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).4–6 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.⁷

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%.⁸ 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.^9–11 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).¹¹ 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.¹² All were susceptible to carbapenems. Nonsusceptibility to both ampicillin and gentamicin was present in 10.1% (22 of 218) early-onset infections.

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.^13,14

Meningitis with early-onset sepsis evaluations in preterm infants admitted to the NICU with respiratory distress syndrome is very uncommon.¹¹ 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).¹⁵ 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.^15,16 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.¹⁷

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.

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.^18,19 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.^20–25 These noninfectious biomarkers are really host markers and may better trend host response to complex infections but are not diagnostic.^25,26 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.¹⁷

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/mm³ 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.^27,28 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.²⁹ 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.³⁰ Significant thrombocytopenia could increase the risk of a local hematoma which can cause medullary compression and in rare cases lead to paralysis.²⁹

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.¹⁵ In VLBW infants, the average age of late-onset meningitis is 26 days (median 19 days; range 4–102 days).¹⁵ Therapeutic decisions with regard to antibiotic choices can be made only if one knows whether the CNS is involved.

Early stylet removal and local anesthetic improve success of obtaining CSF and having a nontraumatic tap. Studies have found this more than doubles the success rate of both obtaining CSF and having a nontraumatic lumbar puncture.³¹ Once just a few millimeters through the skin (epidermis and dermis), the stylet can be safely removed. The stylet is needed during skin penetration to reduce introduction of epidermoid cells in the CSF that can subsequently lead to an intraspinal epidermoid tumor. The needle is then slowly advanced until CSF is obtained. After CSF is obtained, replace stylet into the needle and remove it from the patient.

In general, antimicrobial therapy for neonatal sepsis is dependent on the agents commonly seen in a particular nursery and their susceptibility pattern. For early-onset sepsis, ampicillin combined with an aminoglycoside, usually gentamicin, has been the empiric therapy of choice since group B Streptococcus, other streptococcal species, Listeria monocytogenes, and gram-negative bacilli predominate.¹¹

For late-onset sepsis, a penicillinase-resistant, semisynthetic penicillin such as oxacillin or nafcillin in combination with an aminoglycoside is the preferred choice. For CNS infections, nafcillin is preferred because of improved penetration. Empiric vancomycin should not be used unless there is a prior history of colonization with methicillin-resistant Staphylococcus aureus (MRSA) or the infant has not been screened for MRSA and >10% of the infants in the NICU are colonized with MRSA to decrease the risk for emergence of vancomycin-resistant organisms.^32,33 Empiric vancomycin is not needed when there is a suspicion of a CoNS infection because outcomes are similar when initially treated with nafcillin and then changed to vancomycin when culture results are known.

The use of a penicillinase-resistant penicillin antibiotic such as nafcillin to treat a possible staphylococcal infection in this infant is based on the goal of reducing vancomycin use in NICUs. Clinical experience and intervention trials suggest that such a practice is safe.^32,33 Bloodstream infections caused by CoNS are rarely fulminant or fatal, and they are not associated with an increased case-fatality rate over that seen among uninfected VLBW infants.^34,35 The clinical outcome of CoNS bacteremia is similar whether the initial antibiotic therapy is vancomycin or another agent that does not reliably treat CoNS infections. In addition, only one of five evaluations for sepsis yields a causative organism. The observation that more than 80% of blood cultures that yield CoNS are positive by 24 hours of incubation makes it possible for the clinician to change antibiotic therapy in a timely fashion if needed. An additional concern of vancomycin therapy has been the association of prior vancomycin use with subsequent development of gram-negative bacteremia among hospitalized pediatric patients.³⁶

Aminoglycosides have been the time-honored choice for empiric treatment of infections caused by gram-negative bacilli. They effectively cover the most common and severe gram-negative organisms including pseudomonas, E. coli, Klebsiella, Serratia, Citrobacter, and Enterobacter as well as other gram-negative pathogens. With extended-interval dosing, higher peak concentrations are achieved which increase concentration-dependent microbial killing in addition to a post antibiotic effect. Once-daily or extended dosing of gentamicin is based on sound pharmacodynamic and pharmacokinetic considerations and should be used for both full-term and preterm infants to achieve optimal peak concentrations for gram-negative pathogens and is associated with reduced toxicity and cost.³⁷ Extended-interval dosing maximizes the bactericidal activity of the aminoglycoside while minimizing its potential toxicity.

Aminoglycosides have the distinct advantage of exerting less selective pressure for development of resistance in closed units like the NICU, thus minimizing the risk of emergence of resistant bacteria.³⁸ This is in contrast to the rapid emergence of cephalosporin resistance when these agents are provided routinely for possible late-onset sepsis.³⁹ When used for empirical therapy of early-onset infection, cefotaxime has been associated with increased neonatal mortality.⁴⁰ However, because CSF penetration of aminoglycosides is poor, their use in meningitis is problematic. If a lumbar puncture is not performed as part of the initial evaluation for possible sepsis, and only an aminoglycoside is used, then effective therapy for gram-negative meningitis may not be provided. Delay in the determination of whether a neonate has meningitis will delay optimal therapy for this condition. Targeting the primary use of third- and fourth-generation cephalosporins and carbapenems for suspected meningitis and confirmed pathogens is important in preventing and controlling the emergence of resistance against these antimicrobials.

Once meningitis is confirmed or ruled out and susceptibilities are known, antibiotics should be narrowed and broad-spectrum antibiotics reserved for when they are needed.

Continuation of Case History

At 18 hours after collection, the blood cultures yielded gram-negative rods. Cefotaxime was added to the antibiotic regimen. E. coli was subsequently identified from the blood cultures. A lumbar puncture was then performed that demonstrated 4160 white blood cells/mm³ (90% polymorphonuclear cells, 10% mononuclear cells); 8320 red blood cells/mm³; protein of 433 mg/dL; and glucose of 84 mg/dL (serum glucose of 180 mg/dL). Culture of CSF yielded E. coli.

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