Intrarenal distribution of vancomycin in endotoxemic rats

Abstract

We previously observed that the intrarenal distribution of aminoglycosides was modified by Escherichia coli endotoxin in the absence of any major renal physiological disturbance or histological changes. In the present study, we evaluated the role of E. coli endotoxin on the intrarenal distribution of vancomycin. At the beginning of the experiment, female Sprague-Dawley rats were infused intravenously with saline (control) or endotoxin (0.25 mg/kg) during 15 min. Thereafter, saline was constantly infused for the following 4 h. Two hours after the beginning of the infusion, animals were injected intravenously with a single dose of vancomycin (20 mg/kg).The drug levels in serum; renal cortex, medulla, and papilla; and urine were evaluated from 0.08 to 24 h after injection. Analysis of the area under the curve of the drug concentration in the different kidney components versus time showed a higher accumulation of vancomycin in the renal cortex and medulla in the endotoxininfused rats than in the normal rats (P < 0.01). Endotoxin was associated with an increase in the half-life in serum (P < 0.01) and a lower elimination rate constant. The total clearance of vancomycin from plasma was significantly decreased in endotoxin-treated rats (P < 0.01). These results demonstrate that endotoxin modifies the renal handling of vancomycin.Vancomycin is a glycopeptide antibiotic with potent activity against gram-positive bacteria which may increase the nephrotoxic potential of aminoglycosides. The early preparation introduced in the 1950s had many impurities (14). During that period, although the nephrotoxic potential was not clearly established, up to 25% of patient were reported to have increased azotemia (29). When less toxic antistaphylococcal antibiotics, including the semisynthetic penicillins and cephalosporins, appeared, vancomycin use drastically diminished; but the emergence of methicillin-resistant staphylococci has prompted the resurgence of its use (27). The currently available compound has been purified and is believed to be less toxic than the parent compound. The incidence of nephrotoxicity with the new vancomycin has been less than 8% (11,23,27). In animals, large doses of antibiotics are needed to induce renal damage, and the mechanism of renal toxicity has not been determined. It seems that vancomycin accumulates within the renal parenchyma and induces an interstitial nephritis and proximal tubular necrosis.Endotoxin, an important constituent of the cell wall of gram-negative bacteria, has been classified as a major offender that is responsible for many complications associated with severe infections, including septic shock and renal failure. Endotoxin, which is liberated in infected patients and released in excess during antibiotic therapy (25), is able to modify the hemodynamic status of the host (13), to activate the immunological and inflammatory processes (6), to induce vasoconstriction (28), and to act directly on target cells and organelles to induce cell injuries (15,18).Previous experimental studies fr...

Effects of endotoxin derived from Escherichia coli lipopolysaccharide on the pharmacokinetics of drugs

“…Following the intravenous administration of 20-mg/kg vancomycin, an antibiotic, to female SD rats, 2 h after 15-min intravenous infusion of 0.25-mg/kg ECLPS and 4 h infusion of 0.5% NaCl solution, the Cl of vancomycin was significantly slower (39.7% decrease) than that in control rats (Ngeleka et al, 1989). However, the V dβ of vancomycin was comparable between two groups of rats (Ngeleka et al, 1989).…”

“…After one week, 0.5-µg/kg ECLPS was given intravenously. After cats had an increase in rectal temperature of at least Tanira et al, 1997Tarif et al, 1990Bergeron and Bergeron, 1986Jernigan et al, 1988Wilson et al, 1983Halkin et al, 1981Halkin et al, 1981Wilson et al, 1984 2 Netilmycin Significantly higher (112% increase) serum concentration of netilmycin at 1 h and decrease (58.3% decrease) in Ae 0-3 h of intravenous netilmycin at 3 h in rats Bergeron and Bergeron, 1986 3 Tobramycin Significantly higher (155% increase) serum concentration of tobramycin at 1 h and decrease (81.4% decrease) in Ae 0-3 h of intravenous tobramycin at 3 h in rats Bergeron and Bergeron, 1986 4 Amikacin Significantly higher (60.9% increase) serum concentration of amikacin at 1 h and comparable Ae 0-3 h of intravenous amikacin at 3 h in rats Bergeron and Bergeron, 1986 5 Cefalothin Significantly higher (124% increase) serum concentration of cefalothin at 1 h and decrease (43.2% decrease) in Ae 0-3 h of intravenous cefalothin at 3 h in rats Bergeron and Bergeron, 1986 6 PAH Significantly slower (18.2% decrease) intravenous Cl of PAH at 3 h in rats Bergeron and Bergeron, 1986 7 Inulin Significantly slower (29.4% decrease) intravenous Cl of inulin at 3 h in rats Bergeron and Bergeron, 1986 8 Vancomycin Significantly slower (39.7% decrease) intravenous Cl of vancomycin at 6 h in rats Ngeleka et al, 1989 9 SP-D The faster Cl of SP-D in rat lung tissue Herbein and Wright, 2001 10 1 o C, 3-mg/kg gentamicin was administered by the same routes mentioned above. Following the intravenous administration, the Cl and the V ss of gentamicin were comparable between two groups of cats (Jernigan et al, 1988).…”

Review of vancomycin-induced renal toxicity: an update

“…In severe sepsis, increase in the volume of distribution ultimately results from widespread endothelial injury and excess administration of resuscitative fluids. Furthermore, as evident in animal experiments, endotoxemia per se increases the intrarenal distribution of vancomycin while there is a reduction in its elimination kinetics [Ngeleka et al 1989]. Finally, due to the variability of pharmacokinetic parameters and the greater susceptibility to renal injury, therapeutic drug monitoring has been recommended in critically ill patients [Roberts et al 2011].…”

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.…”

“…Ngeleka et al [47] Vancomycin Increase Bergeron and Bergeron [41] Cephalothin No effect Beauchamp et al [48] Age Gentamicin Decrease Beauchamp et al [49] Fasting Gentamicin Increase Lin et al [50] Tobramycin Increase…”