Neonatal Meningitis: What Is the Correlation Among Cerebrospinal Fluid

Cultures, Blood Cultures, and Cerebrospinal Fluid Parameters?

Harmony P. Garges, M. Anthony Moody, C. Michael Cotten, P. Brian Smith, Kenneth
F. Tiffany, Robert Lenfestey, Jennifer S. Li, Vance G. Fowler, Jr and Daniel K.
Benjamin, Jr
Pediatrics 2006;117;1094
DOI: 10.1542/peds.2005-1132

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pediatrics.aappublications.org/content/117/4/1094.full.html

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2006 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Uppsala Medicinska on October 2, 2014

ARTICLE

Neonatal Meningitis: What Is the Correlation Among

Cerebrospinal Fluid Cultures, Blood Cultures, and
Cerebrospinal Fluid Parameters?
Harmony P. Garges, MD, MPHa, M. Anthony Moody, MDa, C. Michael Cotten, MDa, P. Brian Smith, MDa, Kenneth F. Tiffany, MDa,
Robert Lenfestey, MDa, Jennifer S. Li, MDa,b, Vance G. Fowler, Jr, MDc, Daniel K. Benjamin, Jr, MD, PhD, MPHa,b

Departments of aPediatrics and cMedicine, Duke University, Durham, North Carolina; bDuke Clinical Research Institute, Durham, North Carolina

The authors have indicated they have no financial relationships relevant to this article to disclose.

ABSTRACT
BACKGROUND. Meningitis is a substantial cause of morbidity and mortality in neo-
nates. Clinicians frequently use the presence of positive blood cultures to deter-
www.pediatrics.org/cgi/doi/10.1542/
mine whether neonates should undergo lumbar puncture. Abnormal cerebrospi- peds.2005-1132
nal fluid (CSF) parameters are often used to predict neonatal meningitis and doi:10.1542/peds.2005-1132
determine length and type of antibiotic therapy in neonates with a positive blood
Key Words
culture and negative CSF culture. CSF pleocytosis, neonatal sepsis, spinal tap
Abbreviations
METHODS. We evaluated the first lumbar puncture of 9111 neonates at ⱖ34 weeks’
CSF— cerebrospinal fluid
estimated gestational age from 150 NICUs, managed by the Pediatrix Medical LP—lumbar puncture
Group, Inc. CSF culture results were compared with results of blood cultures and WBC—white blood cell
EGA— estimated gestational age
CSF parameters (white blood cells [WBCs], glucose, and protein) to establish the CBC— complete blood cell count
concordance of these values in culture-proven meningitis. CSF cultures positive IQR—interquartile range
RBC—red blood cell
for coagulase-negative staphylococci and other probable contaminants, as well as
Accepted for publication Oct 3, 2005
fungal and viral pathogens, were excluded from analyses.
Address correspondence to Daniel K.
Benjamin, Jr, MD, PhD, MPH, Department of
RESULTS. Meningitis was confirmed by culture in 95 (1.0%) neonates. Of the 95 Pediatrics, PO Box 17969, Duke Clinical
patients with meningitis, 92 had a documented blood culture. Only 57 (62%) of 92 Research Institute, Durham, NC 27715. E-mail:
danny.benjamin@duke.edu
patients had a concomitant-positive blood culture; 35 (38%) of 92 had a negative
PEDIATRICS (ISSN Numbers: Print, 0031-4005;
blood culture. In neonates with both positive blood and CSF cultures, the organ- Online, 1098-4275). Copyright © 2006 by the
isms isolated were discordant in 2 (3.5%) of 57 cases. In each case, the CSF American Academy of Pediatrics

pathogen required different antimicrobial therapy than the blood pathogen. For
culture-proven meningitis, CSF WBC counts of ⬎0 cells per mm3 had sensitivity at
97% and specificity at 11%. CSF WBC counts of ⬎21 cells per mm3 had sensitivity
at 79% and specificity at 81%. Culture-proven meningitis was not diagnosed
accurately by CSF glucose or by protein.
CONCLUSIONS. Neonatal meningitis frequently occurs in the absence of bacteremia
and in the presence of normal CSF parameters. No single CSF value can reliably
exclude the presence of meningitis in neonates. The CSF culture is critical to
establishing the diagnosis of neonatal meningitis.

1094 GARGES, et al
Downloaded from pediatrics.aappublications.org at Uppsala Medicinska on October 2, 2014
N EONATAL MENINGITIS IS a devastating infection that
is often difficult to diagnose.1–5 Signs of meningitis
are often subtle in the neonate; thus, the diagnosis of
meningitis must be made by cerebrospinal fluid (CSF)
examination.6 However, lumbar puncture (LP) is often
not performed as part of the initial neonatal sepsis eval-
uation in the first days of life.7,8 Instead, the decision to
perform an LP is often based on the isolation of a poten-
tial pathogen from blood cultures. Although basing the
decision to perform LP on blood culture results occurs in
clinical practice, the diagnostic accuracy of this strategy
is unknown.
Maternal antibiotic prophylaxis or delayed LP in an-
tibiotic-treated neonates make interpreting CSF cultures
difficult, because CSF cultures may be negative within
hours of antibiotic administration.9,10 In these cases of
antibiotic pretreatment, clinicians must rely on the CSF
parameters to determine the presence of meningitis. The
cellular and biochemical abnormalities in the CSF of
older patients with bacterial meningitis are present for
44 to 68 hours.11 Similar values for neonates are un-
known. Several studies have examined the CSF param-
eters of the noninfected neonate to define the normal
values. These studies, although small and often from a
single center, have resulted in the widespread teaching
that 21 WBCs per mm3 in the CSF is a normal value.12–14
However, the clinical use of CSF parameters in the iden-
tification of subsequent culture-confirmed meningitis
has not been evaluated previously.
The objective of this investigation was to evaluate the
accuracy of current clinical diagnostic strategies in the
identification of meningitis among term or near-term
neonates. To accomplish this goal, we examined CSF
parameters from ⬎9000 term or near-term neonates in
an attempt to develop an algorithm for predicting neo-
natal meningitis. We compared blood and CSF culture
positivity rates and looked for the presence of concor-
dance between these results.
METHODS
Patient Selection
The Duke University Institutional Review Board ap-
proved this investigation. We assembled a cohort of ne-
onates from an administrative database. Clinical data for
these neonates were recorded prospectively for the da-
tabase and analyzed retrospectively for this article. Ne-
onates eligible for inclusion in the study were discharged
from 150 NICUs managed by the Pediatrix Medical
Group, Inc, from 1997 through 2004, were ⱖ34 weeks
in estimated gestational age (EGA), and had an LP per-
formed. The Pediatrix Group cared for 16 395 neonates
during this time who underwent LP; 9171 neonates
were ⱖ34 weeks’ EGA and had a report of a CSF culture.
We excluded 60 patients in whom the culture was re-
Downloaded from pediatrics.aappublications.org at Uppsala Medicinska on October 2, 2014
ported from a ventricular tap or shunt. The total sample
size in this analysis was 9111 patients.
Data Source
The Pediatrix Group database is an administrative data-
base and the method of data collection has been de-
scribed previously.15–18 We collected data on birth
weight, EGA (based on the examination of the neona-
tologist), gender, race, Apgar scores, admission type, day
of life, maternal age, peripheral complete blood count
(CBC), blood and CSF culture results, CSF parameters
and mortality. CSF data were codified and triple checked
for accuracy.
Definitions
Meningitis was defined by a positive CSF culture for
bacteria. CSF cultures positive for organisms generally
considered contaminants (coagulase-negative staphylo-
cocci, other skin flora [viridans streptococci and dipthe-
roids], or mixed organisms) were not included in the
positive CSF results. Blood cultures taken within 3 days
(average time for bacterial cultures to be read and or-
ganisms identified) of the CSF culture were reviewed for
concordance. Blood and CSF cultures were considered
concordant if both were positive with the same organ-
ism. CSF and blood cultures were considered discordant
if the CSF was positive and the blood culture was neg-
ative or if the organism isolated from the CSF was a
different organisms than the blood isolate.
Statistical Analysis
Only the first CSF result for any patient was included in
this investigation. Only blood cultures obtained within 3
days of the LP were considered in the analyses. In the
primary analysis, positive blood and CSF cultures and
CSF parameters were tabulated. We calculated sensitiv-
ity, specificity, and likelihood ratios for CSF parameters
to diagnose meningitis. We evaluated different CSF
WBC counts as threshold values for a negative test. We
conducted the data analysis using Stata 8.1 (Stata Corp,
College Station, TX). Secondary analyses using blood
cultures obtained within 10 days of the LP, CSF and
RBCs ⬍100 cells per mm3, were also conducted and
yielded similar results to the primary analysis. Therefore,
only the primary analysis is reported.
RESULTS
A total of 9111 infants ⱖ34 weeks’ EGA with no ven-
tricular shunts underwent LP during the study period
(Table 1). The mean EGA was 38 weeks (range: 34 – 44
weeks), and the mean birth weight was 3.16 kg (range:
0.55–5.7 kg); 56.4% of the cohort were male infants,
and 43.5% were female. Admission to the NICU was
variable, with 41.5% of admissions from the newborn
nursery, 35.8% of admissions from the hospital delivery,
3% of admissions from home delivery, and 11.7% of
PEDIATRICS Volume 117, Number 4, April 2006 1095
 TABLE 1 Demographics of the Cohort (n ⴝ 9111) bacterial pathogen (Table 2) and included Gram-positive
Demographic n % organisms other than skin flora (62 of 95 [65.3%]) and
Gestational age, wk Gram-negative rods (31 of 95 [33.6%]). Mortality data
34–37 3121 34.2 are available on 8550 patients, and those with culture-
38–40 5162 56.7 confirmed meningitis were significantly more likely to
⬎40 828 9.1 die than neonates with CSF cultures yielding no growth
Gender
(4 of 73 vs 40 of 8477; relative risk: 11.61; 95% confi-
Female 3970 43.5
Male 5139 56.4 dence interval: 4.27–31.61).
Missing 2 0.01
Race Blood Culture Discordance
White 3744 41.1 CSF cultures were matched to a blood culture within 3
Black 1433 15.7
days of the LP in 8596 (94.1%) infants, and 398 (4.5%)
Hispanic 3183 34.9
Other 751 8.3 of 8596 blood cultures were positive (Table 2). Of the
Birth weight, kg 95 patients with a CSF culture positive for a bacterial
⬎2.5 7664 84.1 pathogen, 92 (96.8%) had a documented blood culture
1.5–2.5 1299 14.3 within 3 days of LP. Of those 92 neonates, the majority
⬍1.5 55 0.01
65 (71%) of 92 had blood and LP cultures performed on
Missing 93 0.01
Apgar score at 1 min the same day. The remaining neonates had a time dif-
0–3 647 7.1 ference between the blood culture and CSF culture of 1
4–6 1105 12.1 day (21 of 92 [22.8%]), 2 days (4 of 92 [4.3%]), or 3
7–10 7103 78 days (2 of 92 [2.2%]).
Missing 256 2.8
Of those neonates with accompanying blood cultures,
Apgar score 5 min
0–3 90 1 57 (62.0%) of 92 patients had a concomitant positive
4–6 371 4.1 blood culture; 35 (38.0%) of 92 had a negative blood
7–10 8392 92.1 culture. Of those 35 neonates with discordant blood and
Missing 258 2.8 CSF cultures, 21 (60%) of 35 had a blood culture and LP
Maternal age, y
on the same day, and 11 (31%) of 35 had 1 day between
13–19 1464 16
20–29 4661 51.2 the time of blood and CSF culture. Of the remaining
30–39 2803 30.8 neonates, 3 (9%) of 35 had 2 or 3 days between blood
40–49 179 1.9
Missing 4 0.1
Admission type
From hospital delivery 3259 35.8 TABLE 2 CSF and Blood Culture Data From 9111 Infants
From home delivery 289 3.1 Variable CSF Blood
From newborn nursery 3782 41.5
n % n %
Hospital transfer 1035 11.4
Other 498 5.5 Negative 8912 97.8 8375 95.5
Missing 248 2.7 Positive for bacteria 184 2.2 398 4.5
Day of life at time of culture Contaminants 89 112
0 2450 26.9 Pathogens 95 1.0 286 3.4
1 2489 27.3 Gram-positive organisms 62 65.3 217 75.9
2 1362 14.9 Enterococcus spp. 6 10
3 687 7.5 Group B streptococcus 37 151
4–7 919 10.1 Listeria monocytogenes 1 1
8–28 1021 11.2 Staphylococcus aureus 4 22
29–60 144 1.6 Streptococcus pneumoniae 2 4
61–150 33 0.4 Gram-positive cocci not specified 12 29
Missing 6 0.1 Gram-negative organisms 32 32.6 56 19.6
Acinetobacter spp. 3 2
Citrobacter spp. 1 1
E coli 12 37
admissions from hospital transfers. Median Apgar scores Enterobacter spp. 4 1
at 1 and 5 minutes were ⬎7 (78% and 92%, respec- Haemophilus influenzae 2 2
tively), and the majority of the LPs, 6988 (76.6%) of Klebsiella 0 3
9111 , were performed in the first 3 days of life. Proteus spp. 1 1
Pseudomonas spp. 3 2
Of the 9111 LPs performed, 184 CSF cultures were Salmonella spp. 1 0
positive for bacterial growth. CSF cultures positive with Serratia spp. 2 2
a mixture of bacterial organisms, coagulase-negative Stenotrophomonas multiphilia 0 1
staphylococci, and other skin flora were excluded. Nine- Neisseria spp. 2 2
ty-five (1.0%) of 9111 CSF cultures grew a potential Gram-negative rod not specified 2 4

1096 GARGES, et al
Downloaded from pediatrics.aappublications.org at Uppsala Medicinska on October 2, 2014
and CSF culture. In those neonates with both positive
blood and CSF cultures, the organisms isolated were
discordant in 2 (3.5%) of 57, as shown in Table 3. In
both discordant pairs, the CSF pathogen required differ-
ent antimicrobial therapy than the blood pathogen.
CSF Parameters
We evaluated CSF parameters to determine their predic-
tive value in diagnosing meningitis, and these results are
shown in Table 4. Neonates with negative CSF cultures
had a range of 0 to 90 000 CSF WBCs per mm3, with a
median of 6/mm3 (interquartile range [IQR]: 2–15). In
neonates with bacterial meningitis, the range of CSF
WBCs was from 0 to 15 900/mm3, with a median of
477/mm3 (IQR: 38 –1950). However, 5% of neonates
with bacterial meningitis had either 0 or 1 CSF WBCs per
mm3, and 10% of neonates with bacterial meningitis
had ⱕ3 CSF WBCs per mm3.
CSF glucose and protein values were highly variable
in infants both with and without meningitis. Neonates
without meningitis had CSF glucose values ranging from
0 to 1089 mg/dL, (median: 49 mg/dL; IQR: 43–58).
Neonates with bacterial meningitis had CSF glucoses
ranging from 0 to 199 mg/dL (median: 20 mg/dL; IQR:
3–55). Infants without meningitis had CSF protein
levels ranging from 3 to 4122 mg/dL (median: 103 mg/
dL; IQR: 77–142). Infants with bacterial meningitis had
CSF protein ranging from 41 to 1964 mg/dL (median:
273 mg/dL; IQR: 125–550). CSF RBC values are likewise
highly variable. CSF RBCs ranged from 0 to 4 070 000
cells per mm3, with a median of 190 RBCs per mm3
(IQR: 12–2250). Infants with bacterial meningitis had a
median of 257 RBCs per mm3 (IQR: 26 –1400).
Diagnosis
We determined the sensitivity, specificity, and likelihood
ratios of CSF WBC counts, glucose, and protein to pre-
dict the presence of meningitis using different thresholds
for these values (Table 4). Highest sensitivity was ob-
tained when the threshold was any presence of WBCs in
the CSF (97%), but this also led to the lowest specificity
(11%). Using 21 WBCs as the upper limit of the thresh-
TABLE 3 Discordance Among CSF and Blood Culture Results
Variable
Negative
Blood Culture
Positive CSF culture 35
Gram-negative rod 12
Gram-positive cocci 23
a Discordant pair (CSF pathogen/blood pathogen).
b Pseudomonas: group B streptococcus.
c Enterobacter: streptococcus spp.
Downloaded from pediatrics.aappublications.org at Uppsala Medicinska on October 2, 2014
old led to a sensitivity of 79% and a specificity of 81%.
The CSF glucose values were less sensitive predictors
of culture positivity but had higher specificities than CSF
WBCs, as shown in Table 4. We attempted to con-
struct an algorithm that could be used to predict men-
ingitis in the absence of a CSF culture. However, given
the variability in the CSF parameters and the lack of
sensitivity and specificity of traditional threshold values,
we were unable to develop an algorithm that would
accurately and precisely predict meningitis based on CSF
parameters alone. Detailed information regarding the 12
neonates with culture-proven meningitis and CSF WBC
counts of ⱕ21 cells per mm3 is shown in Table 5.
Peripheral WBCs
Peripheral WBC data obtained within 3 days of the LP
was also analyzed, because the CBC is often used in
conjunction with blood culture data to determine
whether an LP should be completed. CBC data were
available on 8312 (91.2%) of 9111 patients. Of the
8312 neonates with CBC data, 66 (0.8%) had WBC
counts of ⬍3000/mm3, 1438 (17.3%) had WBC counts
between 3000 and 10 000/mm3, 2416 (29.1%) had
WBC counts between 10 001 and 15 000/mm3, and
2156 (25.9%) had WBC counts between 15 001 and
20 000/mm3. There were 2236 neonates (26.9%) with
WBC counts ⬎20 000/mm3. The peripheral WBC
count was neither sensitive nor specific for bacterial
meningitis. There were 85 neonates with a positive CSF
culture with a pathogen and with a peripheral CBC
within 3 days. Of these neonates, 17 (20%) of 85 had
WBC counts of ⬍3000/mm3, 36 (43.4%) of 85 had
WBC counts of ⱖ3000 and ⬍10 000/mm3, 13 (15.3%)
of 85 had WBC counts of ⱖ10 000 and ⬍15 000/mm3,
and 9 (10.6%) of 85 had WBC counts of ⱖ15 000
and ⬍20 000/mm3. In all of the cases, using peripheral
WBCs as a predictor for meningitis had a positive like-
lihood ratio ⬍1.0.
DISCUSSION
Prior studies have described the difficulties of diagnosing
neonatal meningitis based on clinical examination and
Discordant Results Concordant Total
Results
Positive Positive
Blood Culturea Blood Culture
(Organism Different (Organism Same
From CSF) as CSF)
2 55 92
2b,c 16 31
— 39 62
PEDIATRICS Volume 117, Number 4, April 2006 1097
 TABLE 4 CSF Parameters by Culture Results Showing Test Parameters and Positive (ⴙ) and Negative (ⴚ) Likelihood Ratios
Variable Negative Positive Sensitivity, % Specificity, % LR⫹ LR⫺
(n ⫽ 8912) (n ⫽ 95)a (95% CI) (95% CI)
WBC count, mm3
0 506 2
1–8 2293 8 97 (88–99) 11 (10–12) 1.09 0.92
9–21 891 2 83 (71–91) 61 (60–63) 2.13 0.47
22–100 591 8 79 (67–89) 81 (80–82) 4.16 0.24
⬎100 285 38 66 (52–78) 94 (93–95) 11 0.09
Unknown 4346 37
Glucose, mg/dL
⬍20 25 24 44 (30–58) 98 (97–99) 22 0.05
20–60 3504 25 89 (78–96) 20 (18–21) 1.11 0.90
⬎60 860 6
Unknown 4523 40
Protein, mg/dL
0–40 83 0
41–90 1616 9 100.00 (84–100) 2 (1–3) 1.02 0.98
90–120 1073 4 84 (71–92) 28 (27–29) 1.17 0.86
⬎120 1624 42 76 (63–87) 63 (62–64) 2.05 0.49
Unknown 4516 40
LR indicates likelihood ratio; CI, confidence interval.
a Coagulase-negative staphylococci and known skin flora are excluded here.

TABLE 5 Parameters of 12 Neonates With Meningitis and Normal CSF WBC Countsa
Organism CSF WBC, CSF CSF Blood CSF Bacterial Gestational Day of
cells per mm3 Glucose, Protein, Culture Gram-stain Antigen Age, wk Life at
m/dL mg/dL CSF Culture
Acinetobacter 3 — — — — — 39 26
E coli 1 58 56 Pos — — 40 3
Enterobacter 5 52 81 Neg — Neg 36 0
Enterococcus 3 59 216 Neg — — 36 0
Enterococcus 0 45 41 Neg Neg — 39 6
Gram-positive cocci 3 49 126 Neg — — 40 1
Gram-positive cocci 1 52 43 Neg — — 40 17
Gram-positive cocci 3 74 167 Pos Neg — 34 1
Group B streptococcus 15 — — Neg — — 37 3
Pseudomonas aeruginosa 2 60 102 Neg — — 35 1
Pseudomonas aeruginosa 13 60 159 Neg — — 38 0
Staphylococcus aureus 0 51 110 Neg — — 42 1
Neg indicates negative; Pos, positive; — missing values.

laboratory data (such as CBC and blood culture).1,2,6,19–22
These studies have been limited by sample size20–22 and
lack of CSF parameters2 or focused on premature neo-
nates.1 Our study focuses on the near-term and term
infants, has a large sample size, and includes data on CSF
parameters.
The most common pathogens (group B streptococcus
and Escherichia coli) we report are similar to those re-
ported by Wiswell et al.2 Similar to previous reports,22–24
we also found that the finding of a positive CSF culture
in neonates who have an LP is rare: 10 in 1000. How-
ever, these results underestimate the true incidence of
disease, because many of the CSF cultures were obtained
after antibiotics were started or from neonates born to
mothers who had received antibiotics.
We had hoped to identify factors that would allow
clinicians to rapidly assess the likelihood of meningitis in
neonates based on CSF findings. However, we were
unable to do this, because our analysis of CSF parame-
ters confirmed that meningitis can occur in the presence
of normal CSF WBC, glucose, and protein levels. Our
study results reinforce the finding of others studies that
report that a substantial proportion (33% [ref 2] to 53%
[ref 25]) of neonates with culture-proven meningitis
have negative blood cultures. We suspect that our rate
(38%) may be related to an increased use of antibiotics
that has been advocated to prevent group B streptococ-
cal disease.25 Even more disturbing are the 2 neonates
with Gram-negative rod meningitis who had Gram-pos-
itive organisms in blood culture (Table 3). If LP had not
been performed in these neonates and presumptive
therapy based on the blood culture, these cases would
have been missed, or the diagnosis delayed, with likely
serious consequences.

1098 GARGES, et al
Downloaded from pediatrics.aappublications.org at Uppsala Medicinska on October 2, 2014
 Even more problematic, we were unable to find any
CSF parameter that could be used to exclude meningitis.
The commonly used threshold value of 21 cells as the
upper limit of normal for the term neonate12–14 would
have lead to 12.6% of meningitis cases being missed.
Our analysis of CSF parameters demonstrates that men-
ingitis can occur in the presence of normal CSF WBC,
glucose, and protein levels. All of the cases outlined in
Table 5 would have been missed without LP results
except for the 2 that also had a positive blood culture
with the same organisms. Because meningitis occurs in
the face of normal CSF parameters, it is impossible to
construct an algorithm to predict meningitis based on
abnormal CSF values. This finding reinforces the need to
perform the LP at the onset of the sepsis evaluation.
The strengths of this study include the large size, the
focus on term or near-term infants, and the incorpora-
tion of CSF parameters with blood and CSF culture
results. The study is limited in that it is a retrospective
analysis of an administrative data set and has missing
data. Although 95% of patients with meningitis had
blood culture data available, 42% of patients with men-
ingitis and 50% overall were missing CSF parameter
information, which decreased the sample size and may
affect the results. Although data are missing, the conclu-
sions are based on ⬃4500 complete observations and
provide evidence that neonatal meningitis can be missed
if the LP is not performed as a routine part of the sepsis
evaluation.
In addition, the study cohort is based on those infants
who had a CSF culture obtained rather than those in-
fants who had bacteremia. Therefore, we do not capture
those neonates who had a blood culture obtained but did
not have an LP performed or those neonates with bac-
teremia who underwent LP but did not have a CSF
culture sent. Despite eliminating the obvious bacterial
contaminants, some of the pathogenic organisms iso-
lated from CSF cultures may have been contaminants.
However, given the immunocompromised status of ne-
onates and the substantial impact that meningitis has on
neurodevelopmental outcomes, failure to treat patho-
gens isolated from the CSF is ill advised, and these
pathogens, therefore, were included in our analysis.
We are left with the dilemma of how to best treat the
neonate who was pretreated with antibiotics or born to
a mother who was pretreated with antibiotics. Although
some authors have suggested that the “asymptomatic”
term neonates are at low risk of having meningitis,
defining symptomatology to accurately identify the
newborn with serious sepsis or meningitis has not been
accomplished.24 Symptoms of partially treated menin-
gitis begin to appear 72 hours after the last dose of
antibiotics.20 Thus, a short course of antibiotics (per
local standard of care) and close follow-up of these in-
fants should be considered. For example, in a pretreated,
asymptomatic neonate with a negative blood culture,
Downloaded from pediatrics.aappublications.org at Uppsala Medicinska on October 2, 2014
negative CSF culture, and elevated CSF WBC count (21
cells per mm3), 48 hours of antibiotics21 followed by
either in-hospital observation or outpatient scheduled
clinic visit 48 to 72 hours after discharge may be war-
ranted.20
Neonatal meningitis remains a substantial cause of
sepsis-related morbidity and mortality in the term and
near-term infant. Our data demonstrate that there is no
set of clinical parameters that excludes the diagnosis of
meningitis in a neonate other than CSF cultures. The
diagnosis of meningitis is, therefore, dependent on ob-
taining a timely and adequate culture of the spinal fluid.
CONCLUSIONS
Neonatal meningitis occurs in the absence of bacteremia
and in the presence of normal CSF values. No single CSF
value can be used to exclude meningitis, and peripheral
WBC counts are also poor predictors of neonatal men-
ingitis. The CSF culture is critical to the diagnosis, re-
gardless of other laboratory results. These data suggest
that an LP should be incorporated in a sepsis evaluation
of an infant.
ACKNOWLEDGMENTS
Dr Benjamin received support from National Institute of
Child Health and Human Development grant HD044799,
and Dr Garges received support from Ruth L. Kirschstein
National Research Service Award Training grant T32-
HD43029. We thank the Pediatrix Medical Group, Inc,
and the Duke Clinical Research Institute for supporting
this study. It was completed under a collaborative agree-
ment between Pediatrix Medical Group, Inc, and Duke
University.
REFERENCES
1. Stoll BJ, Hansen N, Fanaroff AA, et al. To tap or not to tap: high
likelihood of meningitis without sepsis among very low birth
weight infants. Pediatrics. 2004;113:1181–1186
2. Wiswell TE, Baumgart S, Gannon CM, Spitzer AR. No lumbar
puncture in the evaluation for early neonatal sepsis: will men-
ingitis be missed? Pediatrics. 1995;119:803– 806
3. Klein JO. Bacterial sepsis and meningitis. In: Remington JS,
Klein JO, eds. Infectious Diseases of the Fetus and Newborn Infant.
5th ed. Philadelphia, PA: WB Saunders; 2001:943–998
4. Davies PA, Rudd PT. Neonatal Meningitis. London, United
Kingdom: MacKeith Press; 1994:1–177
5. Harvey D, Holt DE, Bedford H. Bacterial meningitis in the
newborn: a prospective study of mortality and morbidity. Semin
Perinatol. 1999;23:218 –225
6. Haworth JC. The diagnosis of acute meningitis in infancy.
Lancet. 1953;1(19):911–914
7. Fielkow S, Reuter S, Gotoff SP. Cerebrospinal fluid examina-
tion in symptom-free infants with risk factors for infection.
J Pediatr. 1991;119:971–973
8. Weiss MG, Ionides SP, Anderson CL. Meningitis in premature
infants with respiratory distress: role of admission lumbar
puncture. J Pediatr. 1991;119:973–975
9. Riordan FAI, Cant AJ. When to do a lumbar puncture. Arch Dis
Child. 2002;87:235–237
10. Kanegaye JT, Soliemanzadeh P, Bradley JS. Lumbar puncture
PEDIATRICS Volume 117, Number 4, April 2006 1099
 in pediatric bacterial meningitis: determining the time interval
for recovery of cerebrospinal fluid pathogens after parenteral
antibiotic pretreatment. Pediatrics. 2001;108:1169 –1174
11. Feigin RD, Pearlman E. Bacterial meningitis beyond the neo-
natal period. In: Feigin RD, Cherry JD, eds. Textbook of Pediatric
Infectious Diseases. 4th ed. Philadelphia, PA: WB Saunders; 1998
12. Berman RE, Kliegman RM, Arvin AM. Nelson Textbook of Pedi-
atrics. 17th ed. Philadelphia, PA: WB Saunders; 2004
13. Oski FA. Principles and Practice of Pediatrics. 2nd ed. Philadelphia,
PA: JB Lippincott; 1994
14. Ahmed A, Hickey SM, Ehrett S, et al. Cerebrospinal fluid values
in the term neonate. Pediatr Infect Dis J. 1996;15:298 –303
15. Thorp JA, Jones PG, Peabody PL, Knox E, Clark RH. Effect of
antenatal and postnatal corticosteroid therapy on weight gain
and head circumference growth in the nursery. Obstet Gynecol.
2002;99:109 –115
16. Benjamin DK, DeLong E, Cotten CM, Garges HP, Steinbach
WJ, Clark RH. Mortality following blood culture in premature
infants: increased with Gram-negative bacteremia and candi-
demia, but not Gram-positive bacteremia. J Perinatol. 2004;24:
175–180
17. Benjamin DK Jr, DeLong ER, Cotten CM, Garges HP, Clark RH.
Postconception age and other risk factors associated with mor-
tality following Gram-negative rod bacteremia. J Perinatol.
2004;24:169 –174
18. Benjamin DK Jr, DeLong ER, Steinbach WJ, Cotton CM, Walsh
1100 GARGES, et al
Downloaded from pediatrics.aappublications.org at Uppsala Medicinska on October 2, 2014
TJ, Clark RH. Empirical therapy for neonatal candidemia in
very low birth weight infants. Pediatrics. 2003;112:543–547
19. Visser VE, Hart RT. Lumbar puncture in the evaluation of
suspected neonatal sepsis. J Pediatr. 1980;96:1063–1067
20. Andersen J, Christensen R, Hertel J. Clinical features and ep-
idemiology of septicaemia and meningitis in neonates due to
Streptococcus agalactiae in Copenhagen County, Denmark: a
10 year survey from 1992 to 2001. Acta Paediatr. 2004;93:
1334 –1339
21. Kumar S. Missed and delayed diagnosis of neonatal meningitis.
Indian Pediatr. 2004;41:959 –960
22. Ajayi OA, Mokuolu OA. Evaluation of neonates with risk for
infection/suspected sepsis: is routine lumbar puncture neces-
sary in the first 72 hours of life? Trop Med Int Health. 1997;2:
284 –288
23. Stoll BJ, Hansen NI, Adams-Chapman I, et al. Neurodevelop-
mental and growth impairment among extremely low-birth-
weight infants with neonatal infection. JAMA. 2004;292:
2357–2365
24. Johnson CE, Whitwell JK, Pethe K, Saxena K, Super DM. Term
newborns who are at risk for sepsis: are lumbar punctures
necessary? Pediatrics. 1997;99(4). Available at: www.pediatrics.
org/cgi/content/full/99/4/e10
25. Baker CJ, Kanto WP Jr. Implementing new GBS guidelines
requires coordinated care. AAP News. 2003;22:79 – 86
 Neonatal Meningitis: What Is the Correlation Among Cerebrospinal Fluid
Cultures, Blood Cultures, and Cerebrospinal Fluid Parameters?
Harmony P. Garges, M. Anthony Moody, C. Michael Cotten, P. Brian Smith, Kenneth
F. Tiffany, Robert Lenfestey, Jennifer S. Li, Vance G. Fowler, Jr and Daniel K.
Benjamin, Jr
Pediatrics 2006;117;1094
DOI: 10.1542/peds.2005-1132
Updated Information & including high resolution figures, can be found at:
Services http://pediatrics.aappublications.org/content/117/4/1094.full.h
tml
References This article cites 19 articles, 5 of which can be accessed free
at:
http://pediatrics.aappublications.org/content/117/4/1094.full.h
tml#ref-list-1
Citations This article has been cited by 16 HighWire-hosted articles:
http://pediatrics.aappublications.org/content/117/4/1094.full.h
tml#related-urls
Subspecialty Collections This article, along with others on similar topics, appears in
the following collection(s):
Fetus/Newborn Infant
http://pediatrics.aappublications.org/cgi/collection/fetus:newb
orn_infant_sub
Infectious Diseases
http://pediatrics.aappublications.org/cgi/collection/infectious_
diseases_sub
Permissions & Licensing Information about reproducing this article in parts (figures,
tables) or in its entirety can be found online at:
http://pediatrics.aappublications.org/site/misc/Permissions.xht
ml
Reprints Information about ordering reprints can be found online:
http://pediatrics.aappublications.org/site/misc/reprints.xhtml

PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly

publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2006 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.

Downloaded from pediatrics.aappublications.org at Uppsala Medicinska on October 2, 2014