Pediatric bacterial meningitis is a life-threatening illness that results from bacterial infection of the meninges and leaves some survivors with significant sequelae. Therefore, meticulous attention must be paid to appropriate treatment and monitoring of patients with this disease.
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/µL or higher
CSF protein level 80 mg/dL or higher
Peripheral blood absolute neutrophil count 10,000/µL or higher
History of seizure before or at the time of presentation
Specific hematologic, radiographic (eg, computed tomography [CT] and magnetic resonance imaging [MRI]), and other studies assist in diagnosis. CT and MRI may reveal ventriculomegaly and sulcal effacement (see the image below).
View Image
Acute bacterial meningitis. This axial nonenhanced CT scan shows mild ventriculomegaly and sulcal effacement.
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 child’s 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:
Neisseria meningitidis - 7 days
Haemophilus influenzae - 7 days
Streptococcus pneumoniae - 10-14 days
S agalactiae (GBS) - 14-21 days
Aerobic gram-negative bacilli - 21 days or 2 weeks beyond the first sterile culture (whichever is longer)
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.
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, 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), 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.
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 A2 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.
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 and Pseudomonas, Citrobacter, and Bacteroides species.
Infection with Citrobacter diversus, Citrobacter koseri, Salmonella species, and Proteus 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.
A cohort study of infants < 90 days of age with bacterial meningitis by Ouchenir et al reported that E coli (33%) and GBS (31%) remain the most common causes of bacterial meningitis in the first 90 days of life. The study also concluded that if there is evidence for Gram-negative meningitis, a third-generation cephalosporin (plus ampicillin for at least the first month), can be considered.[4]
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 pneumoniae meningitis.
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 bean–shaped 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.
A systematic review by Sridhar et al indicated that in most countries around the world, the annual incidence of invasive N meningitidis serogroup B between January 2000 and March 2015 was less than 2 cases per 100,000 people, although the incidence was higher in Australia, Europe, North America, and South America.[5]
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 with neonatal meningitis
Use of Hib and pneumococcal vaccines decreases the likelihood of infection from these agents.
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 pneumoniae meningitis 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.[6] Nearly half of cases of pneumococcal disease are caused by nonvaccine serotypes.[7, 8]
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.[9] Overall, approximately 4100 cases of bacterial meningitis occurred annually in the United States from 2003 to 2007, with approximately 500 deaths.[9]
A study that reported on the epidemiology of infant meningococcal disease in the United States from 2006 to 2012 found that an estimated 113 cases of culture-confirmed meningococcal disease occurred annually among infants aged < 1 year in the United States from 2006 through 2012, for an overall incidence of 2.74 per 100,000 infants. Among these cases, an estimated 6 deaths occurred. Serogroup B was responsible for 64%, serogroup C for 12%, and serogroup Y for 16% of infant cases. Based on the expanded data collection forms, a high proportion of infant cases (36/58, 62%) had a smoker in the household and the socioeconomic status of the census tracts where infant meningococcal cases resided was lower compared with the other Active Bacterial Core surveillance areas and the United States as a whole.[10]
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.[11]
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.[12] 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.[13] 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.
Mortality and morbidity depend on the infectious agent, the age of the child, the child’s 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 patient’s 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 pneumoniae meningitis was essentially the same for penicillin-sensitive strains as for penicillin-resistant strains; this study also showed that dexamethasone did not improve outcomes.[14]
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.[15] 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.
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.
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)
The younger the child, the less likely he or she is to exhibit the classic symptoms of fever, headache, and meningeal signs.
Meningitis in the neonatal period is associated with maternal infection or pyrexia at delivery. A child younger than 3 months may have very nonspecific symptoms, including hyperthermia or hypothermia, change in sleeping or eating habits, irritability or lethargy, vomiting, high-pitched cry, or seizures. Meningismus and a bulging fontanel may be observed but are not needed for diagnosis. A child who is quiet at rest but who cries when moved or comforted may have meningeal irritation (paradoxical irritability).
After the age of 3 months, the child may display symptoms more often associated with bacterial meningitis, with fever, vomiting, irritability, lethargy, or any change in behavior. After the age of 2-3 years, children may complain of headache, stiff neck, and photophobia.
The clinical course may be brief and fulminant with rapid progression of symptoms or may follow a more gradual course with several days of upper respiratory infection progressing to more severe symptoms. The fulminant course is more often associated with N meningitidis infection.
Signs and symptoms in patients with listerial meningitis tend to be subtle, and diagnosis is often delayed.
Note that patients also may have other foci of infection. The presenting symptoms may point toward those foci, causing unnecessary delay in diagnosis of bacterial meningitis.
Physical examination findings vary widely, depending on the infecting organism and the patient’s age. In general, the younger the child, the less specific the symptoms. As the child grows older, the physical examination becomes more reliable.
Neonates
A high index of suspicion and awareness of risk factors usually results in early diagnosis and prompt treatment of bacterial meningitis in neonates. 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 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 may also 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 central nervous system (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.
Obtundation and coma occur in 15-20% of patients and are more frequent with pneumococcal meningitis.
Approximately 6% of affected infants and children show signs of disseminated intravascular coagulation (DIC) and endotoxic shock. These signs are indicative of a poor prognosis.
Seizures are a common complication of bacterial meningitis, affecting almost one third of the patients. Persistent seizures, seizures late in the course of disease, and focal seizures are more likely to be associated with neurologic sequelae.
Other complications that can be seen during the course of bacterial meningitis include the syndrome of inappropriate antidiuretic hormone secretion (SIADH), subdural effusions, and brain abscesses. Subdural effusions are generally asymptomatic and resolve without neurologic sequelae.
Long-term sequelae are seen in as many as 30% of children; they vary according to the infecting organism, the patient’s age, the presenting features, and the hospital course. Long-term close follow-up care of children is crucial for the early detection of sequelae.
Although most patients have subtle CNS changes, serious complications are occasionally observed. These complications include nerve deafness, cortical blindness, hemiparesis, quadriparesis, muscular hypertonia, ataxia, complex seizure disorders, mental motor retardation, learning disabilities, obstructive hydrocephalus, and cerebral atrophy.
Mild-to-severe impairment of hearing is noted in as many as 20-30% of affected children with H influenzae disease but is less common with other pathogens. Early administration of dexamethasone reduces the incidence of audiologic complications in Hib meningitis. Severe hearing impairment interferes with the development of normal speech; thus, frequent audiologic evaluation and developmental assessment must be performed during healthcare visits.
Whenever motor sequelae are detected, physical, occupational, and rehabilitation services should evaluate the patient to prevent further damage and to provide optimal functional status.
Bacterial meningitis is a medical emergency. A firm diagnosis is usually made when bacteria are isolated from the cerebrospinal fluid (CSF) and evidence of meningeal inflammation is demonstrated by increased pleocytosis, elevated protein level, and low glucose level in the CSF. Timely collection and processing of CSF and isolation of an organism allows optimization of choice of antimicrobial agent and duration of therapy. CSF chemistries and cytology vary, depending on the maturity and age of the newborn.[17]
A lumbar puncture (LP) may be contraindicated in some of the following conditions: unstable patients with hypotension or respiratory distress who may not be able to tolerate the procedure, brain abscess, brain tumors or other cause of raised intracranial pressure, and occasionally infection at the lumbar puncture site.
The Bacterial Meningitis Score, a clinical decision rule developed by Nigrovic et al,[18] has shown high accuracy and usability and continues to be evaluated with respect to its effectiveness as an aid to identify those children with CSF pleocytosis who are at low risk for bacterial meningitis.[1] The components of the score include the following:
Positive CSF Gram stain
CSF absolute neutrophil count of 1000/µL or higher
CSF protein level of 80 mg/dL or higher
Peripheral blood absolute neutrophil count of 10,000/µL or higher
History of seizure before or at the time of presentation
Specific hematologic, radiographic (eg, computed tomography [CT] and magnetic resonance imaging [MRI]), and other studies assist in diagnosis.
Blood studies that may be indicated include the following:
Complete blood count (CBC) with differential
Blood cultures
Coagulation studies
Serum glucose
Electrolytes
Measurement of the serum glucose level close to the time of CSF collection is helpful for interpreting CSF glucose levels and assessing the likelihood of meningitis.
Bacterial antigen studies can be performed on urine and serum and can be useful in cases of pretreated meningitis; however, a negative bacterial antigen study result does not rule out meningitis. The group B streptococcal (GBS) antigen test in urine is unreliable and should not be used to make a diagnosis of sepsis or meningitis.
Some data suggest that procalcitonin may be a useful biomarker for distinguishing bacterial meningitis from aseptic meningitis. Its use may enhance the sensitivity of the Bacterial Meningitis Score.[19, 20, 18] In a retrospective analysis of admitted patients with meningitis, Dubos et al found procalcitonin at a level of 0.5 ng/mL to have a sensitivity of 99% and a specificity of 83% for differentiating bacterial from aseptic meningitis.[19]
Definitive diagnosis is based on examination of CSF obtained via lumbar puncture. Opening and closing pressures should be measured in the cooperative patient. Similarly, the color of the CSF (eg, turbid, clear, or bloody) should be recorded. If the CSF is not crystal clear, administer treatment immediately without waiting for the results of CSF tests.
In a traumatic lumbar puncture, where bleeding occurs and the CSF is contaminated with blood, interpretation becomes especially difficult. In this situation, it is better to initiate treatment before the results of the CSF culture are available. In very bloody lumbar punctures, a drop of the fluid on the sterile dressing usually will produce a double ring if CSF is present. Generally, when in doubt, proceed with treatment and attempt the lumbar puncture again later.
In particular, if the patient shows signs of pending herniation, consider treatment without performing a lumbar puncture. The puncture can be performed later, when intracranial pressure (ICP) has been controlled and the patient is clinically stable. CT or MRI is helpful in managing patients who require control of ICP and herniation.
CSF studies
Perform total and differential cell counts, chemistries (ie, glucose and protein), Gram stains, and cultures on all CSF specimens. In a setting of antibiotic pretreatment, rapid bacterial antigen testing may be considered. Note that patients with both fulminant disease and poor immune response may not show cytologic or chemical changes in CSF. In about 2-3% of bacterial meningitis cases, bacterial cultures may be positive even when the Gram stain is negative and the cell counts and glucose and protein levels are normal.
White blood cell (WBC) counts higher than 1000/µL are usually caused by bacterial infections. Counts of 500-1000/µL may be bacterial or viral and call for further evaluation. Lower counts are usually associated with viral infections.
The total WBC count cannot definitely distinguish between bacterial and other causes. At one time, it was generally believed that a predominance of polymorphonuclear leukocytes (PMNs) pointed to bacterial meningitis, but this has been an unreliable indicator; bacterial meningitis may also present with a lymphocytic predominance. Attempts to differentiate bacterial and aseptic meningitis on the basis of percentage and absolute number of premature neutrophils (ie, bands) have not yielded diagnostic results.[21]
The use of a corrected ratio of WBCs to red blood cells (RBCs)—that is, 1:500—or the percentage of neutrophils to “normalize” the cell count was shown to have limited utility in predicting which patients would have meningitis. The “corrected CSF” was shown to underestimate the true WBC count, causing clinicians to underdiagnose borderline meningitis cases. Formulas to adjust the WBC count have not increased the specificity or sensitivity of CSF analysis in traumatic lumbar punctures in neonates.[22]
The CSF protein concentration is usually elevated in bacterial meningitis (greater than 50 mg/dL), but it is also elevated by a traumatic lumbar puncture. The CSF glucose concentration is usually reduced in bacterial meningitis. A normal CSF glucose level should be higher than two thirds of the serum glucose level; a CSF level lower than 50% of the serum level is suggestive of bacterial meningitis. In patients with very early disease, however, CSF protein and glucose values may be within the reference range.
A study by Thomson et al that included CSF profiles from 7,766 infants ≤60 days old reported that in infants ≤28 days of age, CSF WBC counts and protein concentrations were higher and CSF glucose concentrations lower than in infants 29 to 60 days of age.[40]
A Gram stain of cytocentrifuged CSF may reveal bacterial morphology. The CSF should be plated immediately onto a chocolate and blood agar media. Smears of petechial lesions may reveal microorganisms on Gram stain. Although Gram stain may aid in diagnosis, the diagnosis may be missed in up to 30-40% of cases of culture-proven disease. The sensitivity of a positive Gram stain is 67%.[23]
Examination of a buffy coat smear also may reveal intracellular microorganisms. The results of a retrospective cohort study found that WBC counts in the CSF of febrile infants without bacterial or enteroviral infection are lower than was previously reported.[24]
Even when CSF results are otherwise normal, the fluid should still be sent for culture. Both N meningitidis meningitis and S pneumoniae meningitis are known to give normal CSF results. In an evidence-based article, Ray et al found that meningitis may still exist in 10% of children who have normal CSF analysis.[25] Their recommendation is to treat any child with antibiotics if there is a risk of bacterial meningitis.
Several tests based on the principle of agglutination are available for the detection of bacterial antigens in body fluids. Bacterial antigen detection can be carried out in samples of CSF, blood, and urine. A negative result, however, does not rule out bacterial infection. Antigen detection tests are most helpful in patients with partially treated meningitis in whom bacteria may not grow from CSF but antigens persist in body fluids. Antigen detection in urine is particularly helpful in such circumstances because urine can be concentrated severalfold in the laboratory.
Several gram-negative bacteria and higher serotypes of S pneumoniae have capsular antigens that cross-react with H influenzae type b polyribophosphate. Capsular antigens of group B meningococcus cross-react with K1-containing Escherichia coli. Gram stains of CSF are more sensitive than these rapid diagnostic tests for the detection of N meningitidis.
A study by Ye et al suggested that pediatric bacterial meningitis can be differentiated from similar disorders by assessing the concentration of IL-6 in the CSF and by evaluating the CSF/blood IL-6 ratio. The study found that these values were significantly higher in pediatric patients with bacterial meningitis than in healthy controls and in children with viral encephalitis, epilepsy, or febrile convulsions. The study also found that following treatment of the meningitis, CSF IL-6 levels fell by a significant amount, indicating that IL-6 concentrations may be a means of determining the efficacy of bacterial meningitis therapy.[26]
Partially treated meningitis
Many children receive antibiotics before definitive diagnosis is made. As a rule, a few doses of oral antimicrobial agents, or even a single injection of an antibiotic, do not significantly alter CSF findings, including bacterial cultures, especially in patients with H influenzae type b (Hib) disease. Oral antibiotics have never convincingly been shown to render patients with bacterial meningitis CSF culture–negative.
CSF cultures may become sterile rapidly if the pathogen was a pneumococcus or meningococcus, though cellular changes, an increase in protein, and low glucose levels persist. In such cases, CSF, blood, and urine should be tested for bacterial antigens; however, the presence of a negative antigen result does not entirely rule out a bacterial source.
In cases where antibiotic administration leads to CSF sterilization, polymerase chain reaction (PCR) testing may have a role to play in identifying the pathogen. PCR testing is able to identify the pathogen quickly and accurately and does not require a large number of organisms; however, it does require further validation in this setting.
Nigrovic et al found that Gram stain results (WBC count and absolute neutrophil count) in CSF were not affected by pretreatment with antibiotics; however, the rates of positive CSF culture and blood culture were lower with antibiotic pretreatment.[27] After pretreatment with antibiotics for 12 hours or longer, the patients had higher CSF glucose levels and lower CSF protein levels.
Prehospital care of children with bacterial meningitis usually is confined to transporting children who are critically ill or have experienced a seizure. General supportive care is required, depending on the child’s condition. Subsequent diagnosis of a potentially transmissible disease must be communicated to prehospital care providers, especially with N meningitidis infections.
Patients must be treated in a facility where emergencies can be managed and nursing and medical staff are experienced in caring for critically ill patients. Accordingly, they may require a transfer to a pediatric hospital or large general hospital. Depending on the child’s condition, admission to a pediatric intensive care unit (ICU) may be warranted.
If the child is critically ill or experiencing a seizure, immediate stabilization and support are necessary. If the child is hemodynamically stable, intravenous (IV) fluids should be administered at maintenance. Careful record of the patient’s weight, urine specific gravity, and serum osmolarity will help guide further fluid therapy. Patients who present with dehydration should be rehydrated and should not undergo fluid restriction. Seizures should be treated promptly and should be expected at any time during the initial management.
Whenever bacterial meningitis is suspected, a lumbar puncture is indicated (see Workup). Adequate analgesia is essential; in one study, only 1 in 7 infants received any pain management during lumbar puncture.[28] If the child’s condition is unstable or there is suspicion of increased intracranial pressure (ICP), the lumbar puncture should be delayed. In ill children, this delay should not delay the commencement of antibiotic therapy.
If lumbar puncture cannot be performed promptly, administration of antibiotics should be initiated. However, sterilization of cerebrospinal fluid (CSF) will occur. Date suggest that complete CSF sterilization occurs within 2 hours for meningococcal meningitis and within 4 hours for pneumococcal infections.
Consultation with a pediatrician, an infectious disease specialist, or a critical care specialist may be needed. The primary care physician must coordinate the follow-up care and keep all involved specialists informed so that prompt action can be taken if any concerns exist.
In general, pediatric patients with bacterial meningitis require hospitalization to complete their entire parenteral antibiotic course. However, in view of the constant pressure to decrease hospital stays, there are very select occasions when older pediatric patients may reasonably be discharged from the hospital to continue parenteral antibiotics at home.
In a retrospective study of children with bacterial meningitis complicated by stroke, treatment with heparin or aspirin appeared to be safe and to discourage stroke recurrence, with heparin possibly being the more effective of the two medications. Sixteen patients were treated with heparin (6 patients) or aspirin (10 patients), either after an initial infarction or following a recurrence. None of the heparin patients had a stroke following treatment, while four of the aspirin patients (40%) did. However, the 14 patients who received no antithrombotic therapy after an initial stroke had the greatest incidence of infarction, with eight of them (57%) suffering an additional stroke. None of the treated patients experienced an intracranial hemorrhage.[29]
Initiate treatment as soon as bacterial meningitis is suspected. Ideally, blood and CSF cultures should be obtained before antibiotics are administered. If a newborn is on a ventilator and clinical judgment dictates that a lumbar puncture may be hazardous, it can be deferred until the infant is stable. A lumbar puncture performed a few days after initial treatment still reveals cellular and chemical abnormalities, but culture results may be negative.
Establish IV access, and meticulously monitor fluid administration. Neonates with meningitis are prone to develop hyponatremia as a consequence of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). These electrolyte changes also contribute to the development of seizures, especially during the first 72 hours of disease.
Increased ICP secondary to cerebral edema is rarely a management problem in infants. Monitor blood gas levels closely to ensure adequate oxygenation and metabolic stability.
Magnetic resonance imaging (MRI) with gadoteridol, ultrasonography, or computed tomography (CT) with contrast is needed to delineate intracranial pathology. Certainly, some instances warrant automatic CNS imaging (eg, meningitis caused by gram-negative enterics, a complicated course). However, the efforts of a Pediatric Academic Societies meeting resulted in the suggested recommendation that contrast MRI should be performed for neonates with uncomplicated meningitis 7-10 days after treatment initiation to ensure that no complicating pathology is present. All newborns recovering from meningitis should undergo auditory evoked potential studies to screen for hearing impairment.
Infants and children
Management of acute bacterial meningitis in infants and older children involves both supportive measures and appropriate antimicrobial therapy. All patients should have an audiologic evaluation upon completion of therapy.
Closely monitor patients’ fluid and electrolyte status. Check vital signs and neurologic status, and ensure that an accurate record of intake and output is maintained.
By prescribing the correct type and volume of fluid, the risk of brain edema can be minimized. The child should receive sufficient amounts of fluid to maintain systolic blood pressure at around 80 mm Hg, urinary output at 500 mL/m2/day, and adequate tissue perfusion. Although it is important to avoid SIADH, it is equally important to avoiding underhydration of the patient and the risk of decreased cerebral perfusion.
Dopamine and other inotropic agents may be necessary to maintain blood pressure and adequate circulation.
In neonates with bacterial meningitis, antibiotics should be administered as soon as venous access is established (see Tables 1 and 2 below). Traditionally, initial antimicrobial treatment consists of ampicillin plus an aminoglycoside (ampicillin plus cefotaxime is also appropriate). If S pneumoniae is suspected, vancomycin should be added. Initial empiric therapy for late-onset disease in preterm infants should include an antistaphylococcal agent plus ceftazidime, amikacin, or meropenem.
Table 1. Antibiotic Dosages for Neonatal Bacterial Meningitis, Adjusted by Weight and Age
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Table 2. Antibiotics for Neonatal Bacterial Meningitis That Must Be Dosed According to Serum levels
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Ampicillin provides good coverage for gram-positive cocci, including group B streptococci (GBS), enterococci, L monocytogenes, some strains of E coli, and H influenzae type b (Hib). Ampicillin also achieves adequate levels in CSF.
Aminoglycosides (eg, gentamicin, tobramycin, and amikacin) have good activity against most gram-negative bacilli, including P aeruginosa and S marcescens. However, aminoglycosides achieve only marginal levels in both CSF and ventricular fluid, even when the meninges are inflamed.
Several third-generation cephalosporins, such as cefotaxime and ceftriaxone, achieve good CSF levels and have emerged as effective agents against gram-negative infections. Ceftriaxone competes with bilirubin for binding of albumin, and therapeutic levels of ceftriaxone decrease the reserve albumin concentration in newborn serum by 39%; thus, ceftriaxone may increase the risk of bilirubin encephalopathy, especially in high-risk newborns. Ceftriaxone also causes sludging of bile.
None of the cephalosporins have any activity against L monocytogenes and enterococci; therefore, they should not be used alone for initial treatment. A combination of ampicillin and a third-generation cephalosporin is required.
If the offending pathogen is proved to be an ampicillin-susceptible bacterium with a low minimum inhibitory concentration (MIC) for ampicillin, ampicillin may be continued alone. Cefotaxime and ceftriaxone also provide good activity against most penicillin-resistant strains of S pneumoniae. Both vancomycin and cefotaxime should be administered in patients with S pneumoniae meningitis before antibiotic susceptibility results are available.
Among the aminoglycosides, gentamicin and tobramycin have been used extensively in combination with ampicillin. Despite concerns about the adequacy of their CSF levels, these agents have proven effective when combined with a beta-lactam antibiotic for the treatment of meningitis caused by organisms such as GBS and susceptible enterococci. Routine intrathecal administration of aminoglycosides offers no additional benefit in this setting.
Infections involving S aureus, anaerobes, or P aeruginosa may require other antimicrobials, such as oxacillin, methicillin, vancomycin, or a combination of ceftazidime with an aminoglycoside. Use of antimicrobial agents should be determined by their CSF penetration and safety.
The duration of antibiotic therapy is dictated by the pathogen responsible for the meningitis and the patient’s clinical course. In most cases, 14-21 days of treatment is adequate for GBS infection. With gram-negative bacillary meningitis, however, it may take longer to sterilize the CSF, and 3-4 weeks of treatment is usually necessary.
If no clinical improvement is noted or the meningitis is determined to be caused by resistant S pneumoniae strains or gram-negative enteric bacilli, repeat lumbar puncture is indicated. In neonates with gram-negative bacillary meningitis, examination of CSF during treatment is necessary to verify that cultures are sterile. Reexamination of CSF for chemistries and culture should be performed 48-72 hours after treatment initiation; further specimens are obtained if CSF sterilization is not demonstrated or clinical response is not apparent.
Infants and children
Prompt administration of antibiotics to a patient with suspected bacterial meningitis is essential (see Table 3 below). Initial antibiotic selection should provide coverage for the 3 most common pathogens: S pneumoniae, N meningitidis, and H influenzae. All antibiotics should be administered IV to achieve adequate serum and CSF levels. An intraosseous route is acceptable if venous access is not an option.
Table 3. Dosages and Dosing Intervals for Intravenous Antimicrobials in Infants and Children With Bacterial Meningitis
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According to the 2004 Infectious Diseases Society of America (IDSA) practice guidelines for bacterial meningitis, vancomycin plus either ceftriaxone or cefotaxime is recommended for those with suspected bacterial meningitis, with targeted therapy based on the susceptibilities of isolated pathogens.[2] This combination provides adequate coverage for most penicillin-resistant pneumococci and beta-lactamase–resistant Hib. Ceftazidime has poor activity against pneumococci and should not be substituted for cefotaxime or ceftriaxone.
Because vancomycin penetrates the central nervous system (CNS) poorly, a higher dosage (60 mg/kg/day) is recommended when this agent is used to treat CNS infections. Cefotaxime or ceftriaxone is adequate if pneumococci are susceptible to cefotaxime. However, if S pneumoniae isolates have a higher MIC for cefotaxime and fall in the intermediate-resistance group, sterilization of the CSF may not be achieved promptly, and a high dosage of cefotaxime (300 mg/kg/day) plus vancomycin (60 mg/kg/day) may be preferred.
In the rare event that a pneumococcal isolate has high resistance to cefotaxime or ceftriaxone, vancomycin alone may not be adequate for prompt sterilization of the CSF, and rifampin should be added to the regimen to provide 4- to 8-fold bactericidal activity against the pathogen. Carbapenem treatment is another valid option for cephalosporin-resistant carbapenem-susceptible isolates. Meropenem is preferred to imipenem because of the risk of seizures associated with the latter.
The roles of other classes of antibiotics, such as the oxazolidinones (eg, linezolid), in the treatment of bacterial meningitis in infants and children remain to be determined. Fluoroquinolones may be an option for patients in whom either other antibacterials cannot be used or previous therapy has failed, but they should be used with caution because resistance may develop during treatment.
When there is a history of significant hypersensitivity to beta-lactam antibiotics (ie, penicillins and cephalosporins), the choice of alternative agent varies with the cause of the meningitis. Vancomycin and rifampin should be considered for S pneumoniae. Chloramphenicol can also be used if the MIC is 4 µg/mL or less. It is recommended for patients with meningococcal meningitis who have significant hypersensitivity to beta-lactam antimicrobial agents.
Examination of the CSF at the end of treatment has not proved helpful for predicting relapses or recrudescence of meningitis. Hib isolates can persist in the nasopharyngeal secretions even after successful treatment of meningitis. For this reason, rifampin 20 mg/kg must be given once daily for 4 days if high-risk children are at home or at a childcare center (unless the medication was ceftriaxone). N meningitidis and S pneumoniae are usually eradicated from the nasopharynx after successful treatment of meningitis.
Phlebitis at the IV site and antibiotic fever are the most common of several causes of secondary fever in patients with meningitis. Thoroughly evaluate any patient with fever.
Duration of antimicrobial therapy
The IDSA 2004 guidelines for management of bacterial meningitis provide the following recommendations for the duration of antibiotic therapy, with the caveat that “the guidelines are not standardized and that duration of therapy may need to be individualized on the basis of the patient’s clinical response”:
N meningitidis - 7 days
H influenzae - 7 days
S pneumoniae - 10-14 days
S agalactiae (GBS) - 14-21 days
Aerobic gram-negative bacilli - 21 days or 2 weeks beyond the first sterile culture (whichever is longer)
L monocytogenes - 21 days or longer
A meta-analysis of randomized controlled trials evaluated the efficacy and safety of short-course antibiotic therapy for bacterial meningitis.[30] Five open-label trials were included, involving children aged 3 weeks to 16 years. No differences between short-course (4-7 days) and long-course (7-14 days) treatment with IV ceftriaxone were demonstrated with respect to end-of-therapy clinical success, long-term neurologic complications, long-term hearing impairment, total adverse events, and secondary nosocomial infections.
However, the American Academy of Pediatrics (AAP) does not endorse courses of therapy shorter than 5-7 days for meningococcus, 10 days for H influenzae, and 14 days for S pneumoniae.[3] Although the available evidence is limited, some studies show no difference between short-course and long-course antibiotic regimens for treatment of bacterial meningitis in children.[31]
A double-blind, placebo-controlled, randomized, multicountry equivalence study compared 5-day and 10-day ceftriaxone regimens for treatment of purulent meningitis in children (aged 2 months to 12 years).[16] The investigators concluded that antibiotic treatment of purulent meningitis caused by Hib, N meningitidis, or S pneumoniae could be safely discontinued in children who are stable by day 5. However, this should not be considered the standard of care.
Experimental studies have revealed a correlation between outcome and the severity of the inflammatory process in the subarachnoid space.[32] In animal models of bacterial meningitis, the use of dexamethasone has been associated with decreased inflammation, reduced cerebral edema and ICP, and lesser degrees of brain damage.
Subsequent controlled, double-blind clinical trials demonstrated the beneficial effects of adjunctive dexamethasone in infants and children with Hib meningitis. The incidence of neurologic and audiologic sequelae was significantly decreased on follow-up examination; clinical benefit was greatest for overall hearing impairment. As a result, the IDSA guidelines recommend adjunctive dexamethasone for these patients in a dosage of 0.15 mg/kg q6h for 2-4 days, initiated 10-20 minutes before (or at least concomitant with) the first antimicrobial dose.
A meta-analysis by Mongelluzzo et al did not find corticosteroids to be beneficial in children with bacterial meningitis.[33] Survival and time to hospital discharge did not differ significantly between the corticosteroid treatment group and the untreated group, even when the 2 groups were subcategorized according to age or causative organism.
A prospective, double-blind, placebo-controlled, multicenter trial in adults with bacterial meningitis documented benefit (a lower percentage of unfavorable outcomes, including death) in patients with pneumococcal meningitis but not in others. Although dexamethasone has not yet been convincingly shown to offer a clear clinical benefit in pediatric patients with S pneumoniae meningitis, a Cochrane review recommended that corticosteroids be considered in nonneonates with bacterial meningitis in high-income countries.[32]
Given the lack of a clear benefit favoring the use of dexamethasone in older infants and children and the concerns that such use may lead to decreased antibiotic penetration in the CSF, the decision to give dexamethasone must be made on a case-by-case basis after the potential risks and benefits have been carefully weighed. The data are likewise insufficient to allow recommendation of adjunctive steroid therapy in neonates with bacterial meningitis.
Prevention is an important aspect of the management of pediatric bacterial meningitis because it has been shown to reduce mortality and morbidity. Preventive measures can be divided into 2 broad categories, chemoprophylaxis and immunization.
The use of rifampin, ceftriaxone, and ciprofloxacin has been effective chemoprophylaxis (see Table 4 below). Ciprofloxacin and ceftriaxone are more effective against resistant strains of N meningitidis up to 4 weeks after treatment. Routine childhood immunizations have been shown to effectively decrease the incidence of certain types of meningitis.
Table 4. Chemoprophylaxis for Bacterial Meningitis Caused by Haemophilus influenzae or Neisseria meningitidis
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Haemophilus influenzae type b
The risk of invasive Hib disease is increased among unimmunized household contacts younger than 4 years. Rifampin eradicates the organism from the pharynx of approximately 95% of carriers. The efficacy of rifampin in preventing disease in childcare groups is not established.
Recommendations for rifampin chemoprophylaxis for contacts of index cases of invasive Hib disease include the following:
All household contacts with at least one contact younger than 4 years who is unimmunized or partially immunized; those with a child younger than 12 months who has not received the primary series; and those with an immunocompromised child (even if older than 4 years), regardless of immunization status
Nursery and childcare center contacts regardless of age, when 2 or more cases of invasive disease have occurred within 60 days
The index case if younger than 2 years or with a susceptible household contact and treated with ampicillin or chloramphenicol
Immunizations should be administered in accordance with AAP guidelines.[34] Universal immunization against Hib infection has led to a dramatic decline in the incidence of invasive Hib meningitis.[35]
In June 2012, MenHibrix, a combination vaccine providing immunization against both Hib and meningococcal serogroups C and Y, was approved by the US Food and Drug Administration (FDA) for use in infants. This combination vaccine is indicated in children aged 6 weeks to 18 months for active immunity against invasive disease. It is given as a 4-dose series, usually at well-baby checkups.
The Advisory Committee on Immunization Practices (ACIP) recommends HibMenCY be given to infants at increased risk for meningococcal disease, in 4 doses at 2, 4, 6, and 12 through 15 months; at-risk infants are those with complement component deficiencies, those with known asplenia or sickle cell disease, and those exposed to community outbreaks of serogroup C or Y disease.[36, 37]
Neisseria meningitidis
Administration of antimicrobial agents to contacts is divided into high- and low-risk categories. Only contacts stratified as high-risk require prophylaxis. Candidates for chemoprophylaxis against meningococcal disease include the following:
All household contacts
Childcare or nursery school contacts during the 7 days before illness onset
Contacts directly exposed to index case secretions through kissing, sharing toothbrushes or eating utensils, or other markers of close social contact during the 7 days before illness onset
Persons who had mouth-to-mouth resuscitation or unprotected contact during endotracheal intubation in the 7 days before illness onset
Contacts who frequently slept or ate in the same dwelling as the index patient during the 7 days before illness onset
Outbreaks or clusters must be managed as mandated by local public health authorities.
A quadrivalent (ie, A, C, Y, W-135) meningococcal conjugate vaccine is recommended for high-risk groups, including patients with immunodeficiency, patients with functional or anatomic asplenia, and patients with deficiencies of terminal components of complement. It has been given to high-risk children as young as 9 months (Menactra) or 2 months (Menveo). The vaccine is also valuable in controlling the epidemics of meningococcal disease.
The ACIP has recommended the quadrivalent meningococcal conjugate vaccine for all children aged 11-12 years, for first-year college students who will be living in a dormitory or a dormitorylike setting, and for other high-risk groups.[38, 39]
As noted above, a combination vaccine against both meningococcal serogroups C and Y conjugate and Hib has been approved by the FDA for use in infants. The HibMenCY is recommended by the ACIP for infants at increased risk for meningococcal disease, such as those: (1) with complement component deficiencies, (2) with known asplenia or sickle cell disease, and (3) exposed to community outbreaks of serogroup C or Y disease.[36, 37]
Streptococcus pneumoniae
Routine chemoprophylactic measures for invasive disease secondary to S pneumoniae are limited to people with specific medical conditions.
The heptavalent pneumococcal conjugate vaccine has been introduced into the primary childhood vaccination schedule. Immunizations should be administered according to AAP guidelines. The polysaccharide vaccine is generally used for those with specific medical conditions.
Clinical Context:
Cefotaxime is a third-generation cephalosporin with a gram-negative spectrum; it has lower efficacy against gram-positive organisms. It arrests bacterial cell wall synthesis, which, in turn, inhibits bacterial growth.
Clinical Context:
Ceftazidime is a third-generation cephalosporin with broad-spectrum gram-negative activity; it has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. It arrests bacterial growth by binding to 1 or more penicillin-binding proteins (PBPs).
Clinical Context:
Ampicillin has bactericidal activity against susceptible organisms. It is used as an alternative to amoxicillin when the patient is unable to take medication orally.
Clinical Context:
Ceftriaxone is a third-generation cephalosporin with broad-spectrum gram-negative activity; it has lower efficacy against gram-positive organisms and higher efficacy against resistant organisms. It arrests bacterial growth by binding to 1 or more penicillin-binding proteins (PBPs).
Clinical Context:
Gentamicin is an aminoglycoside used for gram-negative coverage. It is given intravenously (IV) or intramuscularly (IM) in combination with both an agent that covers gram-positive organisms and one that covers anaerobes. It is not the drug of choice but may be considered if penicillins or other less toxic drugs are contraindicated, when clinically indicated, and in mixed infections caused by susceptible staphylococci and gram-negative organisms. Dosing regimens are numerous. Adjust the dose on the basis of creatinine clearance and changes in volume of distribution.
Clinical Context:
Since the introduction of third-generation cephalosporins, chloramphenicol has been less frequently used. It binds to 50S bacterial-ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. It is effective against gram-negative and gram-positive bacteria.
Clinical Context:
Vancomycin is a potent antibiotic directed against gram-positive organisms and active against Enterococcus species. It is indicated for patients who cannot receive or have failed to respond to penicillins and cephalosporins or who have infections caused by resistant staphylococci. For abdominal penetrating injuries, it is combined with an agent active against enteric flora, anaerobes, or both.
To prevent toxicity, the current recommendation is to assay vancomycin trough levels after the third dose, 30 minutes before the next dose. Use the creatinine clearance to adjust dosing in patients diagnosed with renal impairment.
Clinical Context:
Meropenem is a carbapenem with slightly increased activity against gram-negative organisms and slightly decreased activity against staphylococci and streptococci compared with imipenem. It is less likely to cause seizures and has superior penetration of blood-brain barrier compared with imipenem.
Clinical Context:
Penicillin G interferes with synthesis of cell-wall mucopeptide during active multiplication, resulting in bactericidal activity against susceptible microorganisms. It can be given alone to treat GBS meningitis when susceptibility of CSF isolates to the drug has been demonstrated.
Clinical Context:
Tobramycin is used in skin, bone, and skin-structure infections caused by S aureus, P aeruginosa, Escherichia coli, and Klebsiella, Proteus, and Enterobacter species. It is indicated for staphylococcal infections when penicillin or potentially less toxic drugs are contraindicated and when bacterial susceptibility and clinical judgment justify its use. Dosing regimens are numerous and are adjusted on the basis of creatinine clearance and changes in the volume of distribution.
Clinical Context:
Amikacin irreversibly binds to the 30S subunit of bacterial ribosomes; it blocks the recognition step in protein synthesis and causes growth inhibition. It is indicated for gram-negative bacterial coverage of infections resistant to gentamicin and tobramycin. Amikacin is effective against P aeruginosa. Use patient's ideal body weight (IBW) for dosage calculation. The same principles of drug monitoring for gentamicin apply to amikacin.
Clinical Context:
This drug combination inhibits the biosynthesis of cell wall mucopeptide and is effective during the stage of active growth. It consists of an antipseudomonal penicillin plus a beta-lactamase inhibitor and provides coverage against most gram-positive, most gram-negatives, and most anaerobic organisms.
Clinical Context:
Oxacillin is a bactericidal antibiotic that inhibits cell wall synthesis. It is used in the treatment of infections caused by penicillinase-producing staphylococci. It may be given as initial therapy when a staphylococcal infection is suspected.
Clinical Context:
Rifampin inhibits DNA-dependent RNA polymerase activity in susceptible cells. Specifically, it interacts with bacterial RNA polymerase but does not inhibit the mammalian enzyme. It should be taken on an empty stomach. The use of rifampin, ceftriaxone, and ciprofloxacin has been effective as chemoprophylaxis.
Clinical Context:
Ciprofloxacin is a fluoroquinolone with activity against pseudomonads, streptococci, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, and most gram-negative organisms, but with no activity against anaerobes. It inhibits bacterial deoxyribonucleic acid (DNA) synthesis and, consequently, growth. The use of ciprofloxacin has been effective as chemoprophylaxis and, along with ceftriaxone, more effective against resistant strains of N meningitidis up to 4 weeks after treatment. It is used in patients older than 18 years.
Intravenous (IV) antibiotics are required for bacterial meningitis. If the causative organism is unknown, antibiotics regimens can be based on the child’s age, as follows:
- For infants younger than 30 days, ampicillin and an aminoglycoside or a cephalosporin (cefotaxime) are recommended
- For children aged 30-60 days, ampicillin and a cephalosporin (ceftriaxone or cefotaxime) can be used; because Streptococcus pneumoniae occasionally occurs in this age range, vancomycin should be considered instead of ampicillin
- In older children, a cephalosporin (cefotaxime or ceftriaxone) plus vancomycin (needs to be added secondary to the possibility of cephalosporin resistant Streptococcus pneumonia) can be used
The incidence of resistant S pneumoniae is increasing. If this organism is considered to be a potential cause of the meningitis, add vancomycin to the therapeutic regimen. Use of penicillin or ampicillin in the 3 months before illness is associated with increased risk of infection with resistant S pneumoniae.
In adults, corticosteroids, given before or along with the first dose of antibiotics, reduce morbidity and mortality (hearing loss, long-term neurologic sequelae, and death); these findings were applicable to high-income countries. In pediatric patients, however, it is uncertain whether corticosteroids are beneficial as adjuvant therapy for bacterial meningitis.
Clinical Context:
This vaccine contains antigenic capsular polysaccharides (ie, meningococcal serogroups A and C, H influenzae type b) that convey active immunity by stimulating endogenous antibody production; antibodies have been associated with protection from invasive meningococcal disease. It is approved by the US Food and Drug Administration (FDA) for use in infants. This combination vaccine is indicated in children aged 6 weeks to 18 months for active immunity against invasive disease. It is given as a 4-dose series, usually at well-baby checkups.
Clinical Context:
This vaccine is used for routine immunization of children against invasive diseases caused by H influenzae type b by decreasing nasopharyngeal colonization. The CDC Advisory Committee on Immunization Practices (ACIP) recommends that all children receive one of the conjugate vaccines licensed for infant use beginning routinely at age 2 months.
Clinical Context:
This vaccine is a diphtheria toxoid conjugate vaccine that induces the production of bactericidal antibodies specific to capsular polysaccharides of serogroups A, C, Y, and W-135. The meningococcal conjugate vaccine is recommended for high-risk groups, including patients with immunodeficiency, patients with functional or anatomic asplenia, and patients with deficiencies of terminal components of complement. It has been given to high-risk children as young as 9 months (Menactra) or 2 months (Menveo). The vaccine is also valuable in controlling epidemics of meningococcal disease.
Clinical Context:
This is a quadrivalent vaccine for meningitis prophylaxis. It is considered an adjunct to antibiotic chemoprophylaxis. The meningococcal conjugate vaccine is recommended for high-risk groups, including patients with immunodeficiency, patients with functional or anatomic asplenia, and patients with deficiencies of terminal components of complement. It has been given to high-risk children as young as 9 months. The vaccine is also valuable in controlling epidemics of meningococcal disease.
Vaccines with inactivated bacteria are used to induce active immunity against most common pathogens responsible for causing bacterial meningitis in the pediatric population. Prevention is an important aspect of the management of pediatric bacterial meningitis because it has been shown to reduce mortality and morbidity.
What are classic signs and symptoms of pediatric bacterial meningitis?What are the signs and symptoms of pediatric bacterial meningitis in neonates?What are the signs and symptoms of pediatric bacterial meningitis in infants and children?How is pediatric bacterial meningitis definitively diagnosed?What is the bacterial meningitis score for diagnosis of pediatric bacterial meningitis?What is the basis for IV antibiotic selection to treat pediatric bacterial meningitis?What are the IDSA guidelines on the duration of antibiotic treatment of pediatric bacterial meningitis?What are AAP guidelines on duration of antibiotic treatment for pediatric bacterial meningitis?How is pediatric bacterial meningitis prevented?What is pediatric bacterial meningitis?What is the pathophysiology of pediatric bacterial meningitis?What is the pathophysiology of pediatric bacterial meningitis in neonates?What are causes of pediatric bacterial meningitis in neonates?What are causes of pediatric bacterial meningitis in infants and children?What is the role of Streptococcus pneumoniae in the etiology of pediatric bacterial meningitis?What is the role of Neisseria meningitidis in the etiology of pediatric bacterial meningitis?Which factors increase the mortality risk for N meningitidis-caused pediatric bacterial meningitis?What is the role of Haemophilus influenzae type b (Hib) in the etiology of pediatric bacterial meningitis?What is the role of Listeria monocytogenes in the etiology of pediatric bacterial meningitis?What causes of pediatric bacterial meningitis in select populations?What are the risk factors for pediatric bacterial meningitis?What is the prevalence of pediatric bacterial meningitis in the US?What is the global prevalence of pediatric bacterial meningitis?Which patient groups have the highest prevalence of pediatric bacterial meningitis?What is the prognosis of pediatric bacterial meningitis?What is included in the patient education about pediatric bacterial meningitis?What are the nonspecific symptoms of bacterial meningitis in neonates?Which clinical history findings are characteristic of pediatric bacterial meningitis in infants and children?Which clinical history findings are characteristic of bacterial meningitis in neonates, infants and young children?Which factors may delay the diagnosis of pediatric bacterial meningitis?Which physical findings are characteristic of pediatric bacterial meningitis in neonates?Which physical findings are characteristic of pediatric bacterial meningitis in infants and children?What are the possible complications of pediatric bacterial meningitis?How is pediatric bacterial meningitis diagnosed?Which conditions should be included in the differential diagnoses of pediatric bacterial meningitis?What is the role of CSF analysis in the workup of pediatric bacterial meningitis?When is a lumbar puncture contraindicated in the workup of pediatric bacterial meningitis?What are components of the bacterial meningitis score for the diagnosis of pediatric bacterial meningitis?Which imaging studies are performed in the diagnosis of pediatric bacterial meningitis?What is the role of blood and urine studies in the workup of pediatric bacterial meningitis?What is the role of lumbar puncture in the workup of pediatric bacterial meningitis?What is included in cerebrospinal fluid (CSF) studies for the diagnosis of pediatric bacterial meningitis?How does prior antibiotic administration affect CSF findings in the workup of pediatric bacterial meningitis?What is the role of CT and MRI in the workup of pediatric bacterial meningitis?How is pediatric bacterial meningitis treated?What is included in the initial treatment of acute bacterial meningitis in neonates?What is included in the initial treatment of acute bacterial meningitis in infants and children?What are the antibiotic doses for treatment of pediatric bacterial meningitis in neonates?What is the role of ampicillin in the treatment of pediatric bacterial meningitis in neonates?What is the role of aminoglycosides and cephalosporins in the treatment of pediatric bacterial meningitis in neonates?Which factors affect the duration of antibiotic therapy for pediatric bacterial meningitis in neonates?What steps should be taken when there is no clinical improvement following antibiotic therapy for pediatric bacterial meningitis in neonates?What are the antibiotic doses for treatment for pediatric bacterial meningitis in infants and children?What is the role of combination therapies in the treatment of pediatric bacterial meningitis in infants and children?What is the role of oxazolidinones and fluoroquinolones in the treatment of pediatric bacterial meningitis in infants and children?How is pediatric bacterial meningitis treated in infants and children with a hypersensitivity to beta-lactam antibiotics?How is relapse of pediatric bacterial meningitis prevented in infants and children?What causes secondary fever in pediatric bacterial meningitis?What is the duration of antimicrobial therapy for pediatric bacterial meningitis?What is the role of dexamethasone therapy in the treatment of pediatric bacterial meningitis?What is the role of chemoprophylaxis in the prevention of pediatric bacterial meningitis?What is the role of rifampin in the prevention of invasive Haemophilus influenzae type b (Hib)-caused pediatric bacterial meningitis?What is the role of Hib immunization in the prevention of pediatric bacterial meningitis?When is chemoprophylaxis against N meningitidis indicated for the prevention of pediatric bacterial meningitis?What is the role of vaccines in the prevention of pediatric bacterial meningitis?How is pediatric bacterial meningitis caused by Streptococcus pneumoniae prevented?What are the goals of drug treatment for pediatric bacterial meningitis?Which medications in the drug class Vaccines, Inactivated, Bacterial are used in the treatment of Pediatric Bacterial Meningitis?Which medications in the drug class Corticosteroids are used in the treatment of Pediatric Bacterial Meningitis?Which medications in the drug class Antibiotics are used in the treatment of Pediatric Bacterial Meningitis?
Martha L Muller, MD, MPH, Professor of Pediatrics, Division of Infectious Diseases, University of New Mexico School of Medicine
Disclosure: Nothing to disclose.
Specialty Editors
Mary L Windle, PharmD, Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Joseph Domachowske, MD, Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University
Disclosure: Received research grant from: Pfizer;GlaxoSmithKline;AstraZeneca;Merck;American Academy of Pediatrics, Novavax, Regeneron, Diassess, Actelion<br/>Received income in an amount equal to or greater than $250 from: Sanofi Pasteur.
Chief Editor
Russell W Steele, MD, Clinical Professor, Tulane University School of Medicine; Staff Physician, Ochsner Clinic Foundation
Disclosure: Nothing to disclose.
Acknowledgements
Joseph Domachowske, MD Professor of Pediatrics, Microbiology and Immunology, Department of Pediatrics, Division of Infectious Diseases, State University of New York Upstate Medical University
Joseph Domachowske, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Society for Microbiology, Infectious Diseases Society of America, Pediatric Infectious Diseases Society, and Phi Beta Kappa
Disclosure: Nothing to disclose.
Robert Allan Felter, MD, FAAP, CPE, FACPE Professor of Clinical Pediatrics, Department of Pediatrics, Georgetown University School of Medicine; Medical Director, Pediatric Emergency Medicine and Inpatient Services, Inova Loudoun Hospital
Robert Allan Felter, MD, FAAP, CPE, FACPE is a member of the following medical societies: American Academy of Pediatrics and American College of Physician Executives
Disclosure: Nothing to disclose
Jeffrey Hom, MD, MPH, FACEP, FAAP Assistant Professor, Department of Pediatrics/Emergency Services and Department of Emergency Medicine, New York University School of Medicine
Jeffrey Hom, MD, MPH, FACEP, FAAP is a member of the following medical societies: American Academy of Pediatrics, American College of Emergency Physicians, and Society for Academic Emergency Medicine
Disclosure: Nothing to disclose.
David Jaimovich, MD Chief Medical Officer, Joint Commission International and Joint Commission Resources
David Jaimovich, MD is a member of the following medical societies: American Academy of Pediatrics
Disclosure: Nothing to disclose.
Garry Wilkes, MBBS, FACEM Director of Emergency Medicine, Calvary Hospital, Canberra, ACT; Adjunct Associate Professor, Edith Cowan University, Western Australia
Disclosure: Nothing to disclose.
Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Nothing to disclose.
Grace M Young, MD Associate Professor, Department of Pediatrics, University of Maryland Medical Center
Grace M Young, MD is a member of the following medical societies: American Academy of Pediatrics and American College of Emergency Physicians
Mahoney D. ACIP gives nod to meningitis vaccine for high-risk infants. Medscape Medical News. October 26, 2012. Accessed Nov 13, 2012.:
Centers For Disease Control and Prevention. CDC Advisory Committee on Immunization Practices Recommends HibMenCY for Infants at Increased Risk for Meningococcal Disease. Oct 24, 2012. Available at: Accessed Nov 13, 2012.
Novartis Vaccines. FDA expands age indication for Menveo®, first and only quadrivalent meningococcal vaccine for infants as young as 2 months of age. Available at http://www.novartisvaccines.com/newsroom/media-releases/2013/US_Menveo_Infant_FDA_Approval_Press_Release_US.pdf. Accessed: August 7, 2013.
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