Journal of Tropical Pediatrics Advance Access published February 13, 2015

Journal of Tropical Pediatrics, 2015, 0, 1–7

doi: 10.1093/tropej/fmv002
Original Paper

Evaluation of duration of antibiotic therapy in

neonatal bacterial meningitis: a randomized

Downloaded from http://tropej.oxfordjournals.org/ at University of California, San Francisco on February 20, 2015
controlled trial
by N. B. Mathur,1 Prarthana Kharod1, and Surinder Kumar2
1
Department of Neonatology, Maulana Azad Medical College, New Delhi, India
2
Department of Microbiology, Maulana Azad Medical College, New Delhi, India
Correspondence: N. B. Mathur, Department of Neonatology, Maulana Azad Medical College, New Delhi. Tel: þ919968604308.
E-mail <drnbmathur@ gmail.com>

SU M MAR Y
Objectives: To compare the effect of 10 days versus 14 days of antibiotic therapy in neonatal
meningitis on treatment failure rate.
Methods: The study was a randomized controlled trial conducted at a referral neonatal unit. The
participants were 70 neonates with meningitis randomized to receive 10 days (study group) or 14
days (control group) of antibiotics. The primary outcome measure studied was treatment failure in
each group within 28 days of enrolment.
Results: None of the neonates among either of the groups had occurrence of meningitis during
follow-up. Occurrence of sepsis was observed after discharge in three neonates in the control group
and none in the study group. Brainstem-evoked response audiometry was abnormal in one neonate
in the study group. Adverse effects of drugs and neurological deficits were not observed in the study
population.
Conclusions: Short course of antibiotic therapy (10 days) is effective, with potential benefits of
shorter hospital stay.

K E Y W O R D S : duration of antibiotics, effectiveness, meningitis, treatment failure.

INTRODUCTION exposure to antibiotics tends to increase probability

Neonatal meningitis causes significant mortality and
neurological sequelae in developing countries [1–5].
To the best of our knowledge, there is no study eval-
uating the duration of antibiotic treatment in neo-
natal meningitis [6–8]. Shorter course of antibiotic
therapy can potentially decrease the duration of
hospitalization, number of adverse events and health-
care costs and could conserve the limited resources
available in low-income countries [9]. Prolonged
of emergence of resistant strains of bacteria. The
problem of antibiotic resistance has spread all around
the world and it is affecting the developing nations
much harder than developed countries. Excessive
over-utilization of antibiotics in hospitalized patients
is one of the major risk factors for development
of antibiotic resistance [10]. Although dexa-
methasone-treated neonates have been shown to
have significantly lower mortality and normalization

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V

 1
2  Evaluation of duration of antibiotic therapy in neonatal bacterial meningitis
of cerebrospinal fluid (CSF) by day 7, shorter dur-
ation of antibiotic therapy has not been evaluated in
neonates with meningitis administered dexametha-
sone [5]. The objective of the present study was to
compare the effect of a 10-day course (study group)
with a 14-day course (control group) of antibiotic
treatment in neonatal meningitis on treatment failure
rate (recurrence of serious bacterial infection within
28 days of enrolment).
MATERIALS AND METHODS
This pilot randomized controlled trial was conducted
in the referral neonatal unit of a teaching government
hospital providing tertiary care to outborn neonates
delivered in community hospitals or at home. Eligible
neonates consecutively admitted with meningitis dur-
ing the period from May 2012 through January 2013
were enrolled. Neonates with major congenital mal-
formations were excluded. A sample size of 70 neo-
nates with meningitis was calculated based on the
number of neonates admitted to the referral neonatal
unit with meningitis in the previous year. The diagno-
sis of neonatal meningitis was made on the basis of
presence of >32 cells/mm3 in the CSF examination
[11, 12] in a sick neonate along with any of the fol-
lowing: abnormal total leukocyte count defined as
less than 5,000 or more than 20,000/mm3, raised im-
mature/total neutrophil count ratio (>0.2), elevated
micro-erythrocyte sedimentation rate and raised
C-reactive protein. CSF examination was done at ad-
mission (baseline) for cells, protein, sugar, Gram
stain, culture and sensitivity. Blood culture was per-
formed under aseptic conditions by collecting 1 ml of
venous blood in a bottle containing tryptic soy broth.
The sensitivity of the organisms to the commonly
used antibiotics was tested. Cranial ultrasonography
was done by day 7 of antibiotic therapy. All cases of
neonatal meningitis who by day 7 of antibiotic treat-
ment had clinical remission, normal CSF and no evi-
dence of infection on cranial ultrasonography were
enrolled in the study (on day 7 of antibiotic therapy).
The randomization sequence was generated using
random allocation software in variable blocks of 2 or
4 and concealed by placing the group allocation
in sealed opaque envelopes. The study was not
blinded. However, the persons who examined
CSF and performed cranial ultrasonography and
brainstem-evoked response audiometry (BERA) were
blinded. Informed consent was taken from the par-
ents in a written format. All eligible neonates were
randomized to receive a total of 10 days (study
group) or 14 days (control group) of antibiotic treat-
ment. Rest of the treatment was similar in both the
groups. All neonates in both the groups received
dexamethasone in the dose of 0.15 mg/kg intraven-
ously every 6 h for 48 h as per unit protocol [5].
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Temperature, respiratory rate, heart rate, blood pres-
sure, capillary filling time, peripheral pulses, mental
status, urine output, oxygen saturation and blood gas
analysis were recorded in all cases. Neonates in the
study group were admitted at least for 14 days (4
days after cessation of antibiotics) for close observa-
tion. The patients were followed up daily for 1 week
and then weekly till day 28 of enrolment (i.e. day 35
of starting antibiotics). Danger signs (poor feeding,
lethargy, cough, chest retractions, diarrhea, seizures
and abdominal distension) were explained at the
time of discharge with the advice to report immedi-
ately in case of any symptoms. Outcome parameters
studied were treatment failure in each group within
28 days of enrolment (defined as clinical sepsis along
with abnormal CSF picture), adverse effects of drugs,
neurological deficit and sensorineural hearing loss by
BERA. BERA was performed using click stimuli de-
livering monophasic square pulses of 100 ms duration
at the rate of 10 Hz through headphones.
Contralateral ear was masked with continuous white
noise. It was done after 3–4 weeks of discharge and
repeated further after 4 weeks if initial study showed
abnormality. The study was approved by the institu-
tional ethical committee.
Statistical analysis was done using the software
version SPSS 16. The continuous variables were
tested by using Student t-test and categorical vari-
ables by Pearson chi-square test. For variables with
non-Gaussian distribution, Mann–Whitney test was
applied. Wilcoxon signed-rank test was used to com-
pare pre- and post-intervention variables within the
same group. Probability of less than 5% (p < 0.05)
was considered significant.
RESULTS
A flowchart of participants in the study is presented
in Fig. 1. A total of 130 neonates were admitted with
 Evaluation of duration of antibiotic therapy in neonatal bacterial meningitis
Assessed for eligibility (n=130)
Randomized (n=70)
Allocated to intervention (Study group, n=35)
Received Allocated intervention (n=35)
Lost to follow up (n=0)
Discontinued intervention (n=0)
Analysed till day 28 after enrolment
(n=35)
Occurrence of sepsis during follow up: 0
Death during follow up: 1
FIG. 1. Flow of study.
neonatal meningitis during the study period. Out of
these, 60 did not meet inclusion criteria (Fig. 1,
Table 1). Both the groups were comparable with ref-
erence to age, weight, gestational age, gender, onset
of sepsis and neurological signs and physiological in-
stability at admission (Table 2). CSF parameters
were comparable in both the groups at admission
and on day 7 of antibiotic therapy (Table 3). Blood
culture was positive at admission in 11 of 70 patients
(six in the study group and five in the control
group). Most common isolate was Klebsiella, present
 3
DID NOT MEET INCLUSION CRITERIA
(by day 7 of antibiotic therapy) (n= 60)
Refused to participate: 0
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Allocated to intervention (Controls, n=35)
Received Allocated intervention (n=35)
Lost to follow up (n=0)
Discontinued intervention (n=0)
Analysed till day 28 after enrolment
(n=35)
Occurrence of sepsis during follow up: 3
Death during follow up: 2
in three patients in the study group and one patient
in the control group. The antibiotic sensitivity of
Klebsiella isolates was 66% to ceftriaxone, 75% to
amikacin and 50% to meropenam. Positive blood/
CSF culture was observed in six cases in the
study group and seven cases in the control group
(Table 4). None of the neonates in both groups had
occurrence of meningitis during follow-up. In
the control group, three neonates had occurrence of
sepsis during follow-up (on days 18, 21 and 23),
whereas none of the neonates in the study group had
4  Evaluation of duration of antibiotic therapy in neonatal bacterial meningitis

the same (p ¼ 0.24). The three patients with occur-
rence of sepsis were hospitalized, treated for sepsis
and discharged. Their blood cultures were sterile and
CSF examination was normal. BERA was abnormal
in one neonate in the study group. However, this
neonate had associated perinatal asphyxia, a known
cause of abnormal BERA. One neonate expired dur-
ing follow-up in the study group (on day 27), as
compared with two in the control group (on days 20
and 24; p ¼ 1.00) (Table 5). None of them could
reach the hospital before death. On follow-up,
mothers were questioned to ascertain the cause of
death (verbal autopsy). The neonate who belonged
to the study group had history of lethargy and chok-
ing attack. Both the neonates in the control group
had history of decreased activity and poor oral intake
before expiry. The probable cause of death appeared

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to be sepsis in all. Adverse effects of antibiotics and
Table 1. Cases of neonatal meningitis not meet- dexamethasone and neurological deficits were not
ing inclusion criteria (by day 7 of antibiotic observed till day 28 after enrollment in any neonate
therapy) in the study and control groups.
Cause of ineligibility Number (n ¼ 60)

Not remitted clinically: DISCUSSION

Progression of SIRS
Persistence of poor feeding
Persistently lethargic
Abnormal cranial ultrasonography
Persistence of CSF abnormality
Persistently positive blood culture
Expired before day 7
Left against medical advice
28 According to the National Neonatal Perinatal
7 Database, septicemia/meningitis has been the com-
3 monest cause (38%) of death among the extramural
4 neonates in India [13]. Physiological instability at ad-
2 mission is high in extramural neonates in developing
2 countries, as they destabilize during transportation,
10 resulting in higher fatality [14]. In the present study,
4 mortality in post-discharge follow-up was found to
be 2.9% in the study group and 5.7% in the

Table 2. Baseline characteristics of patients of study population

Variable Study group Control group p value

Age at admission (h) Mean (SD) 274.46 (196.4) 328 (211.4) 0.29
Weight (g) Mean (SD) 2108 (529.1) 2087.7 (771.5) 0.9
Gestational age (Mean (SD) 37.37 (2.0) 36.4 (3.1) 0.45
Male gender n (%) 25 (71.4) 25 (71.4) 1
Delivery conducted by doctor 24 (68.6) 23 (65.7) 0.9
Small for gestational age n (%) 17 (48.6) 17 (48.6) 1
Early onset 72 h of age n (%) 4 (11.4) 4 (11.4) 1
Duration (h) of symptoms Mean (SD) 46.94 (32.64) 50.74 (40.01) 0.87
Hypothermia 21 27
Mild 6 (17.1) 8 (22.9) 0.55
Moderate 13 (37.1) 17 (48.6) 0.33
Severe 2 (5.7) 2 (5.7) 1.00
Hypoxia 6 (17.1) 7 (20.0) 0.76
Shock 2 (5.7) 3 (8.6) 1.00
Hypoglycemia 1 (2.9) 2 (5.7) 1.00
Small pupil 2 (5.7) 2 (5.7) 0.90
Dilated pupil 2 (5.7) 3 (7.1)
Acute renal failure 16 (45.7) 16 (45.7) 1.00
 Evaluation of duration of antibiotic therapy in neonatal bacterial meningitis  5

Table 3. Comparison of CSF parameters in study population

Variable mean (SD) Study group Control group p value

Cells
At admission 114 (80) 134 (140) 0.15
Day 7 1 (4) 1 (6) 0.96
Proteins mg/dl
At admission 194.66 (50.4) 184.17 (48.5) 0.16
Day 7 130.83 (40.5) 140.64 (31.5) 0.28

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Sugar mg/dl
At admission 49.37 (34.4) 52.26 (42.2) 0.94
Day 7 53.97 (14.370) 59.24 (17.7) 0.33
Positive blood culture N (%) 6 (17.1) 5 (14.3) 0.35
Positive CSF culture 0 2 (5.7)
Negative blood and CSF cultures 29 (82.9) 28 (80.0)

Table 4. Organisms isolated in blood/CSF cultures in study population

Organism isolated Study group (n ¼ 35) Control group (n ¼ 35) p value

Klebsiella 3 (8.6) 1 (2.9) 0.54

E. coli 1 (2.9) 1 (2.9)
Staphylococcus aureus 1 (2.9) 0
Coagulase-negative Staphylococcus 1 (2.9) 1 (2.9)
Nontyphoidal Salmonella 0 1 (2.9)
Pseudomonas 0 1 (2.9)
Acinetobacter 0 2 (5.8)

Table 5. Adverse outcomes in the study population

Outcome (follow-up till day 35) Study group n (%) Control group n (%) p value

Occurrence of sepsis 0 3 (8.6) 0.24

Death 1 (2.9) 2 (5.7) 1.00
Abnormal BERA 1 (2.9) 0 1.00
Total 2 (5.7) 5 (14.3) 0.43

control group. Adverse outcome (abnormal BERA,
occurrence of sepsis after discharge and death) was
higher in the control group (14.3%) as compared
with the study group (5.7%). The study revealed
that 10 days of antibiotics in neonatal meningitis was
as effective as 14 days of therapy and associated with
lower mortality and adverse outcome. The duration
of treatment in neonatal bacterial meningitis is based
on clinical condition of the patient as well as
bacteriological response to therapy. Bacteriological
response to therapy is monitored by sampling of
CSF every 2–3 days in the first week after initiation
of therapy [15]. However, the issue of the appropri-
ate duration of antibiotic treatment had not been
subjected to adequate and conclusive research.
Scientific studies are available for effectiveness of
short duration of antibiotic therapy in childhood
(post-neonatal) meningitis [8, 16–21] and neonatal
6  Evaluation of duration of antibiotic therapy in neonatal bacterial meningitis
sepsis [22–24]. However, absence of studies to
evaluate the duration of antibiotic therapy for neo-
natal bacterial meningitis is highlighted in literature
[6–8]. To the best of our knowledge, present study
is the first randomized controlled trial on duration of
antibiotic therapy in neonatal meningitis. The dur-
ation of treatment of childhood bacterial infection in
general, and of meningitis specifically, has not been
based on solid evidence [3, 25]. Early diagnosis and
prompt use of antibiotics are probably more import-
ant in reducing the mortality and morbidity than an
extended antibiotic treatment regimen [20]. A large
number of septic neonates have pleocytosis in CSF,
often with negative blood and CSF cultures. All of
them end up receiving long course of antibiotics for
lack of guidelines. The duration of treatment in neo-
natal bacterial meningitis is based on the clinical con-
dition of the patient, CSF findings as well as on the
bacteriological response to therapy [26]. We did not
include neonates who had not remitted by day 7
with reference to clinical condition, CSF findings or
cranial ultrasonography because of perceived risk. A
total of 60 neonates (46.2%) did not meet inclusion
criteria but were followed up. Major causes of ineligi-
bility were need for change of antibiotics within 7
days (28 babies), absence of clinical remission by
day 7 of antibiotic therapy (10 babies), leaving
against medical advice within 7 days of antibiotic
therapy (4 babies) and death within 7 days of antibi-
otic therapy (10 babies). If 14 babies in the last two
categories are excluded, 61% of all neonates with
meningitis (46 out of 116) would be eligible for the
potential benefits of short duration of antibiotics.
Shorter course of antibiotic therapy can potentially
decrease the duration of hospitalization, number of
adverse events and healthcare costs and could con-
serve the limited resources available in low-income
countries [9]. Prolonged exposure to antibiotics
tends to increase probability of emergence of resist-
ant strains of bacteria. The problem of antibiotic re-
sistance has spread all around the world and it is
affecting poor and developing nations much harder
than developed countries. Excessive over-utilization
of antibiotics in hospitalized patients is one of
the major risk factors for development of antibiotic
resistance [10]. This could be a probable factor
explaining higher rates of recurrence of sepsis and
mortality in the control group. Larger studies are
required to address this issue. On post hoc analysis,
to detect an 11.4% reduction in occurrence of sep-
sis/ meningitis/death, a sample size of 93 cases in
each group (1:1 ratio) would have a significance level
of 95% and power of 80%.
Anti-inflammatory therapy in bacterial meningitis
has been shown to decrease meningeal inflammation,
blood–brain barrier permeability, intracranial hyper-
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tension, brain edema, tissue damage, long-term
neurological sequelae and mortality rates associated
with this disease [8]. There is a strong support ex-
pressed for the use of adjunctive dexamethasone,
preferably before initiation of antibiotic therapy
[23]. In a randomized controlled trial on dexametha-
sone in neonatal meningitis in our unit [5], mortality
was found to be 12.5% in the dexamethasone
group and 40% in the control group (p ¼ 0.005).
The absolute risk difference was 27.5% (95%
CI ¼ 9.1–45.8%). There was a significant reduction
in cells (62.5 vs. 100 per mm3) and proteins (162 vs.
217.5 mg/dl) after 24 h of treatment in the dexa-
methasone group. IL-1b was significantly reduced
after 24 h in dexamethasone group (290 vs. 665 pg/
ml). TNF-a was significantly lower (157.5 vs.
427.5 pg/ml) and sugar significantly higher (50 vs.
38 mg/dl) in the dexamethasone group after 24 h.
Significant benefit was noted with dexamethasone
therapy in the progression of systemic inflammatory
response syndrome (SIRS). Normalization of CSF
by day 7 was significantly more (p ¼ 0.01) in dexa-
methasone group as compared with the control
group [5]. Yu et al. [27] in a study on purulent men-
ingitis in neonatal period, observed very high mortal-
ity (75%) in the control group as compared with the
steroid group (41%). Present study suggests that
dexamethasone administration may have a role in
reducing the duration of antibiotic therapy. Being a
pilot study, the limitation of our study is small sam-
ple size in a single center. For the purpose of the
study (success of antibiotic therapy in eradicating
infection), a follow-up of 28 days was considered suf-
ficient. However, a longer follow-up is desirable.
CONCLUSION
In conclusion, shorter duration of antibiotic therapy
in neonatal meningitis is associated with lesser
 Evaluation of duration of antibiotic therapy in neonatal bacterial meningitis
adverse events (abnormal BERA and recurrence of
infection). The potential benefits include shorter
duration of hospitalization, lesser exposure to antibi-
otics and reduction in healthcare costs. Further mul-
ticenter trials may be done to validate the results.
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