Single, ultra-high dose aminoglycoside therapy in a rat model of E. coli induced septic shock
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Date
2015
Authors
Pisipati, Amarnath
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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 long term (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 studies of the kidneys and the cochlea of single, ultra-high aminoglycoside dosed animals and untreated control animals were performed after 180 days (6 months). Results indicated that there were no morphological differences between the treated and untreated control animals. Terminal deoxy-nucleotidyl transferase dUTP nick end labeling (TUNEL) assay of kidney tissue indicated that there was no apoptosis of endothelial cells in the tubular and glomerular regions with single, ultra- high dose of aminoglycosides consistent with an absence of ultrahigh dose induced nephrotoxicity. In the septic shock model, the E. coli Bort was below the
limit of detection from the blood of the animals within minutes after single, ultra-high dose
aminoglycoside administration. After necropsy, bacterial load was determined from all the
vital organs and peritoneal fluid (site of infection). The bacterial levels were below the
detection limit from the kidneys and there was a significant reduction in bacterial counts from all the remaining organs compared to the infected control animals. A decrease in serum cytokine and serum lactate levels compared to baseline was observed after ultra-high doses of aminoglycosides in the septic shock animals. Our studies have indicated that the ultra-high dose gentamicin is well tolerated by rats. It is highly effective in clearing E. coli Bort from the blood and reducing the bacterial burden in the organs in an experimental model of bacterial peritonitis/septic shock. Further studies in larger animals such as rabbits, sheep, pigs or dogs are required to confirm these results. If these findings are replicated in larger animals, this therapy may be developed further from
‘lab to bedside’ to treat septic shock patients in intensive care units (ICUs).
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Keywords
Bacteria, Gram positive, Gram negative, infection, inflammation, cytokine storm, sepsis, septic shock, E. coli, hemodynamics, aminoglycosides, toxicity, neuromuscular paralysis, ototoxicity, auditory toxicity, vestibular toxicity