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

Abstract

Bacterial infections are a major cause of morbidity and mortality in both the community and nosocomial settings, particularly among the elderly and chronically ill. Sepsis is the body's response to antigens and toxins released by the invasive pathogenic organisms that cause infection. When infection is not effectively controlled, sepsis may develop and progress to severe sepsis and septic shock. Early diagnosis and treatment is pivotal for survival in severe sepsis and particularly, septic shock. Our research focuses on developing a novel treatment strategy for septic shock by using single, ultra-high doses of aminoglycosides.In this project, the effect of a single, ultra-high dose of gentamicin in clearing bacteria from the blood and reducing the bacterial burden in vital organs was evaluated in a rat model of E. coli (Bort strain) induced peritonitis with severe sepsis/septic shock. Serum cytokine levels and serum lactate levels were serially measured. Further, the potential adverse effects of ultra-high dosing of aminoglycoside antibiotics in a short-term (9 h) invasive study and longterm (180 days) non-invasive study were assessed. Neuromuscular paralyses due to ultra-high doses of aminoglycosides were assessed. In addition, renal injury markers such as serum creatinine and urinary Neutrophil Gelatinase Associated Lipocalin (NGAL) were assayed.The auditory and vestibular function was also assessed after ultra-high dosing of aminoglycoside in the long-term study.We conclude that animals can tolerate ultra-high doses of aminoglycosides with appropriate support. Animals were under neuromuscular paralysis for 28 -50 minutes and were on ventilator support after single ultra-high doses (80 and 160 mg/kg) of aminoglycoside antibiotics (gentamicin and tobramycin). There was no significant acute or delayed renal or ototoxicity associated with the single, ultra-high dose aminoglycoside therapy. Histology gratitude to my committee members Dr. Michelle Alfa, Dr. George Zhanel, Dr. Rob Ariano and Dr. Sheryl Zelenitsky for their continual support, feedback, encouragement and for their insightful comments. Special thanks to Dr. Phillip Gardiner for his support in performing pilot studies. I am thankful to Dr. Brian Blakley for his support for performing auditory brain stem response studies. I am also grateful to Dr.