Mechanisms of cephalosporin nephrotoxicity: A comparison of cephaloridine and cephaloglycin

摘要

Of the various drugs in each of the three major groups of bactericidal antibiotics, the aminoglycosides regularly carry some risk of producing nephrotoxic side effects [1]. Of the approximately two dozen penicillins developed [2], so far only one (guanylureidopenicillin, BL-P1654) has recognized nephrotoxicity [3]. This drug has not been released for general use.Most of the cephalosporins are also not obviously nephrotoxic [1, 4, 5]. The production, however, of acute proximal tubular necrosis by therapeutic-range doses of cephaloridine [6], the second drug developed in this group, and by very large doses of the newer cephalosporins cefazolin [7] and cefa-mandole [8] has caused concern about the cephalosporins in general [4, 9-11]. This concern is influenced by the fact that the aminoglycosides and the cephalosporins are commonly used in combination. The consistent risk of toxicity from any drug in the former group makes a further risk from one in the latter group extremely undesirable.Studies in this laboratory have been mainly concerned with the cephalosporins. Our interest in this group of drugs was brought about by some unusual properties of cephaloridine. This antibiotic stands in sharp contrast to various other cephalosporins [5] and to the structurally related penicillins [2] in undergoing little or no net secretion by the mammalian kidney [12-14]. Cephaloridine is, however, highly cytotoxic to the proximal renal tubule [6, 12-15], the segment of the nephron responsible for the secretion of organic anions [16], including para-am-minohippurate (PAH), as well as the various penicillin and cephalosporin antibiotics [2, 5, 17]. The cytotoxicity of cephaloridine is completely prevented by probenecid [14, 18, 19] and several other inhibitors of organic anion transport [14, 20], including the nearly nontoxic [21] cephalosporin cephalothin [22].