Irritability, Apneic Episodes, and Decreased Appetite: Part 1

Just how common is bacterial meningitis within a neonate’s first month of life?

Case Report:

A 12-day-old African-American female born at 37-weeks and 3 days via vaginal delivery presented to our community emergency department (ED) for fever, decreased appetite, and fussiness. The patient’s medical history was complicated by no prenatal care and a urine drug screen positive for barbiturates. The patient was acting and feeding normally up until 2 days prior to arrival with the highest recorded temperature reportedly at 100.7°F. The remaining review of systems was notable for rhinorrhea, congestion, and an occasional cough for the past 2 days.

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Her vitals on arrival to the ED: temperature of 99.5°F, heart rate of 221 beats/min, blood pressure of 77/52 mmHg, respiratory rate of 42 breaths/min, pulse ox of 80% on room air, and weight of 3.1 kg. The patient was noted to have had multiple apneic episodes while in the ED lasting 20-30 seconds at a time. Oxygenation improved to 100% on 0.25 L/m nasal cannula. On physical exam the patient was irritable with a loud cry and appeared ill. Her anterior fontanelle was patent and soft. There was mild nasal flaring with a small amount of rhinorrhea. Cardiopulmonary exam revealed sinus tachycardia. Her abdomen was soft and without obvious hepatic or splenic enlargement. A neurological exam revealed a positive Brudzinski’s sign, negative Kernig’s sign, and hypertonicity of the lower extremities.

A sepsis workup was initiated, including the administration of 20 cc/kg of intravenous fluid resuscitation. Pertinent positive laboratory evaluation was notable for a white blood cell count (WBC) of 3.2 (5-19.5 bil/L) (neutrophils 1.9, lymphocytes 1.0, monocytes 0.3). Her sodium was 132 (134-144 mmol/L). A nasopharyngeal swab for influenza and respiratory syncytial virus was negative. Her chest radiograph revealed patchy reticular opacities in the right lower lobe.

Urinalysis was significant for a specific gravity of 1.005, pH 8.0, glucose 500 mg/dL, protein 30 mg/dL, but otherwise negative. A lumbar puncture was performed, (Figure 1: Cerebrospinal fluid obtained on LP), that was yellow in color. 

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Cerebral spinal fluid (CSF) glucose was 4 mg/dL, protein >600 mg/dL, red blood cell count 195, and WBC of 2170 with predominant neutrophilia. She was started on ampicillin and gentamicin for neonatal meningitis and she was transferred to a pediatric intensive care unit (PICU).

On arrival to the PICU, Pediatric infectious disease was consulted. The patient was continued on ampicillin, gentamicin, in addition to acyclovir and cefotaxime. The cerebrospinal fluid Gram stain subsequently revealed moderate polymorphonuclear leukocytes and a few gram-positive cocci. The meningitis/encephalitis panel was positive for Streptococcus agalactiae DNA (GBS) with confirmation on CSF culture. Gentamicin and acyclovir were subsequently stopped, and intravenous ampicillin and cefotaxime were continued with a recommended duration of 14 days.

Discussion:

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Bacterial meningitis is more common within a neonate’s first month of life than any other time during their life. The porous nature of the blood brain barrier allows for the hematogenous spread of bacteria (GBS, E. coli, and L. monocytogenes) to the meninges more likely. The incidence in developed countries is 0.3 per 1000 live births.^1,2 With treatment, the mortality rate of neonatal bacterial meningitis ranges from 5-20%, and if left untreated, it approaches 100%.⁸ Some of the risk factors for neonatal meningitis include:

• Low birth weight (<1500 g)
• Preterm birth
• Premature rupture of membranes
• Rectovaginal GBS colonization from the mother
• Chorioamnionitis or maternal fever
• Invasive fetal monitoring
• Traumatic delivery
• Fetal hypoxia
• Presence of external devices like shunts/catheters/reservoirs
• Absence of prenatal care. [^1,3]

In one prospective study involving almost 400,000 neonates, 72% of those neonates with sepsis or meningitis was the result of GBS, becoming the most common cause of a neonatal sepsis and meningitis.[^1]

While presenting signs/symptoms may depend on the duration of the disease process, host response, and age; no single sign is considered pathognomonic. The triad of altered mental status, neck stiffness, and fever has been shown to only be present in 44% of adults, and even less in children. [^4] In clinical practice, the most commonly reported clinical signs suggesting neonatal meningitis include:

• Temperature instability
• Lethargy/irritability
• Vomiting/poor feeding.[^1]

While the most common finding is temperature instability, it is important for the clinician to remember that this encompasses either hyperthermia (rectal temperature >38 C) or hypothermia (rectal temperature <36 C). Those infants born at term are more likely to present febrile, while those that were born pre-term are more likely to present hypothermic.[^1] Neurologic signs like nuchal rigidity, a bulging fontanelle, irritability, and seizures (seen in up to 50% of neonates and present focally secondary to gram-negative bacteria) are considered late findings and associated with poor outcomes.[^1,2]

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As an ED clinician, it is important to note that vomiting, respiratory distress, and poor feeding are present in about 50% of patients, apneic episodes in about 30% of patients, bulging fontanelle in about 25% of patients, and nuchal rigidity in about 15% of patients.[^1] Further, skin manifestations can include purpura and petechiae, however, these are most commonly found in Neisseria meningitidis.[^4]

When the patient’s clinical presentation can be attributed to non-infectious causes, deciding to perform an LP requires clinical judgement. Because the clinical presentation can be vast and non-specific, any suspicion of neonatal meningitis (<28 days old) should result in a complete sepsis workup to include a blood culture, urine cultures, and an LP. Those infants that appear ill regardless of age also need a complete sepsis workup. It is important that a correction is made for any prematurity.[^6] 

The need for a complete sepsis workup in full-term infants older than 28 days, low risk (no prolonged ICU stay, appears well, WBC between 5000-15000, absence of systematic antibiotics within 72 hours) with a focal infection is on a case-by-case basis. [^5,6,8]

While antibiotics should ideally not be given prior to an LP, an LP should not delay the administration of antibiotics, especially in neonates that are critically ill or unstable. A retrospective study was performed involving meningitis in 128 pediatric patients ages 0-16 years old. Approximately 56% (22/39) of the CSF cultures that were positive (Streptococcal pneumoniae, Neisseria meningitidis, and GBS) were given antibiotics prior to an LP being performed. In the pre-treatment group, the LP  was even delayed up to 72 hours in a few cases.[^7]

In the cases involving GBS and S. pneumoniae, the CSF cultures were not sterile until 4 hours after the administration of the first antibiotic.[^7] For cases of N. meningitidis, the window is around 1-2 hours prior to CSF sterilization.[^7] Overall, evidence shows that if an LP is to be delayed, but performed within 2 hour of antibiotics, the CSF culture will not be affected.

Broad spectrum antibiotics are initiated with antimicrobial coverage being adjusted later based on susceptibilities and identification of the pathogen. Dexamethasone, often given prior to the first dose of antibiotics, shows no mortality benefit in infants/children, however, there is a minor reduction in neurologic sequelae. In adults, the only benefit in meningitis is those patients with S. pneumoniae where studies have shown a slight decrease in mortality and hearing loss.

Common antibiotic treatment regimens based on the age and organisms involved:

• Neonates up to 1 month of age (Common organisms include GBS, coli, L. monocytogenes)

Ampicillin 50 mg/kg IV q6hrs + Cefotaxime 50 mg/kg IV q6hours or Gentamicin 2.5 mg/kg IV q8hrs.[^5,8] In some cases, all three are initiated until cultures return. Consider adding acyclovir for any suspicion for herpes simplex virus. In some institutions where cefotaxime is not available, cefepime 30 mg/kg IV q12 hours can be utilized.^9,10 While methicillin-resistant Staphylococcus aureus (MRSA) is uncommon in the neonate, if suspecting MRSA or S. pneumoniae then adding Vancomycin is recommended.[^3]

• Ampicillin shows poor CNS penetration; however, GBS and monocytogenes are susceptible
• Gentamicin shows poor CNS penetration; however, it has a synergistic effect with ampicillin in patients with monocytogenes and is susceptible to E. coli, Pseudomonas, Klebsiella, and Enterobacter.
• Cefotaxime possesses good CNS penetration but has no activity against Enterococcus or L. monocytogenes. Other susceptible bacteria include E. coli, Klebsiella, and Enterobacter.

The minimum recommended length of treatment in an uncomplicated meningitis is based on the organism isolated. GBS, L. monocytogenes, and S. pneumoniae require 14 days, while Pseudomonas and gram-negative enteric bacteria require 21 days.[^3]

In complicated cases involving ventriculitis, development of a brain abscess, or presence of infarctions, longer durations are advised up to 28 days.[^3] Overall, a pediatric infectious disease consult is warranted for further recommendations on duration of therapy.

References:

1. Edwards, M, Baker, C. “Bacterial meningitis in the neonate: Clinical features and diagnosis.” May 9, 2018. https://www.uptodate.com/contents/bacterial-meningitis-in-the-neonate-clinical-features-and-diagnosis
2. Edwards, M, Baker, C. “Bacterial meningitis in the neonate: Neurologic complications.” February 28, 2018. https://www.uptodate.com/contents/bacterial-meningitis-in-the-neonate-neurologic-complications
3. Lawrence, C, Boggess, K, Cohen-Wolkowiez, M. “Bacterial meningitis in the infant.” Journal of Clinical Perinatology.” 2015 Mar; 42(1): 29-45. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4332563/

4. Kaplan, S. “Bacterial meningitis in children older than one month: Clinical features and diagnosis.” April 17, 2018. https://www.uptodate.com/contents/bacterial-meningitis-in-children-older-than-one-month-clinical-features-and-diagnosis
5. Vukovic, A, Sobolewski, B, “The Febrile Infant—University of Cincinnati Emergency Medicine Collaboration.” http://pemcincinnati.com/blog/the-febrile-infant-taming-the-sru-collaboration
6. Zarkesh, M, Hashemian, H, Momtazbakhsh, M, Rostami, T. “Assessment of Febrile Neonates According to Low Risk Criteria for Serious Bacterial Infection.” Iranian Journal of Pediatrics. 2011 Dec; 21(4): 436-440.
7. Kanegaye, J, Soliemanzadeh, P, Bradley, J. “Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment.” Pediatrics. 2001 Nov;108(5):1169-74. https://www.ncbi.nlm.nih.gov/pubmed?term=Lumbar+puncture+in+pediatric+bacterial+meningitis%3A+defining+the+time+interval+for+recovery+of+cerebrospinal+fluid+pathogens+after+parenteral+antibiotic+pretreatment&TransSchema=title&cmd=detailssearch
8. Tesini, B. “Neonatal Bacterial Meningitis.” July 2018. Merck Manual. https://www.merckmanuals.com/professional/pediatrics/infections-in-neonates/neonatal-bacterial-meningitis
9. Levine, B. “EMRA Antibiotic Guide.” 18^th Emergency Medicine Resident Association Antibiotic Guide.
10. Muller-Pebody B, Johnson, A, Heath, P, Gilbert, R, Henderson, K, Sharland, M. Empirical treatment of neonatal sepsis: are the current guidelines adequate? Archives of Disease in Childhood: Fetal and Neonatal Edition. 2011;96(1):F4–F8.