Clinical review: Efficacy of antimicrobial-impregnated catheters in external ventricular drainage - a systematic review and meta-analysis

To assess the efficacy of antimicrobial-impregnated catheters in preventing catheter-related infections during external ventricular drainage (EVD), we performed a meta-analysis and systematic review. We systematically searched Medline, Embase, and the Cochrane Library. All randomized controlled trials (RCTs) and nonrandomized prospective studies (NPSs) related to antimicrobial-impregnated EVD catheters were included. The primary outcome was the rate of cerebrospinal fluid infection (CFI). The secondary outcomes included the rate of time-dependent CFI and catheter bacterial colonization. We further performed subgroup analysis, meta-regression analysis, and microbial spectrum analysis. Four RCTs and four NPSs were included. The overall rate of CFIs was 3.6% in the antimicrobial-impregnated catheter group and 13.7% in the standard catheter group. The pooled data demonstrated that antimicrobial-impregnated catheters were superior to standard catheters in lowering the rate of CFIs (odds ratio (OR) = 0.25, 95% confidence interval (CI) = 0.12 to 0.52, P <0.05). In survival analysis, the 20-day infection rate was significantly reduced with the use of antimicrobial-impregnated catheters (hazard ratio = 0.52, 95% CI = 0.29 to 0.95, P <0.05). Furthermore, a significantly decreased rate of catheter bacterial colonization was noticed for antimicrobial-impregnated catheters (OR = 0.37, 95% CI = 0.21 to 0.64, P <0.05). In subgroup analyses, although significant results remained for RCTs and NPSs, a subgroup difference was revealed (P <0.05). Compared with standard catheters, a significantly lower rate of CFIs was noticed for clindamycin/rifampin-impregnated catheters (OR = 0.27, 95% CI = 0.10 to 0.73, P <0.05) and for minocycline/rifampin-impregnated catheters (OR = 0.11, 95% CI = 0.06 to 0.21, P <0.05). However, no statistical significance was found when compared with silver-impregnated catheters (OR = 0.33, 95% CI = 0.07 to 1.69, P = 0.18). In microbial spectrum analysis, antimicrobial-impregnated catheters were shown to have a lower rate of Gram-positive bacterial infection, particularly the coagulase-negative Staphylococcus. In conclusion, the use of antimicrobial-impregnated EVD catheters could be beneficial for the prevention of CFI and catheter bacterial colonization. Although antibiotic-coated catheters seem to be effective, no sufficient evidence supports the efficacy of silver-impregnated catheters.

exerted by perva sive use of prophylactic antibiotics, an increasing rate of Gram-negative infections has been reported [1, 14,15]. Th e protective eff ects of antimicrobial-impregnated catheters against Gram-positive or Gram-negative infec tions have not been clarifi ed. In light of those pendin g issues, we performed this systematic review and meta-analysis, aiming to evaluate the effi cacy of antimicrobial-impregnated EVD catheters.

Search strategy
Our meta-analysis w as conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statement [16] (see Additional fi le 1). We systematically searched Medline (Ovid), Embase, and the Cochrane Library until October 2012, with language restricted to English, and identifi ed all prospective studies related to the use of antimicrobial-impreg nated EVD catheters. Our search strategy included terms for antimicrobial catheter (antibiotic-impregnated/ coated catheter that includes minocycline/rifampin catheters and clinda my cin/rifampin catheters, and silverimpregnated/coated catheter), procedures (external ventricular drainage, ventriculo stomy, and shunt), and study design (random ized controlled trials, prospective studies). Furthermore, we manually searched the references of identifi ed papers to fi nd additional eligible studies.

Selection criteria
Studies were include d into the meta-analysis if they: were randomized controlled trials (RCTs) or nonrandomized prospective studies (NPSs) of patients with antimicrobialimpregnated catheters; compared the antimicrobial catheter (treatment arm) with the standard catheter (control arm) in the prevention of catheter-related infections in EVD (we eased the criteria for the control arm and allowed the use o f well-matched historical controls); reported original data; and reported a risk estimate (that is, odds ratio (OR), relative risk, or hazard ratio (HR)) for the utilization of antimicrobial-impregnated catheters to subsequent rate of catheter-related infections. We referred to the Centers for Disease Control/National Health care Safety Network defi nition of ventriculitis to identify the infectious outcome. According to the criteria, clinical manifestations are emphasized besides labora tory tests [17]. However, most studies had no defi ned requirements for clinical manifestations. We therefore modifi ed the aforementioned criteria and viewed CFI as the primary outcome, defi ned as positive CSF culture or staining, or a signifi cant increase of CSF white cell count, with or without clinical manifestations [17]. Th e rate of time-dependent CFI and catheter bacterial colonization were explored as secondary outcomes. Catheter bacterial colonization was defi ned as positive culture of explanted catheters in vitro. For multiple reports on the same study, the one with complete information was selected for meta-analysis.

Data extraction and quality assessment
Two assessors (XW and YD) independently reviewed the full manuscripts of eligible studies. Data were extracted in standardized data-collection forms. Th e extracted information included the following items: fi rst author's name; year of publication; sample size; population; gender; treatment arms; usage of PSA; duration of catheter placement; and catheter-related infection outcomes (infec tion rate, organism analyses). Any disagreement was resolved by discussion or by consulting a senior scholar (C-GH). Selected RCTs were critically appraised using the Jadad scale (randomization, 2 points; blinding, 2 points; and attrition information, 1 point) [18]. Th e Newcastle-Ottawa scale was used to evaluate the methodological quality of prospective cohort studies [19]. Th e quality of a study was judged by the selection of the study groups, the comparability of the groups, and the ascertainment of the outcome.

Statistical analysis
Review Manager 5.1.7 (Co chrane Collaboration, Copenhagen, Denmark) was used to perform the meta-analysis. At event rates <1%, Peto's OR is suggested to be the least biased and most powerful method [20]. However, Peto's OR is less appropriate when the event rates are >5%, the treatment eff ects are signifi cant, and the number of treated and control participants is imbalanced [20]. We therefore used diff erent statistical methods. Besides calculating the Peto OR with a fi xed-eff ect model, we calculated the OR with the Mantel-Haenszel method and the random-eff ects model [21,22]. When the event rates were <1%, the treatment eff ects were small to moderate, and the number in each group was balanced. Th e Peto OR was thus chosen as the primary statistical method. Otherwise, the OR was used instead.
Th e comparison of diff erent meta-analytic methods was included into the sensitivity analyses. Additionally, sensitivity analysis was conducted by excluding the individual studies one by one.
Considering the infection events as time-dependent data, the HR was employed for analysis [23]. If available, HRs and associated variances were extracted directly. Otherwise they were estimated indirectly from other summary statistics (95% confi dence intervals (CIs), P values, total number of events) or from data from published Kaplan-Meier curves [23]. Th e Kaplan-Meier curve was read with the Engauge Digitizer version 2.15 free software [24]. Th e log HR and its standard error were calculated and further pooled by Review Manager 5.1.7 with the random-eff ects model. Th e I 2 statistic was used to reveal the heterogeneity of treatment eff ects. I 2 of 0 to 40% indicates unimportant heterogeneity, 30 to 60% indicates moderate heterogeneity, 50 to 90% indicates substantial heterogeneity, and 75 to 100% indicates considerable heterogeneity [25]. Heterogeneity was further explored by subgroup analyses and meta-regression. Four potential sources of heterogeneity were analyzed: study design (RCT or NPS); catheter type (C/R, M/R, or silver); sample size; and publi cation year. Meta-regression analysis was conducted by Stata 12.0 (Stata Corporation, College Station, TX, USA) with the random-eff ects model to assess whether a specifi c covariate infl uenced the eff ect. Th e data were expressed with 95% CIs. Two-tailed P <0.05 was deemed statistically signifi cant. Th e publication bias was examined by the funnel plots on Review Manager 5.1.7, and statistically by Egger's regression model, calculated by Stata 12.0.

Results
We identifi ed 144 relevan t articles from the initial search and 115 were excluded after a preliminary review. Th e remaining 29 studies were retrieved for detailed assessment. Sixteen retrospective cohort studies and four studies of ventriculoperitoneal shunt were excluded, with fi ve RCTs and four NPSs related to EVD remaining. Further, one RCT was dis carded because no infection event was observed in both the intervention and control groups [11]. Excluding the zero-total-event trials from meta-analysis is common practice because they do not contribute to treatment eff ects analysis [26]. Th e fl ow diagram is shown in Figure 1. Eight studies were included in the meta-analysis [6-10,12,13,27]. Th eir charac teristics are presented in Table 1. Th ree NPSs prospectively collected the antimicrobial-impregnated catheter data, and selected well-matched historical controls [8][9][10]. Th e sample size ranged from 39 to 1,634. Most studies involved an adult population and used PSA. Th e quality of RCTs and NPSs were moderately satisfactory.

Infection rate
All stu dies reported the overall rate of CFI in each arm. Accordingly, the OR of the CFI rate could be obtained. Although the defi nition of infection outcomes varied across studies (Table 1), they were in accordance with our predefi ned criteria. As a considerable number of patients underwent EVD several times, we considered the CFI rate to be EVD-frequency related. We thus counted 1,875 EVD events with antimicrobial-impregnated catheters and 1,116 control EVD events with standard catheters. Th e overall rates of CFIs were 3.6% in patients with antimicrobial-impreg nated catheters and 13.7% in patients with standard catheters. Th e pooled data demonstrated that anti microbial-impregnated catheters were signifi cantly superior to standard catheters in lowering the CFI rate (OR = 0.25, 95% CI = 0.12 to 0.52, P <0.05; Figure 2). As for the Peto OR, the overall diff erence remained significant (OR = 0.32, 95% CI = 0.24 to 0.42, P <0.05). When sequentially excluding studies from the main pooled analysis, the results were not signifi cantly aff ected.
Subgroup analyses were warranted in light of the substantial heterogeneity across studies (I 2 = 75%). We analyzed RCTs and N PSs to ascertain the potential bias resulting from study design. Pooled data of four RCTs showed a signifi cant protective eff ect against CFIs for antimicrobial-impregnated catheters (OR = 0.49, 95% CI = 0.27 to 0.89, P <0.05, I 2 = 46%). A signifi cant result was also demonstrated in analysis of four NPSs (OR = 0.12, 95% CI = 0.07 to 0.21, P <0.01, I 2 = 0) ( Figure 2).
Of the eight studies, one RCT and one NPS a ssessed the eff ect of silver-impregnated catheters on CFI pre vention. As shown in Figure 3, less patients with silverimpregnated catheters developed CFIs (10.8%) compared with standard catheters (21.9%), without statistical signifi cance (OR = 0.33, 95% CI = 0.07 to 1.69, P = 0.18). Harrop and colleagues prospectively utilized C/R and M/R catheters in diff erent observational periods and thus they were pooled separately [27]. Overall, fi ve studies examined the eff ect of C/R-impregnated catheters and showed a signifi cant association with a lower rate of CFIs (OR = 0.27, 95% CI = 0.10 to 0.73, P <0.05). Two studies evaluated the eff ect of M/R-impregnated catheters, indicating a signifi cant correlation with a lower rate of CFIs (OR = 0.11, 95% CI = 0.06 to 0.21; P <0.05) (Figure 3). When sensitivity analyses were performed with Peto ORs, the only signifi cant change was found for silver-impregnated catheters (Peto OR = 0.45, 95% CI = 0.25 to 0.81, P <0.05).
To examine the extent to which diff erences in the infection rate could be explained, the study design, publication year, and sample size were considered as independent variables in meta-regression analyses. A signifi cant independent eff ect for study design was indicated (P = 0.018). However, neither the publication year nor the sa mple size had an independent eff ect on the CFI outcome (P = 0.103 and P = 0.399, respectively) ( Figure 4).

Estimation of the time-dependent infection rate
Th e EVD catheter was usually temporarily implanted for a short p eriod. Th eoretically, all EVD catheters may become infected given enough time. In consideration of the time to infection or censoring, a time-dependent infection rate was explored. Four RCTs illustrated a Kaplan-Meier curve that demonstrated EVD without infection [6,7,12,13]. Th e infection rate reached a steady level after day 20 following catheter implantation in all studies, and thus the 20-day infection rate was investigated. Th ree studies presented the P value of the log-rank test [6,12,13], whereas the SILVER trial solely presented the Kaplan-Meier curve [7]. Th e estimated log HR and the standard error of log HR were indirectly calculated, and the pooled results demonstrated that antimicrobial-impregnated catheters were helpful for prolonging the EVD catheter period without infection (HR = 0.52, 95% CI = 0.29 to 0.95, P = 0.03) ( Figure 5).

Microbial spectrum analyses
Th e specifi c microbial spectra in CFIs were investigated in fi ve studies (F igure 7). For coagulase-negative Staphylo coccus, antimicrobial-impregnated catheters were superior to standard catheters in lowering the infection rate (OR = 0.17, 95% CI = 0.06 to 0.53, P <0.05). For Staphylococcus aureus, a trend but no statistical signifi cance to the decre ment of infection rate was shown for the anti microbial-impregnated catheter group (OR = 0.41, 95% CI = 0.07 to 2.33, P >0.05). Similarly, for Gramnegative rods there was a trend of decreasing infection rate in the antimicrobial-impregnated catheter group compared with the standard catheter group without statistical signi fi cance (OR = 0.44, 95% CI = 0.07 to 2.58, P >0.05). When analyzing Gram-positive cocci, antimicrobial-impreg na ted catheters were associated with a lower rate of CFI (OR = 0.18, 95% CI = 0.08 to 0.39, P <0.05). Sensitivity analysis was performed by

Evaluation for publication bias
Th e funnel plots of all data were found to be symmetrical, suggesting a low likelihood of publication bias (Figure 8).
No publication bias was found by Egger's test either (P = 0.178).

Discussion
In our meta-analysis, the pooled Mantel-Haenszel OR demonstrated that antimicrobial-impr egnated catheters were associated with a decreased r ate of CFIs, which was not signifi cantly altered with the Peto OR. A lower rate of catheter bacterial colonization was also indicated in patients with antimicrobial-impregnated catheters. Furthermore, the pooled HR of the 20-day infection rate indicated that patients with antimicrobial-impregnated catheters had a signifi cantly decreased risk of CFI compared with those with standard catheters. Our research suggested a protective eff ect associated with the use of antimicrobial-impregnated catheters for CFI prevention.
In meta-regression analyses, neither the publication year nor the sample size had a sign ifi cant eff ect on the outcome, whereas the study design was shown to exert an independent eff ect. Further, in subgroup analyses, although results stratifi ed by study design were statistically signifi cant, a signifi cant subgroup diff erence was found. Considering that the NPSs contributed 75% of patients to the meta-analysis, most of the observed signals may be related to NPSs and not to RCTs. Antibiotic-coated catheters were shown to be eff ective. However, for the silver-coated catheter, our data did not demonstrate benefi t. Compared with antibiotic agents, sliver is expected to exhibit a more widespread antibiotic spectrum, defending against all Gram-positive and Gram-negative bacteria and Candida spp. Nevertheless, previous clinical experience of the silver central venous line catheter demonstrated that it is inferior to antibioticimpregnated catheters for preventing central venous line infection [28]. Th e comparison of the silver-impregnated catheter with antibiotic-impregnated catheters therefore calls for further investigation.
CFIs often result from contamination along the tract with normal skin fl ora, such as Staphylococc us spp. and Strepto coccus spp. [29]. Gram-positive cocci comprise the majority of isolates in EVD procedures [30]. Coagulasenegative Staphylococci, predominantly Staphylococcus epidermidis, have been identifi ed as the most frequent causative agent of CFIs [31]. Our results demonstrated that antimicrobial-impregnated catheters might reduce the infection risk of Gram-positive cocci, especially S. aureus. Nevertheless, no statistically favorable results showed their eff ects on reducing infection with S. epidermidis or Gramnegative rods. Of note, the reason might be that the sample sizes were overall too small to produce conclusive results.  Our meta-analysis is diff erent from previous reviews in several aspects. In the earlier Cochrane re view, only two RCTs were included without suffi cient data to elucidate the effi cacy of antimicrobial-impregnated catheters [32]. In another systematic review, Sonabend and colleagues investigated both the eff ects of prophylactic antibiotics and antibiotic-coated EVD catheters on ventriculostomyrelated infections, and only one RCT of EVD was selected [2]. For another meta-analysis by Th omas and colleagues, the major limitation is the inclusion of considerable lowquality retrospective studies, and mixed assessment of shunt and EVD. Besides, the neonatal population was mainly evaluated [33]. Compared with previous studies, our research consisted of all up-to-date prospective studies of relatively high quality and employed the Mantel-Haenszel OR and the Peto OR to estimate the time-dependent infection rate. Additionally, the benefi ts of antimicrobial EVD catheters against diff erent microbial spectrums, as well as the effi cacy of diff erent catheters, were explored.
We are aware of the limitations for our meta-analysis. One limitation was the quality of studies. A lthough evidence from RCTs was ideal, only a few RCTs were eligible. Eventually, we identifi ed four RCTs and four NPSs. In three NPSs, historical control groups were employed, which might lead to a failure to identify infections in this group, thus contributing to an under estimated infection rate [8-10]. Although selection bias has been suggested to be reduced by well-matched historical controls [8-10,34], its potential existence should not be neglected. Th e heterogeneity was found to be moderate to considerable, which might arise from the varied infection defi nition, inappropriate study design with multiple confounding factors, and too small a sample size. Kubilay and colleagues suggested that the implementation of a ventriculostomy placement bundle, including antimicrobial-impregnated catheters, administra tion of PSA and a series of sterile techniques, dramatically decreased EVD-related infections [3]. Th e nonstandard surgical procedures between studies therefore probably served as a potential source of heterogeneity. Th e underlying diseases and severity of conditions also play roles in determining the infectious outcomes, beyond the impregnated anti microbial agents. It is implied that the effi cacy of antimicrobial EVD catheters might be most pronounced in patients with elevated intracranial pressure etiologies of higher infection risk (head trauma, prior shunt failure) [13]. However, the indication of antimicrobial-impreg nated catheters for specifi c populations still remains to be clarifi ed. Especially, the potential confounders are diffi cult to balance in NPSs. Th e rate of CFIs is rather low. It has  been suggested that 688 procedures are required to detect a decrease in shunt infection rate from 10% to 5% and that 438 procedures are required to detect a decrease in EVD infection rate from 15% to 7.5% [35]. In fact, it is diffi cult to obtain a sample size large enough for statistical power to fi nd the diff erences. Antibiotic impregnation may increase false-negative cultures, because whether an inhibitor was used to negate the carryover eff ect of the antimicrobial agent into the culture medium is not often recorded [12]. Moreover, the reports of timedependent data were insuffi cient. We could only estimate the HR of overall infection rate indirectly from information of Kaplan-Meier curves.
Th e administration of PSA varied between studies, with one study administering perioperative antibi otics [27], three studies employing prolonged antibiotics until the removal of catheters [6,10,13], one study not using any systemic antibiotics [7], and three studies lacking  Table 1). Th e PSA usage may thus constitute a source of heterogeneity. Additionally, the controversial interaction between antimicrobial-impregnated catheters and PSA deserves further evaluation. Which is preferable in decreas ing CFI, PSA or antimicrobial-impregnated catheters? Are the infection risks of PSA higher than catheter-impregnated antibiotics? Do combined interven tions of catheter-impregnated and systemic antibiotics favor the prevention of infection? Current fi ndings may be a dilution of the true individual eff ect of antimicrobial agent impregnation in the absence of any prophylactic antibiotic therapy.
Another concern is the varied criteria for diagnosing CFIs. . Th e various defi nitions not only contribute the hetero geneity, but also increase the complexity of accurately defi ning EVD infections. In fact, a group of fi ve-grade criteria to describe CSF infections in ventriculo stomy has been proposed, which included contamination, ventriculostomy colonization, suspected ventriculostomy-related infection, ventriculostomy-related infection, and ventriculitis [30]. Notwithstanding the diffi culties in stratifying infection events, the specifi ed classifi cation might be helpful for future studies as demonstrated by Pople and colleagues' trial [13].

Conclusion
Our results demonstrate tha t antimicrobial-impregnated catheters are eff ective and safe in lowering the risk of CFIs and catheter colonization and are helpful in improving EVD catheter use without infection. Especially, the antimicrobial-impregnated catheters play roles against Gram-positive organisms. Antibiotic-impreg nated catheters appear to be reliable options for patients requiring EVD placements. However, no suffi cient evidence supports the use of silver-impregnated catheters. Further well-designed studies are needed to verify the fi ndings of our meta-analysis.  Abbreviations CFI, cerebrospinal fl uid infection; CI, confi dential interval; C/R, clindamycin/ rifampin; CSF, cerebrospinal fl uid; EVD, external ventricular drainage; HR, hazard ratio; M/R, minocycline/rifampin; NPS, nonrandomized prospective study; OR, odds ratio; PSA, prophylactic systemic antibiotics; RCT, randomized controlled trial.

Additional fi le
Authors' contributions XW performed the primary study search, extracted data, carried out statistical analysis, drafted the manuscript, and revised the manuscript. YD performed the primary study search, extracted data, carried out statistical analysis, and revised the manuscript. X-QQ carried out statistical analysis and drafted the manuscript. C-GH proposed the idea, improved the study design, drafted and revised the manuscript. L-JH improved the idea, participated in its design, drafted and revised the manuscript. Y-ML checked the study search and carried out statistical analysis. All authors read and approved the fi nal manuscript.