No abstract

Indwelling medical devices are associated with infectious complications. Incorporating antimicrobials into indwelling materials may reduce bacterial colonization. Bismuth thiols are antibiofilm agents with up to 1,000-fold-greater antibacterial activity than other bismuth salts. Staphylococci are particularly sensitive, as determined by agar diffusion and broth dilution susceptibility testing. Bismuth-ethanedithiol inhibited 10 methicillin-resistant Staphylococcus epidermidis strains at 0.9 to 1.8, Staphylococcus aureus ATCC 25923 at 2.4, and S. epidermidis ATCC 12228 at 0.1 M Bi 3؉ . Antiseptic-resistant S. aureus was sensitive to bismuth-2-3-dimercaptopropanol (BisBAL) at <7 M Bi 3؉ . Hydrogel-coated polyurethane rods soaked in BisBAL inhibited S. epidermidis for 39 days (inhibitory zone diameter in agar, >30 mm for >25 days). Slime from 16 slimeproducing S. epidermidis strains was inhibited significantly by bismuth-3,4-dimercaptotoluene (BisTOL), but not by AgNO 3 , at subinhibitory concentrations. In conclusion, bismuth-thiols are bacteriostatic and bactericidal against staphylococci, including resistant organisms, but are also inhibitors of slime at subinhibitory concentrations. At subinhibitory concentrations, BisTOL may be useful in preventing the colonization and infection of indwelling intravascular lines, since staphylococci are important pathogens in this setting.

The antibacterial properties of bismuth are greatly enhanced when bismuth is combined with certain lipophilic thiol compounds. Antibacterial activity was enhanced from 25- to 300-fold by the following seven different thiols, in order of decreasing synergy: 1,3-propanedithiol, dimercaprol (BAL), dithiothreitol, 3-mercapto-2-butanol, beta-mercaptoethanol, 1-monothioglycerol, and mercaptoethylamine. The dithiols produced the greatest synergy with bismuth at optimum bismuth-thiol molar ratios of from 3:1 to 1:1. The monothiols were generally not as synergistic and required molar ratios of from 1:1 to 1:4 for optimum antibacterial activity. The most-active mono- or dithiols were also the most soluble in butanol. The intensity of the yellow formed by bismuth-thiol complexes reflected the degree of chelation and correlated with antibacterial potency at high molar ratios. The bismuth-BAL compound (BisBAL) was active against most bacteria, as assessed by broth dilution, agar diffusion, and agar dilution analyses. Staphylococci (MIC, 5 to 7 microM Bi3+) and Helicobacter pylori (MIC, 2.2 microM) were among the most sensitive bacteria. Gram-negative bacteria were sensitive (MIC, < 17 microM). Enterococci were relatively resistant (MIC, 63 microM Bi3+). The MIC range for anaerobes was 15 to 100 microM Bi3+, except for Clostridium difficile (MIC, 7.5 microM). Bactericidal activity averaged 29% above the MIC. Bactericidal activity increased with increasing pH and/or increasing temperature. Bismuth-thiol solubility, stability, and antibacterial activity depended on pH and the bismuth-thiol molar ratio. BisBAL was stable but ineffective against Escherichia coli at pH 4. Activity and instability (reactivity) increased with increasing alkalinity. BisBAL was acid soluble at a molar ratio of greater than 3:2 and alkaline soluble at a molar ratio of less than 2:3. In conclusion, certain lipophilic thiol compounds enhanced bismuth antibacterial activity against a broad spectrum of bacteria. The activity, solubility, and stability of BisBAL were strongly dependent on the pH, temperature, and molar ratio. Chelation of bismuth with certain thiol agents enhanced the solubility and lipophilicity of this cationic heavy metal, thereby significantly enhancing its potency and versatility as an antibacterial agent.

This study determined the effects of sodium salicylate combined with several aminoglycoside antibiotics on the growth and capsular polysaccharide (CPS) production of Klebsiella pneumoniae. Salicylate significantly enhanced in inhibitory effect of all aminoglycoside antibiotics against all bacterial strains tested. The production of CPS was decreased by 62-86% when 2.5 mM salicylate was used. Amikacin combined with salicylate reduced CPS only slightly more than salicylate alone. The chelating agents, ethylenediamine tetra-acetic acid and ethylene bis tetraacetic acid, which have similar CPS-reducing properties, did not enhance the inhibitory effect of amikacin. Noncapsular variants of strains of K. pneumoniae were as susceptible to amikacin as the fully encapsulated strains, with or without salicylate present. Therefore, the combination of salicylate and the aminoglycosides acted synergistically to inhibit K. pneumoniae growth, but the increase in antibiotic sensitivity with salicylate was not a result of a reduction in CPS production. The use of salicylate in maximum therapeutic doses may enhance the activity of aminoglycosides sufficiently to allow the dose of aminoglycoside to be reduced when infections due to K. pneumoniae are treated.