Neonatal Meningitis

Continuing Education Activity

Meningitis during the neonatal period is a potentially devastating condition with dire long-term consequences. Despite advances in preventive and critical care medicine, bacterial meningitis continues to have an adverse outcome rate of 20 to 60%. Although the incidence and mortality have declined over the past few decades, it remains difficult to diagnose due to pathogens varying with gestational age at birth, age at presentation, and geographic location, the often subtleness of clinical presentation, and inconsistent findings among infected individuals. Clinical evaluation and empiric treatment guidelines continue to evolve to support clinicians' efforts to decrease the morbidity and mortality associated with neonatal meningitis. This activity primarily reviews the etiology, evaluation, and management of patients with neonatal meningitis and includes a discussion on the roles of interprofessional team members in coordinating patient care.

Objectives:

• Summarize the common etiologies of neonatal meningitis.
• Implement current recommendations, including lumbar puncture, for evaluating patients with neonatal meningitis.
• Select the recommended antimicrobial therapy in patients with neonatal meningitis.
• Explain the interprofessional team's role in caring for patients with neonatal meningitis.

Introduction

Meningitis during the neonatal period is a potentially devastating condition with dire long-term consequences. Despite advances in preventive and critical care medicine, bacterial meningitis continues to have an adverse outcome rate of 20 to 60% among its survivors.[1] Although the incidence and mortality have declined over the past few decades, it remains challenging to diagnose due to pathogens varying with gestational age at birth, age at presentation, and geographic location, the often subtleness of clinical presentation, and inconsistent findings among infected individuals.[2] Additionally, the use of antibiotics before cerebrospinal fluid analysis can lead to ambiguous results, and specialized testing for viral causes is often unavailable. These factors have led experts to hypothesize that this condition's true incidence and prevalence are likely much higher.  

The immature immune system of neonates, especially preterm, puts them at high risk for bacterial meningitis. Their exposure during the peripartum period puts them at risk for unique bacterial and viral pathogens. The major pathogens in industrialized countries are group B Streptococcus, gram-negative rods, with Escherichia coli being the most common, and Listeria monocytogenes.[1] However, fungal and viral causes must be considered to diagnose and treat the condition adequately. Some experts recommend that all infants with proven or suspected sepsis undergo a lumbar puncture to rule out neonatal meningitis, with the goal of early diagnosis and appropriate treatment.[1]

Etiology

Pathogens causing neonatal meningitis vary depending on the neonate's gestational age at birth, age at presentation, and geographic location. The disease is categorized as early-onset or late-onset, defined as clinical signs of infection at ≤72 hours and >72 hours of life, respectively.[2] Late-onset is predominantly seen in premature infants, with patients in the intensive care unit likely affected by pathogens that differ from those with community-acquired infections.

Bacterial and Fungal Etiologies

Well-known risk factors for bacterial meningitis in neonates are preterm birth, maternal group B Streptococcus (GBS) or S agalactiae colonization, premature or prolonged rupture of membranes, and very low birth weight (VLBW, less than 1500 grams).[2] 

The incidence of early-onset meningitis has been greatly reduced by using intrapartum antibiotics for GBS infection. However, GBS remains the most common cause of meningitis and neonatal sepsis, responsible for more than 40% of all early-onset infections.[3][4][5] The next most common pathogen, Escherichia coli, accounts for approximately 30% of all early-onset neonatal meningitis and is documented as the most common cause of early-onset sepsis and meningitis among VLBW and preterm newborns.[2][6] Listeria monocytogenes, Enterococcus sp, and Streptococcus pneumoniae are the other major pathogens causing early-onset bacterial meningitis in neonates.[2][7]

In the late-onset group, the incidence is directly related to gestational age, birth weight, and the setting where the patient presents for care. For community-acquired late-onset sepsis and meningitis, GBS and E coli remain predominant.[5] In patients in the hospital/intensive care unit at the time of presentation, the most common pathogens are coagulase-negative staphylococci and Staphylococcus aureus, followed by E coli and Klebsiella pneumoniae.[2][5][8] Empiric antibiotic therapy for late-onset illness should cover additional organisms in the nosocomial environment, including Pseudomonas aeruginosa and methicillin-resistant S aureus. Late-onset meningitis is a more frequent complication of neonatal sepsis than during other periods.

Some epidemiologic studies have noted a shift from GBS as the most common cause of neonatal meningitis in the last few decades. A recent study in China reported the most common pathogen identified in neonatal meningitis was E. coli (39%), followed by GBS (22.1%). Gram-negative bacteria were more common in preterm infants, whereas GBS was more common in term infants.[9] Data from East Asian populations have revealed an increased frequency of multidrug-resistant (MDR) organisms causing neonatal sepsis and meningitis, especially carbapenem-resistant Acinetobacter baumannii. This study also reported a correlation between lower Apgar scores and the risk of MDR meningitis.[10] An additional nosocomial pathogen that has been associated with meningitis in the neonatal period is Candida sp.[11]

A special mention of the bacteria Cronobacter (Enterobacter) sakazakii is warranted. It has been predominantly associated with outbreaks of sepsis and meningitis during early infancy (67% neonates) who have been fed powdered infant formulas. Meningitis in these patients is often complicated by brain abscesses, subdural empyemas, and hydrocephalus, leading to a high mortality rate.[12] Occasional cases have been reported in infants being fed expressed breast milk that has been stored.[13]

Citrobacter sp are noted to cause invasive disease in neonates and young infants, often with no risk factors. These pathogens are associated with a very high rate of brain abscesses (up to 75%) in patients with meningitis and subsequent central nervous system-related morbidity and mortality.[14]

It is important to note that infants exposed to HIV, even uninfected, are at a higher risk of bacterial infections, including GBS-associated meningitis.[15] Also, neonates with invasive devices, such as indwelling vascular catheters, ventricular shunts and reservoirs, and endotracheal tubes, have a higher risk of meningitis following hematogenous and cerebrospinal fluid (CSF) bacterial spread.

Bacterial and Fungal Etiologies of Neonatal Meningitis

(most common pathogens are in bold)

Table

Late-Onset Meningitis (community-acquired)

Viral Etiologies

Neonates who do not test positive for bacterial etiologies but have abnormal CSF profiles are often presumed to have viral meningitis. Enterovirus infection is a common cause of neonatal meningitis, and human parechovirus type 3 has been identified as an emerging cause of meningoencephalitis.[16][17][18][19][20] 

Neonatal infection with herpes simplex virus (HSV) is rare and, as such, a rare cause of neonatal meningitis. In a multicenter retrospective review of more than 26,000 infants undergoing evaluation for meningitis, HSV infection was identified in only 0.42% of reported cases, with the highest frequency of central nervous system (CNS) infection in the second week of life.[21] The global estimate of neonatal herpes infection is 10 per 100,000 live births, most commonly presenting between 7 and 21 days of life.[22]

Arboviruses such as West Nile virus and Chikungunya have been reported as extremely rare causes of neonatal meningitis and meningoencephalitis.[23]

Epidemiology

According to studies in the United Kingdom, the annual incidence of bacterial meningitis is 0.38 per 1000 live births, and that of viral meningitis is 0.83 per 1000 live births.[24][25][26] This is consistent with other reports that culture-proven neonatal bacterial meningitis is estimated at 0.3 per 1000 live births, but this is likely underestimated because only 30 to 50% of those in the neonatal intensive care unit (NICU) who are evaluated for sepsis have a lumbar puncture done, and 75% of the time, it occurs after the initiation of broad-spectrum antibiotics.[2] Consequently, the culture results may be falsely negative.

One study from Canada reported rates of neonatal meningitis ranging between 2.2 and 3.5/1000 NICU admissions over a 7-year period.[27]

In developing countries, the incidence is higher, at 0.8 to 6.1 per 1000 live births, with a mortality rate of up to 58%. The true incidence is likely higher as the epidemiology is limited in many rural, developing settings.[2][28]

Pathophysiology

Neonates are susceptible to invasive infections due to their "inexperienced" immune system and lack of maternal antibodies if born preterm. The most common mechanism is primary bloodstream infection seeding the CNS. Early-onset infection is mainly maternal in origin because pregnancy and delivery expose the fetus/neonate to many pathogens that can be transmitted through the vagina to ruptured amniotic membranes or via contact with the neonate's skin during passage through the birth canal. Organisms such as L. monocytogenes can be transmitted through the placenta. Late-onset infection is mainly nosocomial, with foreign devices such as endotracheal tubes, catheters, and feeding tubes, increasing the risk of infection.[2][29]

History and Physical

Classical findings such as seizure, bulging fontanelle, coma, and neck stiffness were found in 28%, 22%, 6%, and 3% of cases in one review from the United Kingdom.[4] Nonspecific findings of temperature instability (fever or hypothermia), lethargy, feeding intolerance, and poor perfusion (hypotension) have been reported as the most common presenting signs.[4][30] 

The clinical presentation may vary based on the birthweight and gestational age at birth. For example, the most common signs in neonates weighing over 2500 grams include fever, irritability, seizures, and bulging fontanelle. In contrast, apnea, jaundice, and abdominal distention are most common in those weighing less than 2500 grams.[30] A physically demonstrable Brudzinski sign indicates meningitis, with passive neck flexion resulting in bilateral flexion at the hip joint. 

Table

Temperature instability (fever or hypothermia)

Evaluation

Neonatal meningitis can be difficult to diagnose due to pathogens varying with gestational age at birth, age at presentation, geographic location, the often subtleness of clinical presentation, and inconsistent findings among infected individuals. Well-appearing febrile neonates can become toxic quickly and are at high risk for meningitis due to their immature immune systems. Lumbar puncture (LP) with cultures plus or minus molecular diagnostics of the CSF continues to be the gold standard for diagnosing neonatal meningitis. The current recommendation is to perform an LP on all neonates with confirmed or suspected sepsis.[2][6] Although LP and CSF cultures are essential for diagnosing neonatal meningitis, data shows that 30% of patients with early-onset sepsis and 70% with late-onset sepsis do not have LPs when evaluated.[31][32]

Select recommendations from the American Academy of Pediatrics Clinical Practice Guidelines for the Evaluation of Febrile Infants 8 to 60 Days Old are listed below:[33]

• Obtain CSF for analysis and bacterial culture in the workup of a febrile infant 8 to 21 days old.
• Enterovirus polymerase chain reaction (PCR) should be sent if pleocytosis is present on CSF testing during periods of increased local enterovirus prevalence.
• In infants at high risk for HSV, PCR testing should be obtained.

  • High-risk patients for HSV include infants born to mothers with genital HSV lesions, maternal fever 48 hours before or within 48 hours of delivery, or if the infant has CSF pleocytosis in the absence of a positive Gram stain. 
• Obtain CSF analysis for infants 22 to 28 days if inflammatory markers are abnormal and/or no other source of infection or fever is identified.
• Urinalysis and workup for urinary tract infections are universally recommended in evaluating patients with a fever in this age group.

CSF Indices By Infant Age

(upper limits of normal)[34][35][36][37]

Table

Kestenbaum et al or Shah et al

A multicenter study from 2019 reported that most infants less than 60 days old with bacterial meningitis either have positive Gram stain results or corrected CSF pleocytosis (80.3% sensitivity). The bacterial meningitis score was noted to have poor specificity in this study; therefore, the authors recommend not using this prediction tool in infants less than 60 days old. The authors also noted that infants who did not have pleocytosis or abnormal Gram stain but were later proved to have bacterial meningitis either had peripheral leukocytosis or bandemia on presentation. Notably, correcting the CSF leukocyte count for red blood cells (RBCs) decreased the sensitivity of pleocytosis for meningitis in this population.[38] Results from a recent study suggest that for a traumatic LP subtracting one white blood cell (WBC) for every 400 RBCs in the CSF or using a complex calculation comparing the peripheral WBC to the CSF WBC counts may decrease the number of infants inaccurately diagnosed with meningitis.[39]  

Monitoring in a hospitalized setting is required until culture results are obtained. The time to pathogen detection may vary based on the underlying pathogen and the clinical presentation. A multicenter study from 2018 reported that in infants under 60 days old with an underlying invasive bacterial infection (either bacteremia or meningitis), 88% of the pathogens were detected in blood, and 89% were detected in CSF cultures and/or Gram stain within 24 hours. In "well-appearing infants," the detection rate was 85% at 24 hours. They reported that in all "non–ill-appearing febrile infants," only 0.3% will have a pathogen detected after 24 hours, most commonly S. aureus.[40]

Polymerase Chain Reaction

Real-time PCR assays to detect multiple pathogens, including S pneumoniae, E coli, GBS, S aureus, and L monocytogenes, had a higher detection rate than traditional cultures (72% vs 48%), even if antibiotics had been started (58% vs 29%).[2] Multipathogen PCR films and arrays are now used to simultaneously detect viral and bacterial pathogens. A 2015 study used a PCR panel capable of detecting 14 pathogens in the CSF (E coli, Haemophilus influenzae, L monocytogenes, Neisseria meningitides, S agalactiae (GBS), Streptococcus pneumoniae, cytomegalovirus, enterovirus, Epstein-Barr virus, HSV types 1 and 2, human herpes virus 6, varicella zoster, human parechovirus, and Cryptococcus neoformans/gattii).[41] The study reported that the PCR panel could detect the causative agent in culture-positive and culture-negative meningitis with a 1 hour turn-around time. The authors highlighted the role of PCR panels as a reliable tool in detecting culture-negative CSF infections, especially in those infants who received antibiotics before an LP.[41] Additionally, it has been suggested that the rapid detection of a pathogen like an enterovirus with a more benign clinical course may help limit invasive interventions and antibiotic exposure in young infants with negative cultures.[42]

PCR testing for HSV is essential for diagnosing HSV CNS involvement. A large multicenter study noted significant variation in HSV testing across emergency departments in North America when evaluating neonates for meningitis. This variation did not correlate with local HSV incidence. The authors concluded, "Our data emphasize the need for improved management strategies focused on the early identification of infants at both high and low risk of HSV infection."[21] HSV should be suspected in all patients with neonatal meningitis, especially if there is CSF pleocytosis in the absence of Gram stain findings. HSV PCR should be promptly sent to the appropriate laboratory to ensure the diagnosis is not missed.

When to Defer Lumbar Punctures

The 2012 Committee on Fetus and Newborn recommend performing an LP for all infants with sepsis or bacteremia.[43] However, deferring the LP is appropriate in asymptomatic individuals. In other words, if the neonate is being considered for an LP solely because of maternal risk factors, the LP can be safely deferred in the absence of clinical signs suggestive of infection.[6] Similarly, patients with signs of respiratory distress were found to correlate poorly with CSF positivity; therefore, LP can be deferred in these patients in the absence of bacteremia and clinical improvement after antibiotic initiation for respiratory causes.[6] All patients with culture-confirmed bacteremia should have an LP performed, as up to 25% of these patients may have concurrent meningitis.[44]

Radiographic Evaluation

Expert opinion varies regarding the radiographic evaluation of neonates with meningitis. Some authors recommend a sonographic evaluation of every infant with evidence of meningitis, while some recommend sonography only if there is suspicion of neurologic complications.[45] Most experts recommend cranial sonography as the initial study, with repeat testing if there is evidence of neurologic complications. Magnetic resonance imaging (MRI) of the brain is the recommended follow-up study in stable patients.[45] This is to evaluate neurologic tissue and identify organic complications of the infection. Ventriculitis is a common complication of meningitis and is seen as an irregular and echogenic ependyma with intraventricular debris and stranding on cranial sonography.[45] Other radiographic findings with bacterial meningitis may include subdural empyema, intracranial abscesses, and parameningeal abscesses. Hydrocephalus is a common complication of meningitis that can be detected by neuroimaging.

Treatment / Management

Recommendations for empiric therapy vary by geographic region, local resistance patterns, and expert opinion. For most patients with suspected early-onset neonatal meningitis, ampicillin plus an aminoglycoside (eg, gentamicin) or an expanded spectrum cephalosporin (eg, cefotaxime, ceftazidime, or cefepime) should be started empirically.[2] According to an expert review from the United Kingdom, empiric therapy for meningitis in the first week of life should include ampicillin, cefotaxime, and gentamicin.[46] 

One recent source citing World Health Organization standards indicated that ampicillin or penicillin plus gentamicin are recommended empiric therapy in developing countries, with cephalosporins reserved for second-line treatment.[47] It should be noted that all antimicrobials need to be dosed based on gestational and postnatal age recommendations and at meningeal dosing. This recommendation is due to the growing concern about ampicillin resistance in gram-negative organisms. A study from 2003 evaluated serious bacterial infection in infants less than 90 days old, reporting that 78% of the pathogens causing meningitis in this population were resistant to ampicillin.[48] However, ampicillin must remain part of the initial regimen to cover for GBS and L monocytogenes. Empiric antibiotic therapy for late-onset illness should cover additional organisms in the nosocomial environment, including Pseudomonas aeruginosa and methicillin-resistant S aureus.

In late-onset meningitis, vancomycin should be added to the above empiric regimen when the suspicion of nosocomial pathogens is high.[2] Some experts recommend a carbapenem instead of the expanded-spectrum cephalosporin when late-onset meningitis is suspected in infants with prolonged hospitalization, especially if the CSF Gram stain or the blood culture is suggestive of gram-negative infection.[3] 

It is important to remember that not all late-onset meningitis patients warrant nosocomial organism coverage. If the infant is discharged home after birth and presents in the late-onset period, they will be considered to have late-onset community-acquired neonatal meningitis. In this case, the empiric coverage may be the same as that of early-onset meningitis. 

An LP should be repeated in 24 to 48 hours if the patient does not demonstrate clinical improvement. According to some experts, repeating the LP to show CSF clearance is unnecessary if there is clinical improvement.[2] Others recommend ensuring CSF pathogen clearance after 2 to 3 weeks of continued antibiotic therapy.[46]

Definitive therapy should be instituted when the causative organism and its susceptibilities have been determined. GBS therapy can be modified to ampicillin or penicillin monotherapy once repeat LP notes sterility and response to therapy. E. coli and other gram-negative pathogens are typically treated with a combination of a third-generation cephalosporin plus an aminoglycoside until sterility and response to therapy can be confirmed. At that time, the aminoglycoside is usually stopped. L. monocytogenes infection is commonly treated with ampicillin monotherapy following repeat CSF sampling.

There is no data to help determine the duration of antibiotic therapy for neonatal meningitis. The minimum acceptable duration by European guidelines is 14 days for GBS and L. monocytogenes infections and 21 days for gram-negative organisms.[46] Delayed CSF clearance and/or abnormalities on neuroimaging warrant prolonged therapy.[46] Persistently positive CSF cultures suggest ventriculitis, hemorrhage, or abscess formation. In the United States, the recommended duration of treatment for uncomplicated meningitis is 14 days for GBS, L. monocytogenes, and S. pneumoniae infections and 21 days for Pseudomonas and gram-negative enteric bacteria.[2] 

There are no clear guidelines on when to suspect and initiate empiric therapy for HSV meningitis. According to some infectious disease experts, empiric evaluation and treatment for neonatal HSV are warranted if there are clear signs of HSV infection (skin vesicles, seizures, or liver inflammation or failure) or CSF pleocytosis is found outside of the enteroviral season.[49] They also recommend considering HSV in neonates with CSF pleocytosis regardless of the season if the infant is febrile and without another clear diagnosis of infection. In advocating empiric acyclovir therapy in these patients, this expert identified no risk of adverse effects of acyclovir. This outcome required adequate attention to hydration and rapid viral diagnostic testing, ensuring less than 48 hours of acyclovir therapy in patients who did not have HSV infection.[49]

Intraventricular antibiotics, dexamethasone, intravenous immunoglobulins, granulocyte or granulocyte-macrophage colony-stimulating factor, and oral glycerol are not recommended in routine practice.[2]

Differential Diagnosis

The differential diagnosis includes all noninfectious causes of the typical signs and symptoms associated with neonatal meningitis, such as seizures, irritability, poor feeding, and fever. If CNS bacterial and viral infection have been ruled out, the following should be considered:

• Neonatal seizure disorders
• Inborn errors of metabolism
• Intracranial hemorrhage
• Cerebral aneurysm
• Central venous thrombosis
• Sepsis from non-neurologic foci

Prognosis

Despite the decrease in mortality, neonatal meningitis continues to have high morbidity. Global mortality estimates are approximately 190,000 cases per year.[50] In Western countries, the mortality rate is about 10 to 15%, with the highest rates in preterm neonates.[2] In low-income countries, the mortality rate is as high as 58%, with moderate to severe neurodevelopmental impairment in approximately 23% of survivors.[51] In high-income countries, the rate of neurological sequelae is 20 to 50%.[50][52] A meta-analysis of neurodevelopmental outcomes in children with GBS meningitis noted that 32% had neurodevelopmental impairment at 18 months, including 18% with moderate to severe impairment.[53] Furthermore, compared to the general population, the risk of death remains higher five years after the acute illness.[50][54]

A study from Tunisia revealed a neurologic complication rate of 21.6%. Respiratory distress, low birth weight, shock, and pleocytosis of fewer than 500 cells/mm3 were indicators of a worse prognosis. Adding ofloxacin to the antibiotic regimen was associated with decreased neurological sequelae in survivors.[55] Another study noted that infant feeding difficulties and concomitant pneumonia were prognostic predictors of poor outcomes.[56] Also, high CSF protein, both during and after acute illness, has been linked to poorer outcomes.[56][57]

Most reviews report that infection severity correlates with outcomes, but there is no difference in outcome by pathogens.[46] The exception is an infection due to an MDR organism. A study evaluating the case fatality rate between neonatal MDR and non-MDR meningitis over a 29-year period reported a fatality rate of 58.8% in patients with MDR meningitis versus 9.5% in non-MDR meningitis.[10]

Seizures, irritability, bulging anterior fontanelle, and nuchal rigidity have been associated with poor outcomes. Other predictors of poor outcomes in survivors of neonatal bacterial meningitis include somnolence/coma, hypotension, and leukopenia.[2] Another source noted that seizures and the need for vasopressors predicted complications in patients with neonatal meningitis.[58]

The prognosis for neonates with enteroviral and parechovirus meningitis appears favorable. One study indicated that despite abnormal MRIs in 35% of neonates, all had normal neurodevelopmental, visual, and hearing exams at 12 months of life.[59]

Complications

Persistent bacteremia or CSF infection should raise concern for complications of meningitis, including obstructive ventriculitis, subdural empyema, multiple small vessel thrombi, intracranial abscesses, and parameningeal abscesses.[45][46] A long-term follow-up study from the United Kingdom reported ventriculitis, hydrocephalus, and convulsions as the most frequent complications of bacterial meningitis, occurring at a combined rate of 26%.[26] Ventriculitis is most often seen with gram-negative meningitis and can progress to chronic ventriculitis with septations.[45] Ventriculitis is more common in children with intraventricular hemorrhages associated with prematurity and infection.[57]  

Infections caused by members of the Enterobacteriaceae family are the most common cause of brain abscess formation following CSF infection.[45] Hearing loss is a potential long-term consequence of neonatal meningitis. Some experts recommend studies evaluating the efficacy of adjuvant corticosteroids to reduce hearing loss and neurological complications of this disease.[50] Ischemic stroke is a possible complication of bacterial neonatal meningitis in general[60], and ischemic stroke and cerebral sinovenous thrombosis are possible complications of late-onset GBS meningitis in particular.[61]

Deterrence and Patient Education

Population awareness regarding the risk of bacterial transmission from mother to fetus is essential to decrease the incidence of this disease. World Meningitis Day on April 24 is intended to raise general awareness.[50] Adequate screening and prophylactic treatment are essential preventive measures against neonatal meningitis. Intrapartum prophylactic antibiotic therapy, versus risk factor-based management, is recommended for mothers colonized with GBS to prevent this disease. This practice has dramatically decreased the incidence of early-onset GBS infections, but the incidence of late-onset GBS remains unaffected.[62]

GBS vaccines are being developed to help prevent neonatal meningitis. Early phase 1 and 2 trial results testing GBS vaccines with maternal vaccination to prevent neonatal meningitis are underway.[50] Maternal vaccination against GBS and E coli can potentially decrease neonatal meningitis incidence by two-thirds.[46]

Enhancing Healthcare Team Outcomes

Neonates with suspected meningitis should optimally be in the care of a neonatologist in an intensive care setting. Consultations with a pediatric infectious diseases physician and pediatric neurologist may be warranted based on presenting symptoms. An experienced neuroradiologist may help assess for complications. An audiologist is needed when the neonate is stable to evaluate for hearing problems. Finally, a neurodevelopmental and/or developmental-behavioral pediatrician is recommended to assess and follow patients as they mature after hospital discharge. If complications develop, neurosurgical consultation may be necessary to assist with the management of patients with neonatal meningitis.

Neonatal meningitis requires diligent clinical assessment, with multiple diagnostic tests and early CSF assessment. The emergency medical provider is an essential team member, as they are tasked with performing an LP in all patients with suspected disease. The neonatal intensive care physicians, physician assistants, nurse practitioners, clinical nurse specialists, and nurses help monitor the neonate and will be the first to notice if any neurologic complications arise. Doing so can help address these complications early to minimize long-term consequences. The clinical pathologist must report Gram stain findings as soon as they are confirmed to ensure appropriate antibiotic therapy. The pharmacist will help with adequate dosing of gestational aged and weight-based antimicrobial agents required for treatment. Clinical audiologists are essential for assessing hearing impairment in patients with meningitis in both the inpatient and outpatient settings. A neurodevelopmental team consisting of physicians, nurses, physical therapists, occupational therapists, and social workers can facilitate early intervention and help to maximize positive outcomes in patients with neonatal meningitis. A well-integrated interprofessional team can better ensure timely assessment and management of this potentially devastating condition and help improve clinical outcomes.[Level 5]

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References

1.

Berardi A, Lugli L, Rossi C, China MC, Vellani G, Contiero R, Calanca F, Camerlo F, Casula F, Di Carlo C, Rossi MR, Chiarabini R, Ferrari M, Minniti S, Venturelli C, Silvestrini D, Dodi I, Zucchini A, Ferrari F., Infezioni da Streptococco B Della Regione Emilia Romagna. Neonatal bacterial meningitis. Minerva Pediatr. 2010 Jun;62(3 Suppl 1):51-4. [PubMed: 21089719]

2.

Ku LC, Boggess KA, Cohen-Wolkowiez M. Bacterial meningitis in infants. Clin Perinatol. 2015 Mar;42(1):29-45, vii-viii. [PMC free article: PMC4332563] [PubMed: 25677995]

3.

Ouchenir L, Renaud C, Khan S, Bitnun A, Boisvert AA, McDonald J, Bowes J, Brophy J, Barton M, Ting J, Roberts A, Hawkes M, Robinson JL. The Epidemiology, Management, and Outcomes of Bacterial Meningitis in Infants. Pediatrics. 2017 Jul;140(1) [PubMed: 28600447]

4.

Okike IO, Ladhani SN, Johnson AP, Henderson KL, Blackburn RM, Muller-Pebody B, Cafferkey M, Anthony M, Ninis N, Heath PT., neoMen Study Group. Clinical Characteristics and Risk Factors for Poor Outcome in Infants Less Than 90 Days of Age With Bacterial Meningitis in the United Kingdom and Ireland. Pediatr Infect Dis J. 2018 Sep;37(9):837-843. [PubMed: 29384979]

5.

Giannoni E, Agyeman PKA, Stocker M, Posfay-Barbe KM, Heininger U, Spycher BD, Bernhard-Stirnemann S, Niederer-Loher A, Kahlert CR, Donas A, Leone A, Hasters P, Relly C, Riedel T, Kuehni C, Aebi C, Berger C, Schlapbach LJ., Swiss Pediatric Sepsis Study. Neonatal Sepsis of Early Onset, and Hospital-Acquired and Community-Acquired Late Onset: A Prospective Population-Based Cohort Study. J Pediatr. 2018 Oct;201:106-114.e4. [PubMed: 30054165]

6.

Aleem S, Greenberg RG. When to Include a Lumbar Puncture in the Evaluation for Neonatal Sepsis. Neoreviews. 2019 Mar;20(3):e124-e134. [PubMed: 31261050]

7.

Charlier C, Kermorvant-Duchemin E, Perrodeau E, Moura A, Maury MM, Bracq-Dieye H, Thouvenot P, Valès G, Leclercq A, Ravaud P, Lecuit M. Neonatal Listeriosis Presentation and Outcome: A Prospective Study of 189 Cases. Clin Infect Dis. 2022 Jan 07;74(1):8-16. [PubMed: 33876229]

8.

Wu IH, Tsai MH, Lai MY, Hsu LF, Chiang MC, Lien R, Fu RH, Huang HR, Chu SM, Hsu JF. Incidence, clinical features, and implications on outcomes of neonatal late-onset sepsis with concurrent infectious focus. BMC Infect Dis. 2017 Jul 03;17(1):465. [PMC free article: PMC5496375] [PubMed: 28673280]

9.

Zhai Q, Li S, Zhang L, Yang Y, Jiang S, Cao Y. Changes in pathogens of neonatal bacterial meningitis over the past 12 years: a single-center retrospective study. Transl Pediatr. 2022 Oct;11(10):1595-1603. [PMC free article: PMC9636462] [PubMed: 36345456]

10.

Thatrimontrichai A, Janjindamai W, Dissaneevate S, Maneenil G. Neonatal multidrug-resistant bacterial meningitis: a 29-year study from a tertiary hospital in Thailand. J Infect Dev Ctries. 2021 Jul 31;15(7):1021-1026. [PubMed: 34343128]

11.

Mashau RC, Meiring ST, Dramowski A, Magobo RE, Quan VC, Perovic O, von Gottberg A, Cohen C, Velaphi S, van Schalkwyk E, Govender NP., Baby GERMS-SA. Culture-confirmed neonatal bloodstream infections and meningitis in South Africa, 2014-19: a cross-sectional study. Lancet Glob Health. 2022 Aug;10(8):e1170-e1178. [PMC free article: PMC9296659] [PubMed: 35839815]

12.

Strysko J, Cope JR, Martin H, Tarr C, Hise K, Collier S, Bowen A. Food Safety and Invasive Cronobacter Infections during Early Infancy, 1961-2018. Emerg Infect Dis. 2020 May;26(5):857-65. [PMC free article: PMC7181934] [PubMed: 32310746]

13.

Sundararajan M, Enane LA, Kidwell LA, Gentry R, Danao S, Bhumbra S, Lehmann C, Teachout M, Yeadon-Fagbohun J, Krombach P, Schroeder B, Martin H, Winkjer J, Waltz T, Strysko J, Cope JR. Notes from the Field: Cronobacter sakazakii Meningitis in a Full-Term Neonate Fed Exclusively with Breast Milk - Indiana, 2018. MMWR Morb Mortal Wkly Rep. 2018 Nov 09;67(44):1248-1249. [PMC free article: PMC6223960] [PubMed: 30408018]

14.

Doran TI. The role of Citrobacter in clinical disease of children: review. Clin Infect Dis. 1999 Feb;28(2):384-94. [PubMed: 10064257]

15.

Manzanares Á, Prieto-Tato LM, Escosa-García L, Navarro M, Guillén S, Penin M, Hernanz-Lobo A, Soto-Sánchez B, Beceiro-Mosquera J, Falces-Romero I, Ramos-Amador JT, Orellana-Miguel MÁ, Epalza C. Increased risk of group B streptococcal sepsis and meningitis in HIV-exposed uninfected infants in a high-income country. Eur J Pediatr. 2023 Feb;182(2):575-579. [PubMed: 36383285]

16.

Moliner-Calderón E, Rabella-Garcia N, Turón-Viñas E, Ginovart-Galiana G, Figueras-Aloy J. Relevance of enteroviruses in neonatal meningitis. Enferm Infecc Microbiol Clin (Engl Ed). 2024 Jan;42(1):17-23. [PubMed: 36624031]

17.

Petel D, Barton M, Renaud C, Ouchenir L, Brophy J, Bowes J, Khan S, Bitnun A, McDonald J, Boisvert AA, Ting J, Roberts A, Robinson JL. Enteroviral and herpes simplex virus central nervous system infections in infants < 90 days old: a Paediatric Investigators' Collaborative Network on Infections in Canada (PICNIC) study. BMC Pediatr. 2020 May 26;20(1):252. [PMC free article: PMC7249448] [PubMed: 32456669]

18.

Levorson RE, Jantausch BA, Wiedermann BL, Spiegel HM, Campos JM. Human parechovirus-3 infection: emerging pathogen in neonatal sepsis. Pediatr Infect Dis J. 2009 Jun;28(6):545-7. [PubMed: 19483524]

19.

Ferreras Antolín L, Kadambari S, Braccio S, Tang JW, Xerry J, Allen DJ, Ladhani SN., Parechovirus Surveillance Network. Increased detection of human parechovirus infection in infants in England during 2016: epidemiology and clinical characteristics. Arch Dis Child. 2018 Nov;103(11):1061-1066. [PubMed: 29871901]

20.

Martín Del Valle F, Calvo C, Martinez-Rienda I, Cilla A, Romero MP, Menasalvas AI, Reis-Iglesias L, Roda D, Pena MJ, Rabella N, Portugués de la Red MDM, Megías G, Moreno-Docón A, Otero A, Cabrerizo M., Grupo de Estudio de las infecciones por enterovirus y parechovirus en niños. [Epidemiological and clinical characteristics of infants admitted to hospital due to human parechovirus infections: A prospective study in Spain]. An Pediatr (Engl Ed). 2018 Feb;88(2):82-88. [PubMed: 28365283]

21.

Cruz AT, Freedman SB, Kulik DM, Okada PJ, Fleming AH, Mistry RD, Thomson JE, Schnadower D, Arms JL, Mahajan P, Garro AC, Pruitt CM, Balamuth F, Uspal NG, Aronson PL, Lyons TW, Thompson AD, Curtis SJ, Ishimine PT, Schmidt SM, Bradin SA, Grether-Jones KL, Miller AS, Louie J, Shah SS, Nigrovic LE., HSV Study Group of the Pediatric Emergency Medicine Collaborative Research Committee. Herpes Simplex Virus Infection in Infants Undergoing Meningitis Evaluation. Pediatrics. 2018 Feb;141(2) [PMC free article: PMC5810597] [PubMed: 29298827]

22.

Looker KJ, Magaret AS, May MT, Turner KME, Vickerman P, Newman LM, Gottlieb SL. First estimates of the global and regional incidence of neonatal herpes infection. Lancet Glob Health. 2017 Mar;5(3):e300-e309. [PMC free article: PMC5837040] [PubMed: 28153513]

23.

Ginige S, Flower R, Viennet E. Neonatal Outcomes From Arboviruses in the Perinatal Period: A State-of-the-Art Review. Pediatrics. 2021 Apr;147(4) [PubMed: 33737375]

24.

Okike IO, Johnson AP, Henderson KL, Blackburn RM, Muller-Pebody B, Ladhani SN, Anthony M, Ninis N, Heath PT., neoMen Study Group. Incidence, etiology, and outcome of bacterial meningitis in infants aged <90 days in the United kingdom and Republic of Ireland: prospective, enhanced, national population-based surveillance. Clin Infect Dis. 2014 Nov 15;59(10):e150-7. [PubMed: 24997051]

25.

Kadambari S, Braccio S, Ribeiro S, Allen DJ, Pebody R, Brown D, Cunney R, Sharland M, Ladhani S. Enterovirus and parechovirus meningitis in infants younger than 90 days old in the UK and Republic of Ireland: a British Paediatric Surveillance Unit study. Arch Dis Child. 2019 Jun;104(6):552-557. [PubMed: 30530486]

26.

Holt DE, Halket S, de Louvois J, Harvey D. Neonatal meningitis in England and Wales: 10 years on. Arch Dis Child Fetal Neonatal Ed. 2001 Mar;84(2):F85-9. [PMC free article: PMC1721232] [PubMed: 11207221]

27.

El-Naggar W, Afifi J, McMillan D, Toye J, Ting J, Yoon EW, Shah PS., Canadian Neonatal Network Investigators‖ Epidemiology of Meningitis in Canadian Neonatal Intensive Care Units. Pediatr Infect Dis J. 2019 May;38(5):476-480. [PubMed: 30986789]

28.

Thaver D, Zaidi AK. Burden of neonatal infections in developing countries: a review of evidence from community-based studies. Pediatr Infect Dis J. 2009 Jan;28(1 Suppl):S3-9. [PubMed: 19106760]

29.

Barichello T, Fagundes GD, Generoso JS, Elias SG, Simões LR, Teixeira AL. Pathophysiology of neonatal acute bacterial meningitis. J Med Microbiol. 2013 Dec;62(Pt 12):1781-1789. [PubMed: 23946474]

30.

Liu G, He S, Zhu X, Li Z. Early onset neonatal bacterial meningitis in term infants: the clinical features, perinatal conditions, and in-hospital outcomes: A single center retrospective analysis. Medicine (Baltimore). 2020 Oct 16;99(42):e22748. [PMC free article: PMC7571871] [PubMed: 33080738]

31.

Stoll BJ, Hansen NI, Sánchez PJ, Faix RG, Poindexter BB, Van Meurs KP, Bizzarro MJ, Goldberg RN, Frantz ID, Hale EC, Shankaran S, Kennedy K, Carlo WA, Watterberg KL, Bell EF, Walsh MC, Schibler K, Laptook AR, Shane AL, Schrag SJ, Das A, Higgins RD., Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network. Early onset neonatal sepsis: the burden of group B Streptococcal and E. coli disease continues. Pediatrics. 2011 May;127(5):817-26. [PMC free article: PMC3081183] [PubMed: 21518717]

32.

Stoll BJ, Hansen N, Fanaroff AA, Wright LL, Carlo WA, Ehrenkranz RA, Lemons JA, Donovan EF, Stark AR, Tyson JE, Oh W, Bauer CR, Korones SB, Shankaran S, Laptook AR, Stevenson DK, Papile LA, Poole WK. To tap or not to tap: high likelihood of meningitis without sepsis among very low birth weight infants. Pediatrics. 2004 May;113(5):1181-6. [PubMed: 15121927]

33.

Pantell RH, Roberts KB, Adams WG, Dreyer BP, Kuppermann N, O'Leary ST, Okechukwu K, Woods CR., SUBCOMMITTEE ON FEBRILE INFANTS. Evaluation and Management of Well-Appearing Febrile Infants 8 to 60 Days Old. Pediatrics. 2021 Aug;148(2) [PubMed: 34281996]

34.

Thomson J, Sucharew H, Cruz AT, Nigrovic LE, Freedman SB, Garro AC, Balamuth F, Mistry RD, Arms JL, Ishimine PT, Kulik DM, Neuman MI, Shah SS., Pediatric Emergency Medicine Collaborative Research Committee (PEM CRC) HSV Study Group. Cerebrospinal Fluid Reference Values for Young Infants Undergoing Lumbar Puncture. Pediatrics. 2018 Mar;141(3) [PubMed: 29437883]

35.

Byington CL, Kendrick J, Sheng X. Normative cerebrospinal fluid profiles in febrile infants. J Pediatr. 2011 Jan;158(1):130-4. [PMC free article: PMC2994954] [PubMed: 20801462]

36.

Kestenbaum LA, Ebberson J, Zorc JJ, Hodinka RL, Shah SS. Defining cerebrospinal fluid white blood cell count reference values in neonates and young infants. Pediatrics. 2010 Feb;125(2):257-64. [PMC free article: PMC3033868] [PubMed: 20064869]

37.

Shah SS, Ebberson J, Kestenbaum LA, Hodinka RL, Zorc JJ. Age-specific reference values for cerebrospinal fluid protein concentration in neonates and young infants. J Hosp Med. 2011 Jan;6(1):22-7. [PMC free article: PMC2978786] [PubMed: 20629018]

38.

Fleischer E, Neuman MI, Wang ME, Nigrovic LE, Desai S, DePorre AG, Leazer RC, Marble RD, Sartori LF, Aronson PL., FEBRILE YOUNG INFANT RESEARCH COLLABORATIVE. Cerebrospinal Fluid Profiles of Infants ≤60 Days of Age With Bacterial Meningitis. Hosp Pediatr. 2019 Dec;9(12):979-982. [PMC free article: PMC6877427] [PubMed: 31690569]

39.

García-De la Rosa G, De Las Heras-Flórez S, Rodríguez-Afonso J, Carretero-Pérez M. Interpretation of white blood cell counts in the cerebrospinal fluid of neonates with traumatic lumbar puncture: a retrospective cohort study. BMC Pediatr. 2022 Aug 16;22(1):488. [PMC free article: PMC9380374] [PubMed: 35971102]

40.

Aronson PL, Wang ME, Nigrovic LE, Shah SS, Desai S, Pruitt CM, Balamuth F, Sartori L, Marble RD, Rooholamini SN, Leazer RC, Woll C, DePorre AG, Neuman MI., Febrile Young Infant Research Collaborative. Time to Pathogen Detection for Non-ill Versus Ill-Appearing Infants ≤60 Days Old With Bacteremia and Meningitis. Hosp Pediatr. 2018 Jul;8(7):379-384. [PMC free article: PMC6145376] [PubMed: 29954839]

41.

Arora HS, Asmar BI, Salimnia H, Agarwal P, Chawla S, Abdel-Haq N. Enhanced Identification of Group B Streptococcus and Escherichia Coli in Young Infants with Meningitis Using the Biofire Filmarray Meningitis/Encephalitis Panel. Pediatr Infect Dis J. 2017 Jul;36(7):685-687. [PubMed: 28114152]

42.

Blaschke AJ, Holmberg KM, Daly JA, Leber AL, Dien Bard J, Korgenski EK, Bourzac KM, Kanack KJ. Retrospective Evaluation of Infants Aged 1 to 60 Days with Residual Cerebrospinal Fluid (CSF) Tested Using the FilmArray Meningitis/Encephalitis (ME) Panel. J Clin Microbiol. 2018 Jul;56(7) [PMC free article: PMC6018345] [PubMed: 29669791]

43.

Polin RA., Committee on Fetus and Newborn. Management of neonates with suspected or proven early-onset bacterial sepsis. Pediatrics. 2012 May;129(5):1006-15. [PubMed: 22547779]

44.

May M, Daley AJ, Donath S, Isaacs D., Australasian Study Group for Neonatal Infections. Early onset neonatal meningitis in Australia and New Zealand, 1992-2002. Arch Dis Child Fetal Neonatal Ed. 2005 Jul;90(4):F324-7. [PMC free article: PMC1721922] [PubMed: 15878934]

45.

Yikilmaz A, Taylor GA. Sonographic findings in bacterial meningitis in neonates and young infants. Pediatr Radiol. 2008 Feb;38(2):129-37. [PMC free article: PMC2292499] [PubMed: 17611750]

46.

Heath PT, Nik Yusoff NK, Baker CJ. Neonatal meningitis. Arch Dis Child Fetal Neonatal Ed. 2003 May;88(3):F173-8. [PMC free article: PMC1721548] [PubMed: 12719388]

47.

Obiero CW, Seale AC, Berkley JA. Empiric treatment of neonatal sepsis in developing countries. Pediatr Infect Dis J. 2015 Jun;34(6):659-61. [PMC free article: PMC6858865] [PubMed: 25806843]

48.

Byington CL, Rittichier KK, Bassett KE, Castillo H, Glasgow TS, Daly J, Pavia AT. Serious bacterial infections in febrile infants younger than 90 days of age: the importance of ampicillin-resistant pathogens. Pediatrics. 2003 May;111(5 Pt 1):964-8. [PubMed: 12728072]

49.

Long SS. In defense of empiric acyclovir therapy in certain neonates. J Pediatr. 2008 Aug;153(2):157-8. [PubMed: 18639725]

50.

van der Flier M. Neonatal meningitis: small babies, big problem. Lancet Child Adolesc Health. 2021 Jun;5(6):386-387. [PubMed: 33894158]

51.

Seale AC, Blencowe H, Zaidi A, Ganatra H, Syed S, Engmann C, Newton CR, Vergnano S, Stoll BJ, Cousens SN, Lawn JE., Neonatal Infections Estimation Team. Neonatal severe bacterial infection impairment estimates in South Asia, sub-Saharan Africa, and Latin America for 2010. Pediatr Res. 2013 Dec;74 Suppl 1(Suppl 1):73-85. [PMC free article: PMC3873707] [PubMed: 24366464]

52.

Nakwa FL, Lala SG, Madhi SA, Dangor Z. Neurodevelopmental Impairment at 1 Year of Age in Infants With Previous Invasive Group B Streptococcal Sepsis and Meningitis. Pediatr Infect Dis J. 2020 Sep;39(9):794-798. [PubMed: 32804460]

53.

Kohli-Lynch M, Russell NJ, Seale AC, Dangor Z, Tann CJ, Baker CJ, Bartlett L, Cutland C, Gravett MG, Heath PT, Ip M, Le Doare K, Madhi SA, Rubens CE, Saha SK, Schrag S, Sobanjo-Ter Meulen A, Vekemans J, O'Sullivan C, Nakwa F, Ben Hamouda H, Soua H, Giorgakoudi K, Ladhani S, Lamagni T, Rattue H, Trotter C, Lawn JE. Neurodevelopmental Impairment in Children After Group B Streptococcal Disease Worldwide: Systematic Review and Meta-analyses. Clin Infect Dis. 2017 Nov 06;65(suppl_2):S190-S199. [PMC free article: PMC5848372] [PubMed: 29117331]

54.

Horváth-Puhó E, van Kassel MN, Gonçalves BP, de Gier B, Procter SR, Paul P, van der Ende A, Søgaard KK, Hahné SJM, Chandna J, Schrag SJ, van de Beek D, Jit M, Sørensen HT, Bijlsma MW, Lawn JE. Mortality, neurodevelopmental impairments, and economic outcomes after invasive group B streptococcal disease in early infancy in Denmark and the Netherlands: a national matched cohort study. Lancet Child Adolesc Health. 2021 Jun;5(6):398-407. [PMC free article: PMC8131199] [PubMed: 33894156]

55.

Ben Hamouda H, Ben Haj Khalifa A, Hamza MA, Ayadi A, Soua H, Khedher M, Sfar MT. [Clinical outcome and prognosis of neonatal bacterial meningitis]. Arch Pediatr. 2013 Sep;20(9):938-44. [PubMed: 23829970]

56.

Tan J, Kan J, Qiu G, Zhao D, Ren F, Luo Z, Zhang Y. Clinical Prognosis in Neonatal Bacterial Meningitis: The Role of Cerebrospinal Fluid Protein. PLoS One. 2015;10(10):e0141620. [PMC free article: PMC4625018] [PubMed: 26509880]

57.

Peros T, van Schuppen J, Bohte A, Hodiamont C, Aronica E, de Haan T. Neonatal bacterial meningitis versus ventriculitis: a cohort-based overview of clinical characteristics, microbiology and imaging. Eur J Pediatr. 2020 Dec;179(12):1969-1977. [PMC free article: PMC7666663] [PubMed: 32621136]

58.

Haffner DN, Machie M, Hone E, Said RR, Maitre NL. Predictors of Neurodevelopmental Impairment After Neonatal Bacterial Meningitis. J Child Neurol. 2021 Oct;36(11):968-973. [PubMed: 34256644]

59.

Bucci S, Coltella L, Martini L, Santisi A, De Rose DU, Piccioni L, Campi F, Ronchetti MP, Longo D, Lucignani G, Dotta A, Auriti C. Clinical and Neurodevelopmental Characteristics of Enterovirus and Parechovirus Meningitis in Neonates. Front Pediatr. 2022;10:881516. [PMC free article: PMC9165715] [PubMed: 35669403]

60.

Dunbar M, Shah H, Shinde S, Vayalumkal J, Vanderkooi OG, Wei XC, Kirton A. Stroke in Pediatric Bacterial Meningitis: Population-Based Epidemiology. Pediatr Neurol. 2018 Dec;89:11-18. [PubMed: 30392967]

61.

Tibussek D, Sinclair A, Yau I, Teatero S, Fittipaldi N, Richardson SE, Mayatepek E, Jahn P, Askalan R. Late-onset group B streptococcal meningitis has cerebrovascular complications. J Pediatr. 2015 May;166(5):1187-1192.e1. [PubMed: 25919727]

62.

Puopolo KM, Lynfield R, Cummings JJ., COMMITTEE ON FETUS AND NEWBORN. COMMITTEE ON INFECTIOUS DISEASES. Management of Infants at Risk for Group B Streptococcal Disease. Pediatrics. 2019 Aug;144(2) [PubMed: 31285392]

Disclosure: Lisa Bundy declares no relevant financial relationships with ineligible companies.

Disclosure: Michael Rajnik declares no relevant financial relationships with ineligible companies.

Disclosure: Asif Noor declares no relevant financial relationships with ineligible companies.