Antimicrobial-impregnated and -coated shunt catheters for prevention of infections in patients with hydrocephalus: a systematic review and meta-analysis

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OBJECT

The aim of this study was to evaluate the effectiveness of antimicrobial-impregnated and -coated shunt catheters (antimicrobial catheters) in reducing the risk of infection in patients undergoing CSF shunting or ventricular drainage.

METHODS

The PubMed and Scopus databases were searched. Catheter implantation was classified as either shunting (mainly ventriculoperitoneal shunting) or ventricular drainage (mainly external [EVD]). Studies evaluating antibioticimpregnated catheters (AICs), silver-coated catheters (SCCs), and hydrogel-coated catheters (HCCs) were included. A random effects model meta-analysis was performed.

RESULTS

Thirty-six studies (7 randomized and 29 nonrandomized, 16,796 procedures) were included. The majority of data derive from studies on the effectiveness of AICs, followed by studies on the effectiveness of SCCs. Statistical heterogeneity was observed in several analyses. Antimicrobial shunt catheters (AICs, SCCs) were associated with lower risk for CSF catheter–associated infections than conventional catheters (CCs) (RR 0.44, 95% CI 0.35–0.56). Fewer infections developed in the patients treated with antimicrobial catheters regardless of randomization, number of participating centers, funding, shunting or ventricular drainage, definition of infections, de novo implantation, and rate of infections in the study. There was no difference regarding gram-positive bacteria, all staphylococci, coagulase-negative streptococci, and Staphylococcus aureus, when analyzed separately. On the contrary, the risk for methicillin-resistant S. aureus (MRSA, RR 2.64, 95% CI 1.26–5.51), nonstaphylococcal (RR 1.75, 95% CI 1.22–2.52), and gram-negative bacterial (RR 2.13, 95% CI 1.33–3.43) infections increased with antimicrobial shunt catheters.

CONCLUSIONS

Based on data mainly from nonrandomized studies, AICs and SCCs reduce the risk for infection in patients undergoing CSF shunting. Future studies should evaluate the higher risk for MRSA and gram-negative infections. Additional trials are needed to investigate the comparative effectiveness of the different types of antimicrobial catheters.

ABBREVIATIONSAIC = antibiotic-impregnated catheter; CC = conventional catheter; CoNS = coagulase-negative streptococci; CSF = cerebrospinal fluid; EVD = external ventricular drainage; HCC = hydrogel-coated catheter; MRSA = methicillin-resistant Staphylococcus aureus; RCT = randomized controlled trial; SCC = silver-coated catheter.

OBJECT

The aim of this study was to evaluate the effectiveness of antimicrobial-impregnated and -coated shunt catheters (antimicrobial catheters) in reducing the risk of infection in patients undergoing CSF shunting or ventricular drainage.

METHODS

The PubMed and Scopus databases were searched. Catheter implantation was classified as either shunting (mainly ventriculoperitoneal shunting) or ventricular drainage (mainly external [EVD]). Studies evaluating antibioticimpregnated catheters (AICs), silver-coated catheters (SCCs), and hydrogel-coated catheters (HCCs) were included. A random effects model meta-analysis was performed.

RESULTS

Thirty-six studies (7 randomized and 29 nonrandomized, 16,796 procedures) were included. The majority of data derive from studies on the effectiveness of AICs, followed by studies on the effectiveness of SCCs. Statistical heterogeneity was observed in several analyses. Antimicrobial shunt catheters (AICs, SCCs) were associated with lower risk for CSF catheter–associated infections than conventional catheters (CCs) (RR 0.44, 95% CI 0.35–0.56). Fewer infections developed in the patients treated with antimicrobial catheters regardless of randomization, number of participating centers, funding, shunting or ventricular drainage, definition of infections, de novo implantation, and rate of infections in the study. There was no difference regarding gram-positive bacteria, all staphylococci, coagulase-negative streptococci, and Staphylococcus aureus, when analyzed separately. On the contrary, the risk for methicillin-resistant S. aureus (MRSA, RR 2.64, 95% CI 1.26–5.51), nonstaphylococcal (RR 1.75, 95% CI 1.22–2.52), and gram-negative bacterial (RR 2.13, 95% CI 1.33–3.43) infections increased with antimicrobial shunt catheters.

CONCLUSIONS

Based on data mainly from nonrandomized studies, AICs and SCCs reduce the risk for infection in patients undergoing CSF shunting. Future studies should evaluate the higher risk for MRSA and gram-negative infections. Additional trials are needed to investigate the comparative effectiveness of the different types of antimicrobial catheters.

Cerebrospinal fluid (CSF) shunting is a commonly used surgical procedure for the treatment of hydrocephalus. Infections are among the most common complications following shunt implantation, occurring after 5% to 15% of procedures, and they have been associated with increased morbidity, including lower intellectual ability, higher number of revision surgeries, prolonged hospitalization, and higher cost.4,15,49 In addition, CSF shunt infections were identified as predictors of mortality, which in such cases ranges from 1.5% to 22% in individual studies.4 Skin flora, including Staphylococcus spp., in up to 70% of cases and gram-negative bacilli (Escherichia coli, Klebsiella spp.) in up to 20% of cases are the main causative pathogens in CSF shunt infections.15 In CSF shunting, the risk factors for shunt infections were younger age, including neonatal period and age less than 6 months, prematurity, and postoperative CSF leakage. The identified risk factors for ventricular drainage were previous shunt insertion, a duration of ventriculostomy for more than 5 days, previous craniotomy, and the etiology of hydrocephalus (including intraventricular and subarachnoid hemorrhage).15

Several efforts have been made to reduce the incidence of CSF catheter implantation–associated infections, such as using minimal handling protocols, including changing gloves before handling the catheter and laparoscopic placement of the distal catheter instead of conventional laparotomy.32,38 Perioperative antibiotic prophylaxis, antibioticimpregnated sutures for wound closing, and topical application of methicillin to the operative field have also been shown to reduce infections associated with CSF catheter implantation.37,42,45The development of antimicrobial-impregnated and -coated catheters (antimicrobial catheters)—including antibiotic-impregnated catheters (AICs), silver-coated catheters (SCCs), and hydrogel-coated catheters (HCCs)—has been among the most promising advances. AICs contain a combination of antibiotics—rifampin with either clindamycin or minocycline—which are released through the lumen after the placement of the catheter.1 SCCs contain a combination of metallic silver and an insoluble silver salt that is also released through the lumen of the catheter.12 HCCs have a hydrophilic surface that impedes bacterial adherence.22,24

Although their use has increased over time and they have virtually replaced conventional catheters (CCs) in daily practice,16,24,27 the effectiveness of antimicrobial catheters in reducing CSF catheter implantation infections remains controversial.20,25,33,46,50 Additional topics in debate are whether antimicrobial catheters reduce the risk of infection in lower risk populations (for example adults rather than children), their impact on mortality, and whether they prevent colonization. We conducted a systematic review and meta-analysis to study the effectiveness of antimicrobial catheters in preventing CSF shunting–associated infections.

Methods

Search Strategy, Study Selection, and Data Extraction

Two investigators (A.A.K. and K.A.P.) conducted a systematic search of the PubMed and Scopus electronic databases using the following search terms: “antibiotic OR antimicrobial AND (cerebrospinal fluid OR ventriculoperitoneal OR external ventricular drainage) AND (shunt OR catheter) AND infection.” Additional searches were performed with the keywords: “antibiotic AND shunt”, “external AND ventricular AND drainage”, “silver AND shunt”, “silver AND CSF”, “hydrogel AND shunt”, “hydrogel AND CSF”. The 2 investigators performed a separate, independent search of the literature and extracted relevant data. If discrepancies occurred, they were resolved in meetings with a third investigator (K.Z.V.). We also reviewed the references of the primarily retrieved studies to identify additional potentially eligible studies. The final search was done in January 2014. There was no limit on the year of publication.

A study was eligible for inclusion in the meta-analysis if it met the following criteria: 1) it provided comparative data regarding the development of infection or mortality in patients with any type of antimicrobial and conventional CSF shunt catheters, 2) it was published in a peerreviewed journal, and 3) it was written in the English language. Both primary insertion and revision procedures were considered eligible surgical interventions. Randomized controlled trials (RCTs) and nonrandomized studies in adults, children, infants, or neonates were eligible. A study was excluded if: 1) no control group was defined, 2) it was a case report or included fewer than 10 patients, or 3) it was considered part of a bigger study (multiple publications). The extracted data included study design, geographic region, type of catheters, duration of follow-up period, funding, population characteristics, type of neurosurgical procedure, and outcomes (infection, mortality).

Definitions and Outcomes

The definition of shunt infection was based on the definition provided in each of the included studies. Shunting refers to ventriculoperitoneal, ventriculoatrial, ventriculopleural, lumboperitoneal, cystoperitoneal, and subdural shunting. Ventricular drainage included external ventricular drainage (EVD) and ventriculosubgaleal shunting. Early shunt infection for permanent shunting was defined as infection developing during the first 6 months after the shunt implantation. Late shunt infection for permanent shunting was defined as infection developing more than 6 months after the shunt implantation. The primary outcome of the meta-analysis was development of infections with antimicrobial catheters compared with CCs. Infections due to specific microbes and infection-related and all-cause mortality were considered secondary outcomes.

Statistical Analysis

Since it was expected that many nonrandomized studies were to be included in the analysis and significant clinical and possibly statistical heterogeneity was expected, the Mantel-Haenszel random effects model was applied for all analyses. Pooled risk ratios and 95% confidence intervals were calculated regarding all outcomes. Statistical heterogeneity between studies was assessed by using the chi-square test (p < 0.10 was defined to indicate the presence of heterogeneity) and I2 (for assessing the degree of heterogeneity). Publication bias was assessed using the funnel-plot method. The meta-analysis was performed with Review Manager for Windows, version 5.2.

Quality Assessment

Quality assessment of the randomized and nonrandomized studies was performed with Jadad Scale18 and the Newcastle-Ottawa Scale,51 respectively.

Results

Characteristics of the Included Studies

We identified a total of 36 studies that evaluated 16,796 procedures eligible for systematic review and meta-analysis.1–3,5,6,11–14,16,17,19–24,26–31,34–36,39–41,43,44,52–56 The selection process is depicted in Fig. 1. The main characteristics of included studies are presented in Table 1. Twenty-nine studies were nonrandomized (19 retrospective and 10 prospective) and evaluated 15,335 procedures; 7 were randomized and evaluated 1461 procedures. The quality assessment of the included studies is presented in Appendix Tables 1 and 2. For RCTs, scores ranging from 2 to 5 (median 2) were calculated; for nonrandomized studies, the corresponding range was 5–9 (median 7). There were 27 single-center studies and 9 multicenter studies. Eighteen studies were conducted in Europe, 9 studies in the US, 2 in Africa, 1 in Canada, 1 in Asia, 1 in Australia, and 1 in New Zealand. Three studies were international. Eleven studies were funded either by the manufacturer of the catheter or an independent source.

FIG. 1.
FIG. 1.

Flow diagram of the selection process of the included studies.

TABLE 1

Characteristics of the studies included in meta-analysis

Authors & YearStudy DesignRegion, Study Period or DurationPopulation, Age (mean/range)Type of Implantation: Type of CathetersNo. of Procedures/PatientsFunding*Definitions of InfectionPrimary OutcomeFrequency of Infection in Both ArmsFollow-Up Duration
Symptoms, Signs, or Other Laboratory ExamsCultures
Abla et al., 2011SC, prospective cohortUS, Jan 2007–Jun 2008Adults, 58.4 yrs/18–89 yrsVD: AICs129/129None+CSF VD infection0%NR
Albanese et al., 2009SC, retrospective cohortEurope, Oct 2005–Oct 2007Adults,§ 61.8 yrs/40–79 yrsS: AICs, CCs18/18None+CSF S infection38.8%Min 12 mos
Aryan et al., 2005SC, retrospective cohortUS, Apr 2001–Apr 2003Children, 4.5 yrs/6 mos–17 yrsS: AICs, CCs78/NRNone++CSF S infection10.25%14–37 mos
Eymann et al., 2009SC, retrospective cohortEurope, Jan 2002–Dec 2007Children, 2 days–100 mosS: AICs, CCs56/56None+CSF S infection7.14%6–75 mos
Eymann et al., 2008SC, retrospective cohortEurope, 1998–2006Adults, 18–86 yrsS: AICs, CCs269/269No+CSF S infection1.85%Min 6 mos
Farber et al., 2011SC, retrospective cohortUS, 2004–2009Adults, 60 yrs/21–93 yrsS: AICs, CCs500/500Funded+CSF S infection2.6%12 mos
Fichtner et al., 2010SC, retrospective cohortEurope, Jun 2003–Dec 2005Children & adults, >16 yrsVD: SCCs, CCsNR/160None+CSF VD infection3.75%NR
Govender et al., 2003SC, RCTAfrica, NRChildren & adults,** 1 mo–72 yrsS: AICs, CCs135/110None++CSF S infection9.62%9–28 mos
Gutiérrez-González et al., 2010SC, retrospective cohortEurope, Jan 2004–Oct 2008Children & adultsS: AICs, CCs VD: AICs, CCs231/NRNone+CSF S & VD infec-tion12.55%PS Min 90 days TS Min 5 days
Harrop et al., 2010SC, prospective cohortUS, 2003–2008Children & adultsVD: AICs, CCs1634/NRNone+CSF VD infection2.81%NR
Hayhurst et al., 2008MC, retrospective cohortEurope, Jan 2002–Dec 2006Children, 1 day–16 yrsS: AICs, CCs291/215None++CSF S infection9.96%8–42 mos
James et al., 2014SC, retrospective cohortEurope, 14 yrsChildren, 0–17 yrsS: AICs, CCs2092/NRNone++CSF S infection7.64%Min 24 mos
Kan & Kestle, 2007SC, retrospective cohortUS, Jun 2003–Oct 2005ChildrenS: AICs, CCs160/129None+CSF S infection6.87%Min 9 mos, AICs (11.6 mos), CCs (13.8 mos)
Kandasamyet al., 2011MC, prospective cohortEurope, NRChildren <16 yrsS: AICs, CCs2544/NRNone++CSF S infection7.27%5–47 mos
Kaufmann et al., 2004MC, RCTCanada, NRAdults, >18 yrsVD: HCC, CCsNR/158Funded+CSF VD infection8.22%NR
Keong et al., 2012MC, DB RCTEurope, Jun2005–Sep 2009Adults, 18–84 yrsVD: SCCs, CCs278/278None++CSF VD infection16.90%NR
Kestle et al., 2011MC, prospective cohortInternational, Jun 2007–Feb 2009ChildrenS: HCC, CCs531/NRFunded++CSF S infection7.72%6–12 mos
Lackner et al., 2008SC, prospective cohortEurope, Jun2006–Jan 2007Adults, >18 yrsVD: SCCs, CCsNR/39Funded+CSF VD infection12.82%NR
Lajcak et al., 2013SC, retrospective cohortEurope, Jan2006–Dec 2008Children & adults, 1–89 yrsVD: SCCs, CCs402/402None+CSF VD infection7.21%NR
Lane et al., 2014SC, retrospective cohortAfrica, NRChildren, 11.3 mosS: AICs, CCs160/160Funded++CSF S failure (death, revisionor removal of shunt)9.37%7.6 mos, 113 patients
Lemcke et al., 2012SC, prospective cohortEurope, Jul 2003–Jun 2006Children & adults, 53.6 yrs/12–84 yrsVD: AICs, SCCs, CCs96/95None+CSF VD infection10.41%19 days
Mikhaylov et al., 2014SC, retrospective cohortUS, Jul 2007–Jul 2009AdultsVD: AICs, CCs145/145None+CSF VD infection6.89%NR
Muttaiyah et al., 2010SC, prospective cohortNew Zealand, Jul 2005–Aug 2007Children & adults, 1 mo–87 yrsVD: AICs, CCs144/120None+CSF VD infection8.33%NR
Parker et al., 2009SC, retrospective cohortUS, Jan 1997–Dec 2007Children & adults, 6.5 yrs/1 day–20 yrsS: AICs, CCs1072/NRNone+CSF S infection7.46%AICs (34.6 mos), CCs (72.3 mos)
Pattavilakom et al., 2007SC, prospective cohortAustralia, Jul 1995–Jun 2005Children & adultsS: AICs, CCs794/NRNone++CSF S infection4.91%15 mos/6–42 mos/min 6 mos
Pople et al., 2012MC, RCTInternational, Nov 2004–Sep 2010Adults, >18 yrsVD: AICs, CCs357/357Funded++CSF VD infection19.6%NR
Richards et al., 2009MC, retrospective registryEurope, NRChildren & adultsS: AICs NR, CCs1988/NRFundedCSF S infection3.87%Min 9 mos
Ritz et al., 2007SC, retrospective cohortEurope, 2 yrsChildren & adultsS: AIC, CCs598/258None+CSF S infection2.50%NR
Rivero-Garvía et al., 2011SC, retrospective cohortEurope, 2000–2006Children, <16 yrsVD: AICs, CCs458/NENone+CSF VD infection3.27%NR
Steinbok et al., 2010MC, prospective registryInternational, Jan 2006–Jan 2008Children & adults, 0–84 yrsS: AICs, CCs433/433Funded++CSF S infection3.23%Max 90 days
Tamburrini et al., 2008SC, prospective cohortEurope, Nov 2000–Mar 06ChildrenVD: AICs, CCs91/91None+CSF VD infection16.48%NR
Winkler et al., 2013SC, RCTEurope, Feb 2011–Jun 2012Adults, 56.5 yrs/18–80 yrsVD: AICs, SCCs61/40Funded++CSF VD Infection18%15 days, 3–30 days
Woernle et al., 2011SC, retrospective cohortEurope, Aug 2007–Jun 2009Children & adults,§ 2–89 yrsVD: AICs, CCs124/NENone+Hemorrhage, infection & malplacement of catheters11.29%NR
Wong et al., 2010SC, RCTAsia, Apr 2004–Dec 2008Adults, >18 yrsVD: AICs, CCs184/184Funded+Nosocomial infections2.17%>3 mos
Wright et al., 2013SC, retrospective cohortUS, Feb 2007–Nov 2008Adults, 53.8 yrs/>18 yrsVD: AICs NR, CCs98/98Funded++CSF VD infection16.32%NR
Zabramski et al., 2003MC, RCTUS, Dec 1998–Mar 2001Adults, >18 yrsVD: AICs, CCs288/288Funded+CSF VD infection5.2%NR

DB = double-blinded; MC = multicenter; NE = not estimable; NR = not reported; PS = permanent shunting; S = Shunting; SC = single center; TS = temporary shunting, VD = ventricular drainage.

Any type of funding from the manufacturer of the catheter or any other independent source was included.

Minocycline/rifampin impregnated.

Clindamycin/rifampin impregnated.

Patients with higher risk for infection included.

Presoaked with bacitracin.

Including 6 HIV patients.

APPENDIX TABLE 1

Quality assessment of randomized studies with the Jadad scale

Authors & YearRandomizationAssessment of RandomizationDouble BlindingAssessment of Double BlindingDescription of Withdrawals & DropoutsMethod of Randomization Was Described, But Was InappropriateMethod of Blinding Was Described, But Was Inappropriate
Govender et al., 20031000100
Kaufmann et al., 20041000100
Keong et al., 20121111100
Pople et al., 20121100100
Winkler et al., 20131000100
Wong et al., 20101000100
Zabramski et al., 20031100100
APPENDIX TABLE 2

Quality assessment of nonrandomized studies with Newcastle-Ottawa Scale

Authors & YearRepresentativeness of Exposed CohortSelection of Nonexposed CohortAscertainment of ExposureDemonstration That Outcome of Interest Was Not Present at Start of StudyComparabilityAssessment of Outcome*Was Follow-Up Long Enough for Outcomes to Occur?Adequacy of Follow-Up of CohortsTotal
Abla et al., 2011111121007
Albanese et al., 2009111121119
Aryan et al., 2005111010116
Eymann et al., 2009111011117
Eymann et al., 2008111021118
Farber et al., 2011111021118
Fichtner et al., 2010111121007
Gutiérrez-González et al., 2010111021118
Harrop et al., 2010111011005
Hayhurst et al., 2008111010116
James et al., 2014111010116
Kan & Kestle, 2007111121119
Kandasamy et al., 2011111010116
Kestle et al., 2011111110117
Lackner et al., 2008111121007
Lajcak et al., 2013111011005
Lane et al., 2014111020005
Lemcke et al., 2012111121119
Mikhaylov et al., 2014111121007
Muttaiyah et al., 2010111021006
Parker et al., 2009111021118
Pattavilakom et al., 2007111011117
Richards et al., 2009111020117
Ritz et al., 2007111021006
Rivero-Garvía et al., 2011111011005
Steinbok et al., 2010111111107
Tamburrini et al., 2008111011005
Woernle et al., 2011111011005
Wright et al., 2013111111006

Only studies with definition of infection based on cultures only were considered as a positive result. Clinical definition of infection among the studies was considered as a self-report or a subjective outcome.

Minimum follow-up for EVD and ventriculoperitoneal shunt were considered 5 days and 1 month after the placement of the catheter, respectively.

In 22 studies, a positive culture was considered definitive for shunt infection while in 13 studies the diagnosis of infection was based on the presence of symptoms, signs of infection, laboratory findings in CSF and/or blood, and positive cultures. One study did not provide a definition for CSF shunt infection. The populations across and within the studies were characterized by heterogeneity regarding the proportion of the causes of hydrocephalus and the risk factors for shunt infection.

Prevention of Infections

The meta-analysis and subgroup analyses are presented in Table 2.1–3,5,6,11–14,16,17,19–24,26–31,34–36,39–41,43,44,52–56 Overall, the meta-analysis showed that the use of antimicrobial shunt catheters, after the exclusion of studies evaluating HCCs, was associated with lower risk for infection when compared with CCs (15,949 procedures, risk ratio [RR] 0.44, 95% CI 0.35–0.56, Fig. 2). Publication bias was detected, mainly in the region of small studies with negative results (Appendix Fig. 1). Fewer CSF infections developed in the antimicrobial catheter group regardless of randomization (Fig. 3), number of participating centers, funding (by the manufacturer or independent sources), shunting or ventricular drainage placement of the catheter, population age, definition of infections, and rate of infections in the study. The risk of infection was lower in de novo placement but not in revision surgery. There was no difference regarding gram-positive, staphylococcal, coagulasenegative streptococci (CoNS), and Staphylococcus aureus infections, separately. On the contrary, the risk for methicillin-resistant S. aureus (MRSA) infection was higher with antimicrobial catheters than CCs. Finally, patients treated with antimicrobial catheters had a higher risk for infection due to gram-negative bacteria and nonstaphylococcal species (data for a more detailed analysis according to specific pathogens were not available). No or minimal heterogeneity was observed in the analyses according to microbial etiology.

TABLE 2

Development of infections in subgroup analyses of all studies evaluating antimicrobial catheters

Studied CharacteristicNo. of ProceduresNo. of StudiesRR (95% CI), I2
All studies16,638340.46 (0.36–0.58), 48%
Randomized studies140060.59 (0.39–0.89), 27%
Nonrandomized studies15,238280.44 (0.33–0.57), 50%
Single-center studies9770250.38 (0.28–0.50), 41%
Multicenter studies686890.68 (0.54–0.86), 13%
Funded studies, funded by any source4736110.50 (0.33–0.77), 37%
Funded studies, funded by manufacturer360780.58 (0.40–0.85), 24%
Nonfunded studies11,902230.44 (0.34–0.59), 52%
Permanent (shunting)11,838180.48 (0.37–0.64), 33%
Temporary (ventricular drainage)4800180.44 (0.30–0.65), 60%
Children6461100.58 (0.42–0.80), 23%
Adults2334110.43 (0.28–0.67), 36%
Mixed adults & children7843140.43 (0.29–0.64), 61%
Clinical & laboratory definition of infection7791120.58 (0.45–0.76), 29%
Definition of infection by cultures only7511220.39 (0.28–0.53), 41%
Rate of infection >10%1442100.46 (0.29–0.73), 48%
Rate of infection 5–10%7738110.55 (0.40–0.75), 43%
Rate of infection <5%7458130.36 (0.23–0.57), 51%
De novo implantation182090.50 (0.33–0.74), 0%
Revision implantation190830.83 (0.55–1.26), 0%
Gram-positive infections441200.95 (0.83–1.08), 15%
Staphylococcal infections385170.86 (0.73–1.01), 0%
CoNS infections305160.83 (0.58–1.19), 22%
S. aureus infections342121.02 (0.79–1.31), 0%
MRSA infections12452.64 (1.26–5.51), 0%
Nonstaphylococcal infections371141.75 (1.22–2.52), 10%
Gram-negative infections412162.13 (1.33, 3.43), 0%
FIG. 2.
FIG. 2.

Forest plot depicting the risk ratios for CSF shunting– and ventricular drainage–associated infections for antimicrobial catheters (AMICs [AICs and SCCs]) compared with CCs (studies on HCCs were not included in the figure). The vertical line indicates the “no difference” point between the 2 regimens; squares indicate risk ratios; diamonds, pooled risk ratios for all studies; horizontal lines, 95% confidence intervals; events represent numbers of infections; total refers to number of procedures. M-H = Mantel Haenszel. Figure is available in color online only.

APPENDIX FIG. 1.
APPENDIX FIG. 1.

Funnel plot to assess publication bias. More studies are missing near the middle toward the right, indicating asymmetry. Publication bias in the region of small studies with negative results was observed. SE = standard error. Figure is available in color online only.

FIG. 3.
FIG. 3.

Forest plot depicting the risk ratios for CSF shunting– and ventricular drainage–associated infections for antimicrobial catheters (AMICs [AICs and SCCs]) compared with CCs (studies on HCCs were not included in the figure). The vertical line indicates the “no difference” point between the 2 regimens; squares indicate risk ratios; diamonds, pooled risk ratios for all studies; horizontal lines, 95% confidence intervals; events represent numbers of infections; total refers to number of procedures. Figure is available in color online only.

Antibiotic-Impregnated Catheters

Lower risk for infection was observed when AICs were compared with CCs for all types of CSF catheter implantation (RR 0.42, 95% CI 0.32–0.55).2,3,5,6,11,13,14,16,17,19–21,28–31,34–36,39–41,43,44,53–56 Subgroup analyses (Table 3) showed that AICs were associated with lower risk for infections regardless of randomization (for randomized studies, a trend toward a significant difference was observed), number of participating centers in the study, funding (by the manufacturer or independent sources), shunting or ventricular drainage, early-onset infections in permanent shunting, age of studied population, definition of infection, de novo catheter implantation, and rate of infection in the participating center(s). AICs were not associated with fewer infections in revision surgery in any type of implantation or late-onset infections in permanent shunting. After excluding from sensitivity analyses studies that had significant differences in their designs (studies were excluded because of the use of bacitracin-soaked catheters instead of CCs) and studies involving more than 1000 procedures, we found that the development of CSF shunt infections was also lower with AICs than with CCs. Finally, no difference was observed when rifampin-minocyclin impregnated catheters were compared with rifampin-clindamycin impregnated catheters (RR 1.14, 95% CI 0.25–5.24). No difference was observed in risk for infections due to Staphylococcus spp. (regardless of the type of shunting), CoNS, S. aureus, or gram-positive bacteria, but the risk was higher for infection due to gram-negative bacteria, nonstaphylococcal species, and MRSA.

TABLE 3

Development of infections in subgroup analyses of studies with AICs

Studied CharacteristicNo. of ProceduresNo. of StudiesRR (95% CI), I2
All studies15,006280.42 (0.32–0.55), 54%
Randomized studies96440.43 (0.18–1.03), 54%
Nonrandomized studies14,042240.41 (0.31–0.55), 54%
Single-center studies9105220.35 (0.26–0.49), 44%
Multicenter studies590160.68 (0.52–0.89), 21%
Funded studies, funded by any400880.47 (0.30–0.73), 37%
source
Funded studies, funded by manufacturer341060.57 (0.37–0.86), 29%
Nonfunded studies10,998200.41 (0.29–0.57), 58%
Shunting11,307170.48 (0.37–0.62), 29%
Early infection in permanent shunt150960.34 (0.13–0.88), 28%
Late infection in permanent shunt80741.23 (0.24–6.20), 0%
Ventricular drainage3699120.36 (0.20–0.64), 71%
Neonates13420.39 (0.16–0.96), 0%
Children593090.58 (0.44–0.76), 12%
Adults185980.32 (0.16–0.63), 48%
Mixed adults & children7217110.39 (0.24–0.63), 67%
Clinical & laboratory definition of infection6982100.57 (0.42–0.76), 31%
Definition of infection by cultures6688200.34 (0.24–0.49), 41%
Rate of infection >10%106180.40 (0.21–0.78), 60%
Rate of infection 5–10%664780.49 (0.34–0.70), 47%
Rate of infection <5%7298120.35 (0.22–0.57), 54%
De novo implantation159870.44 (0.28–0.69), 0%
Revision implantation190830.83 (0.55–1.26), 0%
Gram-positive infections422180.94 (0.82–1.09), 18%
Staphylococcal infections366150.87 (0.73–1.03), 0%
CoNS infections286140.86 (0.59–1.25), 27%
S. aureus infections323101.01 (0.78–1.31), 0%
MRSA infections11942.64 (1.26–5.51), 0%
Nonstaphylococcal infections357131.75 (1.16–2.65), 21%
Gram-negative infections406152.08 (1.29–3.37), 0%
Excluding studies w/ >1000 procedures5676230.43 (0.32–0.59), 34%
Excluding studies w/ bacitracin-presoaked CCs14,768260.42 (0.32–0.55), 57%
Rifampin-clindamycin vs rifampin-minocyclin132521.14 (0.25–5.24), NA

NA = not applicable.

Silver-Coated and Hydrogel-Coated Catheters

Data regarding the comparative effectiveness of SCCs and CCs were available only for ventricular drainage catheter placement (Table 4).12,23,26,27,29 SCCs were associated with lower risk for infection compared with CCs (RR 0.60, 95% CI 0.40–0.89). The difference was significant in the single multicenter, randomized trial (RR 0.57, 95% CI 0.33–0.99) but not in the analysis of 4 single-center, nonrandomized studies. SCCs were associated with lower risk for infection in nonfunded studies and in center(s) with a high rate of infection (> 10%), but no difference was found between SCCs and CCs with regard to population age, definition of infection, low rate of infection < 10%, or microbial etiology. Heterogeneity was not observed in these analyses.

TABLE 4

Development of infections in subgroup analyses of studies with SCC

Compared GroupsStudied CharacteristicNo. of PatientsNo. of StudiesRR (95% CI), I2
SCC vs CCAll studies94350.60 (0.40–0.89) 0%
SCC vs CCNonrandomized studies66540.62 (0.35–1.10) 0%
SCC vs CCSingle-center studies53140.62 (0.35–1.10) 0%
SCC vs CCNonfunded studies90440.62 (0.42–0.92) 0%
SCC vs CCVentricular drainage94350.60 (0.40–0.89) 0%
SCC vs CCAdults31720.40 (0.09–1.70) 36%
SCC vs CCChildren & adults62630.67 (0.38–1.20) 0%
SCC vs CCDefinition of infection by cultures66540.62 (0.35–1.10) 0%
SCC vs CCRate of infection >10%38130.55 (0.33–0.90) 0%
SCC vs CCRate of infection <10%56220.69 (0.36–1.32) 0%
SCC vs CCGram-positive infections1930.88 (0.49–1.58) 23%
SCC vs CCStaphylococcal infections1930.68 (0.34–1.37) 0%
SCC vs CCCoNS infections1930.43 (0.10–1.82) 0%
SCC vs CCS. aureus infections1931.49 (0.28–7.84) 6%
SCC vs CCNonstaphylococcal infections1422.67 (0.46–15.48) 0%
SCC vs AICVentricular drainage12521.37 (0.55–3.41) 0%

Two multicenter studies (a randomized trial involving adults and a prospective cohort study involving children) evaluated HCCs compared with CCs for the prevention of shunt infections.22,24 HCCs were not associated with fewer infections than CCs (689 procedures, RR 1.63, 95% CI 0.21–12.96).

Silver-Coated Versus Antibiotic-Impregnated Catheters

SCCs were compared with AICs for ventricular drainage in 2 studies (a randomized trial involving adults and a prospective cohort involving children and adults).29,52 No difference in the risk for infection was observed in either of these studies or the pooled analysis (RR 1.37, 95% CI 0.55–3.41).

Mortality

Eleven studies provided data for all-cause mortality (1910 patients);1,2,12,13,23,26,28,30,43,44,54 8 s tudied A ICs a nd 3 studied SCCs, all in comparison with CCs. No data for mortality was available for HCCs. When all types of antimicrobial catheters were compared with CCs, no difference was observed in all-cause mortality (RR 1.17, 95% CI 0.92–1.49). Table 5 shows the subgroup analyses; no difference in mortality was seen for AICs compared with CCs for ventricular drainage or shunting and no difference in mortality was seen for SCCs compared with CCs in ventricular drainage.

TABLE 5

Mortality in patients treated with CSF shunting or ventricular drainage

ComparisonTypes of CathetersNo. of ProceduresNo. of StudiesRR (95% CI), I2
AICs & SCCs vs CCsAll types1819101.17 (0.92–1.49), 0%
AICs vs CCsVD61731.08 (0.70–1.65), 41%
AICs vs CCsShunting72141.46 (0.76–2.79), 0%
AICs vs CCsAll types133171.17 (0.87–1.56), 0%
SCCs vs CCsVD48131.17 (0.76–1.81), 0%

Outcomes of Multivariate Analysis of Individual Studies

Multivariate analyses were performed in 8 studies. Two studies showed that AICs were independently associated with lower risk for infection in permanent shunting13,14 while 2 others showed no difference between AICs and CCs.20,40 Two studies provided adjusted results in ventricular drainage; in one of them, AICs were independently associated with lower risk for infection,56 while in the second they were not.36 In the single study on SCCs that provided adjusted data, SCCs were associated with lower risk for infection.23 One study showed that HCCs were independently associated with higher risk for CSF shunting–associated infection.24

Discussion

This meta-analysis sought to investigate the protective effectiveness of antimicrobial catheters in reducing CSF shunting–associated infections in comparison with CCs. The majority of the included studies (28 studies, approximately 90% of included procedures) evaluated AICs, followed by SCCs; only 2 studies evaluated the effectiveness of HCCs. Antimicrobial catheters were associated with lower risk for infection compared with CCs regardless of randomization status, number of participating centers, funding, permanent or temporary catheter placement, de novo implantation, population age, timing of infection development, definition of infection, and rate of infections in the individual studies. Although no difference in the development of infections due to gram-positive bacteria, all staphylococci, CoNS, or S. aureus was observed, antimicrobial shunt catheters were associated with higher risk for MRSA, nonstaphylococcal, and gram-negative bacterial infections. It should be emphasized that only half of the included studies provided data regarding either specific bacterial species or gram-positive and gram-negative status.

Since the majority of the studies evaluated the effectiveness of AICs, the outcomes of the subgroup analyses regarding AICs were similar to that of the primary analysis. In addition, in a sensitivity analysis after the exclusion of studies with large populations (more than 1000 procedures), AICs were still associated with lower risk for infections. However, AICs were not more effective than CCs in randomized trials and in reducing the occurrence of late infections. Despite the trend toward lower risk for infection with the use of AICs in an analysis with a large sample size, the lack of statistical significance indicates that further studies are required to define the patient populations that would benefit more from this intervention. The presence of publication bias in the area of small trials with negative results is also an issue that needs to be addressed. The finding that AICs were not associated with prevention of late-onset infections (developing more than 6 months after catheter placement) in permanent shunting denotes that AICs exert their protective effectiveness during the first months after their implantation. However, it has been noted that early shunt infections account for approximately 70% of all episodes.2 Other interventions, and possibly stricter adherence to infection control measures and surgical techniques, are required to reduce the incidence of late-onset infections.

Five studies evaluated the effectiveness of SCCs for ventricular drainage; SCCs were associated with lower risk for infections in all studies and in the single available randomized trial. Overall, far fewer data were available for SCCs. It is possible that the non–statistically significant lower risk for development of infection in the SCC arm was due to the smaller sample size. However, it is note-worthy that statistical heterogeneity was not observed in these analyses. Limited data were also available for the comparative effectiveness of SCCs and AICs as well as of AICs with different antibiotics (rifampin/clindamycin– impregnated vs rifampin/minocycline–impregnated catheters). Although the antimicrobial spectrum of these combinations is quite similar for gram-positive bacteria, the comparative effectiveness could be evaluated in the future.

There are several concerns regarding the use of antimicrobial shunt catheters. The first is the cost-effectiveness of such an approach, which depends on the incidence of infections in an institution, the infection control measures, the surgical technique and expertise, the cost of catheters, and the cost of treatment of a possible subsequent infection in a given country. Klimo et al., in a cost-effectiveness analysis of AICs compared with CCs, concluded that the yearly cost savings from the use of AICs ranged from $90,000 to over $1.3 million in the US.25 I n t his a nalysis it was estimated that the total cost to treat a shunt infection accounted for up to $50,000, while the additional cost of AICs compared with CCs was up to $400 per kit.25 However, the authors acknowledged that in other countries where the cost to treat an infection is lower, the approach might not be cost-effective. Limited data regarding the cost of other types of antimicrobial shunt catheters did not allow a cost saving analysis compared with conventional catheters.

The second concern is the probability of a shift toward more virulent strains than CoNS. In this meta-analysis, AICs were associated with lower risk for any infection for both CSF shunting and ventricular drainage but higher risk for MRSA, nonstaphylococcal, and gram-negative bacterial infections. A large study performed in children showed that when CCs were used, CoNS were the predominant pathogen, accounting for approximately 52% of isolated pathogens, followed by S. aureus (31.6%), Streptococcus or Enterococcus s pp. (8.8%), g ram-negative o rganisms (4.4%), and Propionibacterium acnes (2.2%). When AICs replaced CCs, S. aureus became the predominant pathogen (40%), followed by Streptococcus or Enterococcus spp. (20%), P. acnes and CoNS (both 16%), and gram-negative organisms (4%).19 Although we were not able to study in depth the reasons behind this finding, one could assume that this is probably due to inactivity of antibiotics used in AICs against such bacteria. Nosocomial MRSA strains are probably not susceptible to rifampin, minocycline, and clindamycin in most settings, while Pseudomonas aeruginosa strains are definitively not susceptible. Similarly, the susceptibility of Acinetobacter spp. and multidrugresistant Enterobacteriaceae to the aforementioned antibiotics is expected to be low. This shift toward more virulent pathogens than CoNS is an issue that warrants further study, since few of the included studies provided data for these comparisons, especially in settings where the incidence of MRSA or multidrug-resistant gram-negative bacteria is high. In addition, the impact of this shift on mortality should be explored.

The third issue is development of infections in patients who require replacement of catheters. Data regarding development of infections after de novo implantation showed that antimicrobial catheters reduce the risk for infections, but no difference was observed after revision implantation. Moreover, 1 study showed that patients requiring revision surgery with AICs who had an AIC implanted during the first operation had a higher infection rate (11.7%) than those undergoing primary AIC insertion (1.6%) and those undergoing revision of CCs using AICs (2.5%).19

The meta-analysis showed no difference in all-cause mortality between patients treated with antimicrobial or conventional shunt catheters. Some might argue that for an infection with considerable mortality, the intervention could not be considered successful. However, we should bear in mind that antimicrobial catheters are used for prevention and not for treatment of infections. Factors such as the primary offending organism (CoNS in CSF shunt infections, which are less virulent than other bacteria), the antibiotics or other antimicrobials used in manufacturing the catheters, rates of mortality (provided in only 11 of the 36 included studies, range 0%–23.3%) and infection (range 0%–38% in the included studies) in the medical center(s) where the study was performed, the time end point used in every study (which ranged from 3 days up to 7 years), and all-cause or infection-related mortality all deserve significant attention. Several meta-analyses in other fields of infectious diseases have failed to show a difference in mortality after the implementation of a preventive measure, despite a significant reduction in infection rate.7–10,47,48

To our knowledge, 4 meta-analyses have been published thus far.25,33,46,50 They included patients with ventricular drainage or shunt catheter implantation and concluded that antimicrobial catheters were more effective than CCs in preventing shunt infections. Besides the addition of recently published data, the present analysis outweighs the former ones for several other reasons. First, it included a greater number of studies (36 compared with 19,46 11,33 14,25 and 850) and consequently procedures (almost 17,000 compared with 6171,46 1649,33 9049,25 and 299150). It included more randomized trials (7 compared with 3,46 1,16 1,18 and 450), thus increasing the quality of its outcomes, and showed that randomized and nonrandomized studies have produced similar outcomes in most of the performed analyses. Several subgroup analyses were performed to study the heterogeneity (either statistically proven or suspected due to the different populations included) and provided support for further studies. The previous meta-analyses studied mainly the effects of age, number of participating centers, gram-positive or gramnegative bacteria, and study design on the development of infections. This meta-analysis also evaluated the effects of randomization, shunting or ventricular drainage catheter placement, funding, staphylococcal and nonstaphylococcal species, gram-positive and gram-negative bacteria, CoNS, S. aureus and MRSA, timing of infection development, clinical or microbiological diagnosis, the effectiveness of different types of antimicrobial catheters, and rates of infection in the participating centers. However, the majority of the data referred to AICs, and a lot fewer data were available for SCCs and HCCs. Finally, this meta-analysis provides a comprehensive review regarding the use of antimicrobial shunt catheters.

The most important limitation of the present meta-analysis is that it included mainly nonrandomized studies. Although residual confounding that could have affected the outcomes of the meta-analysis of nonrandomized studies cannot be ruled out, the similar findings in the subgroup analyses of randomized (although a marginally nonsignificant difference was observed in AICs probably due to smaller sample size) and nonrandomized studies reduce this possibility. Second, both clinical heterogeneity and statistical heterogeneity were present. Statistical heterogeneity ranged from 0 (no heterogeneity) up to 67% (considerable heterogeneity), even in subgroup analyses. The patients' demographic and clinical characteristics (including age and the etiology of hydrocephalus), the definition of shunt infection, and perioperative prophylaxis varied in the included studies; few of them provided adjusted results and therefore a meta-analysis of adjusted data were not feasible. Furthermore, ventricular drainage and shunt catheter placements are different surgical interventions that are associated with infections with different microbial etiology. The main cause of shunt-related infections is contamination due to skin flora during surgery, while the main cause of the ventricular drainage–related infections is retrograde colonization of the distal part of the catheter.15 Nevertheless, subgroup analyses did not show differences in outcomes of ventricular drainage and shunting. Finally, the differences in infection rate among the studies reflect the differences in the definition of shunt-associated infections as well as differences in infection control and surgical techniques or expertise.

Conclusions

Based mainly on data from nonrandomized, singlecenter, retrospective studies, this meta-analysis showed that the use of antimicrobial shunt catheters reduce the risk for CSF infections in patients with hydrocephalus. Several subgroup analyses showed that factors related to study design, type of catheter, duration of catheter placement, and whether the procedure is a de novo implantation or a revision may affect this risk. Publication bias in the region of small negative trials was also observed. In addition, a higher risk for infections due to more virulent bacteria than CoNS, namely MRSA and gram-negative bacilli, was observed. Due to the small number of studies providing data on such infections in the meta-analysis, this issue warrants further study. The choice as to whether antimicrobial catheters will be employed in an institution depends on both medical and financial variables. Finally, more data regarding the comparative effectiveness of AICs and SCCs, especially on the selection of specific bacterial species, is needed.

Author Contributions

Conception and design: Falagas, Konstantelias, Vardakas. Acquisition of data: Konstantelias, Polyzos. Analysis and interpretation of data: all authors. Drafting the article: Konstantelias, Polyzos, Tansarli. Critically revising the article: Vardakas. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Falagas. Statistical analysis: Konstantelias, Vardakas, Tansarli. Administrative/technical/material support: Falagas. Study supervision: Falagas, Vardakas.

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Article Information

Correspondence Matthew E. Falagas, Alfa Institute of Biomedical Sciences, 9 Neapoleos St., 151 23 Marousi, Athens, Greece. email: m.falagas@aibs.gr.

INCLUDE WHEN CITING Published online March 13, 2015; DOI: 10.3171/2014.12.JNS14908.

DISCLOSURE The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.

© AANS, except where prohibited by US copyright law.

Headings

Figures

  • View in gallery

    Flow diagram of the selection process of the included studies.

  • View in gallery

    Forest plot depicting the risk ratios for CSF shunting– and ventricular drainage–associated infections for antimicrobial catheters (AMICs [AICs and SCCs]) compared with CCs (studies on HCCs were not included in the figure). The vertical line indicates the “no difference” point between the 2 regimens; squares indicate risk ratios; diamonds, pooled risk ratios for all studies; horizontal lines, 95% confidence intervals; events represent numbers of infections; total refers to number of procedures. M-H = Mantel Haenszel. Figure is available in color online only.

  • View in gallery

    Funnel plot to assess publication bias. More studies are missing near the middle toward the right, indicating asymmetry. Publication bias in the region of small studies with negative results was observed. SE = standard error. Figure is available in color online only.

  • View in gallery

    Forest plot depicting the risk ratios for CSF shunting– and ventricular drainage–associated infections for antimicrobial catheters (AMICs [AICs and SCCs]) compared with CCs (studies on HCCs were not included in the figure). The vertical line indicates the “no difference” point between the 2 regimens; squares indicate risk ratios; diamonds, pooled risk ratios for all studies; horizontal lines, 95% confidence intervals; events represent numbers of infections; total refers to number of procedures. Figure is available in color online only.

References

  • 1

    Abla AAZabramski JMJahnke HKFusco DNakaji P: Comparison of two antibiotic-impregnated ventricular catheters: a prospective sequential series trial. Neurosurgery 68:4374422011

  • 2

    Albanese ADe Bonis PSabatino GCapone GMarchese EVignati A: Antibiotic-impregnated ventriculo-peritoneal shunts in patients at high risk of infection. Acta Neurochir (Wien) 151:125912632009

  • 3

    Aryan HEMeltzer HSPark MSBennett RLJandial RLevy ML: Initial experience with antibiotic-impregnated silicone catheters for shunting of cerebrospinal fluid in children. Childs Nerv Syst 21:56612005

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    Choksey MSMalik IA: Zero tolerance to shunt infections: can it be achieved?. J Neurol Neurosurg Psychiatry 75:87912004

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    Eymann RChehab SStrowitzki MSteudel WIKiefer M: Clinical and economic consequences of antibiotic-impregnated cerebrospinal fluid shunt catheters. J Neurosurg Pediatr 1:4444502008

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    Eymann RSteudel WIKiefer M: Infection rate with application of an antibiotic-impregnated catheter for shunt implantation in children – a retrospective analysis. Klin Padiatr 221:69732009

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