-negative, kidney beanshaped organism that is frequently
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, as well as outbreaks
in military barracks.
The upper respiratory tract frequently is colonized with meningococci, and
transmission is person-to-person via direct contact with infected droplets of
respiratory secretions, often from asymptomatic carriers. The incubation period is
generally less than 4 days (range, 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 is 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, such as the following:
Hypotension
Shock
Neutropenia
Extremes of age
Petechiae and purpura of less than 12 hours duration
Disseminated intravascular coagulation (DIC)
Acidosis
Presence of the organism in white blood cells (WBCs) on peripheral smear
Low erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level
Serogroup C disease
Higher rates of fatality and physical sequelae (eg, scarring and amputation) are
reported in survivors of serogroup C disease. Long-term sequelae are rare in
patients who have an uneventful hospital course.
Haemophilus influenzaetype b (Hib)
Hib is a pleomorphic gram-negative rod whose shape varies from a coccobacillary
form to a long curved rod. Hib meningitis occurs primarily in children who have not
been immunized with Hib vaccine; 80-90% of cases occur 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 Hib, which are protective.
The mode of transmission is person-to-person via direct contact with infected
droplets of respiratory secretions. The incubation period generally is less than 10
days. Current mortality is 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 increasingly being reported: 30-35% of Hib isolates are
now ampicillin-resistant. As many as 30% of cases may have subtle long-term
sequelae. Administration of dexamethasone early in treatment reduces morbidity and
sequelae.
Listeria monocytogenes
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 and 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 a hemolytic streptococcus.
Other organisms
S epidermidis and other coagulase-negative staphylococci frequently cause
meningitis and CSF shunt infection in patients with hydrocephalus or those who have
undergone neurosurgical procedures. Immunocompromised children can develop
meningitis caused by Pseudomonas, Serratia,Proteus, and diphtheroids.
Risk factors
Risk factors for bacterial meningitis include the following:
Age
Low family income
Attendance at day care
Head trauma
Splenectomy
Chronic disease
Children with facial cellulitis, periorbital cellulitis, sinusitis, and septic arthritis have
an increased risk of meningitis.
Maternal infection and pyrexia at the time of delivery are associated withneonatal
meningitis
Use of Hib and pneumococcal vaccines decreases the likelihood of infection from
these agents.
Epidemiology
United States statistics
The advent of vaccine has changed the incidence of pediatric bacterial meningitis.
Before 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 (18 years). N meningitidis caused about 4 cases
per 100,000 children (aged 1-23 months). The rate of S pneumoniaemeningitis was
6.5 cases per 100,000 children (aged 1-23 months). Today, disease caused by H
influenzae, S pneumoniae, and N meningitidis is much less common.
The advent of universal Hib vaccination in developed countries has led to the
elimination of more than 99% of invasive disease. Protection continues even when
Hib is coadministered with other vaccines. Just as important, the vaccine continues
to confer immunity into later childhood.
A similar effect occurs with pneumococcal vaccine. Given at ages 2, 4, and 6
months, this vaccine has reduced invasive disease by more than 90%. Age groups
most affected are those younger than 2 years and those aged 2-5 years. This was
proven in a surveillance study in Louisville, Kentucky.
[4]
Nearly half of cases of
pneumococcal disease are caused by nonvaccine serotypes.
[5, 6]

Vaccine for Neisseria, however, has not been efficacious in younger children. This is
due to poor immunogenic response. Current recommendations target immunization
for children older than 2 years and high-risk patients with asplenic and terminal
complement deficiencies. In addition, young adults living in close quarters, such as
dormitories or military barracks, will benefit.
A study analyzing reported cases of bacterial meningitis among residents in 8
surveillance areas of the Emerging Infections Programs Network during 1998-2007
found a 31% decrease in meningitis cases during this period and an increase in
median patient age from 30.3 years in 1998-1999 to 41.9 years in 2006-2007; the
case fatality rate did not change significantly.
[7]
Overall, approximately 4100 cases of
bacterial meningitis occurred annually in the United States from 2003 to 2007, with
approximately 500 deaths.
[7]

The incidence of neonatal bacterial meningitis is 0.25-1 case per 1000 live births
(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.
After the initiation of intrapartum antibiotics in 1996, the national incidence of early-
onset GBS infection decreased substantially, from approximately 1.8 cases per 1000
live births in 1990 to 0.32 case per 1000 live births in 2003.
International statistics
Worldwide, the use of H influenzae type B and pneumococcal vaccines is increasing
at a rate faster than that observed with the use of hepatitis B vaccines.
[8]

In a survey by the Hib and Pneumococcal Working Group, the incidence of
meningitis in 2000 varied in different regions of the world. The overall incidence of
pneumococcal meningitis was 17 cases per 100,000, with the highest incidence in
Africa, at 38 cases per 100,000, and the lowest incidence in Europe, at 6 cases per
100,000.
[9]
The overall death rate was 10 cases per 100,000. The death rate was
highest in Africa, at 28 cases per 100,000, and lowest in Europe and Western Pacific
regions, at 3 cases per 100,000.
A similar trend was identified for Hib meningitis.
[10]
The overall incidence of Hib
meningitis in 2000 was 31 cases per 100,000. The African region had the highest
rate, at 46 cases per 100,000, and Europe had the lowest, at 13 cases per 100,000.
The overall death rate was 13 cases per 100,000. The highest death rate was in
Africa, at 31 cases per 100,000, and the lowest was in Europe, at 4 cases per
100,000.
Age-, sex-, and race-related demographics
Pediatric bacterial meningitis is most common in children younger than 4 years, with
a peak incidence in those aged 3-8 months.
Male infants have a higher incidence of gram-negative neonatal meningitis. Female
infants are more susceptible to L monocytogenes infection. S agalactiae (GBS)
affects both sexes equally.
Bacterial meningitis occurs more frequently in black, Native American, and Hispanic
children; this is thought to be related to socioeconomic rather than racial factors.
Prognosis
Mortality and morbidity depend on the infectious agent, the age of the child, the
childs general health, and the promptness of diagnosis and treatment. Despite
improvements in antibiotic and supportive therapy, death and complication rates
remain significant.
Overall mortality for bacterial meningitis is 5-10% and varies according to the
causative organism and the patients age. In neonates, mortality is 15-20%, whereas
in older children, it is 3-10%. Of the meningitides caused by the most common
pathogens, S pneumoniae meningitis has the highest mortality, at 26.3-30%; Hib
meningitis has the next highest, at 7.7-10.3%; and N meningitidis has the lowest, at
3.5-10.3%.
As many as 30% of children have neurologic sequelae. This rate varies by organism,
with S pneumoniae being associated with the highest rate of complications. One
study indicated that the complication rate from S pneumoniaemeningitis was
essentially the same for penicillin-sensitive strains as for penicillin-resistant strains;
this study also showed that dexamethasone did not improve outcomes.
[11]

Prolonged or difficult-to-control seizures, especially after hospital day 4, are
predictors of a complicated hospital course with serious sequelae. On the other
hand, seizures that occur during the first 3 days of illness usually have little
prognostic significance.
Approximately 6% of affected infants and children show signs of DIC and endotoxic
shock. These signs are indicative of a poor prognosis.
Studies have documented the development of profound bilateral hearing loss, which
may occur in as many as 4% of all bacterial meningitis cases.
[12]
Sensorineural
hearing loss is one of the most frequent problems. Children at greatest risk for
hearing loss include those with evidence of increased ICP, those with abnormal
findings on computed tomography (CT), males, those with low CSF glucose levels,
those with S pneumoniae infection , and those with nuchal rigidity.
Because many of the children affected are very young and lack mature cognitive and
motor skills, some of the sequelae may not be recognized for years. In a study that
followed children who recovered from meningitis for 5-10 years, 1 of every 4 school-
aged meningitis survivors had either serious and disabling sequelae or a functionally
important behavior disorder or neuropsychiatric or auditory dysfunction that impaired
their performance in school.
For tuberculous meningitis, morbidity and mortality are related to the stage of the
disease. The rate of significant morbidity is 30% for stage I, 56% for stage II, and
94% for stage III.
Patient Education
Because of the high incidence of sequelae, parents should be cautioned from the
beginning that even with appropriate medical care, the child may have some
complications. Respond promptly to parents concerns with adequate
documentation.
Careful neurologic examination and visual and hearing screening tests (brainstem
evoked potentials) should be obtained and reviewed with parents so that parents are
aware of any deficits. Early detection of deficits should result in initiating appropriate
physical and occupational therapy and in acquiring other devices or modalities
required by the patient to achieve the maximum possible benefit.