Antibiotic Prophylaxis For Preventing Meningitis in Patients With Basilar Skull Fractures (Review)

Antibiotic prophylaxis for preventing meningitis in patients
with basilar skull fractures (Review)
Ratilal BO, Costa J, Sampaio C, Pappamikail L
This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2011, Issue 8
http://www.thecochranelibrary.com
Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures (Review)
Copyright © 2011 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Analysis 1.1. Comparison 1 Frequency of meningitis, Outcome 1 Frequency of meningitis by subgroup. . . . . . 23
Analysis 1.2. Comparison 1 Frequency of meningitis, Outcome 2 Frequency of meningitis. . . . . . . . . . 24
Analysis 2.1. Comparison 2 All-cause mortality, Outcome 1 All-cause mortality. . . . . . . . . . . . . . 25
Analysis 3.1. Comparison 3 Meningitis-related mortality, Outcome 1 Meningitis-related mortality. . . . . . . 26
Analysis 4.1. Comparison 4 Need for surgical correction in patients with CSF leakage, Outcome 1 Need for surgical
correction in patients with CSF leakage. . . . . . . . . . . . . . . . . . . . . . . . . . 26
Analysis 5.1. Comparison 5 Non-CNS infection, Outcome 1 Non-CNS infection. . . . . . . . . . . . . 27
APPENDICES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures (Review) i
[Intervention Review]
Antibiotic prophylaxis for preventing meningitis in patients

with basilar skull fractures
Bernardo O Ratilal1 , João Costa2 , Cristina Sampaio2 , Lia Pappamikail1

1 Department of Neurosurgery, Hospital de São José, Lisboa, Portugal. 2 Laboratório de Farmacologia Clínica e Terapêutica, Faculdade
de Medicina de Lisboa, Lisboa, Portugal
Contact address: Bernardo O Ratilal, Department of Neurosurgery, Hospital de São José, Rua José António Serrano, Lisboa, 1150-
199, Portugal. bratilal@yahoo.com.
Editorial group: Cochrane Acute Respiratory Infections Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 8, 2011.
Review content assessed as up-to-date: 16 February 2011.
Citation: Ratilal BO, Costa J, Sampaio C, Pappamikail L. Antibiotic prophylaxis for preventing meningitis in patients with basilar skull
fractures. Cochrane Database of Systematic Reviews 2011, Issue 8. Art. No.: CD004884. DOI: 10.1002/14651858.CD004884.pub3.
ABSTRACT
Background
Basilar skull fractures (BSF) predispose patients to meningitis because of the possible direct contact of bacteria in the paranasal sinuses,
nasopharynx or middle ear with the central nervous system (CNS). Cerebrospinal fluid (CSF) leakage has been associated with a greater
risk of contracting meningitis. Antibiotics are often given prophylactically, although their role in preventing bacterial meningitis is not
established.
Objectives
To evaluate the effectiveness of prophylactic antibiotics for preventing meningitis in patients with BSF.
Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 1), which contains
the Cochrane Acute Respiratory Infections (ARI) Group’s Specialised Register, MEDLINE (1966 to February 2011), EMBASE (1974
to February 2011) and LILACS (1982 to February 2011). We also performed an electronic search of meeting proceedings from the
American Association of Neurological Surgeons (1997 to September 2005) and handsearched the abstracts of meeting proceedings of
the European Association of Neurosurgical Societies (1995, 1999 and 2003).
Selection criteria
Randomised controlled trials (RCTs) comparing any antibiotic versus placebo or no intervention. We also identified non-RCTs to
perform a separate meta-analysis to compare results.
Data collection and analysis
At least two authors independently appraised trial quality and extracted data for each trial.
Main results
We identified five RCTs and 17 non-RCTs comparing different types of antibiotic prophylaxis with placebo or no intervention in
patients with BSF. Most trials presented insufficient methodological detail. All studies included meningitis in their primary outcome.
Overall, we evaluated 208 participants from the five RCTs that were considered suitable for inclusion in the meta-analysis. There were
Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures (Review) 1
no significant differences between antibiotic prophylaxis groups and control groups in terms of reduction of the frequency of meningitis,
all-cause mortality, meningitis-related mortality, and need for surgical correction in patients with CSF leakage. There were no reported
adverse effects of antibiotic administration, although one of the five RCTs reported an induced change in the posterior nasopharyngeal
flora towards potentially more pathogenic organisms resistant to the antibiotic regimen used in prophylaxis. We performed a subgroup
analysis to evaluate the primary outcome in patients with and without CSF leakage. We also completed a meta-analysis of all the
identified controlled non-RCTs (enrolling a total of 2168 patients), producing results consistent with the randomised data.
Authors’ conclusions
Currently available evidence from RCTs does not support prophylactic antibiotic use in patients with BSF, whether there is evidence
of CSF leakage or not. Until more research is completed, the effectiveness of antibiotics in patients with BSF cannot be determined
because studies published to date are flawed by biases. Large, appropriately designed RCTs are needed.
PLAIN LANGUAGE SUMMARY
Antibiotics to prevent infection of the brain coverings (meningitis) in patients with basilar skull fracture
Basilar skull fracture (7% to 15.8% of all skull fractures) places the central nervous system in contact with bacteria from the nose
and throat and may be associated with cerebrospinal fluid leakage (occurring in 2% to 20.8% of patients). Blood or watery discharge
from nose or ears, bruising behind the ear or around the eyes, hearing loss, inability to perceive odours or facial asymmetry may lead
physicians to the diagnosis of basilar skull fracture. Patients with a basilar skull fracture may develop meningitis and some doctors give
antibiotics in an attempt to reduce this risk.
This review examined five randomised controlled trials, comprising a total of 208 participants, that compared those who received
preventive antibiotic therapy and developed meningitis with those who did not receive antibiotics and developed meningitis. The
available data did not support the use of prophylactic antibiotics, as there is no proven benefit of such therapy. There was a possible
adverse effect of increasing susceptibility to infection with more pathogenic organisms. The review authors call for research to address
this question, as there are too few studies available on this subject and they have overall design shortcomings and small combined
numbers of participants studied.
BACKGROUND torn adjacent to the fracture site, placing the central nervous sys-
tem (CNS) in contact with bacteria from the paranasal sinuses,
nasopharynx or middle ear. If the dura mater is torn, CSF leak-
age could occur. BSF will predispose the patient to meningitis. A
Description of the condition greater associated risk has been reported when CSF leakage exists,
The estimated incidence of basilar skull fracture (BSF) from non- in particular if it persists for more than seven days (Leech 1973).
penetrating head trauma varies between 7% and 15.8% of all skull
fractures, with associated cerebrospinal fluid (CSF) leakage occur-
ring in 2% to 20.8% of patients (Buchanan 2004). Clinical signs
that may lead a physician to suspect a BSF include CSF otorrhoea
or rhinorrhoea, bilateral periorbital ecchymosis, Battle’s sign, pe-
Description of the intervention
ripheral facial nerve palsy, haemotympanum or tympanic mem- The role of prophylactic antibiotics for preventing bacterial
brane perforation with blood in the external auditory canal, hear- meningitis in patients with BSF is controversial. Growing concern
ing loss, evidence of vestibular dysfunction and anosmia. High- about the emergence of resistant organisms argues against their
resolution bone computed tomographic (CT) scans have dramat- use. In addition, there are reports of higher incidences of meningi-
ically improved the radiological diagnosis of this type of fracture. tis in patients with BSF who have received prophylactic antibiotics
BSFs are of special significance because the dura mater may be (Choi 1996).
How the intervention might work Types of participants
Chemoprophylaxis with antibiotics in basilar skull fractures may Patients of any age with a recent BSF, independent of the presence
reduce the incidence of meningitis. and severity of CSF leakage.
Types of interventions
Why it is important to do this review
Any antibiotic administered at the time of primary treatment of
A meta-analysis (Brodie 1997) showed a statistically significant re- the BSF compared with placebo or no antibiotic. We excluded
duction in the incidence of meningitis with prophylactic antibiotic trials comparing different antibiotics, different antibiotic dosages,
therapy for patients with post-traumatic CSF leakage. Another routes of administration, or differences in timing or duration of
meta-analysis (Villalobos 1998) concluded that antibiotic prophy- administration.
laxis after a BSF does not appear to decrease the risk of meningitis,
independent of whether or not CSF leakage has occurred. These
studies did not include an extensive review of the literature; both
Types of outcome measures
searched papers only until 1995 and 1996 respectively, and their
conclusions were based mainly on retrospective and observational
studies.
The inadequacies of these reviews and their conflicting conclusions Primary outcomes
led us to decide to search for and analyse evidence for the use Frequency of meningitis: suspected clinically (fever, neck stiff-
of prophylactic antibiotics for preventing bacterial meningitis in
ness, deterioration of neurological status, headache) and confirmed
patients with a BSF.
by lumbar puncture (CSF analysis including biochemistry, Gram
stains or bacteriological cultures (or both)).
Secondary outcomes
OBJECTIVES
1. All-cause mortality/meningitis-related mortality.
The objective of this review was to determine evidence for the 2. Need for surgical correction in patients with CSF leakage.
effectiveness of prophylactic antibiotics in BSF. We investigated 3. Non-CNS infection.
the following primary hypothesis: the frequency of meningitis is
lower when prophylactic antibiotics are administered as soon as a
diagnosis of BSF is made, with or without CSF leakage, compared
with no treatment or placebo. We also aimed to examine whether Search methods for identification of studies
the administration of prophylactic antibiotics may influence out-
comes such as all-cause/meningitis-related mortality, need for sur-
gical correction in patients with CSF leakage, and non-CNS in-
Electronic searches
fection.
For this update, we searched the Cochrane Central Regis-
ter of Controlled Trials (CENTRAL) 2011, Issue 1, part of
The Cochrane Library, www.thecochranelibrary.com (accessed 17
METHODS February 2011), which contains the Cochrane Acute Respiratory
Infections (ARI) Group’s Specialised Register, MEDLINE (2005
to February, Week 3 2011), EMBASE (2005 to February 2011)
and LILACS (2005 to February 2011).
Criteria for considering studies for this review We used the following search strategy to search MEDLINE and
CENTRAL. We combined the MEDLINE search strategy with
the Cochrane Highly Sensitive Search strategy for identifying
randomised trials in MEDLINE: sensitivity- and precision-max-
Types of studies
imising version (2008 revision); Ovid format (Lefebvre 2011).
Randomised controlled trials (RCTs) comparing any antibiotic We adapted the search strategy for EMBASE (Appendix 1) and
versus placebo or no intervention. We also identified non-RCTs LILACS (Appendix 2). The search strategy for the original review
to perform a separate meta-analysis to compare results. is described in Appendix 3.
MEDLINE (Ovid) Three review authors (BR, JC, LP) independently assessed the
1 exp Anti-Bacterial Agents/ studies identified by the search strategy, to identify potentially suit-
2 antibiotic*.tw,nm. able trials for the review according to the criteria outlined above.
3 antimicrob*.tw,nm. We resolved disagreements by discussion with the fourth author
4 antibacter*.tw,nm. (CS).
5 bacteriocid*.tw,nm.
6 antimycobacter*.tw,nm.
7 or/1-6 Data extraction and management
8 exp Central Nervous System Infections/ Two authors (BR, JC) independently assessed the full papers for
9 exp Infection/ type of participants, type and dose of antibiotic used, method-
10 infect*.tw. ological quality, number of patients excluded or lost to follow up
11 exp Meningitis/ and the outcome measures stated in the protocol. We recorded ex-
12 meningit*.tw. tracted data on a data collection form. We resolved disagreements
13 or/8-12 by discussion.
14 exp Brain Injuries/
15 (brain adj3 (injur* or traum* or contusio* or laceratio*)).tw.
16 Craniocerebral Trauma/ Assessment of risk of bias in included studies
17 ((craniocerebral or cranial) adj3 (injur* or traum*)).tw. We investigated sources of bias. Two authors (LP, BR) indepen-
18 Head Injuries, Penetrating/ dently assessed the global quality of included trials using the ’Risk
19 (head adj3 (injur* or traum*)).tw. of bias’ assessment tool, as outlined in the Cochrane Handbook for
20 exp Skull Fractures/ Systematic Reviews of Interventions (Higgins 2011). We resolved
21 (fractur* adj3 (skull or brain or temporal or basilar or fronto- disagreements by discussion.
basilar or basal or base)).tw.
22 (battl* adj2 sign*).tw.
23 Cerebrospinal Fluid/ Measures of treatment effect
24 (cranio* adj3 traum*).tw. We reported results as odds ratios (OR) and 95% confidence in-
25 Subdural Effusion/ tervals (CI) for dichotomous outcomes, using the Peto fixed-effect
26 hygroma*.tw. method.
27 ((csf or cerebrospinal fluid) and (fistula* or leakage*)).tw.
28 cerebrospinal fluid otorrhea/ or cerebrospinal fluid rhinorrhea/
29 exp Intracranial Hemorrhage, Traumatic/ Unit of analysis issues
30 or/14-29
We performed statistical analysis using Review Manager software
31 7 and 13 and 30
(RevMan 2011). We calculated the significance of any differences
between ORs using a standard method (Egger 2001).
Searching other resources
We applied no language or publication restrictions. We screened Dealing with missing data
titles, keywords and abstracts of the citations downloaded from
the electronic searches and obtained full copies of reports of poten- We contacted the original trial authors whenever relevant missing
tially suitable trials for further assessment. The search strategy also data were detected.
included a search of the reference lists of identified trials and BSF
review articles and personal communication with other researchers
Assessment of heterogeneity
in the field. We handsearched abstracts of meeting proceedings
from the European Association of Neurosurgical Societies (1995, We tested heterogeneity between trial results using the I2 statistic.
1999 and 2003).
Assessment of reporting biases
Data collection and analysis We would have assessed publication bias according to the recom-
mendations on testing for funnel plot asymmetry if there had been
sufficient numbers of trials (more than 10) in any meta-analysis
(Sterne 2011). We would have examined possible causes if asym-
Selection of studies metry had been identified.
Data synthesis All trials included participants with a clinical or radiological diag-
We reported results of meta-analysis as odds ratios (OR) and 95% nosis of BSF. Entry criteria did not differ considerably. Exceptions
confidence intervals (CI) for dichotomous outcomes, using the were the Hoff 1976 trial, in which CSF leakage was an exclusion
Peto fixed-effect method. criterion, and the Klastersky 1976 trial, in which the participants
had to have evidence of CSF leakage to be included.
The primary outcome for all trials included the occurrence of
Subgroup analysis and investigation of heterogeneity meningitis. In three trials (Demetriades 1992; Ignelzi 1975a;
We previously planned to investigate heterogeneity by undertaking Klastersky 1976) the primary outcome was a composite outcome
a subgroup analysis of patients with or without CSF leakage in the that also included extracranial infection (wound sepsis, pneumo-
event of uncovering significant heterogeneity. nia, urinary tract infection), bacterial colonisations of bronchial se-
cretions or urine, change in the posterior nasopharyngeal flora, or
death from brain damage. Criteria for these diagnoses were based
Sensitivity analysis on clinical grounds and further investigations and prophylactic
We planned to perform a meta-analysis of all the controlled, non- medication were commenced as soon as the diagnosis of BSF was
randomised studies identified in order to evaluate the consistency made in all trials. None of the studies reported data on outcomes
of the results of the main meta-analysis. of safety and tolerability of prophylactic antibiotics.
Ignelzi 1975a performed a small controlled trial with 10 partici-
pants with BSF that was included in a report of a larger retrospec-
tive study. The presence of CSF fistulae in these participants was
not described and the participants were randomised to one group
RESULTS that received prophylactic ampicillin or cephalothin 1 g six-hourly
for 10 days or another group that did not. The Klastersky 1976
study performed a double-blind controlled trial that enrolled 52
Description of studies participants and compared five mega units of penicillin G given
intravenously (IV) six-hourly for a mean duration of 7.7 days; the
See: Characteristics of included studies; Characteristics of excluded
placebo was given under identical conditions.
studies; Characteristics of ongoing studies.
Hoff 1976 enrolled 160 participants assigned randomly and
blindly to one of three groups: no antibiotic (group 1), 1.2 million
Results of the search units of penicillin IV daily for three days (group 2), 20 million
units of penicillin IV daily for three days (group 3). No cases of
In this 2011 update we retrieved a total of 168 new records (when
meningitis were found but the numbers of participants enrolled
duplicates were removed from searches of MEDLINE (28 records),
in each group were not provided. Although we have contacted the
EMBASE (118 records) CENTRAL (14 records) and LILACS
trial author, further information was no longer available.
(eight records)). This search yielded the addition of one ongoing
Demetriades 1992 randomised 37 participants to three groups: no
trial.
antibiotic (group A), 1 g ceftriaxone IV daily for three days (group
This review identified five RCTs (Demetriades 1992; Eftekhar
B), or combined ampicillin (1 g IV six-hourly)/sulphadiazine (0.5
2004; Hoff 1976; Ignelzi 1975a; Klastersky 1976) and one on-
g IV six-hourly) (group C).
going trial (Eftekhar 2006) comparing prophylactic antibiotics in
Eftekhar 2004 studied 109 participants with acute traumatic pneu-
BSF with placebo or no antibiotics.
mocephalus verified by a CT scan, who were followed until oc-
currence of meningitis or at least for five days post-trauma. They
Included studies randomised the participants to one of two groups: the prophylac-
tic antibiotic treatment given (PAT+) group, in which ceftriaxone
was administered at a dose of 1 g twice a day for five days; and
Meningitis in patients with BSF the prophylactic antibiotic treatment not given (PAT-) group, in
which ceftriaxone was not administered.
We found five RCTs with available data comparing prophylactic
Overall, 368 participants were enrolled in these five studies. Two
antibiotics in BSF with placebo or no antibiotics (Demetriades
of them (Eftekhar 2004; Hoff 1976) enrolled 73% of these par-
1992; Eftekhar 2004; Hoff 1976; Ignelzi 1975a; Klastersky 1976).
ticipants. Since we could not access the number of participants
All these studies were single-centre, conducted in South Africa,
included in each group of the Hoff trial (Hoff 1976), we could
Iran, USA or Belgium, and were published between 1975 and
not include it in the meta-analysis. We analysed a total of 208
2004. All had a parallel design and were stated by the trial authors
participants from four RCTs: 109 participants in the treatment
to be randomised, although the method of randomisation was not
group and 99 in the control group.
clearly described in any trial report.
In three trials (Demetriades 1992; Eftekhar 2004; Klastersky 1983; Einhorn 1978; Eljamel 1993; Frazee 1988; Friedman
1976) participants were well-matched between the treatment and 2001; Helling 1988; MacGee 1970; McGuirt 1995; Raskind
control arms for demographics, clinical status at admission and 1965; Steidtmann 1997; Tos 1973; Zrebreet 1986) and two were
presence of rhinorrhoea or otorrhoea. The other trials (Hoff 1976; prospective observational studies with an historical control group
Ignelzi 1975a) did not describe the characteristics of the popula- (Gonzalez 1998; Ignelzi 1975b). There was no specification about
tion included in each group. the presence of CSF leakage in five of these studies (Ash 1992;
Two studies (Demetriades 1992; Klastersky 1976) provided suf- Gonzalez 1998; Helling 1988; Ignelzi 1975b; Tos 1973). Six
ficient descriptions for withdrawals and dropouts to determine included only participants with CSF leakage, either otorrhoea
the number of participants in each treatment group entering and or rhinorrhoea (Clemenza 1995; Eljamel 1993; Friedman 2001;
completing the trial. MacGee 1970; McGuirt 1995; Raskind 1965).
The remaining six studies included participants with or without
CSF leakage (Choi 1996; Dagi 1983; Einhorn 1978; Frazee 1988;
Meningitis in participants with BSF concerning the presence Steidtmann 1997; Zrebreet 1986). Overall, 2168 participants were
of CSF leakage included in these 17 studies, in which 1141 participants were
There was only one study in which the presence of CSF leakage was treated with antibiotics and 1027 participants were not.
not specified (Ignelzi 1975a). CSF leakage was an exclusion criteria
in the Hoff 1976 study. Traumatic rhinorrhoea or otorrhoea had
Excluded studies
to be present in the participants included in the Klastersky 1976
study. The other two trials (Demetriades 1992; Eftekhar 2004) The Characteristics of excluded studies table contains non-RCTs
included participants with and without CSF leakage. that have been systematically reviewed. We excluded no RCTs.
Non-RCTs that have been systematically reviewed Risk of bias in included studies
We excluded 17 studies. Of these, 15 were retrospective con- The overall risk of bias is presented graphically in Figure 1 and
trolled studies (Ash 1992; Choi 1996; Clemenza 1995; Dagi summarised in Figure 2.
Figure 1. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
Figure 2. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included
study.
Allocation
1. Frequency of meningitis
All studies stated that patients were randomised between the treat- We found no significant differences for this outcome (Peto OR
ment and control groups. The precise method of randomisation 0.69; 95% CI 0.29 to 1.61) (Analysis 1.2). In addition, we found
and details of concealment of allocation were not explained in any no differences in the subgroups of patients with CSF leakage (Peto
trial. We considered the method of allocation to be unclear in all OR 0.44; 95% CI 0.09 to 2.15) (Analysis 1.1.1) or without CSF
trials. leakage (Peto OR 0.77; 95% CI 0.25 to 2.41) (Analysis 1.1.2).
Blinding 2. All-cause mortality/meningitis-related mortality

Only one study (Klastersky 1976) was double-blinded through- We accessed relevant data from the five trials. We found no sig-
out, using identical appearance interventions (antibiotics or nificant differences for all-cause mortality (Peto OR 1.68; 95%
placebo). The other studies were not placebo-controlled and did CI 0.41 to 6.95) (Analysis 2.1) or for meningitis-related mortality
not measure outcomes blindly. In addition, only two studies (Peto OR 1.03; 95% CI 0.14 to 7.40) (Analysis 3.1).
(Demetriades 1992; Klastersky 1976) reported the number of and
reasons for patients leaving the trials.
Data were analysed on a per-protocol basis in all trials. 3. Need for surgical correction in patients with CSF
leakage
Only one study (Eftekhar 2004) provided data for this sec-
Incomplete outcome data ondary outcome and no participants in either treatment or control
groups underwent surgical correction for CSF leakage in this trial
Missing data precluded several planned analyses in this systematic
(Analysis 4.1).
review. We were able partly to overcome this problem because
we had access to further data from the original trial of Eftekhar
(Eftekhar 2004), kindly provided by the author himself. We sought 4. Non-CNS infection
further information for some of the other studies, but without
Only one study (Klastersky 1976) provided data for this outcome.
success. As previously stated, the number of patients in each group
No significant differences were found (Peto OR 0.61; 95% CI
was not accessible in Hoff 1976 study; although none of the 160
0.15 to 2.46) (Analysis 5.1).
patients enrolled had meningitis, we could not include this trial
In order to study the consistency of these results we performed
in the meta-analysis.
a meta-analysis of all the controlled non-randomised studies
identified and previously described in the Excluded studies sec-
tion. Globally, these studies enrolled 2168 participants (treatment
Other potential sources of bias group 1141; control group 1027). Tests for heterogeneity were not
We identified no other potential sources of bias. statistically significant (Chi2 test, P = 0.16; I2 statistic = 26%).
Globally, the frequency of meningitis in the treatment group was
6.92% and in the control group 6.52% (P = 0.65) (random-effects
Effects of interventions model OR 1.13; 95% CI 0.67 to 1.88). Individually, only one
We were able to perform a meta-analysis with five of the RCTs study (Eljamel 1993) showed a significant difference favouring the
included in this review. Since we primarily aimed to compare pro- treatment group (OR 0.47; 95% CI 0.25 to 0.88). This study
phylactic antibiotics with no antibiotic or placebo in patients with contributed most to the results (weight 19.4%), but it did not
BSF and to identify the influence of CSF leakage in the frequency impact significantly on the direction of the results. Additionally,
of meningitis in patients with BSF, we performed a subgroup anal- we performed a subgroup analysis for patients with CSF leakage
ysis of patients with and without CSF leakage. We tested statistical (529 participants in the treatment group and 260 in the control
heterogeneity between trial results using the I2 statistic and found group) and without CSF leakage (334 participants in the treat-
no evidence of heterogeneity in any of the outcomes measured (I ment group and 292 in the control group). In five studies (Ash
2 statistic = 0%). 1992; Gonzalez 1998; Helling 1988; Ignelzi 1975b; Tos 1973)
The efficacy outcomes did not show significant differences be- the presence of CSF leakage was not specified (278 participants in
tween treatment and control groups in any of the included trials, treatment groups and 475 in control groups). The OR (random-
when considering either the total population or the subgroup of effects model) for participants with CSF leakage was 0.61 (95%
patients with CSF leakage. CI 0.37 to 0.99) and for patients without CSF leakage it was 0.86
(95% CI 0.27 to 2.78). In the subgroup of patients for which no randomised. Additionally, the type of participants, interventions,
data were available regarding the presence of CSF leakage, the OR diagnoses and outcome measures were significantly different be-
was 2.01 (95% CI 0.91 to 4.44). tween these studies. This makes the data difficult to interpret.
We found no statistically significant differences for all causes of Nevertheless, we thought it would be interesting to compare data
mortality in the eight studies in which relevant data were available from randomised controlled trials (RCTs) with non-RCTs since
(Ash 1992; Einhorn 1978; Frazee 1988; Friedman 2001; Ignelzi non-randomised studies tend to overestimate treatment effect size,
1975b; MacGee 1970; McGuirt 1995; Zrebreet 1986). These in- which may be the case here.
cluded 460 participants in the treatment group and 265 in the According to the frequencies of events in the treatment and control
control group (random-effects model OR 0.78; 95% CI 0.26 to groups, and the relative risk for meningitis in the subgroup of
2.28). We found no significant differences for meningitis-related patients with CSF leakage (0.64), a sample size of 798 participants
mortality (random-effects model OR 0.43; 95% CI 0.08 to 2.29). was needed in order to show a statistically significant result between
the two interventions, with a power of 90% and the probability
of a type I error of 5%. This figure is similar when considering
the data from the non-randomised case-controlled studies for the
DISCUSSION subgroup of patients with CSF leakage, for which the sample size
necessary to show a significant result was 737 patients.
This is the first systematic review to study the effect of prophylactic
Summary of main results antibiotics in BSF. Based on the analysis of five RCTs, there is
insufficient evidence to support or refute the use of antibiotics to
Curiously, the frequency of meningitis in the Eftekhar 2004 trial
prevent meningitis in patients with BSF.
was significantly higher than in the other trials. The diagnosis of
meningitis was based on cerebrospinal fluid (CSF) analysis in par-
ticipants with compatible clinical findings and was comparable
Overall completeness and applicability of
with the other trials. However, Eftekhar 2004 included only the
evidence
subset of patients with basilar skull fractures (BSF) and pneumo-
cephalus that is associated with a dural tear with an open com- There is no support for routine prophylactic antibiotics in all pa-
munication with air in the paranasal sinuses, mastoid air cells or tients with basilar skull fracture. Further RCTs are needed to assess
petrous temporal regions and the central nervous system (CNS). its benefits and risks clearly.
These participants with pneumocephalus might have had an ad-
ditional risk factor for developing meningitis that may have been
independent of CSF leakage. Further investigations are necessary Quality of the evidence
to clarify this issue. The quality of the evidence available to evaluate the use of pro-
Given the current data, it is not possible to recommend the use of phylactic antibiotics in BSF was indicated by the identification of
prophylactic antibiotics in patients with BSF. Our results did not only five RCTs that we considered suitable for this review. Even
show that the administration of antibiotics had an effect on the these had important methodological shortcomings. In general, the
frequency of meningitis. No significant difference was found in quality of the included trials was poor, as assessed by the ’Risk
the subgroup of participants with CSF leakage, although there was of bias’ tool (Higgins 2011). All trials used a per-protocol based
a tendency to favour the treatment group. Again, no significant analysis. For the Eftekhar 2004 trial we had access to unpublished
difference was found for all-cause or meningitis-related mortality. data that allowed us to perform some comparisons. We were able
Although no significant differences were found, the confidence to study a total of 208 participants.
interval (CI) of all outcomes was wide and we could not exclude
the possibility that antibiotic prophylaxis is either better or worse
than the control. This is partially explained by the relatively small Potential biases in the review process
number of participants enrolled and the small number of events
None known.
recorded.
The global results of the analysis of data extracted from the ex-
cluded studies are in agreement with the randomised data. Sub-
group analysis within the excluded trials suggests a benefit from an-
Agreements and disagreements with other
tibiotic prophylaxis in patients with CSF leakage. However, treat-
studies or reviews
ment interventions caused significantly more meningitis in the Despite the commonality of antibiotic prophylaxis in the treat-
subgroup of patients without specification regarding CSF leak- ment of basilar skull fractures, surprisingly no randomised con-
age status. These analyses should be read with caution since they trolled trial (RCT) has specifically evaluated this treatment’s effi-
are based mostly on retrospective studies and the data are not cacy. We found two meta-analyses (Brodie 1997; Villalobos 1998)
with conflicting conclusions: Brodie concluded there is a benefit Implications for research
with antibiotic prophylaxis (reducing the incidence of meningitis
More appropriately designed RCTs to test the effectiveness of pro-
in patients with post-traumatic cerebrospinal fluid (CSF) leakage),
phylactic antibiotic use following the diagnosis of BSF are needed
whilst Villalobos found no decrease in meningitis in patients with
in order to establish whether or not there is a net benefit from
BSF (with or without CSF leakage) afforded antibiotic prophy-
this intervention. Until more research results are available, firm
laxis. The findings of our systematic review are similar to the ones
conclusions regarding the efficacy of this treatment cannot be pro-
in the Villalobos meta-analysis.
vided. Future trials should evaluate all clinically relevant outcomes
(all-cause mortality, need for surgical correction in patients with
CSF leakage, disability), not only central nervous system infection
endpoints, and should pay attention to subgroups of patients, such
as those with CSF leakage or pneumocephalus (or both).
AUTHORS’ CONCLUSIONS
Implications for practice ACKNOWLEDGEMENTS

This systematic review did not show that prophylactic antibiotics We are grateful to all members of the Cochrane Acute Respira-
had an effect on the prevention of meningitis in patients with tory Infections Group, namely Elizabeth Dooley, Sarah Thorn-
basilar skull fractures (BSF), regardless of cerebrospinal fluid (CSF) ing and Professor Chris Del Mar for their continual assistance
leakage. Currently available evidence from RCTs does not support and to Marta Roque and Josep Garcia for conducting some of
the use of prophylactic antibiotics in patients with BSF. The risk of the electronic searches. We also wish to thank Stephanie Kondos,
adverse reactions and financial costs are factors that should be taken Jonathan Wasserberg, José Luis Ferrero Albert, Nelcy Rodriguez
into account when deciding if antibiotic therapy is appropriate. and Kameshwar Prasad for commenting on the draft review.
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Ash GJ, Peter J, Bass DH. Antimicrobial prophylaxis for
Demetriades 1992 {published data only} fractured base of skull in children. Brain Injury 1992;6(6):
Demetriades D, Charalambides D, Lakhoo M, Pantanowitz 521–7.
D. Role of prophylactic antibiotics in open and basilar
fractures of the skull: a randomized study. Injury 1992;23 Choi 1996 {published data only}
(6):377–80. Choi D, Spann R. Traumatic cerebrospinal fluid leakage:
risk factors and the use of prophylactic antibiotics. British
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Eftekhar B, Ghodsi M, Nejat F, Ketabchi E, Esmaeeli
B. Prophylactic administration of ceftriaxone for the Clemenza 1995 {published data only}
prevention of meningitis after traumatic pneumocephalus: Clemenza JW, Kaltman SI, Diamond DL. Craniofacial
results of a clinical trial. Journal of Neurosurgery 2004;101 trauma and cerebrospinal fluid leakage: a retrospective
(5):757–61. clinical study. Journal of Oral and Maxillofacial Surgery
Hoff 1976 {published data only} 1995;53(9):1004–7.
Hoff JT, Brewin A, Hoi Sang U. Antibiotics for basilar skull Dagi 1983 {published data only}
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Ignelzi 1975a {published data only} prevention of meningitis after basilar skull fracture.
Ignelzi R, VanderArk G. Analysis of the treatment of basilar American Journal of Emergency Medicine 1983;1(3):295–8.
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Einhorn 1978 {published data only}
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Einhorn A, Mizrahi EM. Basilar skull fractures in children.
Klastersky 1976 {published data only} The incidence of CNS infection and the use of antibiotics.
Klastersky J, Sadeghi M, Brihaye J. Antimicrobial American Journal of Diseases of Children 1978;132(11):
prophylaxis in patients with rhinorrhea or otorrhea: a 1121–4.
double blind study. Surgical Neurology 1976;6(2):111–4.
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fistulae. British Journal of Neurosurgery 1993;7(5):501–5.
Frazee 1988 {published data only} pneumocephalus: design and rationale of a placebo-
Frazee RC, Mucha P Jr, Farnell MB, Ebersold MJ. controlled randomized multicenter trial. Trials 2006;18(7):
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25(8):1062–6. Otolaryngology - Head and Neck Surgery 1997;123(7):
Gonzalez 1998 {published data only} 749–52.
Gonzalez JL. Antibiotic prophylaxis in basilar skull fractures. Buchanan 2004
Is it worth it? [Profilaxis con antibioticos en fracturas de Buchanan RJ, Brant A, Marshall LR. Traumatic
base de craneo. Tiene justification esa conducta?]. Revista cerebrospinal fluid fistulas. In: Winn H editor(s). Youmans
Cubana de Cirugía 1998;37(2):5–9. Neurological Surgery. 5th Edition. Philadelphia: Saunders,
Helling 1988 {published data only} 2004:5265–72.
Helling TS, Evans LL, Fowler DL, Hays LV, Kennedy FR. Dickersin 1994
Infectious complications in patients with severe head injury. Dickersin K, Scherer R, Lefebvre C. Identifying relevant
Journal of Trauma 1988;28(11):1575–7. studies for systematic reviews. BMJ 1994;309:1286–91.
Ignelzi 1975b {published data only} Egger 2001
Ignelzi R, VanderArk G. Analysis of the treatment of basilar Egger M, Smith GD, Altman DG. Systematic reviews in
skull fractures with and without antibiotics. Journal of health care. Meta-analysis in context. 2nd Edition. London:
Neurosurgery 1975;43(6):721–6. BMJ Books, 2001.
MacGee 1970 {published data only} Higgins 2011

MacGee EE, Cauthen JC, Brackett CE. Meningitis Higgins JPT, Green S (editors). Cochrane Handbook for
following acute traumatic cerebrospinal fluid fistula. Journal Systematic Reviews of Interventions Version 5.1.0 [updated
of Neurosurgery 1970;33(3):312–6. March 2011]. The Cochrane Collaboration. Available from
www.cochrane-handbook.org 2011.
McGuirt 1995 {published data only}
McGuirt WF Jr, Stool SE. Cerebrospinal fluid fistula: the Leech 1973
identification and management in pediatric temporal bone Leech PJ, Paterson A. Conservative and operative
fractures. Laryngoscope 1995;105(4 Pt 1):359–64. management of cerebrospinal fluid leakage after closed head
injury. Lancet 1973;1:1013–5.
Raskind 1965 {published data only}
Raskind R. Cerebrospinal fluid rhinorrhea and otorrhea. Lefebvre 2011
Diagnosis and treatment in 35 cases. Journal of the Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching
International College of Surgeons 1965;43:141–54. for studies. In: Higgins JPT, Green S editor(s). Cochrane
Handbook for Systematic Reviews of Interventions. Chichester:
Steidtmann 1997 {published data only}
Wiley-Blackwell, 2011.
Steidtmann K, Welge-Lussen A, Probst R. Antibiotic
prophylaxis in laterobasal fractures [Antibiotikaprophylaxe RevMan 2011
bei laterobasalen frakturen]. HNO 1997;45(6):448–52. The Nordic Cochrane Centre. The Cochrane Collaboration.
Review Manager (RevMan). 5.1. Copenhagen: The Nordic
Tos 1973 {published data only}
Cochrane Centre. The Cochrane Collaboration, 2011.
Tos M. Course of and sequelae to 248 petrosal fractures.
Acta Otolaryngologica (Stockholm) 1973;75(4):353–4. Sterne 2011
Sterne JAC, Egger M, Moher D (editors). Chapter 10:
Zrebreet 1986 {published data only} Addressing reporting biases. Cochrane Handbook for
Zrebeet HA, Huang PS. Prophylactic antibiotics in the Systematic Reviews of Intervention. Version 5.1.0 (updated
treatment of fractures at the base of the skull. Delaware March 2011). The Cochrane Collaboration. In: Higgins
Medical Journal 1986;58(11):741–8. JPT, Green S editor(s). Available from www.cochrane-
References to ongoing studies handbook.org. Chichester: Wiley-Blackwell, 2011.
Villalobos 1998
Eftekhar 2006 {unpublished data only} Villalobos T, Arango C, Kubilis P, Rathore M. Antibiotic
Eftekhar B, Ghodsi M, Hadadi A, Taghipoor M, Sigarchi prophylaxis after basilar skull fractures: a meta-analysis.
SZ, Rahimi-Movaghar V, et al.Prophylactic antibiotic for Clinical Infectious Diseases 1998;27:364–9.
prevention of posttraumatic meningitis after traumatic ∗
Indicates the major publication for the study
CHARACTERISTICS OF STUDIES
Characteristics of included studies [ordered by study ID]
Demetriades 1992
Methods Randomised, controlled, 3 arms

Method of randomisation: not specified
Location: 1 centre in South Africa
Duration: 1 year
Participants Inclusion criteria: patients with an open skull fracture or a BSF (diagnosed radiologically
or clinically)
Exclusion criteria: GCS < 6 or requiring neurosurgical intervention, or with major
extracranial injuries
196 patients enrolled
There were 39 withdrawals: 5 because of violation of the protocol, 3 due to death within
5 days and 31 lost to follow up.
The 2 major groups (antibiotic (AB) or no AB) were statistically similar with regard to
age, sex, cause of injury, type of fracture, GCS, bladder catheterisation, endotracheal
intubation
37 patients with BSF were considered for the review:
N = 12 group A
N = 14 group B
N = 11 group C
CSF leakage:
N = 9 group A
N = 14 group B
N = 5 group C
Interventions Patients were randomised to one of 3 groups: no antibiotics (group A), 1 g ceftriaxone
IV daily for 3 days (group B) combined ampicillin (1 g IV 6-hourly)/sulphadiazine (0.
5 g IV 6-hourly) (group C)
Outcomes Primary outcome event was evidence of intracranial or extracranial infection (meningitis
- suspected clinically and confirmed by lumbar puncture, brain abscess, wound sepsis,
pneumonia, urinary tract infection)
Patients were followed for a minimal period of 10 days
Meningitis in patients with BSF:
Group A 1/12
Group B 0/14
Group C 0/11
Notes
Risk of bias
Bias Authors’ judgement Support for judgement
Demetriades 1992 (Continued)
Random sequence generation (selection Unclear risk “The patients were randomised to receive
bias) no antibiotics (group A) or antibiotics for
3 days”, no specification of method of ran-
domisation
Allocation concealment (selection bias) Unclear risk Method of concealment is not described
Blinding of participants and personnel Low risk No blinding of personnel, due to identifi-
(performance bias) able differences in treatment options: “no
All outcomes antibiotics (group A) (...) ceftriaxone intra-
venously 1g daily (a total of 3 injections)
[group B] (...) ampicillin intravenously 1 g
6-hourly (a total of 12 injections) [group
C])”; review authors judge that the out-
come and the outcome measurement are
not likely to be influenced by lack of blind-
ing
Blinding of outcome assessment (detection Low risk Only identifiable difference be-
bias) tween groups concerns treatment options
All outcomes (no antibiotic versus 2 different antibiotic
treatments for 3 days), and review authors
judge that the outcome and outcome mea-
surement are not likely to be influenced by
lack of blinding
Incomplete outcome data (attrition bias) Unclear risk “39 cases were excluded because of viola-
All outcomes tion of protocol, death within 5 days or
lost to follow-up. Analysis was restricted to
the remaining 157 cases”. No comment is
made as to the proportion of missing out-
comes compared with observed event
Selective reporting (reporting bias) Unclear risk The study protocol is not available, mak-
ing it impossible to assess whether the out-
comes reported were all pre-specified or not
Other bias Low risk No other identifiable sources of bias
Eftekhar 2004
Methods Randomised, controlled, not blinded, 2 arms

Method of randomisation: patients assigned according to a list of on-call physicians
Location: 1 centre in Iran
Duration: 27 months
Eftekhar 2004 (Continued)
Participants Inclusion criteria: acute traumatic pneumocephalus verified by CT scan

Exclusion criteria: AB therapy for other reasons; penetrating traumatic brain injury or
open skull fracture; surgery for any reason; discharge from hospital without doctor’s
approval; life-threatening lesions including severe brain, abdominal or vascular injuries;
death from other causes
109 patients enrolled:
PAT+ group N = 53
PAT- group n = 56
Both groups were well-balanced with respect to their characteristics
Interventions Patients were divided into 2 groups: PAT+ group in which prophylactic AB therapy was
given (ceftriaxone, 1 g twice a day, continued for 5 days) and PAT- group in which no
prophylactic AB therapy was given
Outcomes Primary outcome event was occurrence of meningitis (based on clinical and CSF find-
ings)
Follow up 1 month post-trauma
PAT+ group 10/53
PAT- group 12/56
Notes Author was contacted and kindly provided additional information
Risk of bias
Random sequence generation (selection Low risk “The patients were divided into two groups
bias) (...) according to a list of on-call physicians.
The list did not have any predictable se-
quence”
Blinding of participants and personnel Low risk No blinding of personnel, review authors
(performance bias) judge that the outcome and the outcome
All outcomes measurement are not likely to be influenced
by lack of blinding
Blinding of outcome assessment (detection High risk Outcome measure with insensitive instru-
bias) ment in a parcel of the results “five diag-
All outcomes noses were based only on clinical findings.
No antibiograms were obtained”
Incomplete outcome data (attrition bias) Low risk No missing outcome data
All outcomes
Selective reporting (reporting bias) Low risk The study protocol is available and all of
the study’s pre-specified outcomes that are
of interest in the review have been reported
in the pre-specified way
Hoff 1976
Methods Randomised, controlled, blinded, 3 arms

Location: 1 centre in USA
Duration: not specified
Participants Inclusion criteria: diagnosis of BSF based on clinical or radiographic evidence

Exclusion criteria: previous allergy to penicillin; CSF leakage immediately after injury
160 patients enrolled
Numbers in each group not specified
Interventions Patients were assigned randomly and blindly to one of 3 groups:

No AB given (group 1)
1.2 million units of penicillin given IV daily for 3 days (group 2)
20 million units of penicillin given IV daily for 3 days (group 3)
Outcomes Primary outcome event was development of CNS infection

None of the patients enrolled developed signs or symptoms of CNS infection
Notes Author was contacted but further information was no longer available
Risk of bias
Random sequence generation (selection Unclear risk “160 patients (...) were assigned randomly
bias) and blindly to one of three treatment
groups”, no reference to the sequence gen-
eration process
Blinding of participants and personnel Low risk “160 patients (...) were assigned randomly
(performance bias) and blindly to one of three treatment
All outcomes groups”. No blinding of personnel, due
to identifiable differences in treatment op-
tions, but review authors judge that the out-
come and the outcome measurement are
not likely to be influenced by lack of blind-
Hoff 1976 (Continued)
ing
All outcomes
Selective reporting (reporting bias) Unclear risk The study protocol is not available, mak-
ing it impossible to assess whether the out-
comes reported were all pre-specified or not
Other bias Unclear risk Insufficient information to assess whether

an important risk of bias exists
Ignelzi 1975a
Methods Randomised, controlled, 2 arms

Location: 1 centre in USA
Participants Inclusion criteria: diagnosis of BSF

Exclusion criteria: not specified
Interventions Patients were randomised into 2 groups: one group received prophylactic ampicillin or
cephalothin 1 g 6-hourly for 10 days and the other did not receive AB
Outcomes Primary outcome events were the development of CNS infection and change in the
posterior nasopharyngeal flora
None of the patients developed meningitis
Notes This article included both a RCT of 10 patients and a retrospective study of 129 patients
Risk of bias
Random sequence generation (selection Unclear risk 10 patients randomised, method of ran-
bias) domisation not specified
Blinding of participants and personnel Low risk No blinding of personnel, due to identifi-
(performance bias) able differences in treatment options, but
All outcomes review authors judge that the outcome and
the outcome measurement are not likely to
be influenced by lack of blinding
Ignelzi 1975a (Continued)
Blinding of outcome assessment (detection Low risk Only identifiable difference be-
bias) tween groups concerns treatment options
All outcomes (no antibiotic versus antibiotic treatment),
and review authors judge that the outcome
and outcome measurement are not likely
to be influenced by lack of blinding. Out-
come measured by clinical signs and con-
firmed by lumbar puncture, and posterior
naso-oropharynx swab
All outcomes
Klastersky 1976
Methods Randomised, placebo-controlled, double-blind, 2 arms

Method of randomisation: vials containing AB or placebo were distributed in boxes
designated by code numbers only
Location: 1 centre in Belgium
Participants Inclusion criteria: recent cranial trauma and rhinorrhoea or otorrhoea

No clear exclusion criteria defined
AB group N = 26
Placebo group n = 26
Age, sex, presence of diseases other than the cranial trauma, prognosis at the time of
admission had similar frequency in both groups
Interventions Patients were randomised into 2 groups: one group received prophylactic 5 mega units
of penicillin G IV 6-hourly with a mean duration of 7.7 days (range 4 to 13 days) and
the other group received placebo under identical conditions
Outcomes Outcome events were:

Development of meningitis (positive CSF culture: AB group 0/26, placebo group 1/26)
Possible CNS infection, other serious infection (pulmonary, urinary tract)
Death from brain damage (AB group 4/26, placebo group 3/26)
Bacterial colonisations of bronchial secretions or urine
Notes
Risk of bias
Klastersky 1976 (Continued)
Random sequence generation (selection Low risk Vials containing penicillin or placebo in
bias) boxes with code number, which was only
unveiled after diagnosis of infection or
colonisation
Allocation concealment (selection bias) Low risk Code numbered vials of identical appear-
ance
Blinding of participants and personnel Low risk Blinding of participants and all personnel
(performance bias) ensured, and not possible that the blinding
All outcomes had been broken
Blinding of outcome assessment (detection Low risk Blinding of participants and all personnel
bias) ensured, and not possible that the blinding
All outcomes had been broken
All outcomes
AB: antibiotic
BSF: basilar skull fractures
CNS: central nervous system
CSF: cerebrospinal fluid
CT: computed tomography
GCS: Glasgow Coma Scale
IV: intravenous
N: number
PAT+: prophylactic antibiotic treatment given
PAT-: prophylactic antibiotic treatment not given
RCT: randomised controlled trial
Characteristics of excluded studies [ordered by study ID]
Study Reason for exclusion
Ash 1992 Retrospective controlled study, reviewed 48 children with BSF, comparing empirical choice of AB prophylaxis
(penicillin and chloramphenicol or co-trimoxazole alone, N = 23) with no prophylaxis (N = 25)
Choi 1996 Retrospective controlled study, reviewed 270 patients with evidence of CSF leakage or BSF and compared the
incidence of meningitis in those who received AB prophylaxis (type and duration depending on consultant
preference, N = 197) versus those who did not (N = 73)
Clemenza 1995 Retrospective controlled study, reviewed 88 patients with traumatic CSF leakage and the use of prophylactic
AB to prevent meningitis (any or combination of penicillin, chloramphenicol, ampicillin, nafcillin or claforan,
observational N = 48) compared with no AB (N = 40)
Dagi 1983 Retrospective controlled study, evaluated 163 patients with BSF, either with or without CSF leak, and compared
the incidence of meningitis in the group that had received prophylactic AB (N = 91) with the group that did not
(N = 72)
Einhorn 1978 Retrospective controlled study, reviewed 46 patients up to 15 years of age with BSF and the clinical course of
those who were treated with antimicrobial prophylaxis or AB for other reasons (N = 14) compared to those who
did not receive any AB (N = 32)
Eljamel 1993 Retrospective controlled study, evaluated the possible effects of prophylactic AB treatment in 215 patients with
unrepaired traumatic CSF leak. AB prophylaxis (penicillin or sulfonamide) was considered to be adequate if
started within 3 days of the onset of the CSF leak and continued for at least 1 week after the leakage stopped
(either penicillin or sulphonamide, N = 106). The other group did not receive AB (N = 109). Diagnosis of
meningitis was based on clinical signs and confirmation based on CSF chemistry if no growth isolation of a
pathogen form
Frazee 1988 Retrospective controlled study. 347 patients with BSF were divided into 2 groups reflecting individual physician’s
preference: one group treated prophylactically with AB (penicillin or synthetic penicillin either alone or in
combination with another AB, usually an aminoglycoside, N = 251) and a second group initially observed only
(N = 96)
Friedman 2001 Retrospective controlled study, enrolled 43 patients with clinically evident traumatic CSF leak 24 hours or more
after injury and evaluated frequency of meningitis among those who had prophylactic AB (N = 29) compared
with those who did not (N = 14)
Gonzalez 1998 Prospective observational study with historical control group. 380 patients with clinical diagnosis of BSF enrolled.
The prospective group received no AB (N = 309) and were compared with an historical control group that had
had prophylactic AB (penicillin either alone or in combination with chloramphenicol or streptomycin, N = 71)
Helling 1988 Retrospective controlled study that evaluated infectious complications in patients with severe head injury. Fre-
quency of meningitis was compared among 23 patients with a diagnosis of BSF who were divided into 2 groups:
prophylactic AB (N = 12) and no AB (N = 11)
Ignelzi 1975b Prospective observational study with historical group (authors also report a smaller RCT (N = 10), which is one
of the included studies (Ignelzi 1975a)). 50 patients diagnosed with BSF and not treated with AB were studied
(Continued)
prospectively and compared regarding infectious complications with an historical group of 54 patients who had
the same diagnosis but who received prophylactic AB (mainly ampicillin or cephalothin)
MacGee 1970 Retrospective controlled study. 58 patients with acute traumatic CSF fistula were enrolled into 2 groups to study
the effect of prophylactic AB: 1 group that received AB (penicillin, chloramphenicol or sulfadiazine, N = 41) was
compared with another group that did not receive AB (N = 17)
McGuirt 1995 Retrospective controlled group, evaluated 37 children with temporal bone fracture and strong clinical evidence of
CSF fistula persisting more than 24 hours. The use of prophylactic AB was not recommended but some patients
(N = 20) received some form of AB therapy because of a concurrent injury, during fever evaluation or during
periods of lumbar drainage. The other patients (N = 17) did not receive any form of AB
Raskind 1965 Retrospective controlled study. 35 patients with CSF leak were enrolled, among whom 28 were traumatic and
divided into groups that received prophylactic AB (N = 15) or not (N = 13)
Steidtmann 1997 Retrospective controlled study. 78 patients who had suffered lateral skull base fractures with or without CSF leak
were enrolled and the risk of meningitis among those who were given prophylactic AB (N = 23) was compared
with those who were not (N = 55)
Tos 1973 Retrospective controlled study reviewed the incidence of meningitis in 198 patients with petrosal fractures in
groups treated with AB (N = 118) and without AB (N = 80)
Zrebreet 1986 Retrospective controlled study. 42 patients with diagnosis of BSF were reviewed to evaluate the incidence of
meningitis with prophylactic AB (various AB, N = 28) and without (N = 14)
AB: antibiotic
BSF: basilar skull fracture
CSF: cerebrospinal fluid
N: number
Characteristics of ongoing studies [ordered by study ID]
Eftekhar 2006
Trial name or title Prophylactic antibiotic for prevention of posttraumatic meningitis after traumatic pneumocephalus: design
and rationale of a placebo-controlled randomised multicenter trial
Methods Randomised controlled clinical trial
Participants 200 selected head injury patients with traumatic pneumocephalus
Interventions 3 groups: IV (intravenous antibiotics - 2 grams ceftriaxone twice a day), O group (oral antibiotics - azithro-
mycin 500 mg 1st day followed by 250 mg/day) and P group (placebo) for at least 7 days after trauma
Outcomes Primary outcome: frequency of bacterial meningitis

Secondary outcomes: 1. frequency of rhinorrhoea, intracranial haemorrhage and skull base fracture, volume
and location of intracranial air in the population study and each of the IV, O and P groups; 2. mortality rate
in study population and each of the IV, O and P groups
Starting date
Contact information eftekhar@sina.tums.ac.ir
Notes Author contacted on March 2011, with no additional relevant results
IV: intravenous
O: oral
P: placebo
DATA AND ANALYSES
Comparison 1. Frequency of meningitis
No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size
1 Frequency of meningitis by 4 208 Odds Ratio (M-H, Fixed, 95% CI) 0.63 [0.25, 1.59]
subgroup
1.1 CSF leakage (rhinorrhoea 3 92 Odds Ratio (M-H, Fixed, 95% CI) 0.44 [0.09, 2.15]
or otorrhoea)
1.2 No CSF leakage 2 106 Odds Ratio (M-H, Fixed, 95% CI) 0.77 [0.25, 2.41]
1.3 Presence of CSF leakage 1 10 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
not specified
2 Frequency of meningitis 4 208 Odds Ratio (M-H, Fixed, 95% CI) 0.69 [0.29, 1.61]
2.1 Frequency of meningitis 4 208 Odds Ratio (M-H, Fixed, 95% CI) 0.69 [0.29, 1.61]
Comparison 2. All-cause mortality
No. of No. of
1 All-cause mortality 4 208 Odds Ratio (M-H, Fixed, 95% CI) 1.68 [0.41, 6.95]
Comparison 3. Meningitis-related mortality
No. of No. of
1 Meningitis-related mortality 4 208 Odds Ratio (M-H, Fixed, 95% CI) 1.03 [0.14, 7.40]
Comparison 4. Need for surgical correction in patients with CSF leakage
No. of No. of
1 Need for surgical correction in 1 109 Odds Ratio (M-H, Fixed, 95% CI) 0.0 [0.0, 0.0]
patients with CSF leakage
Comparison 5. Non-CNS infection
No. of No. of
1 Non-CNS infection 1 52 Odds Ratio (M-H, Fixed, 95% CI) 0.61 [0.15, 2.46]
1.1 CSF leakage (rhinorrhoea 1 52 Odds Ratio (M-H, Fixed, 95% CI) 0.61 [0.15, 2.46]
or otorrhoea)
Analysis 1.1. Comparison 1 Frequency of meningitis, Outcome 1 Frequency of meningitis by subgroup.
Review: Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures
Comparison: 1 Frequency of meningitis
Outcome: 1 Frequency of meningitis by subgroup
Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio

n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
1 CSF leakage (rhinorrhoea or otorrhoea)

Demetriades 1992 0/19 1/9 16.9 % 0.15 [ 0.01, 3.94 ]
Eftekhar 2004 4/6 4/6 11.6 % 1.00 [ 0.09, 11.03 ]
Klastersky 1976 0/26 1/26 12.8 % 0.32 [ 0.01, 8.24 ]
Subtotal (95% CI) 51 41 41.3 % 0.44 [ 0.09, 2.15 ]

Total events: 4 (Treatment), 6 (Control)
Heterogeneity: Chi2 = 0.92, df = 2 (P = 0.63); I2 =0.0%
Test for overall effect: Z = 1.01 (P = 0.31)
2 No CSF leakage
Demetriades 1992 0/6 0/3 Not estimable
Eftekhar 2004 6/47 8/50 58.7 % 0.77 [ 0.25, 2.41 ]
Subtotal (95% CI) 53 53 58.7 % 0.77 [ 0.25, 2.41 ]

Heterogeneity: not applicable
3 Presence of CSF leakage not specified
Ignelzi 1975a 0/5 0/5 Not estimable
Subtotal (95% CI) 5 5 Not estimable

Test for overall effect: not applicable
Total (95% CI) 109 99 100.0 % 0.63 [ 0.25, 1.59 ]
0.05 0.2 1 5 20
Favours treatment Favours control
(Continued . . . )
(. . .
Continued)
Test for subgroup differences: Chi2 = 0.31, df = 1 (P = 0.58), I2 =0.0%
0.05 0.2 1 5 20
Analysis 1.2. Comparison 1 Frequency of meningitis, Outcome 2 Frequency of meningitis.
Comparison: 1 Frequency of meningitis
Outcome: 2 Frequency of meningitis

1 Frequency of meningitis
Demetriades 1992 0/25 1/12 15.2 % 0.15 [ 0.01, 3.98 ]
Eftekhar 2004 10/53 12/56 73.4 % 0.85 [ 0.33, 2.18 ]
Klastersky 1976 0/26 1/26 11.4 % 0.32 [ 0.01, 8.24 ]
Total (95% CI) 109 99 100.0 % 0.69 [ 0.29, 1.61 ]

Test for subgroup differences: Not applicable
0.05 0.2 1 5 20
Analysis 2.1. Comparison 2 All-cause mortality, Outcome 1 All-cause mortality.
Comparison: 2 All-cause mortality
Outcome: 1 All-cause mortality

Eftekhar 2004 1/53 0/56 15.7 % 3.23 [ 0.13, 81.01 ]
Klastersky 1976 4/26 3/26 84.3 % 1.39 [ 0.28, 6.95 ]
Total (95% CI) 109 99 100.0 % 1.68 [ 0.41, 6.95 ]

0.01 0.1 1 10 100

Analysis 3.1. Comparison 3 Meningitis-related mortality, Outcome 1 Meningitis-related mortality.
Comparison: 3 Meningitis-related mortality
Outcome: 1 Meningitis-related mortality

Eftekhar 2004 1/53 0/56 24.3 % 3.23 [ 0.13, 81.01 ]
Klastersky 1976 0/26 1/26 75.7 % 0.32 [ 0.01, 8.24 ]
Total (95% CI) 109 99 100.0 % 1.03 [ 0.14, 7.40 ]

0.02 0.1 1 10 50
Analysis 4.1. Comparison 4 Need for surgical correction in patients with CSF leakage, Outcome 1 Need for
surgical correction in patients with CSF leakage.
Comparison: 4 Need for surgical correction in patients with CSF leakage
Outcome: 1 Need for surgical correction in patients with CSF leakage

Eftekhar 2004 0/53 0/56 Not estimable
Total (95% CI) 53 56 Not estimable

Test for overall effect: not applicable
0.02 0.1 1 10 50
Analysis 5.1. Comparison 5 Non-CNS infection, Outcome 1 Non-CNS infection.
Comparison: 5 Non-CNS infection
Outcome: 1 Non-CNS infection

1 CSF leakage (rhinorrhoea or otorrhoea)

Klastersky 1976 4/26 6/26 100.0 % 0.61 [ 0.15, 2.46 ]
Total (95% CI) 26 26 100.0 % 0.61 [ 0.15, 2.46 ]

0.02 0.1 1 10 50
APPENDICES
Appendix 1. Embase.com search strategy

31. #27 AND #30
30. #28 OR #29
29. random*:ab,ti OR placebo*:ab,ti OR factorial*:ab,ti OR crossover*:ab,ti OR ’cross over’:ab,ti OR assign*:ab,ti OR allocat*:ab,ti
OR volunteer*:ab,ti OR ((singl* OR doubl*) NEAR/2 (blind* OR mask*)):ab,ti
28. ’randomized controlled trial’/exp OR ’single blind procedure’/exp OR ’double blind procedure’/exp OR
’crossover procedure’/exp
27. #3 AND #9 AND #26
26. #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24
OR #25
25. ’brain hemorrhage’/exp
24. ’cerebrospinal fluid otorrhea’/de OR ’cerebrospinal fluid rhinorrhea’/de
23. (csf NEAR/5 (fistula* OR leakage*)):ab,ti
22. hygroma*:ab,ti
21. ’subdural effusion’/de
20. (cranio* NEAR/3 traum*):ab,ti
19. ’cerebrospinal fluid’/de
18. (battl* NEAR/2 sign*):ab,ti
17. (fractur* NEAR/3 (skull OR brain OR temporal OR basilar OR frontobasilar OR basal OR base)):ab,ti
16. ’skull base fracture’/exp
15. (head NEAR/3 (injur* OR traum*)):ab,ti
14. (penetrat* NEAR/3 head*):ab,ti
13. ((craniocerebral OR cranial) NEAR/3 (injur* OR traum*)):ab,ti
12. ’head injury’/exp
11. (brain NEAR/3 (injur* OR traum* OR contusio* OR lacerat*)):ab,ti
10. ’brain injury’/exp
9. #4 OR #5 OR #6 OR #7 OR #8
8. infect*:ab,ti
7. meningit*:ab,ti
6. ’meningitis’/exp
5. ’infection’/de OR ’bacterial infection’/de
4. ’central nervous system infection’/de
3. #1 OR #2
2. antibiotic*:ab,ti OR antimicrob*:ab,ti OR antibacter*:ab,ti OR bacteriocid*:ab,ti OR antimycobacter*:ab,ti
1. ’antibiotic agent’/exp
Appendix 2. LILACS search strategy
Database: LILACS
Search on: “premedication, ANTIBIOTIC” or “ANTIBIOTIC drugs” or “ANTIBIOTIC premedication” or “ANTIBIOTIC pro-
phylaxis” or “ANTIBIOTICs” or “ANTIBIOTICs, carbapenem” or “ANTIBIOTICs, cephalosporin” or “ANTIBI-
OTICs, cephamycin” or “ANTIBIOTICs, monobactam” or “ANTIBIOTICs, penicillin” [Subject descriptor] and (
“MENINGITIS” ) or “bacterial MENINGITIS” or “MENINGITIS, bacterial” [Subject descriptor] and Tw estud$ OR
Tw clin$ or AB grupo$ or CT COMPARATIVE STUDY OR Tw placebo$ or Tw compara$ or Ti tratamiento or Tw
control$ or MH/dt [Words]
Appendix 3. Previous searches

We searched the Cochrane Register of Controlled Trials (CENTRAL) (The Cochrane Library 2005, Issue 3), which contains the
Cochrane Acute Respiratory Infections (ARI) Group’s Specialised Register, MEDLINE (1966 to September 2005), EMBASE (1974 to
June 2005) and LILACS (1982 to September 2005). We also performed an electronic search of meeting proceedings of the American
Association of Neurological Surgeons (1997 to September 2005) and handsearched the abstracts of meeting proceedings of the European
Association of Neurosurgical Societies (1995, 1999 and 2003).
The search strategy for MEDLINE and CENTRAL is given below. It was combined with all three stages of the optimal trial search
strategy (Dickersin 1994). The search strategy was modified for EMBASE and LILACS.
1. exp Anti Bacterial Agents/
2. antibiotic$.tw
3. antimicrob$.tw
4. antibacter$.tw
5. Bacteriocid$.tw
6. Antimycobacter$.tw
7. or/1-6
8. exp Central Nervous System Infections/
9. exp Infection/
10. infect$.tw
11. meningit$.tw
12. or/8-11
13. exp Brain Injuries/
14. brain and injur$.tw
15. brain and traum$.tw
16. brain and contusio$.tw
17. brain and laceratio$.tw
18. exp Craniocerebral Trauma/
19. cranial and injur$.tw
20. cranial and traum$.tw
21. craniocerebral and injur$.tw
22. craniocerebral and traum$.tw
23. exp Head Injuries, Penetrating/
24. head and injur$.tw
25. head and traum$.tw
26. exp Skull Fractures/
27. skull and fractur$.tw
28. brain and fractur$.tw
29. temporal and fractur$.tw
30. basilar and fractur$.tw
31. Battle$.tw
32. frontobasilar and fractur$.tw
33. basal and skull and fractur$.tw
34. base and skull and fractur$.tw
35. Cerebrospinal fluid/
36. cranio$ and traum$.tw
37. Subdural effusion/
38. hygroma.tw
39. cerebrospinal and fluid and fistul$.tw
40. CSF$ and fistul$.tw
41. cerebrospinal and fluid and leakag$.tw
42. CSF$ and fistul$.tw
43. Cerebrospinal Fluid Rhinorrhea/
44. Cerebrospinal Fluid Otorrheas/
45. or/13-44
46. 7 and 12 and 45
47. limit 46 to human
WHAT’S NEW
Last assessed as up-to-date: 16 February 2011.
Date Event Description
17 February 2011 New search has been performed Searches conducted. No new trials were included or
excluded in this update
10 January 2011 New citation required but conclusions have not A new author joined the review team to update this
changed review.
HISTORY
Protocol first published: Issue 3, 2004
Review first published: Issue 1, 2006
Date Event Description
26 July 2008 Amended Converted to new review format.
25 September 2005 New search has been performed Searches conducted.
CONTRIBUTIONS OF AUTHORS
Drafting of review versions: BR, JC, CS, LP
Search for trials: BR, JC, LP
Obtaining copies of trial reports: BR, JC, LP
Selection of trials for inclusion/exclusion: BR, JC, CS, LP
Extraction of data: BR, JC, LP
Entry of data (in RevMan): BR, JC, LP
Interpretation of data analyses: BR, JC, CS, LP
DECLARATIONS OF INTEREST
None known.
SOURCES OF SUPPORT
Internal sources
• Clinical Therapeutics Institute, Lisbon Faculty of Medicine, Portugal.
• Centro Cochrane Iberoamericano, Spain.
External sources
• No sources of support supplied
INDEX TERMS
Medical Subject Headings (MeSH)

∗ Antibiotic Prophylaxis; Cerebrospinal Fluid Leak; Cerebrospinal Fluid Rhinorrhea [complications]; Meningitis, Bacterial [etiology;
∗ prevention & control]; Randomized Controlled Trials as Topic; Skull Fracture, Basilar [∗ complications]
MeSH check words

Humans

Antibiotic Prophylaxis For Preventing Meningitis in Patients With Basilar Skull Fractures (Review)

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Antibiotic Prophylaxis For Preventing Meningitis in Patients With Basilar Skull Fractures (Review)

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Antibiotic prophylaxis for preventing meningitis in patients

with basilar skull fractures (Review)

Ratilal BO, Costa J, Sampaio C, Pappamikail L

Antibiotic prophylaxis for preventing meningitis in patients

Bernardo O Ratilal1 , João Costa2 , Cristina Sampaio2 , Lia Pappamikail1

de Medicina de Lisboa, Lisboa, Portugal

Editorial group: Cochrane Acute Respiratory Infections Group.

PLAIN LANGUAGE SUMMARY

Assessment of reporting biases

Blinding 2. All-cause mortality/meningitis-related mortality

Implications for practice ACKNOWLEDGEMENTS

MacGee 1970 {published data only} Higgins 2011

Characteristics of included studies [ordered by study ID]

Methods Randomised, controlled, 3 arms

Bias Authors’ judgement Support for judgement

Other bias Low risk No other identifiable sources of bias

Methods Randomised, controlled, not blinded, 2 arms

Participants Inclusion criteria: acute traumatic pneumocephalus verified by CT scan

Notes Author was contacted and kindly provided additional information

Bias Authors’ judgement Support for judgement

Other bias Low risk No other identifiable sources of bias

Methods Randomised, controlled, blinded, 3 arms

Participants Inclusion criteria: diagnosis of BSF based on clinical or radiographic evidence

Interventions Patients were assigned randomly and blindly to one of 3 groups:

Outcomes Primary outcome event was development of CNS infection

Bias Authors’ judgement Support for judgement

Other bias Unclear risk Insufficient information to assess whether

Methods Randomised, controlled, 2 arms

Participants Inclusion criteria: diagnosis of BSF

Bias Authors’ judgement Support for judgement

Other bias Low risk No other identifiable sources of bias

Methods Randomised, placebo-controlled, double-blind, 2 arms

Participants Inclusion criteria: recent cranial trauma and rhinorrhoea or otorrhoea

Outcomes Outcome events were:

Bias Authors’ judgement Support for judgement

Other bias Low risk No other identifiable sources of bias

Study Reason for exclusion

Characteristics of ongoing studies [ordered by study ID]

Methods Randomised controlled clinical trial

Participants 200 selected head injury patients with traumatic pneumocephalus

Outcomes Primary outcome: frequency of bacterial meningitis

Contact information eftekhar@sina.tums.ac.ir

Notes Author contacted on March 2011, with no additional relevant results

Comparison 1. Frequency of meningitis

Comparison 2. All-cause mortality

Comparison 3. Meningitis-related mortality

Comparison 4. Need for surgical correction in patients with CSF leakage

Analysis 1.1. Comparison 1 Frequency of meningitis, Outcome 1 Frequency of meningitis by subgroup.

Comparison: 1 Frequency of meningitis

Outcome: 1 Frequency of meningitis by subgroup

Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio

1 CSF leakage (rhinorrhoea or otorrhoea)

Eftekhar 2004 4/6 4/6 11.6 % 1.00 [ 0.09, 11.03 ]

Klastersky 1976 0/26 1/26 12.8 % 0.32 [ 0.01, 8.24 ]

Subtotal (95% CI) 51 41 41.3 % 0.44 [ 0.09, 2.15 ]

Eftekhar 2004 6/47 8/50 58.7 % 0.77 [ 0.25, 2.41 ]

Subtotal (95% CI) 53 53 58.7 % 0.77 [ 0.25, 2.41 ]

Subtotal (95% CI) 5 5 Not estimable

Analysis 1.2. Comparison 1 Frequency of meningitis, Outcome 2 Frequency of meningitis.

Comparison: 1 Frequency of meningitis

Outcome: 2 Frequency of meningitis

Study or subgroup Treatment Control Odds Ratio Weight Odds Ratio

Eftekhar 2004 10/53 12/56 73.4 % 0.85 [ 0.33, 2.18 ]