Mechanisms of cephalosporin nephrotoxicity: A comparison of cephaloridine and cephaloglycin

Abstract

Certain members of the cephalosporin group of antibiotics have the potential for producing acute proximal tubular necrosis. This renal toxicity is a potential problem with cephaloridine in the therapeutic dose range. Although cefazolin and cefamandole have no documented significant nephrotoxicity in human use, very large doses of these cephalosporins produce the same lesion in laboratory animals as does cephaloridine. The striking toxicity of cephaloridine is closely related to unusually high cortical antibiotic concentrations. Several lines of evidence have been presented that these high concentrations are the result of a relative restriction of movement of cephaloridine into the luminal fluid after its active transport into the proximal tubular cell at the antiluminal side. Evidence is presented here that cephaloridine toxicity is at least partly mediated by an inhibitory effect on tubular cell mitochondrial respiration. Recent studies with cephaloglycin, a cephalosporin released only for oral administration, have shown it to be at least as toxic as cephaloridine in rabbits and guinea pigs. Cortical concentrations of cephaloglycin, however, are much lower than those of cephaloridine and are no higher than those of the nontoxic cephalexin. In further conrast, the prolonged intracellular trapping seen with cephaloridine does not occur with cephaloglycin. Preliminary evidence is discussed that lends support to the hypothesis that cephaloridine may act as a relatively reversible toxin at the intracellular level, with tubular necrosis resulting from persistent and high local concentrations, and further that the molecular toxicity of cephaloglycin is greater and/or more irreversible, resulting in necrosis after the more transient occurrence of lower intracellular concentrations.