The role of antimicrobial surfaces in hospitals to reduce healthcare-associated infections (HAIs)

The role of antimicrobial surfaces in hospitals to reduce healthcareassociated infections (HAIs)

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M.G. Schmidt Medical University of South Carolina, Charleston, SC, United States

13.1 Introduction Healthcare associated infections (HAIs) represent a clear and present danger to all. Individuals acquire these infections while they are receiving medical or surgical care or in any other setting associated with their care. In spite of the best efforts of an interdisciplinary team of environmental service professionals and infection control practitioners HAIs acquired during hospitalization still remain one of the leading causes of morbidity and mortality for hospitals across the globe. The economic consequences of HAIs are not inconsequential. For acute care hospitals within the United States, the public health consequences and financial outlays for HAIs are estimated to range between $96 to $147 billion dollars [1]. Here we will explore the role that antimicrobial surfaces may offer in helping hospitals reduce the incidence of this global problem. The pioneers of infection control, Semmelweis, Holmes, Nightingale, and Lister, all indirectly appreciated the need to limit the transfer of microbes from the hands of healthcare workers and others resident in the healthcare environment in order to improve patient outcomes [2–5]. Nightingale in her seminal observations found that when hospital wards were simply kept clean, deaths attributed to cholera, typhus, and dysentery were significantly reduced from 42% to 2%. Fortunately, infection control has advanced substantially since the time Oliver Wendell Holmes, Sr. advocated in cases of puerperal fever: “If within a short period two cases of puerperal fever happen close to each other, in the practice of the same physician, the disease not existing or prevailing in the neighborhood, he would do wisely to relinquish his obstetrical practice for at least one month, and endeavor to free himself by every available means from any noxious influence he may carry about with him” [5]. We now appreciate that Dr. Holmes was wise beyond his years in offering the following advice to physicians in obstetric practice that “It is the duty of the physician to take every precaution that the disease shall not be introduced by nurses or other assistants, by making proper inquiries concerning them, and giving timely warning of every suspected source of danger” [5]. Today, as has been the practice for many years, hand hygiene control remains the primary means with which healthcare combats the transference of microbes from the built environment to the patient. In addition to the use of soap and warm water, alcohol-based hand sanitizers have revolutionized and made convenient hand hygiene since their widespread introduction in the 1980s. The World Health Organization Decontamination in Hospitals and Healthcare. https://doi.org/10.1016/B978-0-08-102565-9.00013-3 © 2020 Elsevier Ltd. All rights reserved.

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(WHO) requires that alcohol hand rubs contain sufficient alcohol, between 60% and 95% such that when applied to hands there remains sufficient alcohol to inactivate microorganisms and/or temporarily suppress their growth on the hands of the applicant. In 2018 an alarm was raised when it was learned that some hospital isolates of Enterococcus faecium developed a 10-fold higher tolerance against alcohol inactivation [6]. This observation generated significant concern especially given that E. faecium is one of the leading causes of hospital-acquired infections. The natural selection of alcohol-tolerant strains of E. faecium is not surprising, given the emphasis placed on point of care disinfection recommended for hand hygiene applications. In order to achieve a 99.99% reduction to the incident microbial burden on hands the active agent, at its proper concentration, must remain in contact for 15 s. Given the effectiveness of alcohol-gel hand rubs it is especially troubling that strains of Enterococci are developing tolerance to this often life-saving intervention. While strains of Enterococci have yet to break-through the concentration of alcohols used in the majority of hand rubs, the genetic modifications accumulating within the microbe as mutations within genes involved in carbohydrate uptake and metabolism [6], suggest that it is only a matter of time before natural selection succeeds with an emergence of an enterococcus completely tolerant to the lethal effects of exposure to short-chained alcohols used in alcohol-based disinfectant hand hygiene products.

13.2 Relevance of the built environment to HAIs While healthcare will continue to use hand hygiene as its primary, and most effective, measure to limit the transference of microbes between patients, visitors, and providers, it has been slow to appreciate the significance that the built environment contributes to the incidence of infections. In 2013 Salgado and colleagues correlated that the concentration microbes associated with high touch services within the built environment were linked to the incident rate of HAI acquisition [7]. The results from their multihospital trial were contrary to the commonly held view from the 1990s where the environment was estimated only to contribute between 20% and 40% to the incidence rate of HAIs [8] (Fig. 13.1). They equivocally showed that by lowering burden in the built environment, using six high touch/high risk or the most frequently touched surfaces in intensive care units, the incident rate of HAIs decreased by 58% [7]. Their observation was not surprising given the ubiquity and persistence of microbes within the built environment. Further, they showed that of the high touch/high risk objects evaluated the one item that was significantly impacted by the augmentation with copper was the rail of the patient bed. The rails are contained within the patient care ribbon and it is hypothesized that should a high touch/high risk object be resident within the care ribbon it would benefit from an antimicrobial surface augmentation (Fig. 13.1). The other risks being funneled into the room also play a role. Earlier, Attaway and colleagues described that commonly touched surfaces encountered by patients, healthcare workers, and visitors could serve as reservoirs potentially transferring microbes among each other [9]. Their quantitative approach provided a

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Fig. 13.1  HAI acquisition can result from microbial encounters between the patient and healthcare team members, visitors the environment. The patient care ribbon, ~22 m2, represents the largest area and most likely location for the patient, care team, and visitors to facilitate transfer of microbial risk funneled into the care setting, with the en-suite bathroom, ~4.5 m2, serving as 2 degrees area where HAI risk may persist should routine and terminal cleaning fail to minimize the risk through controlling the concentration of microbes resident in this area. The team member workstation area in the room, ~2 m2 represents a new risk area given the increased use of electronic health records and the presence of fomites, e.g., keyboards, trackpads/mice, laptops, mobile phones, phones, tablets, or workstations on wheels, in this area.

p­ erspective that the intrinsic bacterial burden associated with bed rails in medical intensive care units (MICU) is omnipresent, even in spite of the routine and proper use of EPA registered disinfectants. While they showed that disinfectants were successful in their ability to de-bulk the hospital surfaces of microbes, they alarmingly observed that the risk from the microbial burden returned quickly. The bacterial concentrations in patient occupied beds rebounded to 30% of concentrations found prior to cleaning within 6.5 h subsequent to disinfection [9]. While the label claims of registered disinfectants generally stipulate a 4 log10 reduction to the resident microbial burden, the label claims report results from tests conducted in vitro using a protocol validated by the Association of Official Agricultural Chemists (AOAC) test methods, under Good Laboratory Practices (GLP) in the presence of 400 ppm hard water, 10% serum load, and 10 min of contact time on hard nonporous inanimate surfaces under defined conditions [10]. Thus, it is not surprising that the microbial burden rebounded given that within each microbial community, a subset of the population exists as persister cells—dormant variants of microbes present in any microbial community that stochastically form—that are highly tolerant or refractory to antibiotics, disinfectants, and oxidative insults [11].

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To date, multiple protocols or infection control bundles, “bundles,” have been developed that have shown infection control risk mitigation strategies integrating hand hygiene with room cleaning can be effective, but there are few bundles that have been successful in their ability to consistently minimize the microbial burden found in the environment. The standard concentration of aerobic colony forming units on surfaces commonly accepted as benign during patient care is considered to be fewer than a range between 2.50 and 5.0 CFU/cm2 [12–14]. When associated microbial burden on objects exceeds this level it is likely that transmission within care settings, among patients and care team members, will occur at higher rates thereby increasing the risk of HAI acquisition. For the past 50 years CDC guidelines for Disinfection and Sterilization of Healthcare Facilities (for the most recent see Ref. [15]) have attempted to impact HAI acquisition rates through a uniform risk mitigation strategy. These guidelines are based on a disinfection strategy devised by Spaulding [16] that sought to minimize the acquisition of infectious agents by prioritizing the predicted degree of risk involved in the use of inanimate objects. Items classified as critical including items that enter sterile tissue (surgical instruments); semicritical including items that come into contact with mucous membranes or nonintact skin (endoscopes); with noncritical items including items that only come in contact with skin [16–18]. An increasing body of evidence suggests that enhanced cleaning/disinfection of environmental surfaces can reduce contamination of HCWs reducing the transmission of hospital pathogens [19]. However, numerous reports indicate that a high percentage of environmental surfaces are not cleaned well during terminal cleaning [20–22]. When objects from hospital rooms were cultured, 94% of those from rooms housing VRE infected patients and 100% from those housing C. difficile patients were widely contaminated with the organisms, respectively [23].

13.3 Antimicrobial surfaces The development of antimicrobial surfaces and/or coatings offers an opportunity to address the risk to infection control associated with limitations to hand hygiene and lapses in environmental cleaning. Self-cleaning, self-disinfecting, and/or continuously antimicrobial surfaces have been developed, and deployed to a limited extent, over the last 50 years in order to serve as augments to existing practices for infection control. Self-disinfecting surfaces, originally proposed in 1964 by Kingston and Noble, were developed based on the hypothesis that self-disinfecting solutions afford a reduction to the spread of microbes responsible for the infectious diseases occurring in hospital as a consequence of death of the microbe upon its deposition to surfaces within the built environment [24]. All of the aforementioned self-disinfecting materials fall into two principal categories—those that are antiadhesive/antifouling and those that are antimicrobial either through an inhibition of microbial growth or actual killing of the microbes resident on the surface.

13.4 Antiadhesive surfaces Biofilms are a syntrophic association of microbes where cells adhere to each other and surfaces. They are ubiquitous in their distribution and are the dominant form of

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life on inanimate objects and surfaces [25]. This complex amalgamation consists of an aggregate of microbes, embedded within a community-generated matrix of extracellular polymeric substances (EPS), that facilitate adherence of the microbe to themselves, with other members of the community or simply the surfaces with which they are associated. However before undergoing the metabolic transformation from free floating or planktonic cells they must first attach to a surface, cell or each other. Materials that impede the attachment step of biofilm formation represent a method by which healthcare surfaces can be made to intrinsically harbor fewer microbes that in turn should lower the risk of HAI acquisition. Over the years a number of products have been developed possessing either an ability to limit attachment of microbes and/ or an enhanced the ability of the surface to shed microbes secondary to cleaning. Ideally, an antiadhesive surface should limit or repel nonspecific protein adsorption and/or primary bacterial adhesion. The initial step of biofilm formation results from living organisms, ranging in size from 0.5 to 2.0 μm, overcoming the surface repulsion force, described by the theory named for Boris Derjaguin and Lev Landau, Evert Verwey, and Theodor Overbee (DLVO). The DLVO theory takes into consideration the combined effect of van der Waals or distance-dependent interactions between the molecules/structures affiliated with the microbe with those from the surface and the double layer or electric double layer force, in essence, the surface charge, either positive or negative, and the ions attached to the surface charge via the Coulombic force, thereby electrically screening the first layer and generating surface repulsion. The DLVO theory was originally developed for colloidal interactions for surfaces but can be used to account for the initial interaction of how microbes attach to surfaces [26]. Given that it has been shown that the van der Waals attractive force is dominant, nearest to the surface, and that microbes cannot separate from surfaces by Brownian motion, adherence is the consequence. Conversely, as the microbe moves away from the surface, the Coulombic interaction becomes dominant, as distance quickly minimizes the contribution of the van der Waals force manifested by the inherent negative charge of the bacterium. One of the first materials to facilitate an antiadhesive property, capitalizing on an application of the principles manifest in the DLVO theory, was polyethylene glycol. These carboxyl-containing ethylene copolymers can display long-term antibacterial and antifungal properties as these materials were found to limit the growth of microbes on these surfaces, but were not able to kill bacteria [27]. Polyethylene terephthalate films, modified through the addition of polyethylene oxide, were found similarly to display resistance to bacterial adhesion. Here investigators learned that when evaluating three bacterial strains commonly associated with the built environment, and similarly associated with HAIs, Staphylococcus epidermidis, Staphylococcus aureus, and Pseudomonas aeruginosa, it was possible to demonstrate in  vitro, a significant reduction in the adherence of microbes to the polyethylene ­oxide-modified substrate compared to the untreated control polyethylene terephthalate [28]. They concluded that surface modifications using polyethylene oxide might offer an opportunity to reduce the risk of implant-associated infections. The investigators further learned that the presence of plasma fibrinogen was observed to play an important role in the adhesion of all three of microbes on both the polyethylene oxide-­modified and control polyethylene terephthalate materials [28], a finding that

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will likely complicate their wide spread use and/or adoption for use in the built environment where human proteins and sera are often coincidentally resident on surfaces. Similarly, Bridgett and colleagues learned adherence of three clinical isolates of S. epidermidis to model polystyrene surfaces was substantially reduced, by up to 97%, when using Pluronic surfactants conforming to an A-B-A block copolymer configuration [29]. Here the A component was polyethylene oxide and the B component was poly-propylene oxide. As a class Pluronic surfactants function as antifoaming agents, wetting agents dispersants, thickeners, or emulsifiers. Here the investigators attributed the effectiveness of Pluronic materials being able to limit adherence of microbes through sterically stabilizing the surface with the adsorbed polyethylene oxide chains conferring a nonspecific antiadhesive property to the polystyrene surfaces [29]. In yet another example, polyurethane was found amenable to modification in order to limit microbial attachment. In the built clinical environment polyurethane is found in cushioning material for upholstered furniture, mattresses, and carpet underlayments. Polyurethane surfaces can be modified with poly (ethylene glycol) (mol. wt. 1000, PEG1k), carrying a terminal hydroxyl, amino and sulfonate groups, and poly (ethylene glucol) (mol. wt. 3350, PEG3.4k) [30]. These modified surfaces were investigated for their ability to limit bacterial adhesion in vitro, using two common microbes shed from humans, S. epidermidis and Escherichia coli. When evaluated subsequent to the growth of the microbes in tryptic soy broth (TSB), brain heart infusion (BHI), or human plasma each of the PEG modified surfaces were able to significantly reduce bacterial adhesion. Adhesion efficiency was found to be dependent upon the surface evaluated or media in which the microbe was grown [30]. In the case of PEG1k surfaces, there was no reduction in the level of S. epidermidis adhesion observed when the microbe was grown in TSB, regardless of terminal functional groups of PEG1k. While adhesion of the microbes grown in human plasma was reduced to different degrees, it was found to be dependent upon the terminal groups associated with the PEG1k complex, with the least amount of adhesion being associated with those urethane surfaces coated using sulfonated variants of PEG [30]. Park and colleagues also learned that as the PEG surfaces increased in length (PEG3.4k and PEG3.4k with heparin) they were better able to minimize surface bacterial adhesion of microbes grown in either TSB or BHI. In the situations where adhesion of the Gram negative, E. coli was evaluated there were significant reductions in adherence regardless of the PEG modifications (PEG1k, PEG3.4k, and PEG-heparin surfaces) irrespective of the medium in which the microbe was grown [30]. In contrast, there was no reduction in bacterial adhesion observed when poly (propylene glycol) (PPG1k) was grafted onto polyurethane surfaces as compared to control polyurethane. These results were sufficiently encouraging to warrant the investigators' conclusion that such modifications to polyurethane with either, PEG1k-SO3, PEG3.4k, or PEG3.4k-heparin might offer opportunities to limit the establishment of biofilms on critical surfaces that are ubiquitously found in the built hospital environment [30]. However, to date a large-scale clinical evaluation of these materials for their ability to reduce the acquisition rate of HAIs from surfaces within the built clinical environment has yet to be adequately conducted.

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13.5 Nature inspired antifouling surfaces Not to be outperformed by chemists, Mother Nature, through natural selection, has engineered microbicidal surfaces that manifest their activity through a variety of mechanisms. Each of her naturally selected modifications function by either repelling or resisting the initial attachment of microbes by preventing attachment, as described above, or by inactivating the microbe as it comes in contact with the surface resulting in death of the microbe. The aforementioned antifouling surfaces function principally through either the principles attributed to the DLVO theory or by novel biogenesis of topological surfaces that facilitate the killing of the bacterium. One such surface resistant to microbial attack is the leaf surface from Nelumbo nucifera or lotus plant. The lotus leaf has a surface network that facilitates the removal of particulate matter by rainwater [31]. The surface of the leaf is comprised of one these special wettable surfaces whose function is to generate an interface phenomena between a liquid and the solid surface of the leaf such that the behavior of the liquid on the surface results in an alteration to the contact angle (θ), that results in the liquid to bead, rather than flow, across the surface [31]. As a consequence the rolling liquid droplets facilitate removal of foreign particles that are directly dependent on the hydrophobicity of the surface and the inherent surface roughness generated by the microstructures of the leaf. This phenomenon is known as superhydrophobicity and has been observed for other plant microstructures [31]. Such observations have not gone unnoticed by practitioners concerned with controlling the incidence of HAIs. Materials containing chemical and microstructural surface alterations have been shown to reduce microbial colonization from a broad range of microbes, serving to control bioadhesion [32–34]. One of these micropatterns when engineered and imprinted onto surfaces resembles the pattern naturally affiliated with the skin of sharks (Fig. 13.2).

Fig. 13.2  Micropatterned structures inspired by antifouling nature affiliated with shark skin denticles. (A) Electron micrograph of sharkskin denticles; (B) electron micrograph of engineered imprinted surfaces that act biomimetically to resist microbial attachment. Electron micrographs courtesy of Sharklet Technologies/Peaceful Union http://www.sharklet. com/our-technology/what-is-biomimicry/.

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The Sharklet AF design consists of 2 μm rectangular ribs of varying lengths (4–16 μm) that when designed into a diamond like array, using fixed spacing of 2 μm between each row [35–38], can limit the attachment of microbes. One such designed surface was imprinted onto a poly (dimethylsiloxane) elastomer (PDMSE) with an intent to disrupt the formation of bacterial biofilms [36]. The primary material, Dow Corning Silastic T-2, selected as this silicone elastomer is used widely in numerous medical devices including tubing, catheters, and pacemaker leads. Here the smooth surface when imprinted using this sharklet micropattern was assessed for its ability to limit the formation of a biofilm of S. aureus over the course of 21 days [36]. Here they learned that early-stage biofilm colonies were able to establish themselves on the control surfaces by the 7th day, with mature biofilms being evident on control surfaces by day 14. The topographically engineered surface fared much better with only early biofilm colonization arising at approximately day 21 [36]. The investigators were encouraged to conclude that surface modifications using engineered topography mimicking the skin of sharks may offer an effective modification for indwelling medical devices and materials exposed to sterile surfaces that could mitigate and limit the formation of biofilms [36]. In the ensuing years SharkletAF—micropatterned surfaces have been shown to reduce bacterial colonization and biofilm formation, in vitro, suggesting an opportunity for this structural design to be able to limit the colonization of critical surfaces prone to biofilm development. One such application tested evaluated the effect that micropatterned surfaces imprinted onto endotracheal tubes had on the establishment of biofilms by five most significant pathogens associated with endotracheal tube-­ related pneumonia [39]. The pathogens, methicillin-resistant Staphylococcus aureus (MRSA), P. aeruginosa, Klebsiella pneumonia, Acinetobacter baumannii, and E. coli, were each evaluated for their attachment to the Sharklet-micropatterned or unpatterned control silicone surfaces where it was learned that the micropatterned surfaces were found to have limited microbial colonization on this critical clinical surface by a broad range of Gram-negative and Gram-positive pathogens. Moreover, the data presented provided a convincing argument that when micropatterned surfaces were evaluated using clinically simulated conditions, using an especially virulent and recalcitrant pathogen, P. aeruginosa, the Sharklet silicone surfaces were able to offer a 58% reduction (P < 0.01) in biofilm formation when contrasted against unpatterned controls [39]. In a subsequent in vitro study the same group evaluated micropatterned thermoplastic polyurethane surfaces incorporated into central venous catheters that were preconditioned with blood proteins [40]. Here they learned that upon subject to an in vitro bacterial challenge for 1 or 18 h the blood and serum conditioned micropatterned surfaces were found to be colonized by 70% fewer colonies of S. aureus (P ≤ 0.05) and 71% fewer S. epidermidis (P < 0.01) than similarly prepared and preconditioned unpatterned controls [40]. Moreover, platelet adhesion and fibrin sheath formation were also significantly reduced by 86% and 80% (P < 0.05), respectively, when evaluated using the micropatterned central venous catheters as compared to the unpatterned controls [40] offering promise that such surfaces may warrant further in situ clinical evaluation.

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Kim and colleagues also found when investigating the adherence of a nontuberculosis species of mycobacteria, Mycobacterium abscessus, ubiquitous in nature and known for its ability to form recalcitrant biofilms, that micropatterned silicone surfaces fabricated in the biomimetic style resembling shark skin were able to limit the number of viable microbes recovered from these textured surfaces [41]. As with the other studies mentioned it is uncertain as to whether or not these micropatterned surfaces will behave similarly in situ resulting in a reduction in colonizations or infections. In another study employing these engineered topographical micropatterns to limit the concentration of bacteria resident on surfaces likely to be encountered on objects resident in the built environment, the shark-like micropatterns imprinted onto acrylic films and assessed for their ability to control bacterial surface contamination were found to consistently limit the extent of microbial attachment, transference, and survival in experimentally designed “real-world” method of introducing bacteria to the surfaces [42]. In an investigation conducted using a simulation suite, by a team of physician volunteers, during care of a mannequin patient through an emergent cardiac event, investigators assessed whether or not Sharklet micropatterned surfaces would be less prone to transfer microbes from objects in the built environment to the patient and vice versa [43]. Prior to scenario initiation, a defined inoculum of S. aureus was introduced onto the leg of the mannequin as well as onto micropatterned and unpatterned surface films freshly placed onto the code cart, cardiac defibrillator shock button, and epinephrine medication vial, locations all likely to be touched during the running of the code. Six physicians interacted with the mannequin patient using micropatterned surfaces and five physicians interacted with unpatterned surfaces during the conduct of 11 identical scenarios. The microbial concentration transferred from the first contact location, inoculum placed over the femoral pulse of the mannequin, to subsequent unpatterned or micropatterned surface test locations. As anticipated the micropatterned surfaces were found to transfer fewer microbes from micropatterned surfaces than from unpatterned facsimile objects with log reductions of 0.64 being observed for the code cart (P = 0.146), 1.14 for the cardiac defibrillator button (P = 0.023), and 0.58 (P = 0.083) for the epinephrine medication vial [43]. The reductions achieved when using micropatterned surfaces were consistently greater than the reductions observed using unpatterned surfaces, substantiating results observed in vitro for micropatterned-­dependent reductions for microorganism transfer. The investigators went further here in this study and showed through principal component analysis that reduction witnessed for the code cart and the cardiac defibrillator button highly covaried. Thus, they calculated a single mean log reduction from these two locations for each surface type learning that 5.4 times more bacteria attached to the unpatterned surfaces compared to the micropatterned surfaces (P = 0.058). The results with this simulated clinical scenario involving healthcare practitioners and surfaces routinely encountered in the built clinical environment suggest that micropatterned surfaces were able to limit the transfer of bacterial based on the larger reductions observed for the textured surfaces compared to control surfaces. Further investigation in hospital rooms where patients are receiving care will ultimately reveal the capability of micropatterned surfaces to minimize the incidence of HAIs [43]. In the years since the publication of this simulated trial we have yet to see a clinical trial using this material.

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13.6 Nature inspired antibacterial surfaces Insects and plants have evolved more elaborate nanostructures that result in microbicidal consequences secondary to the physical contact of the microbe with the nanostructures [44]. In one such instance the wing of the Clanger cicada, Psaltoda claripennis, provides the first example of a new class of biomaterials that kill bacteria as a consequence of an encounter with a surface, here, the wing of an insect, rather than limiting attachment of microbes through the presence of previously discussed superhydrophobic/self-cleaning surfaces [45]. Ivanova and colleagues observed that the wings of this insect were able to easily support adherence of the ubiquitous Gram negative, microbe P. aeruginosa but once attached to the wing it was found to efficiently kill the bacterium [46]. This property of cicada wings being able to efficiently kill bacteria was confirmed for other Gram-negative microbes such as Branhamella catarrhalis, E. coli, and P. fluorescens, while the bactericidal activity of the wing was found not to kill the Gram positive microbes Bacillus subtilis, Pseudococcus maritimus, or S. aureus. The biophysical model proposed for the bactericidal activity requires that subsequent to adsorption of the bacterial cell membrane onto the cicada wing, the pattern within the wing may introduce a significant alteration to the structure of the membrane of the microbe. Pogodin found that for Gram-negative microbes, as the bacterium was adsorbed onto the nanopillar support structures embedded into the structure of the wing surface, the cell membrane between the regions suspended between the nanopillar structures was stretched [45]. The ultimate consequence resulting from the stretching was loss of integrity of the membrane with subsequent death of the microbe [45]. Given the structural stability manifest by the intrinsic multilayered cross-linked peptidoglycan present in Gram-positive microbes this class of microbe has a greater level of structural rigidity/integrity conferring a natural resistance to the membrane stretching effect manifest by the nanopillars than do Gram-negative cells [45]. One way to easily imagine the challenge that the microbial cell faces when it encounters the wing of the cicada is akin to the microbial cell alighting on a bed of nano-nails. The vertical nanopillars serve to literally poke holes in the Gram-negative microbes, as the nano-nails are easily able to penetrate the bimolecular layer of peptidoglycan resulting in the collapse of the internal pressure vessel secondary to the loss of structural integrity of the outer and inner membranes of the microbe. In recent work Linklater and colleagues investigated high aspect ratio nanotubes in order to characterize the particular mechanism contributing to efficiency of the bactericidal activity inherent to these structures [47]. During the conduct of their study they discovered another class of mechano-bactericidal surfaces—vertically aligned carbon nanotubes (VACNTs), previously referred here as “nano-nails.” VACNTs possess exceptionally high aspect ratios (100−3000) and through their extreme flexibility were found to have enhanced elastic energy stored in the resident carbon nanotube. As the VACNTs come in contact with bacteria and bend, they release elastically stored mechanical energy that is substantially responsible for the physical rupture of both Grampositive and Gram-negative bacteria [47]. As the length of the VACNTs increase so does the effectiveness with which the VACNTs are able to kill bacteria. The highest

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rates of bactericidal activity were observed when P. aeruginosa (99.3%) and S. aureus (84.9%) encountered length modified VACNTs. This work provided insight into how best to identify optimal substratum properties resident in VACNTs to kill different types of bacteria more efficiently [47]. Most encouraging was their observation that the activity of high aspect ratio nano-features were able to outperform natural bactericidal surfaces or other synthetic nanostructured multifunctional surfaces. Their system also exhibited the highest bactericidal activity of carbon nanotube-based substratum against a Gram-negative bacterium reported to date [47]. By virtue of the near 100% bacterial inactivation employing VACNT-based substrata within the materials, they were encouraged that as these structures are incorporated into medical devices and surfaces deployed into the built clinical environment, that it might be possible to substantially reduce the risk of HAIs. In summary the antibiofilm or antifouling activities associated with artificial and/ or naturally inspired antibacterial surfaces capitalizes on their surface chemistry and/ or their surface structures, and in concert with the intrinsic topography of the materials serve to substantially lower the risk of HAIs. It is unfortunate that the technology has yet to find wide scale adoption into materials used to fabricate items resident in the built environment and medical devices. Should the activity of the chemically and structurally modified surfaces continue to demonstrate utility in limiting biofilm development on high value materials like catheters and endotracheal tubes it is likely that they will find their place as a specified component in standard of care bundles used to mitigate the risk of HAIs acquisition.

13.7 Antimicrobial coatings The use of antimicrobial coatings has been heavily investigated for the past 50 years. There have been a variety of materials tested from organic dyes to precious metals. In the remaining sections of this chapter we will discuss the relevant studies that delineate how these materials have been evaluated, relevant in vitro findings and clinical applications that have validated their use case.

13.8 Antimicrobial coatings—Triclosan The first antimicrobial coating seeing wide spread introduction into clinical use was triclosan. This chemical has been widely used for almost 50 years with its incorporation into clinical and consumer products, from cosmetics and soaps to structural plastics [48]. Triclosan, a trichlorinated diphenyl ether, with one hydroxyl group, has bacteriostatic, fungistatic, and antiviral activity (Fig. 13.3) [49]. Its broad-spectrum antimicrobial activities act through its interaction and concentration within the lipids of membranes through rapid fluctuating bond rotations that in turn serve to disrupt membrane activity and function without disrupting structural integrity as evidenced from an absence of initial cell leakage [50]. A mechanism

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OH O

Cl

Cl

Fig. 13.3  Structure of the antimicrobial compound triclosan drawn as a planar structure with absent ether oxygen bond rotation; molecular weight, 289.5.

a­ ccounting for its antimicrobial activity anticipates that its action results from an accumulative effect of triclosan limiting the bacterium’s ability to effectively divide [51, 52]. This supposition is indirectly supported by its limited activity against stationary phase bacteria [53]. As triclosan continues to concentrate in the membrane, it affects leakage and collapse of the membrane potential, ultimately leading to cell death [54, 55]. This multifactor mechanism is especially effective in that subsequent to collapse of the membrane potential a rapid accumulation of free radicals, principally reactive oxygen species (ROS) (e.g., O2−, H2O2) are generated resulting in coincident cytoplasmic oxidation of proteins and lipids, with concomitant destruction of the nucleic acids of the cell. Like the recent finding with microbes developing an enhanced tolerance to ethanol [6], individuals have been concerned with microbes becoming increasingly resistant to higher and higher concentrations of triclosan [56]. One study in 2003 reported an isolate of P. aeruginosa that displayed an uncommonly high tolerance to the molecule with it being able to survive in the presence of triclosan concentrations in excess of 1000 μg/mL; solely attributable to the expression of efflux pumps [57]. More recently, a study evaluating isolates of S. epidermidis collected in the 1960s, prior to introduction of triclosan to the market, found that 34 of the 34 pretriclosan era isolates were sensitive to the chemical while 12.5% of the S. epidermidis isolates collected subsequent to triclosan were found to have tolerance toward triclosan (defined as MIC ≥ 0.25 mg/l). When sensitive isolates were subjected to the presence of triclosan, through successive passage and exposure, both the pre- and post era strains of S. epidermidis were found to adapt to the same MIC level of triclosan as observed in ­present-day tolerant isolates [56]. The mutations accumulated in resistant microbes have been mapped to genes that result in specific mutations that result in enzymatic modifications and active efflux of the triclosan from the cell. DNA sequence analysis of the S. epidermidis isolates characterized by Skovgaard and colleagues revealed that laboratory-adapted strains carried mutations in fabI gene encoding the enoyl-acyl carrier protein reductase isoform, FabI, that is the target of triclosan, with the expression of fabI also increased. Curiously, the majority of the current tolerant isolates of S. epidermidis lack mutations in fabI or its putative promoter region. Thus, Skovgaard and colleagues concluded that widespread use of this effective antimicrobial has resulted in resistance occurring by more than an adaption solely to FabI [56]. In 2003 Redmond and Griffith reported that a substantial proportion of foodborne illnesses are attributed to a lack of adherence to good hygienic practices in the home and food preparation areas [58]. The incorporation of triclosan into surface materials used for flooring in the food industry has been evaluated [59]. Here triclosan

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was incorporated into flooring material of a poultry processing plant. Sampling of the floor revealed tremendous bacterial diversity displaying a wide range of sensitivities of the bacteria recovered from the floor to triclosan; ranging from a MICs from 0.07 to greater than 40 ppm. Staphylococci were found to be the most sensitive to the agent, while two Gram-negative microbes, P. fluorescens and Serratia marcescens were found to be the most tolerant. Remarkably, the MICs for triclosan, for the isolates recovered from the floor, were similar to the MICs reported for control strains from the corresponding genera or species of from other locations. Thus, the microbes recovered from the floor were not selected out for being more tolerant to triclosan as they failed to display any greater tolerance to this agent than other microbes routinely encountered [59]. In the same study, under laboratory conditions, the investigators demonstrated that an ability of bacteria to survive under dry conditions on coupons of the augmented flooring was similar to that for stainless steel with the survival of the bacteria on the floor thus not being linked to their tolerance of triclosan, as determined by the MICs for triclosan [59]. Adherence studies were also conducted and found that while bacteria were able to adhere to coupons resident on the floor a thick biofilm failed to develop by day 3 of incubation [59]. Upon conducting an agar plate assay, the floor produced inhibition zones against staphylococci, which are known to be very sensitive to triclosan, while an inhibition zone was not observed for other bacteria tested [59]. They concluded that the antibacterial effect of the floor was likely very low and speculated that as a consequence of the concentration of triclosan being lower in the floor than other triclosan-incorporated surface materials or that the floor simply failed to deliver a sufficient concentration of the agent to limit and/or kill the microbes resident on the floor [59]. Cutting boards are recognized as one of the most likely sources responsible for the transfer of microbes from raw or undercooked foods to food intended for direct consumption [60, 61]. In order to avoid this a cross contamination study was conducted to assess the antibacterial activity of triclosan upon its incorporation into the structural matrix of cutting boards [62]. Unfortunately, no difference in bacterial counts was observed on cutting boards augmented with triclosan, as compared to equivalent unaugmented cutting boards subsequent to their 1 h exposure to naturally contaminated chicken filets. Similarly, under controlled laboratory conditions, where pathogenic and spoilage microbes were inoculated onto coupons of cutting board material augmented with triclosan, under conditions where the relative humidity was set to 100%, growth of E. coli, Salmonella, S. aureus, coagulase-negative staphylococci (CNS) and Serratia spp. were observed. However, the augmented cutting board material was found to be microbicidal for the cold-tolerant Gram-positive food-borne pathogen, Listeria monocytogenes. Under conditions of lower humidity (70% RH) less growth was observed on the triclosan augmented containing cutting board material than the untreated product after 24 h. After 72 h of incubation, the viable cell counts recovered were found to be reduced on triclosan-containing boards, with the most pronounced antibacterial effects observed against Salmonella, S. aureus and CNS. Repeated washing of the triclosan-containing cutting boards was found to reduced/limit the antibacterial effect leading the investigators to conclude that incorporating triclosan into

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cutting boards in order to augment hygiene practices maybe limited to certain conditions where low humidity, long exposure time, and clean surfaces are likely to be encountered [62]. Taken together, these two studies offer perspective on whether or not triclosan surfaces warrants an investment into components containing this agent for use in the built clinical environment. While the cutting board study showed that bacterial counts were greatly reduced subsequent to exposure to dry conditions, this was also the case for cutting boards without triclosan. Consequently simply allowing equipment and/or surfaces to dry after cleaning will likely reduce the probability of cross-contamination. In further support of this argument against investing in surfaces containing triclosan for use in healthcare applications, one needs to consider the issues associated with the study incorporating triclosan into flooring materials. While the triclosan containing flooring did not select our hyperresistant strains its limited effectiveness suggested that dry conditions augmented with rigorous adherence to the prescribed bundled cleaning schedule may better serve to lower the contamination risk manifest by the microbial burden resident in the built clinical environment. Today, triclosan is found in solid surfaces used for many of the flat surfaces found in many US hospitals. It is marketed under a US-EPA treated article exemption claim, a subsection in the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA) of 1910, US public law 61-152 36 Stat 331, which requires the registration of any substance intended to prevent, destroy, repel, or mitigate pests. Bacteria, viruses, and fungi are considered pests and as such any product intended to prevent, destroy, repel, or mitigate their concentration is considered a pesticide. The treated article exemption allows a claim by the manufacturer to state that an article or a substance treated with/ or containing a pesticide is there to protect the article or substance itself (e.g., paint treated with a pesticide to protect the paint coating, or wood products treated to protect the wood against insects or fungus infestation), if the pesticide is registered for such use. Consequently, the use of triclosan in the built environment carries no public health claim but rather only the claim that microbes that may be found on its surface will simply not harm or alter the product that has incorporated the pesticide. It can offer no claim that agent can serve to control the concentration of microbes resident on the augmented surface. That is not to say the augmented surfaces don’t have an antimicrobial activity, it simply means that the manufacturer cannot claim the surfaces provide disinfection.

13.9 Antimicrobial coatings—Utility of bacteriophages Bacteriophages are a class of virus that solely infect bacteria, and often result in the death of the microbe through the reproduction of the phage. Their targeting is exquisitely precise, with little, to no, cross over between the phage and its intended host. Interestingly, they function abiologically, with their structures interacting with their receptors within the outer layer or structural elements of the microbe. Owing to their small, nanometer size, they can easily penetrate biofilms often being able to reach the most inaccessible locations within these complex communities. While the continuous

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contamination of surfaces and facilities by bacteria is one the main challenges facing healthcare in being able to lower the acquisition rate of HAIs, bacteriophages may offer an opportunity to address the challenges resulting from inefficiencies of cleaning and an absence of disinfectants being able to completely free surfaces of all resident microbes. In a number of fascinating studies bacteriophages have been evaluated for their ability to control the concentration of pathogens resident on food processing and/or preparation surfaces [63–67]. They are principally added to the surface or product resulting in the reduction of the microbes. In one such study a cocktail of bacteriophages, BEC8, specific against enterohemorrhagic variants of E. coli O157:H7, was evaluated for its ability to reduce the concentration of this Shiga toxin producing strain resident on hard surfaces [67]. Using two temperatures for the characterization of the effectiveness of the cocktail, 12°C and 37°C, E. coli O157:H7 dried onto sterile stainless steel coupons, ceramic tile chips, or high density polyethylene chips was virtually eliminated within 1 h of application of the cocktail at room temperature even when the concentration of this Shiga toxin producing pathogen was low [67]. Similarly, a phage specific to L. monocytogenes, Listex P100 (P100) was able to eliminate five serotypes of L. monocytogenes, a cold tolerant, foodborne pathogen from liquids, and the surface of dry cured ham [64]. Moreover, this particular phage cocktail carries an FDA label indication as being Generally Recognized as Safe (GRAS) at the concentrations used to free liquids and food surfaces of Listeria. Remarkably in the broth model used to evaluate the Listex-P100 they learned that when applying the phage at a concentration equal to or greater than 7 log plaque forming units (PFU/mL) it was possible to completely inhibit between 2 log CFU/ cm2 and 3 log CFU/cm2 of L. monocytogenes at 30°C [64]. Listeria is a pathogen that can grow a temperatures typically used for the refrigeration of fresh foods. Food preparation areas are often kept at low temperatures in order to impede the spoilage of food. To that end the cocktail was evaluated over a range of temperatures, 4°C, 10°C, and 20°C, where it was found that its efficiency at reducing the concentration of Listeria surprisingly occurred best at the lowest temperature tested, 4°C. For studies using dry-cured ham slices, the concentration of P100 found necessary to achieve a significant reduction in the concentration of L. monocytogenes associated with the food product ranged between 5 and 8 log PFU/cm2 [64]. The multiplicity of infection (MOI) was also tested over the range of temperatures. The size of the inoculum of phage required to completely eliminate 2 log L. monocytogenes/cm2 and achieve an absence of pathogen in 25 g product, the requirement according to USA food law was 8 log PFU/cm2 [64]. Lower MOIs were found to be insufficient in their ability to completely eradicate L. monocytogenes with an inoculum of approximately of 3.0 and 4.0 log CFU/cm2 using a P100 inoculum ranging from 1 to 7 log PFU/cm2 [64]. The phage cocktail remained stable on the food product tested, dry-cured ham slices, over a 14-day storage period, with only a marginal loss of active phage, 0.2 log PFU/ cm2 from their initial inoculum of approximately 8 log PFU/cm2 [64]. Finally, when evaluated against biofilms and planktonic variants of Listeria resident on machinery surfaces used to produce dry-cured ham production the cocktail was able to eliminate the pathogen from the production surfaces. Collectively, the results from this study

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offer encouragement that GRAS bacteriophage cocktails, like Listex P100, can be listericidal offering encouragement that if it is possible to eradicate pathogens from food production surfaces and foods, phages may be useful for reducing the concentration of pathogens on surfaces within clinical environments and potentially patients thereby offering an opportunity for better infection control. In the studies described, along with others (see Refs. [67–72]), phages have been found to be effective at rendering surfaces and products safe, but still require an active intervention in order to achieve activity. Moreover, their addition requires that temperature, environmental circumstances, and concentration of phages added to the object, surface, product, or individual to be freed of pathogen, must be present at an appropriate MOI. Failure to add the correct concentration of phage will result in breakthrough of the pathogen with an opportunity for the selection of a resistant community of bacteria. A logical outgrowth of the discontinuous application of phages to limit the concentration of bacteria on surfaces is the attachment of phage to surfaces in order to offer continuous production against fugitive deposition of bacteria onto the surfaces. An early example of this can be found in the incorporation of bacteriophages to absorbent pads that will likely be place directly onto food. In an in  vitro study conducted by Meireles and colleagues in 2015 [73] they showed that an adsorbent food pad used in chilled meat trays containing a cocktail of six bacteriophages was effective as a bio-control in a food preservation area [73]. As with the cocktail against Listeria, the investigators appreciated that higher phage concentrations were better able to limit the growth of bacteria owing to higher rates of infections facilitated by the higher MOIs. The phages were active throughout their 48-h evaluation period, given their exponential expansion secondary to the infection of contaminating bacteria. However, they caution that this solution is only an augmentation to the existing preservation methods used to manage the shelf life of foods. Once perfected phage impregnated pads might find use in clinical settings to limit the spread of bacteria.

13.10 Antimicrobial coatings—Silver surfaces Humans have used silver for well over 3000 years, having first learned how to separate it from lead. It has found uses in currency, jewelry, the handling of foods, and to treat infections. Early uses of silver as an antimicrobial agent came in the form of water disinfection and its storage. This practice still continues today with NASA using a more sophisticated variant of the one used by Alexander the Great in 335 BCE, to supply ionic silver to ensure the safety of potable water used in the different subsystems on the International Space Station [74]. Hippocrates, the father of the art of medicine (400 BCE), described its healing properties through treatment of ulcers and ability to alleviate the effects of other skin and soft tissue wounds [75]. In the ensuing years we have witnessed the use of silver compounds to treat a variety of illnesses, from wounds associated with burns and other skin and soft tissue infections, to bacterial conjunctivitis in newborns, secondary to the acquisition of STDs during transit through the birth canal of infected mothers [76].

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Common to all of the antimicrobial applications of silver has been the requirement to supply a steady microbicidal concentration of silver cations. A concentration of 15 μg/mL of ionic silver is capable of blocking the electron transport chain in bacteria that in turn inhibits the oxidation of a wide variety of carbon and energy substrates, such as glucose, glycerol, fumarate, succinate, d-lactate, l-lactate, and other endogenous reduced forms of organic carbon [77–79]. In the late 1960s it was discerned that when silver nitrate was combined with sulfonamide, the resulting product, silver sulfadiazine, was highly effective for limiting infectious complications in burn victims [80]. Today, silver sulfadiazine is the standard of care for burn wounds [81]. Should the area surrounding the burn have sufficient vascularity as much as 10% of silver sulfadiazine may be adsorbed by the patient [82, 83]. Absorption will result in the accumulation of silver in the blood to a concentration exceeding 300 mg/L [82–84]. The antimicrobial spectrum of silver cations is broad, killing both Gram-negative and Gram-positive bacteria through multiple mechanisms (Fig.  13.4). It acts first through disruption of proteins through its interaction with active thiol groups of proteins rendering them inactive. Those microbial cells that have an ability to overproduce

Fig. 13.4  Multimodal mechanism accounting for the antimicrobial properties of silver cations—silver cations (Ag+) are transported into the cytoplasm of the bacteria cell where they facilitate the collapse of the membrane potential of the cell through their inactivation of proteins within the cytoplasm, membrane, periplasm and/or outer membrane in the case of Gram-negative microbes only, resulting in the rapid production of free radical oxygen molecules which in turn serve to further damage cell structures and limit other essential metabolic activities. Adapted from Naik K, Kowshik M. The silver lining: towards the responsible and limited usage of silver. J Appl Microbiol 2017;123(5):1068–87. Epub 2017/06/27. https://doi. org/10.1111/jam.13525. 28650591.

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glutathione, or proteins with large amounts of reduced cysteine, can circumvent the microbicidal activity as other sulfur compounds can serve as a “sink” for the incoming silver ions [79]. Acting coincident to its attack of essential thiol groups, another microbicidal property results from its contact and ultimate disruption of the microbial cell through lethal disruptions cytoplasmic membrane potential and cell wall. A third toxic action of ionic silver results from its interaction with the DNA. Here the silver ions interact with the nucleic acids of the cell by either attacking a nitrogen atom in guanine or, in the presence of ultraviolet light, force the formation of thymine dimers within the helix of DNA [79]. Finally, secondary to the collapse of the membrane potential of the cell, silver ions form silver-free radicals that, through the presence of their unpaired electrons, bind to glutamic acid and arginine within proteins resulting in the formation of organometallic complexes which through subsequent interaction with other proteins rich in cysteine lead to the death of the bacterial cell [79]. Owing to the multiple microbicidal properties inherent to physical nature of the silver cations, resistance is exceedingly uncommon. However, metallic silver, Ag0, in its unoxidized form, lacks any ability to inactivate or kill microbes [85]. Thus, in order for silver to able to control microbes and limit infections it must be continuously supplied in its ionized form where the cation is able to interact with essential structures of the cell prior to its irreversible interaction with oxygen, where it is rendered antimicrobially inert subsequent to the formation of the oxide. To that end silver cations have been incorporated into surfaces used in medicine and have recently seen an expansion into use in consumer markets with the intent to control the concentration of bacteria on commonly encountered objects and surfaces. The branded name of the silver ion product commonly in use is AgION, a silver zeolite technology. This novel material is able to supply active silver via a cleaver form of packaging that in turn facilitates its on-demand delivery mechanism. As its name implies silver and zinc ions are encased into a cuboid ceramic block of zeolite, a microporous aluminosilicate matrix, and as the complex encounters moisture, principally as sodium ions, often supplied by endogenous sources in the form of bodily secretions or moisture from ambient air, the sodium/potassium ions will displace the silver and zinc cations, via ion exchange of sodium for silver or zinc cations, whereupon the microbicidal metals can interact with the bacterium present on the AgION treated surface or fabric [86] (Fig. 13.5) or see YouTube video https://youtu.be/lT-a53Nlf34 or [86] discussing their work (https://youtu.be/qMiKaIrh6s4). Potter and colleagues were able to demonstrate, in a long-term, real-world evaluation of the AgION silver zeolite technology, that its antibacterial effectiveness was apparent for three years when applied to door handles resident on a college campus [86]. One caveat reported was bacteria were unexpectedly and consistently recovered from the silver-coated door handles suggesting that zeolite complex was either only effective against a portion of the microbes affiliated with the door handles or the microbes developed a tolerance to silver. An explanation accounting for the unexpected result may be discerned from an earlier study evaluating silver leaching technology [87]. Here, Michels and colleagues evaluated the in vitro activity of two silver zeolite formulations. In the first, the leachate was principally silver cations incorporated into the zeolite carrier system, as Potter described, and in the second, the leachate was

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Fig. 13.5  Microbicidal ion exchange facilitates the displacement of active forms of silver and zinc cations encased in zeolite. AgION displacement technology requires a sufficient concentration of sodium ions and moisture carrier to facilitate the microbicidal ion-exchange of a sufficient concentration (~100 μM) of zinc and silver cations encased in solid surfaces or coatings used to confer an antimicrobial property to the surface.

displaced silver ions embedded into an organic matrix. Both materials were adhered to stainless steel coupons and were tested under standard conditions employing the Japanese Industrial Standard, JIS Z 2801, a test routinely used to validate the antimicrobial properties of augmented antimicrobial surfaces and fabrics. They found that when using an inoculum of 2 × 107 CFU of methicillin resistant S. aureus (MRSA) the silver ion-containing materials exhibited >5 log reduction to the concentration of MRSA resident on silver coupons subsequent to 24 h of exposure under conditions where the relative humidity (RH) was >90% at 20°C or 35°C [87]. However, when using lower RH levels of 22% at temperatures of 20°C or 35°C, like those likely encountered in the built environment or a chance encounter by a human, the extent of killing observed on the coupons was significantly less with only <0.3 log reduction to the concentration of MRSA resident on the coupon [87]. Consequently, Potter and colleagues may not have been witnessing microbes that had become tolerant to silver exposure but rather the inefficiencies of this displacement/leaching system used to insure that a sufficient concentration of an active microbicidal form silver was continuously available on the surface in order to confer a substantial reduction to the microbial burden present on the augmented surface of the doorknob. This supposition is likely supported from data from Gerba and colleagues who evaluated the wide spectrum of activity of silver impregnated fabrics [88]. Fabrics, such as patient pajama, drapes, pillowcases, and bed sheets, are all potential reservoirs that can harbor substantial concentrations of pathogenic bacteria and viruses. In their study evaluating professional fabrics used in healthcare, in the form of lab coats and pillowcases treated with a silver cation delivery system, they found that the concentration of bacteria affiliated with the fabrics was effective in significantly reducing the concentration of a wide spectrum of ordinary and drug-resistant microorganisms, including Salmonella, MRSA, Cutibacterium acnes, a fungus, Trichophyton mentagrophytes, and the highly infectious, Norovirus. As a caveat, the coated fabrics were

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evaluated in vitro, at 37°C using agar plates where the humidity levels are >90% in that the plates are largely comprised of water. As articulated in their discussion, the efficacy of silver was highly dependent on its formulation and required a longer period of time in order to effect its microbicidal action than surface disinfectants such as chlorine-based bleaches [88]. Silver-based textiles for burn and wound dressings are effective in vitro in that a silver nylon fabric is able to a defeat a challenge of substantial concentrations (1.4 × 107 to 6.9 × 107 per 2 cm2) of three prominent nosocomial pathogens, P. aeruginosa, S. aureus, and Candida albicans [89]. Most interesting to this in  vitro study was the observation that the effectiveness of the fabric was found dependent on the distance of the augmented fabric from the microbe. For each increase in additional agar height of 2 mm, up to a total height of 8 mm, the effectiveness of the silver nylon fabric to limit the growth was decreased by a factor of 10 [89] suggesting that the active concentration of the silver cations was insufficient to inhibit growth. Each of these limitations has helped refine the medicinal use of silver with its applications being extended to medical devices, specifically into the surfaces of catheters, central venous lines, and endotracheal tubes. The form of silver used by these devices still relies on the displacement of silver cations by cations in proximity to surface of the device. Generally in vitro results were found to be superior to those seen in animal and human models [83, 90, 91]; however, chlorhexidine in concert with silver sulfadiazine resulted in a microbicidal synergism with the action manifested by the release of silver cations from the surface of central venous catheters enhancing the antimicrobial effect observed when used in combination with chlorhexidine resulting in an enhanced effect as seen in human clinical trials [92, 93]. An economic assessment remains to be conducted with the principal decision being that while a metaanalysis concluded that silver alloy catheters reduced the incidence of urinary tract infections by threefold the issue remains as to whether or not the use of silver augmented catheters warrants the extra per use cost of $5.30 [91]. In another silver-augmented surface trial, endotracheal tubes were employed in order to assess whether their use would lower the risk of ventilator-associated pneumonia (VAP), a significant source of HAIs. In both animal and human trials (clinicaltrials.gov Identifier: NCT00148642) silver cation delivery system resident on the surface of the endotracheal tubes displayed efficacy in limiting either attachment (animal trials) or infections [94, 95]. In total, the NASCENT Randomized Trial evaluated 2003 patients requiring endotracheal intubation in a multicenter study involving 54 centers with patients being randomized to either the silver or conventional endotracheal tubes. Patients receiving the silver-coated endotracheal tube were found to have a statistically significant reduction in the incidence of VAP and/or delayed time to VAP occurrence compared with those receiving a similar, uncoated endotracheal tube [94]. In 2015 a systematic review of the utility of silver-coated endotracheal tubes for preventing VAP in critically ill patients was published [96]. Three eligible randomized control trials were evaluated using a total of 2081 subjects. The authors concluded that while there was limited evidence, silver-coated endotracheal tubes were able reduce the risk of VAP acquisition, especially during the first 10 days of use [96].

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While clinical trials that used silver displacement technology, where silver augmented devices were directly in contact with patients are promising, to date the data concerning use of silver leaching technologies to facilitate the control of microbes in the built environment are limited. In 2015, Molling and colleagues conducted a comparative performance of a panel of commercially available antimicrobial coatings in Europe [97]. They concluded that silver coatings performed adequately. However, the standard that they used, ISO 22196:2011, requires that a defined inoculum of approximately 100,000 CFU/mL be applied to surfaces after which the samples are required to be covered with a plastic wrap and incubated for 24 h at 35°C and 90% humidity. Consequently, their results are likely subject to the same caveats as those reported by Michels and colleagues in 2009 [87] and indirectly confirmed by Potter and colleagues in 2015 [86]. In the United States, AgION products do not carry a public health claim under the US-EPA FIFRA statute but rather are marketed under a treated article exemption, where its presence in materials is to serve as preservative and bacteriostatic agent when incorporated into polymers, plastics, and latex products.

13.11 Light-activated antimicrobial surfaces An alternate approach for the continuous disinfection of surfaces is one where the augmented material will continuously generate reactive radical molecules/reactive oxygen species (ROSs) in the presence of visible light. Free radicals are indiscriminate in their ability to inactivate essential cell structures and molecules [98]. Presently there are two approaches that use light to activate coatings incorporated into coatings to reduce the concentration of microbes found resident on surfaces in the clinical environment. The first approach requires that the surfaces be augmented with a photosensitive material, either in the form of a reactive organic molecule, e.g., toluidine blue, rose bengal, or methylene blue (Fig. 13.6), or via coating with an inorganic material like titanium dioxide (TiO2), a semiconductor. Photosensitive chemicals render their microbicidal properties through their ability to transfer captured energy to oxygen species within the cytoplasm. Upon receiving a quantum packet of visible light (photons), the chemical agent is activated from its singlet ground state (S0), to an excited form where electrons within the molecule CI CI CI

H3C

N

H2N

S

CI– + CH3 N CH3

O

N

HO

O I

Toluidine blue O, C15H16CIN3S mw 305.83 g/mol

CI

O

I

I

N

S+

CI– N

OH I

Rose bengal, C20H4CI4I4O5 mw 973.67 g/mol

Methylene blue, C16H18CIN3S mw 319.85 g/mol

Fig. 13.6  Light-activated antimicrobial compounds. Two-dimensional chemical structures of three, light-activated organic compounds suitable for embedding within matrices amendable for the augmentation of clinical surfaces.

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spin achieving the *S1 state. The excited state of the molecule can either return to its ground state via a fluorescence emission or through additional steps where the captured photonic energy can be transferred resulting in the formation of singlet oxygen and other reactive radicals [99]. Photo-reactive chemicals embedded into a cellulose acetate matrix at concentrations of 25 μM, upon exposure to visible light, are able to generate sufficient free radicals to inactivate a number of clinically relevant microbes [100]. The energy required in order to activate the toluidine blue needs to be in the visible spectrum, between 400 and 700 nm, with an intensity striking the augmented surface at approximately 780 lux or 0.1142 milliwatts/centimeter2 ((mW/cm2) at 555 nm) [100]. Similarly, Decraene and colleagues were able to demonstrate in vitro microbicidal activities for rose bengal and toluidine blue against a number clinically relevant bacteria and the bacteriophage ϕX174, a surrogate for microbial movement within hospitals [101]. Their data sufficiently demonstrated the feasibility of using photosensitive chemicals to photo-inactivate microbes. They showed that the killing achieved was significant, with reduction rates observed being as high as 6.7 log10 being routinely observed when using light levels of ~3700 lux or 0.542 mW/cm2. The microbicidal properties of titanium dioxide (TiO2), an electrical semiconductor, first appreciated in 1985 by Matsunaga and colleagues has similarly shown great promise [102] with many examples following in the intervening years (e.g., [103– 108]). The highlight of this technology is that the TiO2 photo-catalysis will generate sufficient ROSs, in the form of hydroxyl radicals, at its surface secondary to the interactions of photo-excited TiO2 with adsorbed water, molecular oxygen, or from the oxide moiety resident within the catalyst spontaneously forming the oxy-radicals [103]. While the results have shown the tremendous in vitro microbicidal activity of surfaces augmented with TiO2 we have yet to see the effectiveness of the performance of these materials in a large-scale clinical application. The use of light as a microbicidal agent has generally been associated with light emitted in the ultraviolet spectrum. The microbicidal action is dependent on the dose of light received, measured as Joules per meter2 that in turn is a product of its intensity, measured as Watts per meter2 and exposure duration, measured in seconds (s) [109]. The most lethal variant of this photonic energy is referred to as UVC, light emitted between 100 and 260 nm [109]. Until recently light within the visible spectrum (400– 700 nm) was considered to have little to no microbicidal activity [110]. However, recently laboratory studies have demonstrated that light within the violet-blue range (400–425 nm), possesses microbicidal activities [111–116]. The microbicidal activity is attributed to the fact that lighted emitted at 405 nm, induces an oxygen dependent photo-excitation reaction within the microbes where porphoryins within the cell react with oxygen and other cytoplasmic constituents resulting in the formation of ROSs which in turn result in catastrophic damage to a number of essential cellular processes including energy generation and DNA replication [117]. Bache and colleagues conducted a number of clinical studies using a high-­intensity, narrow spectrum environmental decontamination system (HINS-light EDS) for its ability to continuously disinfect the burn unit in an inpatient and outpatient setting [118–120]. Principally their work demonstrated that a ceiling mounted, 405 nm HINS-light EDS device was able to reduce bacterial contamination of environmental

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s­ urfaces in burn units between 27% and 75%. There was a strong correlation between the number of microbes killed with exposure to light emitted at this spectrum and intensity. The irradiance level delivered to the surface within the unit of one study was relatively small (between 0.0023 and 0.231 mW/cm2) whereas the exposure time (in seconds) was greater over the several days of exposure [120]. As the concentration of ROS generated is a function of mW/cm2 or energy received by the bacterium over time, the irradiance, or mW/cm2 received at any one location was found to be less important than overall exposure. Consequently, one can envision the constant use of a HINS-light EDS where high rates of disinfection might be continuously maintained using low irradiance levels. Rutala and colleagues reported in 2018 that a similar system was able to kill epidemiologically important pathogens under in situ conditions. The HINS-light EDS was found to significantly reduce the concentration of vegetative bacteria and spores at during the course of their 72-h exposure period [121].

13.12 Antimicrobial coatings—Copper surfaces Over the course of the last 35 years an extensive body of peer-reviewed literature has developed concerning the utility of solid copper and its alloys containing greater than 60% copper by weight, with their ability to kill bacteria in the built clinical environment. The modern roots of this field can be traced to a study conducted by Phyllis Kuhn, who in 1983 assessed whether or not doorknobs in hospitals were a source of microbes responsible for nosocomial infections. Here she discovered that even when tarnished brass, an alloy typically comprised of 67% copper and 33% zinc, was bactericidal [122]. In contrast, similar stainless steel door hardware (an alloy comprised approximately of 76% iron, 18% chromium, and 8% nickel) failed to inhibit bacterial growth [122]. Taking her observation further to the built clinical environment, culture results from a stainless steel knob of a door between a burn unit and intensive care unit revealed a potentially serious intrinsic risk of the bacteria present on surfaces. Here the stainless steel doorknob harbored a multiresistant variant of S. epidermidis with an antibiotic susceptibility pattern identical to that found of a microbe recovered from the blood of a septic patient under care in the intensive care unit [122]. Disturbingly cultures collected from other patients in the ICU possessed the same antibiotic susceptibility profile as those recovered from the stainless doorknob [122]. While not directly evidentiary causal, the presence of equivalently identical microbes recovered from frequently touched surfaces and the blood of a septic patient well illustrate the substantial risk that the environment can represent for moving microbes between units and patients. Over the last 10 years, the ability of United States Environmental Protection Agency (US-EPA) registered copper to inhibit the growth of microbes has been well documented in a series of in vitro studies [87, 123–137]. Common to each study was the overwhelming ability of copper to kill microorganisms on a continuous basis. Based on the successes of multiple laboratory trials the infection control community has evaluated the effectiveness of whether or not the continuously active antimicrobial properties attributed to copper can affect a reduction first, to the intrinsic microbial burden associated with critical surfaces within the built environment, and

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then, by virtue of a lower microbial burden, translate into a lower acquisition rate for HAIs. Early clinical trials resulted in O’Gorman and Humphrey’s review of the literature concluding that while promising the potential that copper affords in controlling the concentration of bacteria in the environment requires additional studies in order to establish the clinical utility that its placement may offer to augment existing infection control practices [138]. In 2013, Salgado and colleagues made a seminal contribution to the literature in reporting that subsequent to the limited placement of six, highly touched surfaces in single patient rooms, within three intensive care units (ICUs) located at separate hospitals, it was possible to significantly reduce the incidence rate of HAIs acquired by patients receiving care (ICU) [7]. This paper, and the others leading to this observation [7, 139–144], served to address an earlier critique of Weber and Rutala concerning the general utility of antimicrobial copper surfaces as an effective infection control mediator in their broader commentary on the utility of self-­ disinfecting surfaces [145]. Collectively, key to the success of Salgado and colleagues, was an appreciation of the close linkage between the concentration of burden resident within the built environment and the rate of HAI acquisition [7], which was enhanced by the intrinsic and continuous antimicrobial activity of copper. Specifically, unlike programs for better compliance with infection control such as hand hygiene or barrier precautions, the antimicrobial activity of copper-surfaced objects is not dependent on additional training or supervision. The addition of copper to surfaces does neither require infection control or environmental services to alter existing cleaning practices nor add to the annual environmental cleaning costs in order for copper to provide its continuous antimicrobial activity. Additionally reductions to the bacterial burden manifested by the copper objects observed during active patient care routinely approached the reduction level of 99.9% observed for in vitro tests conducted for registration of copper-based surfaces with the US-EPA [143, 146–148]. As Weber and Rutala noted it is not practical to completely “copperize” the built hospital environment [145]. However, targeted “copperization” of the patient care environment has been successfully used to mitigate the burden in each patient room on high-touch/high-risk surfaces [143, 146, 148]. In fact the work from Hinsa-Leasure and colleagues equivocally demonstrated that high-touch/high-risk surfaces fabricated using copper alloys harbored bacteria at significantly lower levels than control (stainless, wood, plastic) surfaces. This was true in both occupied and unoccupied rooms subsequent to terminal cleaning [146]. Further, the utility of limited “copperization” has been reported from a South African community healthcare facility where copper surfaces (desks, trolleys) were associated with a 71% reduction in microbial burden compared to standard surfaces, when sampled every 6 weeks, for a period of 6 months [149]. Also, a crossover study conducted in a 19-bed acute medical ward found that surfaces selected for “copperization” were associated with significantly decreased microbial burden compared to control surfaces when sampled weekly for 24  weeks with reductions ranging from −0.4 to −80.3 CFU/cm2 [150]. In an outpatient setting, a small trial was conducted in an infectious disease clinic where copper alloys were installed onto the arms, via an inlaid copper alloy strip, and the tray table affiliated with phlebotomy chairs [151]. The chairs served a number of

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different patients each day and were encountered by different healthcare workers over the course of the day. Over the 15-week trial period 437 different patients used the chairs. The total aerobic colony counts (ACC) recovered from the “copperized’ chairs were compared to the ACC recovered from equivalent control chairs. The copper trays associated with the copper phlebotomy chairs had an 88% mean reduction to the total ACC recovered, with the bacterial burden associated with inlaid copper strip being 90% lower than the equivalent wooden arms of the chairs. Surprisingly, the wood, adjacent to chair arms inlaid with the copper alloy, was found to have a 70% lower total ACC concentration than the equivalent area on the control chairs. This was attributed to a lower rate of transfer of bacterial burden from the central area of the chair arm facilitated by the continuous antimicrobial activity of the copper. The results of the clinical evaluation of copper surfaces within the built hospital environment confirm that healthcare staff, patients, and visitors routinely interact with surfaces that carry a substantial microbial burden [143, 146–152]. Collectively these quantitative data underscore the need to insure that cleaning is completed in an effective manner as bacterial concentrations resident on the common touch surfaces and objects sampled were each well above values recommended immediately after terminal cleaning [12, 13, 153–155]. The concentrations of bacteria found on individual objects were found to vary substantially and are likely reflective of the inherent dynamics of patient care, cleaning, and patient characteristics where bacteria move and/or shed onto and between objects and surfaces resulting in a constant challenge for their control. In studies monitoring environmental surfaces within hospitals frank pathogens (e.g., coliforms, MRSA or VRE) were routinely recovered from control surfaces/ objects while equivalent surfaces/objects enhanced with antimicrobial copper were found to have significantly fewer instances of recovery and/or concentrations of the same pathogens [7, 143, 149, 150]. In the study by Schmidt and colleagues, of the approximately 7000 control objects sampled, 169 or only 2.4% were found to harbor MRSA, while VRE was recovered from 239 objects at a rate of 3.4% [143]. During the copper-intervention phase, MRSA and VRE were recovered with far less frequency than from objects in rooms lacking copper surfaces. In considering the risk of acquiring one of these two pathogens from the environment, they found, on a per sample basis, that copper surfaces were approximately six times less likely to harbor one of these pathogens [143]. In considering the risk of a patient acquiring MRSA or VRE directly from highly touched surface over time Schmidt and colleagues summed the concentrations of MRSA and VRE recovered during their study [143]. Their intent was to illustrate the potential value that copper-surfaced objects might offer long term in mitigating the risk associated with the burden manifest by the presence of these two significant nosocomial pathogens. During their intervention period, the combined MRSA and VRE burdens were found to be 96.8% lower on copper surfaces than concentrations recovered from comparable plastic, wood, metal, and painted surfaces and were 98.8% lower on the bed rails, the object found to harbor the greatest concentration of microbes of the samples objects in the room [143]. Given their findings it is tempting to consider how copper surfaces might mitigate the risk from other environmentally acquired

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p­ athogens such as C. difficile, carbapenem-resistant Enterobacteriaceae (CRE), and other nosocomially significant pathogens resident in the built clinical environment. Further underscoring the risk represented by the intrinsic microbial burden associated with the built environment was the consistent observation that the patient bed is the largest reservoir of nosocomially relevant microbial burden [143, 146, 148]. Attaway and colleagues described that while cleaning and subsequent application of ­hospital-approved disinfectants were able to reduce the intrinsic bacterial burden on bed rail surfaces by up to 99%, the concentration of bacteria resident on the rails of occupied hospital beds recovered quickly to levels seen prior to cleaning and disinfection [9]. Hinsa-Leasure showed that once cleaned even unoccupied rooms accumulate burden with time [146]. These data suggested that in order to keep the bacterial burden below the risk-based threshold, for aerobic colony forming units of <2.5 CFU/cm2, occupied ICU beds will likely require cleaning at 4-h intervals resulting in substantial increases to workload for healthcare workers and environmental services. In 2013, they extended this observation by quantitatively assessing the intrinsic bacterial burden pre- and postcleaning in the setting of occupied beds with copper rails [142]. Here they evaluated the rails from 30 occupied beds in an ICU and learned, as before, that plastic rails prior to standard cleaning were significantly burdened at 61.0 CFU/cm2 and upon cleaning they were only able to reduce the mean bacterial burden by 82%. As before, within 6.5 h of cleaning, the bacterial burden rebounded to precleaning levels to 52.0 CFU/cm2 [142]. In contrast, the mean bacterial burden for copper augmented rails precleaning was approximately one log lower at 7 CFU/cm2 for patient occupied beds. Cleaning resulted in an additional 48% decrease to the mean bacterial burden, with only a minor rebound being observed by hour 6.5, where the mean concentration observed was 4.3 CFU/100 cm2 [142]. Collectively these observations lead them to conclude that while cleaning was effective, burden would quickly recover to the same level of risk prior to cleaning [142]. For all cases, copper was consistently able to maintain the bacterial burden at or near a concentration that represented a minimal risk to the patient [142, 143, 146, 148] suggesting that the intrinsic antimicrobial activity of copper might serve to continuously address the HAI risk attributed to the bacterial burden with minimal intervention. Given that bed rails were consistently found to be the most heavily burdened of the high-touch objects evaluated there is a pressing need to place copper on as many of the high-touch areas associated with the patient bed as economically possible [143, 146–148]. Recently a completely copperized bed has entered the commercial market (Fig.  13.7). Beds, from existing hospital inventory, can be modified by applying a US-EPA registered antimicrobial coating to all exposed surfaces [156]. Briefly, copper alloy particles were suspended into resin matrix at a concentration of 62.5% or 0.085 g/cm2 (LuminOre Copper Touch Antimicrobial Copper Alloy Surfaces), in order to achieve a final antimicrobial copper concentration of >60% and which was applied by a skilled applicator according to manufacturer’s recommendations [156]. Subsequent to curing the exposed copper surfaces, were polished in order to uniformly distribute a defined layer of copper metal at the surface. In 2017 a clinical evaluation of the modified beds was conducted at the Highpoint Health Hospital, Lawrenceville, IN [157]. Here it was found to have an equivalent level of activity to that reported in previous studies [143, 146–148].

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Fig. 13.7  Repurposed hospital bed coated with a US-EPA registered antimicrobial copper coating. Copper alloy particles were suspended into resin matrix in order to achieve a final copper concentration of >60%, or density of 0.085 g/cm2 of surface and applied according to manufacturer’s recommendations [156]. Subsequent to the application of copper to the surfaces the coated parts were polished in order to uniformly distribute a defined layer of copper metal to the surface of the augmented parts.

It is intuitive to argue that to minimize the HAI risk to a patient any method that can augment the effectiveness of hand hygiene and routine cleaning will likely translate into lower rates of hospital-associated infections and hospital-associated colonization by MRSA, VRE, and other potential pathogens like Extended Spectrum Beta Lactamase (ESBL) and/or New Delhi metallo-beta-lactamase-1 (NDM-1) producing Gram negative microbes. The demonstration that the antimicrobial activity of copper surfaces was continuous in its effectiveness should greatly enhance routine and ­terminal-cleaning practices required of hospitals with the likely consequence of reductions in colonization and healthcare-acquired infections. Independent of its ability to self-sanitize surfaces in the clinic, solid copper materials have been shown to limit horizontal gene transmission among bacteria [131]. Given the propensity for microbes to persist on touch surfaces for prolonged periods of time, the fact that copper surfaces can prevent plasmid-mediated horizontal transfer of β-lactamase genes between Gram-negative bacterium supports its enhanced value when used as an augmentation for manufactured surfaces and objects used for healthcare. This work was instrumental in elucidating the multiple cellular processes disrupted by copper. In their elucidation of how copper limited horizontal gene transfer, this group learned that exposure to solid metallic copper and its alloys resulted in the rapid uncoupling of the membrane potential of the cell, that resulted in the concomitant generation of free radicals within the cytoplasm along with coincident intracellular degradation of DNA [129–132]. This process commenced with

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the initial exposure of the microbe to the surface of the metal and was especially apparent on “dry” surfaces and likely accounts for its continuous antimicrobial action and broad spectrum of its activity against bacteria, viruses, and fungi.

13.13 Continuous microbial debulking of the environment mitigates HAI risk In addressing the clinical implications of antimicrobial copper surfaces Salgado and colleagues investigated whether the placement of copper-alloy surfaces/objects within the patient’s room in the ICU would reduce the risk of HAI and/or the incidence of a hospital associated colonization by either MRSA or VRE. In their intention to treat clinical trial they learned that the placement of copper alloys onto the six previously described high-touch/high-risk objects within the medical ICU reduced the risk of acquiring an HAI by more than half at the three sites in their trial [7]. The principal outcome revealed that the rate of HAI acquisition and/or MRSA or VRE colonization in patients treated in ICU rooms with copper-alloy surfaces was significantly lower compared to standard ICU rooms (0.071 versus 0.123, P = 0.020, 10.1 per 1000 patient days vs 18.0 per 1000 patient days) and that for HAI only, the rate was reduced from 0.081 to 0.034 (11.8 to 4.8 per 1000 patient days, P = 0.013). The reduction in number and rate HAI was thought to have resulted from the continuous antimicrobial effect of copper on environmental pathogens. These data argued that burden and infection are linked. In considering this question, their study demonstrated that patients in rooms with higher bacterial burdens on the six surveyed objects were significantly more likely to develop HAI than those in rooms with lower burdens, regardless of the presence or absence of copper (Fig. 13.8). Such an observation may be accounted by considering the possibility that persons with an active infection are more likely to shed bacteria captured by environmental sampling, but such an explanation does not fully explain the difference; the environment of patients with infections or colonizations showed an array of bacteria and which were not found to be coincident with the HAI or HAC [143]. Given the data of Salgado and colleagues and those more recently from von Dessauer [7, 158], we now appreciate that the intrinsic microbial burden is relevant in mitigating the acquisition rate of HAIs. Taken in context with other surface debulking interventions mentioned here in this chapter, as well as other antimicrobial interventions referenced in this volume, it is appropriate to conclude that any strategy that applies a comprehensive approach to continuously debulk the environment of bacteria, fungi, and viruses—the intrinsic microbial burden—will likely have significant and far-reaching implications in lowering the HAIs acquisition risk and may help address the significantly greater problem of nosocomial spread of drug and multidrug-resistant microbes plaguing healthcare. Overall, the technologies and strategies referenced here address how to control microbes through attacking fundamental cellular processes. The most successful interventions, copper and light, accomplish their mitigation through the continuous production of ROS. We appreciate that prevention bundles, hand-hygiene programs, and patient screening for pathogen carriage, with subsequent isolation, require engagement and reinforcement behaviors from care team members,

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Fig. 13.8  Concentration of microbes in a patients care setting is significantly associated with the risk of HAI acquisition. Quartile distribution of HAIs stratified by microbial burden affiliated with six frequently touched objects measured in an ICU room during the patient’s stay. There was a significant association between burden and HAI risk (P < 0.038), with 89% of HAIs occurring among patients cared for in a room where the cumulative microbial burden exceeded 500 aerobic colony-forming units (CFU/600 cm2). Adapted after Fig. 3, from Salgado CD, Sepkowitz KA, John JF, Cantey JR, Attaway HH, Freeman KD, Sharpe PA, Michels HT, Schmidt MG. Copper surfaces reduce the rate of healthcare-acquired infections in the intensive care unit. Infect Control Hosp Epidemiol. 2013;34(5):479–86. https://doi.org/10.1086/670207. PubMed PMID: 23571364.

environmental services staff, and leadership. Second, each of these solutions is not without an associated cost, especially important as healthcare is continuously looking for ways to control and limit costs. Therefore, a systems or multimodal approach that is designed to continuously decrease burden will likely be the one ultimately selected for use. It is unfortunate that we have not yet seen the combining of technologies referenced here in order to understand whether or not the solutions presented singly may synergize thereby having a greater effect on lowering HAIs rates. Of the technologies described here, copper incorporated into high-touch/high-risk clinical surfaces in hospitals when used in concert with 405 nm HINS-light EDS may offer the most effective approach to mitigate burden and HAI acquisition when used in combination.

13.14 Perspectives—A role for antimicrobial surfaces in hospitals to reduce hospital-acquired infections The centuries old observations from the pioneers of infection control, Semmelweis, Holmes, Nightingale, and Lister, are still true today. If we are to be successful in our

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battle against HAIs we need to continuously limit the transfer of microbes from the hands of healthcare workers and those resident in environment in order to improve care through lowering the risk intrinsic associated with a microbial encounter. Any infection control strategy worthy of this challenge must take advantage of new surfaces to continuously mitigate this risk manifest by the intrinsic environmental microbial burden. Only through multicenter and multimodal trials will we know which solution combination is best. Given that copper surfaces in concert with established infection guidelines significantly lowered the acquisition of infections in high-risk units (HAI rates ≥8%) by over 50% we next need to determine how this remarkable intervention will perform in, and secondly, assess the impact that such an intervention has on length of stay, readmission rates, and overall treatment costs. The scientific, economic, and practical knowledge gained through such studies will identify both feasible and cost-effective approaches for the prevention and management of HAIs that will lead to better health, better healthcare, and lower costs.

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Further reading [159] Naik K, Kowshik M. The silver lining: towards the responsible and limited usage of silver. J Appl Microbiol 2017;123(5):1068–87. Epub 2017/06/27. https://doi.org/10.1111/ jam.13525, 28650591.