Augmentation of antibiotic nephrotoxicity by endotoxemia in the rabbit

BM Tune and CY Hsu

The acute renal failure complicating bacterial septicemia has multiple potential causes, prominent among which are endotoxemic and antibiotic nephrotoxic injury. Because the toxic interactions of endotoxin and antibiotics cannot be manipulated for study in human disease, we have developed a model of this interaction in the rabbit. Toxicity was assessed by quantification of tubular necrosis and serum creatinine concentrations 48 hr after single-dose i.v. endotoxin and/or antibiotic administration. A minimally nephrotoxic quantity of endotoxin (Escherichia coli lipopolysaccharide 0111:B4, 0.5 mg/kg b.w.) significantly increased the nephrotoxicity of the cephalosporins cephaloglycin (60 mg/kg) and cephaloridine (90 mg/kg) and the aminoglycoside neomycin (60 mg/kg), each of which was mildly-to- minimally damaging by itself. In studies of the acute functional effects of endotoxemia, the lipopolysaccharide had different effects on the renal handling of the two cephalosporins. Endotoxin increased the uptake of cephaloglycin, but decreased uptake of cephaloridine, in renal cortex in the first 0.5 hr after antibiotic administration. However, a prolonged elevation of serum levels of cephaloridine allowed later uptake of toxic amounts of this cephalosporin. Although these findings suggest a role of altered transport in the endotoxin- cephalosporin toxic synergy, the synergy was not reduced when cephaloglycin was given 1.5 hr before the endotoxin, a time which allows substantial elimination of antibiotic before the endotoxemic insult. Studies in another laboratory have demonstrated an endotoxin- induced increase of cortical concentrations of aminoglycosides, which could be a mechanism of the augmented toxicity seen in the present study. It is concluded that endotoxemia causes significant augmentation of the nephrotoxicity of cephalosporin and aminoglycoside antibiotics.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 234, Issue 2, pp. 425-430, 08/01/1985
Copyright © 1985 by American Society for Pharmacology and Experimental Therapeutics