Neonatal meningitis: Current treatment options—an update

Summary

• As many as 40% of infants with meningitis do not have a positive blood culture at the time of their diagnosis.

• Infants with uncomplicated meningitis due to group B streptococcus should receive a 14-day course of antimicrobial therapy. A minimum of a 4-week treatment course is recommended for infants with complicated courses (e.g., abscess).

• The treatment of gram-negative meningitis initially includes the addition of a third- or fourth-generation cephalosporin such as cefotaxime or cefepime for early-onset meningitis and cefepime for late-onset meningitis. Depending on susceptibilities, a carbapenem antibiotic such as meropenem can be used if resistance to third- and fourth-generation cephalosporins is present.

• For meningitis due to gram-negative bacilli, the duration of antimicrobial therapy is a minimum of 21 days.

• Among infants with meningitis, approximately 10% of affected infants die, and neurologic sequelae are found in up to 50% of survivors.

• Polymerase chain reaction for the detection of bacterial, viral and fungal DNA/RNA ultimately may improve detection of CSF pathogens.

Bacterial meningitis occurs in approximately 0.4 neonates per 1000 live births. It is defined as inflammation of the meninges that is manifested by an elevated number of white blood cells in the cerebrospinal fluid (CSF). It often is associated with elevated protein content and a low glucose concentration in CSF. Meningitis generally results as a consequence of hematogenous dissemination of bacteria via the choroid plexus and into the central nervous system (CNS) during a sepsis episode. Invasion of the meninges occurs in about 1% to 2% of infants evaluated for sepsis and is increased to about 10% with bacteremia. Rarely, meningitis develops secondary to extension from infected skin through the soft tissues and skull as may occur with an infected cephalohematoma or direct spread from skin surfaces, as in infants with myelomeningoceles or other congenital malformations of the neural tube. In addition, ventriculoperitoneal shunts or ventricular reservoirs may be the primary site of infection. A potential but infrequent complication of meningitis is brain abscess that results from hematogenous spread of bacteria into tissue that has incurred anoxic injury or severe vasculitis with hemorrhage or infarction.

Virtually all organisms that cause neonatal infection or sepsis can result in CNS disease with severe consequences for the developing brain. A list of the more commonly reported pathogens is provided in Box 11.1 . It is imperative that a correct and timely diagnosis with a specific organism be made because treatment decisions vary by causative agent.

The case of a preterm infant is presented and discussed to highlight the multifaceted nature of this disease. The objective of this chapter is to review the current management of neonatal bacterial meningitis, in the hope of ameliorating the destructive nature of many of these organisms and ultimately improving the outcome of these high-risk infants.

Question 1: What risk factors predispose this infant to have early-onset bacterial meningitis?

Because meningitis is a complication of bacteremia, the risk factors are similar to those that contribute to neonatal sepsis—namely prematurity, prolonged rupture of fetal membranes (≥18 hours), preterm premature rupture of membranes, maternal urinary tract infection, and maternal intrapartum fever or intraamniotic infection (chorioamnionitis). Immune dysfunction as well as lack of transplacentally acquired maternal immunoglobulin G (IgG) antibodies in premature infants also may increase risk of sepsis and CNS infection. Recently, lower neonatal 25-hydroxyvitamin D levels have been associated with early-onset sepsis in term infants.

Likewise, clinical signs suggestive of bacterial meningitis are similar to those of neonatal sepsis. In the full-term infant, fever, lethargy, hypotonia, irritability, apnea, poor feeding, high-pitched cry, emesis, seizures, and bulging fontanelle are prominent clinical signs, whereas in preterm infants, respiratory decompensation consisting of an increased number of apneic episodes predominates. Neonates with meningitis are never “asymptomatic.”

The widespread and routine use of intrapartum antibiotic prophylaxis (IAP) since 1996 has significantly reduced the rate of early-onset group B streptococcal (GBS) infection by more than 70%. While there has not been a reciprocal increase in early-onset bacterial infections among full-term infants caused by gram-negative organisms in the United States, there has been a shift toward more gram-negative infections in preterm infants. Several studies over the past decades from the NICUs comprising the National Institute of Child Health and Human Development (NICHD) Neonatal Research Network centers have helped inform our clinical practice by examining rates, pathogens and resistance patterns. IAP resulted in a significant decrease in early-onset GBS infection. The rate of infections caused by Escherichia coli ( E. coli ) initially increased significantly in infants <1500 g from 3 (1991–1993) to 7 (1998–2000) cases per 1000 live birth, then stabilized at 5.07 per 1000 live births (2006–2009) and most recently (2015–2017) increased again to 8.68 per 1000 live births. The overall rate of early-onset sepsis in the most recent time period (2015–2017), defined as a positive blood or CSF bacterial culture at less than 72 hours of age, was 1.16 infections per 1000 live births with rates inversely related to birth weight (BW; 401–1500 g BW, 15.05/1000; 1501–2500 g BW, 1.78/1000; >2500 g BW, 0.63/1000). Among cases of early-onset meningitis, around 50% are due to E. coli and 50% are due to GBS. In a study of 721 infants from 69 centers with early-onset or late-onset E. coli blood, urine or CSF infection, 66.7% of infections had resistant or intermediate susceptibility to ampicillin, 16.6% to aminoglycosides, and 4.9% to extended-spectrum β-lactamase phenotype antibiotics. All were susceptible to carbapenems. Nonsusceptibility to both ampicillin and gentamicin was present in 10.1% (22 of 218) early-onset infections.

Question 2: Do infants with meningitis have positive blood cultures?

As many as 40% of infants with meningitis who have a gestational age of 34 weeks or more do not have a positive blood culture at the time of their diagnosis. Similarly, among VLBW infants, almost one-half of cases of meningitis occur with sterile blood cultures. Therefore it is imperative that a lumbar puncture be performed if sepsis or meningitis are highly suspected. Evaluation of CSF indices and Gram stain not only will establish a diagnosis but also will help guide initial therapy. Normal CSF indices are provided in Table 11.1 . ^,

Meningitis with early-onset sepsis evaluations in preterm infants admitted to the NICU with respiratory distress syndrome is very uncommon. Therefore, performance of a lumbar puncture in these infants in whom sepsis is not suspected is not mandatory. Similar data are available for full-term infants. However, if the blood culture yields a pathogenic organism with either early or late-onset sepsis, then evaluation of CSF should be done. There is variation in this practice when bacteremia is due to coagulase-negative staphylococcus (CoNS). A lumbar puncture is contraindicated when there is cardiorespiratory instability. Delay in performing a lumbar puncture only delays a potential diagnosis of meningitis and can lead to prolonged and possibly inappropriate antibiotic use. ^, If there is delay in performing a lumbar puncture, meningitis/encephalitis multiplex panel polymerase chain reaction (PCR) assays may help to identify CSF pathogens after antimicrobial initiation.

While awaiting culture results, unless there are CSF abnormalities suggestive of meningitis, for early-onset sepsis evaluations, ampicillin in combination with an aminoglycoside is the preferred choice. Similarly, for late-onset sepsis evaluations, a penicillinase-resistant, semisynthetic penicillin such as oxacillin or nafcillin in combination with an aminoglycoside is the preferred choice.

Question 3: What is the optimal evaluation for possible late-onset sepsis in preterm infants in the NICU-when should a lumbar puncture be included?

Infants suspected of having late-onset sepsis in the NICU should have a complete evaluation that consists of a complete blood cell (CBC) count, blood and urine cultures. In critically ill hospitalized neonates, it is very difficult to distinguish infection from noninfectious clinical deteriorations; however, there should be a low threshold for also performing a lumbar puncture. Unfortunately, there are no laboratory or clinical findings that have a high sensitivity for the diagnosis of neonatal sepsis or meningitis. ^, Such laboratory tools as C-reactive protein; interleukin (IL)-6, IL-8, IL-10; and procalcitonin have suboptimal sensitivity and specificity to replace a blood or CSF culture as the gold standard. These biomarkers do not aid in the decision to initiate an evaluation for infection and whether or not to start antibiotics. In addition, their use has been associated with increased antibiotics and hospital days with no benefit of reduced morbidity or mortality. These noninfectious biomarkers are really host markers and may better trend host response to complex infections but are not diagnostic. ^, PCR for detection of bacterial, viral and fungal DNA/RNA ultimately may lead to an earlier diagnosis as well as detect CSF pathogens during a short window of about 24 hours after antibiotics and antivirals have been started.

It is important to obtain a CBC count with platelets for reasons other than diagnosis. Neonatal sepsis may result in neutropenia, which is associated with a high mortality rate. The finding of a persistent absolute neutrophil count of 500/mm ³ or less after 48 hours of antimicrobial treatment may prompt consideration of adjuvant therapies such as recombinant granulocyte or granulocyte-macrophage colony-stimulating factors by some experts. ^, Routine use of IVIG infusions for suspected sepsis is not recommended, as studies have not demonstrated benefit in early or late morbidity or mortality but there may be special situations where it should be considered such as patient with a primary or secondary hypogammaglobinemia (e.g., chylothorax or sepsis with capillary leak syndrome).

Another reason for performance of a CBC is many infections may be complicated by thrombocytopenia and/or disseminated intravascular coagulation. Thrombocytopenia is common with many neonatal infections and is most severe with gram-negative and fungal infections. The degree of thrombocytopenia should be factored into timing of safely performing the lumbar puncture. While controversial, the benefit of platelet transfusion prior to performing a lumbar puncture should be discussed. If severe thrombocytopenia is present and a lumbar puncture is indicated, administering a platelet infusion prior to procedure if counts <100,000/microliter in preterm infants and <50,000 in term infants are reasonable transfusion thresholds. Significant thrombocytopenia could increase the risk of a local hematoma which can cause medullary compression and in rare cases lead to paralysis.

A lumbar puncture should generally be performed in infants evaluated for possible late-onset sepsis for reasons stated in answer to Question 2. Risk factors for meningitis in preterm infants include low gestational age and prior bloodstream infection. In VLBW infants, the average age of late-onset meningitis is 26 days (median 19 days; range 4–102 days). Therapeutic decisions with regard to antibiotic choices can be made only if one knows whether the CNS is involved.