AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

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

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

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

Pathophysiology

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

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

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

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

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

Pathogenesis of neonatal meningitis

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

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

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

Frequency

United States

Prior to the routine use of the pneumococcal conjugate vaccine, the incidence of bacterial meningitis in the United States was about 6000 cases per year; roughly half of these were in pediatric patients (³18 y). N meningitidis causes about 4 cases per 100,000 children (aged 1-23 mo). The rate of S pneumoniae meningitis was 6.5 cases per 100,000 children (aged 1-23 mo). This number has since declined given the routine use of conjugate pneumococcal vaccine in children. The recent introduction of conjugate meningococcal vaccine in the United States is expected to reduce the incidence of bacterial meningitis even further.

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

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

Mortality/Morbidity

• In general, mortality rates vary with age and pathogen, with the highest being for S pneumoniae. Despite effective antimicrobial and supportive therapy, mortality rates among neonates remain high, with significant long-term sequelae in survivors. Bacterial meningitis also causes long-term sequelae and results in significant morbidity beyond the neonatal period. Mortality rates are highest during the first year of life, decreasing in mid life and increasing again in elderly persons.
• Despite advances in care for patients with bacterial meningitis, the overall case fatality remains steady at approximately 10-30%.

Race

• Incidence rates are higher in African American and Native American populations.

Sex

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

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Neonatal - Symptoms 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
• Infants and children - The following symptoms are readily recognized as associated with meningitis:
• • Nuchal rigidity
  • Opisthotonos
  • Bulging fontanelle
  • Convulsions
  • Photophobia
  • Headache
  • Alterations of the sensorium
  • Irritability
  • Lethargy
  • Anorexia
  • Nausea
  • Vomiting
  • Coma
  • Fever (generally present, although some severely ill children present with hypothermia)

Physical

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

Causes

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

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Viral meningitis/encephalitis
Brain abscess
Subdural/epidural abscess
Brain tumors
CNS leukemia
Lead encephalopathy
Meningitis, fungal
CNS tuberculosis
Hypersensitivity to drugs (trimethoprim-sulfamethoxazole, intravenous immune globulin, antithymocyte globulin)
Disorders associated with vasculitis such as Kawasaki disease and collagen vascular disease

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• General guidelines
• • Meningitis is a medical emergency. A firm diagnosis usually is made when bacteria are isolated from the 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.
  • 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. Specific hematologic, radiographic (eg, CT scan, MRI of the head), and other studies assist in diagnosis.
  • Measurement of serum glucose level close to the time of CSF collection is useful for interpreting CSF glucose levels and the likelihood of meningitis.
  • Group B streptococcal antigen test in urine is unreliable and should not be used to make a diagnosis of sepsis or meningitis.
  • CSF chemistries and cytology vary depending upon the maturity and age of the newborn.
  • The bacterial meningitis score is under continual evaluation as is its effectiveness as an aid to identify those children with CSF pleocytosis at low risk of having bacterial meningitis. The components of the score include the following:
  • • Positive cerebrospinal fluid Gram stain
    • CSF absolute neutrophil count greater than or equal to 1000 cells/mcL
    • CSF protein greater than or equal to 80 mg/dL
    • Peripheral blood absolute neutrophil count greater than or equal to 10000 cells/mcL
    • History of seizure before or at the time of presentation
• Infants and children
• • Definitive diagnosis is based on CSF findings. The opening pressure of CSF should be measured in older children. Similarly, the color of the CSF (eg, turbid, clear, bloody) should be recorded.
  • If the spinal fluid is not crystal clear, administer treatment immediately without waiting for the results of CSF tests.
  • If the patient shows signs of pending herniation, consider treatment without performing a lumbar puncture. A lumbar puncture can be performed later, when intracranial pressure is controlled and the patient is clinically stable. A CT scan or MRI is helpful in managing patients who require control of intracranial pressure and herniation.
  • Perform chemistries (ie, glucose, protein), total and differential cell count, Gram stain, and cultures on all CSF specimens. In a setting of antibiotic pretreatment, rapid bacterial antigen testing may be considered. Generally, CSF glucose is less than 50% of simultaneously obtained blood glucose value, and CSF proteins are greater than 50 mg/dL. However, these values may be within the reference range in patients with very early disease. Patients with both fulminant disease and poor immune response may not show cytological or chemical changes in CSF. Approximately 2-3% of bacterial meningitis cases have a negative Gram stain result and normal cell count, glucose level, and protein level yet positive bacterial cultures.
  • Most untreated patients have an increased WBC count with a predominance of polymorphonuclear leukocytes at the time of diagnosis, although bacterial meningitis may present with a lymphocytic predominance. A Gram stain of cytocentrifuged CSF may reveal bacterial morphology. The CSF should be plated immediately onto a chocolate and blood agar media. Blood cultures also should be obtained. Smears of petechial lesions may reveal microorganisms on Gram stain. Similarly, examination of a buffy coat smear also may reveal intracellular microorganisms.
  • Several tests based upon the principle of agglutination for the detection of bacterial antigens in body fluids are available. Bacterial antigen detection can be carried out in samples of CSF, blood, and urine. Antigen detection tests are most helpful in patients with partially treated meningitis where bacteria may not grow from the CSF but antigens persist in body fluids. Antigen detection in the urine is particularly helpful in such circumstances because urine can be concentrated several fold in the laboratory. Several gram-negative bacteria and higher serotypes of S pneumoniae have capsular antigens, which 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.
• 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 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 pneumococcus or meningococcus, although 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.
  • More sensitive tests, such as amplification of 16S rRNA gene by polymerase chain reaction (PCR), may become readily available in the future to diagnose bacterial meningitis in antibiotic pretreated patients.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Neonatal
• • Initiate treatment as soon as 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 spinal tap may be hazardous, it can be deferred until the infant is stable. A spinal tap performed a few days following initial treatment still reveals cellular and chemical abnormalities but culture results may be negative.
  • Establish intravenous access, and meticulously monitor fluid administration. Neonates with meningitis are prone to develop hyponatremia due to SIADH. These electrolyte changes also contribute to the development of seizures, especially during the first 72 hours of disease.
  • Increased intracranial pressure secondary to cerebral edema is rarely a management problem in infants. Monitor blood gas levels closely to ensure adequate oxygenation and metabolic stability.
  • MRI with gadoteridol, ultrasonography, or CT scanning with contrast is needed to delineate intracranial pathology. A recent Pediatric Academic Societies meeting in May 2005 resulted in the recommendation that MRIs with contrast 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 have auditory evoked potential studies to screen for hearing impairment.
• Infants and children: Management of acute bacterial meningitis involves both appropriate antimicrobial therapy and supportive measures. All patients should have an audiologic evaluation upon completion of therapy.
• Fluid and electrolyte management
• • Closely monitor patients by checking vital signs and neurologic status and by ensuring an accurate record of intake and output.
  • By prescribing the correct type and volume of fluid, the risk of development of brain edema can be minimized. The child should receive fluids sufficient to maintain systolic blood pressure at around 80 mm Hg, urinary output of 500 mL/m²/d, and adequate tissue perfusion. While care to avoid SIADH is important, underhydrating the patient and risk of decreased cerebral perfusion are equally concerning as well.
  • Dopamine and other inotropic agents may be necessary to maintain blood pressure and adequate circulation.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Antimicrobial therapy for neonates

Antibiotics should be administered as soon as venous access is established. Traditionally, initial antimicrobial treatment consists of ampicillin and an aminoglycoside combination (ampicillin and cefotaxime 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 and ceftazidime, amikacin, or meropenem. See Tables 1-2.

Ampicillin provides good coverage for gram-positive cocci, including group B streptococci, enterococci, L monocytogenes, some strains of E coli, and H influenzae type b. Ampicillin also achieves adequate levels in CSF.

Aminoglycosides (eg, gentamicin, tobramycin, 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 achieve good CSF levels and have emerged as effective agents against gram-negative infections. There has been considerable experience with cefotaxime and ceftriaxone. 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 and, therefore, should not be used as a single agent for initial treatment. A combination of ampicillin and a third-generation cephalosporin is required.

If the offending pathogen is proven to be an ampicillin-susceptible bacterium with a low minimum inhibitory concentration (MIC) for ampicillin, then ampicillin may be continued alone. Cefotaxime and ceftriaxone also provide good activity against most penicillin-resistant 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 group B streptococci and susceptible enterococci. Routine intrathecal administration of aminoglycosides offers no additional benefit in this capacity.

Infections involving S aureus, anaerobes, or P aeruginosa may require other antimicrobials, such as oxacillin, methicillin, vancomycin, or a combination of ceftazidime with aminoglycoside. CSF penetration and safety of antimicrobial agents should determine usage.

Etiologic agent and clinical course dictate duration of treatment; however, a 10- to 21-day treatment is usually adequate for group B streptococcal infection. It may take longer to sterilize the CSF with gram-negative bacillary meningitis, and 3-4 weeks of treatment is usually necessary.

Indications for repeat lumbar puncture include lack of clinical improvement or meningitis caused by resistant S pneumoniae strains or by gram-negative enteric bacilli. 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 based upon demonstrating lack of sterilization or lack of apparent clinical response. 

Table 3). Initial antibiotic selection should provide coverage for all 3 common pathogens: S pneumoniae, N meningitidis, and H influenzae.

As per the 2004 Infectious Diseases Society of America (IDSA) practice guidelines for bacterial meningitis, the combination of vancomycin and either ceftriaxone or cefotaxime is recommended for those with suspected bacterial meningitis, with targeted therapy based upon susceptibilities of isolated pathogens. This combination provides adequate coverage for most penicillin-resistant pneumococci and beta-lactamase resistant H influenzae type b. Of note, ceftazidime has poor activity against pneumococci and should not be substituted for cefotaxime or ceftriaxone.

Because vancomycin poorly penetrates the CNS, a higher dose of 60 mg/kg/d is recommended when vancomycin 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, there have been concerns regarding prompt sterilization of the CSF, and a high dose of cefotaxime (300 mg/kg/d) with vancomycin (60 mg/kg/d) 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 CSF cidal activity against the pathogen.

Carbapenem treatment is another valid option for cephalosporin-resistant carbapenem-susceptible isolates. Meropenem is preferred over imipenem because of the risk of seizures with the latter antibiotic. The role of other new classes of antibiotics, such as the oxazolidinones (linezolid), remains an area of investigation. Fluoroquinolones may be an option for patients who either cannot use other antibacterials or have failed previous therapy, but they should be used with caution as resistance may develop during treatment.

Administer all antibiotics intravenously to achieve adequate serum and CSF levels. An intraosseous route is acceptable if venous access is not an option. In patients with a history of significant hypersensitivity to beta-lactam antimicrobial agents (penicillins and cephalosporins) the choice of alternative agent varies with the etiology of meningitis. Vancomycin and rifampin should be considered for S pneumoniae. Chloramphenicol can also be used if minimum bactericidal concentration is <4 µg/mL. Chloramphenicol 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 proven helpful in predicting relapses or recrudescence of meningitis. H influenzae type b isolates can persist in the nasopharyngeal secretions, even after a successful treatment of meningitis. For this reason, the patient must be given rifampin 20 mg/kg 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 usually are eradicated from the nasopharynx after successful treatment of meningitis.

Phlebitis at the intravenous site and antibiotic fever are the most common of several causes of secondary fever in patients with meningitis. Thoroughly evaluate any patient with fever. 

Table 3. Dose Guidelines of Intravenous Antimicrobials in Infants and Children With Bacterial Meningitis

Antibiotic	Dose (mg/kg/d) IV	Maximum Daily Dose	Dosing Interval
Ampicillin	400	6-12 g	q6h
Vancomycin	60	2-4 g	q6h
Penicillin G	400,000 U	24 million	q6h
Cefotaxime	200-300	8-10 g	q6h
Ceftriaxone	100	4 g	q12h
Ceftazidime	150	6 g	q8h
Cefepime*	150	2-4 g	q8h
Imipenem†	60	2-4 g	q6h
Meropenem	120	4-6 g	q8h
Rifampin	20	600 mg	q12h

*Minimal experience in pediatrics and not licensed for treatment of meningitis.

†Caution in use for treatment of meningitis because of possible seizures.

Duration of antimicrobial therapy

The IDSA 2004 guidelines for management of bacterial meningitis provide the following information on length of therapy with antibiotics 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 - 14-21 days
• Aerobic gram-negative bacilli - 21 days or 2 weeks beyond first sterile culture (whichever is longer)
• L monocytogenes - >21 days

Dexamethasone administration

Experimental studies have revealed a correlation between outcome and the severity of the inflammatory process in the subarachnoid space.¹ Animal models of bacterial meningitis have shown decreased inflammation, reduction in cerebral edema and intracranial pressure, and lessening brain damage with use of dexamethasone.

Better understanding of the mechanisms of inflammation in meningitis led to controlled double-blind clinical trials. In these trials, the beneficial effects of adjunctive dexamethasone were demonstrated in infants and children with H influenzae type b meningitis. Follow-up examination demonstrated a significant decrease in the incidence of neurologic and audiologic sequelae, with evidence of clinical benefit being greatest for overall hearing impairment. As a result, the IDSA guidelines recommend the use of adjunctive dexamethasone in cases of H influenzae type b meningitis to be initiated 10-20 minutes prior to or at least concomitant with the first antimicrobial dose at 0.15 mg/kg q6h for 2-4 days.

A prospective double-blind placebo-controlled multicenter trial in adults with bacterial meningitis showed benefits (lower percentage of unfavorable outcomes including death) in the subgroup of patients with pneumococcal meningitis but not others. Although, data from pediatric patients so far does not demonstrate a clear clinical benefit with dexamethasone use in patients with S pneumoniae meningitis, a recent Cochrane review recommended consideration of the use of corticosteroids in children (non-neonates) with bacterial meningitis in high-income countries. However, given the lack of clear benefit favoring dexamethasone use in this setting and the concerns about decreased antibiotic penetration in the CSF with its use, decision to use this agent is considered on a case-by-case basis after weighing the potential risks and benefits. Likewise, data are insufficient to recommend adjunctive steroids in neonates with bacterial meningitis.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Deterrence/Prevention

Prevention is an important aspect of care in bacterial meningitis because it has been shown to reduce mortality and morbidity. It can be divided into 2 categories: chemoprophylaxis and immunization.

H influenzae type b

• Chemoprophylaxis
• • Risk of invasive 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 H influenzae type b 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 aged > 4 y), 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
    • For index case if younger than 2 years old or with a susceptible household contact and treated with ampicillin or chloramphenicol
• Immunization: Immunizations should be administered as per American Academy of Pediatrics guidelines. Universal immunization against H influenzae type b infection has led to a dramatic decline in the incidence of invasive H influenzae disease.

N meningitidis

• Chemoprophylaxis
• • Antimicrobial administration to contacts is divided into high- and low-risk categories. Only those stratified as high risk require prophylaxis.
  • Candidates for prophylaxis include the following:
  • • All household contacts
    • Childcare or nursery school contact during 7 days before illness onset
    • Direct exposure to index case secretions through kissing or sharing toothbrushes or eating utensils, markers of close social contact during 7 days before illness onset
    • Mouth-to-mouth resuscitation, unprotected contact during endotracheal intubation during 7 days before illness onset
    • Frequently slept or ate in the same dwelling as index patient during 7 days before illness onset
  • Outbreaks or clusters need to be managed as per local public health authorities.
• Immunization: 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. The vaccine is also valuable in controlling the epidemics of meningococcal disease. The Advisory Committee on Immunization Practices (ACIP) has recommended this vaccine for all children aged 11-12 years and first-year college students who will be living in a dormitory or dormitorylike setting, and other high-risk groups.

S pneumoniae

• Chemoprophylaxis: Routine chemoprophylactic measures for invasive disease secondary to this organism are limited to people with specific medical conditions.
• Immunizations: The heptavalent pneumococcal conjugate vaccine has been introduced into the primary childhood vaccination schedule. Immunizations should be administered as per American Academy of Pediatrics guidelines. The polysaccharide vaccine is generally used for those with specific medical conditions.

Table 4. Chemoprophylaxis for Contacts of Patients and Index (Case of H influenzae type b and contacts of meningococcal disease)

Drug Name	Age of Contact	Dosage
H influenzae disease
Rifampin	Adults	600 mg PO qd for 4 d
	>1 month	20 mg/kg PO qd for 4 d; not to exceed 600 mg/dose
	<1 month	10 mg/kg PO qd for 4 d
N meningitidis disease
Rifampin	Adults	600 mg PO q12h for 2 d
	>1 month	10 mg/kg PO q12h for 2 d; not to exceed 600 mg/dose
	<1 month	5 mg/kg PO q12h for 2 d
Ceftriaxone	>15 years	250 mg IM once
	<15 years	125 mg IM once
Ciprofloxacin	>18 years	500 mg PO once

Complications

• Seizures: These 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: Numerous other complications that can be seen during the course of bacterial meningitis include SIADH, subdural effusions, and brain abscesses. Subdural effusions are generally asymptomatic and resolve without neurologic sequelae.
• Long-term sequelae: These are seen in as many as 30% of children and vary with etiologic agent, patient's age, presenting features, and hospital course. Long-term, close follow-up care of children is crucial for the early detection of sequelae.
• CNS sequelae: Although most patients have subtle CNS changes, serious complications occasionally are 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.
• Hearing impairment
• • 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 H influenzae type b meningitis.
  • Severe hearing impairment interferes with the development of normal speech; thus, frequent audiologic evaluation and developmental assessment must be performed during healthcare visits.
• Motor sequelae: Whenever motor sequelae are detected, physical, occupational, and rehabilitation services should evaluate the patient to prevent further damage and to provide optimal functional status.

Prognosis

• Prolonged or difficult-to-control seizures, especially after the fourth hospital day, 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 disseminated intravascular coagulopathy and endotoxic shock. These signs are indicative of a poor prognosis

Patient Education

• For excellent patient education resources, visit eMedicine's Children's Health Center and Procedures Center. Also, see eMedicine's patient education articles Meningitis in Children and Spinal Tap.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Meningitis is a life-threatening illness and leaves some survivors with significant sequelae. Therefore, pay meticulous attention in treating and monitoring these patients.
• • Promptly administer antibiotics.
  • Patients must be in a facility where emergencies can be managed and nursing and medical staff are experienced in caring for critically ill patients.
  • 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.
  • 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.
  • Respond promptly to parents' concerns with adequate documentation. Patients also may have other foci of infection. Presenting symptoms may point toward those foci, causing unnecessary delay in diagnosis of bacterial meningitis.
• Signs and symptoms in patients with listerial meningitis tend to be subtle, and diagnosis is often delayed.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jan 4, 2008