Influence of hydrocortisone succinate on intrarenal accumulation of gentamicin in endotoxemic rats

Abstract

Gentamicin is a commonly used antibiotic in the treatment of gram-negative infections including septicemia and pyelonephritis. Bacterial endotoxin is liberated during antibiotic therapy and may lead to endotoxemic shock. Steroids such as hydrocortisone are generally recommended in the treatment of endotoxemic shock. There are very limited data on the influence of endotoxin or corticosteroids on the pharmacology of antibiotics, especially aminoglycosides, which are nephrotoxic. We studied the influence of both Escherichia coli endotoxin and hydrocortisone succinate on the renal uptake of gentamicin in rats. Animals were injected intravenously with endotoxin (0.25 mg/kg) and/or hydrocortisone (25 mg/kg) plus gentamicin (10 mg/kg). Gentamicin levels in the serum and renal parenchyma as well as renal function and histology were evaluated. Both endotoxin and hydrocortisone given alone increased the concentration of gentamicin in the renal cortex (P < 0.05). Normal values in serum were observed in all groups at most time intervals. When administered together, endotoxin and hydrocortisone did not potentiate each other. The combination of endotoxin and hydrocortisone gave significantly higher levels of gentamicin than endotoxin or hydrocortisone alone when endotoxin was injected 3 h before hydrocortisone (P < 0.05). Blood pressure and cardiac frequency were normal when gentamicin was given. Endotoxin alone slightly decreased the glomerular filtration rate, and hydrocortisone alone slightly modified renal plasma flow. The combination of both drugs did not significantly affect renal function. No histological lesion was noted on light microscopy in animals receiving endotoxin. Competitive or synergistic activity of endotoxin, gentamicin, and hydrocortisone at the cellular level, especially on membranes or lysosomes, might explain in part our observation on the renal uptake of gentamicin. By increasing the total amount of drug within the kidney, endotoxin and hydrocortisone might increase the risk of nephrotoxicity associated with aminoglycosides.Previous studies done in our laboratory revealed that the intrarenal distribution of gentamicin is disturbed in experimental pyelonephritis owing to Escherichia coli (7). Pyelonephritic kidneys were also shown to be more susceptible to the nephrotoxic potential of gentamicin than normal kidneys (3). The mechanism by which infection of the kidney influences the intrarenal pharmacology and the nephrotoxic potential of gentamicin is not known. Endotoxin is liberated during antibiotic therapy (29), and it may disturb the intrarenal pharmacokinetics of gentamicin (4). In fact, a greater accumulation of drug is observed in the renal cortex and medulla of endotoxin-treated animals than in the kidneys of normal animals (4). How endotoxin interacts with aminoglycosides at the tubular level is unknown, but it increases the uptake of drugs in both the proximal and distal tubules (5). Endotoxin has been shown to disturb the hemodynamic status of the host (14)

Pharmacologic basis for the treatment of pyelonephritis

“…The intrarenal levels of aminoglycosides [41][42][43][44][45][46] and vancomycin [47] were significantly increased following the injection of endotoxin in rats, whereas endotoxin had no effect on cephalothin [41]. Other factors such as old age are associated with lower levels of gentamicin in the renal tissue [48], whereas kidney levels of gentamicin [49] and tobramycin [50] are increased following a short period of fasting.…”

“…However, studies done in our laboratory suggested a synergistic effect between endotoxin and such anti-inflammatory compounds as hydrocortisone [44], indomethacin [45], and thromboxane A 2 antagonist [46] in increasing the serum and renal levels of aminoglycosides, suggesting a role of the arachidonic cascades in these interactions.…”

“…Bergeron et al [30]; Beauchamp et al [32] Escherichia coli pyelonephritis Gentamicin Increase Leclerc et al [34••] Fleroxacin Increase Unpublished data Temafloxacin Increase Trottier and Bergeron [37] Ampicillin Decrease Bergeron and Marois [33] Cephalothin Decrease Bergeron and Marois [33]; Bergeron et al [35] Trimethoprim No effect Bergeron and Marois [33]; Bergeron et al [35] Sulfamethoxazole No effect Auclair et al [39]; Jullien et al [40] Enterococcus faecalis pyelonephritis Tardif et al [43]; Bergeron et al [44,45]; Tardif et al [46] Endotoxinemia Gentamicin Increase…”

Principes pharmacologiques du traitement de la pyélonéphrite : distribution, efficacité et toxicité rénale des antibiotiques

“…Différentes études ont été effectuées afin d'évaluer les effets de l'inhibition de divers média teurs vasoactifs libérés après l'injec tion d'endotoxine. Des études de pharmacocinétique sérique et tissu laire de la gentamicine chez des ani maux traités avec de l'endotoxine ont montré que des anti-inflammatoires tels que l'hydrocortisone [24] , l'indo métacine [25] et un antagoniste de la thromboxane A 2 [26] avaient un effet qui se surajoutait à celui de l'endo toxine sur l'accumulation corticale de la gentamicine, suggérant un rôle de la cascade des dérivés de l'acide ara chidonique dans ces interactions.…”