Consult the medical resource doctors trust

UpToDate is one of the most respected medical information resources in the world, used by over 360,000 doctors and thousands of patients to find answers to medical questions.

  • Content written by a faculty of over 4,000 physicians from leading medical institutions
  • Unbiased: free of advertising or pharmaceutical funding
  • Evidence-based treatment recommendations
  • Continuously updated to incorporate new medical findings

Related articles included with a subscription

Preview Available
(subscription required for full access)

Metronidazole: An overview

INTRODUCTION

Metronidazole is one of the mainstay drugs for the treatment of anaerobic infections and the treatment of choice for most patients with diarrhea caused by Clostridium difficile. (See "Treatment of antibiotic-associated diarrhea caused by Clostridium difficile".) It is approved by the United States Food and Drug Administration (FDA) for the treatment of anaerobic and protozoal infections. Metronidazole exerts its antimicrobial effects through the production of free radicals, which are toxic to the microbe.

MECHANISM OF ACTION

Metronidazole is cytotoxic to facultative anaerobic bacteria, such as Helicobacter pylori and Gardnerella vaginalis, but the mechanism of this action is not well understood [1]. However, its activity against obligate anaerobes occurs through a four-step process:

  • Entry into the microorganism — Metronidazole is a low molecular weight compound which diffuses across the cell membranes of anaerobic and aerobic microorganisms. However, antimicrobial activity is limited to anaerobes [1].
  • Reductive activation by intracellular transport proteins. Metronidazole is reduced by the pyruvate:ferredoxin oxidoreductase system in the mitochondria of obligate anaerobes, which alters its chemical structure. Pyruvate:ferredoxin oxidoreductase normally generates ATP via oxidative decarboxylation of pyruvate. With metronidazole in the cellular environment, its nitro group acts as an electron sink, capturing electrons that would usually be transferred to hydrogen ions in this cycle. Reduction of metronidazole creates a concentration gradient which drives uptake of more drug, and promotes formation of intermediate compounds and free radicals that are toxic to the cell [1-3].
  • Reduced intermediate particle interacts with intracellular targets. Cytotoxic intermediate particles interact with host cell DNA, resulting in DNA strand breakage and fatal destabilization of the DNA helix [4,5].
  • Breakdown of cytotoxic intermediate products. The toxic intermediate particles decay into inactive end products [6].

Metronidazole exerts rapid bactericidal effects against anaerobic bacteria, with a killing rate proportional to the drug concentration [7,8]. Concentration-dependent killing has also been observed with Entamoeba histolytica and Trichomonas vaginalis [9,10]. Metronidazole kills Bacteroides fragilis and Clostridium perfringens more rapidly than clindamycin [11]. (See "Clindamycin: An overview".)

No apparent antagonism exists between metronidazole and other antimicrobial agents such as clindamycin, rifampin, and ticarcillin against strains of B. fragilis [12].
To continue reading this article you need to subscribe.

Read the rest of this article and others like it

The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use (click here) ©2009 UpToDate, Inc.
References Top
  1. Edwards, DI. Nitroimidazole drugs--action and resistance mechanisms. I. Mechanisms of action. J Antimicrob Chemother 1993; 31:9.
  2. Edwards, DI. Reduction of nitroimidazoles in vitro and DNA damage. Biochem Pharmacol 1986; 35:53.
  3. Muller, M. Reductive activation of nitroimidazoles in anaerobic microorganisms. Biochem Pharmacol 1986; 35:37.
  4. Tocher, JH, Edwards, DI. The interaction of reduced metronidazole with DNA bases and nucleosides. Int J Radiat Oncol Biol Phys 1992; 22:661.
  5. Tocher, JH, Edwards, DI. Evidence for the direct interaction of reduced metronidazole derivatives with DNA bases. Biochem Pharmacol 1994; 48:1089.
  6. Goldman, P, Koch, RL, Yeung, TC, et al. Comparing the reduction of nitroimidazoles in bacteria and mammalian tissues and relating it to biological activity. Biochem Pharmacol 1986; 35:43.
  7. Stratton, CW, Weeks, LS, Aldridge, KE. Comparison of the bactericidal activity of clindamycin and metronidazole against cefoxitin-susceptible and cefoxitin-resistant isolates of the Bacteroides fragilis group. Diagn Microbiol Infect Dis 1991; 14:377.
  8. Stratton, CW, Weeks, LS, Aldridge, KE. Inhibitory and bactericidal activity of selected beta-lactam agents alone and in combination with beta-lactamase inhibitors compared with that of cefoxitin and metronidazole against cefoxitin-susceptible and cefoxitin-resistant isolates of the Bacteroides fragilis group. Diagn Microbiol Infect Dis 1992; 15:321.
  9. Ravdin, JI, Skilogiannis, J. In vitro susceptibilities of Entamoeba histolytica to azithromycin, CP-63,956, erythromycin, and metronidazole. Antimicrob Agents Chemother 1989; 33:960.
  10. Nix, DE, Tyrrell, R, Muller, M. Pharmacodynamics of metronidazole determined by a time-kill assay for Trichomonas vaginalis. Antimicrob Agents Chemother 1995; 39:1848.
  11. Ralph, ED, Kirby, WM. Unique bactericidal action of metronidazole against Bacteroides fragilis and Clostridium perfringens. Antimicrob Agents Chemother 1975; 8:409.
  12. Ralph, ED, Amatnieks, YE. Potentially synergistic antimicrobial combinations with metronidazole against Bacteroides fragilis. Antimicrob Agents Chemother 1980; 17:379.
  13. Cuchural, GJ, Tally, FP, Jacobus, NV, et al. Antimicrobial susceptibilities of 1,292 isolates of the Bacteroides fragilis group in the United States: comparison of 1981 with 1982. Antimicrob Agents Chemother 1984; 26:145.
  14. Musial, CE, Rosenblatt, JE. Antimicrobial susceptibilities of anaerobic bacteria isolated at the Mayo Clinic during 1982 through 1987: Comparison with results from 1977 through 1981. Mayo Clin Proc 1989; 64:392.
  15. Snydman, DR, Jacobus, NV, McDermott, LA, et al. Multicenter study of in vitro susceptibility of the Bacteroides fragilis group, 1995 to 1996, with comparison of resistance trends from 1990 to 1996. Antimicrob Agents Chemother 1999; 43:2417.
  16. Aldridge, KE, Ashcraft, D, O'Brien, M, Sanders, CV. Bacteremia due to Bacteroides fragilis group: distribution of species, beta-lactamase production, and antimicrobial susceptibility patterns. Antimicrob Agents Chemother 2003; 47:148.
  17. van Winkelhoff, AJ, Herrara Gonzales, D, Winkel, EG, et al. Antimicrobial resistance in the subgingival microflora in patients with adult periodontitis. A comparison between The Netherlands and Spain. J Clin Periodontol 2000; 27:79.
  18. Duerden, BI. Role of the reference laboratory in susceptibility testing of anaerobes and a survey of isolates referred from laboratories in England and Wales during 1993-1994. Clin Infect Dis 1995; 20 Suppl 2:S180.
  19. Labbe, AC, Bourgault, AM, Vincelette, J, et al. Trends in antimicrobial resistance among clinical isolates of the Bacteroides fragilis group from 1992 to 1997 in Montreal, Canada. Antimicrob Agents Chemother 1999; 43:2517.
  20. Shore, KP, Pottumarthy, S, Morris, AJ. Susceptibility of anaerobic bacteria in Auckland: 1991-1996. N Z Med J 1999; 112:424.
  21. Brazier, JS, Stubbs, SL, Duerden, BI. Metronidazole resistance among clinical isolates belonging to the Bacteroides fragilis group: time to be concerned? [letter]. J Antimicrob Chemother 1999; 44:580.
  22. Barbut, F, Decre, D, Burghoffer, B, et al. Antimicrobial susceptibilities and serogroups of clinical strains of Clostridium difficile isolated in France in 1991 and 1997. Antimicrob Agents Chemother 1999; 43:2607.
  23. Reysset, G, Haggoud, A, Sebald, M. Genetics of resistance of Bacteroides species to 5-nitroimidazole. Clin Infect Dis 1993; 16 Suppl 4:S401.
  24. Rasmussen, BA, Bush, K, Tally, FP. Antimicrobial resistance in Bacteroides. Clin Infect Dis 1993; 16 Suppl 4:S390.
  25. Narikawa, S, Suzuki, T, Yamamoto, M, Nakamura, M. Lactate dehydrogenase activity as a cause of metronidazole resistance in Bacteroides fragilis NCTC 11295. J Antimicrob Chemother 1991; 28:47.
  26. Results of a multicentre European survey in 1991 of metronidazole resistance in Helicobacter pylori. European Study Group on Antibiotic Susceptibility of Helicobacter pylori. Eur J Clin Microbiol Infect Dis 1992; 11:777.
  27. Adamek, RJ, Suerbaum, S, Pfaffenbach, B, Opferkuch, W. Primary and acquired Helicobacter pylori resistance to clarithromycin, metronidazole, and amoxicillin--influence on treatment outcome. Am J Gastroenterol 1998; 93:386.
  28. Megraud, F, Lehn, N, Lind, T, et al. Antimicrobial susceptibility testing of Helicobacter pylori in a large multicenter trial: the MACH 2 study. Antimicrob Agents Chemother 1999; 43:2747.
  29. Lacey, SL, Moss, SF, Taylor, GW. Metronidazole uptake by sensitive and resistant isolates of Helicobacter pylori. J Antimicrob Chemother 1993; 32:393.
  30. Moore, RA, Beckthold, B, Bryan, LE. Metronidazole uptake in Helicobacter pylori. Can J Microbiol 1995; 41:746.
  31. van Zwet, AA, Thijs, JC, Schievink-de Vries, W, et al. In vitro studies on stability and development of metronidazole resistance in Helicobacter pylori. Antimicrob Agents Chemother 1994; 38:360.
  32. Tankovic, J, Lamarque, D, Delchier, JC, et al. Frequent association between alteration of the rdxA gene and metronidazole resistance in French and North African isolates of Helicobacter pylori. Antimicrob Agents Chemother 2000; 44:608.
  33. Logan, RP, Gummett, PA, Misiewicz, JJ, et al. One week eradication regimen for Helicobacter pylori [see comments]. Lancet 1991; 338:1249.
  34. Owen, RJ, Bell, GD, Desai, M, et al. Biotype and molecular fingerprints of metronidazole-resistant strains of Helicobacter pylori from antral gastric mucosa. J Med Microbiol 1993; 38:6.
  35. Wong, WM, Gu, Q, Wang, WH, et al. Effects of primary metronidazole and clarithromycin resistance to Helicobacter pylori on omeprazole, metronidazole, and clarithromycin triple-therapy regimen in a region with high rates of metronidazole resistance. Clin Infect Dis 2003; 37:882.
  36. Dore, MP, Leandro, G, Realdi, G, et al. Effect of pretreatment antibiotic resistance to metronidazole and clarithromycin on outcome of Helicobacter pylori therapy: A meta-analytical approach. Dig Dis Sci 2000; 45:68.
  37. Krajden, S, Lossick, JG, Wilk, E, et al. Persistent Trichomonas vaginalis infection due to a metronidazole-resistant strain. CMAJ 1986; 134:1373.
  38. Muller, M, Meingassner, JG, Miller, WA, Ledger, WJ. Three metronidazole-resistant strains of Trichomonas vaginalis from the United States. Am J Obstet Gynecol 1980; 138:808.
  39. Dombrowski, MP, Sokol, RJ, Brown, WJ, Bronsteen, RA. Intravenous therapy of metronidazole-resistant Trichomonas vaginalis. Obstet Gynecol 1987; 69:524.
  40. Kulda, J. Trichomonads, hydrogenosomes and drug resistance. Int J Parasitol 1999; 29:199.
  41. Edwards, DI. Nitroimidazole drugs--action and resistance mechanisms. II. Mechanisms of resistance. J Antimicrob Chemother 1993; 31:201.
  42. Quon, DV, d'Oliveira, CE, Johnson, PJ. Reduced transcription of the ferredoxin gene in metronidazole-resistant Trichomonas vaginalis. Proc Natl Acad Sci U S A 1992; 89:4402.
  43. Nguyen, MH, Yu, VL, Morris, AJ, et al. Antimicrobial resistance and clinical outcome of Bacteroides bacteremia: Findings of a multicenter prospective observational trial. Clin Infect Dis 2000; 30:870.
  44. Baron, EJ, Ropers, G, Summanen, P, Courcol, RJ. Bactericidal activity of selected antimicrobial agents against Bilophila wadsworthia and Bacteroides gracilis. Clin Infect Dis 1993; 16 Suppl 4:S339.
  45. Pankuch, GA, Jacobs, MR, Appelbaum, PC. Susceptibilities of 428 gram-positive and -negative anaerobic bacteria to Bay y3118 compared with their susceptibilities to ciprofloxacin, clindamycin, metronidazole, piperacillin, piperacillin-tazobactam, and cefoxitin. Antimicrob Agents Chemother 1993; 37:1649.
  46. Sheikh, W, Pitkin, DH, Nadler, H. Antibacterial activity of meropenem and selected comparative agents against anaerobic bacteria at seven North American centers. Clin Infect Dis 1993; 16 Suppl 4:S361.
  47. Alexander, CJ, Citron, DM, Brazier, JS, Goldstein, EJ. Identification and antimicrobial resistance patterns of clinical isolates of Clostridium clostridioforme, Clostridium innocuum, and Clostridium ramosum compared with those of clinical isolates of Clostridium perfringens. J Clin Microbiol 1995; 33:3209.
  48. Brazier, JS, Levett, PN, Stannard, AJ, et al. Antibiotic susceptibility of clinical isolates of clostridia. J Antimicrob Chemother 1985; 15:181.
  49. Goldstein, EJ, Citron, DM, Cherubin, CE, Hillier, SL. Comparative susceptibility of the Bacteroides fragilis group species and other anaerobic bacteria to meropenem, imipenem, piperacillin, cefoxitin, ampicillin/sulbactam, clindamycin and metronidazole. J Antimicrob Chemother 1993; 31:363.
  50. Jones, BM, Geary, I, Lee, ME, Duerden, BI. Comparison of the in vitro activities of fenticonazole, other imidazoles, metronidazole, and tetracycline against organisms associated with bacterial vaginosis and skin infections. Antimicrob Agents Chemother 1989; 33:970.
  51. Spiegel, CA. Susceptibility of Mobiluncus species to 23 antimicrobial agents and 15 other compounds. Antimicrob Agents Chemother 1987; 31:249.
  52. Bannatyne, RM, Jackowski, J, Cheung, R, Biers, K. Susceptibility of Gardnerella vaginalis to metronidazole, its bioactive metabolites, and tinidazole. Am J Clin Pathol 1987; 87:640.
  53. Easmon, CS, Ison, CA, Kaye, CM, et al. Pharmacokinetics of metronidazole and its principal metabolites and their activity against Gardnerella vaginalis. Br J Vener Dis 1982; 58:246.
  54. Lau, AH, Lam, NP, Piscitelli, SC, et al. Clinical pharmacokinetics of metronidazole and other nitroimidazole anti-infectives. [Review] [188 refs]. Clin Pharmacokinet 1992; 23:328.
  55. Jokipii, AM, Myllyla, VV, Hokkanen, E, Jokipii, L. Penetration of the blood brain barrier by metronidazole and tinidazole. J Antimicrob Chemother 1977; 3:239.
  56. Warner, JF, Perkins, RL, Cordero, L. Metronidazole therapy of anaerobic bacteremia, meningitis, and brain abscess. Arch Intern Med 1979; 139:167.
  57. Karjagin, J, Pahkla, R, Karki, T, Starkopf, J. Distribution of metronidazole in muscle tissue of patients with septic shock and its efficacy against Bacteroides fragilis in vitro. J Antimicrob Chemother 2005; 55:341.
  58. Karjagin, J, Pahkla, R, Starkopf, J. Perioperative penetration of metronidazole into muscle tissue: a microdialysis study. Eur J Clin Pharmacol 2004; 59:809.
  59. Nielsen, ML, Justesen, T. Excretion of metronidazole in human bile. Investigations of hepatic bile, common duct bile, and gallbladder bile. Scand J Gastroenterol 1977; 12:1003.
  60. Jensen, JC, Gugler, R. Single- and multiple-dose metronidazole kinetics. Clin Pharmacol Ther 1983; 34:481.
  61. Kreeft, JH, Ogilvie, RI, Dufresne, LR. Metronidazole kinetics in dialysis patients. Surgery 1983; 93:149.
  62. Lau, AH, Chang, CW, Sabatini, S. Hemodialysis clearance of metronidazole and its metabolites. Antimicrob Agents Chemother 1986; 29:235.
  63. Roux, AF, Moirot, E, Delhotal, B, et al. Metronidazole kinetics in patients with acute renal failure on dialysis: a cumulative study. Clin Pharmacol Ther 1984; 36:363.
  64. Somogyi, A, Kong, C, Sabto, J, et al. Disposition and removal of metronidazole in patients undergoing haemodialysis. Eur J Clin Pharmacol 1983; 25:683.
  65. Guay, DR, Meatherall, RC, Baxter, H, et al. Pharmacokinetics of metronidazole in patients undergoing continuous ambulatory peritoneal dialysis. Antimicrob Agents Chemother 1984; 25:306.
  66. Farrell, G, Baird-Lambert, J, Cvejic, M, Buchanan, N. Disposition and metabolism of metronidazole in patients with liver failure. Hepatology 1984; 4:722.
  67. Farrell, G, Buchanan, N, Baird-Lambert, J. Impaired elimination of metronidazole in decompensated chronic liver disease. Br Med J (Clin Res Ed) 1984; 288:1009.
  68. Daneshmend, TK, Roberts, CJ. Impaired elimination of metronidazole in decompensated chronic liver disease. Br Med J (Clin Res Ed) 1984; 288:405.
  69. Plaisance, KI, Quintiliani, R, Nightingale, CH. The pharmacokinetics of metronidazole and its metabolites in critically ill patients. J Antimicrob Chemother 1988; 21:195.
  70. Lau, AH, Evans, R, Chang, CW, Seligsohn, R. Pharmacokinetics of metronidazole in patients with alcoholic liver disease. Antimicrob Agents Chemother 1987; 31:1662.
  71. Upadhyaya, P, Bhatnagar, V, Basu, N. Pharmacokinetics of intravenous metronidazole in neonates. J Pediatr Surg 1988; 23:263.
  72. Kusumi, RK, Plouffe, JF, Wyatt, RH, Fass, RJ. Central nervous system toxicity associated with metronidazole therapy. Ann Intern Med 1980; 93:59.
  73. Lamp, KC, Freeman, CD, Klutman, NE, Lacy, MK. Pharmacokinetics and pharmacodynamics of the nitroimidazole antimicrobials. Clin Pharmacokinet 1999; 36:353.
  74. Urtasun, RC, Rabin, HR, Partington, J. Human pharmacokinetics and toxicity of high-dose metronidazole administered orally and intravenously. Surgery 1983; 93:145.
  75. Saginur, R, Hawley, CR, Bartlett, JG. Colitis associated with metronidazole therapy. J Infect Dis 1980; 141:772.
  76. Frytak, S, Moertel, CH, Childs, DS. Neurologic toxicity associated with high-dose metronidazole therapy. Ann Intern Med 1978; 88:361.
  77. Halloran, TJ. Convulsions associated with high cumulative doses of metronidazole. Drug Intell Clin Pharm 1982; 16:409.
  78. Knowles, S, Choudhury, T, Shear, NH. Metronidazole hypersensitivity. Ann Pharmacother 1994; 28:325.
  79. McKendrick, MW, Geddes, AM. Neutropenia associated with metronidazole [letter]. Br Med J 1979; 2:795.
  80. Smith, JA. Neutropenia associated with metronidazole therapy. Can Med Assoc J 1980; 123:202.
  81. Celifarco, A, Warschauer, C, Burakoff, R. Metronidazole-induced pancreatitis. Am J Gastroenterol 1989; 84:958.
  82. Sanford, KA, Mayle, JE, Dean, HA, Greenbaum, DS. Metronidazole-associated pancreatitis. Ann Intern Med 1988; 109:756.
  83. Alexander, I. 'Alcohol-antabuse' syndrome in patients receiving metronidazole during gynaecological treatment. Br J Clin Pract 1985; 39:292.
  84. Heath, MJ, Pachar, JV, Perez, MA, Toseland, PA. An exceptional case of lethal disulfiram-alcohol reaction [see comments]. Forensic Sci Int 1992; 56:45.
  85. Teicher, MH, Altesman, RI, Cole, JO, Schatzberg, AF. Possible nephrotoxic interaction of lithium and metronidazole [letter]. JAMA 1987; 257:3365.
  86. Lassen, E. Effects of acute and short-time antibiotic treatment on renal lithium elimination and serum lithium levels in the rat. Acta Pharmacol Toxicol (Copenh) 1985; 56:273.
  87. Blyden, GT, Scavone, JM, Greenblatt, DJ. Metronidazole impairs clearance of phenytoin but not of alprazolam or lorazepam. J Clin Pharmacol 1988; 28:240.
  88. O'Reilly, RA. The stereoselective interaction of warfarin and metronidazole in man. N Engl J Med 1976; 295:354.
  89. Patterson, BD. Possible interaction between metronidazole and carbamazepine [letter]. Ann Pharmacother 1994; 28:1303.
  90. Kounas, SP, Letsas, KP, Sideris, A, et al. QT interval prolongation and torsades de pointes due to a coadministration of metronidazole and amiodarone. Pacing Clin Electrophysiol 2005; 28:472.
  91. Zylber-Katz, E, Rubinger, D, Berlatzky, Y. Cyclosporine interactions with metronidazole and cimetidine [letter]. Drug Intell Clin Pharm 1988; 22:504.
  92. Herzig, K, Johnson, DW. Marked elevation of blood cyclosporin and tacrolimus levels due to concurrent metronidazole therapy [letter]. Nephrol Dial Transplant 1999; 14:521.
  93. Page RL, 2nd, Klem, PM, Rogers, C. Potential elevation of tacrolimus trough concentrations with concomitant metronidazole therapy. Ann Pharmacother 2005; 39:1109.
  94. Nilsson, C, Aschan, J, Hentschke, P, et al. The effect of metronidazole on busulfan pharmacokinetics in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2003; 31:429.
  95. Eradiri, O, Jamali, F, Thomson, AB. Interaction of metronidazole with phenobarbital, cimetidine, prednisone, and sulfasalazine in Crohn's disease. Biopharm Drug Dispos 1988; 9:219.
  96. Mead, PB, Gibson, M, Schentag, JJ, Ziemniak, JA. Possible alteration of metronidazole metabolism by phenobarbital [letter]. N Engl J Med 1982; 306:1490.
  97. Loft, S, Dossing, M, Sonne, J, et al. Lack of effect of cimetidine on the pharmacokinetics and metabolism of a single oral dose of metronidazole. Eur J Clin Pharmacol 1988; 35:65.
  98. Rajnarayana, K, Reddy, MS, Vidyasagar, J, Krishna, DR. Study on the influence of silymarin pretreatment on metabolism and disposition of metronidazole. Arzneimittelforschung 2004; 54:109.
  99. Loft, S, Sonne, J, Dossing, M, Andreasen, PB. Metronidazole pharmacokinetics in patients with hepatic encephalopathy. Scand J Gastroenterol 1987; 22:117.
white circle LOG IN
white circle DEMO