A 9 day old male, born at 36 weeks gestation via normal spontaneous vaginal delivery presents to a pediatric emergency room due to increased fussiness, fever, and decreased oral intake. Maternal perinatal history is unremarkable aside from a mild flu-like illness in her first trimester and pre-term labor. Mother had negative serologies at delivery and no history of sexually transmitted infections. Delivery was uncomplicated, although placenta was noted to have presence of white nodules, and the infant did not require NICU admission. A full septic evaluation was performed with serum glucose 80, serum WBC 18.1 with neutrophilic predominance, and CSF analysis showing WBC 20,000, glucose 25, and protein 125. Blood, CSF, and urine cultures pending. What is the most likely diagnosis and the recommended empiric treatment?

 

A. Herpes simplex meningitis; acyclovir, ampicillin, and gentamicin

B. Group B strep meningitis; ampicillin, ceftriaxone, and gentamicin

C. Listeria monocytogenes meningitis; ampicillin and gentamicin

D. Escherichia coli meningitis; ampicillin and gentamicin

E. Neisseria meningitidis meningitis; ampicillin, ceftriaxone, and gentamicin

 

The correct answer is C.

Answer choice A: Herpes simplex meningitis; acyclovir, ampicillin, and gentamicin

This answer is incorrect because the CSF constituents and ratios are inconsistent with a viral illness. Typically, if a meningitis is virally mediated, the CSF will show <100 WBC per mm^3, with a predominance of lymphocytes, although if caught early, PMNs may predominate. There will also likely be normal to elevated protein, as opposed to typical mild to marked elevation in bacterial meningitis, and a normal CSF: serum glucose ratio, as opposed to being markedly decreased with bacterial meningitis.

 

HSV should be strongly considered when there is a maternal history of infection or there is visualization of cutaneous lesions – especially when they have the classic vesicular appearance. Many times these babies will present with apnea or seizures as well. It is common to obtain surface and serologic testing in addition to rapid CSF panels with HSV included, and when covering with empiric antibiotics, initiate acyclovir treatment for viral coverage,  then discontinue once there is evidence of negativity on testing. After the infant is >28 days of life, the risk of HSV drops precipitously, and acyclovir should only be used if there are specific concerns.

 

Answer choice B: Group B strep meningitis; ampicillin, ceftriaxone, and gentamicin

Empiric antibiotic therapy for a febrile neonate typically includes ampicillin, gentamicin, and acyclovir. Answer choice B is incorrect for two reasons. The first being that group B streptococcus, commonly referred to as ‘GBS’ is not the most likely etiology of meningitis given that the baby is at 9 days of life and the report of a “flu-like illness” during the pre-natal period is highly suspicious of another infection listed in the answer choices. Additionally, the treatment course of a neonatal GBS meningitis case would be with ampicillin and cefotaxime for 14 days and would not include ceftriaxone. Ceftriaxone is not used until an infant is over 1 month old. Research to date states that “Ceftriaxone is contraindicated in neonates because it displaces bilirubin from albumin binding sites, resulting in a higher free bilirubin serum concentration with subsequent accumulation of bilirubin in the tissues. Even more dangerous is ceftriaxone’s interaction with calcium. This interaction precipitates calcium, which results in serious adverse effects.” 

 

Answer choice C: Listeria Monocytogenes meningitis; ampicillin and gentamicin

This is the correct answer choice for this question! The clues in this case leading you to Listeria are the presence of “flu-like symptoms” in the pre-natal period, which is highly suspicious for this infection, and the presence of white nodules in the placenta. These are identified on pathological review as micro-abscesses and are only seen with listeria infections. These two pieces of information lead away from the most common diagnosis of GBS meningitis and instead trend toward the diagnosis of listeria as both can present similarly with pre-term labor and time to symptom onset after delivery. If the mother is described as being asymptomatic in pregnancy – think about GBS – if there is a history being symptomatic, this may lead you towards putting listeria higher on your differential in the appropriate clinical setting. 

 

The treatment for Listeria is initially with ampicillin and gentamicin for at least a 3 week course in an immunocompetent patient. If the patient is immunocompromised for any reason or has evidence of cerebritis or brain abscesses, a longer treatment duration of 6-8 weeks is warranted. In the typical 3-4 week treatment period, gentamicin may not be required for the entire duration,    and in many cases, it is only continued for the first 7-14 days until there is evidence of clinical improvement. At that point, ampicillin monotherapy is continued for the remainder of the treatment course, and gentamicin is discontinued to avoid precipitation of nephrotoxicity and ototoxicity as much as possible.

 

Answer choice D: Escherichia coli meningitis; ampicillin and gentamicin

This answer choice is unfortunately incorrect, but if I’ve learned nothing else in residency, it is to have a high respect for gram negative sepsis, especially in the neonatal population! Given the history discussed above as well as the age of the neonate presenting, E. coli is not the most likely etiology in this patient. Per the literature to date, Escherichia coli meningitis is 7 times more frequent in preterm than term infants. The median age at diagnosis is 14 days; with bimodal peaks of infection present in 70% of cases either at 0–3 days of life in pre-term neonates or 11–15 days of life in term neonates. E. coli is currently the most common cause of early-onset sepsis and meningitis among very low birth weight infants, weighing < 1500 gram.

 

In meningitis due to gram negative rods, including E. coli, the CSF may be cloudy and will very likely show a significant pleocytosis, in which case, cefotaxime should be added to the treatment regimen for its phenomenal CNS penetration and efficacy against these organisms. 

 

Answer choice E: Neisseria meningitidis meningitis; ampicillin, ceftriaxone, and gentamicin

This is an interesting answer choice as the CSF analysis still fits with a bacterial meningitis and would be consistent with a Neisseria picture given the presence of pleocytosis with a predominance of neutrophils (typically 100-50,000), hypoglycorrhachia (which means low CSF glucose) with a ratio of CSF to serum glucose <0.40. Additionally, bacterial meningitis CSF profiles will typically have significantly increased protein compared to viral and a positive gram stain and culture. This answer choice is not the most likely answer choice solely due to the age of the child in addition to the clues given for listeria monocytogenes as the most likely causative agent.  The prevalence of organisms causing bacterial meningitis significantly changes after the first month of life. After 1 month, we start worrying about Neisseria meningitidis, Strep. pneumo, and Hemophilus Influenza B (if unimmunized) much more than the bacteria previously discussed. 

 

Given this shift, empiric antibiotics additionally change with stopping the use of gentamicin and initiation of ceftriaxone and vancomycin instead. You would also consider Ampicillin if immunocompromised. It is additionally important to note that the blood brain barrier is still underdeveloped even at 1 month of age, and a blood culture can be positive in the majority of cases of bacterial meningitis, harboring the need for lumbar puncture in that population. 

 

Resources

  1. Bundy LM, Noor A. Neonatal Meningitis. [Updated 2020 Jun 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK532264/
  2. Charlier C, Perrodeau É, Leclercq A, Cazenave B, Pilmis B, Henry B, Lopes A, Maury MM, Moura A, Goffinet F, Dieye HB, Thouvenot P, Ungeheuer MN, Tourdjman M, Goulet V, de Valk H, Lortholary O, Ravaud P, Lecuit M; MONALISA study group. Clinical features and prognostic factors of listeriosis: the MONALISA national prospective cohort study. Lancet Infect Dis. 2017 May;17(5):510-519. doi: 10.1016/S1473-3099(16)30521-7. Epub 2017 Jan 28. Erratum in: Lancet Infect Dis. 2017 Sep;17(9):897. PMID: 28139432.
  3. Mount HR, Boyle SD. Aseptic and Bacterial Meningitis: Evaluation, Treatment, and Prevention. Am Fam Physician. 2017 Sep 1;96(5):314-322. PMID: 28925647.
  4. Park HZ, Lee SP, Schy AL. Ceftriaxone-associated gallbladder sludge. Identification of calcium-ceftriaxone salt as a major component of gallbladder precipitate. Gastroenterology. 1991;100:1665–70.

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