**4. New technology for infection prevention**

#### **4.1 Types of technology and modes of action**

The technologies aimed at reducing infection in neurosurgical devices must satisfy basic criteria: biocompatibility in tissues of the central nervous system and elsewhere; activity against at least the most common pathogens involved; sufficient duration of activity to cover the period of risk; and ability to be sterilized without significant loss of activity or adverse mechanical changes. These criteria are difficult to achieve.

#### **4.2 Laboratory testing of antimicrobial technologies**

All materials and devices for use in neurosurgery must undergo testing for mechanical properties (to ensure their robustness and suitability for use, including in the case of catheters, measurement of the force needed to disconnect (pull-off), tensile strength and other properties. They also undergo tests for toxicology of component materials, biocompatibility using international standard tests [28, 29], and certification of sterility and shelflife. Any modification of the materials or device has potential to affect all of these and antimicrobial processes such as coatings will require significant further testing. The processing might affect the mechanical properties and this might affect the likelihood of disconnection during use. Biocompatibility of the antimicrobials or the coating material will need to be determined, and this must include the possible chemical effects of sterilization which can give rise to toxic degradation products. Any claim for reduction in infection, at this stage usually expressed as reduction in bacterial attachment, or killing of test bacterial in vitro, will need to be determined, and animal implantation and challenge is often undertaken. However, while all potential neurosurgical implants must pass these tests, the current standards are not sufficiently meshed to the intended use. An example is testing for antimicrobial activity by immersing the processed material in a liquid culture of bacteria and measuring reduction in viability. This rarely has any relevance to the intended use of the material or device, and merely "ticks the box" for regulatory purposes. Another example is implantation subcutaneously into the flank of a rodent of material intended for use as a catheter, again bearing no relevance to intended use or anatomical site, yet giving information for regulatory purposes. For the purposes of this paper, test methods for antimicrobial activity will be discussed.

#### **4.3 Laboratory testing for antimicrobial activity of processed neurosurgical devices**

#### *4.3.1 Surface modification*

Modification of catheter surfaces can take the form of biomaterial modification, coating with a secondary material, or application of an antimicrobial coating. Application of a material intended to reduce or inhibit bacterial attachment, by changing the hydrophobicity or charge of the surface, can be tested by a variety of means including those of surface physics and microbiology. For the latter, simple immersion into a suspension of bacteria followed by counting of attached bacteria might give interesting data, but unless a conditioning film consisting of extracellular matrix proteins similar to that occurring in vivo is applied to the modified surface, the data will be potentially misleading. Such a conditioning film is deposited rapidly on all biomaterials after implantation, and the modified surface is easily obliterated. The conditioning film is the surface that potential device pathogens usually attach to and this must not be omitted. This is also true of antimicrobial coatings, intended to kill bacteria that attach to the material. Test results that do not include a conditioning film are unreliable. A polyvinylpyrrolidone (PVP)—coated shunt catheter was tested without a conditioning film after soaking in antimicrobial [30]. Here they found that the PVP coating reduced bacterial attachment irrespective of any antimicrobial soaking. They also carried out an in vivo study by inserting a coated, inoculated catheter intraventricularly in a rat model. After removal of the catheters 7 days later, they found that both coated and uncoated catheters were colonised. They concluded that, even if attached bacterial numbers were reduced, full colonisation would eventually occur unless bacterial attachment was totally prevented. The PVP-coated catheter was tested with a serum conditioning film after it had been rehydrated in a solution of rifampicin [31], and the deposited serum proteins significantly reduced the antimicrobial activity. The same coated catheter was tested by Bayston et al. [32] who also applied a plasma conditioning film. They also found that the conditioning film further reduced bacterial numbers attached to the catheter even in the absence of antimicrobial. However, they also found that, contrary to claims, the lumen surface of the catheters was uncoated and became fully colonised by bacteria. This is important as most shunt and EVD catheters are, at least initially, colonised on the lumen surface. A rather concerning observation was also made in an animal implantation study [33] that even dead bacteria were able to induce abscess formation around the PVP-coated catheter, suggesting that the PVP coating might modify the local cellular immune response. A heparin-coated catheter was investigated by Nomura et al. [34] with the intention of producing a hydrophilic silicone surface. They soaked their coated catheters in CSF and found that the conditioning film consisting of CSF proteins also reduced bacterial adhesion. CSF protein is mainly albumen, and this has been shown to reduce bacterial attachment to shunt catheter material [35]. Plasma also contains fibrinogen and fibronectin, and these are known to favour bacterial attachment [36, 37], so the choice of conditioning film for in vitro testing is important.

#### *4.3.2 Antimicrobial coatings*

Shunt or EVD catheters can be coated with antimicrobial substances, and the most common is some form of silver. In 1997 Guggenbichler et al. developed a new technique for mixing nanoparticulate silver with polyurethane, the water porosity of which was claimed to ensure release of antimicrobial silver ions for long periods [38]. This was not strictly a coating as the silver was dispersed throughout the polymer, but it was not an impregnation technique. Several publications followed, with variable results in laboratory studies [39, 40]. An explanation of why silver-processed catheters might not be effective has been offered by Schierholz et al. [41] More complex silver-processed catheters have shown reduction in bacterial attachment and biofilm formation in the laboratory [42, 43].

*Infections in Intracranial Pressure Management: Impact of New Technologies on Infection Rates DOI: http://dx.doi.org/10.5772/intechopen.110349*

#### *4.3.3 Antimicrobial impregnation*

A technique for post-manufacture impregnation of silicone materials with antimicrobials has been developed [44]. This process allows even dispersion of molecules of certain antimicrobials throughout the silicone material, and ensures that they are able to migrate freely even in the absence of water. Molecules of antimicrobials removed from the surface by fluid flow are replenished by those migrating from the catheter material. In turn, this gives a long duration of activity. Laboratory testing on shunt and EVD catheters processed by this method have shown that bacterial colonisation and biofilm development can be prevented even with high-number bacterial challenges in flow conditions [44, 45]. The test catheters were perfused for up to 4 weeks with repeated weekly challenges, and were shown to be free of colonisation at the end of this period. Further studies have shown that the antimicrobial material does not prevent bacterial attachment, but that attached bacteria are all killed within 48 hr. (the tK100 test) [45]. The antimicrobials were chosen partly for their known spectrum of activity against common shunt pathogens (mainly staphylococci) and because of their compatibility with the impregnation process and to give the required post-impregnation performance. The two antimicrobials chosen were rifampicin and clindamycin hydrochloride (Bactiseal, Codman, Integra Life Sciences), and the processed catheters have no activity against gram negative bacteria.

Using the same impregnation process, a shunt catheter containing rifampicin alone has been investigated. A very high concentration of rifampicin was used, resulting in visible crystal formation on the catheter surface, and change in mechanical properties, tensile strength reducing by 27% and elasticity by 45% [46]. However, the catheter showed antistaphylococcal activity in vitro for more than 60 days, and protected shunts from bacterial colonisation in a rabbit model [47]. In a later study in two patients with existing shunt infections the rifampicin- impregnated shunt catheters replaced the infected shunts, and the two patients remained free of infection thereafter [48]. However, the shunt catheter was never commercialised, possibly because of the deleterious effect on mechanical properties, and possibly because of the well-known risk of resistance when rifampicin is used alone in any context. Using the same impregnation method, an experimental catheter containing rifampicin, mupirocin and fusidic acid was tested in vitro against *S epidermidis* and gave protective activity for at least 20 days [49]. A catheter containing rifampicin and trimethoprim was tested in vitro against *S aureus* and gave strong killing effect over the short period tested [50]. The same group used the same process to test a catheter impregnated with rifampicin and sparfloxacin against *S epidermidis* and showed prolonged drug release and protection against colonisation for 1 year, after static soaking [51]. A process for coating polyurethane catheters with rifampicin and minocycline was investigated in vitro [52]. The process was then revised to make it suitable for silicone. Though the nature of the process was very different from the impregnation process above [44], an antimicrobial EVD catheter using this process containing rifampicin and minocycline has been described (Ventriclear, Cook Inc) [53]. A legitimate concern has been voiced that antimicrobial devices might lead to increased bacterial resistance. A long-known but not widely recognised principle for avoidance of resistance is the use of two or more antimicrobials, each of which is active against a different bacterial target site, such as RNA polymerase (rifampicin) and DNA gyrase (sparfloxacin) or protein synthesis (clindamycin). This principle was introduced by Ehrlich [54] and has been extended by Zhao and Drlica [55] as the Dual Drug Principle. Experimental studies show clearly that exposure of bacteria

to a single antimicrobial usually results in resistant mutants arising whereas when exposed to dual or triple drugs, this does not happen. Some authors have emphasised this important principle when designing antimicrobial materials [44, 49, 51].
