A Rat Model of Early Sepsis: Relationships between Gentamicin Pharmacokinetics and Systemic and Renal Effects of Bacterial Lipopolysaccharide Combined with Interleukin-2

Abstract

A rat model of early sepsis induced by lipopolysaccharide (LPS) combined with interleukin-2 (IL-2) was developed. The primary aim was to assess the pharmacokinetics of gentamicin and sepsis-induced pathophysiological changes. Moreover, the effects on the glomerular filtration rate and tubular function were studied in septic and control rats. First, an intravenous (i.v.) bolus of LPSIL-2 (1 mg/kg-Pseudomonas aeruginosa, 15 µg/ kg IL-2) or saline (controls, C) was administred. The Wistar rats were treated 30 min after LPSIL-2 with gentamicin as a 3 mg/kg i.v. bolus followed 10 min later by an i.v. 170-min infusion (GE, 0.09 mg/kg·min 1 ). The monitoring of vital functions, biochemistry and GE concentrations was performed. Creatinine clearance was 2-3 times lower and fractional urea excretion was 3-4 times less in septic rats as compared to controls(p<0.05), although urine flow was comparable. Capillary leakage caused a 55% elevation in the volume of distribution (V c ) in the LPSIL GE group vs. C GE (p<0.05). The renal CL ge was less (2.2 0.59 vs. 3.8 0.53 mL/min·kg 1 , p<0.05), while the total CL ge was comparable (5.9 1.5 vs. 6.7 1.1 mL/min·kg 1 ; p 0.30). In the LPSIL GE group relative to C GE, the half-life (t 1/2 ) was 79% higher (p<0.05) and GE concentrations detected at the end of the study in the plasma and kidney were elevated 2.5-fold (p 0.09) and 2.2-fold (p<0.05), respectively. The model reproduced several consequences of early sepsis like in patients such as capillary leak, a decreased glomerular filtration rate (GFR) and the changes in pharmacokinetics of GE (increased values of V c and t 1/2 and a drop in renal CL ge proportional to that of CL cr ). Nonrenal routes which, for the most part, compensate the reduced renal CL ge in septic rats deserve further study.

Endotoxemia-mediated inflammation potentiates aminoglycoside-induced ototoxicity

“…Endotoxemia can change the volume of distribution for drugs, including gentamicin (32). Hydrolyzed Texas Red (hTR; a.k.a.…”

“…Low-dose LPS does not increase paracellular flux across the BLB Endotoxemia can change the volume of distribution for drugs, including gentamicin (32). hTR (also known as sulforhodamine 101; molecular mass, 679) is a membrane-impermeant fluorophore (33,34).…”

Cyclin-dependent kinase 2 protects podocytes from apoptosis

“…Puromycin aminonucleoside (PA) and LPS are known inducers of podocyte injury and apoptosis both in vitro and in vivo 32 33 34 35 . PA is a toxin used to induce experimental minimal change nephrosis in rats 36 , and LPS is an endotoxin from gram-negative bacteria that induces sepsis and proteinuria in mice and rats 12 37 38 . PA-treatment of cultured human podocytes for 48 hours decreased the expression level of CDK2 by 45% ( Fig.…”

Evaluation of Pseudomonas aeruginosa pathogenesis and therapeutics in military‐relevant animal infection models

“…Additionally, P. aeruginosa acute lung infection or intraperitoneal or intramuscular injection can cause bacteremia [197]. For studying P. aeruginosa systemic infection, pigs [198‐200], sheep [201‐204], dogs [205,206], rabbits [50], rats [207‐209], and mice [210,211] have been used. Not surprisingly, the major virulence and pathogenicity factors that are involved in invasiveness and development of other acute P. aeruginosa infections such as T3SS, flagella, pili, and siderophores are important in bacteremia/septicemia.…”