ARTICLE

Early Vancomycin Therapy and Adverse Outcomes in

Children With Pneumococcal Meningitis
Steven C. Buckingham, MDa, Jonathan A. McCullers, MDb, Jorge Lujan-Zilbermann, MDc, Katherine M. Knapp, MDb, Karen L. Orman, MDd,
B. Keith English, MDa

aDepartment of Pediatrics, University of Tennessee Health Science Center and Childrens Foundation Research Center at Le Bonheur Childrens Medical Center, Memphis,

Tennessee; bDepartment of Infectious Diseases, St. Jude Childrens Research Hospital, Memphis, Tennessee; cDepartment of Pediatrics, University of South Florida,
Tampa, Florida; dDepartment of Pediatrics, Kosair Childrens Hospital, Louisville, Kentucky

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

ABSTRACT
BACKGROUND. Experts recommend that children with suspected pneumococcal men-
ingitis should empirically receive combination therapy with vancomycin plus
www.pediatrics.org/cgi/doi/10.1542/
either ceftriaxone or cefotaxime. The relationship between timing of the first dose peds.2005-2282
of vancomycin relative to other antibiotics and outcome in these children, how- doi:10.1542/peds.2005-2282
ever, has not been addressed.
Key Words
Streptococcus pneumoniae, vancomycin,
METHODS. Medical records of children with pneumococcal meningitis at a single
meningitis, dexamethasone, hearing loss
institution from 19912001 were retrospectively reviewed. Vancomycin start time Abbreviation
was defined as the number of hours from initiation of cefotaxime or ceftriaxone CSF cerebrospinal uid
therapy until the administration of vancomycin therapy. Outcome variables were Accepted for publication Nov 3, 2005
death, sensorineural hearing loss, and other neurologic deficits at discharge. As- Address correspondence to Steven C.
Buckingham, MD, Le Bonheur Childrens
sociations between independent variables and outcome variables were assessed in Medical Center, Room 301, 50 N Dunlap St,
univariate and multiple logistic regression analyses. Memphis, TN 38103. E-mail: sbuckingham@
utmem.edu
RESULTS. Of 114 subjects, 109 received empiric vancomycin therapy in combination PEDIATRICS (ISSN Numbers: Print, 0031-4005;
Online, 1098-4275). Copyright 2006 by the
with cefotaxime or ceftriaxone. Ten subjects (9%) died, whereas 37 (55%) of 67 American Academy of Pediatrics
survivors who underwent audiometry had documented hearing loss, and 14
(13%) of 104 survivors were discharged with other neurologic deficits. Subjects
with hearing loss had a significantly shorter median vancomycin start time than
did those with normal hearing (1 vs 4 hours). Vancomycin start time was not
significantly associated with death or other neurologic deficits in univariate or
multivariate analyses. Multiple logistic regression revealed that hearing loss was
independently associated with vancomycin start time 2 hours, blood leukocyte
count 15 000/L, and cerebrospinal fluid glucose concentration 30 mg/dL.
CONCLUSIONS. Early empiric vancomycin therapy was not clinically beneficial in children
with pneumococcal meningitis but was associated with a substantially increased risk of
hearing loss. It may be prudent to consider delaying the first dose of vancomycin
therapy until 2 hours after the first dose of parenteral cephalosporin in children
beginning therapy for suspected or confirmed pneumococcal meningitis.

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C HILDREN WITH MENINGITIS caused by Streptococcus
pneumoniae face a guarded prognosis: in developed
nations, 10% die and one third of survivors are dis-
charged from the hospital with significant neurologic
sequelae.13 Previous studies have identified a multitude
of adverse prognostic indicators in children with pneu-
mococcal meningitis; however, differences across studies
in populations, therapeutic approaches, and statistical
analyses make synthesis of their results problematic.24
Thus, it presently remains unclear which risk factors are
independently associated with the outcomes of death,
hearing loss, and other neurologic sequelae. Particular
uncertainty continues to surround both the use of ad-
junctive dexamethasone therapy and the optimal anti-
biotic therapy for children with pneumococcal meningi-
tis.5
During the 1990s, widespread pneumococcal resis-
tance to penicillin and third-generation cephalosporins
emerged, and some patients with cefotaxime-resistant
pneumococcal meningitis experienced delayed cerebro-
spinal fluid (CSF) sterilization when treated initially
with cefotaxime or ceftriaxone alone.610 In view of these
developments, in 1997, the American Academy of Pedi-
atrics Committee on Infectious Diseases recommended
that patients with definite or probable bacterial menin-
gitis should empirically receive combination therapy
with vancomycin plus either cefotaxime or ceftriaxone
until susceptibility testing results are available.11 The
rationale for the inclusion of vancomycin in initial ther-
apy was based on the known association between de-
layed CSF sterilization and neurologic sequelae in chil-
dren with bacterial meningitis.12
Even before the Committee on Infectious Diseases
issued its recommendation, combination empiric ther-
apy including vancomycin had already become an ac-
cepted practice for children with suspected pneumococ-
cal meningitis at our tertiary childrens medical center.
As we have noted previously, this strategy has effectively
prevented bacteriologic therapeutic failures in children
with pneumococcal meningitis in our institution: from
1991 to 1999, none of 80 children (30 of whom under-
went repeat CSF examinations 24 96 hours into ther-
apy) who received empiric vancomycin therapy suffered
documented delayed CSF sterilization.13 Nevertheless,
patients in this series suffered adverse outcomes at rates
similar to or exceeding those documented elsewhere:
7% died, and 53% of survivors who underwent audio-
metric testing had moderate to profound sensorineural
hearing loss.13 These observations raised 2 questions.
First, is early empiric vancomycin therapy clinically ben-
eficial in children with pneumococcal meningitis? Sec-
ond, how promptly is vancomycin therapy initiated in
these children, and would earlier administration im-
prove outcomes?
We undertook the present study to address these
questions and to identify risk factors for adverse neuro-
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logic outcomes in children with pneumococcal menin-
gitis in the era of early empiric vancomycin therapy.
With these ends in mind, we expanded the data set of
our previous study and subjected it to multivariate anal-
ysis to identify clinical and laboratory characteristics in-
dependently associated with the outcomes of death,
hearing loss, and other neurologic deficits. In particular,
we sought to investigate the relationship between timing
of the first dose of vancomycin and the above outcomes
after controlling for the effects of other predictive vari-
ables.
METHODS
Study Population and Record Review
The study population consisted of children with pneu-
mococcal meningitis identified retrospectively from
computerized records of the microbiology laboratory and
medical records department of a 225-bed pediatric ter-
tiary care childrens medical center from October 6,
1991, to December 31, 2001. Subjects were included if
they met at least 1 of the following criteria: S pneumoniae
isolated in culture of CSF, S pneumoniae antigen detected
in CSF, or S pneumoniae isolated in culture of blood and
CSF examination showing 10 leukocytes per L. Data
from 86 subjects, admitted from 1991 to 1999, were
included in our previous study evaluating penicillin re-
sistance in pneumococcal meningitis.13 The University of
Tennessee Health Science Center Institutional Review
Board and the Le Bonheur Research Committee ap-
proved the study and waived requirements for informed
consent.
Data regarding demography, past medical history,
clinical and laboratory findings, antibiotic susceptibility,
hospital course, therapies administered, and outcome
were abstracted from medical records. Audiometric test-
ing results were abstracted from medical records and
from the electrophysiology laboratory records of the
hospital. The date and time of the initial lumbar punc-
ture were abstracted from medical records, as were the
date and time of the first dose of each parenterally
administered antibiotic. These data were used to calcu-
late the number of hours from the first dose of any
parenteral antibiotic appropriate for pneumococcal men-
ingitis (eg, penicillin G, cefotaxime, and ceftriaxone)14
until the first dose of vancomycin (henceforth called the
vancomycin start time).
Data Analysis
Three outcome variables were investigated: death, mod-
erate to profound sensorineural hearing loss, and other
neurologic deficits at the time of hospital discharge. The
associations of independent variables with each outcome
variable were assessed in univariate analyses using Fish-
ers exact (categorical data) or Wilcoxon rank-sum (con-
tinuous data) tests. Hearing loss was defined by the
PEDIATRICS Volume 117, Number 5, May 2006 1689
absence of an observable response at 50 dB in 1 ear TABLE 1 Demographic, Clinical, and Therapeutic Characteristics of
on audiometric testing. Other neurologic deficits were the Study Population
defined by the presence of functionally significant motor Characteristic Value
or cranial nerve deficits (other than hearing loss) or Age, median (IQR), mo 10 (520)
global encephalopathy at the time of hospital discharge. Female gender, % 45/114 (39)
The analyses of hearing loss and other neurologic deficits Ethnicity, n/N (%)
only included subjects in whom these findings could not Black 74/114 (65)
White 40/114 (35)
be attributed to underlying conditions. Penicillin suscep-
Admission year
tibilities of pneumococcal isolates were interpreted ac- 19911996 63/114 (55)
cording to current Clinical Laboratory Standards Insti- 19972001 51/114 (45)
tute guidelines.15 Abnormal neuroimaging (ie, computed Transferred from outside institution, n/N (%) 27/114 (24)
tomography or MRI) studies were defined as those in- Underlying medical condition, n/N (%) 23/114 (20)
Seizures before presentation, n/N (%) 22/113 (19)
terpreted by a staff radiologist as showing evidence of
Focal neurologic decit at presentation, n/N (%) 20/109 (18)
central nervous system pathology not referable to an Depressed consciousness at admission, n/N (%) 11/114 (10)
underlying condition. Depressed consciousness at ad- ICU admission, n/N (%) 54/112 (48)
mission was defined by documentation of coma; a Glas- Respiratory failure, n/N (%) 27/112 (24)
gow coma score of 14; unresponsiveness; or opistho- Penicillin-resistant isolate, n/N (%) 20/110 (18)
Abnormal neuroimaging study, n/N (%) 40/78 (51)
tonic, decorticate, or decerebrate posturing.
Blood leukocyte count, median (IQR), cells per L 16 500 (972525 300)
Separate multiple logistic regression models were de- Positive Gram-stain, n/N (%) 93/110 (85)
veloped for each outcome variable. Independent vari- CSF glucose, median (IQR), mg/dL 20 (1054)
ables present in 10% of the study population and with CSF protein, median (IQR), mg/dL 197 (116366)
univariate P .20 were included in initial models. A CSF leukocyte count, median (IQR), cells per L 490 (1951600)
CSF % granulocytes (IQR) 75 (6188)
backward elimination approach was used to yield the
Hours from lumbar puncture to rst dose of 1 (01)a
most parsimonious yet descriptive model possible. Inde- parenteral cefotaxime or ceftriaxone,
pendent variables with multivariate P .05 were re- median (IQR)
tained. After a tentative final model was created for each Volume bolus 10 mL/kg, n/N (%) 27/112 (24)
outcome, previously eliminated independent variables Seizures after admission, n/N (%) 24/111 (22)
Corticosteroid therapy n/N (%)
were individually forced back into the model and re-
Any 37/113 (33)
tained if P was then 0.05. Vancomycin start time was Starting 1 h after rst dose of parenteral 16/113 (14)
initially included in all of the models regardless of uni- antibiotics
variate associations. Statistical calculations were per- n/N indicates number with characteristic/number informative. Data were ascertained for 98
formed using Statview (SAS Institute, Cary, NC). subjects (range: 0 141 hours). IQR indicates interquartile range.
a Range: 83 hours before to 21 hours after lumbar puncture.

RESULTS
Demographic, Clinical, and Therapeutic Characteristics
Data regarding the demographic and clinical character-
istics and therapeutic interventions for the 114 included
subjects are presented in Table 1. Documented underly-
ing medical conditions included: skull fracture and/or
CSF leak (7 subjects), sickle cell disease (5), asthma (3),
chronic lung disease and hydrocephalus as complica-
tions of prematurity (3), Chiari I malformation (1), Dan-
dy-Walker cyst (1), human immunodeficiency virus in-
fection (1), Trisomy 21 and atrioventricular canal (1),
chronic subdural hematoma resulting from nonacciden-
tal trauma (1), Klippel-Trenauny-Webber syndrome and
underlying seizure disorder (1), ventricular septal defect
(1), and biliary atresia (1). Abnormalities identified on
neuroimaging studies included: ischemic changes and/or
infarction (17 subjects), cerebral edema (14), subdural
effusions (12), hydrocephalus (8), cerebral atrophy (6),
and cerebritis (3).
Vancomycin was administered to 109 subjects, all of
whom received antecedent or concomitant therapy with
cefotaxime or ceftriaxone. Vancomycin start times could
be calculated for 98 subjects and varied from 0 to 141
hours (median: 1 hour; interquartile range: 0 6 hours).
Vancomycin start times were 1 hour in 38 subjects, 1
to 2 hours in 16, 2 to 5 hours in 16, and 5 hours in 28
subjects.
Outcomes
Ten subjects died: 1 suffered a full arrest shortly after
presentation to the emergency department, and 9 died
after initial intensive care unit (ICU) admission and me-
chanical ventilation. Audiometric testing results were
documented for 67 of 104 subjects who survived to
hospital discharge. Of these, 37 subjects (55%) had mod-
erate to profound sensorineural hearing loss in 1 ear.
Subjects who underwent audiometric testing were less
likely to have underlying disorders than were those who
were not tested (8 of 67 vs 15 of 37; P .001); other-
wise, clinical characteristics of these groups did not sig-
nificantly differ (data not shown). Fourteen surviving
subjects were discharged from the hospital with func-
tionally significant neurologic deficits other than hearing

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loss. These subjects neurologic findings included (num-
ber of subjects): persistent vegetative state (2), spastic
hemiplegia or diplegia (3), hemiparesis (4), and other
motor and/or cranial nerve palsies (6).
Table 2 lists the univariate associations of selected
independent variables with outcome variables, with
continuous variables dichotomized to simplify the pre-
sentation of results. Table 3 presents univariate associa-
tions of vancomycin start time (also dichotomized) with
outcome variables. As shown, early vancomycin admin-
istration was associated with an increased risk of hearing
loss, whereas vancomycin start time was not signifi-
cantly associated with mortality or other neurologic def-
icits. Among children with hearing loss, the median
vancomycin start time was 1 hour (interquartile range:
0 1.5 hours), whereas that of children without hearing
loss was 4 hours (interquartile range: 112 hours; P
.0005). With increasing vancomycin start time, the pro-
portion of tested children with hearing loss decreased in
stepwise fashion: 1 hour, 18 (78%) of 23; 1 to 2 hours,
6 (67%) of 9; 2 to 5 hours, 3 (33%) of 9; 5 hours, 5
(28%) of 18 (P .006).
Multivariate Analyses of Risk Factors
The results of multiple logistic regression modeling for
each of the outcome variables are listed in Table 4. For
the mortality analysis, variables representing ICU admis-
sion, respiratory failure, and abnormal neuroimaging
studies could not be fitted in multivariate models be-
cause of their essential collinearity with outcome. Early
vancomycin administration was independently associ-
ated with an increased risk of hearing loss but not with
mortality or other neurologic deficits. These models
were not significantly altered by the forcing of other
variables, including corticosteroid therapy, into them.
Furthermore, given an expected hearing loss rate of 30%
(the observed rate in subjects with vancomycin start
time 2 hours) and an adjusted odds ratio of 13.5 (the
point estimate from this analysis), the calculated number
needed to harm for vancomycin start time 2 hours is 2
(95% confidence interval: 25) patients.16
DISCUSSION
In this retrospective cohort study, we identified several
prognostic factors associated independently with adverse
outcomes in children with pneumococcal meningitis,
including peripheral leukopenia, low CSF glucose con-
centration, elevated CSF protein concentration, respira-
tory failure, and presence of a focal neurologic deficit at
admission. Whereas these observations are largely con-
sistent with the results of previous studies,24 the most
provocative result of this study must be the observation

TABLE 2 Univariate Associations of Selected Independent Variables With Outcomes of Mortality,

Hearing Loss, and Other Neurologic Decit
Characteristic Odds Ratio (95% Condence Interval)
Mortality Hearing Loss Other Neurologic Decit
Age 1 y 0.3 (0.11.4) a 1.5 (0.53.9) 2.2 (0.77.2)a
Female gender 1.6 (0.45.9) 1.0 (0.42.7) 4.8 (1.416.4)a
Black ethnicity 5.4 (0.744.3)a 3.1 (1.18.5)a 1.2 (0.43.7)
Admission year 19972001 3.2 (0.813.0)a 2.5 (0.96.8)a 1.1 (0.33.3)
Transferred from outside institution 1.3 (0.36.4) 1.1 (0.43.4) 1.2 (0.34.6)
Underlying medical condition 1.8 (0.47.6) 1.1 (0.25.3) 2.1 (0.67.6)
Seizures before presentation 3.1 (0.812.3)a 1.0 (0.33.3) 5.4 (1.518.7)a
Focal neurologic decit at presentation 5.6 (1.421.7)a 6.0 (0.753.0)a 13.7 (3.553.1)a
Isolate with penicillin MIC 2.0 g/mL 2.1 (0.317.7) 6.7 (1.727.3)a 3.6 (0.429.4)
Abnormal neuroimaging study Undened 3.9 (1.013.2)a 28.3 (3.4234)a
ICU admission Undened 2.6 (1.07.1)a 22.3 (2.8179)a
Respiratory failure Undened 1.2 (0.34.1) 24.7 (6.397.0)a
Volume bolus 10 mL/kg 4.6 (1.118.6)a 4.3 (1.117.1)a 2.3 (0.77.7)
Seizures after admission 4.2 (1.018.0)a 2.4 (0.78.7) 8.3 (2.528.3)a
Corticosteroid therapy
Any 0.2 (02.0) 0.9 (0.32.6) 2.1 (0.76.6)
Starting 1 h after rst dose of parenteral antibiotics 0.7 (0.15.6) 0.6 (0.12.5) 3.1 (0.811.7)a
Blood leukocyte count
5000/L 41.1 (7.3232)a 1.2 (0.25.7) 0.9 (0.18.3)
15 000/L Undened 4.1 (1.411.8)a 1.8 (0.65.8)
CSF glucose
30 mg/dL Undened 5.3 (1.815.4)a 1.3 (0.44.7)
20 mg/dL 5.7 (1.128.0)a 3.9 (1.411.0) 0.8 (0.22.9)
CSF protein
200 mg/dL Undened 4.9 (1.714.0)a 4.2 (1.017.0)a
400 mg/dL 22.4 (4.3116)a 2.6 (0.610.7) 8.0 (2.032.3)a
CSF leukocyte count 500/L 1.0 (0.33.7) 1.3 (0.53.6) 1.4 (0.44.9)
a Univariate P .20; investigated in multivariate analysis for given outcome.

PEDIATRICS Volume 117, Number 5, May 2006 1691

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 TABLE 3 Associations of Vancomycin Start Time With Outcome Variables
Outcome Vancomycin Start Time, n/N (%) Pa Odds Ratio
(95% Condence Interval)
2 h 2 h
Mortality 3/54 (6) 3/44 (7) .99 0.80 (0.154.19)
Hearing loss 24/32 (75) 8/27 (30) .0007 7.1 (2.322.5)
Other neurologic decit 6/50 (12) 6/40 (15) .76 0.77 (0.232.61)
a Fishers exact test.

TABLE 4 Multivariate Analyses: Independent Predictors of Death, Hearing Loss, and Other Neurologic
Decits
Outcome Risk Factor P Adjusted Odds Ratio
(95% Condence Interval)
Death (R2 0.50)
Blood leukocyte count 5000/L .0006 32 (4.5233)
Cerebrospinal uid protein 400 mg/dL .006 17 (2.3123)
Hearing loss (R2 0.40)
Vancomycin start time 2 h .003 13.5 (2.573)
Blood leukocyte count 15 000/L .006 12.0 (2.169)
Cerebrospinal uid glucose 30 mg/dL .03 4.9 (1.120.6)
Other neurologic decits
(R2 0.45) Respiratory failure .0001 29.2 (5.1166)
Focal neurologic decit at admission .005 13.6 (2.283)

of significantly increased hearing loss among children
who received vancomycin 2 hours after the first dose
of cefotaxime or ceftriaxone compared with those with
longer vancomycin start times. This unexpected result
raises questions as to the optimal management of pneu-
mococcal meningitis in children and specifically chal-
lenges the dictum that empiric vancomycin therapy
should be administered promptly to all children with
definite or probable pneumococcal meningitis.
Until now, only limited data have been available re-
garding the safety and efficacy of empiric vancomycin
therapy, administered in combination with a third-gen-
eration cephalosporin, in children with pneumococcal
meningitis. In 2002, investigators in Australia published
their analysis of secular trends and concluded that em-
piric vancomycin use was not related to the outcome of
pneumococcal meningitis.17 Also in 2002, Kellner et al18
reported that, among children with penicillin-nonsus-
ceptible pneumococcal meningitis, those who received
empiric vancomycin therapy received fewer mean days
of intravenous antibiotics (12 vs 18.5 days; P .04) but
did not demonstrate reductions in fever duration, ICU
admission, hearing loss, or any neurologic sequelae.
Data from adult patients with pneumococcal meningitis
are similarly sparse; however, a retrospective cohort
study in West Virginia (1978 1997) found that mortality
was increased among adults treated with the combina-
tion of vancomycin and cephalosporin (3 of 5) compared
with those treated with chloramphenicol (1 of 9) or
cephalosporin alone (0 of 9).19 Our study differs from
these previous studies in that we used multivariate anal-
ysis of patient-level data from a sizeable pediatric popu-
lation in which empiric vancomycin therapy is routine.
Thus, we believe that the present report represents the
most complete body of evidence to date concerning the
safety and efficacy of early empiric vancomycin therapy
in children with pneumococcal meningitis.
The mechanisms by which early vancomycin therapy
might increase the risk of hearing loss are uncertain, but
likely involve effects on the host inflammatory response.
Experimental data indicate that the combination of van-
comycin and ceftriaxone induces more rapid killing of
pneumococci than is achieved by either agent alone.2022
This rapid bacterial lysis may then result in increased
liberation of bacterial proinflammatory components (eg,
lipoteichoic acid), resulting in an enhanced host inflam-
matory response that putatively mediates neurologic in-
jury.23 Counterbalancing the potential risks related to
rapid bacterial lysis, however, is the increased risk of
neurologic sequelae associated with delayed (ie, 24
hours) CSF sterilization.12 Therefore, optimal therapy for
pneumococcal meningitis must achieve the dual goals of
sterilizing the CSF while minimizing inflammatory dam-
age to host tissues. The most commonly advocated strat-
egy for achieving these dual ends is the administration of
adjunctive corticosteroid therapy. Although this ap-
proach remains controversial, a growing body of evi-
dence suggests that dexamethasone, initiated concomi-
tantly with or before the first dose of parenteral
antibiotics, decreases rates of mortality in adults and of
neurologic sequelae (including hearing loss) in chil-
dren.2426 Another potentially attractive strategy for ster-
ilizing CSF while minimizing inflammation is to empir-
ically administer a nonbacteriolytic antibiotic, such as

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rifampin, in combination with ceftriaxone or cefo-
taxime. Currently, evidence favoring this strategy is pri-
marily experimental: mortality rates are lower in ri-
fampin-treated mice with pneumococcal meningitis
than in those treated with ceftriaxone,27 and compared
with those treated with ceftriaxone alone, animals who
receive rifampin plus ceftriaxone demonstrate reduc-
tions in CSF pneumolysin concentrations,28 CSF lipotei-
choic acid concentrations, and density of apoptotic neu-
rons in the hippocampal dentate gyrus.29 The inclusion
of nonbacteriolytic antibiotics in initial therapy for bac-
terial meningitis merits further evaluation in human
clinical trials.
Our results are subject to limitations inherent in ret-
rospective studies. First, because of our retrospective
study design, we could only analyze data that was avail-
able in medical and laboratory records. In particular,
audiometry test results were documented in only 64%
of surviving subjects. It is possible that subjects who
underwent audiometry differed systematically from
those who did not; however, the only observed differ-
ence between these groups was a higher rate of under-
lying conditions (which, in many cases, would have
obviated the attribution of hearing loss to the meningitis
episode in any event) in the latter. Second, because this
is a nonrandomized, observational study, our results
could be compromised by the effects of confounding
variables; therefore, we controlled for such confounders
using multiple logistic regression modeling. It is conceiv-
able, for example, that subjects with more severe disease
at the time of presentation might have an inherently
higher risk of hearing loss and might receive vancomy-
cin therapy sooner than those with less severe disease. In
our multivariate analysis, however, clinical measures of
disease severity (eg, ICU admission and respiratory fail-
ure) were not significantly associated with hearing loss,
and, importantly, their inclusion in models did not at-
tenuate the observed association between vancomycin
start time and hearing loss. Another limitation is that we
could not assess the effect, if any, of adjunctive cortico-
steroid therapy on outcomes, because corticosteroids are
infrequently prescribed for children with pneumococcal
meningitis at this center. Although corticosteroid ther-
apy was not significantly associated with any outcome
variable in our multivariate analyses, this lack of associ-
ation may result from insufficient power rather than
absence of efficacy.
Several lines of evidence support the validity of the
observed association between vancomycin start time and
hearing loss. First, the univariate strength of this associ-
ation is substantial. Second, a dose-response gradient is
apparent: the risk of hearing loss progressively increases
with decreasing vancomycin start time. Finally, the as-
sociation strength increases in multivariate analysis and
is independent of other variables, including those asso-
ciated with disease severity. It further merits mentioning
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that the magnitude of this association is clinically rele-
vant, as well as statistically significant: for every 2 pa-
tients who received vancomycin therapy 2 hours after
the first dose of cefotaxime or ceftriaxone, 1 suffered
otherwise unexpected hearing loss.
We recognize that only limited conclusions can be
drawn from a retrospective study and would welcome a
randomized, controlled trial to confirm the safety and
efficacy of early empiric vancomycin therapy in children
with pneumococcal meningitis. Until such a study is
performed, we propose that the approach to empiric
therapy of pneumococcal meningitis in children should
be reconsidered. For the present, empiric vancomycin
use remains justifiable because of the risks of delayed
CSF sterilization in cases of meningitis caused by anti-
microbial-resistant pneumococci, although the inci-
dence of such cases has been reduced in the United
States in the era of conjugate pneumococcal vaccina-
tion.30 Our results suggest that administration of vanco-
mycin 2 hours after the first dose of cefotaxime or
ceftriaxone confers no clinical benefit and, in fact, is
associated with a substantially increased risk of hearing
loss. Given these data, it may be prudent to consider
delaying the first dose of vancomycin therapy until 2
hours after the first dose of parenteral cephalosporin in
children beginning therapy for suspected or confirmed
pneumococcal meningitis. Further investigation is re-
quired to determine whether such a delay is beneficial or
harmful in children who receive early adjunctive corti-
costeroid therapy and to determine whether nonbacte-
riolytic antibiotics, such as rifampin, might prove to be
safer than vancomycin in this clinical scenario.
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 Early Vancomycin Therapy and Adverse Outcomes in Children With
Pneumococcal Meningitis
Steven C. Buckingham, Jonathan A. McCullers, Jorge Lujn-Zilbermann, Katherine
M. Knapp, Karen L. Orman and B. Keith English
Pediatrics 2006;117;1688
DOI: 10.1542/peds.2005-2282

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Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . Pediatrics is owned, published, and trademarked by the
American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois,
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 Early Vancomycin Therapy and Adverse Outcomes in Children With
Pneumococcal Meningitis
Steven C. Buckingham, Jonathan A. McCullers, Jorge Lujn-Zilbermann, Katherine
M. Knapp, Karen L. Orman and B. Keith English
Pediatrics 2006;117;1688
DOI: 10.1542/peds.2005-2282

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/117/5/1688

Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it
has been published continuously since . 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:
.

Downloaded from http://pediatrics.aappublications.org/ by guest on November 15, 2017