Childs Nerv Syst (2008) 24:557–562 DOI 10.1007/s00381-007-0521-4

ORIGINAL PAPER

The impact of antibiotic-impregnated catheters on shunt infection in children and neonates Caroline Hayhurst & Richard Cooke & Dawn Williams & Jothy Kandasamy & Donncha F. O’Brien & Conor L. Mallucci

Received: 19 September 2007 / Published online: 26 October 2007 # Springer-Verlag 2007

Abstract Introduction Infection remains a significant problem with cerebrospinal fluid (CSF) diversion procedures. Antibioticimpregnated shunt catheters (AIS) have been introduced to prevent infection, mainly in the early post-operative period when most infections occur. We evaluate the impact on infection rates in children following the introduction of catheters impregnated with rifampicin and clindamycin. Materials and methods The study was a retrospective analysis of all paediatric shunt procedures undertaken after the introduction of AIS systems in 2003. All procedures where a complete AIS system was implanted were included. For the purpose of analysis, shunt procedures were classified as de novo (group 1), clean revision (group 2) and following external ventricular drainage with either sterile CSF (group 3) or infected CSF (group 4). Results were compared to a historical cohort of shunt procedures undertaken before the introduction of AIS catheters. C. Hayhurst (*) Department of Neurosurgery, The Walton Centre for Neurology and Neurosurgery, Lower Lane, Fazakerley, Liverpool, UK e-mail: [email protected] R. Cooke Department of Microbiology, The Walton Centre for Neurology and Neurosurgery, Liverpool, UK D. Williams : J. Kandasamy : C. L. Mallucci Department of Neurosurgery, Royal Liverpool Childrens Hospital, Alder Hey, Liverpool, UK D. F. O’Brien Department of Neurosurgery, Beaumont Hospital Dublin, Dublin, Ireland

Results A total of 214 AIS were implanted in 150 children between October 2003 and December 2006. There were 4 infections in group 1 (8.5%), 6 infections in group 2 (5.3%) and 11 infections in groups 3 and 4 (20%). The historical control group comprised 77 shunts in 65 children. The infection rate in neonatal de novo shunts reduced from 27 to 10.4% following the introduction of AIS catheters. Conclusions AIS catheters can reduce the number of shunt infections seen in clinical practice in certain subgroups. This has had a significant impact on the neonatal hydrocephalic population. The high risk of shunt infection after a period of external ventricular drainage raises the issue of emergence of bacterial resistance. Keywords Hydrocephalus . Shunt infection . Antibiotic-impregnated catheter

Since their introduction in the 1950s, shunts for cerebrospinal fluid (CSF) diversion have been plagued with the problem of infection. Shunt infection remains a significant global problem today, with reported infection rates of between 3–27 [6, 9, 23]. Despite extensive research into contributing factors such as surgical technique, length of operation and no-touch technique, very low infection rates have not been consistently achieved [7]. Antibiotic-impregnated shunt (AIS) catheters have been tested extensively in vitro, showing promising sustained antibacterial activity. However, there have been few reports of the impact of these catheters on the infection rate in vivo, although initial published data appears to show a significant reduction in infection rates [1, 11, 18]. We report our experience of both permanent ventriculoperitoneal (VP) shunt catheters and external ventricular drains (EVDs) impregnated with clindamycin and rifampi-

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cin (Codman® Bactiseal™, Johnson & Johnson, Raynham, MA, USA) in a large population of children and neonates involving multiple surgeons of all grades and both elective and emergency procedures across two institutions. We have assessed the clinical impact of antibiotic-impregnated catheters on overall infection rates in clinical practice. We have included those VP shunts inserted following external ventricular drainage with antibiotic-impregnated drains, a group not previously reported. In addition, we report a subanalysis of the profile of infections, in terms of infecting organism and time to presentation.

Materials and methods We performed a retrospective review of all shunts implanted, in patients aged 16 and under, since the introduction of antibiotic-impregnated catheters to our institution. From October 2003, all shunt procedures were undertaken using Bactiseal catheters, regardless of the aetiology of hydrocephalus. Only those patients who had implantation of a complete antibiotic-impregnated shunt system were included. A variety of valve types were implanted, and all patients received a single dose of cefuroxime at induction of anaesthesia. Our standard peri-operative practice is to shave immediately before skin preparation with iodine solution. All case notes were reviewed by the first author for primary diagnosis, clinical history and any prior CSF diversion surgery. All episodes of shunt malfunction were recorded. In addition, all microbiological data were reviewed by a consultant microbiologist (RC). For the purposes of analysis, shunt procedures were classified as de novo (group 1), non-infected revisional surgery (group 2) or post-EVD (group 3, sterile CSF, and group 4, infected CSF) to assess variation in infection rate between the groups (Fig. 1). All patients who had a period of external ventricular drainage had Bactiseal antibioticimpregnated EVDs implanted, and it was recorded if the CSF showed a positive culture confirmed on repeat samples. Permanent VP shunts were only implanted following demonstration of sterile CSF with a low white cell count. We defined CSF infection as a patient with symptoms and signs of shunt malfunction with an organism cultured from CSF or shunt apparatus. We also included those with raised CSF white cell count, a clinical suspicion of infection and a clinical response to infection following shunt removal and appropriate antibiotic therapy. Standard laboratory procedures were used for CSF microscopy and cultures. Plates were incubated for 5 days. Enrichment CSF cultures were not performed. We compared the incidence of infection with a historical cohort of all consecutive shunt procedures in children

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GROUP 1 De Novo shunt

GROUP 2 Clean revision

GROUP 3 External ventricular drain - sterile

ANTIBIOTIC IMPREGNATED SHUNT

GROUP 4 External ventricular drain – infected 4A: previous infected non bactiseal shunt replaced with EVD 4B: EVD for meningitis 4C: as group 3 but developed evd related ventriculits 4D: developed infection in Bactiseal shunt, replaced with EVD

Fig. 1 Subgroup analysis algorithm

undertaken in 2002 (before the introduction of AIS catheters), using the same sub-analysis algorithm. Statistical tests were Pearson’s χ2 and Fisher’s exact tests, performed with a significance level of 0.05. Statistical analysis was performed using SAS statistical software.

Results Between October 2003 and December 2006, we performed a total of 214 shunt procedures using the Codman Bactiseal system in 150 children with an age range of 1 day to 16 years. The mean follow-up was 15 months (range 8 to 42 months). Out of 214 antibiotic-impregnated shunts implanted in 150 patients, there were 21 infected shunts occurring in 18 patients (3 patients had two episodes of shunt infection). Therefore, overall, there was a shunt infection rate of 9.8% per procedure. The mean time to shunt infection (defined as days to shunt removal) was 23 days, with a range of 1 to 73 days.

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Subgroup analysis Table 1 demonstrates the breakdown of shunts per subgroup. There were 47 de novo shunts implanted (group 1), and in this group, there were four infections (8.5%). In the first half of the study period from 2003 to 2005, there were no infections seen in this group. There were 113 clean shunt revisions, where entire new AIS systems were implanted, with six infected cases (5.3%). Fifty-four shunts were implanted following external ventricular drainage. Twenty-seven were drained externally for treatment of prior shunt infection or had EVDrelated ventriculitis (group 4). Of these, seven (26%) went on to further infection of their subsequent shunt. In all but two cases, the infecting bacteria remained the same in both episodes of infection. The remaining 27 EVDs were placed for intraventricular haemorrhage, tumoural hydrocephalus and blocked shunt where infection was difficult to exclude on initial presentation or following post-operative wound leaks (group 3). All 27 patients had sterile CSF throughout, and there were four infected shunts in this group (15%). Neonates Within the paediatric cohort studied, there were 33 neonates; 28 of these had de novo shunts with three infections (10.7%). Once again, in the initial half of the study period from 2003 to 2005, there were no infections in the neonatal de novo shunt subgroup. Four neonates had external ventricular drainage before shunting, and two developed subsequent shunt infections, one had a second infected shunt after treatment of the first episode with external drainage and antibiotic therapy. The infecting bacteria for each episode were different (Table 2; cases 5 and 6). Infecting organisms Table 2 shows the organisms responsible for each infective episode. There were four cases of Gram-negative infection (20%), five cases of coagulase-negative staphylococcus (CNS) infection (25%), two cases of methicillin-resistant Staphylococcus aureus (MRSA) infection (10%), three

cases of infection with S. aureus (15%%) and three cases of Staphylococcus epidermidis infection (15%). Overall, 80% of the infections seen were due to Gram-positive organisms. Sensitivities of Gram-positive organisms to rifampicin and clindamycin were not available, as they were not routinely tested in our laboratory at the time of the study. Post-external ventricular drainage infection rate The infection rate in patients who had external ventricular drainage before definitive shunting was 20.3% (11/54). Twenty six percent (7/27) of patients with documented infected CSF during the period of drainage went on to have shunt infections, compared to 15% (4/27) of those whose CSF remained sterile. There was no statistically significant difference in the rate of infection between these two groups (p=0.310). Of the seven cases of shunt infection following an infected EVD, all but two cases cultured the same organism in both episodes. One case initially cultured S. epidermidis from samples during external drainage and subsequently cultured MRSA from the CSF following shunt removal. The second case had an external ventricular drain placed following removal of an infected Bactiseal™ shunt, where the organism grown was Enterobacter aerogenes, and the subsequent shunt infection cultured S. epidermidis. Historical cohort From 1 January 2002 to 31 December 2002, a total of 77 non-antibiotic-impregnated shunts were implanted in 65 children. There was no difference in the surgical procedure other than the type of catheter used. Of the 77 shunts implanted, 8 became infected (10.4%). There is no significant difference in the overall shunt infection rate (p=0.884). In the subgroup analysis, there were 30 de novo shunts (group 1) with 5 infections (17%). In group 2 clean revision surgery, there were 36 procedures and 2 infections (5.5%), no infections in four group 3 post-EVD shunts and in seven group 4 shunts, one infection (14%). In the neonatal de novo shunt group, there were 3 infections in 11 shunts (27%), compared to an 11% infection rate in the AIS group. However, no subgroup displayed a reduction in infection rate which reached statistical significance (p=0.208 for neonates).

Table 1 Subgroup analysis total infection rate Group

Infected shunt (%) No infected shunt Total (214)

Discussion

1

2

3

4

4 (8.5%) 43 47

6 (5.3%) 107 113

4 (15%) 23 27

7 (26%) 20 27

Infection remains a major complication of shunting for hydrocephalus with potential long-term sequelae, including reduced intellectual function and death [10, 13, 16, 17, 22]. Neonates and young infants have a significantly higher risk

560 Table 2 Infecting organisms associated with shunt infections

IVH Intraventricular haemorrhage

Childs Nerv Syst (2008) 24:557–562 Age at shunt

Shunt type (group)

Time to infection (days)

Organism

84 days 15 112 days 13 years 11 days 32 days

De novo, group 1 Revision, group 2 Post-EVD infection, group 4B Revision, group 2 Post-EVD-IVH, group 3 Post-EVD infected shunt, group 4D

3 6 20 24 2 28

28 days

56

112 days

Post-EVD–EVD ventriculitis, group 4C Post-EVD infected shunt, group 4D

1 year

Post-EVD infected shunt, group 4A

14

1 year

Post-EVD blocked shunt, group 3

11

3 years 13 year 140 days

Post-EVD blocked shunt, group 3 Revision, group 2 Revision, group 2

14 51 21

2 days 26 5 days 24 days

De Novo, group 1 De Novo, group 1 De Novo, group 1 Revision, group 2

2 70 20 1

10 days 56 days

Post-EVD CSF leak, group 3 Post-EVD infected Bactiseal shunt, group 4 D Post-EVD meningitis, group 4B Revision, group 2

3 30

Streptococcus mitis Enterococcus faecalis Staphylococcus epidermidis Staphylococcus aureus Enterobacter aerogenes Coagulase-negative staphylococci Methicillin-resistant Staphylococcus aureus Methicillin-resistant Staphylococcus aureus Coagulase-negative staphylococci Coagulase-negative staphylococci Haemophilus influenzae WBC 310 no orgs Coagulase-negative staphylococci Staphylococcus epidermidis Staphylococcus aureus Streptococcus milleri Coagulase-negative staphylococcus Enterobacter aerogenes Staphylococcus epidermidis

28 7

Staphylococcus aureus Enterococcus faecalis

3 10

of infection than adults. Pople et al. [15] demonstrated an infection rate of 15% in children less than 6 months of age, compared to 5.6% in those aged more than 6 months. The majority of shunt infections (90%) are caused by staphylococcal species, predominantly CNS, implanted at the time of surgery, with most shunt infections manifesting within 2 months of surgery [2, 8, 9]. Choux et al. [7] demonstrated a reduction in the infection rate from 7.75 to 0.17% per procedure following the introduction of a strict protocol for shunt implantation, including limiting the duration of operation, restricting the number of theatre staff, scheduling shunt cases first on operating lists and surgeon seniority. However, such strict protocols do not take into account the need for emergency procedures, and such low infection rates are difficult to achieve reliably in mixed groups with surgeons of different grades. The Bactiseal shunt catheter is impregnated with 0.15% clindamycin and 0.054% rifampicin, a combination aimed at eliminating colonization with Gram-positive organisms, without conferring additional morbidity due to toxicity. In addition, the combination of antibiotics has shown a clear advantage over single agents alone and reduces the potential risk of resistance [3].

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Initial in vivo studies of impregnated catheters, challenged with five staphylococcal species including S. epidermidis, S. aureus, Staphylococcus haemolyticus and Staphylococcus hominis, showed no colonization of processed catheters at 28 days [4]. Antibiotic impregnation of the shunt catheter does not prevent bacterial adherence but kills bacteria which become adherent [5]. Therefore in principle, a relatively high bacterial load introduced at the time of shunt implantation can be eliminated. However, antimicrobial activity reduces over time, with in vitro studies showing effective bacteriocidal activity up to 56 days [4]. However, recent in vivo measurement of the duration of activity using non-infected explanted Bactiseal catheters showed significant remaining antibiotic activity even at 3 months post-implantation [14]. The overall infection rate per procedure in our series was 9.8%, which is comparable with published data for nonantibiotic-impregnated shunt catheters. However, there appears to be an advantage in certain subgroups, a trend which has not previously been reported. When comparing to our own historical cohort, our infection rate in neonatal de novo shunts reduced from 27 to 11%. During our initial experience with the AIS catheters, we experienced no

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infections in the de novo subgroup for 2 years. However, there was an unacceptably high infection rate in patients with prior EVDs (20.3%), which did not appear to be related to the presence of drain-related ventriculitis. This raises the question of the development of organisms resistant to clindamycin or rifampicin whilst the antibioticimpregnated EVD is in situ, negating the protective effect of the subsequent shunt. Unfortunately, in this retrospective study, no microbiological samples were tested for resistance against clindamycin or rifampicin. In addition, only those EVDs which were subsequently replaced with definitive shunts were included in this study. Therefore, a larger study of the infection rates of all Bactiseal EVDs is warranted, including investigation of organism resistance. Our results have also prompted us to review our protocols for EVDs, including the use of antibiotic-impregnated drains. Zambramski et al. [24] demonstrated a reduction in the infection rate with minocycline- and rifampicin-impregnated EVD catheters from 9.4% in the control group to 1.3% in the treatment group. However, the two infections recorded in the treatment group involved Gram-negative organisms. In their study, all organisms isolated from culture of removed catheters remained sensitive to minocycline. However, rifampicin has limited Gram-negative activity. Therefore, a higher frequency of Gram-negative infection may be expected; however, our series demonstrates a Gramnegative infection rate comparable to published data (20%). From the literature, approximately 15–20% of episodes of shunt infection are due to Gram-negative organisms [8, 20]. To date, only one prospective randomized study of the Bactiseal antibiotic-impregnated catheter has been published demonstrating a per-procedure infection rate of 13.3% in the control group and 5% in the AIS group [11]. This study includes de novo (group 1), revision (group 2) and post-infective (group 4) patients but does not report the infection rates separately. They noted that only one of three infections in the AIS group presented within 2 months of surgery. In our series, the mean time between shunt implantation and presentation with infection was 24 days, in keeping with previously published data. In addition, in the prospective series by Govender et al. [11], no staphylococci were cultured from any AIS infection. However, this series did not include neonates and did not analyse infection rates separately for the different types of shunt procedure as in our series. A retrospective review of Bactiseal AIS catheters in a paediatric population (not including those below 1 year of age) by Sciubba et al. [18] shows a 2.4-fold decreased likelihood of shunt infection in the AIS group, based on 6-month follow up. These studies together reported a total of only five infections in the AIS subgroups. Therefore, no significant conclusions can be made regarding infecting organism profile or time to onset of infection. Aryan et al. [1] reported a reduction in the

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infection rate from 15.2 to 3.1% following the introduction of Bactiseal antibiotic-impregnated catheters. Again, this small series did not include neonates. In our series, there is no significant difference between the overall shunt infection rate in children, with a risk reduction of only 0.6% (from 10.4 to 9.8%). This supports the conclusions of Kan and Kestle [12], who also demonstrated a much smaller reduction in infection rates than has previously been reported. Shunt blockage may be caused by shunt infection which is not clinically apparent, and repeated frequent revisions raises suspicion further. Vanaclocha et al. [21] report shunt malfunction in relation to subclinical infection, demonstrating 59.3% of malfunctioning shunts yielding positive culture results from CSF or shunt components. About 40.6% of those shunts had been revised multiple times. Only four patients in our series have had multiple episodes of shunt malfunction. In addition, the mean time to shunt infection does not appear to have changed with the introduction of AIS systems, as may be expected, as the bacteriocidal properties of the catheter reduce over time, with the majority in our series occurring within 4 weeks of surgery. Scuibba et al. [19] also found no increase in the number of late shunt infections when using AIS catheters.

Conclusions Whilst there does not appear to be a significant impact on the overall shunt infection rate in the paediatric population in this series, the reduction in infection rates in the de novo neonatal shunt group is encouraging. In this respect, antibiotic-impregnated catheters appear to be a significant addition to the armamentarium for shunt surgery. However, this study raises the question of the development of resistant organisms given the high rate of infection following external ventricular drainage. Further microbiological studies are warranted to address the long-term risk of organism resistance. In addition, only an adequately powered prospective randomized study will ascertain the true efficacy of the antibiotic-impregnated shunt. Disclosure The authors confirm that no financial support has been received for the inception or preparation of this manuscript.

References 1. Aryan HE, Meltzer HS, Park MS, Bennett RL, Jandial R, Levy ML (2005) Initial experience with antibiotic-impregnated silicone catheters for shunting of cerebrospinal fluid in children. Childs Nerv Syst 21:56–61 2. Bayston R (1989) Hydrocephalus shunt infections. Chapman and Hall, London

562 3. Bayston R, Grove N, Siegel J, Lawellin D, Barsham S (1989) Prevention of hydrocephalus shunt catheter colonisation in vitro by impregnation with antimicrobials. J Neurol Neurosurg Psychiatry 52:605–609 4. Bayston R, Lambert E (1997) Duration of protective activity of cerebrospinal fluid shunt catheters impregnated with antimicrobial agents to prevent bacterial catheter-related infection. J Neurosurg 87:247–251 5. Bayston R, Ashraf W, Bhundia C (2004) Mode of action of an antimicrobial biomaterial for use in hydrocephalus shunts. J Antimicrob Chemother 53:778–782 6. Borgbjerg BM, Gjerris F, Albeck MJ, Borgesen SE (1995) Risk of infection after cerebrospinal fluid shunt: an analysis of 884 firsttime shunts. Acta Neurochir (Wien) 136:1–7 7. Choux M, Genitori L, Lang D, Lena G (1992) Shunt implantation: reducing the incidence of shunt infection. J Neurosurg 77:875–880 8. Drake JM, Sainte-Rose C (1995) The Shunt book. Blackwell Science, Cambridge, Mass 9. Enger PO, Svendsen F, Wester K (2003) CSF shunt infections in children: experiences from a population-based study. Acta Neurochir (Wien) 145:243–248 discussion 248 10. Fan-Havard P, Nahata MC (1987) Treatment and prevention of infections of cerebrospinal fluid shunts. Clin Pharm 6:866–880 11. Govender ST, Nathoo N, van Dellen JR (2003) Evaluation of an antibiotic-impregnated shunt system for the treatment of hydrocephalus. J Neurosurg 99:831–839 12. Kan P, Kestle J (2007) Lack of efficacy of antibiotic-impregnated shunt systems in preventing shunt infections in children. Childs Nerv Syst 23:773–777 13. Kulkarni AV, Drake JM, Lamberti-Pasculli M (2001) Cerebrospinal fluid shunt infection: a prospective study of risk factors. J Neurosurg 94:195–201 14. Pattavilakom A, Kotasnas D, Korman TM, Xenos C, Danks A (2006) Duration of in vivo antimicrobial activity of antibiotic-

Childs Nerv Syst (2008) 24:557–562

15.

16. 17. 18.

19.

20.

21. 22.

23.

24.

impregnated cerebrospinal fluid catheters. Neurosurgery 58:930– 935 discussion 930–935 Pople IK, Bayston R, Hayward RD (1992) Infection of cerebrospinal fluid shunts in infants: a study of etiological factors. J Neurosurg 77:29–36 Ronan A, Hogg GG, Klug GL (1995) Cerebrospinal fluid shunt infections in children. Pediatr Infect Dis J 14:782–786 Schiff SJ, Oakes WJ (1989) Delayed cerebrospinal-fluid shunt infection in children. Pediatr Neurosci 15:131–135 Sciubba DM, Stuart RM, McGirt MJ, Woodworth GF, Samdani A, Carson B, Jallo GI (2005) Effect of antibiotic-impregnated shunt catheters in decreasing the incidence of shunt infection in the treatment of hydrocephalus. J Neurosurg 103:131–136 Sciubba DM, McGirt MJ, Woodworth GF, Carson B, Jallo GI (2007) Prolonged exposure to antibiotic-impregnated shunt catheters does not increase incidence of late shunt infections. Childs Nerv Syst 23:867–871 Shapiro S, Boaz J, Kleiman M, Kalsbeck J, Mealey J (1988) Origin of organisms infecting ventricular shunts. Neurosurgery 22:868–872 Vanaclocha V, Saiz-Sapena N, Leiva J (1996) Shunt malfunction in relation to shunt infection. Acta Neurochir (Wien) 138:829–834 Walters BC, Hoffman HJ, Hendrick EB, Humphreys RP (1984) Cerebrospinal fluid shunt infection. Influences on initial management and subsequent outcome. J Neurosurg 60:1014–1021 Wang KW, Chang WN, Shih TY, Huang CR, Tsai NW, Chang CS, Chuang YC, Liliang PC, Su TM, Rau CS, Tsai YD, Cheng BC, Hung PL, Chang CJ, Lu CH (2004) Infection of cerebrospinal fluid shunts: causative pathogens, clinical features, and outcomes. Jpn J Infect Dis 57:44–48 Zabramski JM, Whiting D, Darouiche RO, Horner TG, Olson J, Robertson C, Hamilton AJ (2003) Efficacy of antimicrobialimpregnated external ventricular drain catheters: a prospective, randomized, controlled trial. J Neurosurg 98:725–730