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Antimicrobial Devices

Brendan F. Gilmore and Sean P. GormanFaculty of Medicine, Health and Life Sciences, Queen’s University Belfast, Belfast, Northern Ireland, UK

20.2

Introduction

The use of indwelling medical devices such as catheters, stents and artificial prostheses has become a cornerstone of modern surgical and clinical practice. In fact, it is estimated that each person will host an indwelling medical device at least once in their lifetime, and that tens of millions of devices are used in patients each year. The general trend in industrialized nations towards a steadily aging population has driven increasing reli-ance upon, and unprecedented demand for, medical devices that support the normal physiological functioning of the body, and improve pre- and post-operative care, diagnosis and patient quality of life. Such devices provide solutions for a diverse range of acute and chronic medical conditions and surgical procedures (Table 20.2.1). However, despite the technological advances made in the fields of biomaterials and medical device manufac-ture, a number of fundamental issues still plague their use in vivo. While complications may be specific to the type and place-ment of a given device, every type of indwelling medical device in current use is susceptible to microbial colonization and

biofilm formation, which remains the primary complication inherent to their use. The development of medical device-associated infections generally necessitates complete device removal which, depending on the type and site of the device, can either be relatively simple (i.e. a urological catheter) or require complete surgical removal.

In attempts to resolve the infectious complications associated with the use of indwelling medical devices, significant research has been directed towards the development of devices which are inherently antimicrobial or anti-infective, by either direct incor-poration of antimicrobial agents or chemical/physical modifica-tion of the biomaterial surface. In addition to increased demand for indwelling medical devices, an unprecedented growth in high-value combination products (drug–device combinations) such as drug-eluting arterial stents and antimicrobial devices (primarily urological and central venous catheters) is fueling an average annual growth rate of c. 12.4% in the global medical device coatings market. By 2010, annual worldwide sales (medical device coatings) are forecast to reach US$5.31 billion. Clearly, there is an urgent need to develop devices that prevent or retard microbial colonization and biofilm formation, to

Russell, Hugo & Ayliffe’s: Principles and Practice of Disinfection, Preservation and Sterilization, Fifth Edition. Edited by Adam P. Fraise, Jean-Yves Maillard,

and Syed A. Sattar.

© 2013 Blackwell Publishing Ltd. Published 2013 by Blackwell Publishing Ltd.

Introduction, 500Definition of medical device, 501Biomaterials, 501Complications associated with

indwelling medical devices, 503Healthcare-associated infections, 504Device-associated infections:

Events following device implantation, 504

Clinical management of device-related infections, 505

Development of antimicrobial biomaterials, 506

Antimicrobial devices, 508The future: Emerging strategies for anti-

infective biomaterials, 511Conclusions, 512References, 512

Antimicrobial Surfaces and Devices20

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Chapter 20.2 Antimicrobial Devices

Biomaterials

The term biomaterial has been defined as any substance (other than a drug) or combination of substances, natural or synthetic, which can be used for any time as a whole or part of a system that treats, augments or replaces any tissue, organ or function of the body [3]. By definition, therefore, all materials employed in the manufacture of indwelling medical devices are described as biomaterials. The design of biomaterials will ultimately be dictated by their intended applications and the functional life-time of the device, which can be temporary use (urinary cath-eters, sutures, central venous catheters, etc.) or permanent implant (orthopedic/dental implants, prosthetic heart valves, etc.). Importantly, biomaterials are characterized not only by their intended function, but also by their continuous or inter-mittent contact with bodily fluids and/or tissues. Therefore, biomaterials must be also be designed to reduce adverse events associated with intimate (direct or indirect) contact between the body and the material/medical device and must therefore exhibit biocompatibility.

Such is the extent of utilization of biomaterials that almost every human in technologically advanced societies will host a biomaterial at some point [4]. The high incidence of adverse side effects associated with biomaterials and implanted medical device usage has stimulated significant research into the design and pro-duction of materials to minimize the complications inherent in the clinical use of these devices.

Medical device applications of biomaterialsThe medical device-related applications of biomaterials are con-tained within three broad categories: (i) extracorporeal applica-tions, such as catheters, tubing and fluid lines, dialysis devices, ocular devices, wound dressings, etc.; (ii) permanently implanted devices such as orthopedic, dental or cardiovascular devices; and (iii) temporary implants, such as temporary vascular grafts, arte-rial stents, scaffolds for tissue growth or organ replacement, degradable sutures, implantable drug delivery systems, etc.

Biomaterials in medical device manufactureThroughout the history of indwelling or implantable medical devices a wide range of materials have been employed in their manufacture, from natural materials to metals. Today, a diverse range of materials are employed in device manufacture including natural macromolecules (biopolymers), synthetic polymers, bio-degradable polymers, metals, carbons and ceramics. Polymeric materials remain the most popular medical device material, thanks to their ease of processing, favorable mechanical and phys-ical attributes and ease of modification post manufacture (e.g. coating) to increase biocompatibility. The development of vul-canized rubber in 1839 may be regarded as the pioneering step towards more patient-acceptable devices. The most common bio-materials employed in the manufacture of indwelling medical devices are discussed below.

address the ubiquitous problem of device-associated infection and to alleviate not only the unacceptably high levels of patient morbidity and mortality associated with their use, but also to reduce the significant financial implications to healthcare pro-viders associated with increased patient morbidity and extended care costs. Currently, healthcare-associated infections (HAIs) are estimated to cost the UK National Health Service £1 billion per year [1].

Definition of medical device

According to the Medicines and Healthcare Products Regulatory Agency (MHRA), the regulator of medical devices in the UK, a medical device may be defined as:

. . . any instrument, apparatus, appliance, material or other article,

whether used alone or in combination, including the software

necessary for its proper application intended by the manufacturer

to be used for human beings for the purpose of:

• diagnosis, prevention, monitoring, treatment or alleviation of

disease,

• diagnosis, monitoring, treatment, alleviation of or compensa-

tion for an injury or handicap,

• investigation, replacement or modification of the anatomy or of

a physiological process,

• control of conception,

and which does not achieve its principal intended action in or

on the human body by pharmacological, immunological or meta-

bolic means, but which may be assisted in its functions by such

means. [2]

Medical devices typically fulfill their intended functions by physi-cal means (e.g. mechanical action, physical barrier, support/replace organs, normal physiological functioning), but may contain a medicinal substance that acts on the body in a manner auxiliary to the device.

Table 20.2.1 Number of medical implants used in the USA (adapted from [5]).

Device Number/year

Intraocular lens 2,700,000Contact lens 30,000,000Vascular graft 250,000Hip and knee prostheses 500,000Catheter 200,000,000Heart valve 80,000Stent (cardiovascular) >1,000,000Breast implant 192,000Dental implant 300,000Pacemaker 130,000Renal dialyzer 16,000,000

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a plasticizer is present the material is not sufficiently elastic to enable it to be comfortably utilized in the manufacture of ind-welling devices.

PolytetrafluoroethylenePolytetrafluoroethylene (PTFE, Teflon), has been employed since the mid 1960s as a catheter coating thanks to its low coefficient of friction and hydrophobic nature, thought to increase patient comfort and reduce device degradation in situ. Despite initial claims of reduced biofilm/encrustation formation, little evidence has emerged of any benefit of these devices over other materials. The characteristic paved texture of this material has been pro-posed to act as a nidus for bacterial attachment, promoting microbial adhesion and biofilm formation and facilitating the swarming of Proteus spp. [8]. leading to encrustation deposition in urological applications [9]. PTFE is generally applied over a latex core, by dipping the latex device into a solution of PTFE particles in a binder (usually polyurethane). For this reason an even application is not always possible and, as the binder cures, tiny cracks may become evident. A PTFE coating may decrease water absorbency of the latex core of devices and allow for a potential 28-day indwelling duration.

PolyurethanePolyurethanes are polymers containing the urethane linkage –OC(O)NH–. The term “polyurethane” refers to a broad variety of elastomers that are usually formed by the addition of a polyg-lycol to an isocyanate. They can be readily tailored for many applications by changing the chemicals used and thus a high degree of versatility in physical, chemical and biological/biocompatible characteristics is possible. Polyurethanes have good mechanical properties and are commonly used in perma-nent or semipermanent implanted medical devices (e.g. pace-makers, ureteral stents). This class of polymer also benefits from being relatively inexpensive.

HydrogelsHydrogels possess a number of physical characteristics such as biocompatibility, which make them attractive for medical device applications, and hydrophilicity, which can impart desirable release characteristics especially in combination devices (such as antimicrobial devices) where controlled drug release from a poly-meric system is required. Hydrogels represent a relatively recent development in the manufacture of indwelling medical devices and are commonly employed as coatings over latex or silicone devices. At equilibrium, hydrogels swell to hold from 10% to 98% of water within their polymeric matrix. As such, they have at a minimum a moderately hydrophilic character and the extent of polymeric swelling is governed by both the polymer cross-link density and the degree of hydrophilicity of the polymer itself.

The trapping of water reduces the coefficient of friction, helping reduce patient discomfort since frictional irritation is reduced along with cell adhesion at the biomaterial–tissue interface. Various studies related to patient comfort and acceptability, for

LatexNatural rubber latex (polyisoprene) had been utilized in the Americas for thousands of years but was first brought to Europe by Columbus in the late 1500s. It was the material employed for the manufacture of the first Foley urinary catheters and to this day is still widely employed, primarily as a base for “coated” devices. The material exhibits many properties desirable for use in medical devices, for example high tensile strength and superb elastic recovery. Latex is inexpensive, easily processed and hence production costs are low. Unfortunately, latex is neither especially biocompatible nor resistant to the development of biofilm forma-tion. Additionally, latex may absorb up to 40% of its own weight in water, potentially increasing the external diameter of devices and reducing the lumen size. For this reason the useable lifespan of all-latex devices is generally only 14 days.

SiliconeSilicone was first developed by the chemist Kipping in the early 1900s and was thus named due to its similarity in structure with ketones. The resinous, polymeric material was first isolated as an impurity [5] and largely ignored until a commercially viable pro-duction process was developed in the 1940s. Its application in medical device manufacture followed shortly thereafter. Poly-dimethylsiloxane (PDMS) is the most widely utilized silicone polymer in modern medicine due to its stability and ease of manufacture. Silicone is widely used as a biomaterial of choice for catheter production. Exhibiting the mechanical benefits of latex rubber, silicone’s inherent strength allows for the design of a large lumen within the device since the walls remain thin. However, although it appears that there is a slight reduction in the susceptibility for encrusted deposits to form on urological catheters, silicone is still highly susceptible to biofilm formation and, in the case of urological devices where it is widely used, development of encrustation [6, 7].

The primary disadvantage with all-silicone devices is the greater level of discomfort experienced by patients. Such discom-fort is associated with the higher levels of rigidity when compared with all-latex or other coated devices and silicone’s relatively low lubricity, particularly during insertion and removal of devices. For these reasons manufacturers favor the application of lubri-cious coatings on silicone and latex devices. Silicone may also be applied as a coating over latex devices, resulting in a device with improved mechanical characteristics while the propensity for stricture formation is reduced due to the latex base being “masked” beneath the more biocompatible polymer.

Polyvinyl chloridePolyvinyl chloride (PVC) is widely employed in the manufacture of intermittent catheters since it is mechanically strong, inexpen-sive and has a relatively smooth, lubricious surface. The rigidity of the material is overcome in practice through the addition of plasticizers to yield a sufficiently flexible product that may be employed clinically. When compared with latex, the devices can have thinner walls and hence a larger lumen; however, even when

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Chapter 20.2 Antimicrobial Devices

mainly on placement within the body and intended function, i.e. load-bearing or non-load-bearing devices), can contribute to mechanical failure. This includes environmental stress cracking, material degradation, time-dependent deformation (creep), brittle fracture or fatigue. Mechanically-induced biological failure occurs when the functional demands on the medical device result in degradation of the device or liberation of particles of material, which results in the establishment of an inflammatory response in vivo, necessitating device removal.

BiocompatibilityBiomaterials by definition are designed to be in contact with host tissue or bodily fluids, a feature which distinguishes them from other materials commonly encountered in daily life, commerce or technology. A widely cited definition of biocompatibility is “the ability of a material to perform with an appropriate host response in a specific application” [14]. The interactions of a material within the host are undoubtedly complex and in many cases poorly elucidated; however, the concept of achieving an appropri-ate biocompatibility is a central tenet in the development of medical devices. The tests for assessment of biocompatibility of medical devices and the materials from which they are manufac-tured are described in the international standard ISO 10993, which covers the evaluation of genotoxicity, teratogenicity, antigenicity, thrombogenicity and carcinogenicity, basic in vitro screens for cytotoxicity, in vivo evaluation of biological response following implantation, toxicity of leachable or degradation by-products of medical devices, systemic toxicity, irritation and hypersensitivity. Furthermore, since the sterile device itself, not simply the material from which it was manufactured, must pass biocompatibility testing protocols, ISO 10993 also evaluates potential toxicities resulting from sterilization processes (e.g. ethylene oxide steriliza-tion residuals). The specific potential bio compatibility complica-tions (in common with all potential complications) will be dictated by the functional requirements of the device, as well as the site and duration of placement in vivo, and indeed may be related to mechanical and infectious complications resulting in degradation of the device and the resulting biological response.

Infectious complicationsAll implanted medical devices are susceptible to device-related infections, where microorganisms colonize the indwelling device and rapidly establish sessile, or surfaced-adhered, populations on the device surface. The development of microbial biofilms, surface-adhered microbial populations encased in a matrix of extracellular polymeric material (or “glycocalyx”) under the control of a population density-dependent gene regulation mech-anism (known as “quorum sensing”), is a ubiquitous survival strategy among microorganisms. It represents the predominant mode of growth of microorganisms in both the natural environ-ment and in chronic infectious disease.

Critically, at least half of all cases of HAIs are associated with the use of implanted medical devices [15], with medical device use the greatest external predictor of HAIs. Indeed, many

example that of Bull and colleagues [10], indicate that when con-trasted with previous devices fitted, high proportions of patients indicated a preference for hydrogel-coated devices. A range of hydrogel materials have been employed including, hydroxyethyl methacrylate, n-vinyl pyrollidone and polyvinyl alcohol.

Although many benefits of hydrogel-coated devices have been proposed, evidence from trials has returned inconsistent results. A randomized controlled trial of device materials with a suffi-ciently large number of patients enrolled would be desirable to resolve the question of comparative benefits of materials. Gorman and co-workers [11] noted lower levels of encrustation compared with standard latex devices although there was increased adherence of hydrophilic bacterial strains. Sabbuba and colleagues [12] found that hydrogel coatings aid migration of pathogenic bacteria over samples. In contrast, Denyer and co-workers [13] noted significant reductions in the adherence of staphylococci to polyvinylpyrrolidine (PVP) and pHEMA. Coat-ings based upon polyethylene oxide (PEO) based multiblock copolymer/segmented polyurethane (SPU) blends have also demonstrated promise in the reduction of bacterial adherence and encrustation formation.

Complications associated with indwelling medical devices

Despite significant advances in the field of biomaterials over the past 50 years, the same complications associated with the earliest use of materials in human medicine remain a feature of modern devices. These include mechanical complications, adverse biologi-cal responses to implanted biomaterials and biomaterial- and device-related infections. In the case of mechanical failure, and biological adverse effects, many of these have been circumvented by the design of new polymeric materials, biologically inspired materials and materials capable of modulation of biological response either by virtue of drug release or surface modification. While much industry has been directed towards what is potentially the most serious and problematic of these complications – that is microbial colonization, biofilm formation and device infection – and while there has undoubtedly been progress in reducing the incidences of infections short term, there has been little in the way of real progress towards a biomaterial capable of ultimately resist-ing infection, especially in long-term use in patients.

Mechanical complicationsAs demand continues to grow for biomaterials that mimic as closely as possible the host tissue and environment with respect to biological, chemical, functional and mechanical attribute, sig-nificant advances in material design continue to deliver improved medical devices. The greatest potential diversity of properties, which can be tailored to a particular functional niche, exists within polymeric materials, driving the massive popularity of synthetic polymers in biomedical applications. As with any mate-rial, the functional demands placed on a device in situ (depending

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The incidences of three of these HAIs (pneumonia, urinary tract infections and bloodstream infections) are commonly associated with the use of medical devices, since each of these sites is ame-nable to instrumentation.

The urinary tract is the most common site for nosocomial infections, accounting for 23.2% of such infections in the UK, and greater than 30% of infections reported by acute care hospitals in the USA. The majority of these (up to 95%) follow instrumenta-tion of the urinary tract, mainly urinary catheterization. In the USA alone, up to 13,000 deaths are associated with UTIs. This is followed closely by infections of the respiratory tract (22.9% of incidences), again commonly related to the use of implanted devices (more than 85% of cases) such as endotracheal tubes; the infection exhibiting the highest incidence is ventilator-associated pneumonia (VAP) [15]. SSIs account for 15% and 17% of all HAIs in the UK and US, respectively, and are associated with considerable morbidity, leading to an estimated doubling in the length of hospital stay. SSIs are also a significant cause of mortal-ity among hospitalized patients, with one study estimating annual mortality rates associated with SSIs as high as 8% of all deaths attributable to HAIs (8000 in 100,000 HAI cases) [18]. However, significant reductions in SSI incidence can be achieved by improvements in pre- and postoperative care. In the UK, the highest incidences of SSIs are, perhaps unsurprisingly, recorded for small and large bowel surgery; however, the rate of SSI fol-lowing orthopedic surgery has decreased significantly since 2004. Finally, it is estimated that approximately 248,000 bloodstream infections occur in US hospitals each year, with a large proportion of these associated with central venous catheters. In the UK, catheter-related blood stream infections (CRBSIs) represent between 10% and 20% of all HAIs. In general, of all device-associated infections, CRBSIs carry the highest rate of mortality.

Microorganisms typically encounter the implanted medical device either by gaining direct access to the device during place-ment or as systemically circulating opportunistic pathogens which colonize the device postimplantation (a latent infection). Therefore, the main causative organisms of medical device-related nosocomial infections are frequently normal skin biota including Staphylococcus aureus and coagulase-negative sta-phylococci, predominantly Staphylococcus epidermidis. The latter has been shown to be the most common cause of infections related to intravascular catheters and other implanted medical devices. A number of other key microorganisms have been shown to be significant causative organisms of medical device-related nosocomial infections, including Pseudomonas aeruginosa (VAP), enterococci, Escherichia coli (UTI, septicemia) and Proteus species, for example Proteus mirabilis (UTI, device encrustation).

Device-associated infections: Events following device implantation

The specter of medical device-related infection is one common to all types of implanted, indwelling medical devices. While

biomaterials in current use exhibit surface characteristics that favor microbial surface colonization, such as poorly controlled, dynamic interfacial responses in physiological milieu, surface charge, hydrophobicity and microrugosity. While it is difficult to establish the exact magnitude and cost (in terms of patient mor-bidity, mortality and financial impact) of medical device-associated infections, Table 20.2.2 gives estimated rates of infection and attributable mortality for commonly implanted medical devices.

Factors that further increase the risk of implanted device infec-tions include prolonged hospitalization, multiple surgical proce-dures at the time of implant, remote infections in other body parts, surgery duration and the amount of tissue devitalization [17]. The increased use of implanted medical devices and the growing number of immunocompromised and critically ill patients requiring interventions involving medical devices have also contributed to the rising number of medical device-related infections.

Healthcare-associated infections

Healthcare-associated infections are localized or systemic condi-tions resulting from an adverse reaction to the presence of an infectious agent(s) or its toxin(s). There must be no evidence that the infection was either present or incubating at the time of admis-sion to the acute care setting. The causative organisms of HAIs may be from exogenous sources (e.g. patient carers, visitors, equipment, medical devices, healthcare environment) or endogenous sources (e.g. migration of organisms from normally colonized body sites: skin, mouth, nose, gastrointestinal tract, genitourinary tract).

The vast majority of nosocomial or HAIs occur at four major body sites, leading to their designation by the US Centers for Disease Control and Prevention (CDC) as the “Big Four” HAIs, namely surgical site infections (SSIs), pneumonia (PNEU), bloodstream infections (BSIs) and urinary tract infections (UTIs).

Table 20.2.2 Rate of infection and attributable mortality of device-associated infections (adapted from [16]).

Medical device Rate of infection (%)

Attributable mortality

Urinary catheters 10–30 LowCentral venous catheters 3–8 ModerateFracture fixation devices 5–10 LowDental implants 5–10 LowJoint prostheses 1–3 LowVascular grafts 1–5 ModerateCardiac pacemakers 1–7 ModerateMammary implants, in pairs 1–2 LowMechanical heart valves 1–3 HighPenile implants 1–3 LowHeart assist devices 25–50 High

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Chapter 20.2 Antimicrobial Devices

Bacterial colonization of the surface and the production of extensive exopolysaccharide glycocalyxes provides a confluent-protected biofilm on medical devices. The biofilm provides and maintains an advantageous, protected microenvironment where organic nutrients and ions may be sequestered from the environ-ment, antimicrobial penetration is retarded and cooperative activities such as genetic exchange, resistance transfer and cross-feeding are facilitated. Indeed, in some respects, biofilm com-munities may be regarded as a form of primitive tissue with channels present for the mass transit of both waste substances and nutrients, and a sophisticated quorum-sensing, population-dependent gene regulation system. The formation of a biofilm on a device–host tissue interface confers significant advantages to the bacteria within, in terms of tolerance/resistance to host defense mechanisms and antimicrobial agents [21]. The privileged micro-environment of the biofilm also facilitates, for example: (i) modu-lation of the physiological environment through maintenance of pH and electrochemical gradients; (ii) increased protection from phagocytosis and antimicrobial agents; (iii) improved ability to avoid recognition by natural defense mechanisms as capsular pro-teins of certain bacterial strains can mimic host structures; (iv) improved sustainability of growth through localization and con-centration of nutrients and extracellular components within the interfaces of microcolonies with the exclusion of oxygen; and (v) increased access of extracellular enzymes, facilitating the absorp-tion of molecules, may also occur, resulting in synergy within mixed cultures. The polysaccharide matrix also acts as an ion-exchange resin sequestering iron from host transferrin and lacto-ferrin. Irregular biofilm surfaces may increase turbulence at the interface between its surface and the surrounding medium, increasing the transfer of substrates from the medium up to three-fold [25].

Clinical management of device-related infections

The traditional management of device-associated infections involves the use of conventional antibiotic therapy directed

causative organism may vary according to site or device, the process of biofilm formation on the biomaterial/device surface follows a series of discrete, well-characterized sequence of events, as shown in Figure 20.2.1 and described in detail in Chapter 21.2.

Deposition of conditioning film, colonization and biofilm formationIt is now well established that immediately after implantation the native medical device surface becomes rapidly modified, depend-ing on the site, by adsorption of host-derived proteins, extracel-lular matrix proteins and coagulation products [20]. This is followed by rapid primary attachment of microorganism to the material surface and biofilm formation. Subsequent to the attach-ment of bacterial cells to the surface of a material, a number of phenotypic changes occur within the cells which lead to the for-mation of a microenvironment, conferring significant survival advantages over planktonic growth [21]. A biofilm can be defined as a microbially-derived sessile community of cells irreversibly attached to a substratum (biotic or abiotic), embedded within a matrix of extracellular polymeric substances that they have pro-duced, and exhibiting an altered phenotype with respect to growth rate and gene transcription [22]

After the initial adherence of bacterial cells, the production of capsular exopolysaccharides is increased and coats the surface of the material and, for the majority of species, acts as an anchor to bind the bacterial colonies to the surface. The bacteria continue to divide within this protective matrix, with the rate of growth dependent upon the nutrient composition of the medium, its flow rate and whether there are any antimicrobial agents present [23]. The population of cells within a biofilm is heterogeneous with respect to metabolic activity, which contributes to their lack of sensitivity to standard antibiotic agents. Even so, the cells within the biofilm matrix reproduce, spreading over the surface of the material to form a more confluent coating. Cells are con-tinually shed that may in turn form new colonies, the rate of which is determined by various factors including shear forces in the medium [24]. As a result, biofilms forming on indwelling medical devices may be considered a reservoir of infection.

Figure 20.2.1 Medical device colonization by microorganisms showing surface attachment and biofilm formation (adapted from [19]).

Planktonicbacteria

1. Adsorption 3. Growth and division

Extracellularpolymeric matrix

Chemoattractant

Signalmolecules

Waterchannel

5. Dispersion

4. Mature macrocolony2. Irreversible attachment

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Development of antimicrobial biomaterials

The high incidences of device-associated infections and the sig-nificant limitations of conventional antimicrobial chemotherapy in their effective management, has prompted the development of device-based approaches. These are aimed at preventing the establishment of microbial biofilms rather than attempting to eradicate the infection once established as a sessile population. These approaches are focused on the development of bioactive, anti-infective or antimicrobial devices, which inhibit microbial adherence (by surface modification or irreversible tethering of antimicrobial to the surface) or microbial growth (by elution of the active agent).

In an effort to combat microbial adherence and biofilm forma-tion on the surfaces of indwelling medical devices, a number of methods have been employed to modify polymer surfaces and/or load antimicrobial agents into medical device polymers, with the aim of producing bacteria-inhibitory and bactericidal surfaces (Figure 20.2.2). Bacteria-inhibitory surfaces prevent/discourage both bacterial colonization and proliferation, whereas bactericidal surfaces elute bactericides with the intent of killing planktonic and early colonizing microorganisms. Both systems aim to prevent microbial contamination from occurring on the surface of the medical device in the first instance and to inhibit bacterial colo-nization and subsequent biofilm formation. Such materials benefit from relatively low manufacturing costs, long shelf-lives and ease of processing (manufacturing/sterilization), and the overall func-tion of a device is not compromised by the presence of the active agent [29]. Examples of methods employed in the loading of polymeric matrices with antimicrobial agents include immersion, coating, matrix loading and drug polymer conjugates [26].

Although straightforward, a major limitation of direct antimi-crobial loading into a polymeric biomaterial matrix by coating or immersion is the optimization of drug release. Since release of standard antibacterial agents from the surface of the medical device is not coordinated with the presence of infecting organ-isms, the release of antimicrobial from a drug-loaded polymer matrix generally follows (according to Fick’s law) a “burst” release

against the identified or suspected causative organism, with the final choice of antibiotic ideally depending on microbiological susceptibility assay, as well as consideration of the pharmacologi-cal and toxicological properties of the antibacterial agent. At the biomaterial–device surface, antibiotics may induce direct kill or inhibit bacterial growth and can negatively affect the adhesion of microorganisms to the surface by interfering with bacterial adhesions, resulting in prevention of binding of planktonic bac-teria [21]. Accepted clinical practice often includes combination therapy in which two or more antimicrobials are used to treat biofilm-associated infections. This approach introduces a broader spectrum of activity compared with single-agent treatment. Lower concentrations of the antimicrobials are required, resulting in more effective therapy and a decreased likelihood of resistance development [26]. Such approaches may also eradicate microor-ganisms, which despite being important mediators in mixed species biofilms, are not identified by standard culture techniques. Administration of prophylactic antibiotic therapy to prevent colonization is also common practice during surgical insertion of most devices. However, even in the presence of antibiotics, adher-ence, colonization and the establishment of infection can occur at medical device surfaces.

As discussed, a general characteristic of medical device-associated infections (and biofilm-mediated infections generally) is their recalcitrance to typical antimicrobial therapy and host defenses; such infections prove extremely difficult to eradicate and relapses occur frequently. Numerous factors contribute to the high antimicrobial tolerance of biofilm-mediated, medical device-associated infections including the distinct mode of growth displayed by biofilm populations and multidrug antimicrobial resistance.

Furthermore, standard susceptibility assays which often dictate antimicrobial choice may not be good predictors of the appropri-ate antimicrobial or concentration for biofilm eradication. This is because there may be no correlation between planktonic sus-ceptibility to antimicrobial challenge (as assessed by the minimum inhibitory concentration (MIC)) and biofilm susceptibility of the same strain [27], thus contributing to the clinical failure rate of treating chronic biofilm-associated infections [17].

Figure 20.2.2 Antibacterial coating of medical devices. (a) Impregnation/loading of device coating with a polymeric layer (e.g. hydrogel) containing biocidal agents. (b) Permanent surface modification of a device with conjugates with either cidal or antiadherent activity. (Adapted from [28].)

Microbicide LoadedPolymer Coating

Surface ModifiedPolymer Coating

Biomedical Device BulkBiomedical Device Bulk

Release of microbicides over timeA B Surface group kill bacteria ofprevent bacterial adsorption

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Chapter 20.2 Antimicrobial Devices

catheter-associated urinary tract infection (CAUTI) [31]. While much research has focused on the reduction of CAUTI by using silver-impregnated, silver-eluting or silver-coated urological cath-eters, silver (in various presentations and usually in combination with a broad-spectrum biocidal agent such as chlorhexidine) has been employed in commercially available endotracheal tubes, central venous catheters and wound dressings.

Silver ions have often been less effective than expected in vivo in relation to antimicrobial effects, although this may be related to their high reactivity with electron-donating groups such as sulfur, oxygen and nitrogen which are present in biological mol-ecules. A sufficiently high concentration of free silver ions must be present since the rate of bacterial killing is directly propor-tional to concentration and, in the presence of albumin and/or Cl− ions, activity may be reduced [31].

Due to the divergent views on the subject, Saint and co-workers [32] conducted a meta-analysis of eight clinical trials, the results indicating that there was a statistically significant benefit in the reduction of CAUTI in all patients where silver-coated catheters were used. However, their analysis indicated a significant benefit in silver alloy-coated catheters over silver oxide-coated catheters. The lack of evidence for benefit of these latter devices was a key factor in their withdrawal from the market. A more recent review [33] of antimicrobial catheters notes that more recent (post 1995) studies involving silver-coated devices demonstrate less significant advantages over control devices in reducing CAUTI. The authors argue that a combination of factors may be involved – the use of silicone devices rather than all-latex catheters as controls, better clinical practice and reduced background rates of bacteriuria due to improved clinical practice.

The Cochrane review of catheter trials [34] also criticizes the quality of most clinical trials involving the use of silver alloy- and silver oxide-containing urological catheters. The study did con-clude, however, that silver alloy-containing catheters appeared to reduce levels of asymptomatic bacteriuria in patients catheterized for less than 7 days. Silver oxide-containing devices were not associated with significantly reduced risks of bacteriuria.

While debate continues to rage regarding the clinical effective-ness of silver-coated/impregnated devices, Niël-Weise and co-workers [35] concluded that, at present, there is insufficient evidence to justify recommendation of urological devices incor-porating silver for routine use, based on current clinical trial data.

AntibioticsSeveral antibiotics have been investigated as actives, either alone or in combination with a non-antibiotic, antimicrobial agent. The potential of nitrofurazone-impregnated devices against urinary pathogens was discussed as long ago as 1993 by Johnson and col-leagues, with the growth of 75% of clinical isolates being inhibited [36] by cross-sections of catheter material placed on growth media. In vivo results, however, have been less conclusive, with several studies finding no significant benefit of this type of “active” device over standard silicone catheters in the reduction of CAUTI, except in patients catheterized for 5–7 days or in

profile (a major proportion of the drug is released at an early stage following implantation). This is followed by a slow leaching of potentially subinhibitory levels of the antimicrobial, which may be insufficient to prevent infection but may facilitate the selection of antimicrobial-resistant strains. The concentration of the polymer reservoir is then depleted and the “exhausted” device becomes susceptible to colonization by bacteria or fungi encountering the device surface at any time following the “burst” of antimicrobial release. Concerns have been raised that prophylaxis of device-associated infections using antibiotic-coated or loaded medical devices may lead to the proliferation of antimicrobial resistance, though further, long-term studies are necessary to confirm this.

Clinical experience with antimicrobial devices clearly indicates that due consideration must be given to mechanisms for achiev-ing appropriate drug-release kinetics. Drug release which is uncontrolled and rapid, from a few hours to a few days, will in most clinical scenarios be inappropriate for preventing device-related infections [29]. Additionally, the mass of drug that can be incorporated is often insufficient for maintenance of prolonged bactericidal or bacteriostatic concentrations.

The formation of drug–polymer conjugates involves the cova-lent linkage of an agent to a monomer, prior to polymerization, resulting in the production of an extremely resilient drug–polymer material. Drug–polymer conjugates have been shown to signifi-cantly reduce bacterial adherence and encrustation in urinary catheters indicating the therapeutic potential of this approach for urinary catheter use in a site-specific manner. However, this approach is not without limitations, including increased cost of manufacture and limited antimicrobial choice (according to chemical compatibility of therapeutic agents with the synthetic reaction scheme) [26]. Furthermore, deposition of conditioning film or cellular material on the device surface may be sufficient to “mask” the antimicrobial activity of the biomaterial surface and to permit the establishment of a sessile microbial population.

AntisepticsAntimicrobial impregnation/loading is not limited exclusively to conventional antibiotics. Coatings that release metals, namely silver and copper ions, and nonspecific antiseptic coatings (tri-closan, hexetidine chlorhexidine, benzalkonium chloride) have been used effectively against device-associated infections. Proteus mirabilis is highly sensitive to triclosan with MICs of strains cul-tured from devices being reported as 0.5 µg/ml [30], with other key pathogens also exhibiting high sensitivity to the compound. Triclosan has also been shown to inhibit in vitro biofilm growth of E. coli, Klebsiella pneumoniae, S. aureus and P. mirabilis, thus reducing encrustation formation. However, biofilm formation by some key pathogens such as Serratia marcescens, Morganella mor-ganii and P. aeruginosa was not inhibited.

SilverThe use of silver in active medical devices has been the subject of much debate, with conflicting results from many studies since the first investigation indicating the potential for reduction in

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viable adhered methicillin-resistant S. aureus (MRSA), E. coli or Candida parapsilosis when compared with silver/hydrogel-coated urinary catheters or control uncoated catheters [43].

Darouiche and co-workers [44] demonstrated a significant reduction in Gram-positive bacteriuria in patients when con-trasted with silicone control devices at both 7 days (15.2% versus 39.7%) and 14 days (58.5% versus 83.5%) using a silicone cath-eter impregnated with minocycline and rifampicin. The study did not demonstrate any increased efficacy with respect to Gram-negative organisms or Candida. This study also involved a small number of patients and concern has been expressed over selection of resistant strains.

The use of biomaterials combined with standard antimicrobial agents is a simple and straightforward strategy to reduce the chances of bacterial colonization and subsequent biofilm forma-tion. In spite of significant limitations, the use of antimicrobial medical devices is now a common feature of clinical practice, with differing opinions regarding their long-term effectiveness in the prevention of medical device-associated infections.

Antimicrobial devices

Antimicrobial urological devicesUrethral catheters are widely used with approximately 96 million devices being sold worldwide annually, 25% of these sales being within the USA alone [45]. Studies estimate that somewhere in the region of 11% of hospitalized patients within Europe are catheterized at some point during their hospitalization and it is estimated that some 5 million patients in acute care hospitals are catheterized annually [46]. Levels of catheterization are generally higher in the USA, with estimates ranging from 15% to 25% of hospitalized patients. Within the secondary care setting, nosoco-mial infections are one of the key contributors to patient morbid-ity and mortality, with the urinary tract being the most common site of infection. Infection of the urinary tract is dependent on the duration of device insertion, with the incidence of bacteriuria being approximately 5–8% per day and, as such, 90% of patients undergoing long-term catheterization will develop bacteriuria within 4 weeks [47]. Approximately 10–25% of patients with bacteriuria progress to develop a UTI and around 3% to develop potentially life-threatening bacteriuria. Urinary tract infections account for 40% of all nosocomial infections, with 80% of these being CAUTIs [33]. Gram-negative organisms tend to be impli-cated most commonly with E. coli, Proteus mirabilis, P. aeruginosa and Klebsiella pneumoniae being the primary pathogenic species, although Gram-positive strains such as S. epidermidis and Ente-rococcus faecalis may also be implicated.

The potential of nitrofurazone- and nitrofuroxone-impregnated devices to prevent bacteraemia has been investigated and they have been shown to demonstrate efficacy in the reduction of nosocomial CAUTIs in postoperative orthopedic and trauma patients. The incorporation of synergistic combinations of anti-microbials may offer greater promise, however, with synergistic

elderly patients. Al-Habdan and co-workers [37] did, however, suggest the potential for these devices to reduce the occurrence of nosocomial CAUTI in postoperative orthopedic and trauma patients catheterized short term. A randomized controlled trial by Maki and colleagues [38] indicated a significant risk reduction for CAUTI. However, this study involved a small number of patients and concerns over selection of antimicrobial drug-resistant uropathogens were not satisfactorily resolved.

Norfloxacin release from catheters coated with poly(ethylene covinyl) acetate (EVA) and an amphiphilic multiblock copolymer composed of PEO and PDMS has also been examined for periods of up to 30 days. Significant inhibition of E. coli, Klebsiella pneu-moniae and Proteus vulgaris growth was only demonstrated for 10 days [39]. Cho and colleagues [40] demonstrated that a gen-tamicin sulfate-coated catheter reduced both biofilm formation and bacteriuria in a rabbit model at 3- and 5-day intervals. However, the sample size used in the investigation was small and the issues of efficacy and resistance in the longer term remain unanswered. The widespread use of an important broad-spectrum antimicrobial such as gentamicin in this manner may, however, be irresponsible since it may well encourage resistance. This issue is especially important s this antimicrobial is one of the most useful in the armamentarium of the urologist when treating potentially life-threatening septicemias which may result as a complication of CAUTIs. The use of rifampicin and minocycline in central venous catheters and urological catheters has been associated with signifi-cant reductions in CRBSIs and bacteriuria, respectively. The use of a range of active devices employing standard antibiotics will be discussed later in the chapter under specific devices.

Antimicrobial combinationsIt has been demonstrated that synergistic combinations of a number of antimicrobials may result in increased efficacy and a broader spectrum of activity. Gaonkar and colleagues [41] dem-onstrated that latex and silicone catheters containing silver sul-fadiazine, triclosan and chlorhexidine showed greater efficacy and broader spectrum than nitrofurazone-containing devices or any of the individual compounds or pairs, in terms of inhibition of bacterial colonization to the outer wall of devices. In addition, the benefits proposed for silver-containing devices must be weighed against the slightly increased costs associated with them.

Hydrogel coatings for catheters have significant advantages over other materials in modifying the “active” properties of the device. By tailoring the cross-linking agents employed, the rate of release of active agent may be easily altered according to the desired properties. This strategy has been elegantly employed to alter the release of chlorhexidine and fusidic acid from potential catheter coatings with the rate of drug release being directly pro-portional to the concentration of the cross-linking agent utilized in the manufacture of the polymers [42].

Soaking devices in solutions of antimicrobials has been demon-strated as a simple technique to reduce bacterial adherence. Devices soaked in gendine, a novel antiseptic containing Gentian violet and chlorhexidine, have exhibited promise, reducing the counts of

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antimicrobial CVCs have been developed and are commercially available in the UK and USA. Fundamentally, these devices rely on either non-antibiotic agents such as silver sulfadiazine and chlorhexidine or antibiotic agents such as rifampicin and mino-cycline. A summary of currently available antimicrobial CVCs is given in Table 20.2.4.

Data on the use of these devices are not currently available for the USA; however, data from National Health Service Logistics (UK) for the period 2003–2004 indicate that only 4.2% of all CVCs issued in this period were antimicrobial. Recent meta-analysis data suggest that, with respect to reduction in device colonization and CRBSI, antimicrobial CVCs performed better than standard devices. However, benzalkonium chloride-impregnated, silver alloy-coated, silver iontophoretic or silver-impregnated devices did not reduce colonization or CRBSI. First-generation chlorhexidine-silver sulfadiazine CVCs did, however, significantly reduce catheter colonization and CRBSI. Superior activity was recorded with rifampicin-minocycline cath-eters, which were shown to reduce the risk of both colonization and CRBSI. Rifampicin-miconazole catheters also significantly reduced catheter colonization, although a reduction in CRBSI was not demonstrated by limited clinical assessment [52].

Antimicrobial endotracheal tubesThe first in vitro study of an antimicrobial, silver-coated endotra-cheal tube (ETT) was published by Hartmann and co-workers [53]. These devices significantly reduced colonization by P. aeru-ginosa. Hexetidine-impregnated PVC ETTs were also shown to significantly reduce adherence of both S. aureus and P. aeruginosa [54]. Combinations of antiseptic and silver salts have also been examined, and in the case of chlorhexidine/silver carbonate-coated ETTs, significant reduction or total prevention of coloni-zation of a range of pathogens was observed over 5 days. Animal models of ETT-associated infections have yielded positive data supporting the use of antimicrobial ETTs. Olson and co-workers [55] demonstrated the benefits of a silver/hydrogel-coated ETT in vivo, which resulted in a decreased bacterial burden in the lungs of mechanically ventilated dogs. Silver sulfadiazine and chlorhex-idine have also shown significant promise for the prevention of bacterial colonization in a recent in vitro study [56]. A silver-coated ETT utilizing the patented Bacti-Guard® silver alloy

combinations of chlorhexidine, silver sulfadiazine and triclosan exhibiting a broader spectrum of activity and longer-term inhibi-tion of bacterial colonization to the outer wall of devices when compared with nitrofurazone- or silver-containing devices in an in vitro model. The use of silver as a coating for urological cath-eters has also been investigated and the interpretation of clinical data has provoked much debate.

Urease-producing bacteria, primarily Proteus mirabilis, are implicated in the formation of encrusted deposits on urological devices (catheters and stents); these may damage the uroepithe-lium or block the device lumen, leading to device failure requiring removal. Colonization of the biomaterial surface with urease-producing bacteria causes alkalinization of the urine and the biofilm matrix (urease hydrolyzes urea, forming ammonia and carbon dioxide, and the ammonia becomes protonated, causing alkalinization of the urine). This lowers the solubility and initiates the precipitation of poorly soluble Mg2+ and Ca2+ salts in the form of struvite and hydroxyapatite, resulting in surface deposition and crystal formation. Encrustations associated with an infec-tious origin are primarily composed of magnesium ammonium phosphate (struvite) [MgNH4PO46H2O] or calcium phosphate (hydroxyapatite) [Ca10(PO4)6(OH)2]. In attempts to prevent biofilm formation and encrustation of ureteral stents, several bio-cidal agents have been evaluated for use in antimicrobial eluting stents. Currently, a number of triclosan eluting ureteral stents are commercially available (e.g. Triumph stent, Boston Scientific) for this application and have shown promise in reducing bacteriuria and biofilm formation, with clinical trials currently underway.

Antimicrobial central venous access devices/cathetersIn common with other types of catheter and access devices, infec-tion and biofilm formation leading to patient morbidity and mor-tality remain the most common and perplexing complications associated with central venous catheters (CVCs). CVCs are used in a vast array of primary and secondary care applications, often in critical care situations. In the USA, 5 million CVCs are used in patients annually [48] and are a major cause of nosocomial infec-tions. Between 100,000 and 500,000 CRBSIs occur in the USA every year, contributing to increased patient morbidity, increased care costs (estimated between US$3700 and 28,000 per patient) and mortality – more than 25,000 patients die annually of CRBSIs [49]. Furthermore, CVCs are responsible for the highest propor-tion of nosocomial bacteremias and are the most common cause of nosocomial endocarditis [50]. Perhaps unsurprisingly, the most common causative organisms of catheter-related infections are derived from the patient’s own skin microflora. The predominant causative organisms are the Gram-positive cocci, coagulase-negative staphylococci (e.g. S. epidermidis), followed by S. aureus and Gram-negative bacilli (Enterobacteriaceae). Candida species are also emerging as important pathogens in catheter-related infections. The range of microorganisms causing CVC-related infections is shown in Table 20.2.3.

Systemic or oral administration of antibiotic agents is not gen-erally the preferred treatment option, therefore a number of

Table 20.2.3 Microorganisms causing central venous catheter-related infections (adapted from [51]]).

Organism Approximate percentage

Coagulase-negative staphylococci, e.g. S. epidermidis 60–70Staphylococcus aureus 15Methicillin-resistant Staphylococcus aureus (MRSA) <5Candida species <5Enterococci 2–4Enterobacteriaceae (coliforms) 5–10

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infections, peritonitis) are common and problematic. Since the introduction of continuous ambulatory peritoneal dialysis (CAPD) in the 1970s, around 150,000 worldwide are on the treatment, some 15% of the global dialysis population [58]. Two prominent studies have placed the combined overall incidence of peritonitis and exit-site tunnel infections at between 11% and 13% [59, 60]. Both studies are in agreement that peritonitis rates are approximately 1 incidence per 16.7 patient-months. In common with other types of catheter infections (especially CVC-related infections), the most common causative organism of such infections is S. epidermidis. Recent studies (in this case the Network Nine Study) indicated that the most common causative organism of peritoneal catheter-associated infection and peritonitis was S. epidermidis, which accounted for 43% of Gram-positive organisms isolated, S. aureus (26%), enterococci (5%) and other Gram-positives (26%). Pseu-domonas spp. accounted for 11% of all Gram-negative peritonitis cases recorded. Currently, there are no commercially available antimicrobial peritoneal catheters, although an antimicrobial modified silicone peritoneal catheter impregnated with rifampicin, triclosan and trimethoprim has been reported recently, which exhibits long-term activity against a range of clinically relevant pathogens in in vitro and in vivo animal studies [61].

Antimicrobial catheters for neurosurgeryCatheters are employed for a variety of indications in neurosur-gery, primarily in the management of intracranial pressure in hydrocephalus by direct drainage of cerebrospinal fluid (CSF). Catheters, depending on placement, are referred to as either shunts (permanent) or external (short-term) ventricular drainage devices (EVDs). Around 4000 shunts are inserted annually in the UK; EVD data are not available but the numbers are likely to be significantly higher [62]. Infections remain serious complications and are associated with poor outcome, and generally require removal and replacement of the device. In shunt infections, the primary causative agents of catheter infection are the coagulase-negative staphylococci and S. aureus. Infections of EVDs are also caused by these organisms, though a greater proportion of Gram-negative organisms are implicated. The use of prophylaxis anti-biotic cover during catheter insertion is an almost universal practice, most commonly using gentamicin, cephalosporins or

system is commercially available (Agento I.C., C.R. Bard Inc., USA) and marketed for prevention of VAP in patients at risk of intubation for 24 hours or longer.

Antimicrobial orthopedic devicesGiven the nature and placement of orthopedic medical devices, the consequences of device-associated infections can be particu-larly acute, giving rise to increased morbidity and mortality in patients. Often the development of infection will require a further operation to remove and replace the infected device. To avoid the risks of device-associated infection a number of approaches have been adopted, including improvements to pre- and postoperative care and the use of antimicrobial devices such as antibiotic-loaded bone cements, fillers and implant coatings. Antibiotic-impregnated acrylic bone cements have been commercially available in Europe for more than 20 years, with gentamicin the most commonly employed antibiotic agent. Tobramycin-containing bone cements (e.g. Simplex P, Stryker Orthopedics) are also commercially available. It is common in practice for surgeons to mix a range of antibiotic agents directly into com-mercially available bone cements, depending on the infecting organism. Gentamicin-loaded polyurethane sheaths designed for external fixator pins to prevent pin-track infections are also com-mercially available (OrthoGuard AB, Smith & Nephew, USA). For a comprehensive review, see [57].

Antimicrobial peritoneal cathetersA number of complications are inherent to the use of peritoneal catheters. Catheter-related problems cause significant morbidity and often necessitate catheter removal. Indeed, up to 20% of patient transfers from peritoneal dialysis to hemodialysis are directly related to catheter complications. While a significant number of mechanical complications have been reported for peritoneal access devices – such as occlusion, infusion pain, peri-catheter leaks and cuff extrusion from the abdominal wall – these problems have been largely resolved either by improved design of the device/appropriate device selection, improved biomaterial design or by improvements to clinical practice [58].

However, in common with all types of implantable medical device, infectious complications (exit-site infection, tunnel

Table 20.2.4 Commercially available adult antimicrobial central venous catheters (USA and UK) (adapted from [52]).

Active Activity Name (manufacturer) USA UK

Silver with platinum and carbon (iontophoretic) External and internal Vantex CVC kits (Edwards Life Sciences) ✓ ✓Silver in ceramic zeolite matrix (impregnated) External and internal Multicath Expert range (Vygon Ltd) × ✓1st generation chlorhexidine and silver sulfadiazine External ARROWg + ard Blue (Arrow International, Inc.) ✓ ✓2nd generation chlorhexidine and silver sulfadiazine External (internal chlorhexidinde coating) ARROWg + ard Blue Plus (Arrow International, Inc.) ✓ ✓Benzalkonium chloride External and internal Hydrocath Assure (BD Ltd) ✓ ✓Benzalkonium chloride-heparin bonded External and internal AMC Thrombosure (Edwards Life Sciences) ✓ ✓Minocycline and rifampicin External and Iinternal Cook Spectrum (Cook Medical, Inc.) ✓ ✓Miconazole and rifampicin External and internal Multistar (Vygon Ltd) × ✓

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Chapter 20.2 Antimicrobial Devices

for the introduction of microorganisms to soft tissues. A number of recent studies have demonstrated the benefits of antimicrobial sutures in reducing SSIs. Triclosan is the antiseptic of choice, due to its broad spectrum of activity and a history of use in topical applications. The commercially available Vicryl Plus (triclosan-coated polyglactin) have been extensively studied and has dem-onstrated efficacy against a broad range of microorganisms as well as prevention of colonization and improved wound healing in vivo [63].

The future: Emerging strategies for anti-infective biomaterials

Elucidation of the molecular mechanisms of biofilm formation, and the production and regulation of virulence factors in micro-organisms implicated in medical device-associated infections, has facilitated the development of a number of strategies. These strat-egies target functional molecules, gene systems and regulatory pathways, which maintain and control the overall development and maturation of the biofilm and, subsequently, the etiology of medical device-associated infection. Table 20.2.5 summarizes

vancomycin. While some studies appear to show improved clini-cal outcome with respect to device infection, others demonstrate no benefit [62]. Antimicrobial CSF shunt or EVD catheters have been the subject of considerable research and development and a number of commercially available examples are discussed below.

Silver has been widely employed in the design of antimicrobial catheters for neurosurgery, with a polyurethane-silver-impreg-nated EVD catheter (Silverline, Spiegelberg (GmbH & Co.)) com-mercially available. As with other devices using silver as an antimicrobial agent, there is significant debate surrounding the preclinical or clinical efficacy, with few data as yet available on patient outcomes. The impregnation of catheters with antibiotics has been examined, with both rifampicin and minocycline (Ven-triclear) and rifampicin and clindamycin (Bactiseal) combina-tions commercially available.

Antimicrobial suturesThe development of wound or surgical site infections is common and the use of antimicrobial sutures or other closure devices has been the subject of debate for many years. In fact, it is known that suture-associated polymicrobial biofilms are responsible for chronic SSIs, and that contaminated sutures may act as a vector

Table 20.2.5 Novel approaches for biofilm dispersal and eradication (adapted from [64]).

Approach Mechanism of action Target

Quorum-sensing (QS) inhibitors QS interruptionReducing adhesion and colonization

Population density-dependent gene regulation (adhesion, glycocalyx production)

Impairing adhesionBiosurfactants including RC14 biosurfactant “surlactin”

Anti-adhesive activity; interference with initial bacterial attachment

Microbial adhesion

Diterpenoids (salvipisone and aethiopinone) Destabilizing biofilm matrix allowing detachment and altering bacterial cell surface hydrophobicity

Biofilm matrix and bacterial cell surface

Targetting slime formationN-acetyl-D-glucosamine-1-phosphate acetyltransferase (GlmU) inhibitors; N-substituted maleimides

Inhibiting bacterial cell wall synthesis and polysaccharide intercellular adhesion (PIA) formation

PIA biosynthetic enzymes; GlmU enzyme

N-acetylcysteine (NAC) Reducing production of extracellular polysaccharide matrix and promoting disruption of mature biofilm

Extracellular polymeric matrix

Bacteriophage therapy Lytic activity on biofilm cells Biofilm glycocalyx (lysins) and biofilm cellsImmunotherapyFibronectin (FN)-binding receptor monoclonal antibodies (MAbs)

Blocking adhesion FN-binding receptor

Anti-PIA antibodies Inhibition of PIA formation PIASurface-binding protein/Fbe antibodies Blocking adhesion Fibronectin/fibrinogen binding protein (Fbe)Anti-Aap domain B antiserumAap antibodies

Inhibiting accumulation and intercellular adhesion Aap

Enzymatic removalOxidoreductases and polysaccharide-hydrolyzing enzymes

Enzymatic removal and disinfection of biofilm Biofilm matrix

Lysostaphin (staphylolytic endopeptidase) Disruption of biofilm matrix and killing of released bacteria Peptidoglycan pentaglycine interpeptide bridges of staphylococcal cell wall

Dispersin B (DspB) Enzymatic degradation of cell-bound exopolysaccharide adhesin, an essential component of the biofilm polymeric matrix

B-1,N-acetyl-D-glucosamine

Serratiopeptidase Induces biofilm degradation via proteolytic activity, also enhances antibiotic activity

Biofilm slime matrix

ImmunomodulationInterferon γ

Reversal of macrophage deactivation in the vicinity of implanted biomaterial

Macrophages

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11 Gorman, S.P. et al. (1991) Microbial adherence and biofilm formation on latex

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17 Choong, S.K. and Whitfield, H.N. (2000) Urinary encrustation of alloplastic

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20 Fuller, R.A. and Rosen, J.J. (1986) Materials for Medicine. Scientific American,

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21 Habash, M. and Reid, G. (1999) Microbial biofilms: their development and

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22 Donlon, R.M. and Costerton, J.W. (2002) Biofilms: survival mechanisms

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23 Donlan, R.M. (2001) Biofilms and device-associated infections. Emerging Infec-

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24 Gristina, A.G. (1987) Biomaterial-centered infection: microbial adhesion versus

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25 Fletcher, M. (1991) The physiological activity of bacteria attached to solid sur-

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26 Gorman, S.P. and Jones, D.S. (2002) Antimicrobial Biomaterials for Medical

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27 Smith, A.L. et al. (2003) Susceptibility testing of Pseudomonas aeruginosa isolates

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29 Lin, T.L. et al. (2001) Antimicrobial coatings: a remedy for medical device-

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30 Stickler, D. et al. (2003) Why are Foley catheters so vulnerable to encrustation

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33 Johnson, J.R. et al. (2006) Systematic review: antimicrobial urinary catheters to

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novel targets and the mode of action of a number of approaches that have been developed recently for the treatment and preven-tion of device-related infections, particularly with respect to S. epidermidis. These approaches have not, as yet, replaced the widely employed, standard antimicrobial combination devices since their evaluation has been, for the greater part, small-scale in vitro laboratory trials. Therapeutic strategies are aimed at the disintegration of established biofilms and include quorum sensing perturbation, which leads to the downregulation of molecules stabilizing the biofilm architecture, or the use of enzymes to dis-solve the biofilm matrix.

Conclusions

Much progress has been made in the development of antimicro-bial medical devices for the control and prevention of the ubiq-uitous specter of medical device-associated infections. The susceptibility of all implanted or indwelling medical devices to succumb to microbial infection remains the major disadvantage and complication associated with their use in patients. The changing global demographics towards a steadily aging popula-tion will impose even greater demands on healthcare providers and for the provision of improved devices that can resist infection and thus reduce patient morbidity and mortality. Improving the useful lifetime of a device also reduces the necessity for its removal and replacement and the attendant costs associated with increased hospitalization and care costs.

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