Triclosan as a systemic antibacterial agent in a mouse model of acute bacterial challenge

Abstract

The upsurge of multiple-drug-resistant microbes warrants the development and/or use of effective antibiotics. Triclosan, though used in cosmetic and dermatological preparations for several decades, has not been used as a systemic antibacterial agent due to problems of drug administration. Here we report the striking efficacy of triclosan in a mouse model of acute systemic bacterial infection. Triclosan not only significantly extends the survival time of the infected mice, it also restores blood parameters and checks liver damage induced by the bacterial infection. We believe that the excellent safety track record of triclosan in topical use coupled with our findings qualifies triclosan as a candidate drug or lead compound for exploring its potential in experimental systems for treating systemic bacterial infections.

FIG. 1.

Survival times based on a a low-dose, galactosamine-sensitized mouse model of an acute, systemic E. coli infection. The survival time of the mice was 48 h (±5 h) upon triclosan treatment compared to only 8 h (±1 h) for untreated and 28 h (±3 h) and 24 h (±2 h) for ampicillin- and tetracycline-treated mice, respectively. Statistical significance was tested by one-way ANOVA (P < 0.001, n = 5). (Inset) Triclosan administration along with, instead of prior to, infection as well as intraperitoneal administration instead of subcutaneous administration also increased the survival time to 48 h.

FIG. 2.

Liver histopathology (methylene blue and eosin yellow staining) indicates normal biliary parenchyma in control (a) and triclosan-administered (b) mice. Liver sections of infected mice (c) show hydropic and fatty changes with areas of hemorrhage, indicative of severe liver damage, which is considerably reduced in infected mice administered triclosan (d).

FIG. 3.

The serum TNF-α level, undetectable in the untreated mice, was elevated in mice with bacterial infection. Triclosan, ampicillin, or tetracycline administration prior to infection resulted in a significantly lower level of TNF-α. Animals not infected with bacteria but treated with triclosan showed no TNF-α in their sera. Animals treated with 500 μg of LPS/kg had TNF-α levels of 5.2, 6.0, and 4.6 at 1, 2, and 3 h, respectively.

FIG. 4.

Counts of viable bacteria in the blood of infected control mice (bars labeled “1”), ampicillin-treated mice (bars labeled “2”), or triclosan-treated mice (bars labeled “3”) after 3 h (open bars), 7 h (hatched bars), 10 h (checkerboard bars), and 45 h (solid bar). Triclosan or ampicillin administration resulted in lower bacteremia.

FIG. 5.

FPLC detection of triclosan levels in blood with a C₁₈ reverse-phase column by monitoring absorbance at 230, 240, and 280 nm. Triclosan levels in blood were detectable by 3 h after intraperitoneal injection. Triclosan levels were detected at 3, 7, 10, 20, and 36 h after infection. Additional dosages of triclosan were given at 12, 24, and 36 h, respectively.

FIG. 6.

Inhibition curves of ampicillin (MIC, 8 μM) (a), tetracycline (MIC, 5 μM) (b), and triclosan (MIC, 600 nM) (c). The IC₅₀ of triclosan was found to be around 150 nM, and the MIC was 600 nM. OD₆₀₀, optical density at 600 nm.