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 Wounds UK 51 p.51-61White and Cooper.indd 3 18/7/05 10:11:16 am Clinical REVIEW 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