Beta-lactam antibiotics

  • Constantin Cojocel

The large family of β-lactams comprises penicillins, cephalosporins, cephamycins, monobactams, carbacephems and carbapenems and are so named since they all containing the β-lactam moiety.

Penicillin was the first β-lactam antibiotic and was discovered in 1928 by Sir Alexander Fleming at St. Mary’s Hospital, London [1]. The β-lactam chemical structure for penicillin was first proposed by Abraham and Chain in 1943 and finally established in 1945 by X-ray crystallographic analysis. In the same year, Giuseppe Brotzu, a Sardinian professor of bacteriology, isolated Cephalosporium acremonium from the sea near a sewage outfall at Cagliari, which produced antibiotic material with a broad spectrum of activity. It was almost eight years later in 1953 when Newton and Abraham, while studying the production of antibiotics by Brotzu’s Cephalosporium, that they discovered a penicillin-like substance providing resistance to hydrolysis by penicillinases which was named cephalosporin C.


Renal Cortex Acute Interstitial Nephritis Cephalosporin Antibiotic Nephrotoxic Potential Renal Cortical Slice 
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  1. 1.
    Fleming A. On the antibacterial action of cultures of Penicillium with special reference to their use in the isolation of B.influemzae. Brit J Exper Pathol 1929; 10: 228-236.Google Scholar
  2. 2.
    Abraham EP, Newton GGF. The structure of cephalosporin C. Biochem J 1961; 79: 377-393.PubMedGoogle Scholar
  3. 3.
    Nagarajan R, Boeck LD, Gorman M, Hamil RC, Higgens CE, Hoehn MM, Stark WM, Whitney, JG. β-lactam antibiotics from Strep- tomyces. J Am Chem Soc 1971; 93: 2308-2310.PubMedGoogle Scholar
  4. 4.
    Page MG. B-Lactamase inhibitors. Drug Resist Updat 2000; 3(2): 109-125.PubMedGoogle Scholar
  5. 5.
    Cooper RD. The carbacephems: a new β-lactam antibiotic class. Am J Med 1992; 92(6A): 2S-6S.Google Scholar
  6. 6.
    Tally FP, Jacobus NV, Gorbach SL. In vitro activity of thienamycin. Antimicrob Agents Chemother 1978; 14 (3): 436-438.PubMedGoogle Scholar
  7. 7.
    Sader HS, Gales AC. Emerging strategies in infectious diseases: new carbapenem and trinem antibacterial agents. Drugs 2001; 61(5): 553-564.PubMedGoogle Scholar
  8. 8.
    Cimarusti CM, and Sykes RB. Monocyclic β-lactam antibiotics. Med Re. Rev 1984; 4(1): 1-24.Google Scholar
  9. 8a.
    Jacoby GA and Munoz-Price LS. The new β-lactamases. New Eng J Med 2005;352:380-391PubMedGoogle Scholar
  10. 8b.
    Zhang Q, Matsumura Y, Teratani T, Yoshimoto S, Mineno T, Nakagawa K, Nagahama M, Kuwata S, Takeda H. The application of an institutional clinical data warehouse to the assessment of adverse drug reactions (ADRs). Methods Inf Med 2007;46:516-522PubMedGoogle Scholar
  11. 9.
    Yousif T, Pooyeh S, Hannemann J, Baumann J, Tauber R, Baumann K. Nephrotoxic and peroxidative potential of meropenem and imipenem/cilastatin in rat and human renal cortical slices. Inter. J Clin Pharmacol Therap 1999; 10: 475-486.Google Scholar
  12. 10.
    Duwe J, Cojocel C, Baumann K. Effect of paraquat-like substances and cephalosporins on accumulation of p-aminohippurate and tetraethylammonium in rat renal cortical slices, and on lipid peroxidation in rat renal microsomes and cortical alices. In: Nephrotoxicity. Mechanisms, early diagnosis, and therapeutic management. Bach PH, Gregg NJ, Wilks MF, Delacruz L (editors). Marcel Dekker Inc, New York 1991; p. 13-17.Google Scholar
  13. 11.
    Tune BM. The nephrotoxicity of cephalosporin antibiotics-structure-activity relationships. Comm Toxicol 1986; 1(2): 145-170.Google Scholar
  14. 12.
    Goldstein RS, Smith PF, Tarloff, JB, Contardi L, Rush GF, Hook JB. Biochemical mechanisms of cephaloridine nephrotoxicity. Life Sci 1988; 42(19): 1809-1916.PubMedGoogle Scholar
  15. 13.
    Kaloyanides GJ. Metabolic interactions between drugs and renal tubulo-interstitial cells. Role in nephrotoxicity. Kidney Int 1991; 39: 531-540.PubMedGoogle Scholar
  16. 14.
    Schnellmann RG, Griner RD. Mitochondrial mechanisms of tubular injury. In: Mechanisms of injury in renal disease and toxicity. Goldstein RS, Editor.CRC Press Inc, Boca Raton, Florida, USA 1994; p. 247-265.Google Scholar
  17. 15.
    Tomita M, Okuyama T, Watanabe S, Watanabe H. Quantitation of the hydroxyl radical adducts of salicylic acid by micellar elec- trokinetic capillary chromatography: oxidizing species formed by a Fenton reaction. Arch Toxicol 1994; 68: 428 - 433.PubMedGoogle Scholar
  18. 16.
    Tomita M., and Okuyama T. Effect of paraquat on the malondialdehyde level in rat liver microsomes (in vitro). Arch. Toxicol 1994; 68: 187-192.PubMedGoogle Scholar
  19. 17.
    Tune BM, Hsu C-H, Fravert D. Cephalothin and carbacephem nephrotoxicity. Role of tubular cell uptake and acylating potential. Biochem Pharmacol 1996; 51: 557-561.PubMedGoogle Scholar
  20. 18.
    Roselle GA, Clyne DH, Kaufman CA. Carbenicillin nephrotoxicity. South Med J 1978; 71(1): 84-86.PubMedGoogle Scholar
  21. 19.
    Elis D, Fried WA, Yunis EJ, Blau EB. Acute interstitial nephritis in children: a report of 13 cases and review of the literature. Pediatrics 1981; 67(6): 862-870.Google Scholar
  22. 20.
    Pommer W, Offerman G, Schultze G, Krause PH, Molzhan M. Acute interstitial nephritis caused by drugs. Dtsch Med Wochenschr 1983; 108(20): 783-788.PubMedGoogle Scholar
  23. 21.
    Browning MC, Tune BM. Reactivity and binding of β-lactam antibiotics in rabbit renal cortex. J Pharmacol. Exp Ther 1983; 226(3): 640-644.PubMedGoogle Scholar
  24. 22.
    Geller RJ, Chevalier RL, Spyker DA. Acute amoxicillin nephrotoxicity following an overdose. J. Toxicol Clin Toxicol 1986; 24(2): 175-182.PubMedGoogle Scholar
  25. 23.
    Schellie SF, Groshong T. Acute interstitial nephritis following amoxicillin overdose. Mo Med 1999; 96(6): 209-211.PubMedGoogle Scholar
  26. 24.
    Hedstrom SA, Hybbinette CH. Nephrotoxicity in isoxazolylpenicillin prophylaxis in hip surgery. Acta Orthop Scand 1988; 59(2): 144-147.PubMedGoogle Scholar
  27. 25.
    Dunn GL. Ceftizoxime and other third-generation cephalosporins: Structure activity relationships. J Antimicrob Chemother 1982; 10: 1-10.PubMedGoogle Scholar
  28. 26.
    Cojocel C, Goettsche U., Toelle K-L., Baumann, K. Nephrotoxic potential of first-, second-, and third-generation cephalosporins. Arch Toxicol 1988; 62: 458-464.PubMedGoogle Scholar
  29. 27.
    Fillastre JP, Kleinknecht D. Acute renal failure associated with cephalosporin therapy. Am Heart J 1975; 89(6): 809-810.PubMedGoogle Scholar
  30. 28.
    Silverblatt F, Turck M, Bulger R. Nephrotoxicitydue to cephaloridine: a light- and electron-microscopy study in rabbits. J Infect Dis 1970; 122(1): 33-44.PubMedGoogle Scholar
  31. 29.
    Yamada Y. Studies on the mechanisms of renal damage induced by nephrotoxic compounds. Nippon Hoigaku Zasshi 1995; 49(6): 447-457.PubMedGoogle Scholar
  32. 30.
    Tune BM. Effect of organic transport inhibitors on renal uptake and proximal tubular toxicity of cephaloridine. J Pharmacol Exper Therap 1972; 181: 250-256.Google Scholar
  33. 31.
    Cojocel C, Laeschke KH, Insellman G, Baumann K. Inhibition of cephaloridine-induced lipid peroxidation. Toxicology 1985; 35(4):295-305.PubMedGoogle Scholar
  34. 32.
    Takeda M, Tojo A, Sekine T, Hosoyamada M, Kanai Y, Endou H. Role of organic anion transporter 1 (OAT1) in cephaloridin (CER)- induced nephrotoxicity. Kidney Int 1999; 56: 2128-2136.PubMedGoogle Scholar
  35. 33.
    Jariyawat S, Sekine T, Takeda M, Apiwattanakul N, Kanai Y, Sophasan S, Endou H. The interaction and transport of β-lactam anti- biotics with the cloned rat renal organic anion transporter 1. J Pharmacol Exp Ther 1999; 290 (2): 672-677.PubMedGoogle Scholar
  36. 34.
    Kuo C-H, Maita, K, Sleight SD, Hook JB. Lipid peroxidation: a possible mechanism of cephaloridine-induced nephrotoxicity. Toxicol Appl Pharmacol 1983; 67: 78-88.PubMedGoogle Scholar
  37. 35.
    Tune B, Fravert D, Hsu C-Y. Oxidative and mitochondrial toxic effects of cephalosporin antibiotics in the kidney. A comparative study of cephaloridine and cephloglycine. Biochem Pharmacol 1989; 38(3): 795-802.PubMedGoogle Scholar
  38. 36.
    Cojocel C, Mayer D. Protection by glutathione and antioxidants against cephaloridine-induced lipid peroxidation. Biochem. Pharmacol (Life Sci Adv) 1991; 10: 41-51.Google Scholar
  39. 37.
    Goldstein RS, Pasino DA, Hewit WR, Hook JB. Biochemical mechanisms of cephaloridine nephrotoxicity: time and concentration dependence of peroxidative injury. Toxicol Appl Pharmacol 1986; 83: 261-270.PubMedGoogle Scholar
  40. 38.
    Rush GF, Ponsler GD. Cephaloridine-induced biochemical changes and cytotoxicity in suspensions of rabbit isolated proximal tubules. Toxicol Appl Pharmacol 1991; 109: 314-326.PubMedGoogle Scholar
  41. 39.
    Rush GF, Heim RA, Ponsler GD, Engelhardt J. Cephaloridine-induced renal pathological and biochemical changes in female rab- bits and isolated proximal tubules in suspension. Toxicol Pathol 1992; 20(2): 155-168.PubMedGoogle Scholar
  42. 40.
    Cojocel C, Hannemann J, Baumann K. Cephaloridine-induced lipid peroxidation initiated by reactive oxygen species as a possible mechanism of cephaloridine nephrotoxicity. Biochim Biophys Acta 1985; 834: 402-410.PubMedGoogle Scholar
  43. 41.
    Suzuki Y, Sudo J. Lipid peroxidation and generation of oxygen radicals induced by cephaloridine im renal cortical microsomes of rats. Jpn J Pharmacol 1990; 52(2): 233-243.PubMedGoogle Scholar
  44. 42.
    Kuo C-H, Hook JB. Depletion of renal gluthathione content and nephrotoxicity of cephaloridine in rabits, rats, and mice. Toxicol Appl Pharmacol 1982; 63: 292-302.PubMedGoogle Scholar
  45. 43.
    Cojocel C, Inselmann G, Laeschke KE, Baumann K. Species differences in cephalosporin-induced lipid peroxidation. Drugs Exptl Clin Res 1984; 10(11): 781-784.Google Scholar
  46. 44.
    Kays SE, Crowell WA, Johnson MA. Cephaloridine nephrotoxicity is potentiated by selenium deficiency but not by copper defi- ciency in rats. J Nutr 1992; 122: 1232-1241.PubMedGoogle Scholar
  47. 45.
    Alitalo R, Ruutu M, Valtonen V, Lehtonen T, Pentkäinen PJ. Hyoprothrombinaemia and bleeding during administration of cefa- mandole and cefoperazone. Ann Clin Res 1985; 17: 116-119.PubMedGoogle Scholar
  48. 46.
    Wachsmuth ED. Nephrotoxicity of cefotiam (CGP 14221/E) in rats and rabbits. Arch Toxicol 1996; 48: 135-156.Google Scholar
  49. 47.
    Norrby SR, Burman LA, Linderhol H, Trollfors B. Ceftazidime: pharmakokinetics in patients and effects on renal function. J Anti- microb Chemother 1982; 10(3): 199-206.Google Scholar
  50. 48.
    Alestig K, Trollfors B, Andersson R, Oolaison L, Suurkula M, Norrby SR. Ceftazidime and renal function. J Antimicrob Chemother 1984; 13(2): 177-181.PubMedGoogle Scholar
  51. 49.
    Cojocel C. Biochemical aspects of the renal tolerance for cefpirome and other cephalosporins. rzneimittelforschung 1990; 40(10):1140-1144.Google Scholar
  52. 50.
    Suzuki H, Imamura K, Yoshida T, Shibata M, Matsuzawa T, Ozaki H, Sakai T, Shiobara Y, Tachibana A, Yanko K. Animal pharmacoki- netis and toxicology of cefotetan - a new cephamycin antibiotic. J Antimicrob Chemother 1983; 11(Suppl): 179-183.PubMedGoogle Scholar
  53. 51.
    Thieme RE, Caldwell SA, Lum GM. Acute interstitial nephritis associated with loracarbef therapy. J Pediatr 1995; 127(6): 997- 1000.PubMedGoogle Scholar
  54. 52.
    Birnbaum J, Kahan FM, Kropp H, Macdonald JS. Carbapenems, a new class of β-lactam antibiotics: discovery and development of imipenem/cilastatin. Am J Med 1985; 78(Suppl 6A): 3-21.PubMedGoogle Scholar
  55. 53.
    Kropp H, Sundelof JG, Hajdu R, Kahan FM. Metabolism of thienamycin and related carbapenem antibiotics by the renal dipepti- dase, dehydropeptidase-1. Antimicrob Ag Chemother 1982; 22: 62-70.Google Scholar
  56. 54.
    Cunha BA. Meropenem in elderly and renally impaired patients. Int J Antimicrob Agents 1988; 10: 107-117.Google Scholar
  57. 55.
    Asbel LE, Levison ME. Cephalosporins, carbapenems, and monobactams. Infect Dis Clin North Am 2000; 14(2): 435-437.PubMedGoogle Scholar
  58. 56.
    Tune BM., Fravert D, Hsu C-Y. Thienamycin nephrotoxicity. Mitochondrial injury and oxidative effects of imipenem in the rabbit kidney. Biochem Pharmacol 1989; 38(21): 3779-3783.PubMedGoogle Scholar
  59. 57.
    Hirouchi Y, Naganuma H, Kawahara Y, Okada R, Kammiya A, Inui K, Hori R. Preventive effect of ßmipron on nephrotoxicity and uptake of carbapenems in rabbit renal cortex. Jpn J Pharmacol 1994; 66(1): 1-6.PubMedGoogle Scholar
  60. 58.
    Cunha BA. Aztreonam. Urology 1993; 41(3): 249-258.PubMedGoogle Scholar
  61. 59.
    Moore RD, Lerener SA, Levine, DP. Nephrotoxicity and ototoxicity of aztreonam versus aminoglycoside therapy. J Infect Dis 1992; 165(4): 683-688.PubMedGoogle Scholar
  62. 60.
    Chartrand SA. Safety and toxicity profile of aztreonam. Pediatr Infect Dis J 1989; 8(Suppl 9): 120-123.Google Scholar
  63. 61.
    Ohya S, Yamazaki M, Sugawara S. Effect of 7 α substitution of cephems on their β-lactamase stability and affinity for penicillin- binding proteins in Morganella morganii. Antimicrob Agents Chemother 1983; 23(4): 522-525.PubMedGoogle Scholar
  64. 62.
    Patel IH, Kaplan SA. Phrmacokinetic profile of ceftriaxone in man. Am J Med 1984; 77(4C): 17-25PubMedGoogle Scholar
  65. 63.
    Sattler FR, Weitekamp MR, Ballard JO. Potential for bleeding with the new β-lactam antibiotics. Ann Intern Med 1986; 105(6): 924-931.PubMedGoogle Scholar
  66. 64.
    Goto K, Oda M, Saitoh H, Nishida M, Takada M. Effect of side chains including N-methyl-tetrazole-thiol group of β-lactam anti- biotics on transport in cultured kidney epithelial cells LLC-PK1. Biol Pharm Bull 1988; 21(10): 113-116.Google Scholar
  67. 65.
    Williams PD, Laska DA, Tay LK, Hottendorf, GH. Comparative toxicities of cephalosporin antibiotics in a rabbit kidney cell line (LLC-RK1). Antimicrob Agents Chemother 1988; 32(3): 314-318.PubMedGoogle Scholar
  68. 66.
    Viotte G, Morin GP, Godin M, Fillastre JP. Chamges in the renal function of rats treated with cefoxitin and a comparison with other cephlosporins and gentamicin. J Antimicrob Chemother 1981; 7(5): 537-550PubMedGoogle Scholar
  69. 67.
    Tune BM. The renal toxicity of β-lactam antibiotics: mechanism and clinical impications. In: Clinical nephrotoxins - renal injury from drugs and chemicals. 1st Ed.. De Broe ME, Porter GA, Bennett WM, Verpooten GA (editors). Kluwer Academic Publ, Dordrecht, 1998; p. 121-134.Google Scholar
  70. 68.
    Topham JC, Murgatroyd LB, Johns DV, Goonetilleke UR, Wright J. Safety evaluation of meropenem in animals: studies on the kidney. J Antimicrob Chemother 1989; 24(Suppl A): 287-386.PubMedGoogle Scholar
  71. 69.
    Harrison MP, Jones DV, Pickford RJ, Wilson ID. ß-Hydroxybutyrate: a urinary marker of imipenem induced nephrotoxicity in the cynomolgus monkey detected by high field spectroscopy. Biochem Pharmacol 1991; 41(12): 2045-2049.PubMedGoogle Scholar
  72. 70.
    Nouda H, Matsumura H, Tanio T, Sunagawa M. Structural feature of carbapenem compounds or nephrotoxicity: effect of C-2 side chain. J Antibiotics 1996; 49(6): 603-606.Google Scholar
  73. 71.
    Kohda Y, Gemba M. Modulation by cyclic AMP and phorbol myristate acetate of cephaloridine-induced injury in rat renal cortical slices. Jpn J Pharmacol 2001; 85(1): 54-59.PubMedGoogle Scholar
  74. 72.
    Cojocel C, Maita K, Pasino DA, Kuo, C-H, Hook JB Metabolic heterogeneity of proximal and distal tubules. Life Sci 1983; 33: 855- 861.PubMedGoogle Scholar
  75. 73.
    Lock EA. Renal drug-metabolizing enzymes in experimental animals and humans. In: Mechanisms of injury in renal disease and toxicity. Goldstein R S (editor). CRC Press Inc, Boca Raton, Florida 1994; p. 173-206.Google Scholar
  76. 74.
    Cojocel C, Kramer W, Mayer D. Depletion of cytochrome P450 and alterations in activities of drug metabolizing enzymes induced by cephaloridine in rat kidney cortex. Biochemical Pharmacol 1988; 37(19): 3781-3785.Google Scholar
  77. 75.
    Kramer W, Cojocel C, Mayer D. Specific alterations of rat renal microsomal proteins induced by cephaloridine. Biochem Pharmacol 1988; 37 (21): 4135-4140.PubMedGoogle Scholar
  78. 76.
    Olivier MF, Dutertre-Catella H, Thevenin M, Martin C, Warnet JM, Claude JR. Increased reduced glutathione and glutathione S- transferase activity in chronic cephaloridine nephrotoxicity studies in the rat. Drug Chem Toxicol 1990; 13(1-2): 209-219.PubMedGoogle Scholar
  79. 77.
    Kramer W, Cojocel C, Mayer D. Effect of cephaloridine treatment on transport systems of the rat renal brush border membrane. Biochem Pharmacol (Life Sci Adv) 1990; 9: 127-133.Google Scholar
  80. 78.
    Fry M, Plummer DT. The interaction of cephaloridine with model membrane systems and rat kidney lysosomes. Chem Biol Interact 1979; 25(1): 113-124.PubMedGoogle Scholar
  81. 79.
    Ngaha EO. Further studies on the in vivo effect of cephaloridine on the stability of rat kidney lysosomes. Biochem Pharmacol 1982; 31(10): 1843-1847.PubMedGoogle Scholar
  82. 80.
    Yamagouchi A, Hiruma R, Sawai T. Phospholipid bilayer oermeability of β-lactam antibiotics. J Antibiot (Tokyo) 1982; 35(12): 1692-1696.Google Scholar
  83. 81.
    Kojima R, Ito M, Suzuki Y. Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects (4). Effects of tobramycin alone and in combination with latamoxef on the stability of rat kidney lysosomal membranes. Jpn J Pharmacol 1987; 43(1): 73-80.PubMedGoogle Scholar
  84. 82.
    Ullrich KJ, Rumrich G, Kloss S. Contraluminal organic anion and cation transport in the proximal renal tubule: V. Interaction with sulfamoyl- and phemoxy diuretics, and with β-lactam antibiotics. Kidney Int 1989; 36(1): 78-88.PubMedGoogle Scholar
  85. 83.
    Van Aubel RAMH, Masereeuw R, Russsel FGM. Molecular pharmacology of renal organic anion transporters. Am J Physiol Renal Physiol 2000; 279(2): F216-F232.PubMedGoogle Scholar
  86. 84.
    Williams PD, Hitchcock MJ, Hottendorf GH. Effect of cephalosporins on organic ion transport in renal membrane vesicles from the rat and rabbit kidney cortex. Res Commun Chem Pathol Pharmacol 1985; 47(3): 357-371.PubMedGoogle Scholar
  87. 85.
    Ullrich KJ, Rumrich G, Wieland T, Dekant W. Contraluminal para-aminohippurate (PAH) transport in the proximal tubule of the rat kidney. VI. Specificity: amino acids, their N-methyl-, Nacetyl- and N-benzoylderivatives; glutathione- and cysteine conjugates, di- and oligopeptides. Pflügers Arch 1989; 415(3): 342-350.PubMedGoogle Scholar
  88. 86.
    Atkinson RM, Curie LP, Prat PAH, Sharpe HM, Tomich EG. Acute toxicity of cephaloridine, an antibiotic derived from cephalosporin C. Toxicol Appl Pharmacol 1966; 8(3): 398-406.PubMedGoogle Scholar
  89. 87.
    Schaub TP, Kartenbeck J, König J, Spring H, Dorsam J, Sthaeler G, Störkel S, Thon WF, Keppler D. Expression of the MRP2 gene- encoded conjugate export pump in human kidney proximal tubule and in renal carcinoma. J Am Soc Nephrol 1999; 10(6): 1159-1169.PubMedGoogle Scholar
  90. 88.
    Ganapathy ME, Huang W, Rajan DP, Carter AL, Sugawara M, Iseki K, Leibach FH, Ganapathy V. β-lactam antibiotics as substrates for OCTN2, an organic cation/carnitine transporter. J Biol Chem 2000; 275(3): 1699-1707.PubMedGoogle Scholar
  91. 89.
    Terada T, Saito H, Mukai M, Inui K-I. Recognition of β-lactam antibiotics by rat peptide transportrers, PEPT1 and PEPT2 in LLC-Pk1 cells. Am J Physiol Renal Physiol 1997; 273(42): F706-F711.Google Scholar
  92. 90.
    Daniel H, Herget M. Cellular and molecular mechanisms of renal peptide transport. Am J Physiol Renal Physiol 1987; 273:F1- F8.Google Scholar
  93. 91.
    Hori R, Ishikawa Y, Takano M, Okano T, Kitazawa S, Inui K. The interaction of cephalosporin antibiotics with renal cortex of rats: accumulation to cortical slices and binding to purified plasma membranes. Biochem Pharmacol 1982; 31(13): 2267-2272.PubMedGoogle Scholar
  94. 92.
    McMurty RJ, Mitchell JR. Renal and hepatic necrosis after metabolic activation of 2-sustituted furans and thiophenes, including furosemide and cephaloridine. Toxicol Appl Pharmacol 1977; 42: 285-300.Google Scholar
  95. 93.
    Spurling NW, Harcourt RA, Hyde JJ. An evaluation of the safety of cefuroxime axetil during six months oral administration to beagle dogs. J. Toxicol Sci 1986; 11(4): 237-277.PubMedGoogle Scholar
  96. 94.
    Johns RN. A review of cephalosporin metabolism: a lesson to be learned for future chemotherapy. Diagn. Microbial Infect Dis 1989; 12(1): 25-32.Google Scholar
  97. 95.
    Marone P, Navarra A, Monzillo V, Traverso A. Antibacterial activity of combined cefotaxime and desacetyl-cefotaxime against aerobic gram-negative bacilli. Drugs Exp Clin Res 1990; 16(12): 629-633.PubMedGoogle Scholar
  98. 96.
    Hottendorf GH, Laska DA, Williams PD, Ford SM. Role of desacetylation in the detoxification of cephalothin in renal cells in culture. J Toxicol Environ Health 1987; 22(1): 101-111.PubMedGoogle Scholar
  99. 97.
    Indelicato JM, Dinner A, Peters LR, Wilham WL. Hydrolysis of 3-chloro-3-cephems. Intramolecular nucleophilic attack in cefaclor. J Med Chem 1977; 20: 961-963PubMedGoogle Scholar
  100. 98.
    Tune BM, Hsu C-Y. The renal mitochondrial toxicity of β-lactam antibiotics: In vitro effects of cephaloglycin and imipenem. J Amer Soc Nephrol 1990; 1(5): 815-821.Google Scholar
  101. 99.
    Masereeuw R, van den Bergh EJ, Bindels RJ, Russel Fg. Characterization of fluorescein transport in isolated proximal tubular cells of the rat: Evidence for mitochondrial accumulation. J Pharmacol Exp Ther 1994; 269: 1261-1267.PubMedGoogle Scholar
  102. 100.
    Miller DS, Stewart DE, Pitchard JB. Inracellular compartimentation of organic anions within renal cells. Am J Physiol 1993; 264: R882-R890.PubMedGoogle Scholar
  103. 101.
    Terlouw SA, Tanriseven O, Russel FGM, Masereeuw R. Metabolite anion carriers mediate the uptake of the anion drug fluorescein in renal cortical mitochondria. J Pharmacol Exp Ther 2000; 293(3): 968-973.Google Scholar
  104. 102.
    Schnellmann R G, Gilchrist S M, Mandel L J. Intracellular distribution and depletion of glutathione in rabbit renal proximal tubules. Kidney Int 1988; 34: 229-233.PubMedGoogle Scholar
  105. 103.
    Meister A, Anderson M A. Glutathione. Annu Rev Biochem 1985; 52: 711-760.Google Scholar
  106. 104.
    Reed D J. Regulation of reductive processes by glutathione. Biochem Pharcol 1986; 35(1): 7-13.Google Scholar
  107. 105.
    Moldeus P, Quanguang J. Importance of the glutathione cycle in drug metabolism. Pharmacol Ther 1987; 33: 37-40.PubMedGoogle Scholar
  108. 106.
    Elfarra AA, Anders MW. Renal processing of glutathione conjugates. Role in nephrotoxicity. Biochem Pharmacol 1984; 33(23): 3729-3732.PubMedGoogle Scholar
  109. 107.
    Beuter W, Cojocel C, Muller W, Donaubauer HH, Mayer D. Peroxidative damage and nephrotoxicity of dichlorovinylcysteine in mice. J Appl Toxicol. 1989; 9(3): 181-186.PubMedGoogle Scholar
  110. 108.
    Tune BM, Hsu C-Y, Fravert D. Mechanisms of bacterial endotoxin-cephaloridine toxic synergy and the protective effects of saline infusion in the rabbit kidney. J Pharmacol Exp Ther 1988; 244(2): 520-525.PubMedGoogle Scholar
  111. 109.
    Cojocel C, Beuter W, Müller W, Maye, D. Lipid peroxidation: a possible mechanism of trichloroethylene-induced nephrotoxicity. Toxicology 1989; 55: 131-141.PubMedGoogle Scholar
  112. 110.
    Mitchell JB, Biaglow JE, Russo A. Role of glutathione and other endogenous thiols in radiation protection. Pharmacol Ther 1988; 39(1-3): 269-274.PubMedGoogle Scholar
  113. 111.
    Bus JS, Gibson JE. Paraquat: model for oxidant-initiated toxicity. Environ Health Persp 1984; 55: 37-46.Google Scholar
  114. 112.
    Tomita M. Comparison of one-electron reduction activity against the bipyridylium herbicides, paraquat and diquat, in microsomal and mitochondrial fractions of liver, lung and kidney (in vitro). Biochemical Pharmacol 1991; 42(2): 303-309.Google Scholar
  115. 113.
    Gianni L, Zweier JL, Levy A, Mayers CE. Characterisation of the cycle of iron-mediated electron transfer from adriamycin to mo- lecular oxygen. J Biol Chem 1985; 260(11): 6820- 6826.PubMedGoogle Scholar
  116. 114.
    Mimnaugh EG. Potentiation by reduced glutathione of adriamycin-stimulated lipid peroxidation in kidny microsomes. Biochem Pharmacol 1986; 35(23): 4337-4339.PubMedGoogle Scholar
  117. 115.
    Fridovich I. Biological effects of the superoxide radical. Arch Biochem Biophys 1986; 247: 1-11.PubMedGoogle Scholar
  118. 116.
    Halliwell B, Gutteridge JMC. Oxygen free radicals and iron in relation to biology and medicine: some problems and concepts. Arch Biochem Biophys 1986; 246: 501-514.PubMedGoogle Scholar
  119. 117.
    Li W, Zhao Y, Chou IN. Paraquat-induced cytoskeletal injury in cultured cells. Toxicol Appl Pharmacol 1987; 91: 96-106.PubMedGoogle Scholar
  120. 118.
    Miller DM, Woods JS. Urinary porphyrins as biological indicators of oxidative stress in the kidney. Interaction of mercury and cephaloridine. Biochem Pharmacol 1993; 46 (12): 2235-2241.PubMedGoogle Scholar
  121. 119.
    Thomas CE, Aust SD. Reductive release of iron from ferritin by cation free radicals of paraquat and other bipyridils. J Biol Chem 1986; 261(28): 13064-13070.PubMedGoogle Scholar
  122. 120.
    Minotti G, Aust SD. The role of iron in the initiation of lipid peroxidation. Chem Phys Lipids 1987; 44(2-4): 191-208.PubMedGoogle Scholar
  123. 120a.
    Kohda Y, Gemba M. Enhancement of protein kinase C activity and chemiluminescence intensity in mitochondria isolated from the kidney cortex of rats treated with cephaloridine. Biochem Pharmacol 2002;64:543-549.PubMedGoogle Scholar
  124. 120b.
    Kohda Y, Matsunaga Y, Katsuya Y, Yoshiko K, Aways A, Gemba M. Protective effect of serum thymic factor, FTS, on cepholridine- induced nephrotoxicity in rats. Biol Pharm Bull 2005;28:2087-2091.PubMedGoogle Scholar
  125. 121.
    Zenser TV, Mattammal MB, Davis BB. Differential distribution of the mixed-function oxidase activities in rabbit kidney. J Pharmacol Exp Ther 1978; 207(3): 719-725.PubMedGoogle Scholar
  126. 122.
    Swann JD, Acosta D. Failure of gentamicin to elevate cellular malondialdehyde content or increase generation of intracellular reactive oxygen species in primary cultures of renal cortical epithelial cells. Biochem Pharmacol 1990; 40(7): 1523-1526.PubMedGoogle Scholar
  127. 123.
    Tune BM, Kuo CH, Hook JB, Hsu CY, Fravert D. Effects of piperonyl butoxide on cephalosporin nephrotoxicity in the rabbit. An effect on cephaloridine transport. J Pharmacol Exp Ther 1983; 224(3): 520-524.PubMedGoogle Scholar
  128. 123a.
    Cojocel C, Tolle K-L, El-Hajj H, Baumann K. Protection against cephalosporin-induced lipid peroxidation and nephrotoxicity by (+)-cyanidanol-3 and vitamin E. Brazilian J Med Biol Res. 2007;40:867-875.Google Scholar
  129. 124.
    Roy K, Saha A, De K, Sengupta C. Ceftriaxone induced lipid peroxidation and its inhibition with various antioxidants: Part II. Evaluation of glutathione and probucol as antioxidants. Acta Pol Pharm 2000; 57(5): 385-390.PubMedGoogle Scholar
  130. 125.
    Kawai Y, Gemba M. Amelioration by cAMP of cephaloridine-induced injury in the porcine kidney cell line LLC-PK1. Jpn J Pharmacol 1996; 72(1): 67-70.PubMedGoogle Scholar
  131. 126.
    Tune BM, Wu KY, Longerbeam DF, Kempson RL. Transport and toxicity of cephaloridine in the kidney. Effect of furosemide, p- aminohippurate and saline diuresis. J Pharmacol Exp Ther 1977; 202(2): 472-478.PubMedGoogle Scholar
  132. 127.
    Kasher JS, Holohan PD, Ross CR. Na+ gradient-dependent p-aminohippurate (PAH) transport in rat basolateral membrane vesicles. J Pharmacol Exp Ther 1983; 227(1): 122-129.PubMedGoogle Scholar
  133. 128.
    Tune BM, Fernholt M. Relationship between cephaloridine and p-aminohippurate transport in the kidney. Am J Physiol 1973; 225(5): 1114-1117.PubMedGoogle Scholar
  134. 129.
    Tune BM, Fernholt M, Schwartz A Mechanism of cephaloridine transport in the kidney. J Pharmacol Exp Ther 1974; 191(2): 311- 317.PubMedGoogle Scholar
  135. 130.
    Mizuno M, Hamaura T, Hashida M, Sezaki H. Changes in D-glucose uptake by brush-border vesicles from small intestine of rats treated with mitomycin C. Biochem Pharmacol 1986; 35(7): 1153-1158.PubMedGoogle Scholar
  136. 131.
    Mizuno M, Yoshino H, Hashida M, Sezaki H. Decreased transport of D-glucose and L-alanine across brush-border membrane vesicles from small intestine of rats treated with mitomycin C. Biochim Biophys Acta 1987; 902(1): 93-100.PubMedGoogle Scholar
  137. 132.
    Weinberg JM, Venkatachalam MA, Roeser NF, Davis JA, Varani J, Johnson KJ. Amino acid protection of cultured kidney tubule cells against calcium ionophore-induced lethal cell injury. Lab Invest 1991; 65: 671-678.PubMedGoogle Scholar
  138. 133.
    Inui K, Saito H, Takano M, Okano T, Kitazawa S, Hori R. Enzyme activities and sodium-dependent active D-glucose transport in apical membrane vesicles isolated from kidney epithelial cell line (LLC-PK1). Biochim Biophys Acta 1984; 769(2): 514-518.PubMedGoogle Scholar
  139. 133a.
    Jung KY, Takeda M, Shimoda M, Narikawa S, TojoA, Kim DK, Chairoungdua A, Choi BK, Kusuhara H, SugiyamaY, Sekine T, Endou H. Involvement of rat organic anion transporter 3 (rOAT3) in cephaloridine-induced nephrotoxicity: in comparion with rOAT1. Life Sci 2002;70:1861-1874PubMedGoogle Scholar
  140. 133b.
    Takeda M, Babu E, Narikawa S, Endou H. Interaction of human organic anion transporters with various cephalosporin antibiotics. Eur J Pharmacol 2002;438:137-142.PubMedGoogle Scholar
  141. 133c.
    Khamdang S, Takeda M, Babu E, Noshiro R, Onozato ML, Tojo A, Enomoto A, Huang XL, Narikawa S, Anzai N, Piyachaturawat P, Endou H. Interaction of human and rat organic anion transporter 2 with various cephalosporin antibiotics. Eur J Pharmacol 2003;465:1-7.PubMedGoogle Scholar
  142. 134.
    Cersosimo E, Garlick P, Ferretti J. Renal substrate metabolism and gluconeogenesis during hypoglycemia in humans. Diabetes 2000; 49: 1186-1193.PubMedGoogle Scholar
  143. 135.
    Goldstein RS, Contardi LR, Pasino DA,Hook JB. Mechanisms mediating cephaloridine inhibition of renal gluconeogenesis. Toxi- colApplPharmacol 1987; 87: 297-305.Google Scholar
  144. 136.
    Stroo WE, Hook JB. Dissociation of renal organic anion transport from renal lipid metabolism. I. Endogenous nonesterified fatty acids (NEFA) as determinants of transport. J Pharmacol Exp Ther 1983; 227(1): 55-59.PubMedGoogle Scholar
  145. 137.
    Wagner S, Deufel T, Guder WG. Carnitine metabolism in isolated rat kidney cortex tubules. Biol Chem Hoppe Seyler 1986; 367(1): 75-79.PubMedGoogle Scholar
  146. 138.
    Arrigoni-Martelli E, Caso V. Carnitine protects mitochondria and removes toxic acyls from xenobiotics. Drugs Exp Clin Res 2001; 27(10): 27-49.PubMedGoogle Scholar
  147. 139.
    Bieber LL, Farel SS. Carnitine acyl transferases. Enzymes 1983; 16: 624-644.Google Scholar
  148. 140.
    Ramsay RR, Gandour RD, van der Leij FR. Molecular enzymology of carnitine transfer and transport. Biochem Biophys Acta 2001; 1546(1): 21-43.PubMedGoogle Scholar
  149. 141.
    Cojocel C, Smith JH, Maita K, Sleight SD, Hook JB. Renal protein degradation: a biochemical target of specific nephrotoxicants. Fund Appl Toxicol 1983; 3: 278-284.Google Scholar
  150. 141a.
    Bond CA and Raehl CL. Adverse drug reactions in United States hospitals. Pharmacother 2006;26:601-608Google Scholar
  151. 141b.
    Falagas ME, Matthaiou DK, Karveli EA, Peppas G. Meta-analysis: randomized controlled trials of clindamycin/aminoglycoside vs. β-lactam monotherapy for the treatment of intra-abdominal infections. Aliment Pharmacol Ther. 2007;25:537-556.PubMedGoogle Scholar
  152. 142.
    Hori R, Shimakura M, Aramata Y, Kizawa K, Nozawa I, Takahata M, Minami S. Nephrotoxicity of piperacillin combined with furo- semide in rats. Jpn J Antibiot 2000; 53(8): 582-591.PubMedGoogle Scholar
  153. 143.
    Wade JC, Smith CR, Petty BG, Lipski JJ, Conrad G, Ellner J, Lietman PS. Nephrotoxicity of piperacillin combined with furosemide in rats. Jpn J Antibiot 2000; 53(8): 582-591.Google Scholar
  154. 144.
    Bendirdjian JP, Prime DJ, Browning MC, Hsu CY, Tune BM. Additive nephrotoxicity of cephalosporins and aminoglycosides in the rabbit. J Pharmacol Exp Ther 1981; 218(3): 681-685.PubMedGoogle Scholar
  155. 145.
    Kosmidis J, Daikos GK. Prospective randomized comparative studies of mezlocillin/cefotaxime vs. gentamicin/cefoxitin. J Anti- microb Chemother 1983; 11(Suppl C): 91-95.Google Scholar
  156. 146.
    Itoh F, Sato K, Harauchi T, Hirata M, Mizushima Y. Modification of vancomycin nephrotoxicity by other antibiotics in rats. Jpn J Antibiot 1995; 48(3): 380-388.PubMedGoogle Scholar
  157. 147.
    Toyoguchi T, Nakagawa Y. Nephrotoxicity and drug interaction of vancomycin (2). Nippon Yakurigaku Zasshi 1996; 107(5): 225- 235.PubMedGoogle Scholar
  158. 148.
    Reitbroeck RC, Hoitsma AJ, Koene RA. Aztreonam can be safely used with cyclosporin without aggravating nephrotoxicity. Transpl Int 1989; 2(4): 232-234.Google Scholar
  159. 149.
    Fanos V, Musap M, Verlato G, Plebani M, Padovani EM. Evaluation of the antibiotic-induced nephrotoxicity in preterm neonates by determining urinary a1-microglobulin. Pediatr Nephrol 1996; 10: 645-647.PubMedGoogle Scholar
  160. 150.
    Greenlee ML, DiNinno F, Herrmann JJ, Jaworsky C, Muthard DA, Salzmann TN. 2-Naphthylcarbapenems: broad spectrum antibiot- ics with enhanced potency against MRSA. Bioorg Med Chem Lett 1999; 9(19): 2893-2896.PubMedGoogle Scholar
  161. 151.
    Kanno O, Shimoji Y, Ohya S, Kawamoto I. Synthesis and biological evaluation of novel tricyclic carbapenems (trinems). J Antib (Tokyo) 2000; 53(4): 404-414.Google Scholar
  162. 152.
    Kar GK, Roy BC, Adhikari SD, Ray JK, Brahama NK. Synthesis of some thieno γ lactam monocyclic acids with high antibacterial activity: a new look at an old molecular system. Bioorg Med Chem 1998; 6(12): 2397-2402.PubMedGoogle Scholar
  163. 153.
    Hayashi T, Watanabe Y, Kumano K, Kitayama R, Yasuda T, Saikawa I, Katahira J, Kumada T, Shimizu K. Protective effect of piperacillin against nephrotoxicity of cephaloridine and gentamicin in animals. Antimicrob Agents Chemother 1988; 32(6): 912-918.PubMedGoogle Scholar
  164. 154.
    Tune BM, Browning MC, Hsu CY, Fravert D. Prevention of cephalosporin nephrotoxicity by other cephalosporins and by penicillins without significant inhibition of renal cortical uptake. J Infect Dis 1982; 145(2): 174-180.PubMedGoogle Scholar
  165. 155.
    Beauchamp D, Theriault G, Grenier L, Gourde P, Perron S, Bergeron Y, Fontaine L, Bergeron MG. Ceftriaxone protects against tobramycin nephrotoxicity. Antimicrob Agents Chemother 1994; 38(4): 750-756.PubMedGoogle Scholar
  166. 156.
    Kojima R, Ito M, Suzuki Y. Studies on the nephrotoxicity of aminoglycoside antibiotics and protection from these effects (3). Protective effect of latamoxef against tobramycin nephrotoxicity and its protective mechanism. Jpn J Pharmacol 1986; 42(3): 397-404.PubMedGoogle Scholar
  167. 157.
    Sausen PJ, Elfarra AA, Cooley AJ. Methimazole protection of rats against chemically induced kidney damage in vivo. J Pharmacol Exp Ther 1992; 260(1): 393-401.PubMedGoogle Scholar
  168. 158.
    Valentovic M, Ball JG, Rogers BA, Meadows MK, Harmon RC, Moles J. Cephaloridine in vitro toxicity and accumulation in renal slices from normoglycemic and diabetic rats. Fundam Appl Toxicol 1997; 38(2): 184-190.PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Constantin Cojocel
    • 1
  1. 1.Kuwait UniversityKuwait

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