Prevention hydrocephalus catheter - BMJ

Journal ofNeurology, Neurosurgery, and Psychiatry 1989;52:605-609

Prevention of hydrocephalus shunt cathetercolonisation in vitro by impregnation withantimicrobialsR BAYSTON,* N GROVE,t J SIEGEL,: D LAWELLIN,§ S BARSHAM*

From the Department of Paediatric Surgery, Institute of Child Health, London, UK*, Colorado Biomedical Inc,Denver;t Codman and Shutleft Inc, Randolf4: and the Kempe Research Center, Children's Hospital, Denver,§USA

SUMMARY A process is described by which hydrocephalus shunt catheters can be impregnated withantimicrobials. The processed catheters showed antimicrobial activity at their surfaces for longperiods and could be sterilised by autoclaving. When tested in vitro in a model of cathetercolonisation using large challenge doses of Staphylococcus epidermidis and prolonged perfusion,some antimicrobials failed to protect against colonisation whereas others protected against one ortwo challenges. A combination of rifampicin and clindamycin gave best results, protecting againstthree successive challenges over a 28 day perfusion period. Resistant organisms did not develop. Theprocess is likely to be useful in prevention of hydrocephalus shunt infection.

The reported incidence of hydrocephalus shuntinfections ranges from 1% to 39% of operations'2with a national average of about 10%. In most casesthe causative organisms originate on the patient's skinand gain access to the shunt system during its insertionor revision.3 There is an additional slight risk later dueto needling of the shunt for pressure measurement orfluid aspiration.The organisms most commonly involved are gram

positive, with coagulase negative staphylococcipredominating.

Various attempts to prevent shunt infections havebeen made, including modifications oftechnique'3 andthe use of prophylactic antibiotics,4 and in some casesthe rate of infection has diminished. However, shuntinfection is still a major problem in most centres,causing considerable morbidity and some mortality aswell as consuming resources extensively.

Similar infections are encountered with mostimplantable devices, including cardiac valves andpatches, central venous catheters, vascular grafts andpacemaker capsules. Attempts have been made tomake such implants resistant to infection by variousmethods involving direct or indirect bonding ofantimicrobials to the implant surface,5'0 with variable

Address for reprint requests: Dr R Bayston, Department of PaediatricSurgery, Institute of Child Health, 30 Guilford Street, LondonWCIN IEH.

Received 29 July 1988 and in revised form 10 November 1988.Accepted 18 November 1988

success. Using a different approach, Kingston et al"mixed a disinfectant into three implantable polymersbefore processing. With one exception,9 the processeshave involved polymers such as polytetra-fluoro-ethylene (PTFE), polyethylene and dacron, which areused mainly for vascular grafts, but they have not beenused with silicone elastomer. Varieties of this materialare widely used for central venous catheters, pace-maker capsules, artificial urinary sphincters and smalljoint replacements as well as for hydrocephalusshunts. Several methods have been developed andassessed for incorporating antimicrobials into siliconeelastomer'2'5 and one has been found suitable foruse after the manufacturing process has beencompleted. '4'" The process results in completeincorporation of the antimicrobial into the elastomermatrix without discernible effect on its appearance onelectron microscopy or on its mechanical properties,while conferring long-lasting antimicrobial activity atthe surface of the implant, which may be autoclavedwithout significant loss of activity. Evaluation in vitroof the protection against bacterial colonisationconferred by this process is reported here.

Methods

Incorporation ofantimicrobialsThe antimicrobials studied were rifampicin, trimethoprim,spiramycin [Sigma Chemical Company UK), clindamycinhydrochloride (Upjohn Ltd., UK), and diethanolaminefusidate (Leo Pharmaceutical Products, Denmark). Solu-

605

Protected by copyright.

on January 29, 2022 by guest.http://jnnp.bm

j.com/

J Neurol N

eurosurg Psychiatry: first published as 10.1136/jnnp.52.5.605 on 1 M

ay 1989. Dow

nloaded from

http://jnnp.bmj.com/

606tions of the antimicrobials, singly or in combinations, were

made in chloroform to give a concentration of each (w/v) of0-2%. No adjustment was made for potency. Supplementarystudies were carried out with rifampicin and clindamycinhydrochloride (0.025%, 005% and 0-1%) and rifampicinand diethanolamine fusidate (0-1%) combinations. A total ofnine catheters processed with rifampicin and clindamycinhydrochloride each in a 0-2% solution were tested.For each experiment three 25 cm lengths of silicone shunt

catheter (Dow Coming Corporation USA) were totallysubmerged in the antimicrobial solution, taking care toensure filling ofthe tubing, for one hour at room temperaturewith shaking. The tubing was then removed, shaken toremove excess solution and rinsed and flushed in ethanol.After further shaking and blotting the catheters were air-dried overnight at room temperature.

Preliminary testfor activityPlates of DST agar (Oxoid UK) which had been seeded withthe Oxford strain of Staphylococcus aureus (NCTC 6571)were prepared and two wells, 1 cm diameter and 2mm apart,were cut using a specially made punch. After autoclaving at121°C for 20 minutes, three segments of each processedcatheter, 0 5 cm long, were placed aseptically on the 2 mmbridge so that they lay at right angles to it (fig). The purposeof the technique is to avoid contact between the seeded agar

and the cut surface of the tubing as this has given misleadingresults in the past. After incubation the diameters ofthe zonesof inhibition at right angles to the long axis of the cathetersegments were measured. Segments of unprocessed cathetersand of catheters processed without antimicrobials served as

controls.

Fig Processed, autoclaved catheter segments screenedforantimicrobial activity by the bridge plate method. Afterinoculation the diameters of the zones of inhibition are

measured in millimetres at right-angles to the long axes of thecatheter segments.

Bayston, Grove, Siegel, Lawellin, BarshamIn Vitro ChallengeThe model of catheter colonisation was that describedpreviously.'67 Briefly, the test catheter is insertedinto a controlled-environment chamber and autoclaved. Thechamber is then connected to a heated water circuit andmaintained at 37°C throughout. The catheter is perfusedwith nutrient fluid, in this case brain-heart infusion medium(Oxoid UK), at a controlled rate. All procedures are carriedout using vigorous aseptic technique to avoid contamination.The challenge organism was a strain of Staphylococcus

epidermidis whose biochemical and other characteristics wereknown in detail, and which had been isolated from acolonised shunt. It was susceptible to all the antimicrobialsused in the process. The challenge dose consisted of 1 ml ofanovernight culture of the organism in brain heart infusion,found by viable counting to contain 1 x 107 - 1 x 108colony-forming units per ml. After injection of the challengedose, the catheters were perfused at a rate of 10 ml per hour.An unprocessed translucent catheter was included as acontrol to ensure that the challenge organism was capable ofcolonising, and all were tested in triplicate. A detaileddescription of the model and of the challenge and monitoringprocedure is given elsewhere."' The catheters were examinedvisually each day and samples of perfusion fluid werecollected periodically for culture. If no colonisation wasdetected after 2 weeks' perfusion, a second challenge dosewas given, with a second control catheter. Again, if the testcatheters remained free of colonisation after a further 2weeks' perfusion, a third challenge was made with a thirdcontrol catheter, followed again by monitoring and perfusionfor 2 weeks. Any catheters remaining apparently uncolonisedwere then removed from the system and examinedthoroughly for bacteria using a flushing technique.'8 Anyorganisms isolated from the catheters at any stage werecarefully identified and their characteristics compared tothose of the challenge organisms in order to discountcontamination. They were also tested for susceptibility to theantimicrobials present in the catheter from which they hadbeen recovered.

Results

The combination of trimethoprim and clindamycinhydrochloride could not be tested owing to chemicalincompatibility of the two antimicrobials in theimpregnation process.

Preliminary testing of all processed, autoclavedcatheters on bridge plates showed antimicrobialactivity (fig). Segments not containing antimicrobialsshowed no activity.

Results of challenge of catheters which had beenprocessed using a concentration of each antimicrobialof0-2% w/v are shown in table 1. The combinations ofdiethanolamine fusidate with trimethoprim and one ofthe three catheters containing rifampicin withspiramycin failed to protect against the first challenge,as did all the catheters containing single antimicrobialswith the exception of rifampicin. The remaining twocatheters with rifampicin and spiramycin, those withrifampicin and trimethoprim, and those with rifam-



j.com/

J Neurol N


ay 1989. Dow

nloaded from


Prevention ofhydrocephalus shunt catheter colonisation in vitro by impregnation with antimicrobialspicin alone withstood the first challenge but failed toprotect against the second. Only those catheterscontaining rifampicin with clindamycin hydrochloridewithstood all three challenges.The results of further studies using different concen-

trations of rifampicin and clindamycin are shown intable 2. Those catheters processed with less than 0-1%of each antimicrobial failed to withstand the firstchallenge. Of the six catheters processed with 0-1%,five withstood the first two challenges but becamecolonised after the third. Impregnation with die-thanolamine fusidate and rifampicin, both at 01I%,resulted in colonisation of four catheters on firstchallenge and the remaining two on second challenge.Once again, only those processed with 0-2% ofrifampicin and clindamycin hydrochloride withstoodall three challenges.None of the organisms isolated from the catheters

which became colonised showed resistance to theantimicrobials used, all minimum inhibitory concen-trations (MIC) remaining unchanged compared tothose of the inocula.

Discussion

The antimicrobials were chosen according to severalcriteria. The first was that they should be capable ofmolecular migration through crosslinked siliconeelastomer, an index of this being solubility inchloroform.'9 The second criterion was that theyshould be active against most strains of staphylococci,and the third was that they should have been admin-istered systemically in humans without known sig-nificant risk of hypersensitivity or toxicity. The fourth

Table 1 Resistance to colonisation ofprocessed cathetersafter three consecutive challengesfourteen days apart, duringconstant perfusion

Challenge Nwmber ofcatheters

Antimicrobial (all 02%) * 1 2 3 tested

Rifampicin - + (6) ND 6Trimethoprim + (3) ND ND 3Clindamycin + (3) ND ND 3Spiramycin + (3) ND ND 3Fusidate +(3) ND ND 3Trimethoprim + fusidate +(3) ND ND 3Trimethoprim + rifampicin - +(3) ND 3Spiramycin + rifampicin + (1) +(2) ND 3Rifampicin + fusidate +(2) +(4) ND 6Rifampicin + clindamycin - - - 3

Clindamycin = clindamycin hydrochlorideFusidate = diethanolamine fusidate- = No colonisation+ = ColonisedND = Not doneFigures in parentheses are the number of catheters becomingcolonised on each occasion.*The concentration of each antimicrobial in the impregnation fluid.

Table 2 Resistance to colonisation ofcatheters processedwith different concentrations ofantimicrobials after threeconsecutive challengesfourteen days apart, during constantperfusion

Challenge Number ofAntimnicrobial and cathetersconcentration* 1 2 3 tested

Rifampicin 0,2%+ clindamycin 0-2% - - - 6

Rifampicin 0 1%+ clindamycinO-1% - +(1) +(5) 6

Rifampicin 0 05%+ clindamycin 0-05% +(3) ND ND 3

Rifampicin 0 025%+ clindamycin 0-025% +(3) ND ND 3

Rifampicin 0 1%+ fusidate0-1% +(4) +(2) ND 6

Abbreviations as in table 1.

criterion was that they should be sufficiently stableto allow sterilisation by autoclaving. Manyantimicrobials were excluded on one or more of thesegrounds.

Hypersensitivity caused by the antimicrobials usedhere has been reported only occasionally, and toxicside-effects have been associated with prolongedtherapeutic use or high dosage. The total concentra-tion of antimicrobial in a processed shunt has beenfound to be less than a single therapeutic dose, and thisis released slowly over several weeks, making majororgan toxicity such as hepatic dysfunction very un-likely. A further possibility is the local accumulation ofantimicrobial in the tissues immediately adjacent tothe catheter with local toxicity or irritation. However,animal toxicological studies have not shown any suchlocal or systemic irritation or toxicity in a variety oftissues including neonatal brain (Bayston et al,unpublished). When processed autoclaved catheterswere incubated on bridge plates they showed accept-able activity. This test serves as a preliminary screenprior to perfusion and challenge tests. While themethod tests the external surface of the catheter ratherthan the luminal surface, the antimicrobial activity ateach surface is similar after this process and thescreening test gives a useful indication of activity at theluminal surface.The drug combination which appeared to give best

results in the perfusion test was rifampicin withclindamycin hydrochloride, both at a concentration of0-2% w/v in the impregnation fluid. Attempts todecrease the concentration of the antimicrobials led tofailure of protection for the target period, as shown intable 2. The 28 day period of protection in vitro waschosen in order to ensure protection over the operativeand immediate postoperative period and in terms ofthe main period of risk of infection in shunts isprobably excessive, but the period of risk in other

607



j.com/

J Neurol N


ay 1989. Dow

nloaded from


608implants sometimes extends beyond this. Also, noprotection by this process would be expected againstshunt infection arising later from causes such asvisceral perforation.Almost all coagulase negative staphylococci

isolated from colonised shunts are susceptible torifampicin, and the majority are susceptible toclindamycin hydrochloride.20 When rifampicin is usedalone therapeutically, resistance develops rapidly2'and this is the main reason for combining it withanother antimicrobial. There may be other benefitsfrom the use of the chosen combination of rifampicinand clindamycin hydrochloride, as combinations withother antimicrobials were shown to be inferior. Forexample, it has been suggested that clindamycinprevents attachment of organisms to implants,22though this antimicrobial alone had no effect in ourstudy.No resistant organisms were found among those

isolated from catheters which became colonised,suggesting that failure to protect was probably due toinadequate antimicrobial activity at the surface of thecatheter. In those catheters where protection failed atthe time ofsecond or third challenge, implying that theadequate antimicrobial activity present on firstchallenge had waned, colonising organisms still hadthe same MIC as the inoculum. This shows thatresistance does not develop even when theantimicrobials are present in sub-lethal amounts. Thefinding also suggests that development of resistance inclinical use will not be a problem. The hydrocephalusshunt is not continuously exposed to skin flora as inthe central venous catheter, where resistance coulddevelop around the entry site. In addition, animalstudies indicate that tissue, plasma and urine levels ofantimicrobials are likely to be far too low to affect thenormal flora of the skin, alimentary tract and mucousmembranes (Bayston et al, unpublished).The in vitro model of catheter colonisation is

intentionally concerned with colonisation of theluminal surface. Very soon after silicone elastomerimplants are inserted into the body, their surfaceswhich are in contact with blood or tissue becomecoated with fibronectin, fibrin, albumen and othermaterials which significantly change the nature of thesurface of the implant.23 However, such biocoatingsare not usually seen on the luminal surfaces ofhydrocephalus shunts. In addition, luminal colonisa-tion, usually by coagulase negative staphylococci, ismuch more common than external infection whichconstitutes a wound infection around a foreign bodyand is usually due to Staph. aureus or gram negativebacteria. The impregnation process is intended toprotect against luminal colonisation though it may insome cases also reduce the risk of external infections.The size of the bacterial challenge is several orders

Bayston, Grove, Siegel, Lawellin, Barshamof magnitude higher than that to be expected clini-cally2425 but is similar to that used in animal challengestudies and in our hands was found to be necessary toensure consistent colonisation of control catheters invitro. Even so, the catheters impregnated with rifam-picin and clindamycin hydrochloride using a 0-2%solution were able to withstand three successivechallenges of this size.

Several attempts have been made by others to conferantibacterial activity on implants. Early attemptsinvolved the bonding ofpenicillin or oxacillin to PTFEusing benzalkonium chloride or tridodecylmethyl-ammonium chloride (TDMAC).'9 This method hasthe disadvantage of short duration of activity, notexceeding a few days. Also, catheters with bondedantimicrobial cannot be sterilised8 and wouldtherefore be at risk of contamination from gramnegative bacteria, especially pseudomonas, and fungi.The coating process is not likely to be suitable forhydrocephalus shunts as benzalkonium chloride andTDMAC cannot be used in contact with nervoustissue, and the coating might have a deleterious effecton the function of valve mechanisms which are knownto be susceptible to changes in surface properties oftheelastomer. Similarly, the coating method described byModak et al '° for PTFE grafts has short duration,cannot be sterilised and uses potentially neurotoxicmaterials.The method described by Kingston et al," in which

the disinfectant trichlorohydroxydiphenylether(Irgasan DP 300, Ciba-Geigy) was mixed intoimplantable thermoplastics before moulding, gavevery long-lasting activity but once again the agent hasnot been tested for neurotoxicity by the authors.Manufacturer's data on toxicology suggest that thesubstance would be irritant or toxic to some tissues ifimplanted. In addition the concentrations required inorder to give the desired activity would almostcertainly have deleterious mechanical effects onsilicone valve mechanisms.'4 The process describedhere using rifampicin and clindamycin hydrochloridehas been shown to result in intimate incorporation ofthe antimicrobials in the matrix of the siliconeelastomer,'9 with the absence of particles or cavita-tions. The mixing of particles into the matrix wouldalso be likely to lead to significant changes inmechanical properties if they were to be removed byaqueous dissolution after implantation, leaving aspongiform texture.

Catheters processed with rifampicin and clinda-mycin hydrochloride using a 0-2% solution have beenshown to resist three consecutive massive challengesover 28 days ofconstant perfusion. While resistance ofthe first challenge only, as was found with these twoantimicrobials at 0-1% as well as with trimethoprimwith rifampicin and rifampicin alone, would probably



j.com/

J Neurol N


ay 1989. Dow

nloaded from


Prevention ofhydrocephalus shunt catheter colonisation in vitro by impregnation with antimicrobialsbe beneficial in covering the period of risk in mostcases, the prolonged period of activity should alsoprovide protection at early revisions or during post-operative needling for pressure studies or fluid aspira-tion. In addition, shunts resistant to colonisation formore than just a few days might be useful in patientswith hydrocephalus who have shunt-associated ven-triculitis. The recommended treatment involves shuntremoval and a period of external ventricular drainagewith antimicrobial therapy before reshunting. There isa considerable risk of secondary infection duringexternal drainage, which also provides imperfect con-trol of cerebrospinal fluid pressure in many cases.Here, external ventricular drainage could perhaps bedispensed with, and a new processed shunt insertedimmediately on removal of the colonised one withoutrisk of colonisation of the new one, while providingregulated internal control of intracranial pressure andeliminating the need for a further surgical procedure.However, the effects of constant exposure of theprocessed catheter similar to that expected during thefirst 24-48 hours in this clinical situation need to beevaluated in vitro.

Thanks are due to the Essex, Wigan and Leigh andNorwich branches of the Association for Spina Bifidaand Hydrocephalus and the Wade Fund for financialsupport and to Mrs Roz Sullivan for typing themanuscript.

References

I Tabara Z, Forrest DM. Colonisation of CSF Shunts: PreventiveMeasures. Z Kinderchir 1982;37:156-8.

2 Wald S, McLaurin RL. Cerebrospinal Fluid Antibiotic Levelsduring treatment of Shunt Infections. J Neurosurg 1980;52:41-6.

3 Fitzgerald R, Connelly B. An operative technique to reduce valvecolonisation. Z Kinderchir 1984;39 Suppl 11:107-9.

4 Haines SJ. Systemic Antibiotic Prophylaxis in NeurologicalSurgery. Neurosurg 1980;6:355-61.

5 Jagpal R, Greco RS. Studies ofa graphite-benzalkonium-oxacillinsurface. Am Surg 1979;45:774-9.

6 Moore WS, Chvapil M, Seiffert G, Keown K. Development of aninfection-resistant vascular prosthesis. Arch Surg 1981;116:1403-7.

7 Harvey RA, Greco RS. The noncovalent bonding of antibiotics toa polytetrafluoroethylene-benzalkonium graft. Am Surg 1981;

194:642-7.8 Donetz AP, Harvey RA, Greco RS. Stability of antibiotics bound

to polytetrafluoroethylene with cationic surfactants. J ClinMicrobiol 1984;19:1-3.

9 Trooskin SZ, Donetz AP, Harvey RA, Greco RS. Prevention ofcatheter sepsis by antibiotic bonding. Surgery 1985;97:547-5 1.

10 Modak SM, Sampath L, Fox CL, Benvenisty A, Nowygrod R,Reemstmau K. A new method for the direct incorporation ofantibiotic in prosthetic vascular grafts. Surg Gynecol Obstet1987;164: 143-7.

11 Kingston D, Seal DV, Hill ID. Self-disinfecting plastics forintravenous catheters and prosthetic inserts. J Hyg1986;96: 185-98.

12 Bayston R. Preliminary Studies on the impregnation of silasticelastomers with antimicrobial substances. Devel Med ChildNeurol 1975;18 SuppI 37:50-4.

13 Bayston R. The antibacterial effects ofimpregnated silastic and itspossible applications in surgery. J Ped Surg 1977;12:55-61.

14 Bayston R. The effect ofantibiotic impregnation on the function ofslit valves used to control hydrocephalus. Z Kinderchir1980;31:353-9.

15 Bayston R, Milner RDG. Antimicrobial activity ofsilicone rubberused in hydrocephalus shunts, after impregnation withantimicrobial substances. J Clin Pathol 1981;34:1057-62.

16 Bayston R, Adroyewski V, Barsham S. Use ofan in vitro model tostudy eradication of catheter colonisation by Staphylococcusepidermidis. J Infect 1988;16:141-6.

17 Bayston R, Barsham S. Catheter colonisation: A laboratory modelsuitable for aetiological, therapeutic and preventive studies.Med Lab Sci 1988;45:235-9.

18 Bayston R, Leung TSM, Wilkins BM, Hodges B. Bacteriologicalexamination of removed cerebrospinal fluid shunts. J ClinPathol 1983;36:987-90.

19 Bayston R. The Impregnation of medical silicone elastomers andacrylic bone cements with antimicrobial drugs. PhD Thesis,University of Sheffield, 1979.

20 Archer GL. Antimicrobial Susceptibility and selection of resis-tance among Staphylococcus epidermidis isolates recoveredfrom patients with infections of indwelling foreign devices.Antimicrob Ag Chemother 1978;14:353-9.

21 Binda G, Domenichini E, Gottardi A, Orlandi B, Ortelli E, PaciniB, Fowst G. Rifampicin, a general review. Arzneim Forsch1971;21:1907-77.

22 Pfaller M, Davenport D, Bale M, Barrett M, Koontz F, MasanariM. Development of a semiquantitative test for slime produc-tion: Application to the study of sub-inhibitory effects ofantistaphylococcal agents. Abstract No L43. In: Abstract ofthe Annual Meeting of the American Society for Microbiology,Washington DC, American Society for Microbiology 1986.

23 Dankert J, Hogt A, Feizen J. Biomedical Polymers: BacterialAdhesion, colonisation and infection. CRC Critical Reviews inBiocompatibility 1986;2:219-301.

24 Raahave D. Bacterial Density in operation wounds. Acta ChirScand 1974;140:585-93.

25 Benediktsdottir E, Hambraeus A. Isolation of anaerobic andaerobic bacteria from clean surgical wounds: an experimentaland clinical study. J Hosp Infect 1983;4:141-8.

609



j.com/

J Neurol N


ay 1989. Dow

nloaded from


Documents

Prevention hydrocephalus catheter - BMJ