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

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 μCi) was administered. Despite a substantial elevation in plasma levels of the proinflammatory cytokines tumor necrosis factor alpha, interleukin-1β, 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.