Effect of E. coli pyelonephritis on the intracortical accumulation kinetics of gentamicin and netilmicin in rats.

The role of serum levels on the intrarenal accumulation kinetics of gentamicin and netilmicin in normal and infected kidneys was evaluated in a short-term infusion model in conscious rats. Female Sprague-Dawley rats were infused over a period of 6 h with gentamicin and netilmicin achieving individual steady-state serum levels ranging from 0.5 to 120 micrograms/ml. The model of pyelonephritis used resulted in severe left pyelonephritis and mild right pyelonephritis. Only the right infected kidneys were studied. Gentamicin and netilmicin cortical concentrations were analysed as a function of serum levels by linear (least-squares regression analysis) and non-linear regression. For the non-linear regression analysis, the Michaelis-Menten kinetic was the best fitting curve. Steady-state elevation of serum concentrations of gentamicin and netilmicin was associated with a non-linear increase of cortical concentrations in normal kidneys, suggesting a saturable process. By contrast, in the mildly-infected right kidneys, the steady-state elevation of serum concentrations of gentamicin was associated with a linear increase of cortical concentrations while the accumulation kinetic of netilmicin showed a saturable process. At lower serum levels (therapeutic range, from 0.5 to 15 micrograms/ml) both gentamicin and netilmicin showed a first order kinetics of accumulation and netilmicin accumulated less than gentamicin in normal kidneys (p = 0.0004). By contrast, the uptake of netilmicin was higher in the right infected kidneys, as compared to the uptake of netilmicin in the normal kidneys, (p = 0.00005), and as compared to gentamicin in the respective kidneys. We conclude that renal infection modifies the intrarenal accumulation of aminoglycosides.