Fluoroquinolone-Associated Disability: A Rodent Model Reveals Transient Neuropsychiatric and Persistent Gastrointestinal Effects of Low-Dose Ciprofloxacin

Background/Objectives: Fluoroquinolones (FQs) are broad-spectrum antibiotics associated with a constellation of severe, long-lasting adverse effects termed Fluoroquinolone-Associated Disability (FQAD), which often includes neuropsychiatric and gastrointestinal (GI) symptoms. Despite patient reports, GI dysfunction is not formally recognized within FQAD. This study aimed to establish a rodent model to investigate whether ciprofloxacin (CPX), the most commonly prescribed FQ, exposure induced long-lasting anxiety-like behavior and/or GI motility alterations. Methods: To test our hypothesis, Sprague Dawley rats were orally administered 20 mg/kg CPX, amoxicillin (AMX, antibiotic control), or saline (CTL) daily for 14 days. Anxiety-like behaviors were assessed weekly for 4 weeks post-treatment using the Elevated Plus-Maze, Marble Burying, and Open Field tests. GI transit was measured 2 weeks post-treatment via phenol red dye recovery analysis from the stomach and portions of the small intestine. Results: Our results demonstrated that CPX induced a transient, mild anxiety-like phenotype in rats, with behavioral changes largely resolving by week 4, becoming statistically indistinguishable from the CTL group. In contrast, CPX significantly accelerated GI transit, similar to the known prokinetic AMX, as evidenced by increased fractional dye recovery in the stomach and distal small intestine. This accelerated GI motility persisted weeks after CPX discontinuation. Conclusions: These findings establish a putative rodent model for FQAD, providing evidence that even small doses of CPX can induce acute, transient neuropsychiatric effects and, critically, persistent GI dysmotility. This supports the inclusion of GI dysfunction in FQAD symptomatology and highlights the need for judicious FQs prescription and comprehensive patient monitoring.