The Indian Journal of Pediatrics

https://doi.org/10.1007/s12098-020-03454-1

ORIGINAL ARTICLE

Seven versus Ten Days Antibiotics Course for Acute Pyogenic

Meningitis in Children: A Randomized Controlled Trial
N. D. Vaswani 1 & Nishu Gupta 1 & Ravi Yadav 1 & Anuradha Nadda 2

Received: 11 January 2020 / Accepted: 15 July 2020

# Dr. K C Chaudhuri Foundation 2020

Abstract
Objectives To compare the efficacy and safety of 7 d vs. 10 d empirical antibiotic therapy in cases of acute pyogenic meningitis in
children aged 3 mo to 14 y with rapid initial recovery.
Methods A total of 96 children aged 3 mo to 14 y with acute pyogenic meningitis were randomized to either 7 d or 10 d therapy
on Day 5 of the therapy, if they were in clinical remission and had improving cerebrospinal fluid (CSF) abnormalities. The
primary outcome was treatment failure in each group within 10 d of enrolment or relapse of meningitis defined as recurrence of
signs and symptoms of meningitis within 2 wk of discharge. Secondary outcome was the presence of sequelae in patient at 30 d
and 90 d follow-up post discharge.
Results Out of 111 screened children, 96 patients completed the trial, 48 in each group. There were 7 treatment failures and
relapses each in the group receiving 7 d antibiotics while 6 failures and relapses each were seen in 10 d antibiotics group. There
was no statistically significant difference in treatment failure in both the groups [2.1 (-0.12–0.16); p = 0.76]. No deaths or
significant adverse effects of the drugs occurred during this study. Four cases of nosocomial sepsis were reported with 2 cases
in each group. On subsequent 30 d and 90 d follow-up, no statistically significant difference was found between the two groups
regarding frequency of hearing impairment, frequency of hydrocephalus [-2.1 (-0.09–0.13); p = 0.65] and various neurological
sequelae [6.2 (−0.06–0.19); p > 0.05].
Conclusions Short course antibiotic therapy may be adequately effective for treatment of acute pyogenic meningitis beyond
neonatal age in children with initial rapid recovery.

Keywords Acute pyogenic meningitis . Short course antibiotic therapy . Treatment failure . Effectiveness . Safety

Introduction textbooks ABM should be treated with 10–14 d of antibiotics

Acute bacterial meningitis (ABM) has a sufficiently high inci-
dence in the pediatric population of developing countries. It can
lead to acute complications and is associated with considerable
risk of residual neuro-developmental sequelae by causing per-
manent damage. The exact incidence of ABM in India is not
known. In early childhood period, Streptococcus pneumoniae
followed by Neisseria meningitides and Hemophilus influenzae
b are the commonest causes [1]. According to standard
* Nishu Gupta
nishigupta.medico@gmail.com
1
Department of Pediatrics, PGIMS, Rohtak, Haryana, India
2 ideal antibiotic therapy duration with these newer regimens is
Department of Community Medicine, PGIMS, Rohtak, Haryana,
India
[1] but there are no conclusive guidelines for the duration of
treatment of ABM. However, a short antibiotic course, if equal-
ly effective, will be a more cost-effective option especially in
countries with limited resources.
Many studies have suggested that a shorter course of anti-
biotics may be as effective as the conventionally suggested
longer ones. This could be very beneficial for patients saving
them from unnecessary adverse effects of prolonged antibi-
otics regimens and also lessening the economic burden as well
as incidence of nosocomial sepsis and antibiotic resistance
[2–6]. However, most of this data is from developed countries
and experience with shorter duration of antibiotics course in
India is limited with last published research in this age group
being almost 15-y-old [3]. Many newer and more effective
antibiotic regimens have been introduced over time; however,
largely understudied till now. Results of researches carried out

in developed countries may not apply in entirety to the devel-
oping countries like India owing to different clinical scenarios
prevalent in the latter where physicians still prefer to give
antibiotics for longer duration due to potentially serious nature
of the disease as well as factors like delayed presentation and
malnutrition often complicating the disease course. Also, poor
supportive laboratory facilities often fail to document micro-
biological infections in a large number of the cases. Therefore,
this prospective study was undertaken with the aim to com-
pare the efficacy and safety of 7 d vs. 10 d empirical antibiotic
therapy with ceftriaxone and vancomycin in cases of acute
pyogenic meningitis in children aged 3 mo to 14 y.
Material and Methods
This randomized control trial was carried out in the
Department of Pediatrics of a tertiary care referral hospital in
North India. The study was initiated in March 2014 and con-
tinued till June 2015. An informed consent was taken from the
parents of enrolled children. Ethical clearence was sought
from the Institutional Review Board.
The inclusion criteria was, all children aged 3 mo to 14 y
admitted for fever with meningeal signs and CSF profile
depicting any of the following: CSF culture positive for any
bacteria; CSF gram stain positive with two of the following
three abnormalities: more than 100 white blood cells per ml
with more than 50% granulocytes and CSF glucose <40 mg/dl
(or < 50% of blood glucose) or proteins >40 mg/dl; CSF cul-
ture and gram stain both negative, but all the three abnormal-
ities: more than 100 white blood cells per ml with more than
50% granulocytes and CSF glucose <40 mg/dl (or < 50% of
blood glucose) and proteins >40 mg/dl; CSF leukocytes
>1000/ml with >75% polymorphonuclear cells.
The exclusion criteria was children with congenital anom-
alies, pre-existing neurosurgical conditions and neurological
disorders, severely malnourished children and children with
bleeding disorders, brain abscess, severe head injury, immu-
nodeficiency states, prior history of hypersensitivity to ceph-
alosporins/vancomycin, previous use of parenteral antibiotics
for more than 24 h and patients with recurrent meningitis, or
lack of clinical improvement or positive CSF gram stain or
culture on day 5 of treatment.
A treatment comprising of ceftriaxone (100 mg/kg/d in 2
divided doses administered every 12 h) and vancomycin
(60 mg/kg/d in 4 divided doses administered every 6 h) as
per the unit protocol based on recent guidelines on manage-
ment of acute bacterial meningitis was initiated in all the study
participants [7].
This was a prospective, open label, non-blinded compara-
tive randomized control trial. Detailed history of all the study
subjects was taken at the time of admission and a thorough
clinical examination was carried out. The blood samples were
Indian J Pediatr
taken for complete blood count, plasma glucose, serum elec-
trolytes, peripheral smear for malaria and blood culture.
Lumbar puncture was done and treatment was initiated.
Second lumbar puncture was done on day 5 after starting
treatment to look for improvement in CSF cytology, sugar
and protein levels. All the study participants, on day 5, were
randomized into two groups if they were in clinical remission
or analysis of CSF report indicated improvement of CSF ab-
normalities. Randomization was done using random alloca-
tion software in variable blocks of 2 or 4 by 1:1 ratio and
group allocation was placed in sealed opaque envelopes. An
independent observer did random allocation on day 5 of the
therapy. One group received ceftriaxone and vancomycin for
7 d while the other group received same antibiotics for 10 d.
Each patient received the course of antibiotics as per his/her
randomly allocated group during the hospital stay. At the end of
7 d treatment in group I and 10 d treatment in group II, children
were assessed based on clinical parameters like presence of fever,
meningeal signs, seizures and altered sensorium. Primary out-
come of the study was treatment failure rate, defined as lack of
clinical improvement indicated by the presence of anyone of the
following: fever along with meningeal signs, seizures and altered
sensorium at the end of the therapy or relapse of meningitis,
defined as the recurrence of signs and symptoms of meningitis
within 2 wk of discharge from hospital.
The treatment was discontinued for cured children but
those who were counted as treatment failure as per study
criteria were further treated as per unit protocol. The children
who recieved antibiotics for 7 d were kept in hospital for 3
additional days to monitor for any evidence of clinical wors-
ening. Further neuroimaging was planned for children who
were suspected to have developed complications like hydro-
cephalus, brain abscess, infarct etc. based on clinical findings.
All the cured children were discharged from the hospital on
day 10 and were asked to follow-up on day 7, 15, 30 and 90
after discharge.
On follow-up, all the children were evaluated for any signs
and symptoms of recurrence of meningitis. Those children who
were suspected of recurrence were advised admission for inves-
tigation and treatment as per the unit protocol. Full clinical ex-
amination, hearing and neurological assessment was done in
detail to look for any sequelae. Neurodevelopmental assessment
was done using Denver Development Screening Test (DDST).
Hearing assessment was done using Pure tone audiometry (PTA)
or Brain stem evoked responses (BERA), if required. Secondary
outcome was presence of sequelae in patient at 30 d and 90 d
follow-up post discharge.
A sample size calculation was done by using the formula
for equivalent randomized control trial having categorical out-
come [8]. Management with change of treatment schedule
was taken as outcome indictor; 0.15 difference was considered
as equivalence margin between group 1 and group 2 (0.19 for
group 1 and 0.04 for group 2) [6]. Assuming α of 0.05 and
Indian J Pediatr
power of the study 80%, final sample size came out to be 144;
72 in each group. The authors were able to screen a total of
111 consecutive children who fulfilled the eligibility criteria
during the study period (within timeline March 2014 through
June 2015). Due to constraint of time and resources, actual
sample size used in the study was 96, smaller than the calcu-
lated size The data was collected as per a predesigned
proforma. The data was analyzed using SPSS 20 (IBM corp.,
Armonk, NY, USA). For comparing the difference in out-
comes between the two groups, the Chi-square/ Fischer
Exact test was used for categorical variables, whereas the un-
paired student-t test/ non-parametric Wilcoxon Mann
Whitney test was used in case data did not follow a normal
distribution of baseline. At the end of the study, as all of the
subjects did not turnup for follow-up, the data was assessed by
intention to treat analysis. The level of significance was taken
as p < 0.05.
Results
Out of 111 children screened, a total of 96 patients success-
fully completed the trial, 48 in each group (Fig. 1). Both the
groups were comparable in baseline characteristics like
Fig. 1 Trial profile. LAMA Left Enrollment
against medical advise
Allocated to 7 d antibiotic group (n= 52)
♦ Completed 7 d antibiotic therapy (n=48)
♦ Did not complete 7 d antibiotic course (n=4;
3 LAMA, 1 diagnosis changed)
Lost to follow-up (n=3; patients did not turn up
for follow-up at day 90)
Analysed (n= 45)
♦ Excluded from analysis (n=3; Long term
sequelae could not be analysed)
weight, gender, age, nutritional status, frequency of various
signs and symptoms and CSF parameters. All the patients had
fever (n = 96, 100%) at initial presentation. Altered sensorium
was the most common (69.79%) presentation other than the
fever, while 36 (37.5%) patients presented with seizures
(Table 1).
Over 50% of the patients had received antibiotics prior to
admission in the hospital, though majority of them had taken
oral antibiotics. None of the cases had positive blood culture
or CSF culture. CSF profile of both the groups is as shown in
Table 2. Majority of the patients had evidence of CSF
pleocytosis with neutrophilic predominance along with elevat-
ed proteins and reduced sugars in CSF, suggestive of pyogen-
ic meningitis. Gram staining of CSF on day 1 showed gram
positive cocci in 7 patients of group I and 9 patients of group II
(Table 2).
There were 7 treatment failures (14.58%) in group who
received 7 d antibiotics (group I) while 6 failures (12.5%)
were seen in group receiving 10 d antibiotics (group II).
After discharge, 13 children had recurrence of signs and
symptoms within 14 d and these cases were classified as re-
lapse. The difference in failure rates in both the groups was not
statistically significant. No deaths or significant adverse ef-
fects of the drugs were reported during the study period.
Assessed for eligibility (n=111)
Excluded (n=7)
♦ Diagnosis changed (n=3)
♦ Declined to participate (n=1)
♦ LAMA (n=3)
Randomized (n= 104)
Allocation
Allocated to 10 d antibiotic group (n=52)
♦ Completed 10 d antibiotic therapy (n=48)
♦ Did not receive 10 d antibiotic course (n=4; 2
LAMA, 2 diagnosis changed)
Follow-Up
Lost to follow-up (n=2; patients did not turn up
for follow-up at day 90)
Analysis
Analysed (n=46)
♦ Excluded from analysis (n=2; Long term
sequelae could not be analysed)
 Indian J Pediatr

Table 1 Baseline profile in both

the groups Characteristics Group 1 Group 2
(n = 48) (n = 48)

Age in months (Mean ± S.D.) 56.06 ± 53.024 62.33 ± 56.755

Sex; n (%)
Male 35 (72.9) 33 (68.8)
Female 13 (27.1) 15 (31.2)
Age group; n (%)
< 12 mo 12 (25.0) 14 (29.2)
1–5 y 18 (37.5) 15 (31.2)
>5y 18 (37.5) 19 (39.6)
Clinical Features at presentation
Fever; n (%) 48 (100) 48 (100)
Meningeal signs; n (%) 48 (100) 48 (100)
Altered sensorium; n (%) 31 (64.6) 36 (75)
Seizures; n (%) 19 (39.6) 17 (35.4)
Headache; n (%) 29 (60.41) 31 (64.58)
Irritability; n (%) 33 (68.75) 29 (60.4)
Duration (days) of illness before admission; (Mean ± S.D.) 4.7 ± 3.2 (3–10) 5.2 ± 3.6 (4–10)
Antibiotics used prior to admission; n (%) 28 (58.3) 31 (64.5)
History of prior hospitalization; n (%) 4 (8.3) 3 (6.2)
Drowsiness; n (%) 25 (52) 23 (47.9)
Vomiting; n (%) 19 (40.6) 22 (45.83)
Poor feeding; n (%) 29 (60.4) 28 (58.33)
Weight for age Z score; (Median, IQR) 0.48 (-1.8_1.67) 0.56 (-1.34_1.28)
Height for age Z score; (Median, IQR) 0.06 (-0.32–0.84) -0.22 (0.74–0.82)
Temperature at admission (°C); (Mean ± S.D.) 39.4 ± 1.0 39.2 ± 1
Systolic blood pressure (mm Hg), mean (SD) 96.3 (15.3) 97.6 (14.2)
Glasgow coma score < 8; n (%) 11 (22.9) 12 (28.5)
Shock; n (%) 4 (8.3) 6 (12.5)
Respiratory distress; n (%) 7 (14.5) 5 (10.4)
Total leucocyte count/mm3; n (%)
< 5000 11 (22.9) 11 (22.9)
5000–12,000 20 (41.7) 22 (45.8)
> 12,000 17 (35.4) 15 (31.3)

Four cases of nosocomial sepsis were reported in the study
with 2 cases in each group (Table 3). On follow-up, eleven
patients in group I survived with significant sequelae includ-
ing hearing deficits, neurological deficits and hydrocephalus,
whereas 9 patients of the group II who received treatment for
10 d survived with sequelae. However, no significant differ-
ence was found between two groups with regard to treatment
failure, relapse of meningitis, nosocomial sepsis and all these
sequelae (Tables 3 and 4).
Discussion
In this prospective study, authors found no statistically signif-
icant differences regarding treatment success, adverse events,
hospital acquired infections, neurological sequelae and hear-
ing deficit in patients treated with short-course antibiotic reg-
imen compared to the group receiving long-course antibiotic
regimens (Tables 3 and 4). The results of this study are com-
parable with those of previous studies [2–6, 9]. Molyneux
et al. in a multi country trial concluded that in children with
ABM above 3 mo of the age, if there are signs of clinical
improvement, ceftriaxone treatment can be stopped on day 5
of therapy [2].
Singhi et al. also did not find any difference in treatment
failure rate between two groups treated with 7 d ceftriaxone
therapy and 10 d therapy, and also concluded that there is
lesser incidence of hospital acquired infections as there is early
hospital discharge in 7 d group [3]. Similar results were seen
in a randomized trial conducted by Roine et al. [4]. Duration
Indian J Pediatr

Table 2 CSF profile for both the groups at Day 1 & Day 5 of hospital Though total duration of hospitalisation, in present study
admission
was defined by protocol but the results suggested that with the
CSF Parameters Group I (n = 48) Group II (n = 48) shorter course of therapy, hospital stay can be reduced by 2 d.
Hearing deficit is one the important complication of ABM
CSF glucose (Median, IQR) and its incidence varies from 5% to 36% in these patients
Day 1 28 (15–49) 19 (10–50) [11–15]. Both groups had similar incidence of hearing deficit
Day 5 59 (45–74) 56 (49–78) during study period and at follow-up visit. The authors have
CSF protein (Median, IQR) suggested that by the day 5 of clinical therapy, cochlear dam-
Day 1 204 (99–304) 236 (84–360) age had already occurred most probably due to direct inflam-
Day 5 78 (38–126) 72 (42–142) mation of the auditory nerve early in the course of disease and
CSF leucocytes/mm3 (Median, IQR) there is no more role left for the antibiotics by this time.
Day 1 643 (106–1130) 566 (108–1260) However, group I had a greater number of patients with neu-
Day 5 86 (112–206) 75 (108–210) rological sequelae than group II in present study, although the
Gram stain positive, n (%) difference was not statistically significant. This can be attrib-
Day 1 7 (14.6) 9 (18.8) uted to the fact that inflammatory and ischemic neural damage
Day 5 0 (0.0) 0 (0.0) resulting in death or long-term sequelae peaks before or in the
early stages of antibiotic treatment [16]. Thus it can safely be
assumed that early diagnosis and prompt use of antibiotics are
probably more important in reducing the mortality and mor-
bidity than an extended antibiotic treatment regimen.
of fever, clinical signs or serum C-reactive protein concentra- Though attributable to the practical constraints, present
tion were similar between the two groups; treated with 4 d and study was limited by a small sample size and being single
7 d of ceftriaxone in this comparative study. On follow-up centric. The findings of this study support the need for further
visit, it was observed that the 4 d group had fewer sequelae multicentric research on shortened antibiotic therapy for bac-
than the 7 d group (0% vs. 5% neurologic sequelae, p = 0.39 terial meningitis in appropriately selected pediatric patients.
and 3% vs. 9% hearing loss, p = 0.49, respectively), these As the study did not include patients with severe disease,
results being in line with present study findings. results should be applied with caution in patients with increased
Similar results were found in two prospective randomized risk characteristics. No mortality was observed during the study
trials conducted by Martin et al. and Kavaliotis et al. in period in either group; this can be explained by the fact that
Switzerland and Greece respectively [5, 6]. These studies found patients with specific risk factors were excluded from the study.
out that 4, 6 and 7 d treatment was adequate for Neisseria Duration of therapy for individual pathogens of bacterial menin-
meningitidis, Hemophilus influenzae and Streptococcus gitis could not be assessed separately due to the lack of docu-
pneumoniae, respectively. A meta-analysis done by mentation of specific bacterial etiology as analysis of CSF from
Karageorgopoulos et al. also did not find any difference (intra- patients already receiving antibiotics tend to be negative on gram
venous ceftriaxone) regarding: clinical success of therapy (95% stain and culture. PCR and triple antigen testing of CSF were not
CI 0.29 to 1.27); hearing deficit (95% CI 0.28 to 1.23); total available at authors’ centre and majority of the patients being
adverse events (95% CI 0.57 to 2.91); or secondary nosocomial poor, could not afford it from outside. Despite negative cultures,
infections (95% CI 0.05 to 3.71), between shorter course (4–7 d) presumptive diagnosis of pyogenic meningitis can, however, be
and longer course (7–14 d) of antibiotics treatment. Shorter made based on evidence of CSF pleocytosis with neutrophilic
course treatment helped in reducing the total duration of hospital predominance, elevated proteins and reduced sugars. The study
stay (95% CI -3.85 to −0.50) [10]. did not take into account effects of adjunctive therapy such as

Table 3 Primary short term outcome (within Day 14 of hospitalisation) of the patients in two groups

Outcome variable Group I (n = 48) Group II (n = 48) Total (n = 96) Risk difference (%; 95% CI) χ2 and p value

Therapy successfully completed 48 (100%) 48 (100%) 96 (100%) 0

Treatment failure 7 (14.58%) 6 (12.5%) 13 (13.5%) 2.1 (−0.12–0.16) χ2 = 0.089, 0.76
Adverse events related to drugs 0 0 0 0
Death 0 0 0 0
Nosocomial sepsis 2 (4.16%) 2 (4.16%) 4 (4.2%) 0 (−0.09–0.11) χ2 = 0.260, 0.60
Relapse of meningitis 7 (14.58%) 6 (12.5%) 13 (13.5%) 2.1 (−0.12–0.16) χ2 = 0.089, 0.76
 Indian J Pediatr

Table 4 Secondary long term outcomes of the two groups at 1 mo and 3 mo post discharge

Outcome variable Group I (n = 48) Group II (n = 48) Total (n = 96) Risk difference (%; 95% CI) χ2 and p value

Hearing loss 3 (6.3%) 3 (6.3%) 6 (6.3%) 0

Neurological sequelae 6 (12.5%) 3 (6.25%) 9 (9.3%) 6.2 (-0.06–0.19) χ2 = 1.103, 0.29
(motor deficit, nerve palsies)
Recurrent afebrile seizures 3 (6.3%) 2 (4.1%) 5 (5.2%) 6.2 (-0.09–0.13) χ2 = 0.211, 0.65
Hydrocephalus 2 (4.16%) 3 (6.25%) 5 (5.2%) -2.1 (-0.09–0.13) χ2 = 0.211, 0.65

dexamethasone. Despite all these limitations, study successfully
shows that shorter antibiotic treatment is as effective as the longer
one in children with uncomplicated pyogenic meningitis.
Conclusions
Results of the study imply that short term antibiotic course in
acute pyogenic meningitis could be very beneficial for pedi-
atric patients in developing countries. However, the findings
of this study are limited only to patients presenting with un-
complicated disease and in whom the clinical condition as
well as CSF parameters showed rapid improvement by day
5 of the treatment. Nevertheless, on the basis of the findings
from the index study and by cumulative data from the previ-
ous similar studies, short term antibiotic course was found to
be comparable to the long term antibiotic course in children
with uncomplicated pyogenic meningitis.
Authors’ Contributions NDV: Conceived the study; NG, RY: Collected
the data and reviewed the literature; NG and AN: Statistical analysis,
interpretation and drafting of the manuscript. The final version was ap-
proved by all the authors. NDV will act as guarantor for this paper.
Compliance with Ethical Standards
Conflict of Interest None.
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