A Single, Ultra‐High Dose Aminoglycoside Therapy in a Rat Model of E. coli Induced Septic Shock

Abstract

IntroductionSeptic shock is a life threatening condition often due to Gram negative bacterial infections and is responsible for around 200,000 deaths every year in United States of America alone. Our research focuses on determining the potential of a single, ultrahigh dose aminoglycoside therapy for accelerated bacterial clearance with minimal to manageable side effects in a rat model of E. coli induced septic shock.Methods: Study in uninfected animalsGentamicin was administered intravenously at 80 and 160 mg/kg doses to anesthetized and intubated Sprague Dawley rats. Mean arterial pressure, heart rate, respiratory rate and percentage oxygen saturation were determined. The occurrence and time course of neuromuscular paralysis/ventilator dependency, renal injury and auditory toxicity after ultra‐high dosing of gentamicin was determined. Renal injury was determined by Creatinine clearance and histology. Auditory brain stem response studies were performed to assess the auditory toxicity.Septic shock induced animalsSeptic shock was induced in rats by surgical, intra‐peritoneal implantation of a gelatin capsule containing E. coli bort (ATCC 700973) in a fibrinogen and alfa‐cellulose matrix. Gentamicin was intravenously administered at 5, 10, 20, 40, 80 and 160 mg/kg doses.ResultsUltra high gentamicin dosed animals were found to develop neuromuscular paralysis with ventilator dependency for 20 – 40 minutes and recovered thereafter. Rats did not exhibit any auditory and renal toxicity. Complete eradication of bacterial counts from blood occurred following ultra‐high doses.ConclusionRats were able to tolerate single, ultra‐high doses of gentamicin with complete eradication of bacterial counts from blood.Research is supported by University of Manitoba