Silver sulfadiazene

Silver and mercury salts have a long history of use as antibacterial agents.241-243 The use of mercurochrome ((40), Figure 18) as a topical disinfectant is now discouraged. Silver sulfadiazene (38) finds use for treatment of severe burns the polymeric material slowly releases the antibacterial Ag+ ion. Silver nitrate is still used in many countries to prevent ophthalmic disease in newborn children.244 The mechanism of action of Ag and Hg is through slow release of the active metal ion—inhibition of thiol function in bacterial cell walls gives a rationale for the specificity of bacteriocidal action. 

Sulfonamides have been extensively used in medicine for their antibacterial properties. Silver sulfadiazene (Af-pyrimidin-2-ylsulfanilamide, 41), when applied topically, has proved effective in preventing infections in bums victims.335,336... 

Many agents have been employed in attempts to treat the injuries caused by bums. One of these, which has become established in the topical treatment of severe burns is silver in the form of silver sulfadiazene, which is applied as a cream. 

The early studies in the use of silver sulfadiazene were reviewed and widely popularized by Moyer (Monafo and Moyer 1968). The entire subject area covering the early uses of silver, through to present-day applications, has been extensively reviewed by iQasen (2000a,b). The first topical application in the treatment of wounds and ulcers employed silver nitrate or lunar caustic, and this material became widely used in the treatment of burns and inflammation. 

At about the time silver nitrate was introduced to clinical practice, silver sulfadiazene was also introduced (Fox 1983). This combination of silver nitrate and sodium sulfadia-... 

The action of SSD relies on its interaction with serum and other NaCl-containing fluids, which permits a slow release of silver ions (Fox and Modak 1974). Treatment of acute burn wounds with silver sulfadiazene has remained common in clinical practice to the present day indeed, it has become widely accepted as the standard treatment. However, concerns have been raised with respect to the potential toxicity of silver when in intimate contact with tissue for relatively long periods of time. In particular, there is concern that SSD may pass into the bloodstream and be distributed systemi-cally (Tsipsouras et al. 1997). Most studies have shown that very little silver is transported beyond the superficial layer of the wound (Harrison 1979), though some studies have demonstrated the potential for silver ion transport and subsequent toxicity (Sun et al. 1994). 

The toxic dose levels of silver and silver compounds have been determined in animal toxicity studies (Sweet 1989). In mice, orally administered silver nitrate had an LD50 of 50 mg kg (the LD50 is the dose required to kill 50% of the test group), whilst silver sulfadiazene had an LD50 of 5000 mg kg. In occupational medicine, the MAK-value (maximum allowable concentration at the workplace) has been set at 0.1 mg m for metallic silver and 0.01 mg m for silver salts as Ag (DFG 2002). The same values were set as TLV (Threshold Limit Values) in the USA (ACGIH 2002). 

Fox cl (1983) Topical therapy and the development of silver sulfadiazene. Surg Gynecol Obstet 157 82-... 

Fox cl and Modak SA (1974) Mechanism of silver sulfadiazene action on burn wound infections. Antimicrob Agents Chemother 5 582-588. 

Harrison HN (1979) Pharmacology of silver sulfadiazene. Arch Surg 114 281-285. 

Huth TS, Burke JP, Larsen RA, Classen DC and Stevens LE (1992) Randomised trial of metal care with silver sulfadiazene cream for the prevention of catheter associated bacteriuria. J Infect Dis 165 14-18. 

Tsipsouras N, Rix CJ and Brady PH (1995) Solubility of silver sulfadiazene in physiological media and relevance to treatment of thermal burns with silver sulfadiazene cream. Clin Chem 41 87-91. 

Many common antibacterial agents are silver- and mercury-based - such as silver sulfadiazene and mercurochrome. Their uses and purported mechanisms have been summarized in a previous monograph and will not be presented in great length in this volume. 

Fig. 9.2. A schematic structure of silver sulfadiazene (AgSD). The R group is P-QH4NH2. The coordination around Ag is approximately tetrahedral. From Reference 19.

Silver sulfadiazene is a characterized silver complex used as an antibacterial in the treatment of burns. The polymeric aggregation of the material renders it almost insoluble in water but allows for slow release of the active silver ion. Mercury salts, probably acting by non-specific thiol binding, have been known to be bacteriostatic for many years and were of undoubted chemotherapeutic utility in earlier centuries. 

Antibacterial complexes such as silver sulfadiazene and some mercurials also manifest antiviral activity [51, 52]. Mersalyl, a diuretic (Chapter 12), has some in vivo action when mice treated with lethal doses of coxsackie virus are then administered the mercury complex [53]. The levels needed for 100% inactivation in vitro by mercurials is dependent on the virus, and thiols reverse the antiviral effect [54]. Conformational changes and breakdown into subunits have also been observed after mercury treatment [51],... 

Silver sulfadiazene inhibited the infectivity of both types of HSV Herpesvirus hominis) rapidly in vitro and much more effectively than did AgN03 [55]. Application in vivo was effective against development of herpetic keratoconjunctivitis, which leads to encephalitis [56]. A silver metachloridine complex has been claimed to have similar properties to that of the sulfadiazene [57]. Miscellaneous species whose antiviral effects have been reported include the Rh(I) organometallic complex, [Rh(acac)(COD)] [58] and Mn(II) Schiff base complexes [59]. 

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