Nephrotoxicity of Cephalosporin Antibiotics

Mechanisms and Modifying Factors
  • Bruce M. Tune


Several of the cephalosporins produce acute proximal tubular necrosis when given in large single doses (Tune and Fravert, 1980b). The degree of nephrotoxicity varies considerably among the individual cephalosporins. As recently reviewed in a clinical context (Prime and Tune, 1981), toxicity is severe enough with some to restrict their use significantly, but ranges from relatively mild to absent with others (Tune and Fravert, 1980b). The reasons for these individual differences have not been fully elucidated.


Ureteral Obstruction Organic Anion Transport Mixed Function Oxidase Tubular Fluid Cephalosporin Antibiotic 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Atkinson, R. M., Currie, J. P., Davis, B., Pratt, D. A. H., Sharpe, H. M., and Tomich, E. G., 1966, Acute toxicity of cephaloridine, an antibiotic derived from cephalosporin C., Toxicol. Appl. Pharmacol 8:398.CrossRefGoogle Scholar
  2. Barany, E. H., 1973, The liver-like anion transport system in rabbit kidney, uvea and choroid plexus. I. Selectivity of some inhibitors, direction of transport, possible physiological substrates, Acta Physiol. Scand. 88:412.CrossRefGoogle Scholar
  3. Barza, M., 1978, The nephrotoxicity of cephalosporins: An overview, J. Infect. Dis. 137:S60.CrossRefGoogle Scholar
  4. Barza, M., Pinn, V., Tanguay, P., and Murray, T., 1978, Comparative nephrotoxicity of newer cephalosporins and aminoglycosides alone and in combination in a rat model, in: Current Chemotherapy, Volume II (W. Siegenthaler and R. Luthy, eds.), American Society for Microbiology, Washington, D.C., p. 964.Google Scholar
  5. Bendirdjian, J.-P., Prime, D. J., Browning, M. C., Hsu, C.-Y., and Tune, B. M., 1981, Additive nephrotoxicity of cephalosporins and aminoglycosides in the rabbit, J. Pharmacol. Exp. Ther. 218:681.Google Scholar
  6. Beyer, K. H., Woodward, F., Peters, L., Verwey, W. F., and Mattis, P. A., 1944, Prolongation of penicillin retention in body by means of para-aminohippuric acid, Science 100:107.CrossRefGoogle Scholar
  7. Boyd, M. R., 1976, Role of metabolic activation in the pathogenesis of chemically induced pulmonary disease: Mechanism of action of the lung-toxic furan, 4-ipomeanol, Environ. Health Persp. 16:127.CrossRefGoogle Scholar
  8. Brogard, J. M., Comte, F., and Pinget, M., 1978, Pharmacokinetics of cephalosporin antibiotics, Anti-biot. Chemother. 25:123.Google Scholar
  9. Butterworth, D., Cole, M., Hanscomb, G., and Rolinson, G. N., 1979, Olivanic acids, a family of β-lactam antibiotics with β-lactamase inhibitory properties produced by streptomyces species. I. Detection, properties and fermentation studies, J. Antibiot. 32:287.CrossRefGoogle Scholar
  10. Child, K. J., and Dodds, M. G., 1967, Nephron transport and renal tubular effects of cephaloridine in animals, Br. J. Pharmacol. Chemother. 30:354.CrossRefGoogle Scholar
  11. Dellinger, P., Murphy, T., Pinn, V., Barza, M., and Weinstein, L., 1976, Protective effect of cephalothin against gentamicin-induced nephrotoxicity in rats, Antimicrob. Agents Chemother. 9:172.CrossRefGoogle Scholar
  12. Dolislager, D., Fravert, D., and Tune, B. M., 1979,. Interaction of aminoglycosides and cephaloridine in the rabbit kidney, Res. Comm. Chem. Pathol. Pharmacol. 26:13.Google Scholar
  13. EORTC International Antimicrobial Therapy Project Group, 1978, Three antibiotic regimens in the treatment of infection in febrile granulocytopenic patients with cancer, J. Infect. Dis. 137:14.CrossRefGoogle Scholar
  14. Fanning, W. L., Gump, D., and Jick, H., 1976, Gentamicin and cephalothin associated rises in blood urea nitrogen, Antimicrob. Agents Chemother. 10:80.CrossRefGoogle Scholar
  15. Foord, R. D., 1975, Cephaloridine, cephalothin and the kidney, J. Antimicrob. Chemother. 1:119.CrossRefGoogle Scholar
  16. Harrison, W. O., Silverblatt, F. J., and Turck, M., 1975, Gentamicin nephrotoxicity: Failure of three cephalosporins to potentiate injury in rats, Antimicrob. Agents Chemother. 8:209.CrossRefGoogle Scholar
  17. Kahan, J. S., Kahan, F. M., Goegelman, R., Currie, S. A., Jackson, M., Stapley, E. O., Miller, T. W., Miller, A. K., Hendlin, D., Mochales, S., Hernandez, S., Woodruff, H. B., and Birnbaum, J., 1978, Thienamycin, a new β-lactam antibiotic. I. Discovery, taxonomy isolation and physical properties, J. Antibiot. 32:1.CrossRefGoogle Scholar
  18. Klastersky, J., Hensgens, C., and Debusscher, L., 1975, Empiric therapy for cancer patients: Comparative study of ticarcillin-tobramycin, ticarcillin-cephalothin, and cephalothin-tobramycin, Anti-microb. Agents Chemother. 7:640.CrossRefGoogle Scholar
  19. Kropp, H., Sundelof, J. G., Kahan, J. S., Kahan, F. M., and Birnbaum, J., 1980, MK0787 (N-formimidoyl thienamycin): Evaluation of in vitro and in vivo activities, Antimicrob. Agents Chemother. 17:993.CrossRefGoogle Scholar
  20. Luft, F. C., Patel, V., Yum, M. N., and Kleit, S. A., 1976, Nephrotoxicity of cephalosporin-gentamicin combinations in rats, Antimicrob. Agents Chemother. 9:831.CrossRefGoogle Scholar
  21. McMurtry, R. J., and Mitchell, J. R., 1977, Renal and hepatic necrosis after metabolic activation of 2-substituted furans and thiophenes, including furosemide and cephaloridine, Toxicol. Appl. Pharmacol. 42:285.CrossRefGoogle Scholar
  22. Mitchell, J. R., McMurtry, R. J., Statham, C. N., and Nelson, S. D., 1977, Molecular basis for several drug-induced nephropathies, Am. J. Med. 62:518.CrossRefGoogle Scholar
  23. Perkins, R. L., Apicella, M. A., Lee, I. S., Cuppage, F. E., and Saslaw, S., 1968, Cephaloridine and cephalothin: Comparative studies of potential nephrotoxicity, J. Lab. Clin. Med. 71:75.Google Scholar
  24. Prime, D. L., and Tune, B. M., 1981, The nephrotoxicity of antimicrobial drugs, in: Pediatrics Update (A. J. Moss, ed.), Elsevier/North-Holland, New York.Google Scholar
  25. Roos, R., and Jackson, G. G., 1978, Protective effect of cephalothin on gentamicin nephrotoxicity: Effect of cephalothin anion, not sodium cation, in: Current Chemotherapy, Volume II (W. Siegenthaler and R. Luthy, eds.), American Society for Microbiology, Washington, D.C., p. 962.Google Scholar
  26. Sakamoto, M., Iguchi, H., Okamura, K., Hori, S., Fukugawa, Y., and Ishikura, T., 1979 PS-5, a new β-lactam antibiotic. II. Antimicrobial activity, J. Antibiot. 32: 272.CrossRefGoogle Scholar
  27. Tune, B. M., 1972, Effect of organic acid transport inhibitors on renal cortical uptake and proximal tubular toxicity of cephaloridine, J. Pharmacol. Exp. Ther. 181:250.Google Scholar
  28. Tune, B. M., 1975, Relationship between the transport and toxicity of cephalosporins in the kidney, J. Infect. Dis. 132:189.CrossRefGoogle Scholar
  29. Tune, B. M., and Fernholt, M., 1973, Relationship between cephaloridine and p-aminohippurate transport in the kidney, Am. J. Physiol. 225:1114.Google Scholar
  30. Tune, B. M., and Fravert, D., 1980a, Cephalosporin nephrotoxicity. Transport, cytotoxicity and mitochondrial toxicity of cephaloglycin, J. Pharmacol. Exp. Ther. 215:186.Google Scholar
  31. Tune, B. M., and Fravert, D., 1980b, Mechanisms of cephalosporin nephrotoxicity. A comparison of cephaloridine and cephaloglycin, Kidney Int. 18:591.CrossRefGoogle Scholar
  32. Tune, B. M., and Kempson, R. L., 1973, Nephrotoxic drugs, Br. Med. J. 3:635.CrossRefGoogle Scholar
  33. Tune, B. M., Burg, M. B., and Patlak, C. S., 1969, Characteristics of p-aminohippurate transport in proximal renal tubules, Am. J. Physiol. 217:1057.Google Scholar
  34. Tune, B. M., Fernholt, M., and Schwartz, A., 1974, Mechanism of cephaloridine transport in the kidney, J. Pharmacol. Exp. Ther. 191:311.Google Scholar
  35. Tune, B. M., Wu, K. Y., and Kempson, R. L., 1977a, Inhibition of transport and prevention of toxicity of cephaloridine in the kidney. Dose-responsiveness of the rabbit and the guinea pig to probenecid, J. Pharmacol. Exp. Ther. 202:466.Google Scholar
  36. Tune, B. M., Wu, K. Y., Longerbeam, D. F., and Kempson, R. L., 1977b, Transport and toxicity of cephaloridine in the kidney. Effect of furosemide, p-aminohippurate and saline diuresis, J. Pharmacol. Exp. Ther. 202:472.Google Scholar
  37. Tune, B. M., Wu, K. Y., Fravert, D., and Holtzman, D., 1979, Effect of cephaloridine on respiration by renal cortical mitochondria, J. Pharmacol. Exp. Ther. 210:98.Google Scholar
  38. Tune, B. M., Browning, M. C., Hsu, C.-Y., and Fravert, D., 1982. Prevention of cephalosporin nephrotoxicity in other cephalosporins and by penicillins without significant inhibition of renal cortical uptake. J. Infect. Dis. 145:174–180.CrossRefGoogle Scholar
  39. Tune, B. M., Kuo, S., Hook, J. B., Fravert, D., Hsu, C.-Y., 1983, Effects of inhibitors of mixed function oxidase activity on cephalosporin nephrotoxicity in the rabbit. A possible effect on transport, in press.Google Scholar
  40. Wade, J. C., Petty, B. G., Conrad, G., Smith, C. R., Lipsky, J. J., Ellner, J., and Lietman, P. S., 1978, Cephalothin plus an aminoglycoside is more nephrotoxic than methicillin plus an aminoglycoside, Lancet 2:604.CrossRefGoogle Scholar
  41. Wang, P. L., Prime, D. J., Hsu, C.-Y., and Tune, B. M., 1982, Effects of ureteral obstruction on the toxicity of the cephalosporin in the rabbit kidney, J. Infect. Dis. 145:574.CrossRefGoogle Scholar
  42. Welles, J. S., Gibson, W. R., Harris, P. N., Small, R. M., and Anderson, R. C., 1966, Toxicity, distribution, and excretion of cephaloridine in laboratory animals, Antimicrob. Agents Chemother. 1965: 863.Google Scholar
  43. Whelton, A., and Walker, W. G., 1974, Intrarenal antibiotic distribution in health and disease, Kidney Int. 6:131.CrossRefGoogle Scholar
  44. Wold, J. S., and Turnipseed, S. A., 1977, Determination of cephaloridine in serum and tissue by high-performance liquid chromatography, J. Chromatog. 136:170.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 1982

Authors and Affiliations

  • Bruce M. Tune
    • 1
  1. 1.Division of Nephrology, Department of PediatricsStanford University School of MedicineStanfordUSA

Personalised recommendations