Clinical REVIEW Silver sulphadiazine: A review of the evidence

This review provides a summary of the literature on the antimicrobial and clinical effects of silver sulphadiazine, and, on emerging patterns of resistance. This will, by nature of the two components, require separate focus on both silver and on the sulphonamide sulphadiazine. Silver has become a popular ingredient in wound dressings. Silver sulphadiazine has a novel use as a coating for various catheters and endotracheal tubes. The evidence points to silver sulphadiazine being a valuable topical agent in the treatment of burns and of lesser value in numerous other applications. It is silver that has emerged as the antimicrobial of greatest current interest.

Richard J White, Rose Cooper

avoid the need for chemical oxidation in topical treatment of infected burns. More KEY WORDS order to provide the ‘active’ species as recently, it has been utilized in chronic Silver sulphadiazine is the case with metallic silver (Gibbins, wounds and the latest application is Antibacterial 2003). Thus, the availability of silver ions its incorporation into medical devices, is dependent upon dissociation of silver such as catheters and dressings, for the Antimicrobial salts, or, on their solubility in wound prevention and treatment of infections. Resistance fluid; this is pH dependent. However, Wound wound fluid is a complex mixture which SSD has largely been marketed as a Catheter can vary considerably in composition; 1% SSD cream as Flamazine™ (Smith it is broadly similar in composition to and Nephew, Hull), and as a cream serum as it contains proteins, lactate with 1% SSD in combination with 0.2% and electrolytes (e.g. Na+, K+, Cl-), urea chlorhexidine digluconate as Silvadene™ ilver and silver compounds have and glucose. Ionic silver Ag+ is a highly (Monarch Pharmaceuticals, Tennessee, been routinely used as general reactive chemical species, which interacts USA). This review will examine the Santimicrobial agents for over a with functional organic groups such as laboratory evidence of its antimicrobial century (Klasen, 2002; Lansdown, 2002; thiols. As integral protein side-groups, activity and cytotoxicity, and the clinical White, 2002). Silver, as the common thiols and chemically similar species evidence of its efficacy. The advantages and ionic (active) form (Ag+), is generally are key components of most proteins limitations of SSD will also be explored. recognised as a safe, broad-spectrum – including enzymes, and prokaryotic antimicrobial agent. It is only the (bacterial) cell wall structures, and also Human pharmacology ionic form that has the antimicrobial nucleic acids. It is this binding that forms Sulphadiazine is one member of four activity (Russell and Hugo, 1994). the basis of antimicrobial activity. sulphonamide groups (others include Silver ions are made bioavailable sulfacetamide, mafenide, sulfasalazine through the interaction of aqueous Silver was formulated as the salt of and sulfisoxazole); it is characteristically fluid, typically wound exudate, with the sulphonamide antibiotic, sulphadiazine, rapidly absorbed and excreted from the metallic (elemental) silver, or directly in the 1960s by Fox (Fox, 1968). Silver gastrointestinal tract (Goodman and from silver salts (coumpound). This sulphadiazine (SSD) is a non-ionised, Gilman, 1990). From the topical route, latter mechanism is the basis for the water insoluble, fluffy white powder that Ag110 (radiolabelled silver) clearance antimicrobial activity of silver nitrate, is formed when sulphadiazine, a weak has been measured in rats, and in ex- chloride and sulphadiazine, and may acid, reacts with silver nitrate to form the vivo, burned human skin (Harrison, complex silver salt. A polymeric structure 1979). Peak attachment of radiolabelled Richard J White is Senior Research Fellow, for SSD has been proposed, where six silver was observed to be 1% of the Department of Tissue Viability, Aberdeen Royal Ag+ ions bind to six sulphadiazines via administered dose in 24 hours, leading Infirmary and Director of Medical Communications the nitrogen atoms of the sulphadiazine to the deduction that SSD functions (UK) Ltd, Highbury House, Whitstone, and Rose pyrimidine rings (Fox, 1983). via the slow release of silver. Whereas Cooper, is Principal Lecturer, Centre for Biomedical low concentrations of silver may be Sciences, School of Applied Sciences, University of Since the introduction of SSD into clinical distributed into the tissues, the plasma Wales Institute Cardiff, Cardiff use, it has been used extensively in the concentration of sulphadiazine may

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approach therapeutic concentrations, cell surface, inhibiting respiration (Bragg The effect of halides, e.g. chloride depending on the surface area treated. et al, 1974). Moderate concentrations of on susceptibility to silver has been Hence, silver is largely confined to chloride remove the silver as insoluble studied in two strains of E. coli by Gupta cutaneous tissues and the sulphadiazine silver chloride precipitate, and, at higher et al (1998). High concentrations of penetrates into the systemic circulation chloride concentrations (such as might be halides increased sensitivity of both (Lockhart et al, 1983). This differential found in exudate) silver is brought back a silver sensitive strain and a silver distribution pattern is reflected in into solution as the bioavailable anion resistant strain to silver in in vitro tests, varying therapeutic- and side-effects, AgCl2- (Gupta et al, 1998). The ability of whereas low concentrations of chloride which will be discussed later. The human highly diluted heavy metals (including silver emphasised the differences between the pharmacology of silver sulfadiazine was in water) to inhibit micro-organisms was sensitivities of the strains. reviewed in depth by Fox (1985). termed ‘oligodynamic’ by von Nägeli in 1893; this term has often been applied Most published studies on the mode Antimicrobial mode of action to silver. Silver products are thought of action of SSD concern bacterial of silver sulphadiazine to interact with microbial thiol groups, cells, but irreversible inactivation of The mode of action of SSD is not carboxylates, phosphates, hydroxyls, amines, phosphomannose isomerase by silver clearly elucidated, and whether the imidazoles, and indoles, either singly, or, in sulphadiazine was demonstrated in broad-spectrum antimicrobial activity is various combinations (Grier, 1983). Candida albicans (Wells et al, 1995). attributable to either the silver or the Phosphomannose isomerase is a sulphadiazine moieties, or a synergistic In wound treatment it is zinc metalloenzyme essential for the combination of both, has been debated probable that SSD functions biosynthesis of cell walls in fungi; and (McDonnell and Russell, 1999). In general, a cysteine residue, at position 150, has sulphonamides are broad-spectrum by delivering sustained, low been shown to be the site of action of antibiotics that are predominantly concentrations of silver SSD. The same enzyme in E. coli was bacteriostatic by inhibiting the formation (approx 1–2 ppm) into the unaffected by SSD (Wells et al, 1995). of dihydropteroic acid, an intermediate wound environment, and of the folate pathway. SSD has been seen that this interferes with, or In addition to the antimicrobial to cause surface and membrane blebs modulates, multiple cellular effects of silver, positive benefits to in susceptible (but not SSD-resistant) the wound healing process have been bacteria (Coward et al, 1973). Fox and processes. reported (Lansdown et al, 1997; Modak (1974) showed that silver, rather Demling and DeSanti, 2001; Kirsner et than sulphadiazine, binds to bacteria, al, 2002). These focus on theoretical and suggested that only a relatively small Trevors (1987) reviewed the mechanisms involving: amount of available sulphadiazine appears possible cellular effects of silver toxicity. 8The displacement of zinc from to be active in this context. These include: metallothionines 8Binding of silver to base pairs in DNA, 8Changes in metalloprotein levels There is evidence of antifungal (Wright and thereby blocking transcription within the wound et al, 1999) and antiviral activity 8Binding to cell surface components, 8Effects on inflammatory cytokines. (Thurman and Gerba, 1989), attributable interfering with bacterial respiration Research is required to confirm and to the silver moiety. and uncoupling ATP synthesis to clarify these mechanisms. 8Preventing uptake of phosphate, and In wound treatment, it is probable that causing the release of components Antimicrobial spectrum of activity of SSD SSD functions by delivering sustained, low (such as glutamine, proline, succinate When SSD was introduced in 1968 it was concentrations of silver (approx 1–2 ppm) and phosphate from Escherichia coli). recommended as a topical prophylactic into the wound environment, and that therapy for Pseudomonas spp. (Fox, 1968); this interferes with, or modulates, multiple Certain effects (such as phosphate since then it has been shown to possess cellular processes. There are multiple release) may be reversed by the inhibitory activity against a wide range deleterious effects in micro-organisms presence of thiol groups; such thiolated of microbial species. Initially, bacteria rather than a single, specific inhibitory compounds as dithiothreitol and were tested and both gram positive and mechanism (Fox and Modak, 1974). mercaptoethanol can combine with gram negative species were found to Given the anionic content of wound fluid, silver to form a stable, inactive complex be susceptible with minimum inhibitory it is interesting to consider how silver that reduces toxicity to bacteria. Fox concentrations (MICs) determined by solubility and available ions might exert a (1968) suggested that prolonged contact serial doubling dilutions in trypticase soy bactericidal effect. The chloride anion (Cl-) of SSD with biological fluids containing broth ranging between <0.78 and 100 is found in serum, and wound exudate. chloride and sulphydryl groups, leads to μg SSD/ml (Carr et al, 1973). Antifungal It will influence the availability of Ag+ in the solubilisation of sulphadiazine, and activity was determined in 50 clinical solution. At low chloride concentrations thus enhances the oligodynamic action isolates of C. albicans by incorporating (around a 100mM) as present in wound of silver with the additional antibacterial SSD into agar and inoculating with a fluid. soluble silver will bind to the bacterial activity of the released sulphonamide. multipoint inoculator, and MICs similar

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to those quoted above were reported study, Maple et al (1992) compared in Using two selected strains of (Wlodkowski and Rosenkranz, 1973). vitro activities of 4 topical agents against staphylococci, the effect of SSD on Activity against dermatophytes was 80 strains of MRSA collected from clinical the production of further virulence established using both liquid and agar specimens from sources throughout the factors was tested in vitro. Again, strain

dilution techniques described in the world. SSD gave MIC50 of 85 μg/ml and differences were seen, but sub-lethal previous two studies, and all of the strains was recommended for clearance of MRSA concentrations of SSD were able to tested were inhibited at 100 μg SSD/ml or carriage. SSD killed sulphonamide-sensitive stimulate the release of coagulase, less (Speck and Rosenkranz, 1974). Binding and sulphonamide-resistant strains equally proteases and enterotoxin A and C of silver to phage DNA is the likely basis of rapidly, and no SSD resistant mutants were (Edwards-Jones and Foster, 2002). This antiviral activity (Rahn et al, 1973). recovered from inocula of 109 cfu. study provides further evidence that inappropriate concentrations of topical Hamilton-Miller et al (1993) utilised agents such as SSD may enhance the 409 clinical isolates from 12 different ...inappropriate virulence of wound pathogens. genera to provide reliable data of in vitro concentrations of topical susceptibility to SSD. Precise details were agents such as SSD may The clinical evidence for the efficacy of SSD provided of the methodology used to enhance the virulence of Early evidence that Silvadene™ had a determine MICs, minimum bactericidal wound pathogens. beneficial effect on wounds, additional to its concentrations (MBC) and time-kill antimicrobial activity, came from an animal studies, including how stable suspensions model. In clean wounds in pigs, rates of of SSD were prepared. Strains tested The effect of sub-lethal concentrations epithelialisation were increased by 28% by were 20 each of coagulase negative of SSD on bacteria topical application of SSD (Geronemus et staphylococci, Streptococcus pyogenes, Two studies have investigated the effects al, 1979). Best known as the Flamazine™ Enterococci, C. albicans, E. coli, Klebsiella of sub-lethal concentrations of SSD on 1% cream (Smith & Nephew, Hull), SSD pneumoniae, Enterobacter spp., Proteus staphylococci (Edwards-Jones and Foster, has been a mainstay of topical burns mirabilis, indole-positive Proteus spp., 1994; 2002). In the first report, 300 therapy (Pruitt, 1987), and has been used Providencia stuartii and Pseudomonas cultures of S. aureus isolated from wound successfully in acute (Buckley et al, 2000) aeruginosa. Also, 97 strains of methicillin- swabs were tested for the production and chronic wounds (Bishop et al, 1992) resistant Staphylococcus aureus (MRSA) of toxic shock syndrome toxin 1 (TSST- to treat infection. A variety of topical silver and 92 strains of Acinetobacter spp. were 1). The isolates were recovered from preparations have been evaluated on included. Furthermore, for all isolates, surgical in-patients, burns patients and chronic wounds (systematic review by sulphonamide sensitivity was tested using from community patients. All cultures O’Meara et al, 2000; 2001) in clinical trials diffusion from a disk impregnated with were screened for the production with generally favourable results. Clinical 50μg sulphamethoxazole. All organisms, of TSST-1, and 17% were found to evidence on SSD formulations is largely in including the multi-resistant species such be positive. TSST-1 producing strains the area of burns treatment (Hoffmann, as MRSA and Acinetobacter spp. were were grown in vitro and incubated 1984; Stern, 1989; Fakhry et al, 1995; Klasen, sensitive to SSD, irrespective of their in sub-lethal concentrations of five 2002) although there are reports on use sensitivity or resistance to sulphonamide. topical antimicrobial agents. Levels of in chronic leg ulcers (Blair et al, 1988; TSST-1 produced in the presence Bishop et al, 1992), and acute wounds Most MICs were between 16 and of antimicrobials were compared (Buckley et al, 2000). 64 μg SSD/ml, and SSD was bactericidal to cultures without additions. With close to MICs. The figures reported in this SSD, effects were strain dependent, In a study on non-healing leg study tended to be higher than those of but in 47% of cultures tested, TSST-1 ulcers treated with split-thickness skin previous studies, but the authors criticised production was stimulated at least grafts, van den Hoogenband (1984) 12 cited publications of in vitro studies four times the level observed in demonstrated that pre-treatment with completed between 1973 and 1991 (of control cultures and, in some cases, SSD cream for five days before grafting which 3 are cited above) for incomplete 16 times higher. resulted in better healing. This was descriptions of methodology. attributed to marked reduction in pre- Preliminary data also suggested that SSD operative levels of pathogens such as S. As SSD is insoluble and unstable at induced TSST-1 synthesis earlier during aureus, Pseudomonas spp., Enterobacter alkaline pH, they commented that previous the growth cycle. Although TSST-1 is and ß-haemolytic streptococci in the studies could not be accurately reproduced primarily associated with use of tampons, SSD-treated group. without details of how suspensions of it has been detected in other infections, SSD were prepared. Time-kill studies including burns. Since SSD is often used In a study on 71 patients with venous with selected strains of staphylococci in the prophylactic treatment of burns, leg ulcers, Ouvry (1989) found that the showed that sulphonamide-resistant S. and S. aureus is a common cause of burn use of SSD cream was effective in wound aureus (but not Staphylococcus epidermidis) infection, this study indicates the need to cleansing and subsequent granulation were killed significantly more slowly than employ concentrations of SSD in vivo tissue formation. This is supported by sulphonamide-sensitive strains. In a similar that are microbicidal. evidence that super-infections responded

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well to the cream. Further supportive, The role of SSD in medical products Another application for silver in the but not conclusive, evidence on the use Micro-organisms rarely exist in natural control of biofilms is in medical devices. of SSD on leg ulcers is provided in the environments as single cells or pure Catheters have been used in hospitals systematic review by O’Meara et al (2001). cultures of an individual species, but since 1945, and a wide range of indwelling The authors cite clinical trial reports by usually as relatively stable communities medical devices is now available. Infections Bishop et al (1992) and Blair et al (1988), of mixed species embedded in associated with these devices are linked to drawing the conclusion that ‘silver-based slime layers, called biofilms. Cells in biofilm formation, especially with coagulase products may be useful for leg ulcers’. The biofilms exhibit decreased sensitivity negative staphylococci. One strategy systematic review highlighted trial design to antimicrobial agents and also to to control such infections has been to as the single most important reason why host immunological responses, and incorporate antimicrobial agents — and conclusive evidence was not available; have therefore been implicated in silver products are candidates. most studies were flawed in their design persistent infections (Costerton et al, resulting in type 2 errors. 1999). Biofilms have been shown to Bach et al (1994) compared form in wounds created in two animal colonisation of catheters impregnated SSD cream has also been evaluated models (Akiyama et al, 1993; Serralta with silver sulphadiazine and chlorhexidine in pressure ulcer treatment. In a et al, 2001; Akiyama et al, 2002), and (SSC) against control (C) catheters comparison of 1% SSD (Silvadene™ are thought to be important in chronic implanted into the jugular veins of rats, cream) with povidone-iodine solution wounds (Mertz, 2003). Biofilms have and demonstrated that impregnated (PVP-I Betadine™) or sterile saline, also been implicated in infections catheters reduced the incidence and Kucan et al (1981) found SSD alone to with coagulase negative staphylococci extent of colonisation. Despite the reduce wound bioburden below 105 per associated with medical devices retention of antiseptic activity in SSC- gramme of tissue. The difference between (Tunney et al, 1996). Hence, factors impregnated catheters in vivo, incidence of the mean bacterial levels reached after that limit the development of biofilms bacteraemia was not affected and efficacy treatment was highly significant for SSD are pertinent to the management of has been questioned (Bach et al, 1996). vs PVP-I (P<0.01), but less so for SSD vs wounds and the clinical use of certain However, a review supports the use of saline (P<0.10). This translated into an medical devices. antiseptic-coated catheters in reducing the improved clinical response at three weeks incidence of both catheter colonization for the SSD group (P≤0.022). and catheter-related bloodstream infection Micro-organisms rarely exist (Veenstra et al, 1999). A recent study on The neuropathic foot ulcer, in natural environments as 184 patients with haemato-oncological associated with diabetes, is another single cells or pure cultures disease demonstrated that SSC chronic wound that is compromised of an individual species, but impregnation reduces the overall risk of by microbial colonisation and frequent usually as relatively stable catheter colonisation and catheter-related infection. SSD has been used on these communities of mixed infection (Ostendorf et al, 2005), and these wounds with good effect (Sturm et al, findings have been recently corroborated 1993), although there are no reports of species embedded in slime in a clinical trial on neutropenic patients controlled clinical trials. layers, called biofilms. (Jaeger et al, 2005). Susceptibility of coagulase negative staphylococci isolates The published data on SSD in The effects of antimicrobial agents on from bloodstream infections to SSC- chronic wounds such as leg ulcers, a biofilm model of clinical isolates of S. impregnated central catheter has been pressure ulcers and diabetic foot aureus were studied by Akiyama et al demonstrated (Rosato et al, 2004). ulcers, support the control of wound (1998). Immature biofilms of S. aureus Cultures collected before and after the bioburden as a pre-requisite to healing, were formed on plastic coverslips in introduction of SSC catheters did not and, for the active management of plasma after incubation for 24 hours, differ in their sensitivity to SSC in vitro, but existing wound infection by the topical and levofloxacin or 10% povidone- the proportion of S. epidermidis isolated route. In terms of bioburden control, this iodine, in combination with 70% after their introduction diminished. may be at the colonisation stage, or, in sucrose and silver sulphadiazine or the pre-infection or ‘critical colonisation’ silver nitrate, was effective in eliminating Methods of incorporating antimicrobial stage described for chronic wounds S. aureus cells in the biofilm model. agents into catheters have not been (Kingsley, 2001; Fumal et al, 2002). Because silver was more effective in completely optimised to date but the The treatment of critical colonisation eliminating cells in biofilm than floating incorporation of antimicrobial agents is, as yet, controversial until there is cells, it was suggested that silver might between inner- and outer-sheath materials clear evidence that such treatment can be effective in treating wounds with S. seems to be more effective than coating preclude the development of infection, aureus colonisation as well as infections catheters (Tcholakian and Raad, 2001). facilitate healing, and reduce morbidity. (Akiyama et al, 1998). Recently, The advantages of antibiotic- or antiseptic- There is accumulating evidence that cadexomer iodine has been found to coated catheters have also been debated, bacterial activity may impair healing be effective in killing S. aureus in biofilms and central venous catheters coated with (Wall et al, 2002; Stephens et al, 2003). (Akiyama et al, 2004). minocycline/rifampicin have been judged

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to be more cost-effective than SSC Enterobacter cloacae and Pr. mirabilis were severe burns patients, S. aureus was more catheters for patients catheterised for at recovered after 24 hours exposure. One frequently isolated from wounds treated least 7 days (Marciante et al, 2003). The limitation in testing dressings rather than with SSD, and coliforms were more prospect of bacteria developing resistance active components alone is that the frequently isolated from SN patients. When to antibiotics and antiseptics incorporated contribution of excipients to observed the efficacy of SSD was compared to a into medical devices is causing concern, activity is not tested. cream containing SN and chlorhexidine although the selection of antibiotic-resistant Another formulation of SSD is in (SNC) in patients with extensive burns, bacteria is more probable than the the Urgotul® SSD dressing, (Urgo- sulphonamide-resistant gram negative development of antiseptic-resistant strains Parema, Loughborough).This comprises bacteria became predominant. (Tambe et al, 2001). a polyester mesh impregnated with carboxymethylcellulose, white soft During the clinical evaluation of In 1971 an outbreak of resistant paraffin and 3.75% SSD. Preliminary antimicrobial agents in the treatment of S. aureus in the burns unit in the clinical data on burns patients showed burns patients in Birmingham between Royal Melbourne hospital led to the good clinical and microbiological 1965 and 1974, resistance to sulphonamide development of a dressing containing outcomes (Carsin et al, 2004). was monitored in clinical isolates using SSD and 0.2% chlorhexidine digluconate the ditch plate method where 100mg as Silvazine™ (Sigma Pharmaceuticals, Limitations of SSD sulphadiazine/litre was incorporated into Melbourne). Until recently, no in vitro Undesirable characteristics associated the ditch. SSD was first utilised there in study had compared the antimicrobial with the clinical use of SSD are the 1969, but until 1972 it was restricted to efficacy of dressings such as Flamazine™, emergence of resistant strains of patients with small burns, after which time it Silvazine™ and Acticoat™ (Smith and microbial species, the claimed retardation was applied to extensive burns. Nephew, Hull). Survival curves of eight of wound healing and the development common burn wound pathogens were of systemic side-effects. Delayed In 1974, increased recovery of obtained by inoculating 1 cm2 samples of wound healing is claimed to be the sulphonamide-resistant strains was dressings into bacterial suspensions and clinical manifestation of mild toxicity, as observed in Acinetobacter anitratus, monitoring microbial viability with time evidenced from in vitro studies involving Klebsiella spp., E. coli, Enterobacter spp., (Fraser et al, 2004). No viable bacteria various skin cells lines (Hidalgo and Pr. mirabilis and other Proteus species. of any cultures were detected after 30 Dominguez, 1998; Poon and Burd, 2004). For a selection of these organisms, MICs minutes exposure to Silvazine™, whereas determined by the agar dilution method SSD and Acticoat™ were less effective. Resistance to silver sulphadiazine exceeded 1000 mg sulphadiazine/litre. Although SSD and Acticoat™ had similar The mechanisms of bacterial resistance Sulphadiazine resistance was detected activities, Acticoat™ was reported to be to silver, encoded by plasmid-based in more strains recovered from SSD- only bacteriostatic against Enterococcus genes, have been described in detail treated patients (41/59, 70%) than from faecalis and MRSA, and viable cells of (Silver, 2003). Silver resistance results SN treated patients (23/50, 44%). The from an energy-dependent ion efflux emergence of resistant gram negative Key Points from the cell (Gupta et al, 1999). Silver bacteria reduced the effectiveness of SSD bioaccumulation by bacteria has been in the prophylactic treatment of extensive 8 Silver sulphadiazine is reported (Starodub, 1990) but the burns, and caused the suspension of a combination of two relationship between accumulation and SSD cream, and limited use of systemic antimicrobial agents; silver and a resistance is not clear (Slawson et al, sulphonamides and co-trimoxazole until sulphonamide antibiotic. 1992). Silver resistant organisms have proportions of sulphonamide-resistant frequently been found in environments isolates diminished. 8 SSD is best used in topical where silver toxicity may be expected delivery; most evidence is based to select for resistance, for example Bridges and Lowbury (1977) on the cream, increasingly it hospital burn wards (Klasen, 2000). A demonstrated that cessation of all has been used to coat medical bacterial resistance pattern to silver, sulphonamide treatment in the ward devices such as catheters and as used in a variety of topical wound resulted in a reduction in incidence endotracheal tubes to reduce treatments, has been reviewed (Percival of sulphadiazine-resistant strains. bacterial growth. et al, 2005). The authors concluded that, Conjugation experiments with E. coli 8 SSD has a long history of although no widespread resistance had K12, and resistant strains, showed that effective clinical use, notably been developed, increased usage of sulphadiazine resistance was transferable in burns. silver gives cause for some concern. in Klebsiella and some other (but not all) strains. Heggars and Robson (1978) 8 Much of the evidence acquired The emergence of SSD-resistant and Modak and Fox (1981) have also on SSD has been used to bacteria in a Burns Unit in Birmingham recovered SSD-resistant strains of support the use of silver as a was recorded by Lowbury et al (1976). bacteria. The validity of sensitivity testing topical antimicrobial. When the prophylactic effects of SSD has been questioned by P. aeruginosa were compared to silver nitrate (SN) in cultures isolated from burns patients in

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several countries that were observed sputum samples, the latter was more is most unlikely. However, in a study on to be resistant to SSD in vitro, but not frequently recovered from burn wound severely burned patients, where a large in vivo when tested in an animal model swabs. Primary reservoirs were not body surface area was treated with a (Modak and Fox, 1981). Sensitivity to detected. In this study, the AWD was topical SSD emulsion, measurable toxicity, sulphadiazine in this study was measured used to test for SSD resistance, and the including allergic contact reactions to in a tube dilution assay in nutrient broth. authors suggested that this test might the formulation excipients, eg. propylene be of value in eliminating inappropriate glycol and cetyl alcohol has been reported Another method for assessing the use of SSD for burns patients colonised (Degreef and Dooms-Goossens, 1985). effectiveness of topical antimicrobial agents Similar responses to the sulfadiazine were is the agar well diffusion test (AWD), Undesirable characteristics reported (Kulick et al, 1985) although this where agar is seeded with the culture is contradicted by Degreef and Dooms- being screened, and agents being tested associated with the Goossens (1985) who maintain that , are introduced into wells cut into the plate. clinical use of SSD are the ‘there is no evidence that SSD is contra- Although differential diffusion rates of emergence of resistant indicated for patients with a history of various agents might influence the size of strains of microbial species, sulfonamide hypersensitivity’. resultant zones of inhibition, Thomson et al the claimed retardation (1989) found good correlation between of wound healing and the Toxic effects of silver include skin clinical efficacy and in vitro inhibition of SSD. irritation and discolouration (argyria) development of systemic which is widely reported for silver In another similar study (Hendy and side-effects. nitrate solutions and colloidal silver Smith, 1979), hospital isolates collected but rarely associated with topical SSD between 1975 and 1979 were routinely (Gettler et al, 1927; Buckley, 1963; screened for sensitivity to silver by with SSD-resistant strains. McManus et al Marshall and Schneider, 1977; Wright et plating onto media containing 0.5mM (1983) described a transferable multiple- al, 1998). Allergic contact dermatitis to silver nitrate. Silver-resistant strains of antibiotic resistance plasmid that carried silver as SSD and as the nitrate has been Enterobacteriaceae that were detected selectable sulphonamide resistance reported, although with SSD most such included E. coli, Ent. cloacae, Kleb. determinants, and warned that use of SSD reactions are to the excipients (Fisher, pneumoniae, Pr. mirabilis and Citrobacter could select not only for SSD-resistant 2003; Agarwal and Gawkrodger, 2002; freundii. Eleven in-patients whose burns strains, but antibiotic-resistant strains. Iliev and Elsner, 1998). had been treated prophylactically with Plasmid-mediated resistance to silver has SSD yielded silver-resistant bacteria. been noted in a number of gram negative Cytotoxicity in vitro has been Of the 230 cultures collected during bacteria, such as E. coli, Pseudomonas, described and postulated as a cause the study period, 211 were resistant to Acinetobacter and Salmonella. Occasionally, of delayed wound healing as reported sulphonamide, 97 of which were also resistance to silver is lost on sub-culture anecdotally (Poon and Burd, 2004). silver-resistant, but 38 were not tested in the laboratory (Bridges et al, 1979). In wound treatment, any potential for for silver sensitivity. Coincidentally, seven Detailed analysis of Salmonella identified a cytotoxicity arising from silver-releasing silver-resistant (but sulphonamide- cluster of seven genes that were organised wound dressings or SSD creams, can sensitive) strains were isolated from into three divergently transcribed units. be avoided through the prudent use of four non-burns patients with silver The gene products are thought to such products – particularly avoidance tracheotomy tubes, and one similar function as a periplasmic protein that of unnecessary or prolonged use. isolate came from a burns patient in A&E, binds silver, and two efflux pumps that whose previous treatment history was export silver (Gupta et al, 1999). Serum silver levels have been found not recorded. At a later date (Trevors, to rise after topical SSD treatment 1987), these cultures were reported to Cytotoxicity of SSD (Maitre et al, 2002). Upon dissociation, contain one or more plasmids. Resistance The systemic toxicity of the the sulphonamide clears from the body of Pseudomonas spp. to silver has been sulphonamide antibiotics is dependent more rapidly than does silver (Boosalis et reviewed (Cervantes and Silver, 1996). upon their individual chemistry and al, 1987). Elevated serum silver (over 20mg metabolism (Shear et al, 1986). In L-1) is reported to cause renal dysfunction, The epidemiology of P. aeruginosa in general, the sulphonamides are known liver and nerve toxicity: this occurs after a burn centre has been studied (Pirnay to induce agranulocytosis (Willoughby, prolonged exposure of leg ulcers and et al, 2003). Essentially, two predominant 1977). Certainly, neutropaenia has been acute burns to 1% SSD (Maitre et al, 2002; genotypes were responsible for recurrent reported in burns treated with topical Tsipouras et al, 1997), and, agranulocytosis outbreaks and the colonisation of patients. SSD, but this cannot be directly attributed in neonates (Viala et al, 1997). One endemic strain developed multiple to the sulphadiazine. It would appear to drug resistance at the end of the study be the case that systemic or local toxicity Historically, silver nitrate was period, and the other was antibiotic from sulphadiazine, as delivered from probably the first silver compound sensitive, but resistant to SSD. Whereas 1% topical emulsion formulations dosed used on wounds, where it has the former strain was more prevalent in according to manufacturer’s instructions, an astringent and irritating effect.

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Due to these problems, and lack in a burns ward. J Clin Path 30: 160–4 Fraser JF., Bodman J, Sturgess R, et al (2004) of evidence, it is rarely used today Bridges K, Kidson A, Lowbury EJL, Wilkins An in vitro study of the anti-microbial except for the occasional reduction of MD (1979) Gentamicin- and silver-resistant efficacy of a 1% silver sulphadiazine and hypergranulation. pseudomonas in a burns unit. Br Med J (i): 0.2% chlorhexidine digluconate cream, 1% 446–50 silver sulphadiazine cream and a silver coated Buckley WR (1963) Localised argyria. Arch dressing. Burns 30: 35–41 Conclusions Dermatol 88: 531–9 Fumal I, Braham C, Paquet P, Pierard- Since its first appearance as a cream Buckley SC, Scott K, Das K (2000) Late Franchimont C, Pierard GE (2002) The formulation for topical use some thirty review of the use of silver sulphadiazine beneficial toxicity paradox of antimicrobials in years ago, SSD has become a very dressing for the treatment of fingertip leg ulcer healing impaired by a polymicrobial injuries. Injury Int J Care Injured 31: 301–4 flora: a proof-of-concept study. Dermatology valuable antimicrobial agent, especially 204(suppl1): 70–4 in burns therapy. It has, through Carr HS, Wlodkowski TJ, Rosenkranz HS (1973) Silver sulphadiazine: in vitro Geronemus RG, Mertz PM, Eaglestein WH widespread clinical usage, been proven antibacterial activity. Antimicr Agents (1979) Wound healing. The effects of topical to be remarkably safe with relatively Chemother 4: 585–7 agents. Arch Dermatol 115(1): 1311–14 low resistance potential. The advent of Carsin H, Wasserman D, Pannier M et al Gettler AO, Rhoads CP, Weiss S (1927) A a new generation of silver-containing (2004) A silver sulphadiazine-impregnated contribution to the pathology of generalised dressings and of SSD impregnation of lipidocolloid wound dressing to treat second- argyria with a discussion of the fate of silver in degree burns. J Wound Care 13(4): 145–8 the human body. Am J Pathol 3: 631–51 medical devices has served to confirm Gibbins B (2003) The antimicrobial benefits of the clinical utility of silver and of SSD in Cervantes C, Silver S (1996) Metal resistance in Pseudomonas; genes and silver and the relevance of microlattice technology. modern medicine. mechanisms. In: Nakazawa T, Furakawa Ostomy/Wound Management 49: Suppl 4–7 K, Haas D, eds.Molecular biology of Goodman LS, Gilman A (1990) Goodman References Pseudomonads. Silver S. American Society for and Gilman’s The Pharmacological Basis of Microbiology, Washington DC, USA Therapeutics. 8th edn. McGraw Hill, New York: Agarwal S, Gawkrodger DJ (2002) Occupational chap 45, ‘Antimicrobials’ allergic contact dermatitis to silver and Costerton JW, Stewart PS, Greenberg Grier N (1983) Silver and its compounds.In: Block colophonium. Am J Contact Derm 13(2): 74 EP (1999) Bacterial biofilms: a cause of persistent infections. Science 284: 1318–22 SS, ed. Disinfection, Sterilization and Preservation. Akiyama H, Kanzaki H, Tadi J, Arata J (1993) 3rd edn. Lea and Febiger, Philadelphia Staphylococcus aureus infection on cut wounds Coward JS, Carr HS, Rosenkranz HS Gupta A, Matsui K, Lo JF, Silver S (1999) in the mouse skin: experimental staphylococcal (1973) Silver sulphadiazine effect on the Molecular basis for resistance to silver cations botryomycosis. J Dermatol Sci 11: 2334–8 ultrastructure of Pseudomonas aeruginosa. Antimicr Agents Chemother 3: 621–4 in Salmonella. Nat Med 5: 183–8 Akiayama H, Yamasaki O, Kanzaki H, Tada J, Gupta A, Maynes M, Silver S (1998) Effects of Arata J (1998) Effects of sucrose and silver on Degreef H, Dooms-Goossens A (1985) halides on plasmid-mediated silver resistance Staphylococcus aureus biofilms. J Antimicrob Patch testing with silver sulfadiazine cream. in Escherichia coli. Appl Environ Micro 64(12): Chemother 42: 629–34 Contact Dermatitis 12(1): 33–7 5042–45 Akiyama H, Huh W-K, Yamasaki O et al Demling RH, DeSanti L (2001) The role Hamilton-Miller JMT, Shah S, Smith C (1993) (2002) Confocal laser scanning microscopic of silver in wound healing. Part 1: Effects Silver sulphadiazine: a comprehensive in vitro examination of glycocalyx production by of Silver on Wound Management. Wounds reassessment. Chemother 39: 405–9 Staphylococcus aureus in mouse skin: does 13(1): SupplA3–A15 S.aureus generally produce a biofilm on Edwards-Jones V, Foster HA (1994) The Harrison N (1979) Pharmacology of damaged skin? Br J Dermatol 147: 879–85 effects of topical antimicrobial agents on the sulfadiazine silver. Arch Surg 114(3): 281–5 Akiyama H, Oono T, Saito M, Iwatsuki K production of toxic shock syndrome toxin Heggars JP, Robson MC (1978). The (2004) Assessment of cadexomer iodine – 1. J Med Micro 41: 408–13 emergence of silver sulphadiazine resistance in against Staphylococcus aureus biofilm in vivo Edwards-Jones V, Foster HA (2002) Effects Pseudomonas aeruginosa. Burns 5: 184–7 and in vitro using confocal laser scanning of silver sulphadiazine on the production Hendy AT, Smith IO (1979) Silver-resistant microscopy. J Dermatol 31: 529–34 of exoproteins by Staphyloccus aureus. J Med Enterobacteriaceae from hospital patients. Can Bishop J, Phillips LG, Mustoe TA et al (1992) Micro 51: 50–5 J Microbiol 25: 915–21 A prospective randomised evaluator blinded Fakhry SM, Alexander J, Smith D (1995) Hidalgo E, Dominguez C (1998) Study of trial of two potential wound healing agents Regional and institutional variations in burn cytotoxicity mechanisms of silver nitrate in for the treatment of venous stasis ulcers. J Vasc care. J Burn Care Rehab 16: 86–90 human dermal fibroblasts. Tox Letts 98: 169–79 Surg 16: 251–7 Fisher NM, Marsh E, Lazova R (2003) Scar Hoffmann S (1984) Silver sulphadiazine: an Blair SD, Backhouse CM, Wright DD et al localized argyria secondary to silver sulfadiazine antibacterial agent for topical use in burns. (1988) Do dressings influence the healing of cream. J Am Acad Dermatol 49(4): 730–2 Scand J Plast Reconstr Surg 18: 119–26 chronic leg ulcers? Phlebology 3: 129–34 Fox CL, Modak SM (1974) Mechanisms of Iliev D, Elsner P (1998) Unusual edge effect in Boosalis MG, McCall JT, Ahrenholtz DH et silver sulphadiazine action on burn wound patch testing with silver nitrate. Am J Contact al (1987) Serum and urinary silver levels in infections. Antimicrob. Agents Chemother Dermat 9(1): 57–9 thermal injury patients. Surgery 101: 40–3 5(6): 582–8 Jaeger K, Zenz S, Juttner B et al (2005) Bowler PG, Duerden BI, Armstrong DG Fox CL (1968) Silver sulphadiazine — a Reduction of catheter-related infections in (2001) Wound microbiology and associated new topical therapy for Pseudomonas in neutropenic patients: a prospective controlled approaches to wound management. Clin Micro burns. Arch Surg 96: 184–8 randomized trial using a chlorhexidine and Rev 14(2): 244–69 Fox CL (1983) Topical therapy and the silver sulfadiazine-impregnated central venous Bragg PD, Rainnie DG (1974) The effect of development of silver sulphadiazine. Surg catheter. Ann Haematol 84(4): 258–62 silver ions on the respiratory chain of E coli. Gynecol Obstet 157: 82–8 Kingsley A (2001) A pro-active approach to Can J Microbiol 20(6): 883–9 Fox CL (1985) The human pharmacology wound infection. Nurs Standard 15(30): 50–5 Bridges K, Lowbury EJL (1977) Drug resistance of silver sulphadiazine. Burns Inc Therm Inj Kirsner RS, Orsted H, Wright JB (2002) Matrix in relation to use of silver sulphadiazine cream 11(4): 306–7 metalloproteinases in normal and impaired

60 Wounds UK

p.51-61White and Cooper.indd 12 18/7/05 10:11:20 am Clinical REVIEW ClinicaClinical l REWIEWREVIEW

wound healing: a potential role of nanocrystalline patients — a double-blind, randomised, Stephens P, Wall IB, Wilson MJ, et al (2003) silver. Wounds 13(3): Suppl C, 5–12 prospective, controlled trial. Supp Care Cancer: Anaerobic cocci populating the deep tissues of Klasen HJ (2002) A historical review of the 16 April, E-pub ahead of print chronic wounds impair cellular wound healing use of silver in burns. Burns 26: 117–30 Ouvry PA (1989) Essai de la sulfadiazine responses in vitro. Br J Dermatol 148(3): 456–66 Kucan JO, Robson MC, Heggers JP, Ko F argentique dans le traitement local de l’ulcere Sturm LJ, Rimler RJ, Fendell HS (1993) (1981) Comparison of silver sulfadiazine, veineux. Phlebologie 42(4): 673–9 Alternative treatment for diabetic neuropathic povidone-iodine and physiologic saline in Percival SL, Bowler PG, Russell AD (2005) ulcerations. JAMA 83: 426 the treatment of chronic pressure ulcers. J Am Bacterial resistance to silver in wound care. J Tambe SM, Sampath L, Modak SM (2001) Geriatr Soc 29: 232–5 Hosp Infect 60: 1–7 In vitro evaluation of the risk of developing Kulick MI, Wong R, Okarma TB, et al (1985) Pirnay J-P, de Vos D, Cochez C, et al (2003). bacterial resistance to antiseptics and Prospective study of side-effects associated Molecular epidemiology of Pseudomonas antibiotics used in medical devices. J Antimic with the use of silver sulfadiazine in severely aeruginosa colonisation in a burn unit: Chemother 47: 589–98 burned patients. Ann Plast Surg 14(5): 407–18 persistence of a multidrug-resistant clone Tcholakian RK, Raad II (2001) Durability of Lansdown A B G, Sampson B, et al (1997). and a silver sulfadiazine-resistant clone. J Clin anti-infective effect of long-term silicone sheath Silver aids healing in the sterile skin wound: Microbiol 41(3): 1192–1202 catheters impregnated with antimicrobial agents. experimental studies in the laboratory rat. Br J Poon VKM, Burd A (2004) In vitro Antimic Agents Chemother 45(7): 1990–93 Dermatol 137: 728–35 cytotoxicity of silver: implication for clinical Thomson PD, Taddonio TE, Tait MJ, Prasad Lansdown ABG (2002) Silver 1: its wound care. Burns 30: 140–7 JK (1989) Susceptibility of pseudomonas antibacterial properties and mechanism of Pruitt BA (1987) Opportunistic infections in and staphylococcus wound isolates to topical action. J Wound Care 11: 125–30 burn patients: diagnosis and treatment. In: Root antimicrobial agents: a ten-year review and Lockhart SP, Rushworth A, Azmy AAF, Raine P R, Trunkey R, Sande MA, eds. New Surgical clinical evaluation. Burns 15: 190–2 (1983) Topical silver sulphadiazine: side-efects and Medical Approaches to Infectious Diseases. Thurman RB, Gerba CP (1989) The molecular and urinary excretion. Burns 10(1): 9–12 Churchill Livingstone, New York: 245–61 mechanisms of copper and silver ion Lowbury EJL, Babb JR, Bridges K, Jackson DM Rahn RO, Setlow JK, Landry LC (1973) disinfection of bacteria and viruses. CRC Critical (1976) Topical chemoprophylaxis with silver Ultraviolet irradiation of nucleic acids Reviews in Environmental Control 18(4): 295–315 sulphadiazine and silver nitrate chlorhexidine complexed with heavy metals.III. Influence Trevors JT(1987) Silver resistance and accumulation creams: emergence of sulphonamide-resistant of Ag+ and Hg+ on the sensitivity of phage in bacteria. Enzyme Microb Technol 9: 331–3 Gram-negative bacilli. Br Med J 1: 493–6 and of transforming DNA to ultraviolet Tsipouras N, Rix CJ, Brady PH (1997) Passage Maitre S, Jaber K, Perrot JL, et al (2002) radiation. Photochem Photobiol 18: 39 –41 of silver ions through membrane-mimetic Increased serum and urinary levels of silver Rosato AE, Tallent SM, Edmonds MB, materials, its relevance to treatment of burn during treatment with topical silver sulfadiazine. Bearman GML (2004) Susceptibility of wounds with silver sulfadiazine cream. Clin Ann Dermatol Venereol 129(2): 217–19 coagulase-negative staphylococcal nosocomial Chem 43(2): 290–301 Maple PAC, Hamilton-Miller JMT, Brumfitt W bloodstream isolates to the chlorhexidine/ Tunney MM Gorman S, Patrick S (1996) (1992) Comparison of the in-vitro activities of the silver sulfadiazine-impregnated central venous Infection associated with medical devices. Rev topical antimicrobials azelaic acid, nitrofurazone, catheter. Am J Infect Control 32(8): 486–8 Med Micro 7(4): 195–205 silver sulphadiazine and mupirocin against Russell AD, Hugo WB (1994) Antimicrobial Veenstra DL, Saint S, Saha S, Lumley T, Sullivan SD methicillin-resistant Staphylococcus aureus. J activity and action of silver. Prog Medicinal (1999) Efficacy of antiseptic-impregnated central Antimic Chemother 29: 661–8 Chemistry 31: 351–70 catheters in preventing catheter-related bloodstream Marciante KD, Veenstra DL, Lipsky BA, Saint S Saffle JR, Schnebly WA (1994) Burn wound infection: a meta-analysis. JAMA 281: 261–7 (2003) Which antimicrobial impregnated central care. In: Richard RL, Stanley MJ, eds. Burn Viala J, Simon L, Le Pommelet C, et al (1997) venous catheter should we use? Modeling the Care and Rehabilitation: Principles and Practice. Agranulocytosis after application of silver costs and outcomes of antimicrobial catheter use. Davis Co, Philadelphia, USA: 137–9 sulfadiazine in a 2-month old infant. Arch Am J Infect Control 31(1): 1–6 Scott Ward R, Saffle JR (1995) Topical agents Pediatr 4(11): 1103–06 Marshall J P, Schneider R P (1977) Systemic in burn wound care. Phys Ther 75(6): 526–38 Wall IB, Davies CE, Hill KE, et al (2002) Potential argyria secondary to topical silver nitrate. Arch Serralta AW, Harrison-Balestra C, Cazzaniga role of anaerobic cocci in impaired human wound Dermatol 113: 1077–78 AL, Davis S, Mertz PM (2001) Lifestyles of healing. Wound Repair Regen 10(6): 346–53 McDonnell G, Russell AD (1999) Antiseptics bacteria in wounds: presence of biofilms? Wells TNC, Scully P, Paravincini G, Proudfoot and disinfectants: activity, action and Wounds 13(1): 29–34 AEI, Payton MA (1995) Mechanism of resistance. Clin Microbiol Rev 12(1): 147–79 Speck WT, Rosenkranz HS (1974) Activity of irreversible inactivation of phosphomannose McManus AT, Denton CL, Mason AD silver sulphadiazine against dermatophytes. isomerase by silver ions and Flamazine. (1983) Mechanisms of in vitro sensitivity to Lancet (ii): 895–6 Biochem 34: 7896–7903 sulfadiazine silver. Arch Surg 118: 161–6 Shear NH, Spielberg SP, Grant DM, et White RJ (2002) A historical overview of the use of Mertz P (2003) Cutaneous biofilms; friend or al (1986). Differences in metabolism of silver in wound management. Br J Nurs: S3–S8 foe? Wounds 15(5): 129–32 sulfonamides predisposing to idiosyncratic Willoughby ML (1977) Disorder of granulocytes, Modak SM, Fox CL (1981) Sulfadiazine silver- toxicity. Ann Int Med 105: 179–84 monocytes and lymphocytes. In: Paediatric resistant Pseudomonas in burns. Arch Surg 116: Silver S (2003) Bacterial silver resistance: Haematology. Churchill Livingstone, Edinburgh 854–7 molecular biology and uses and misuses of Wlodkowski TJ, Rosenkranz HS (1973) O’Meara SO, Cullum N, Majid M, Sheldon silver compounds. FEMS Micro Rev 27: 341–53 Antifungal activity of silver sulphadiazine. T (2000) Systematic reviews of wound care Slawson RM, Van Dyke M, Lee H (1992) Lancet (i): 739–40 management: (3) Antimicrobial agents. Health Germanium and silver resistance, accumulation Wright JB, Lam K, Burrell RE (1998) Wound Technol Assess 4(21): 1–237 and toxicity in MOs. Plasmid 27(1): 72–9 management in an era of increasing bacterial O’Meara S O, Cullum N, Majid M, Sheldon T Stern HS (1989) Silver sulphadiazine and the antibiotic resistance: A role for topical silver (2001) Systematic review of antimicrobial agents healing of partial thickness burns: a prospective treatment. Am J Infect Control 26(6): 572–7 used for chronic wounds. Br J Surg 88: 4–21 clinical trial. Br J Plast Surg 42(5): 581–5 Wright JB, Lam K, Hansen DL, Burrell RE Ostendorf T, Meinhold A, Harter C, et al (2005) Starodub ME, Trevors JT (1990) Silver (1999) Efficacy of topical silver against fungal Chlorhexidine and silver sulfadiazine coated accumulation and resistance in E. coli. J burn wound pathogens. Am J Infect Control central venous catheters in haematological Inorganic Biochem 39(4): 3017–25 27(4): 344–50

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