the efficacy of antibacterial prophylaxis against the

Original Article

The Efficacy of Antibacterial Prophylaxis Against the Development of Meningitis After
Craniotomy: A Meta-Analysis
Amal F. Alotaibi2, M. Maher Hulou1, Matthew Vestal1, Faisal Alkholifi2, Morteza Asgarzadeh3, David J. Cote1,

Wenya Linda Bi1, Ian F. Dunn1, Rania A. Mekary1-3, Timothy R. Smith1-3

-OBJECTIVE: Prophylactic antibioticsarewidely usedbeforecraniotomy to prevent postoperative infections. A systematicreviewandmeta-analysiswasconducted to examine theeffectof prophylactic antibiotics on meningitis after craniotomy.

-METHODS: PubMed, EMBASE, and Cochrane databaseswere searched throughOctober 2014 for randomized controlledtrials that evaluated the effect of prophylactic antibiotics onmeningitis after craniotomy. Pooled effect estimates werecalculated using fixed-effects and random-effects models.

-RESULTS: Seven studies with 2365 patients were includedin the final analysis. All studies were randomized controlledtrials with different antibiotic regimens. Prophylactic antibi-otic use reduced the rate of meningitis after neurosurgery,with a pooled Peto odds ratio of 0.34 (95% confidence interval0.18e0.63). Cochran’s Q test indicated no significant hetero-geneity among studies (I2 [ 0; P value for heterogeneity [0.44). Subgroup analysis based on Gram-negative coverage,blinding design, and study quality demonstrated no statisti-cally significant difference among these groups (P> 0.05 forall). A meta-regression on surgery duration (P[ 0.52) and onantibiotics duration (P [ 0.59) did not show significant dif-ferences in the results among studies.

-CONCLUSIONS: This meta-analysis shows that prophy-lactic antibiotic use significantly decreases meningitisinfections after craniotomy.

Key words- Antibiotic prophylaxis- Craniotomy- Infections- Meningitis- Meta-analysis- Neurosurgery

Abbreviations and AcronymsCI: Confidence intervalCSF: Cerebrospinal fluidOR: Odds ratioRCT: Randomized controlled trial

WORLD NEUROSURGERY 90: 597-603, JUNE 2016

INTRODUCTION

lthough meningitis after craniotomy is a rare neurosur-gical complication, it can result in significant morbidity
Aor death if it is improperly diagnosed or treated.1,2 Men-
ingitis after craniotomy results in an increased length of hospitalstay and is far more dangerous than many, more commonneurosurgical complications.3,4 Decreasing the number andseverity of postoperative infections is critical in any neurosurgicalpractice.Antibiotic prophylaxis is recommended in patients undergoing

craniotomy.5 Although the use of prophylactic antibiotics has beenshown to decrease the rate of postoperative infections, it does notprevent them entirely.6-8 Although several randomized controlledtrials (RCTs) in the 1980s and 1990s found prophylaxis to beeffective in preventing site infections after neurosurgery,9 thosestudies suffered from different flaws and limitations such assmall sample size and early termination. Regarding meningitisinfections, antibiotics that have been investigated includevancomycin, cloxacillin, oxacillin, piperacillin, clindamycin, andcefotiam, which were found to have a significant effect on theprevention of meningitis in a previous meta-analysis.10 Atpresent, the study by Barker10 in 2007, which consisted of 6RCTs, is the only meta-analysis that has examined the efficacyof prophylactic antibiotic use in meningitis after craniotomy. Thetreatment effect in this meta-analysis was calculated using thetraditional odds ratio method that, in the presence of rare eventsand zero cell counts, gave highly unstable effect estimates and verywide confidence intervals for 3 of the 6 studies included. Hence, toexamine the effects of prophylactic antibiotics on the rate ofmeningitis after craniotomies, we took into account the rarity of

From the 1Department of Neurosurgery, Cushing Neurosurgery Outcomes Center, Brighamand Women’s Hospital, Harvard Medical School; 2Massachusetts College of Pharmacy andHealth Sciences University; and 3Harvard School of Public Health, Boston, Massachusetts,USA

To whom correspondence should be addressed: M. Maher Hulou, M.D.[E-mail: [email protected]]

Amal F. Alotaibi and M. Maher Hulou contributed equally.

Supplementary digital content available online.

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ORIGINAL ARTICLE

AMAL F. ALOTAIBI ET AL. ANTIBACTERIAL PROPHYLAXIS MENINGITIS AFTER CRANIOTOMY

meningitis after craniotomy by using the appropriate effect esti-mate,11 including an additional RCT, and explored potential effectmodification by different trial-level covariates.

METHODS

Literature SearchThe search for relevant articles was conducted by searchingPubMed, EMBASE, and Cochrane Library from their establishmentdate through October 2014 for studies evaluating the efficacy ofusing prophylactic antibacterial agents to prevent meningitis aftercraniotomy. The search strategy combined various terms forcraniotomy surgery (e.g., craniotomy, neurosurgery, neurosurgeryprocedures, brain surgery), meningitis infection (e.g., meningitis,bacterial meningitis), and prophylaxis antibiotics (e.g., antibioticprophylaxis, cephalosporins, penicillin, vancomycin) by usingmultiple versions of medical terms and text words. The detailedsearch items are included in Appendix 1. Additional articles wereidentified from the reference list of relevant studies and reviews.

Study SelectionStudies were considered for inclusion in the current meta-analysisif they met the following criteria: 1) RCTs conducted on neuro-surgical craniotomy patients, 2) included patients who wererandomly assigned to prophylactic antibiotics or placebo, and 3)reported data on meningitis infections after craniotomy. Articleswere excluded if they were not in English, did not report menin-gitis as a separate complication, did not explicitly state the type ofantibacterial prophylaxis, or reported <15 patients. Titles andabstracts were screened and potentially relevant articles wereselected for full-text evaluation, which was performed indepen-dently by 4 investigators (A.F.A., F.A., M.M.H., M.V.). Discrep-ancies were resolved by consultation with the senior author(T.R.S.). The quality of the RCTs was evaluated using JADADscore, which assesses for randomization, double blinding, andwithdrawals/dropouts.12

Data ExtractionFor each identified article, the following information was extrac-ted: study characteristics (authors, publication year, country oforigin, sample size, study design), participants’ characteristics(sex, age, inclusion/exclusion criteria, diagnosis), operationcharacteristics (surgery type, surgery duration), interventioncharacteristics (antibiotic, dose, frequency, primary end points),and outcome results (number of events in each group, total in-fections, meningitis, deep/superficial infections, type of organ-isms isolated). Data extraction was conducted independently by 2investigators (A.F.A., F.A.).

Data AnalysisData analysis was performed using Comprehensive Meta-Analysis,version 3. The fixed-effects model was used to obtain the overallPeto odds ratio (OR) estimates and the 95% confidence intervals(CIs) to assess the antibacterial prophylaxis effect in preventingmeningitis infections after craniotomy. Peto’s method,11 using thehypergeometric variance, was used to derive the weights of thestudies in this analysis as it performs well with low-rate events(�1%). For comparison, the Mantel-Haenszel weighting

598 www.SCIENCEDIRECT.com WORLD NEU

procedure using a zero-cell correction of 0.5 was also used toweigh the included studies and to obtain the overall Mantel-Haenszel OR estimate. Furthermore, a random-effects model ac-cording to the method of DerSimonian and Laird,13 whichaccounts for variation between studies and within each study,was used for comparison. Forest plots were used to visualize theindividual and summary estimates. Heterogeneity was evaluatedamong studies by using Cochran’s Q test (P< 0.10) and using I2

to measure the proportion of total variation due to thatheterogeneity. An I2 value >50% was considered to be high.14

Potential sources of heterogeneity were explored using subgroupanalyses by categorical covariates (antibiotic spectrum [Gram-negative coverage or not], blinding design [single or double],and quality of the study [�3 or >3]). A univariate meta-regressionconducted on each continuous covariate separately (surgeryduration in minutes; antibiotics duration in hours) and joint in amultivariate meta-regression analysis were also used to exploresources of heterogeneity. Dose frequency was not considered inthe meta-regression due to the different antibiotics used amongthe 7 studies. A sensitivity analysis was conducted to examine theinfluence of individual studies on the overall risk estimate, whichwas investigated by recalculating the pooled estimates for theremainder of the studies by removing 1 study at a time.Potential publication bias was assessed by using funnel plots,

Egger’s linear regression test, and Begg’s and Mazumdar rankcorrelation test at the P value of < 0.05 level of significance. Ifpublication bias was indicated, the number of missing studies in ameta-analysis were evaluated by the trim and fill method. A Pvalue < 0.05 was considered significant except where otherwisespecified.

RESULTS

We identified 277 articles from PubMed, 1159 articles fromEmbase, and 30 articles from the Cochrane Library (Figure 1).After the removal of duplicates and articles that did not meetthe inclusion criteria based on title and abstract, 52 articlesremained for full-text review. After full-text review, 32 articlesthat did not meet the inclusion criteria were excluded: 10 articleswith no placebo group and 5 articles with missing informationabout meningitis events. Two relevant studies15,16 were includedbased on the bibliography of another relevant study.17 Sevenarticles15-21 with 41 meningitis events after neurosurgery reportedfrom 2365 participants. These articles were included in the meta-analysis.Characteristics of the 7 randomized clinical trials included in

our meta-analysis are shown in Table 1. The total number ofparticipants ranged from 53e711 and the number of meningitiscases from 1e14. Overall, there were 10 cases of meningitisamong the 1157 antibiotics treated patients (0.86%) and 31meningitis cases among the 1208 placebo patients (2.6%). Allstudies included both men and women, with the percentage ofmen ranging from 44%e69%. Four studies were conducted inEurope, 1 in South Africa, 1 in Israel, and 1 in the United States.Dose frequency varied from a single dose up to 6 doses.Spectrum of activity ranged between a narrow spectrum, whichonly covered Gram-positive bacteria (e.g., vancomycin, oxacillin,and cloxacillin), to a broad spectrum with Gram-negative activity

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Figure 1. Study selection process of the identified articles.

ORIGINAL ARTICLE


(e.g., cefotiam and piperacillin). Surgery duration also variedacross studies (107e312 minutes). Missing data regarding surgeryduration was imputed using the mean of the other reported data.Blinding was either single or double, and this was reflected in theJADAD score. Assessment of study quality using the JADAD scoreyielded an average score of 3.5, ranging from 2e5. The definition


of meningitis varied across the RCTs (Table 2).15-22 Some of thecriteria used to define meningitis were having clinical symptoms,positive cerebrospinal fluid (CSF) culture, and CSF leukocytosis.Of the 7 studies included in the meta-analysis, only 1 study16

showed a significant reduction in meningitis rates, 1 study15 wasborderline significant, and the remaining 5 trials showed a



Table 1. Characteristics of the Studies Included in the Meta-Analysis

Author, year, ref Country AntibioticDose/Frequency/

DurationGram Negative

Coverage

SurgeryDuration(minutes)

StudyDesign

JADADScore Blinding

Antibioticgroup n (N)

ˇ

Controlledgroup n (N)

ˇ

Blomstedt andKytta, 198818

Finland Vancomycin 1 g IV/single dose/1hour

No 183 RTC 3 Single 0 (169) 1 (191)

Djindjian et al.,199017

France Oxacillin 1 g IV 1/6 doses/24hours

No 219 RTC 4 Double 0 (171) 3 (185)

Ek et al., 198819 Netherlands Cloxacillin 1 g IV/4 doses/24hours

No 140 RTC 4 Double 2 (183) 2 (195)

Gaillard andGilsbach, 199120

Germany Cefotiam 2 g/single dose/13hours*

Yes 312 RTC 3 Single 5 (356) 9 (355)

Bullock et al.,198815

SouthAfrica

Piperacillin 2 g/3 doses/19hoursy

Yes 107 RTC 5 Double 0 (192) 4 (205)

Savitz and Malis,197616

USA Clindamycin 200 mg/single dose/1 hourz

No 183 RTC 3 Double 1 (60) 9 (50)

Shapiro et al.,198621

Israel Vancomycin/Gentamicin

(vancomycin 10 mg/kg/gentamicin2 mg/kg)/singledose/1 hourx

Yes 138 RTC 2 Double 2 (71) 3 (77)

*Second dose was used in 5 cases with extremely prolonged operations >12 hours.yFirst dose was given 30 and 60 minutes before the surgery; then 2 further doses were given 6 and 12 hours later.zSecond dose used if a surgery lasts >4 hours.xMaximum dose is 500 mg of vancomycin and 120 mg of gentamicin.

ORIGINAL ARTICLE


nonsignificant benefit. However, when pooling these resultstogether, we found a protective association between antibioticprophylaxis and meningitis after neurosurgery (Figure 2). Thepooled Peto OR of meningitis was 0.34 (95% CI 0.18e0.63;fixed-effects model). The pooled Mantel-Haenszel OR was 0.35(95% CI 0.18e0.63). Results from the random-effects model weresimilar (OR, 0.41; 95% CI 0.20e0.84) and no significant hetero-geneity was observed (I2 ¼ 0; P value for heterogeneity ¼ 0.44).

Table 2. Definitions of Meningitis After Neurosurgery as Reported in

Study (ref. no.)

Blomstedt and Kytta,198818

No definition for meningitis was mentioned. There was 1 r

Djindjian et al., 199017 Infection was defined by the criteria proposed by Malis LI (1intensive care workers.

Ek et al., 198819 Infection was considered craniotomy-related if there was 1)the cerebrospinal fluid samples, and/or 3) purulent material

Gaillard and Gilsbach,199120

Bacterial meningitis with clinical symptoms and bacterial co

Bullock et al., 198815 Development of clinical features of meningitis confirmed w

Savitz and Malis, 197616 Bacterial meningitis with or without inflammation of the wleukocytosis, inflammation of the wound, and clinical impro

Shapiro et al., 198621 Isolation of an organism from the cerebrospinal fluid sampl


There was no significant difference in the following groups:antibiotic spectrum (P ¼ 0.28), blinding design (P ¼ 0.34), orstudy quality (P ¼ 0.81). Furthermore, the univariate meta-regression on surgery duration (P ¼ 0.52) and on antibioticsduration (P ¼ 0.59) did not explain the differences in results be-tween the included studies. Likewise, the multivariate meta-regression (adjusting for antibiotic spectrum, study quality, sur-gery duration, and antibiotics duration; overall P value ¼ 0.99) did

the Included Randomized Controlled Trials

Definition

eported.

979) and was confirmed jointly by the surgeon directing the study and 1 of the 2

purulence at the incision site, 2) a positive Gram stain and/or a positive culture ofs obtained by puncture biopsy at the site of the operation or reoperation.

ntamination of cerebrospinal fluid.

ith a low glucose and high polymorphonuclear count.

ound, or meningismus without positive cultures but with cerebrospinal fluidvement after the institution of additional antibiotics.

es with compatible clinical and/or biochemical findings.




Figure 2. Forest plot represents the Peto odds ratio for developingmeningitis after craniotomy (95% confidence interval [CI]) with differentprotective antibiotics compared with placebo regimens from 7 randomizedcontrolled studies in adults (n ¼ 2460). Horizontal lines denote 95% CIs;solid squares represent the point estimate of each study and the diamond

represents the pooled estimate of the intervention effect. The size of thesolid squares is proportional to the weight of the study. Weights are fromthe fixed-effects analysis using the Peto method using the hypergeometricvariance in the event count in the intervention group. The I2 and P valuesfor heterogeneity are shown.

ORIGINAL ARTICLE


not explain the differences among trials. A symmetrical invertedfunnel plot suggested the absence of publication bias (Figure 3).Begg’s rank correlation test (P ¼ 0.88) and Egger’s linearregression test (P ¼ 0.64) indicated no publication bias. Thefail-safe N was 14 suggesting that 14 “null” studies would need

-2.0 -1.5 -1.0 -0.5 0

0

1

2

3

Stan

dard

Err

or

Log Peto

Funnel Plot of Standard E

Figure 3. Funnel plot of log odds ratio according to their standarodds ratio, and the other two lines represent the expected 95%shows no significant publication bias. Trim and fill method shoto the original risk estimate.


to be located and included for the combined 2-tailed P value toexceed 0.05. The trim-and-fill method was used to recalculate thepooled risk estimate. The analysis suggested that the imputed riskestimate was 0.34 (95% CI 0.18e0.63). No missing studies wereimputed in the contour enhanced funnel plot. The one-study

.0 0.5 1.0 1.5 2.0

odds ratio

rror by Log Peto odds ratio

d errors. The vertical solid line is drawn at the pooled logconfidence interval for a given standard error. The plot

ws that the recalculated pooled risk estimate is identical



ORIGINAL ARTICLE


removal sensitivity analysis did not change the summary estimate(not shown).

DISCUSSION

Since the development of penicillin mold extract by AlexanderFleming, penicillin-derived antibiotics have been used by neuro-surgeons prophylactically to prevent the potentially devastatingconsequences of meningeal infection postoperatively.10 Given theseverity of this type of infection and that it is among the mostcommon after craniotomy, it is important to determine theefficacy of antibacterial prophylaxis in preventing meningitis.In the present study, the odds of meningitis were significantly

reduced by 66% when comparing the prophylaxis treated group tothe placebo group. There was no statistically significant differencein the effect of prophylaxis on meningitis prevention based onsurgery duration, study quality, blinding design, or Gram-negativecoverage. A meta-analysis by Barker10 found that prophylaxis usehad a strong effect on preventing meningitis (OR ¼ 0.43; 95% CI0.20e0.92) without considering study quality or study duration.The present study also confirmed the findings of Barker thatprophylactic antibiotic use was effective against meningitis andthe effect was even stronger (OR ¼ 0.34), independent of Gram-negative coverage, blinding design, study quality, and surgeryduration. In addition, our current meta-analysis included 1 addi-tional RCT for analysis.20

Prophylactic antibiotic uses for surgery have been controversialdue to several observational reports that failed to detect their ef-ficacy. Its use in preventing infections after craniotomy has sincefallen in favor after a series of RCTs.10 The absence of benefitfound for use of prophylaxis in preventing postoperativemeningitis in previous studies15,17-21 is likely because the patho-genesis of postoperative meningitis is different from that ofincision infections. In most cases, meningitis is probably not ac-quired at the time of surgery but postoperatively, due to CSFleakage.6 CSF leakage has been found to be a significant risk factor


for meningitis.6,7,23,24 This association has already been suggestedin a subgroup of patients19 included in our meta-analysis. Pre-operative antibiotic prophylaxis may not be beneficial in this pa-tient population, but a longer period of antibiotic coverage mayprevent meningitis in patients at risk for CSF leakage.At present, there is debate on whether or not clean wounds

should require antibiotic prophylaxis. Most craniotomies are inthe category of clean wounds, and with the low infection rates.Opponents of prophylaxis argue that its use is inappropriate andcontributes to increasing rates of antibiotic resistance.9 They alsopoint to low rates of infection in the early years of neurosurgery,for example, when Harvey Cushing was able to keep infectionrates to <1% by using only water and soap.25 The rates ofmeningitis infection after craniotomy are 1%e2%, whereasoverall infection rates after craniotomy have been reported to be4.2%e8.1%.3,8 Considering this already low risk, it is importantto proceed with caution. Antibiotic prophylaxis for all patients tolower risk of infections may not only lead to the creation of su-perinfections but also to increased health care costs.A limitation of this meta-analysis is that the search was only

limited to studies in English, and it is possible that other non-English trials existed and could be included in future meta-ana-lyses.26 Although publication bias remains a major limitation tometa-analyses, therefore by using a funnel plot, no statisticallysignificant publication bias was found. Strengths of our meta-analysis include the exploration of an effect modification bydifferent trial-level covariates and the use of the appropriate effectestimate (Peto method) that deals with rare events unlike thetraditional OR method.

CONCLUSION

The use of prophylactic antibiotics significantly decreases the rateof meningitis after craniotomy. Further research is needed toidentify the best prophylactic regimen for patients who may be atan increased risk of acquiring meningitis.

REFERENCES

1. McClelland Iii S, Hall WA. Postoperative centralnervous system infection: incidence and associ-ated factors in 2111 neurosurgical procedures. ClinInfect Dis. 2007;45:55-59.

2. Weisfelt M, van de Beek D, Spanjaard L, deGans J. Nosocomial bacterial meningitis in adults:a prospective series of 50 cases. J Hosp Infect. 2007;66:71-78.

3. Reichert MCF, Medeiros EAS, Ferraz FAP. Hos-pital-acquired meningitis in patients undergoingcraniotomy: incidence, evolution, and risk factors.Am J Infect Control. 2002;30:158-164.

4. Wang KW, Chang WN, Huang CR, Tsai NW,Tsui HW, Wang HC, et al. Post-neurosurgicalnosocomial bacterial meningitis in adults:microbiology, clinical features, and outcomes.J Clin Neurosci. 2005;12:647-650.

5. Bratzler DW, Dellinger EP, Olsen KM, Perl TM,Auwaerter PG, Bolon MK, et al. Clinical practiceguidelines for antimicrobial prophylaxis in sur-gery. Am J Health Syst Pharm. 2013;70:195-283.

6. Korinek AM, Golmard JL, Elcheick A, Bismuth R,van Effenterre R, Coriat P, et al. Risk factors forneurosurgical site infections after craniotomy: acritical reappraisal of antibiotic prophylaxis on4578 patients. Br J Neurosurg. 2005;19:155-162.

7. Korinek AM, Baugnon T, Golmard JL, vanEffenterre R, Coriat P, Puybasset L. Risk factorsfor adult nosocomial meningitis after craniotomy:role of antibiotic prophylaxis. Neurosurgery. 2006;59:126-132.

8. Kourbeti IS, Jacobs AV, Koslow M, Karabetsos D,Holzman RS. Risk factors associated with post-craniotomy meningitis. Neurosurgery. 2007;60:317-325.

9. Liu W, Ni M, Zhang Y, Groen RJ. Antibioticprophylaxis in craniotomy: a review. Neurosurg Rev.2014;37:407-414 [discussion: 414].

10. Barker Ii FG. Efficacy of prophylactic antibioticsagainst meningitis after craniotomy: a meta-analysis. Neurosurgery. 2007;60:887-894.

11. Bradburn MJ, Deeks JJ, Berlin JA, RussellLocalio A. Much ado about nothing: a comparison

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of the performance of meta-analytical methodswith rare events. Stat Med. 2007;26:53-77.

12. Jadad AR, Moore RA, Carroll D, Jenkinson C,Reynolds DJ, Gavaghan DJ, et al. Assessing thequality of reports of randomized clinical trials: isblinding necessary? Control Clin Trials. 1996;17:1-12.

13. DerSimonian R, Laird N. Meta-analysis in clinicaltrials. Control Clin Trials. 1986;7:177-188.

14. Higgins JPT, Thompson SG, Deeks JJ, Altman DG.Measuring inconsistency in meta-analyses. Br MedJ. 2003;327:557-560.

15. Bullock R, Van Dellen JR, Ketelbey W,Reinach SG. A double-blind placebo-controlledtrial of perioperative prophylactic antibiotics forelective neurosurgery. J Neurosurg. 1988;69:687-691.

16. Savitz MH, Malis LI. Prophylactic clindamycin forneurosurgical patients. N Y State J Med. 1976;76:64-67.

17. Djindjian M, Lepresle E, Homs JB. Antibioticprophylaxis during prolonged clean neurosurgery.

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ORIGINAL ARTICLE


Results of a randomized double-blind study usingoxacillin. J Neurosurg. 1990;73:383-386.

18. Blomstedt GC, Kyttä J. Results of a randomizedtrial of vancomycin prophylaxis in craniotomy.J Neurosurg. 1988;69:216-220.

19. Ek B, Dijkmans BA, Dulken H, Furth R. Antibioticprophylaxis in craniotomy: a prospective double-blind placebo-controlled study. Scand J Infect Dis.1988;20:633-639.

20. Gaillard T, Gilsbach JM. Intra-operative antibioticprophylaxis in neurosurgery. A prospective, ran-domized, controlled study on cefotiam. Acta Neu-rochir. 1991;113:103-109.

21. Shapiro M, Wald U, Simchen E, Pomeranz S,Zagzag D, Michowiz SD, et al. Randomized clin-ical trial of intra-operative antimicrobial

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prophylaxis of infection after neurosurgical pro-cedures. J Hosp Infect. 1986;8:283-295.

22. Malis LI. Prevention of neurosurgical infection byintraoperative antibiotics. Neurosurgery. 1979;5:339-343.

23. Erman T, Demirhindi H, Gocer AI, Tuna M,Ildan F, Boyar B. Risk factors for surgical site in-fections in neurosurgery patients with antibioticprophylaxis. Surg Neurol. 2005;63:107-112.

24. Palabiyikoglu I, Tekeli E, Cokca F, Akan O,Unal N, Erberktas I, et al. Nosocomial meningitisin a university hospital between 1993 and 2002.J Hosp Infect. 2006;62:94-97.

25. Cushing H. Concerning the results of operationsfor brain tumor. J Am Med Assoc. 1915;LXIV:189-195.

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Conflict of interest statement: The authors declare that thearticle content was composed in the absence of anycommercial or financial relationships that could be construedas a potential conflict of interest.

Received 1 December 2015; accepted 9 February 2016

Citation: World Neurosurg. (2016) 90:597-603.http://dx.doi.org/10.1016/j.wneu.2016.02.048

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APPENDIX 1

PubMed Search(“Craniotomy”[Mesh] OR “Neurosurgical Procedur-es”[Mesh:NoExp] OR“Neurosurgery”[Mesh] OR “Intracranial Pressure”[Mesh] OR

“Brain/surgery”[Mesh] OR craniotom*[tw] OR neurosurg*[tw]OR brain surg*[tw] OR intracranial pressure[tw])AND(“Meningitis”[Mesh] OR “Meningitis, Bacterial”[Mesh] OR

meningitis[tw])AND(“Antibiotic Prophylaxis”[Mesh] OR ”Cephalosporins”[Mesh]

OR “Penicillins”[Mesh] OR “Ampicillin”[Mesh] OR “Carbape-nems”[Mesh] OR “Vancomycin”[Mesh] OR “Gentamicins”[Mesh]OR “Clindamycin”[Mesh] OR cephalosporin*[tw] OR penicillin*[tw] OR vancomycin*[tw] OR Cefazolin[tw] OR Cefotaxime[tw]OR Cefixime[tw] OR Cefmenoxime[tw] OR Cefotiam[tw] ORCeftizoxime[tw] OR Ceftriaxone[tw] OR Cefuroxime[tw] ORCephalexin[tw] OR Cefaclor[tw] OR Cefadroxil[tw] OR Cefatrizine[tw] OR Cephaloglycin[tw] OR Cephradine[tw] OR Amdinocillin[tw] OR Amdinocillin Pivoxil[tw] OR Cyclacillin[tw] OR Methi-cillin[tw] OR Nafcillin[tw] OR Oxacillin[tw] OR Cloxacillin[tw]OR Dicloxacillin[tw] OR Floxacillin[tw] OR Penicillanic Acid[tw]OR Penicillin G[tw] OR Ampicillin[tw] OR Amoxicillin[tw] ORCarbenicillin[tw] OR Penicillin G Benzathine[tw] OR Penicillin GProcaine[tw] OR Sulbenicillin[tw] OR Penicillin V[tw] OR Sul-bactam[tw] OR Ticarcillin[tw] OR Azlocillin [tw] OR Mezlocillin

603.e1 www.SCIENCEDIRECT.com WORLD NEU

[tw] OR Piperacillin [tw] OR Pivampicillin[tw] OR Talampicillin[tw] OR meropenem[tw] OR Gentamicins[tw] OR Gentamycin[tw] OR Clindamicin[tw] OR Clindamycin [tw] )

Embase Search(exp craniotomy/ or craniotomy.tw. or exp neurosurgery/ or neu-rosurgery.tw. or exp intracranial pressure/)and(exp meningitis/ or exp bacterial meningitis/ or Meningitis.tw.)and(exp antibiotic prophylaxis/ or exp cephalosporin derivative/or exp penicillin derivative/or exp ampicillin/or exp carbapenem derivative/or exp vancomycin/or exp gentamicin/or exp clindamycin/)

Cochrane Searchcraniotom* OR neurosurg*AND“surgical infection*” OR “wound infection*” OR meningitis OR

“gram negative infection”AND“antibiotic prophylaxis” OR Cephalosporin* OR Penicillin* OR

vancomycin* OR Cefazolin OR Cefotaxime OR Cephalexin ORgentamycin




the efficacy of antibacterial prophylaxis against the

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