Effect of Systemic Infection Induced by Pseudomonas aeruginosa on the Brain Uptake of Colistin in Mice

Abstract

In view of reports of colistin-induced neurotoxicity in infected patients, the aim of this study was to assess whether the integrity of the blood-brain barrier (BBB) and the brain uptake of colistin are altered in the presence of systemic Pseudomonas aeruginosa infection. Bacteremia was confirmed 8 h after intramuscular administration of P. aeruginosa ATCC 27853 to Swiss Outbred mice, at which time a single subcutaneous dose of colistin sulfate (40 mg/kg of body weight) or an intravenous dose of [ 14 C]sucrose (2 Ci) was administered. Despite a substantial elevation in plasma levels of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1␤, and interleukin-6 during bacterial infection, the brain uptake of colistin was similar between infected and noninfected mice with AUC brain /AUC plasma (where AUC brain is the area under the brain concentration-time curve and AUC plasma is the area under the plasma concentration-time curve) ratios of 0.023 and 0.024, respectively. Similarly, the brain-to-plasma ratios of [ 14 C]sucrose were no different between infected and noninfected mice, consistent with a lack of effect of bacteremia on BBB integrity. To further correlate any relationship between BBB disruption and plasma levels of proinflammatory cytokines, BBB integrity, colistin brain uptake, and plasma proinflammatory cytokines were measured following the administration of Salmonella enterica lipopolysaccharide (LPS), an agent known to induce BBB disruption. Despite LPS inducing a 4-fold increase in colistin brain uptake and a significant (P < 0.05) 1.2-fold increase in [ 14 C]sucrose BBB penetration, plasma cytokine levels were lower with LPS treatment relative to those obtained with bacterial infection with P. aeruginosa. This study demonstrates that the brain uptake of colistin is not increased in mice during P. aeruginosa-induced systemic bacteremia despite a significant increase in plasma levels of three proinflammatory cytokines.

Species-Dependent Blood-Brain Barrier Disruption of Lipopolysaccharide: Amelioration by ColistinIn VitroandIn Vivo

“…Studies have demonstrated that direct administration of cytokines significantly enhances BBB permeability both in animals and in brain endothelial cell monolayers (10)(11)(12)(13)(14). However, in our previous studies involving inoculation of Pseudomonas aeruginosa to mice, despite significant increases in the plasma concentrations of the three above-mentioned cytokines, the BBB paracellular integrity was not compromised (15). These studies suggested a lack of correlation between the release of these three cytokines and BBB disruption.…”

“…In order to address whether the disparity resulted from the differences between the bacterial species, the effect of LPS from P. aeruginosa on BBB dynamics was assessed. After being administered in the same dosing regimen used for LPS from S. enterica (i.e., 3 mg/kg at 0, 6, and 24 h) (15), the brain uptake of [ 14 C]sucrose and colistin in mice treated with P. aeruginosa LPS was not different from that in saline-treated mice. In contrast, significantly higher […”

“…These studies suggested a lack of correlation between the release of these three cytokines and BBB disruption. This lack of correlation was further strengthened by the observations that LPS from S. enterica, which induced a lower proinflammatory response than P. aeruginosa bacterial infection, caused greater BBB disruption (15). This suggests that there may be a direct TJ-disrupting effect of LPS via activation of LPS receptors expressed at the brain endothelial cells.…”

“…injections of LPS from S. enterica (9). This suggested that the brain uptake of this antibiotic may also be enhanced during bacterial infection; however, with bacteremia caused by P. aeruginosa, BBB integrity and brain uptake of colistin remained unaltered in mice (15). In order to address whether the disparity resulted from the differences between the bacterial species, the effect of LPS from P. aeruginosa on BBB dynamics was assessed.…”

“…No absorbance was detected with untreated plasma, suggesting that the assay was not affected by the endogenous components within plasma. These plasma cytokine concentrations were compared to those obtained following administration of LPS from S. enterica under the same experimental conditions (15).…”