Use of Silver in the Prevention and Treatment of Infections: Silver Review

Abstract

Background

The use of silver for the treatment of various maladies or to prevent the transmission of infection dates back to at least 4000 b.c.e. Medical applications are documented in the literature throughout the 17th and 18th centuries. The bactericidal activity of silver is well established. Silver nitrate was used topically throughout the 1800s for the treatment of burns, ulcerations, and infected wounds, and although its use declined after World War II and the advent of antibiotics, Fox revitalized its use in the form of silver sulfadiazine in 1968.

Method

Review of the pertinent English-language literature.

Results

Since Fox's work, the use of topical silver to reduce bacterial burden and promote healing has been investigated in the setting of chronic wounds and ulcers, post-operative incision dressings, blood and urinary catheter designs, endotracheal tubes, orthopedic devices, vascular prostheses, and the sewing ring of prosthetic heart valves. The beneficial effects of silver in reducing or preventing infection have been seen in the topical treatment of burns and chronic wounds and in its use as a coating for many medical devices. However, silver has been unsuccessful in certain applications, such as the Silzone heart valve. In other settings, such as orthopedic hardware coatings, its benefit remains unproved.

Conclusion

Silver remains a reasonable addition to the armamentarium against infection and has relatively few side effects. However, one should weigh the benefits of silver-containing products against the known side effects and the other options available for the intended purpose when selecting the most appropriate therapy.

Silver has been used for centuries in the treatment of various maladies or to prevent the transmission of infection [1–3]. It has been applied topically, by ingestion, and as a container for or deposit in liquids to decontaminate or preserve them [1,2]. Although its use fell out of favor with the advent of antibiotics, refrigeration, and pasteurization, silver has seen a rebirth as a component of various medical devices with the intention of reducing infection (Table 1). We review the literature pertaining to many of the modern medical uses of silver.

Table 1.

Summary of Silver Applications for Treatment of Infections

Modality	Pros	Cons	Cost effectiveness	Recommendation
Topical application for burns	• Several preparations available • Reduced infection rates • Prolonged silver ion release with some preparations • Potentially fewer dressing changes • Better wound healing and skin graft adherence	• Several preparations available • Concern about toxicity for host cells • Electrolyte leaching with silver nitrate	Favors use of prolonged-release silver, although no comparison of all products is available [53]	Difficult to compare wide variety of applications; recommended for initial/early decontamination of burn wounds
Topical application for ulcers	• Several preparations available • Potentially longer wear time for dressings • Reduction in wound size; less odor and exudate • Less pain	• Several preparations available • Potentially more frequent office visits and longer total duration of wound care • Several studies failed to show benefit in overall wound healing	Some studies favor use of silver-releasing foam dressing [55,60,62], whereas others show higher cost [59,61]	Current data do not support routine use of silver for this application
Surgical incisions	• Fewer surgical site infections in cardiac, colorectal, or lower extremity revascularizations • Shorter time to re-epithelialization of skin graft donor sites [69]	• Longer time to re-epithelialization of skin graft donor sites in one study [68] • Studies of silver-impregnated mesh or suture material are still in early phases	Cost comparison data not available	Current data do not support routine use of silver for this application
Blood stream infections	• Reduced catheter colonization and CR-BSI rates with CSS catheters (more so with second-generation catheters)	• Benefit may not be seen with low institutional baseline infection rates • Use of antibiotic-impregnated catheters may confer greater reduction of infections	Favors use of CSS and RM catheters in high-risk patients or with high baseline infection rates [96,97]	Recommended if elevated institutional CR-BSI rates despite a comprehensive control program
Urinary tract infections	• Reduced infection rates in some studies with use of silver-alloy catheters	• Studies are heterogeneous • Several large studies did not find benefit	Favors use of silver alloy catheters [109]	Recommended if baseline infection rates are high
Ventilator/ endotracheal tubes	• Lower incidence of VAP • Reduced mortality rate in patients with VAP	• Higher mortality rate in patients without VAP • Use of care bundles may negate contribution of silver-coated tubes	Favors use of silver-coated tubes [131]	Recommended if elevated institutional VAP rates despite a comprehensive control program
Orthopedic hardware	• Decreased bacterial adherence to silver-coated external fixation pins • Better cyto-compatibility • Fewer infections when combined with chlorhexidine for pin-site dressings • Lower infection rates with silver-coated implant devices	• Increased serum silver concentrations in one study • Early-phase studies only; need further investigation	Cost comparison data not available	Current data do not support routine use of silver for this application
Vascular prostheses	• Lowered rates of infection when used as primary prosthesis, although differing results have been reported	• Inconsistent data regarding risk of reinfection • May activate neutrophils and inhibit their antibacterial properties	Cost comparison data not available	Current data do not support routine use of silver for this application
Heart valves	• Low rates of recurrent endocarditis in early studies	• Higher rates of embolization • More moderate and severe paravalvular leaks • Substantial need for reoperation	No longer available	Not recommended

CR-BSI=catheter-related blood stream infection; CSS=chlorhexadine–silver sulfadiazine; RM=rifampicin–minocycline; VAP=ventilator-associated pneumonia.

History

The use of silver for the treatment or prevention of infection dates back to at least 4000 b.c.e. [1] and was well documented in the medical literature throughout the 17th and 18th centuries [2]. There are several treatises dedicated to the historical applications of silver [1–3]. Persian kings insisted on drinking only out of silver vessels, not because such cups denoted wealth but for their ability to preserve fresh water [1]. Silver nitrate was used topically throughout the 1800s for the treatment of ulcerations and infected wounds and to prevent gonococcal ophthalmic infections in newborns and was ingested for the treatment of stomach ulcers [1,2].

Other noteworthy medical applications of silver include wire or coated suture [1,4,5], topical therapy for osteo-cutaneous fistulae, and foil coverings for burn wounds [2]. For example, Sims used silver wire to close vesicovaginal fistulae in post-partum women when closure with silk sutures had failed [1,5]. Doctor Sims also advocated the use of silver urinary catheters during the recovery period. With the advent of antibiotics circa World War II, the use of silver for many of these functions declined, only to be revived in the 1960s by Moyer and Fox, as described below [reviewed in 3].

Mechanism of Action

Although silver and other metals have been known to have antimicrobial activity for some time [2], the mechanisms behind this bactericidal activity have been elucidated only recently. The term “oligodynamic action,” coined in the 1890s [6], refers to the toxic effect of metal ions on microorganisms and often has been used to describe the antimicrobial action of silver [6–8]. Silver was shown to complex with DNA in vitro using radio-labeled silver sulfadiazine (SSD), and both silver nitrate and SSD had the greatest degree of bacterial binding of all silver salts tested [7]. Additional studies have demonstrated that silver causes precipitation of DNA within bacteria [9,10]. Furthermore, the combination of sub-inhibitory concentrations of sodium sulfadiazine and SSD resulted in bacterial inhibition, suggesting a synergistic effect [7].

Silver also exerts bactericidal activity by binding strongly with membranes and cell wall proteins [6,9,11], likely because of its interaction with thiol groups on enzymes [11–13]. Although high concentrations of silver have been shown to interact with skin cells, the concentration required to alter cell respiration is 25 times that needed to halt growth of Pseudomonas aeruginosa [14]. However, silver cations complex with chloride in wound exudate, precipitating the metal and rendering it inactive against pathogens [14]. In order to overcome this effect, patients treated with silver nitrate or SSD require more frequent dressing changes for reapplication of the silver compound [15].

More recently, silver technology has focused on the use of nanoparticles (nanocrystalline silver) as an antimicrobial agent. Nanocrystalline silver releases sub-crystalline particles of uncharged metallic silver containing fewer than eight atoms [15]. These particles react less rapidly with chloride ions, allowing silver to be released from the carrier dressing for a longer period of time [15]. Free radicals produced from silver nanocrystals may perpetuate membrane damage [12,16–20].

Silver nanoparticles also permeate cells, interfering with bacterial respiratory chain enzymes [12,18,20] to inhibit energy production and growth. The bactericidal activity of silver is dependent on particle size; 10-nm particles exhibit complete interaction with the bacteria, whereas larger particles do not, suggesting that nanoparticles exert greater bactericidal effects [20]. Although the molecular mechanisms of the action of silver against bacteria continue to be investigated, it is clear that silver nanoparticles are powerful bactericidal agents.

Topical Application for Burns

Although topical silver historically was used on burns [1,2], it had fallen out of favor after the advent of antibiotics and was not widely considered again until the 1960s. Moyer published on the use of silver nitrate topical solution for burns, and Fox is credited with revitalizing its use in the form of SSD [2,21,22].

Gauze bandages soaked in silver nitrate solution and used to dress burn wounds were believed to reduce water loss from the burn surface as well as provide antimicrobial protection [23]. However, this technique required frequent attention, with reapplication of silver nitrate solution every two hours and dressing changes at least twice daily, and caused electrolyte imbalance secondary to the egress of electrolytes into the dressing in response to the hypotonicity of the silver nitrate solution [23]. This imbalance continues until wound epithelialization is complete and is treated initially by frequent monitoring and repletion of electrolytes and subsequently by routine dietary supplementation with less frequent monitoring [8,23,24]. If electrolyte depletion persists, an isotonic colloidal silver albuminate solution is recommended [8].

The novel combination of silver nitrate and sodium sulfadiazine to create SSD cream has hastened complete recovery in patients [22]. In addition, dressing changes are needed less frequently and electrolyte abnormalities are less likely with this formulation [22,25].

Silver sulfadiazine has been modified by co-compounding with other molecules. The addition of cerium was purported to increase activity against gram-negative bacteria, although several studies comparing the two compounds failed to demonstrate direct benefit [26–28]. One study showed a reduced time to re-epithelialization or grafting and overall shorter hospital stays in patients treated with the cerium–SSD combination [29]. Addition of 0.2% chlorhexadine to SSD decreased burn wound colonization, specifically with Staphylococcus aureus [30–32] and Enterococcus faeaclis [32,33], but did not lower the infection rate or improve overall healing significantly [30]. The addition of hyaluronic acid to SSD improved time to healing and reduced local edema [34,35].

In contrast to the uses of silver salts described above, more recent products utilize nanocrystalline silver particles incorporated into various dressing materials such as mesh, activated charcoal, hydrofibers or hydrocolloids, or polymer matrices [25]. These products are numerous and have been reviewed elsewhere [25,36–38]. Nanocrystalline silver releases small particles of silver over a long period of time, increasing the wound surface area in contact with the silver particles and the duration of that contact [38,39]. A systematic literature review showed a lower incidence of infection (p<0.0001) with nanocrystalline applications compared with either silver nitrate or SSD for the treatment of burn patients, as well as lower costs and decreased pain scores [40].

The use of silver-impregnated nylon cloths with an applied weak direct current results in electrochemical oxidation of the silver particles with periodic or sustained release of the ion [39,41]. This method increases silver penetration and is active against a wide variety of pathogens [39,41,42]. In infected burn animal models, the application of a current to a silver-coated nylon surface anode achieved greater survival than in animals treated without current, whereas both were superior to uncoated nylon either with or without applied current [43]. This method also improved survival following escherotomy of the infected wound at up to three days [44]. Additionally, use of silver nylon with applied direct current on either split-thickness or meshed composite skin grafts was associated with significantly less wound contraction, more rapid adherence and epithelialization, and increased hair follicle regeneration compared with silver nylon without current [45–47].

Studies comparing SSD with other forms of burn therapy have suggested that SSD may not be the best treatment. In a randomized trial, early surgical debridement and split-thickness skin grafting of indeterminate-thickness burns was associated with shorter hospital stays and lower costs, whereas patients treated with SSD had irregular burn scars and more late complications [48]. Burn wound coverage with other temporary biologics also has demonstrated faster and less painful healing [49–51]. Thus, although silver treatments may have a role in the management and decontamination of burn wounds, both the variety of dressing choices and the various other surgical options must be considered when selecting the appropriate treatment for each patient.

A cost-effectiveness analysis comparing SSD with a silver-containing soft silicone dressing found reduced costs for treatment and better treatment-related analgesia, less frequent dressing changes, shorter hospitalization, and reduced outpatient interventions with the silicone dressing compared with SSD [52]. Although the difference was not statistically significant, time to healing was shorter on average with the silicone dressing. A separate study comparing SSD/chlorhexidine with a nanocrystalline silver dressing found reduced infections and antibiotic use, shorter hospitalization time, and lower overall costs with the nanocrystalline preparation [53].

Topical Application for Ulcers

Following its resurgence for the treatment of burns, the ability of topical silver to reduce bacterial burden and promote healing of chronic wounds and ulcers was evaluated. The results of these studies differ widely, and a recurring theme in the relevant meta-analyses is the need for more rigorous trials before any conclusive statements can be made [54–58]. Because of the countless products available for the management of chronic wounds, both with and without silver, an in-depth review of each is beyond the scope of this review but can be found elsewhere [25,36,37]. The variety of products and the heterogeneity of studies evaluating them provide insufficient evidence that silver dressings are consistently superior to non-silver dressings for the treatment of chronic or infected ulcers, but there is some evidence supporting the use of silver-containing products for short-term wound care in specific patient populations. The major studies, systematic reviews, and meta-analyses are summarized below.

The VULCAN trial randomized patients with lower-extremity venous ulcers present for longer than six weeks to receive either a silver-releasing dressing or a non-adherent dressing. There was no significant difference between the groups in wound healing at 12 weeks, but the silver dressings were associated with much higher costs [59]. However, a comparison study found a silver-releasing foam dressing to be more cost-effective than other silver-containing products, including an ionic silver hydrofiber dressing and a silver-impregnated activated charcoal dressing [60]. Other concerns related to use of silver dressings are a greater frequency and number of visits and longer total duration of wound care, which may increase costs [61]. Additional studies have had differing results [57], but some suggest that silver dressings increase wear time and therefore improve cost-effectiveness [55,62].

In one systematic review, three trials comparing topical SSD with placebo or inert dressings failed to show superiority in ulcer healing with SSD [56]. The same review evaluated six studies of silver-impregnated dressings; only one trial demonstrated a positive result for the silver arm [63], and the meta-analysis showed no overall benefit [56].

A 2006 Cochrane review of three randomized trials for infected or contaminated ulcers found no difference in complete wound healing, but did see a greater reduction of ulcer size with silver foam compared with conventional therapy [54,62,63]. Other benefits of the silver dressings were seen with respect to odor reduction and decreased drainage [54]. Two other meta-analyses demonstrated a significant reduction in the size of chronic, non-healing or infected wounds, pain, odor, and exudates, as well as improvements in wound bed composition, wound edge maceration, and patient satisfaction with a silver dressing [55,57]. A more recent meta-analysis again supported the benefit of silver in providing greater reduction in wound size in the short term, but long-term results and data on complete healing are lacking [58].

Surgical Incisions

Silver dressings have been used on operative incisions. The use of a silver-impregnated dressing (with or without concomitant vacuum apparatus) in post-operative mediastinitis with continued positive cultures despite surgical debridement and antibiotic therapy showed conversion to negative cultures and ultimate wound closure with the silver dressing [64]. Another analysis compared mediastinitis rates after cardiac surgery when a silver dressing was used routinely and found a significant decrease in the incidence of infection compared with standard dressings, although the methodology of this study was less rigorous [65]. A randomized controlled study evaluated post-operative application of silver nylon dressings following colorectal surgery and found a significantly lower rate of surgical site infection in the silver-treated group [66]. A before-and-after cohort trial demonstrated similar significant results after lower-extremity vascular reconstruction [67].

In addition, silver dressings have been tested as donor site dressings following split-thickness skin grafting. One study found no differences in bacterial colonization of the wound, but noted that the silver nanocrystalline-impregnated dressings had a longer time to re-epithelialization than a hydrophilic occlusive polyurethane dressing [68]. However, another study showed decreased time to re-epithelialization and less pain associated with use of a silver-ionic hydrofiber dressing compared with a paraffin gauze dressing [69].

The application of a silver coating to the specialized foam used with the wound vacuum system has been shown in vitro to maintain those characteristics unique to the foam's specific structure, as well as to provide antibacterial activity against S. aureus and P. aeruginosa [70]. This technology may assist in preparing infected chronic venous stasis wounds for skin grafting, ultimately leading to better healing [71].

Other applications of silver for infection control in surgical procedures can be found throughout the literature. In vitro analysis of a nanocrystalline silver-coated polypropylene mesh suggested that the bactericidal actions are dose-dependent for the concentration of silver applied to the mesh, but that medium and high doses maintained a zone of bacterial inhibition around the mesh even in biological fluids and could prove beneficial for infection reduction in implantable devices [72].

Since the previously described use of silver wire as a suture material, the notion has been revisited, and several in vitro and in vivo animal studies are investigating the antibacterial properties and biocompatibility of silver-coated silk, nylon, and Vicryl (polyglactin 910; Ethicon, Somerville, NJ) sutures [73–75]. Pratten et al. [74] demonstrated decreased attachment of S. epidermidis to silver-doped bioactive glass-coated silk sutures compared with uncoated silk. Testing of these sutures is in the early phases, and how they will compare with commercially available triclosan-impregnated sutures is unclear.

Blood Stream Infections

Catheter-related blood stream infections (CR-BSI) remain a substantial concern for patients in intensive care units (ICUs), as such infections are associated with longer ICU and hospital stays, death, and higher cost [76–80]. Similar to what has been seen with ventilator care and the incidence of pneumonia, educational and behavioral campaigns can reduce these risks [81,82]. In addition, several variations of catheter design have been introduced, including silver alloy, silver iontophoretic, first- (external only) or second- (external and internal) generation chlorhexadine–silver sulfadiazine (CSS) catheters, and antibiotic-impregnated catheters [83–91].

In multiple studies, silver alloy-coated catheters did not confer a benefit over standard catheters [83,84], and silver iontophoretic catheters produced mixed results [85,86]. Several independent trials and meta-analyses have demonstrated reduced central venous catheter colonization and CR-BSI with the use of CSS rather than uncoated catheters [87–92]. One of the most cited meta-analyses showed a significant reduction in catheter colonization (odds ratio [OR] 0.44; 95% confidence interval [CI] 0.36, 0.54; p<0.001) as well as in CR-BSI (OR 0.56; 95% CI 0.37, 0.84; p=0.005) with CSS catheters [92]. When separated by catheter type, second-generation CSS catheters showed significantly less colonization and, although the difference was not statistically significant, lower CR-BSI rates than in patients having first-generation catheters [89].

Not all studies have shown the same benefit, however [93–95]. Implementation of behavioral and educational measures in one ICU decreased the CR-BSI rate. Subsequently, this group performed a before-and-after study of routine use of a CSS catheter and found it did not confer any additional benefit with regard to the rate of CR-BSI [93]. Additionally, although CSS catheters may reduce the rates of catheter colonization or CR-BSI compared with uncoated catheters, in studies that included rifampicin–minocycline (RM) catheters, the antibiotic-coated devices conferred even greater benefit [89–91].

Current recommendations are to use either a CSS or an RM-impregnated central venous catheter for patients expected to require a catheter for longer than five days if the institutional rate of CR-BSI is not decreasing despite a comprehensive infection-control program. This program should include education, appropriate site selection (avoiding the femoral vessels), maximum sterile barrier application during catheter insertion, and chlorhexidine skin preparation [81]. In the setting of high-risk patients or high baseline rates of CR-BSI, use of CSS catheters has been cost-effective [96]. Additionally, a decision-model analysis supported use of either CSS- or RM-coated catheters over uncoated catheters as more cost-effective, although the RM-coated catheters yielded greater cost savings [97].

Urinary Tract Infections

The first study investigating the incorporation of silver ions into a urinary catheter with the intention of reducing the risk of infection was done by Akiyama and Okamoto [98]. They demonstrated a lower incidence of bacteriuria in patients having the new catheter design rather than conventional catheters. Since then, several studies have examined this question, although they have differed in the silver application used (silver oxide vs. silver alloy), trial design (retrospective cohort, randomized, or block randomized), and outcomes [99–107].

Early large-scale trials evaluating silver oxide-coated catheters failed to show any benefit and even suggested they were associated with a higher rate of staphylococcal infections [104,107]. However, one study noted a significant benefit for women who received the silver oxide catheters [107]. A meta-analysis of eight clinical trials found an overall reduction in the risk of bacteriuria in patients receiving silver-coated urinary catheters (OR 0.59; 95% CI 0.42, 0.84) [108]. There was significant heterogeneity between these trials, and further evaluation showed that the benefit was obtained only with the silver alloy catheters (OR 0.24; CI 0.11, 0.52) and not silver oxide-coated catheters (OR 0.79; CI 0.56, 1.10). However, the trials using silver alloy catheters were completed at a single institution and therefore have been criticized by some authors [102,108]. Another single-institution study evaluating silver-alloy/hydrogel urinary catheters demonstrated a 57% risk reduction (p=0.002) in a two-year period compared with a similar period using uncoated catheters and found this reduction to be associated with significant cost savings [109].

Two subsequent large studies failed to demonstrate a protective effect of silver alloy catheters [102,105]. A 2008 Cochrane review reported no significant reduction in infection rates with silver oxide catheters but found a significant decrease in asymptomatic bacteriuria with silver alloy catheters when catheterization lasted either less than (RR 0.54; 95% CI 0.43, 0.67) or greater than one week (RR 0.64; 95% CI 0.51, 0.80) [110]. Silver oxide catheters are no longer available in the United States [108].

Additional methods employing silver to decrease the incidence of urinary tract infections include a catheter system with a device that releases silver ions into the collected urine [111] and application of silver sulfadiazine cream to the urethral meatus [112]. The silver-releasing collection device showed no significant decrease in infections, leading to the conclusion that silver should not be limited to the intraluminal system. Especially in women, it appears that perineal contamination tracking on the extraluminal surface of the catheter is the method of inoculation of the bladder, especially with gram-negative organisms [113]. In addition, the use of topical silver at the meatus did not decrease the incidence of infection [112].

Ventilator/Endotracheal Tubes

Ventilator-associated pneumonia (VAP) is the most common hospital-acquired infection [114] and is associated with substantial morbidity, many deaths, and high cost [115–117]. Several measures have been investigated with the goal of reducing the incidence of VAP. These include practice care bundles [118] and improvements in the design of endotracheal tubes to resist colonization, decrease accumulation of secretions, and reduce the transmission of secretions from above to below the cuff [119–123].

Early animal studies, laboratory investigations, and randomized trials of the effect of silver-coated endotracheal tubes on device colonization, airway colonization, and device safety and tolerability have shown positive results [124–127]. Intubation with a silver-coated tube for less than 24 h prevented biofilm formation and decreased intraluminal mucus accumulation but did not affect airway colonization compared with an uncoated tube [124]. Additional studies have reported lower bacterial burdens in lung parenchyma in a dog model [126], decreased airway colonization for as long as seven days [127], reduced transmission of bacteria to the lower airway following buccal inoculation [125], and less bacterial contamination of the tube after extubation [125,127] with the use of silver-coated tubes. The continued presence of silver on coated tubes has been shown for as long as three weeks, and coated tubes have demonstrated lower colonization rates for 19 of 21 bacterial strains tested [125]. However, although many of these studies assessed colonization, few correlated that event with VAP [127], and no explanation was offered for the greater adherence of two bacterial species to the silver-coated tubes than to uncoated tubes [128].

The NASCENT trial compared silver-coated and uncoated endotracheal tubes for patients expected to be intubated for greater than 24 h and observed rates of VAP of 4.8% in those patients who received a silver-coated tube compared with 7.5% in those receiving the uncoated tube (p=0.03). Patients with silver-coated tubes had a lower risk of VAP at any time and showed a delay in time to occurrence of VAP compared with the control group [121]. Retrospective cohort analysis of the NASCENT data showed fewer deaths in patients with VAP who had the silver tube, but in patients without a diagnosis of VAP, the mortality rate was significantly higher in the group having a silver tube [129]. The authors suggested that use of the silver tube in patients with VAP may have contributed to a lower overall bacterial burden and less multi-drug-resistant organisms ultimately causing pneumonia, a finding that also explains the fact that delayed-onset VAP was protective in this study even though it was a risk factor for death from VAP in other reports [130].

These studies suggest that there is at least some benefit from silver-coated endotracheal tubes in reducing bacterial burden both on the tube and in the airway. However, even if the decrease is small, two studies have shown that there is a low cost associated with the silver-coated endotracheal tube compared with uncoated tubes [131,132], which may argue in favor of their cost-effectiveness. On the other hand, some authors have suggested that recent declines in rates of VAP are related to the wider application of ventilator bundles [118] designed to provide a small and manageable number of measures designed to reduce risk factors for VAP [133,134]. From that standpoint, both the bundles and the silver-coated tubes share a commonality, in that they both are designed to be simple, routine measures that are more likely to be implemented and adhered to consistently without extraordinary effort by healthcare providers [118,121].

Orthopedic Hardware

In addition to the use of temporary devices containing silver to reduce infections, permanently implanted silver-based hardware has been investigated. These devices are predominantly temporary and permanent orthopedic devices and vascular prostheses.

External fixation pins for fracture management are both extra- and intra-corporeal and therefore carry a risk of contiguous spread of bacteria [135]. Early studies of external fixation pins demonstrated decreased bacterial presence on the intra-corporeal tips of silver-coated pins than on stainless steel pins, as well as less motion with silver pins in animal models [136]. Decreased adherence of all pathogens tested except S. hemolyticus to silver-coated pins has been seen in vitro [135]. Furthermore, in one in vitro study, silver coatings were non-cytotoxic and more cyto-compatible than stainless steel pins [137].

A randomized trial using silver-coated pins in lower-extremity fractures noted a non-significant decrease in culture positivity, although this study was notably underpowered [138]. However, an increase in serum silver concentrations prompted the authors to conclude that it was unethical to continue the study without evidence of a clinical benefit. No silver toxicity was reported despite the elevated serum concentration of the metal.

Two prospective trials evaluated the use of an SSD dressing applied to the pin site as a method to decrease infections. Compared with a dry dressing, SSD alone did not show any benefit [139], but a combination of 1% SSD and 5% chlorhexadine produced significant reductions in infection rates (p=0.03) [140].

Initial investigations of silver-coated titanium nanotubules in the construction of implants showed both increased antibacterial activity and better osteoblast adhesion with minimal toxic effects [141,142]. Another investigation of the incorporation of silver into a silicone polymer coating for prostheses demonstrated significant activity in vitro and ex vivo against S. aureus and methicillin-resistant S. aureus [143]. Here, the silver-coated prostheses were explanted at various times and incubated with bacteria to test adherence. Conversely, a model of direct inoculation of the femoral canal prior to implantation of silver-coated titanium or silver-coated stainless steel wires in a rabbit model failed to demonstrate any difference from the results obtained with uncoated prostheses [144].

A large study of the use of a silver-coated proximal femur or tibia replacement compared with a retrospective cohort of non-coated titanium hardware showed a decrease in the peri-prosthetic infection rate from 17.6% to 5.9%, although this difference did not reach statistical significance [145]. However, clinical outcomes were improved in patients with the silver-coated implant, as none required amputation after developing an infection, whereas 57% of those who developed infections after insertion of titanium prostheses required amputation. Although these investigators reported absence of toxic effects of the silver-coated prosthesis [146], one patient developed localized argyria secondary to a venous insufficiency that led to skin discoloration [145]. As this is the first study addressing the use of silver-coated megaprosthetics and the initial results are encouraging, further evaluation is warranted.

Vascular Prostheses

Silver-coated vascular grafts have been tested in both animal models and prospective clinical trials. As described above, the rationale behind the use of these grafts is that the action of the silver ions will eradicate bacteria that may otherwise adhere to and infect the synthetic material.

When compared with arterial homografts for the treatment of infected aortic grafts, silver-impregnated grafts were equally effective at preventing recurrent infection [147]. Batt et al. [148] used a silver-coated prosthetic graft for replacement of total or partial excision of infected aortic grafts in 24 patients, including several patients with aortoenteric fistulae. These grafts demonstrated primary and secondary patency rates of 100% at 24 mos and were associated with only one recurrent infection. All other patients remained infection-free by repeated computed tomography (CT) scanning [148]. Additional data from one institution participating in that study suggested that although silver is an acceptable material, the risk of reinfection remains significant [149].

A separate group of investigators used a silver-impregnated graft as the primary prosthesis for treatment of aortic disease in 289 patients and noted low rates of post-operative thrombosis and surgical site or graft infection [150]. A larger retrospective analysis of more than 900 patients showed no difference in the rates of complications between silver-impregnated and standard grafts for both aortoiliac and femorodistal bypasses, with no apparent complications arising from use of the silver grafts [151]. These cases included both primary and repeat procedures but excluded cases of prior graft infection, and the authors found that use of a silver graft did not decrease the risk of subsequent graft infections [151].

One of the effects of silver is to activate neutrophils in vitro, which may inhibit their ability to function against pathogens and aid in wound healing or even cause release of enzymes that promote tissue destruction [152]. Thus, although studies continue to assess the risks and benefits of silver-impregnated vascular grafts, long-term data are lacking, and the routine use of this technology has not become widespread.

Heart Valves

Silver coatings for the sewing ring of prosthetic heart valves have been employed to reduce episodes of valve-related endocarditis. Early reports on animal models had differing results, with some showing reduced inflammation or increased resistance to infection [153,154], whereas another showed no difference in colonization or infection rates compared with uncoated fabric [155].

The Artificial Valve Endocarditis Reduction Trial (AVERT) began enrollment in July 1998 as a multicenter, randomized, controlled comparison of the St. Jude Medical Silzone artificial valve with the conventional cuff [156]. Reports from this trial and others showed promising results, with no increase in hospital morbidity or mortality rates and no recurrent endocarditis at as long as two months and at nine months [157,158]. Another series had one post-operative death from pneumonia, but no evidence of recurrent disease in the remaining patients at 14 months' follow-up [159]. In a trial in 126 patients with more than a year of mean follow-up, patients had a low post-operative stroke rate, and none required reoperation for paravalvular leaks [160].

Despite these positive early results, several reports of higher rates of adverse events began surfacing. One case report documented recurrent endocarditis in a patient with a Silzone valve that required two subsequent replacements [161]. Follow-up studies found a higher rate of embolism in the early post-operative period after mitral valve replacement [162] and a non-significant increase in paravalvular leak diagnosed by echocardiogram at a mean of more than a year from valve replacement [163] with the Silzone valves. Other studies documented a significant increase in the need for reoperation secondary to paravalvular leaks, especially in the first two years after initial surgery [164–166].

Although this finding was not consistent in all studies [167–169], the AVERT trial was stopped in January 2000 because of the need for reoperation for moderate to severe paravalvular leaks, and St. Jude Medical voluntarily withdrew the Silzone valve from the market [164]. Histologic examination of explanted valves showed less dense cellular infiltrates than were obtained with the standard cuff valves [170]. Although enrollment in the AVERT study was at only 807 of the target 4,400 patients at the time the trial was suspended, it is estimated that 36,000 patients had received the Silzone valve before it was removed from the market [164]. Studies did not demonstrate any benefit of the Silzone valves in reducing the risk of prosthetic valve endocarditis compared with the conventional cuffed valve [164,171].

Adverse Effects

The most commonly described side effect of long-term silver use is argyria, a permanent bluish or grayish discoloration of the skin [172]. In fact, this may have been the origin of the term “blue blood” [1]. Although the silver deposit results in a change that can be quite pronounced, there do not appear to be any meaningful adverse consequences of such discoloration [172,173]. A similar discoloration of the eyes is termed “argyrosis” [172]. Absorption of silver occurs predominantly through the mucous membranes and burn wound surfaces [174]. Once absorbed, silver can be deposited in the skin, liver, spleen, kidney, cornea, and muscle tissues [172,174,175]. Localized argyria has been reported in conjunction with implantation of silver-coated orthopedic hardware [145]. In persons with long-term occupational exposure to silver, the degree of ocular deposition correlates with the total duration of exposure, whereas blood silver is more indicative of recent exposure [172,174].

There has been concern about the effect of silver absorption on renal, hepatic, and neurologic function. Silver is cleared from the body in part by the kidneys [176]. In one case report of a dialysis-dependent patient who suffered from a 30% total body surface area burn, an elevated serum silver concentration correlated with a comatose state; plasma exchange and cessation of topical SSD treatment resulted in reversal of the mental status changes and decreased blood silver concentration, whereas reinstitution of SSD correlated with a high serum concentration of silver and return of the adverse mental changes [177]. In this patient, silver was deposited in neural tissue despite reduced serum concentrations after plasma exchange, and silver concentrations in the brain tissue were elevated at autopsy. However, a review of the neurotoxic effects of silver suggests that blood–brain barrier penetration is minimal and that neurologic sequelae are rare [178]. Additionally, one case report described an increase in liver enzymes in a burn patient after treatment with SSD that resolved after discontinuation of therapy [179], although other studies were unable to correlate changes in liver enzymes with serum silver concentrations [180].

Rarer events have been reported. One paper described acute hemolytic anemia following treatment with SSD in a burn patient [181]. The anemia resolved after cessation of SSD use, and subsequent testing revealed a glucose-6-phosphate dehydrogenase deficiency. Other myelopoietic effects of silver therapy include transient leukopenia that does not necessarily increase the incidence of infectious complications [182–184]. Here again, these effects appear to be short-lived and did not result in any serious problems. Cutaneous reaction to silver was seen in a patient with a history of metal sensitivity [185]. In addition, there have been several reports of adverse reactions to the sulfadiazine component of SSD [173].

As described previously, one sequela of the use of silver nitrate as a topical application for the treatment of burn wounds is an electrolyte imbalance caused by ionic exchange at the surface of the burn [3,23]. This often is short-lived and has not been reported with other forms of topical silver. In addition, some studies have shown that silver has a cytotoxic effect on host cells, specifically fibroblasts and keratinocytes [25,186,187]. Although the implications of this laboratory research for the clinical setting warrant further in vivo analysis, these data suggest that discontinuing silver agents once the wound bioburden has been reduced promotes healing. However, the ability of silver to exert toxic effects on human cells may lend it value in the treatment of neoplastic cells, which have poorer recovery from mitotic arrest than do healthy fibroblasts [188].

Conclusion

The bactericidal activity of silver is well documented. Its benefit in reducing or preventing infection can be seen in several applications, including as a topical treatment for burns and chronic wounds and as a coating for both temporary and permanent medical devices. However, silver has been unsuccessful in certain settings, such as the failed silver-coated sewing ring of the Silzone heart valve, and its benefit remains unproved in other settings, such as orthopedic hardware coatings. Continued evaluation of such devices will be necessary to define further those areas in which silver confers benefit.

As new devices incorporating silver into their infection-prevention design are surfacing rapidly, an up-to-the minute tally is nearly impossible. This review aimed to cover the major areas in which silver has been used in medical applications. Whereas for some of these applications, other products have emerged with antibacterial properties, silver remains a reasonable addition to the armamentarium against infection and with relatively few side effects. However, one should weigh the benefits of silver-containing products against the known side effects and the other options available for the specific purpose in selecting the most appropriate therapy.

Author Disclosure Statement

No competing financial interests exist.