Neonatal Bacterial Meningitis
(See also Overview of Meningitis in adults, Bacterial Meningitis in Infants Over 3 Months of Age, and Overview of Neonatal Infections.)
Neonatal bacterial meningitis occurs in 2/10,000 full-term and 2/1,000 low-birth-weight (LBW) neonates, with a male predominance. It occurs in about 15% of neonates with sepsis and occasionally occurs in isolation.
The predominant pathogens are
Other reported pathogens include enterococci, nonenterococcal group D streptococci, alpha-hemolytic streptococci, Staphylococcus aureus, coagulase-negative staphylococci, gram-negative enteric organisms (eg, Klebsiella species, Enterobacter species, Citrobacter diversus), Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae.
Neonatal bacterial meningitis most frequently results from the bacteremia that occurs with neonatal sepsis; the higher the colony count in the blood culture, the higher the risk of meningitis. Neonatal bacterial meningitis may also result from scalp lesions, particularly when developmental defects lead to communication between the skin surface and the subarachnoid space, which predisposes to thrombophlebitis of the diploic veins. Rarely, there is direct extension to the central nervous system (CNS) from a contiguous otic focus (eg, otitis media).
Frequently, only those findings typical of neonatal sepsis (eg, temperature instability, respiratory distress, jaundice, apnea) are manifest. CNS signs (eg, lethargy, seizures [particularly focal], vomiting, irritability) more specifically suggest neonatal bacterial meningitis. So-called paradoxical irritability, in which cuddling and consoling by a parent irritates rather than comforts the neonate (because movement of inflamed meninges is painful), is more specific for the diagnosis. A bulging or full fontanelle occurs in about 25% and nuchal rigidity in only 15%. The younger the patient, the less common are these findings. Cranial nerve abnormalities (particularly those involving the 3rd, 6th, and 7th nerves) may also be present.
Meningitis due to group B streptococcus (GBS meningitis) may occur in the first week of life, accompanying early-onset neonatal sepsis and frequently manifesting initially as a systemic illness with prominent respiratory signs. Often, however, GBS meningitis occurs after this period (most commonly in the first 3 months of life) as an isolated illness characterized by absence of antecedent obstetric or perinatal complications and the presence of more specific signs of meningitis (eg, fever, lethargy, seizures).
Ventriculitis frequently accompanies neonatal bacterial meningitis, particularly when caused by gram-negative enteric bacilli. Organisms that cause meningitis together with severe vasculitis, particularly C. diversus and Cronobacter sakazakii (formerly Enterobacter sakazakii), are likely to cause cysts and abscesses. Pseudomonas aeruginosa, E. coli K1, and Serratia species also may cause brain abscesses. An early clinical sign of brain abscess is increased intracranial pressure (ICP), commonly manifested by vomiting, a bulging fontanelle, and sometimes enlarging head size. Deterioration in an otherwise stable neonate with meningitis suggests progressive increased ICP caused by abscess or hydrocephalus, or rupture of an abscess into the ventricular system.
Definitive diagnosis of neonatal bacterial meningitis is made by CSF examination via lumbar puncture (LP), which should be done in any neonate suspected of having sepsis or meningitis. However, LP can be difficult to do in a neonate, and there is some risk of hypoxia. Poor clinical condition (eg, respiratory distress, shock, thrombocytopenia) makes LP risky. If LP is delayed, the neonate should be treated as though meningitis is present. Even when the clinical condition improves, the presence of inflammatory cells and abnormal glucose and protein levels in CSF days after illness onset can still suggest the diagnosis. A needle with a trocar should be used for LP to avoid introducing epithelial rests and subsequent development of epitheliomas.
The CSF, even if bloody or acellular, should be cultured. About 15 to 35% of neonates with negative blood cultures have positive CSF cultures depending on the population studied. If CSF cultures are negative, multiplex PCR panels to test CSF for multiple common pathogens can be done if bacterial meningitis is suspected (eg, if culture may have been affected by prior antibiotic use). LP should be repeated at 24 to 48 hours if clinical response is questionable and at 72 hours when gram-negative organisms are involved (to ensure sterilization).
Repeating the CSF analysis helps guide duration of therapy and predict prognosis. Some experts believe that a repeat LP at 24 to 48 hours in neonates with GBS meningitis has prognostic value. LP should not be repeated at the end of therapy if the neonate is doing well.
Normal CSF values are controversial and in part age-related. In general, both term and preterm infants without meningitis have ≤ 20 white blood cells/mcL (one fifth of which may be polymorphonuclear leukocytes) in their CSF. CSF protein levels in the absence of meningitis are more variable; term infants have levels of < 100 mg/dL (1 g/L), whereas preterm infants have levels up to 150 mg/dL (1.5 g/L). CSF glucose levels in the absence of meningitis are > 75% of the serum value measured at the same time. These levels may be as low as 20 to 30 mg/dL (1.1 to 1.7 mmol/L). Bacterial meningitis has been identified by culture in neonates with normal CSF indices, showing that normal CSF values do not exclude a diagnosis of meningitis.
Ventriculitis is suspected in a neonate not responding appropriately to antimicrobial therapy. The diagnosis is made when a ventricular puncture yields a white blood cell count greater than that from the LP, by a positive Gram stain or culture of ventricular fluid, or by increased ventricular pressure. When ventriculitis or brain abscess is suspected, ultrasonography or MRI or CT with contrast may aid diagnosis; dilated ventricles also confirm ventriculitis.
Without treatment, the mortality rate for neonatal bacterial meningitis approaches 100%. With treatment, prognosis is determined by birth weight, organism, and clinical severity. Mortality rate for treated neonatal bacterial meningitis is 5 to 20%. For organisms that cause vasculitis or brain abscess (necrotizing meningitis), the mortality rate may approach 75%. Neurologic sequelae (eg, hydrocephalus, hearing loss, intellectual disability) develop in 20 to 50% of infants who survive, with a poorer prognosis when gram-negative enteric bacilli are the cause.
Prognosis also depends partly on the number of organisms present in CSF at diagnosis. The duration of positive CSF cultures correlates directly with the incidence of complications. In general, CSF cultures from neonates with GBS are usually sterilized within the first 24 hours of antimicrobial therapy. Those from gram-negative bacillary meningitis remain positive longer, with a median of 2 days.
GBS meningitis has a mortality rate significantly lower than that of early-onset GBS sepsis.
Initial empiric treatment depends on patient age and is still debated. For neonates, many experts recommend ampicillin plus an aminoglycoside (see table Recommended Dosages of Select Aminoglycosides for Neonates). A 3rd-generation cephalosporin (eg, cefotaxime) is also added until culture and sensitivity results are available if meningitis due to a gram-negative organism is suspected. However, resistance may develop more rapidly when cefotaxime is used routinely for empiric therapy, and prolonged use of 3rd-generation cephalosporins is a risk factor for invasive candidiasis. Ampicillin is active against organisms such as GBS, enterococci, and Listeria. Gentamicin provides synergy against these organisms and also treats many gram-negative infections. Third-generation cephalosporins provide adequate coverage for most gram-negative pathogens.
Hospitalized neonates who previously received antibiotics (eg, for early-onset sepsis) may have resistant organisms; fungal disease may also be considered in a septic-appearing neonate after prolonged hospitalization. Ill neonates with hospital-acquired infection should initially receive vancomycin (see table Vancomycin Dosage for Neonates) plus an aminoglycoside with or without a 3rd-generation cephalosporin or a carbapenem with activity against Pseudomonas aeruginosa, such as cefepime or meropenem, depending on the concern for meningitis.
Antibiotics are adjusted when results of CSF culture and sensitivities are known. The results of the Gram stain should not be used to narrow coverage before culture results are available.
The recommended initial treatment for GBS meningitis in neonates < 1 week of age is penicillin G 100,000 units/kg IV every 6 hours or ampicillin 100 mg/kg IV every 8 hours for infants ≤ 7 days or 75 mg/kg every 6 hours for infants > 7 days. Additionally, gentamicin is given for synergy at age-appropriate dosing (see Table: Recommended Dosages of Select Aminoglycosides for Neonates). If clinical improvement occurs or sterilization of CSF is documented, gentamicin can be stopped.
For enterococci or L. monocytogenes, treatment is generally ampicillin plus gentamicin for the entire course.
In gram-negative bacillary meningitis, treatment is difficult. The traditional regimen of ampicillin plus an aminoglycoside results in a 15 to 20% mortality rate, with a high rate of sequelae in survivors. Instead, a 3rd-generation cephalosporin (eg, cefotaxime) should be used in neonates with proven gram-negative meningitis. If antibiotic resistance is a concern, both an aminoglycoside and a 3rd-generation cephalosporin or extended-spectrum beta-lactam (eg, meropenem) may be used until sensitivities are known.
Parenteral therapy for gram-positive meningitis is given for a minimum of 14 days, and for complicated gram-positive or gram-negative meningitis, a minimum of 21 days. Intraventricular instillation of antibiotics is not recommended.
Because meningitis may be considered part of the continuum of neonatal sepsis, the adjunctive measures used in treating neonatal sepsis should also be used to treat neonatal meningitis. Corticosteroids are not used in treatment of neonatal meningitis. Patients should be closely monitored for neurologic complications during early childhood, including for sensorineural hearing loss.
The most common causes of neonatal bacterial meningitis are group B streptococcus, E. coli, and L. monocytogenes.
Manifestations are often nonspecific (eg, temperature instability, respiratory distress, jaundice, apnea).
Although central nervous system signs (eg, lethargy, seizures, vomiting, irritability) may be present, classic findings such as a bulging or full fontanelle and nuchal rigidity are not common.
Cerebrospinal fluid (CSF) culture is critical because some neonates with meningitis have normal CSF indices (eg, white blood cell count, protein and glucose levels).
Begin empiric treatment with ampicillin, gentamicin, and cefotaxime followed by specific drugs based on the results of cultures and susceptibility testing.
Corticosteroids are not used in neonatal meningitis.