PubMed · 9739249
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L A Mermel. 1998. Reducing risks with bacteriostatic flush solutions.. https://doi.org/10.1097/00152193-199808000-00017
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Triclosan is used widely as an antibacterial agent in dermatological products, mouthwashes, and toothpastes. Recent studies imply that antibacterial activity results from binding to enoyl (acyl carrier protein) reductase (EACPR, EC 1.3.1.9). We first recognized the ability of triclosan to inhibit EACPR from Escherichia coli in a high throughput screen where the enzyme and test compound were preincubated with NAD(+), which is a product of the reaction. The concentration of triclosan required for 50% inhibition approximates to 50% of the enzyme concentration, indicating that the free compound is depleted by binding to EACPR. With no preincubation or added NAD(+), the degree of inhibition by 150 nM triclosan increases gradually over several minutes. The onset of inhibition is more rapid when NAD(+) is added. Gel filtration and mass spectrometry show that inhibition by triclosan is reversible. Steady-state assays were designed to avoid depletion of free inhibitor and changes in the degree of inhibition. The results suggest that triclosan binds to E-NAD(+) complex, with a dissociation constant around 20-40 pM. Triclosan follows competitive kinetics with respect to NADH, giving an inhibition constant of 38 pM at zero NADH and saturating NAD(+). Uncompetitive kinetics are observed when NAD(+) is varied, giving an inhibition constant of 22 pM at saturating NAD(+). By following regain of catalytic activity after dilution of EACPR that had been preincubated with triclosan and NAD(+), the rate constant for dissociation of the inhibitor (k(off)) is measured as 1.9 x 10(-4) s(-1). The association rate constant (k(on)) is estimated as 2.6 x 10(7) s(-1) M(-1) by monitoring the onset of inhibition during assays started by addition of EACPR. As expected, the ratio k(off)/k(on) = 7.1 pM is similar to the inhibition constants from the steady-state studies. The crystal structure of E. coli EACPR in a complex with coenzyme and triclosan has been determined at 1.9 A resolution, showing that this compound binds in a similar site to the diazaborine inhibitors. The high affinity of triclosan appears to be due to structural similarity to a tightly bound intermediate in catalysis.
CONTEXT: A recent randomized controlled trial and meta-analysis indicated that central venous catheters impregnated with an antiseptic combination of chlorhexidine and silver sulfadiazine are efficacious in reducing the incidence of catheter-related bloodstream infection (CR-BSI); however, the ultimate clinical and economic consequences of their use have not been formally evaluated. OBJECTIVE: To estimate the incremental clinical and economic outcomes associated with the use of antiseptic-impregnated vs standard catheters. DESIGN: Decision analytic model using data from randomized controlled trials, meta-analyses, and case-control studies, as well as safety data from the US Food and Drug Administration. SETTING AND PATIENTS: A hypothetical cohort of hospitalized patients at high risk for catheter-related infections (eg, patients in intensive care units, immunosuppressed patients, and patients receiving total parenteral nutrition) requiring use of a central venous catheter. INTERVENTION: Short-term use (2-10 days) of chlorhexidine-silver sulfadiazine-impregnated multilumen central venous catheters and nonimpregnated catheters. MAIN OUTCOME MEASURES: Expected incidence of CR-BSI and death attributable to antiseptic-impregnated and standard catheter use; direct medical costs for both types of catheters. RESULTS: In the base-case analysis, use of antiseptic-impregnated catheters resulted in a decrease in the incidence of CR-BSI of 2.2% (5.2% for standard vs 3.0% for antiseptic-impregnated catheters), a decrease in the incidence of death of 0.33% (0.78% for standard vs 0.45% for antiseptic-impregnated), and a decrease in costs of $196 per catheter used ($532 for standard vs $336 for antiseptic-impregnated). The decrease in CR-BSI ranged from 1.2% to 3.4%, the decrease in death ranged from 0.09% to 0.78%, and the costs saved ranged from $68 to $391 in a multivariate sensitivity analysis. CONCLUSION: Our analyses suggest that use of chlorhexidine-silver sulfadiazine-impregnated central venous catheters in patients at high risk for catheter-related infections reduces the incidence of CR-BSI and death and provides significant saving in costs. Use of these catheters should be considered as part of a comprehensive nosocomial infection control program.
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