, Volume 38, Issue 1, pp 3–11 | Cite as

Hepatotoxicity of Antibacterials: Pathomechanisms and Clinical Data

  • J. M. LeitnerEmail author
  • W. Graninger
  • F. Thalhammer


Drug-induced hepatotoxicity is a frequent cause of liverdisease and acute liver failure, particularly in patients treatedwith multiple drugs. Several antibacterial drugs have thepotential to cause severe liver injury and failure. This articleaims to increase the awareness and understanding of druginducedliver injury (DILI) due to antibacterial drugs. Itreviews the pattern of antibacterial DILI and provides detailson molecular mechanisms and toxicogenomics, as well asclinical data based on epidemiology studies. Certain antibacterialdrugs are more frequently linked to hepatotoxicity thanothers. Therefore, the hepatotoxic potential of tetracyclines,sulfonamides, tuberculostatic agents, macrolides, quinolones,and beta-lactams are discussed in more detail. Efforts toimprove the early detection of DILI and the acquisition ofhigh-quality epidemiological data are pivotal for increasedpatient safety.


Human Leukocyte Antigen Cholestasis Minocycline Autoimmune Hepatitis Acute Liver Failure 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Hughes B: Industry concern over EU hepatotoxicity guidance. Nat Rev Drug Discov 2008; 7: 719.CrossRefPubMedGoogle Scholar
  2. 2.
    Meier Y, Cavallaro M, Roos M, Pauli-Magnus C, Folkers G, Meier PJ, Fattinger K: Incidence of drug-induced liver injury in medical inpatients. Eur J Clin Pharmacol 2005; 61: 135–143.CrossRefPubMedGoogle Scholar
  3. 3.
    Marschall HU, Wagner M, Zollner G, Trauner M: Clinical hepatotoxicity. Regulation and treatment with inducers of transport and cofactors. Mol Pharm 2007; 4: 895–910.CrossRefPubMedGoogle Scholar
  4. 4.
    Zimmerman HJ: Drug-induced liver disease. Clin Liver Dis 2000; 4: 73–96vi.CrossRefPubMedGoogle Scholar
  5. 5.
    Polson JE: Hepatotoxicity due to antibiotics. Clin Liver Dis 2007; 11: 549–561vi.CrossRefPubMedGoogle Scholar
  6. 6.
    Steele MA, Burk RF, DesPrez RM: Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991; 99: 465–471.CrossRefPubMedGoogle Scholar
  7. 7.
    Saukkonen JJ, Cohn DL, Jasmer RM, Schenker S, Jereb JA, Nolan CM, Peloquin CA, Gordin FM, Nunes D, Strader DB, Bernardo J, Venkataramanan R, Sterling TR: An official ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit Care Med 2006; 174: 935–952.CrossRefPubMedGoogle Scholar
  8. 8.
    Yew WW, Leung CC: Antituberculosis drugs and hepatotoxicity. Respirology 2006; 11: 699–707.CrossRefPubMedGoogle Scholar
  9. 9.
    Trauner M, Wagner M, Fickert P, Zollner G: Molecular regulation of hepatobiliary transport systems: clinical implications for understanding and treating cholestasis. J Clin Gastroenterol 2005; 39: S111–S124.CrossRefPubMedGoogle Scholar
  10. 10.
    Wagner M, Zollner G, Trauner M: New molecular insights into the mechanisms of cholestasis. J Hepatol 2009; 51: 565–580.CrossRefPubMedGoogle Scholar
  11. 11.
    Zollner G, Trauner M: Mechanisms of cholestasis. Clin Liver Dis 2008; 12: 1–26vii.CrossRefPubMedGoogle Scholar
  12. 12.
    Fuchs M, Sanyal AJ: Sepsis and cholestasis. Clin Liver Dis 2008; 12: 151–172ix.CrossRefPubMedGoogle Scholar
  13. 13.
    Thiim M, Friedman LS: Hepatotoxicity of antibiotics and antifungals. Clin Liver Dis 2003; 7: 381–399vi–vii.CrossRefPubMedGoogle Scholar
  14. 14.
    Lee WM: Drug-induced hepatotoxicity. N Engl J Med 2003; 349: 474–485.CrossRefPubMedGoogle Scholar
  15. 15.
    Watkins PB, Seeff LB: Drug-induced liver injury: summary of a single topic clinical research conference. Hepatology 2006; 43: 618–631.CrossRefPubMedGoogle Scholar
  16. 16.
    Björnsson E, Olsson R: Outcome and prognostic markers in severe drug-induced liver disease. Hepatology 2005; 42: 481–489.CrossRefPubMedGoogle Scholar
  17. 17.
    Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J: Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924–1934, 1934.e1-4.CrossRefPubMedGoogle Scholar
  18. 18.
    Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, García-Ruiz E, García-Muñoz B, González-Grande R, Pizarro A, Durán JA, Jiménez M, Rodrigo L, Romero-Gomez M, Navarro JM, Planas R, Costa J, Borras A, Soler A, Salmerón J, Martin-Vivaldi R: Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129: 512–521.PubMedGoogle Scholar
  19. 19.
    Müller M: Pharmacogenomics and drug response. Int J Clin Pharmacol Ther 2003; 41: 231–240.PubMedGoogle Scholar
  20. 20.
    Lee SS, Buters JT, Pineau T, Fernández-Salguero P, González FJ: Role of CYP2E1 in the hepatotoxicity of acetaminophen. J Biol Chem 1996; 271: 12063–12067.CrossRefPubMedGoogle Scholar
  21. 21.
    Huang YS, Chern HD, Su WJ, Wu JC, Chang SC, Chiang CH, Chang FY, Lee SD: Cytochrome P450 2E1 genotype and the susceptibility to antituberculosis drug-induced hepatitis. Hepatology 2003; 37: 924–930.CrossRefPubMedGoogle Scholar
  22. 22.
    Huang YS, Chern HD, Su WJ, Wu JC, Lai SL, Yang SY, Chang FY, Lee SD: Polymorphism of the N-acetyltransferase 2 gene as a susceptibility risk factor for antituberculosis drug-induced hepatitis. Hepatology 2002; 35: 883–889.CrossRefPubMedGoogle Scholar
  23. 23.
    Mitchell JR, Zimmerman HJ, Ishak KG, Thorgeirsson UP, Timbrell JA, Snodgrass WR, Nelson SD: Isoniazid liver injury: clinical spectrum, pathology, and probable pathogenesis. Ann Intern Med 1976; 84: 181–192.PubMedGoogle Scholar
  24. 24.
    Enomoto A, Itoh K, Nagayoshi E, Haruta J, Kimura T, O’Connor T, Harada T, Yamamoto M: High sensitivity of Nrf2 knockout mice to acetaminophen hepatotoxicity associated with decreased expression of ARE-regulated drug metabolizing enzymes and antioxidant genes. Toxicol Sci 2001; 59: 169–177.CrossRefPubMedGoogle Scholar
  25. 25.
    O’Donohue J, Oien KA, Donaldson P, Underhill J, Clare M, MacSween RN, Mills PR: Co-amoxiclav jaundice: clinical and histological features and HLA class II association. Gut 2000; 47: 717–720.CrossRefPubMedGoogle Scholar
  26. 26.
    Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte C, Maxwell D, James I, Christiansen FT: Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet 2002; 359: 727–732.CrossRefPubMedGoogle Scholar
  27. 27.
    Fréneaux E, Labbe G, Letteron P, The Le Dinh, Degott C, Genève J, Larrey D, Pessayre D: Inhibition of the mitochondrial oxidation of fatty acids by tetracycline in mice and in man: possible role in microvesicular steatosis induced by this antibiotic. Hepatology 1988; 8: 1056–1062.CrossRefPubMedGoogle Scholar
  28. 28.
    Peters RL, Edmondson HA, Mikkelsen WP, Tatter D: Tetracycline-induced fatty liver in nonpregnant patients. A report of six cases. Am J Surg 1967; 113: 622–632.CrossRefPubMedGoogle Scholar
  29. 29.
    Schultz JC, Adamson JS Jr, Workman WW, Norman TD: Fatal liver disease after intravenous administration of tetracycline in high dosage. N Engl J Med 1963; 269: 999–1004.CrossRefPubMedGoogle Scholar
  30. 30.
    Björnsson E, Lindberg J, Olsson R: Liver reactions to oral low-dose tetracyclines. Scand J Gastroenterol 1997; 32: 390–395.CrossRefPubMedGoogle Scholar
  31. 31.
    Carson JL, Strom BL, Duff A, Gupta A, Shaw M, Lundin FE, Das K: Acute liver disease associated with erythromycins, sulfonamides, and tetracyclines. Ann Intern Med 1993; 119: 576–583.PubMedGoogle Scholar
  32. 32.
    Gough A, Chapman S, Wagstaff K, Emery P, Elias E: Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome. BMJ 1996; 312: 169–172.PubMedGoogle Scholar
  33. 33.
    Goldstein NS, Bayati N, Silverman AL, Gordon SC: Minocycline as a cause of drug-induced autoimmune hepatitis. Report of four cases and comparison with autoimmune hepatitis. Am J Clin Pathol 2000; 114: 591–598.CrossRefPubMedGoogle Scholar
  34. 34.
    Boudreaux JP, Hayes DH, Mizrahi S, Hussey J, Regenstein F, Balart L: Fulminant hepatic failure, hepatorenal syndrome, and necrotizing pancreatitis after minocycline hepatotoxicity. Transplant Proc 1993; 25: 1873.PubMedGoogle Scholar
  35. 35.
    Pohle T, Menzel J, Domschke W: Minocycline and fulminant hepatic failure necessitating liver transplantation. Am J Gastroenterol 2000; 95: 560–561.PubMedGoogle Scholar
  36. 36.
    Losanoff JE, Holder-Murray JM, Ahmed EB, Cochrane AB, Testa G, Millis JM: Minocycline toxicity requiring liver transplant. Dig Dis Sci 2007; 52: 3242–3244.CrossRefPubMedGoogle Scholar
  37. 37.
    D’Arcy PF: Nitrofurantoin. Drug Intell Clin Pharm 1985; 19: 540–547.PubMedGoogle Scholar
  38. 38.
    Dujovne CA, Chan CH, Zimmerman HJ: Sulfonamide hepatic injury. Review of the literature and report of a case due to sulfamethoxazole. N Engl J Med 1967; 277: 785–788.CrossRefPubMedGoogle Scholar
  39. 39.
    Ilario MJ, Ruiz JE, Axiotis CA: Acute fulminant hepatic failure in a woman treated with phenytoin and trimethoprim-sulfamethoxazole. Arch Pathol Lab Med 2000; 124: 1800–1803.PubMedGoogle Scholar
  40. 40.
    Kouklakis G, Mpoumponaris A, Zezos P, Moschos J, Koulaouzidis A, Nakos A, Pehlivanidis A, Iosiphidis M, Molyvas E, Nikolaidis N: Cholestatic hepatitis with severe systemic reactions induced by trimethoprim-sulfamethoxazole. Ann Hepatol 2007; 6: 63–65.PubMedGoogle Scholar
  41. 41.
    Lazar HP, Murphy RL, Phair JP: Fansidar and hepatic granulomas. Ann Intern Med 1985; 102: 722.PubMedGoogle Scholar
  42. 42.
    Zitelli BJ, Alexander J, Taylor S, Miller KD, Howrie DL, Kuritsky JN, Perez TH, Van Thiel DH: Fatal hepatic necrosis due to pyrimethamine-sulfadoxine (Fansidar). Ann Intern Med 1987; 106: 393–395.PubMedGoogle Scholar
  43. 43.
    Junghanss BG: Increase in transaminases in HIV infection. Toxic liver cell damage with trimethoprim/sulfamethoxazole administration in HIV infection. Praxis (Bern 1994) 1998; 87: 361–362.Google Scholar
  44. 44.
    Wenisch C, Krause R, Fladerer P, El Menjawi I, Pohanka E: Acute rhabdomyolysis after atorvastatin and fusidic acid therapy. Am J Med 2000; 109: 78.CrossRefPubMedGoogle Scholar
  45. 45.
    Christiansen K: Fusidic acid adverse drug reactions. Int J Antimicrob Agents 1999; 12: [Suppl 2] S3–S9.CrossRefPubMedGoogle Scholar
  46. 46.
    Bode KA, Donner MG, Leier I, Keppler D: Inhibition of transport across the hepatocyte canalicular membrane by the antibiotic fusidate. Biochem Pharmacol 2002; 64: 151–158.CrossRefPubMedGoogle Scholar
  47. 47.
    Forget EJ, Menzies D: Adverse reactions to first-line antituberculosis drugs. Expert Opin Drug Saf 2006; 5: 231–249.CrossRefPubMedGoogle Scholar
  48. 48.
    Brummer DL: Isoniazid and liver disease. Ann Intern Med 1971; 75: 643–644.PubMedGoogle Scholar
  49. 49.
    Maddrey WC: Isoniazid-induced liver disease. Semin Liver Dis 1981; 1: 129–133.CrossRefPubMedGoogle Scholar
  50. 50.
    Pugh AJ, Barve AJ, Falkner K, Patel M, McClain CJ: Drug-induced hepatotoxicity or drug-induced liver injury. Clin Liver Dis 2009; 13: 277–294.CrossRefPubMedGoogle Scholar
  51. 51.
    Centers for Disease Control and Prevention (CDC):, American Thoracic Society: Update: adverse event data and revised American Thoracic Society/CDC recommendations against the use of rifampin and pyrazinamide for treatment of latent tuberculosis infection-United States, 2003. MMWR Morb Mortal Wkly Rep 2003; 52: 735–739.Google Scholar
  52. 52.
    Knobel B, Buyanowsky G, Dan M, Zaidel L: Pyrazinamide-induced granulomatous hepatitis. J Clin Gastroenterol 1997; 24: 264–266.CrossRefPubMedGoogle Scholar
  53. 53.
    Derby LE, Jick H, Henry DA, Dean AD: Erythromycin-associated cholestatic hepatitis. Med J Aust 1993; 158: 600–602.PubMedGoogle Scholar
  54. 54.
    Braun P: Hepatotoxicity of erythromycin. J Infect Dis 1969; 119: 300–306.PubMedGoogle Scholar
  55. 55.
    Chandrupatla S, Demetris AJ, Rabinovitz M: Azithromycin-induced intrahepatic cholestasis. Dig Dis Sci 2002; 47: 2186–2188.CrossRefPubMedGoogle Scholar
  56. 56.
    Christopher K, Hyatt PA, Horkan C, Yodice PC: Clarithromycin use preceding fulminant hepatic failure. Am J Gastroenterol 2002; 97: 489–490.PubMedGoogle Scholar
  57. 57.
    Brinker AD, Wassel RT, Lyndly J, Serrano J, Avigan M, Lee WM, Seeff LB: Telithromycin-associated hepatotoxicity: clinical spectrum and causality assessment of 42 cases. Hepatology 2009; 49: 250–257.CrossRefPubMedGoogle Scholar
  58. 58.
    Ross DB: The FDA and the case of Ketek. N Engl J Med 2007; 356: 1601–1604.CrossRefPubMedGoogle Scholar
  59. 59.
    Navarro VJ, Senior JR: Drug-related hepatotoxicity. N Engl J Med 2006; 354: 731–739.CrossRefPubMedGoogle Scholar
  60. 60.
    Hussaini SH, O’Brien CS, Despott EJ, Dalton HR: Antibiotic therapy: a major cause of drug-induced jaundice in southwest England. Eur J Gastroenterol Hepatol 2007; 19: 15–20.CrossRefPubMedGoogle Scholar
  61. 61.
    Fontana RJ, Shakil AO, Greenson JK, Boyd I, Lee WM: Acute liver failure due to amoxicillin and amoxicillin/clavulanate. Dig Dis Sci 2005; 50: 1785–1790.CrossRefPubMedGoogle Scholar
  62. 62.
    Gresser U: Amoxicillin-clavulanic acid therapy may be associated with severe side effects - review of the literature. Eur J Med Res 2001; 6: 139–149.PubMedGoogle Scholar
  63. 63.
    García Rodríguez LA, Stricker BH, Zimmerman HJ: Risk of acute liver injury associated with the combination of amoxicillin and clavulanic acid. Arch Intern Med 1996; 156: 1327–1332.CrossRefPubMedGoogle Scholar
  64. 64.
    Salvo F, Polimeni G, Moretti U, Conforti A, Leone R, Leoni O, Motola D, Dusi G, Caputi AP: Adverse drug reactions related to amoxicillin alone and in association with clavulanic acid: data from spontaneous reporting in Italy. J Antimicrob Chemother 2007; 60: 121–126.CrossRefPubMedGoogle Scholar
  65. 65.
    Leone R, Venegoni M, Motola D, Moretti U, Piazzetta V, Cocci A, Resi D, Mozzo F, Velo G, Burzilleri L, Montanaro N, Conforti A: Adverse drug reactions related to the use of fluoroquinolone antimicrobials: an analysis of spontaneous reports and fluoroquinolone consumption data from three Italian regions. Drug Saf 2003; 26: 109–120.CrossRefPubMedGoogle Scholar
  66. 66.
    Rubinstein E: History of quinolones and their side effects. Chemotherapy 2001; 47: [Suppl 3] 3–8, discussion 44-48.CrossRefPubMedGoogle Scholar
  67. 67.
    Drug Committee of the German Medical Association: hepatotoxicity of fluoroquinolones. Deutsches Ärzteblatt 2002; A 3490.Google Scholar
  68. 68.
    Shlaes DM, Moellering RC: Telithromycin and the FDA: implications for the future. Lancet Infect Dis 2008; 8: 83–85.CrossRefPubMedGoogle Scholar
  69. 69.
    Van Bambeke F, Tulkens PM: Safety profile of the respiratory fluoroquinolone moxifloxacin: comparison with other fluoroquinolones and other antibacterial classes. Drug Saf 2009; 32: 359–378.CrossRefPubMedGoogle Scholar
  70. 70.
    Motola D, Vargiu A, Leone R, Cocci A, Salvo F, Ros B, Meneghelli I, Venegoni M, Cutroneo PM, Vaccheri A, Velo G, Montanaro N: Hepatic adverse drug reactions: a case/non-case study in Italy. Eur J Clin Pharmacol 2007; 63: 73–79.CrossRefPubMedGoogle Scholar
  71. 71.
    Derby LE, Jick H, Henry DA, Dean AD: Cholestatic hepatitis associated with flucloxacillin. Med J Aust 1993; 158: 596–600.PubMedGoogle Scholar
  72. 72.
    Carbon C: Levofloxacin adverse effects, data from clinical trials and pharmacovigilance. Therapie 2001; 56: 35–40.PubMedGoogle Scholar

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© Urban & Vogel 2010

Authors and Affiliations

  1. 1.Dept. of Internal Medicine I, Division of Infectious Diseases & TropicalMedicineMedical University of Vienna, General Hospital of Vienna(AKH Wien)ViennaAustria

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