Antibiotic prophylaxis for preventing meningitis in patients with basilar skull fractures

Abstract

Background

Basilar skull fractures 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 has not been established.

Objectives

To evaluate the effectiveness of prophylactic antibiotics for preventing meningitis in patients with basilar skull fractures.

Search methods

We searched CENTRAL (2014, Issue 5), MEDLINE (1966 to June week 1, 2014), EMBASE (1974 to June 2014) and LILACS (1982 to June 2014). 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 in order to compare results.

Data collection and analysis

Three review authors independently screened and selected trials, assessed risk of bias and extracted data. We sought clarification with trial authors when needed. We pooled risk ratios (RRs) for dichotomous data with their 95% confidence intervals (CIs) using a random‐effects model. We assessed the overall quality of evidence using the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach.

Main results

In this update we did not identify any new trials for inclusion. We included five RCTs with 208 participants in the review and meta‐analysis. We also identified 17 non‐RCTs comparing different types of antibiotic prophylaxis with placebo or no intervention in patients with basilar skull fractures. Most trials presented insufficient methodological detail. All studies included meningitis in their primary outcome. When we evaluated the five included RCTs, there were 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), which produced results consistent with the randomised data from the included studies.

Using the GRADE approach, we assessed the quality of trials as moderate.

Authors' conclusions

Currently available evidence from RCTs does not support prophylactic antibiotic use in patients with basilar skull fractures, whether there is evidence of CSF leakage or not. Until more research is available, the effectiveness of antibiotics in patients with basilar skull fractures 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

Review question

Is it beneficial for patients with basilar skull fractures to receive a course of intravenous antibiotics?

Background

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 the 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.

Study characteristics

This review examined five randomised controlled trials, comprising a total of 208 participants with basilar skull fracture, which compared those who received preventive antibiotic therapy with those who did not receive antibiotics, to establish how many participants developed meningitis. The evidence is current to June 2014.

Key results

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 increased susceptibility to infection with more pathogenic (disease‐causing) organisms. We suggest that research is needed 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.

Quality of the evidence

We ranked the evidence as being of moderate quality because it is based on randomised data, although with some methodological limitations in design that caused us to downgrade the quality of the trials.

Summary of findings

for the main comparison.

Antibiotic prophylaxis compared with placebo for preventing meningitis in BSF
Patient or population: patients with a recent BSF independent of the presence or severity of CSF leakage Settings: in‐hospital care Intervention: antibiotic prophylaxis Comparison: placebo
Outcomes	Relative effect (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)	Comments
Frequency of meningitis	OR 0.69 (0.29 to 1.61)	208 (4)	⊕⊕⊕⊝ moderate1
All‐cause mortality	OR 1.68 (0.41 to 6.95)	208 (4)	⊕⊕⊕⊝ moderate1
Meningitis‐related mortality	OR 1.03 (0.14 to 7.40)	208 (4)	⊕⊕⊕⊝ moderate1
Need for surgical correction in patients with CSF leakage	Not estimable	109 (1)	⊕⊕⊝⊝ low2
Non‐CNS infection	OR 0.61 (0.15 to 2.46)	52 (1)	⊕⊕⊕⊕ high
BSF: basilar skull fracture; CI: confidence interval;CNS: central nervous system; CSF: cerebrospinal fluid; OR: odds ratio
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

¹Downgraded for limitations in study design as two of the four studies had unclear blinding of allocation and outcome assessment leading to possible selection and detection bias; also unclear risk of reporting bias in one study.

² Downgraded this single study, with concurrent limitations in study design (non‐blinded outcome assessment, leading to potential detection bias).

Background

Description of the condition

The estimated incidence of basilar skull fracture from non‐penetrating head trauma varies between 7% and 15.8% of all skull fractures, with associated cerebrospinal fluid (CSF) leakage occurring in 2% to 20.8% of patients (Buchanan 2004). Clinical signs that may lead a physician to suspect a basilar skull fracture include CSF otorrhoea or rhinorrhoea, bilateral periorbital ecchymosis, Battle's sign, peripheral facial nerve palsy, haemotympanum or tympanic membrane perforation with blood in the external auditory canal, hearing loss, evidence of vestibular dysfunction and anosmia. High‐resolution bone computed tomographic (CT) scans have dramatically improved the radiological diagnosis of this type of fracture. Basilar skull fractures are of special significance because the dura mater may be torn adjacent to the fracture site, placing the central nervous system (CNS) in contact with bacteria from the paranasal sinuses, nasopharynx or middle ear. If the dura mater is torn, CSF leakage could occur. Basilar skull fractures will predispose the patient to meningitis. A greater associated risk has been reported when CSF leakage exists, in particular if it persists for more than seven days (Leech 1973).

Description of the intervention

The role of prophylactic antibiotics for preventing bacterial meningitis in patients with basilar skull fractures is controversial. Growing concern about the emergence of resistant organisms argues against their use. In addition, there are reports of a higher incidence of meningitis in patients with basilar skull fractures who have received prophylactic antibiotics (Choi 1996).

How the intervention might work

Chemoprophylaxis with antibiotics in basilar skull fractures may reduce the incidence of meningitis.

Why it is important to do this review

A meta‐analysis showed a statistically significant reduction in the incidence of meningitis with prophylactic antibiotic therapy for patients with post‐traumatic CSF leakage (Brodie 1997). Another meta‐analysis concluded that antibiotic prophylaxis after a basilar skull fracture does not appear to decrease the risk of meningitis, independent of whether or not CSF leakage has occurred (Villalobos 1998). These studies did not include an extensive review of the literature; both 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 led us to decide to search for and analyse evidence for the use of prophylactic antibiotics for preventing bacterial meningitis in patients with a basilar skull fracture.

Objectives

To evaluate the effectiveness of prophylactic antibiotics for preventing meningitis in patients with basilar skull fractures.

Methods

Criteria for considering studies for this review

Types of studies

Randomised controlled trials (RCTs) comparing any antibiotic versus placebo or no intervention. We also identified non‐RCTs to perform a separate meta‐analysis in order to compare results.

Types of participants

Patients of any age with a recent basilar skull fracture, independent of the presence and severity of CSF leakage.

Types of interventions

Any antibiotic administered at the time of primary treatment of the basilar skull fracture compared with placebo or no antibiotic. We excluded trials comparing different antibiotics, different antibiotic dosages, different routes of administration, or differences in the timing or duration of administration.

Types of outcome measures

Primary outcomes

1. Frequency of meningitis: suspected clinically (fever, neck stiffness, deterioration of neurological status, headache) and confirmed by lumbar puncture (CSF analysis including biochemistry, Gram stains or bacteriological cultures (or both)).

Secondary outcomes

1. All‐cause mortality/meningitis‐related mortality.

2. Need for surgical correction in patients with CSF leakage.

3. Non‐CNS infection.

Search methods for identification of studies

Electronic searches

For this update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 5) (accessed 18 June 2014), which contains the Cochrane Acute Respiratory Infections (ARI) Group's Specialised Register, MEDLINE (January 2011 to June week 1, 2014), EMBASE (January 2011 to June 2014) and LILACS (2011 to June 2014). Previous searches are described in Appendix 1.

We used the search strategy described in Appendix 2 to search MEDLINE and CENTRAL. We used no filter for the MEDLINE search as we wished to identify both randomised and non‐randomised studies and the number of search results was manageable without a filter. We adapted the search strategy for EMBASE (Appendix 3) and LILACS (Appendix 4). We applied no language or publication restrictions.

Searching other resources

We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for completed and ongoing trials (27 June 2014). We screened titles, keywords and abstracts of the citations downloaded from the electronic searches and obtained full copies of reports of potentially suitable trials for further assessment. The search strategy also included a search of the reference lists of identified trials and basilar skull fracture review articles, and personal communication with other researchers in the field. We handsearched abstracts of meeting proceedings from the European Association of Neurosurgical Societies (1995, 1999 and 2003). We were unable to search the latter source in this 2014 update (see Differences between protocol and review).

We contacted researchers active in the field, for information regarding unpublished trials. We also contacted authors of published trials for further information and unpublished data. We did not apply any language restrictions.

Data collection and analysis

Selection of studies

Three review authors (BR, JC, LP) independently assessed the studies identified by the search strategy, to identify potentially suitable trials for the review according to the criteria outlined above. We resolved disagreements by discussion with the fourth author (CS).

Data extraction and management

Three authors (BR, JC, LP) independently assessed the full papers for type of participants, type and dose of antibiotic used, methodological quality, number of patients excluded or lost to follow‐up and the outcome measures stated in the protocol. We recorded extracted data on a data collection form. We resolved disagreements by discussion.

Assessment of risk of bias in included studies

We investigated sources of bias. Two authors (LP, BR) independently assessed the global quality of included trials using the 'Risk of bias' assessment tool, as outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We resolved disagreements by discussion.

Unit of analysis issues

We performed statistical analysis using Review Manager software (RevMan 2014). We calculated the significance of any differences between ORs using a standard method (Egger 2001).

Dealing with missing data

We contacted the original trial authors whenever relevant missing data were detected.

Assessment of heterogeneity

We performed statistical analyses using the statistical software provided by the Cochrane Collaboration (RevMan 2014). We investigated statistical heterogeneity between trial results using the I² statistic (Higgins 2002).

Assessment of reporting biases

We would have assessed publication bias according to the recommendations 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 asymmetry had been identified.

Data synthesis

We reported the results of meta‐analysis as odds ratios (ORs) and 95% confidence intervals (CIs) for dichotomous outcomes.

Subgroup analysis and investigation of heterogeneity

We previously planned to investigate heterogeneity by undertaking a subgroup analysis of patients with or without CSF leakage in the event of uncovering significant heterogeneity.

Sensitivity analysis

We performed a meta‐analysis of all the controlled, non‐randomised studies identified in order to evaluate the consistency of the results of the main meta‐analysis.

Summarising and interpreting results

We used the GRADE (Grades of Recommendation, Assessment, Development and Evaluation) approach to interpret findings (Schünemann 2011) and used GRADE profiler (GRADEpro 2014) to import data from RevMan 2014 to create Table 1. This table provides information on the quality of evidence from studies, the magnitude of effects of the interventions examined, and the sum of available data on all important outcomes from each study included in the comparison. The GRADE approach (Schünemann 2011) considers 'quality' to be a judgement of the extent to which we can be confident that the estimates of effect are correct. We downgraded evidence from randomised controlled studies that was initially graded as 'high quality', by one or two levels on each of five domains after full consideration of any limitations in the design of the studies, indirectness (or applicability) of the evidence, inconsistency, imprecision of the effect estimates, and the possibility of publication bias.

A GRADE quality level of 'high' reflects confidence that the true effect lies close to the estimate of the effect of a given outcome. A judgement of 'moderate' quality indicates that the true effect is likely to be close to the estimate of the effect, but acknowledges that it could be substantially different. Evidence of 'low' and 'very low' quality limits our confidence in the effect estimate (Balshem 2011).

We selected the following outcomes for Table 1.

1. Frequency of meningitis.

2. All‐cause mortality.

3. Meningitis‐related mortality.

4. Need for surgical correction of CSF leakage.

5. Non‐CNS infection.

Results

Description of studies

Results of the search

In this 2014 update we retrieved a total of 794 records. The 2011 update retrieved a total of 168 new records (when duplicates were removed from searches of MEDLINE (28 records), EMBASE (118 records), CENTRAL (14 records) and LILACS (eight records)) (Figure 1). This 2014 update yielded the addition of six new excluded studies.

1.

Study flow diagram.

This review identified five RCTs comparing prophylactic antibiotics in basilar skull fracture with placebo or no antibiotics (Demetriades 1992; Eftekhar 2004; Hoff 1976; Ignelzi 1975a; Klastersky 1976).

Included studies

Meningitis in patients with basilar skull fractures

We found five RCTs with available data comparing prophylactic antibiotics in basilar skull fractures with placebo or no antibiotics (Demetriades 1992; Eftekhar 2004; Hoff 1976; Ignelzi 1975a; Klastersky 1976) (see Characteristics of included studies). All these studies were single‐centre, conducted in South Africa, Iran, USA or Belgium, and were published between 1975 and 2004. All had a parallel design and were stated by the trial authors to be randomised, although the method of randomisation was not clearly described in any trial report.

All trials included participants with a clinical or radiological diagnosis of basilar skull fracture. Entry criteria did not differ considerably. Exceptions were the Hoff 1976 trial, in which CSF leakage was an exclusion 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 meningitis. In three trials the primary outcome was a composite outcome that also included extracranial infection (wound sepsis, pneumonia, urinary tract infection), bacterial colonisation of bronchial secretions or urine, change in the posterior nasopharyngeal flora, or death from brain damage (Demetriades 1992; Ignelzi 1975a; Klastersky 1976). Criteria for these diagnoses were based on clinical grounds and further investigations and prophylactic medication were commenced as soon as the diagnosis of basilar skull fracture was made in all trials. None of the studies reported data on outcomes of safety and tolerability of prophylactic antibiotics.

Ignelzi 1975a performed a small controlled trial with 10 participants with basilar skull fractures that was included in a report of a larger retrospective study. The presence of CSF fistulae in these participants was not described and the participants were randomised to one group 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 participants and compared five mega units of penicillin G given intravenously six‐hourly for a mean duration of 7.7 days; the placebo was given under identical conditions.

Hoff 1976 enrolled 160 participants assigned randomly and blindly to one of three groups: no antibiotic (group 1), 1.2 million units of intravenous penicillin daily for three days (group 2), or 20 million units of intravenous penicillin daily for three days (group 3). No cases of meningitis were found but the numbers of participants enrolled in each group were not provided. Although we have contacted the trial author, further information was no longer available.

Demetriades 1992 randomised 37 participants to three groups: no antibiotic (group A), 1 g intravenous ceftriaxone daily for three days (group B), or combined ampicillin (1 g intravenous six‐hourly)/sulphadiazine (0.5 g intravenous six‐hourly) (group C).

Eftekhar 2004 studied 109 participants with acute traumatic pneumocephalus verified by a CT scan, who were followed until occurrence of meningitis or at least for five days post‐trauma. They randomised the participants to one of two groups: the prophylactic antibiotic treatment given (PAT+) group, in which ceftriaxone was administered at a dose of 1 g twice a day for five days; and the prophylactic antibiotic treatment not given (PAT‐) group, in which ceftriaxone was not administered.

Overall, 368 participants were enrolled in these five studies. Two of them enrolled 73% of these participants (Eftekhar 2004; Hoff 1976). Since we could not access the number of participants included in each group of the Hoff 1976 trial, we could not include it in the meta‐analysis. We therefore analysed a total of 208 participants from four RCTs: 109 participants in the treatment group and 99 in the control group.

In three trials participants were well matched between the treatment and control arms for demographics, clinical status at admission and presence of rhinorrhoea or otorrhoea (Demetriades 1992; Eftekhar 2004; Klastersky 1976). The other trials did not describe the characteristics of the population included in each group (Hoff 1976; Ignelzi 1975a).

Two studies provided sufficient descriptions for withdrawals and dropouts to determine the number of participants in each treatment group entering and completing the trial (Demetriades 1992; Klastersky 1976).

Meningitis in participants with basilar skull fracture concerning the presence of CSF leakage

There was only one study in which the presence of CSF leakage was not specified (Ignelzi 1975a). CSF leakage was an exclusion criteria in the Hoff 1976 study. Traumatic rhinorrhoea or otorrhoea had to be present in the participants included in the Klastersky 1976 study. The other two trials included participants with and without CSF leakage (Demetriades 1992; Eftekhar 2004).

Excluded studies

The Characteristics of excluded studies table contains all studies that have been systematically reviewed. We excluded 23 studies. Of these, 15 were retrospective controlled studies (Ash 1992; Choi 1996; Clemenza 1995; Dagi 1983; Einhorn 1978; Eljamel 1993; Frazee 1988; Friedman 2001; Helling 1988; MacGee 1970; McGuirt 1995; Raskind 1965; Steidtmann 1997; Tos 1973; Zrebeet 1986), four were prospective observational studies with an historical control group (Gonzalez 1998; Ibrahim 2012; Ignelzi 1975b; Lauder 2009), three were author statements and opinion (Bellamy 2013; Prosser 2011; Sherif 2012), and one was a randomised controlled trial with both groups receiving antibiotics for orbital blow‐out fractures (Zix 2013). There was no specification about the presence of CSF leakage in seven of these studies (Ash 1992; Gonzalez 1998; Helling 1988; Ignelzi 1975b; Lauder 2009; Prosser 2011; Tos 1973). Eight included only participants with CSF leakage, either otorrhoea or rhinorrhoea (Clemenza 1995; Eljamel 1993; Friedman 2001; Ibrahim 2012; MacGee 1970; McGuirt 1995; Raskind 1965; Sherif 2012), and one excluded participants with CSF leak (Zix 2013).

The remaining six studies included participants with or without CSF leakage (Choi 1996; Dagi 1983; Einhorn 1978; Frazee 1988; Steidtmann 1997; Zrebeet 1986). Overall, 2168 participants were included in these 17 studies, in which 1141 participants were treated with antibiotics and 1027 participants were not.

Risk of bias in included studies

The overall risk of bias is presented graphically in Figure 2 and summarised in Figure 3. (See Characteristics of included studies).

2.

'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages across all included studies.

3.

'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.

Allocation

All studies stated that patients were randomised between the treatment and control groups. The precise method of randomisation and details of concealment of allocation were not explained in any trial. We considered the method of allocation to be unclear in all trials.

Blinding

Only one study was double‐blinded throughout, using interventions of identical appearance (antibiotics or placebo) (Klastersky 1976). The other studies were not placebo‐controlled and did not measure outcomes blindly. In addition, only two studies reported the number of and reasons for patients leaving the trials (Demetriades 1992; Klastersky 1976).

Data were analysed on a per‐protocol basis in all trials.

Incomplete outcome data

Missing data precluded several planned analyses in this systematic 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 further information for some of the other studies, but without success. As previously stated, the number of patients in each group was not accessible in the Hoff 1976 study; although none of the 160 patients enrolled had meningitis, we could not include this trial in the meta‐analysis.

Other potential sources of bias

We identified no other potential sources of bias.

Effects of interventions

See: Table 1

We were able to perform a meta‐analysis with five of the randomised controlled trials (RCTs) included in this review. Since we primarily aimed to compare prophylactic antibiotics with no antibiotic or placebo in patients with basilar skull fractures and to identify the influence of cerebrospinal fluid (CSF) leakage on the frequency of meningitis in these patients, we performed a subgroup analysis of patients with and without CSF leakage. We tested statistical heterogeneity between trial results using the I² statistic and found no evidence of heterogeneity in any of the outcomes measured (I² statistic = 0%).

The efficacy outcomes did not show significant differences between treatment and control groups in any of the included trials, when considering either the total population or the subgroup of patients with CSF leakage. (See Summary of main results).

Primary outcome

1. Frequency of meningitis

We found no significant differences for this outcome (odds ratio (OR) 0.69; 95% confidence interval (CI) 0.29 to 1.61) (Analysis 1.2). In addition, we found no differences in the subgroups of patients with CSF leakage (OR 0.44; 95% CI 0.09 to 2.15) or without CSF leakage (OR 0.77; 95% CI 0.25 to 2.41) (Analysis 1.1 ‐ 1.1.1 and 1.1.2). Using GRADE, we graded the evidence as being of moderate quality since there was potential selection and detection bias in two of the four RCTs as well as unclear risk of reporting bias in one study (Table 1).

1.2. Analysis.

Comparison 1 Comparison of frequency of meningitis with antibiotic prophylaxis versus no antibiotic, Outcome 2 Frequency of meningitis.

1.1. Analysis.

Comparison 1 Comparison of frequency of meningitis with antibiotic prophylaxis versus no antibiotic, Outcome 1 Frequency of meningitis by subgroup.

Secondary outcomes

1. All‐cause mortality/meningitis‐related mortality

We accessed relevant data from the five trials. We found no significant differences for all‐cause mortality (OR 1.68; 95% CI 0.41 to 6.95) (Analysis 2.1) or for meningitis‐related mortality (OR 1.03; 95% CI 0.14 to 7.40) (Analysis 3.1). We rated the evidence using GRADE as moderate quality, since there was potential selection and detection bias in two of the four RCTs as well as unclear risk of reporting bias in one study (Table 1).

2.1. Analysis.

Comparison 2 Comparison of all‐cause mortality with antibiotic prophylaxis versus no antibiotic, Outcome 1 All‐cause mortality.

3.1. Analysis.

Comparison 3 Comparison of meningitis related mortality with antibiotic prophylaxis versus no antibiotic, Outcome 1 Meningitis‐related mortality.

2. Need for surgical correction in patients with CSF leakage

Only one study provided data for this secondary outcome and no participants in either treatment or control groups underwent surgical correction for CSF leakage in this trial (Eftekhar 2004) (Analysis 4.1). We rated the quality of evidence as low quality according to GRADE, since it pertained to a single study with potential detection bias (Table 1).

4.1. Analysis.

Comparison 4 Comparison of the need for surgical correction in patients with CSF leakage with antibiotic prophylaxis versus no antibiotic, Outcome 1 Need for surgical correction in patients with CSF leakage.

3. Non‐central nervous system (CNS) infection

Only one study provided data for this outcome (Klastersky 1976). No significant differences were found (OR 0.61; 95% CI 0.15 to 2.46) (Analysis 5.1). We rated the evidence as high quality, since although extracted from a single RCT, there was little risk of bias and few concerns raised regarding inconsistency, indirectness or imprecision (Table 1).

5.1. Analysis.

Comparison 5 Comparison of frequency of non‐CNS infection with antibiotic prophylaxis versus no antibiotic, Outcome 1 Non‐CNS infection.

Meta‐analysis of controlled non‐randomised studies identified

In order to study the consistency of these results we performed a meta‐analysis of all the controlled non‐randomised studies identified and previously described in the Excluded studies section. Globally, these studies enrolled 2168 participants (treatment group 1141; control group 1027). Tests for heterogeneity were not statistically significant (Chi² test, P value = 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 value = 0.65) (random‐effects model OR 1.13; 95% CI 0.67 to 1.88). Individually, only one study showed a significant difference favouring the treatment group (OR 0.47; 95% CI 0.25 to 0.88) (Eljamel 1993). This study contributed most to the results (weight 19.4%), but it did not impact significantly on the direction of the results. Additionally, we performed a subgroup analysis for patients with CSF leakage (529 participants in the treatment group and 260 in the control group) and without CSF leakage (334 participants in the treatment group and 292 in the control group). In five studies the presence of CSF leakage was not specified (278 participants in treatment groups and 475 in control groups) (Ash 1992; Gonzalez 1998; Helling 1988; Ignelzi 1975b; Tos 1973). The OR (random‐effects model) for participants with CSF leakage was 0.61 (95% 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 data were available regarding the presence of CSF leakage, the OR was 2.01 (95% CI 0.91 to 4.44).

We found no statistically significant differences for all‐cause mortality in the eight studies in which relevant data were available (Ash 1992; Einhorn 1978; Frazee 1988; Friedman 2001; Ignelzi 1975b; MacGee 1970; McGuirt 1995; Zrebeet 1986). These included 460 participants in the treatment group and 265 in the control group (random‐effects model OR 0.78; 95% CI 0.26 to 2.28). We found no significant differences for meningitis‐related mortality (random‐effects model OR 0.43; 95% CI 0.08 to 2.29).

Discussion

Summary of main results

Curiously, the frequency of meningitis in the Eftekhar 2004 trial was significantly higher than in the other trials. The diagnosis of meningitis was based on cerebrospinal fluid (CSF) analysis in participants with compatible clinical findings and was comparable with the other trials. However, Eftekhar 2004 included only the subset of patients with basilar skull fractures and pneumocephalus that is associated with a dural tear with an open communication with air in the paranasal sinuses, mastoid air cells or petrous temporal regions and the central nervous system (CNS). These participants with pneumocephalus might have had an additional risk factor for developing meningitis that may have been independent of CSF leakage. The same authors developed a trial with the intent to clarify this hypothesis but it was not completed and no data were available upon contacting the author (Eftekhar 2006). Further investigations are necessary to clarify this issue.

Given the current data, it is not possible to recommend the use of prophylactic antibiotics in patients with basilar skull fractures. Our results did not show that the administration of antibiotics had an effect on the frequency of meningitis. No significant difference was found in the subgroup of participants with CSF leakage, although there was a tendency to favour the treatment group. Again, no significant difference was found for all‐cause or meningitis‐related mortality. Although no significant differences were found, the confidence interval (CI) for 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 number of participants enrolled and the small number of events recorded.

The global results of the analysis of data extracted from the excluded studies are in agreement with the randomised data. Subgroup analysis within the excluded trials suggests a benefit from antibiotic prophylaxis in patients with CSF leakage. However, treatment interventions caused significantly more meningitis in the subgroup of patients without specification regarding CSF leakage status. These analyses should be read with caution since they are based mostly on retrospective studies and the data are not randomised. Additionally, the types of participants, interventions, diagnoses and outcome measures were significantly different between these studies. This makes the data difficult to interpret. Nevertheless, we thought it would be interesting to compare data from randomised controlled trials (RCTs) with non‐RCTs since non‐randomised studies tend to overestimate treatment effect size, which may be the case here.

According to the frequency of events in the treatment and control groups, and the relative risk for meningitis in the subgroup of patients with CSF leakage (0.64), a sample size of 798 participants 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 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 antibiotics in basilar skull fractures. Based on the analysis of five RCTs, there is insufficient evidence to support or refute the use of antibiotics to prevent meningitis in patients with basilar skull fractures.

Overall completeness and applicability of evidence

There is no support for routine prophylactic antibiotics in all patients with a basilar skull fracture. Further RCTs are needed to assess the benefits and risks clearly.

Quality of the evidence

The quality of the evidence available to evaluate the use of prophylactic antibiotics in basilar skull fractures was indicated by the identification of only five RCTs that we considered suitable for this review. Even these had important methodological shortcomings. In general, the quality of the included trials was poor, as assessed by the 'Risk of bias' tool (Higgins 2011). All trials used a per‐protocol based analysis. For the Eftekhar 2004 trial we had access to unpublished data that allowed us to perform some comparisons. We were able to study a total of 208 participants.

We assessed the quality of evidence using the GRADE method (GRADEpro 2014). We judged the quality of evidence for the effect on frequency of meningitis, all‐cause mortality and meningitis‐related mortality as being of moderate quality due to potential selection, detection and reporting bias in two of the four studies. We assessed the evidence for the effect on need for surgical correction for CSF leakage to be of low quality, since it was extracted from a single study with potential detection bias. We judged the evidence on the effect of antibiotic prophylaxis on the frequency of non‐CNS infections as high quality, as there were few concerns regarding inconsistency, indirectness or imprecision, with low risk of bias of the RCT (See Table 1).

Potential biases in the review process

We attempted to minimise publication bias by checking the reference lists of all related studies for further references and searching multiple databases with a comprehensive search strategy without any language restrictions; we did not identify any ongoing trials in three clinical trial registries. We believe we reduced other sources of bias by having three authors independently conducting the study selection, quality assessment and data extraction.

Agreements and disagreements with other studies or reviews

Despite the commonality of antibiotic prophylaxis in the treatment of basilar skull fractures, surprisingly no systematic review had previously specifically evaluated the efficacy of this treatment. We found two meta‐analyses with conflicting conclusions: Brodie concluded there is a benefit of antibiotic prophylaxis (reducing the incidence of meningitis in patients with post‐traumatic cerebrospinal fluid (CSF) leakage), whilst Villalobos found no decrease in meningitis in patients with basilar skull fractures (with or without CSF leakage) afforded antibiotic prophylaxis (Brodie 1997; Villalobos 1998). The findings of our systematic review are similar to those in the Villalobos meta‐analysis.

Authors' conclusions

Implications for practice.

This systematic review did not show that prophylactic antibiotics had an effect on the prevention of meningitis in patients with basilar skull fractures, regardless of cerebrospinal fluid (CSF) leakage. Currently available evidence from RCTs does not support the use of prophylactic antibiotics in patients with basilar skull fractures. The risk of adverse reactions and financial costs are factors that should be taken into account when deciding if antibiotic therapy is appropriate.

Implications for research.

More appropriately designed RCTs to test the effectiveness of prophylactic antibiotic use following the diagnosis of basilar skull fracture are needed in order to establish whether or not there is a net benefit from this intervention. Until more research results are available, firm conclusions regarding the efficacy of this treatment cannot be provided. 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).

What's new

Date	Event	Description
17 June 2014	New search has been performed	We reran the searches in June 2014. We identified no new trials for inclusion. We excluded six new trials (Bellamy 2013; Ibrahim 2012; Lauder 2009; Prosser 2011; Sherif 2012; Zix 2013).
17 June 2014	New citation required but conclusions have not changed	Our conclusions remain unchanged.

History

Protocol first published: Issue 3, 2004
 Review first published: Issue 1, 2006

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 changed	A new author joined the review team to update this review.
26 July 2008	Amended	Converted to new review format.
25 September 2005	New search has been performed	Searches conducted.

Appendices

Appendix 1. Previous searches

For our previous update, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2011, Issue 1) (accessed 17 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).

Prior to this we searched the Cochrane Register of Controlled Trials (CENTRAL 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

Appendix 2. MEDLINE (Ovid) search strategy

1 exp Anti‐Bacterial Agents/
 2 antibiotic*.tw,nm.
 3 antimicrob*.tw,nm.
 4 antibacter*.tw,nm.
 5 bacteriocid*.tw,nm.
 6 antimycobacter*.tw,nm.
 7 or/1‐6
 8 exp Central Nervous System Infections/
 9 exp Infection/
 10 infect*.tw.
 11 exp Meningitis/
 12 meningit*.tw.
 13 or/8‐12
 14 exp Brain Injuries/
 15 (brain adj3 (injur* or traum* or contusio* or laceratio*)).tw.
 16 Craniocerebral Trauma/
 17 ((craniocerebral or cranial) adj3 (injur* or traum*)).tw.
 18 Head Injuries, Penetrating/
 19 (head adj3 (injur* or traum*)).tw.
 20 exp Skull Fractures/
 21 (fractur* adj3 (skull or brain or temporal or basilar or frontobasilar or basal or base)).tw.
 22 (battl* adj2 sign*).tw.
 23 Cerebrospinal Fluid/
 24 (cranio* adj3 traum*).tw.
 25 Subdural Effusion/
 26 hygroma*.tw.
 27 ((csf or cerebrospinal fluid) and (fistula* or leakage*)).tw.
 28 cerebrospinal fluid otorrhea/ or cerebrospinal fluid rhinorrhea/
 29 exp Intracranial Hemorrhage, Traumatic/
 30 or/14‐29
 31 7 and 13 and 30

Appendix 3. Embase.com search strategy

The following search strategy was combined with filters for randomised trials and observational studies

#1.28 #1.3 AND #1.27 #1.27 #1.9 AND #1.26  #1.26 #1.10 OR #1.11 OR #1.12 OR #1.13 OR #1.14 OR #1.15 OR #1.16 OR #1.17 OR #1.18 OR #1.19 OR #1.20 OR #1.21 OR #1.22 OR #1.23 OR #1.24 OR #1.25 #1.25 ('traumatic intracranial' NEAR/2 (haemorrhage* OR hemorrhage* OR hematoma* OR haematoma*)):ab,ti  #1.24 'cerebrospinal fluid otorrhea'/de OR 'cerebrospinal fluid rhinorrhea'/de AND [embase]/lim  #1.23 ((csf OR 'cerebrospinal fluid') NEAR/5 (fistula* OR leakage*)):ab,ti AND [embase]/lim  #1.22 hygroma*:ab,ti AND [embase]/lim  #1.21 'subdural effusion'/de  #1.20 (cranio* NEAR/3 traum*):ab,ti AND [embase]/lim  #1.19 'cerebrospinal fluid'/de AND [embase]/lim  #1.18 (battl* NEAR/2 sign*):ab,ti AND [embase]/lim  #1.17 (fractur* NEAR/3 (skull OR brain OR temporal OR basilar OR frontobasilar OR basal OR base)):ab,ti AND [embase]/lim  #1.16 'skull base fracture'/de AND [embase]/lim  #1.15 (head NEAR/3 (injur* OR traum*)):ab,ti AND [embase]/lim  #1.14 (penetrat* NEAR/3 head*):ab,ti AND [embase]/lim  #1.13 ((craniocerebral OR cranial) NEAR/3 (injur* OR traum*)):ab,ti AND [embase]/lim  #1.12 'head injury'/de AND [embase]/lim  #1.11 (brain NEAR/3 (injur* OR traum* OR contusio* OR laceratio*)):ab,ti AND [embase]/lim  #1.10 'brain injury'/exp AND [embase]/lim  #1.9 #1.4 OR #1.5 OR #1.6 OR #1.7 OR #1.8  #1.8 meningit*:ab,ti AND [embase]/lim #1.7 'meningitis'/exp AND [embase]/lim #1.6 infect*:ab,ti AND [embase]/lim  #1.5 'infection'/de AND [embase]/lim  #1.4 'central nervous system infection'/exp AND [embase]/lim  #1.3 #1.1 OR #1.2  #1.2 antibiotic*:ab,ti OR antimicrob*:ab,ti OR antibacter*:ab,ti OR bacteriocid*:ab,ti OR antimycobacter*:ab,ti AND [embase]/lim  #1.1 'antibiotic agent'/exp AND [embase]/lim

Filter for randomised trials

#2.8 #2.3 NOT #2.7 #2.7 #2.4 NOT #2.6  #2.6 #2.4 AND #2.5  #2.5 'human'/de AND [embase]/lim  #2.4 'animal'/de OR 'nonhuman'/de OR 'animal experiment'/de AND [embase]/lim  #2.3 #2.1 OR #2.2  #2.2 random*:ab,ti OR placebo*:ab,ti OR crossover*:ab,ti OR 'cross over':ab,ti OR allocat*:ab,ti OR trial:ti OR (doubl* NEXT/1 blind*):ab,ti AND [embase]/lim  #2.1 'randomized controlled trial'/exp OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'crossover procedure'/exp AND [embase]/lim

Filter for finding observational studies (based on SIGN observational filter)

'case control':ab,ti OR 'case‐control':ab,ti OR (cohort NEAR/1 (study OR studies OR analys*)):ab,ti OR ('follow up' NEAR/1 (study OR studies)):ab,ti OR (observation* NEAR/1 (study OR studies)):ab,ti OR longitudinal:ab,ti OR retrospective:ab,ti OR 'cross sectional':ab,ti AND [embase]/lim
 'case control study'/exp OR 'cohort analysis'/exp OR 'follow up'/de OR 'observational study'/de OR 'longitudinal study'/de OR 'retrospective study'/de OR 'cross‐sectional study'/de AND [embase]/lim

Appendix 4. LILACS search strategy

Database:

LILACS

Search on:

tw:((mh:"Anti‐Bacterial Agents" OR antibacterianos OR antibiotic* OR mh:d27.505.954.122.085* OR antibióticos OR antimicrob* OR antibacter* OR bacteriocid* OR antimycobacter*) AND (mh:"Central Nervous System Infections" OR mh:c01.395* OR mh:c10.228.228* OR mh:infection OR mh:c01.539* OR infect* OR infección OR infecção OR mh:meningitis OR mh:c10.228.228.507* OR mh:c10.228.566* OR meningit*) AND (mh:"Brain Injuries" OR mh:c10.228.140.199* OR mh:c10.900.300.087* OR mh:c26.260.118* OR mh:c26.915.300.200* OR "Traumatismos Encefálicos" OR "brain injuries" OR "brain injury" OR "brain trauma" OR "brain contusion" OR "brain contusions" OR "brain laceration" OR "brain lacerations" OR "Lesión Cerebral" OR "Lesiones Encefálicas" OR "Traumatismo Cerebral" OR "Traumatismos Cerebrales" OR "Contusión Encefálica" OR "Lesiones Traumáticas del Encéfalo" OR "Lesiones Encefálicas Traumáticas" OR "Laceraciones del Encéfalo" OR "Laceraciones Encefálicas" OR "Traumatismo Encefálico" OR "Lesiones del Encéfalo Traumáticas" OR "Lesão Cerebral" OR "Lesões Encefálicas" OR "Traumatismo Cerebral" OR "Traumatismos Cerebrais" OR "Contusão Encefálica" OR "Lesões Encefálicas Traumáticas" OR "Lacerações Encefálicas" OR "Traumatismo do Encéfalo" OR "Lesão Encefálica Traumática" OR mh:"Craniocerebral Trauma" OR "Traumatismos Craneocerebrales" OR "Traumatismos Craniocerebrais" OR "head injury" OR "head injuries" OR "head trauma" OR "Trauma Craneocerebral" OR "Lesión Craneocerebral" OR "Trauma Craniano" OR mh:"Head Injuries, Penetrating" OR "Traumatismos Penetrantes de la Cabeza" OR "Traumatismos Cranianos Penetrantes" OR mh:"Skull Fractures" OR mh:c10.900.300.918* OR mh:c26.260.836* OR mh:c26.404.750* OR mh:c26.915.300.745* OR "Fracturas Craneales" OR "Fraturas Cranianas" OR "skull fracture" OR "basilar fracture" "frontobasilar fracture" OR "basal fracture" OR "basilar skull fracture" OR "battle sign" OR "battle's sign" OR mh:"Cerebrospinal Fluid" OR "Líquido Cefalorraquídeo" OR "Líquido Cefalorraquidiano" OR mh:"Subdural Effusion" OR "Efusión Subdural" OR "Derrame Subdural" OR hygroma* OR mh:"Cerebrospinal Fluid Otorrhea" OR "Otorrea de Líquido Cefalorraquídeo" OR "Otorreia de Líquido Cefalorraquidiano" OR "Cerebrospinal Otorrhea" OR "Otorrea del Líquido Cerebroespinal" OR "Otorrea Cefalorraquídea" OR "Otorreia Liquórica" OR mh:"Intracranial Hemorrhage, Traumatic" OR "Traumatic Intracranial Hemorrhage" OR mh:c10.228.140.300.535.450* OR mh:c10.900.300.837* OR mh:c14.907.253.573.400* OR mh:c26.260.616* OR mh:c26.915.300.490* OR "Hemorragia Traumática Intracraneal")) AND (instance:"regional") AND ( db:("LILACS") AND year_cluster:("2012" OR "2011" OR "2013" OR "2014"))

Data and analyses

Comparison 1. Comparison of frequency of meningitis with antibiotic prophylaxis versus no antibiotic.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Frequency of meningitis by subgroup	4	208	Odds Ratio (M‐H, Fixed, 95% CI)	0.63 [0.25, 1.59]
1.1 CSF leakage (rhinorrhoea or otorrhoea)	3	92	Odds Ratio (M‐H, Fixed, 95% CI)	0.44 [0.09, 2.15]
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 not specified	1	10	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]
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. Comparison of all‐cause mortality with antibiotic prophylaxis versus no antibiotic.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 All‐cause mortality	4	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.68 [0.41, 6.95]

Comparison 3. Comparison of meningitis related mortality with antibiotic prophylaxis versus no antibiotic.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Meningitis‐related mortality	4	208	Odds Ratio (M‐H, Fixed, 95% CI)	1.03 [0.14, 7.40]

Comparison 4. Comparison of the need for surgical correction in patients with CSF leakage with antibiotic prophylaxis versus no antibiotic.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Need for surgical correction in patients with CSF leakage	1	109	Odds Ratio (M‐H, Fixed, 95% CI)	0.0 [0.0, 0.0]

Comparison 5. Comparison of frequency of non‐CNS infection with antibiotic prophylaxis versus no antibiotic.

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Non‐CNS infection	1		Odds Ratio (M‐H, Fixed, 95% CI)	Totals not selected
1.1 CSF leakage (rhinorrhoea or otorrhoea)	1		Odds Ratio (M‐H, Fixed, 95% CI)	0.61 [0.15, 2.46]

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
Random sequence generation (selection bias)	Unclear risk	"The patients were randomised to receive no antibiotics (group A) or antibiotics for 3 days"; no specification of method of randomisation
Allocation concealment (selection bias)	Unclear risk	Method of concealment is not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	No blinding of personnel, due to identifiable differences in treatment options: "no antibiotics (group A) (...) ceftriaxone intravenously 1 g daily (a total of 3 injections) [group B] (...) ampicillin intravenously 1 g 6‐hourly (a total of 12 injections) [group C])"; however, we judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Only identifiable difference between groups concerns treatment options (no antibiotic versus 2 different antibiotic treatments for 3 days), and we judge that the outcome and outcome measurement are not likely to be influenced by lack of blinding
Incomplete outcome data (attrition bias) All outcomes	Unclear risk	"39 cases were excluded because of violation 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 outcomes compared with observed event
Selective reporting (reporting bias)	Unclear risk	The study protocol is not available, making it impossible to assess whether the outcomes 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
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 findings) 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
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The patients were divided into two groups (...) according to a list of on‐call physicians. The list did not have any predictable sequence"
Allocation concealment (selection bias)	Unclear risk	Method of concealment is not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	No blinding of personnel; however, we judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	High risk	Outcome measure with insensitive instrument in a parcel of the results; "five diagnoses were based only on clinical findings. No antibiograms were obtained"
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
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
Other bias	Low risk	No other identifiable sources of bias

Hoff 1976.

Methods	Randomised, controlled, blinded, 3 arms Method of randomisation: not specified 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	We contacted the author but further information was no longer available
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	"160 patients (...) were assigned randomly and blindly to one of three treatment groups"; no reference to the sequence generation process
Allocation concealment (selection bias)	Unclear risk	Method of concealment is not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"160 patients (...) were assigned randomly and blindly to one of three treatment groups". No blinding of personnel, due to identifiable differences in treatment options, but we judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	—
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
Selective reporting (reporting bias)	Unclear risk	The study protocol is not available, making it impossible to assess whether the outcomes 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 Method of randomisation: not specified Location: 1 centre in USA Duration: not specified
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
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Unclear risk	10 patients randomised; method of randomisation not specified
Allocation concealment (selection bias)	Unclear risk	Method of concealment is not described
Blinding of participants and personnel (performance bias) All outcomes	Low risk	No blinding of personnel, due to identifiable differences in treatment options, but we judge that the outcome and the outcome measurement are not likely to be influenced by lack of blinding
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Only identifiable difference between groups concerns treatment options (no antibiotic versus antibiotic treatment), and we judge that the outcome and outcome measurement are not likely to be influenced by lack of blinding. Outcome measured by clinical signs and confirmed by lumbar puncture and posterior naso‐oropharynx swab
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
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
Other bias	Low risk	No other identifiable sources of bias

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 Duration: not specified
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 and 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
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	Vials containing penicillin or placebo in 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 appearance
Blinding of participants and personnel (performance bias) All outcomes	Low risk	Blinding of participants and all personnel ensured, and not possible that the blinding had been broken
Blinding of outcome assessment (detection bias) All outcomes	Low risk	Blinding of participants and all personnel ensured, and not possible that the blinding had been broken
Incomplete outcome data (attrition bias) All outcomes	Low risk	No missing outcome data
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
Other bias	Low risk	No other identifiable sources of bias

AB: antibiotic
 BSF: basilar skull fracture
 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 that 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)
Bellamy 2013	Retrospective chart review of all admitted patients with frontal sinus fracture (with or without skull base involvement), all receiving antibiotic treatment
Choi 1996	Retrospective controlled study that 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 that 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 that 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 that 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 that 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 the 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 that enrolled 43 patients with clinically evident traumatic CSF leak 24 hours or more after injury and evaluated the 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 a 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. Frequency 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)
Ibrahim 2012	Retrospective chart review study; no reference to antibiotic treatment; surgical technique case report
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 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)
Lauder 2009	Retrospective controlled study. 223 patients with traumatic facial injury undergoing surgical repair were enrolled into 4 groups to study the effect of prophylactic AB: A (pre‐ and perioperatively, N = 6), B (perioperatively, N = 43), C (peri‐ and postoperatively, N = 106), D (pre‐, peri‐ and postoperatively, N = 68). Different antibiotics and delivery routes
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 that evaluated 37 children with temporal bone fracture and strong clinical evidence of CSF fistula persisting for 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
Prosser 2011	Review of the published medical literature
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)
Sherif 2012	Retrospective study, with all patients receiving antibiotics
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 that reviewed the incidence of meningitis in 198 patients with petrosal fractures in groups treated with AB (N = 118) and without AB (N = 80)
Zix 2013	Randomised controlled trial with both groups receiving prophylactic AB for 5 days (N = 29) or 1 day plus 4 days placebo (N = 31), for orbital blow‐out fractures
Zrebeet 1986	Retrospective controlled study. 42 patients with a 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
 RCT: randomised controlled trial

Differences between protocol and review

Searching other sources

We were unable to handsearch the abstracts from the meeting proceedings of the European Association of Neurosurgical Societies (EANS) in this updated review as we do not have access to these sources.

Contributions of authors

2014 updated review: Bernardo O Ratilal (BR), João Costa (JC), Cristina Sampaio (CS), Lia Pappamikail (LP).

All correspondence: BR, LP.
 Drafting of review versions: BR, JC, LP.
 Searching for trials: BR, JC, LP.
 Obtaining copies of trial reports: BR, LP.
 Selection of trials for inclusion and exclusion: BR, JC, LP.
 Extraction of data: BR, JC, LP.
 Entry of data (into RevMan 2014): BR, LP.
 Interpretation of data analyses: BR, JC, LP, CS.

Sources of support

Internal sources

• Clinical Therapeutics Institute, Lisbon Faculty of Medicine, Portugal.

• Centro Cochrane Iberoamericano, Spain.

External sources

• No sources of support supplied

Declarations of interest

Bernardo O Ratilal: none known.
 João Costa: none known.
 Cristina Sampaio: none known.
 Lia Pappamikail: none known.

New search for studies and content updated (no change to conclusions)