Antimicrobial treatment ameliorates delirium-like phenotypes in a murine model of urinary tract infection.

Practice guidelines recommend withholding antimicrobial therapy (ABX) in delirious patients with suspected urinary tract infection (UTI) who do not endorse classic genitourinary symptoms, citing both a lack of a causal relationship between bacteriuria and delirium and benefit from ABX. In this study, we tested the hypothesis that UTI induces delirium-like phenotypes that are mitigated by ABX. Escherichia coli (CFT073) UTI was induced in female C57BL/6 J mice aged 4-5 months. Mice were randomized to receive one dose of ceftriaxone 600 mg/kg (n = 23) or saline (n = 21) one day after induction of UTI. Delirium-like behaviors were assessed using Open Field, Elevated Plus Maze, and Y-maze, while neurostructural changes were evaluated using neuronal cleaved caspase-3 (CC3) and interleukin-6 (IL-6) via immunohistochemistry. Plasma IL-6 was quantified using ELISA. Compared to vehicle-treated mice, ABX mice with UTI demonstrated: 1) decreased time in the periphery of the Open Field maze (p = 0.017), 2) decreased time in the closed arms of the Elevated Plus Maze (p = 0.013), and 3) increased spontaneous alternations in Y-maze (p = 0.015). These behavioral changes were accompanied by significantly lower frontal/hippocampal CC3 (p = 0.0038, p = 0.0003, respectively) and IL-6 (p = 0.015) levels in ABX- compared to vehicle-treated UTI mice. ABX significantly lowered plasma IL-6 compared to vehicle-treated UTI mice (p < 0.01). This study suggests a causal relationship between UTI and functional/neurostructural delirium-like phenotypes that are attenuated with ABX. These findings provide strong rationale for a randomized clinical trial to evaluate the role of ABX in patients with delirium as the isolated presumed sign of UTI.