Metronidazole is one of the mainstay drugs for the treatment of anaerobic bacterial infections, protozoal infections, and microaerophilic bacterial infections. It is cytotoxic to facultative anaerobic microorganisms.
Metronidazole is FDA-approved for the treatment of protozoal infections such as Trichomoniasis vaginalis, Entamoeba histolytica, Giardia lamblia, blastocysts, and Balantidium coli. It is also FDA approved to treat anaerobic bacterial infections caused by Bacteroides species, Fusobacterium species, Clostridium species, Gardnerella vaginalis, Helicobacter pylori, Prevotella species, Porphyromonas species, and Biophilia Wadsworth. Therefore, it is not surprising that metronidazole is widely accepted and FDA-approved for the treatment of a broad range of infections: intestinal amebiases, liver amebiasis, bacterial septicemia, bone and joint infections, central nervous system (CNS) infections (meningitis and brain abscess), endocarditis, gynecologic infections (endometritis, tubo-ovarian abscess, bacterial vaginosis), intra-abdominal infections, lower respiratory tract infections, skin structure infections, and surgical prophylaxis (colorectal surgeries).
Metronidazole has additional off-label uses in the management of other conditions and infections including balantidiases, bite wound infections, animal and human bites, clostridioides (formerly Clostridium difficile), Crohn disease, post-surgical resection management, perianal fistulas, Dietamoeba fragilis infections, giardiasis, Helicobacter pylori eradication, periodontitis, post ileal pouch-anal anastomosis (pouchitis), and tetanus.
Metronidazole has rapid bactericidal effects against anaerobic bacteria with a killing rate proportional to the drug concentration. Concentration-dependent bactericidal properties have been demonstrated against Entamoeba histolytica and Trichomonas vaginalis. Furthermore, it kills Bacteroides fragilis and Clostridium perfringens more rapidly than treatment doses of clindamycin. It also penetrates the blood-brain barrier.
Metronidazole diffuses into the organism, inhibits protein synthesis by interacting with DNA and causing a loss of helical DNA structure and strand breakage. Therefore, it causes cell death in susceptible organisms.
The mechanism of action of metronidazole occurs through a four-step process. Step one is the entry into the organism by diffusion across the cell membranes of anaerobic and aerobic pathogens. However, antimicrobial effects are limited to anaerobes. Step two involves reductive activation by intracellular transport proteins by altering the chemical structure of pyruvate-ferredoxin oxidoreductase. The reduction of metronidazole creates a concentration gradient in the cell that drives uptake of more drug and promotes free radical formation that is cytotoxic. Step three, interactions with intracellular targets, is achieved by cytotoxic particles interacting with host cell DNA resulting in DNA strand breakage and fatal destabilization of the DNA helix. Step four is the breakdown of cytotoxic products. Metronidazole is also cytotoxic to facultatively anaerobic bacteria like Helicobacter pylori and Gardnerella vaginalis, but the mechanism of action to these pathogens is not well understood.
Metronidazole may be administered orally, intravenously, or topically. It comes in capsule, tablet, topical and intravenous forms. The standard capsule dosing is 375 mg. Standard tablet dosing is 250 mg or 500 mg. Standard intravenous preparation and dosing is 5mg/mL (100mL) and 500 mg (100 mL), respectively. When administered intravenously, the drug solution should not come in contact with equipment containing aluminum. Infusion of the intravenous solution should be over 30 to 60 minutes. Oral administration can be taken with food to help minimize stomach discomfort. The extended-release tablets should be administered on an empty stomach 1 hour before or 2 hours after meals. It should not be split or crushed. The topical application gel is 0.75% and 37.5 mg per applicator and is applied vaginally.
The primary adverse effects of metronidazole include confusion, peripheral neuropathy, metallic taste, nausea, vomiting, and diarrhea. Adverse events seen in greater than 10% of the population include headache (18%), vaginitis (15%), and nausea (10% to 12%). Adverse events affecting less than 10% of the population are metallic taste (9%), dizziness (4%), genital pruritus (5%), abdominal pain (4%), diarrhea (4%), xerostomia (2%), dysmenorrhea (3%), urine abnormality (3%), urinary tract infection (2%), bacterial infection (7%), candidiasis (3%), flu-like symptoms (6%), upper respiratory tract infection (4%), pharyngitis (3%), and sinusitis (3%). Rarely, there are reports of transient leukopenia and neutropenia as well.
Metronidazole comes with a black box warning that it may be carcinogenic based on some animal studies in mice and rats. However the risks are considered low, and additional follow-up studies of patients treated do not reveal an increased incidence of cancer. As with any medication choice, physicians and patients must decide whether the benefit from therapy outweighs the potential risk. The use of metronidazole should be reserved for conditions approved by the FDA; it should not be used prophylactically or unnecessarily.
Additional warnings and precautions for metronidazole exist. Prolonged courses of the drug can cause severe neurological disturbances due to the risk of cumulative neurotoxicity. Monitor for neurologic sequela and discontinue therapy if any abnormal neurologic symptoms occur. Prolonged use may also result in fungal or bacterial superinfection, including C. difficile-associated diarrhea (CDAD) and pseudomembranous colitis. There are reports of CDAD even after more than 2 months of postantibiotic treatment. Candidiasis infection may also be more prominent during metronidazole treatment.
Metronidazole is contraindicated in patients with documented hypersensitivity to the drug or its components, and it should be avoided in first-trimester pregnancy. Patients should also avoid consuming alcohol or products containing propylene glycol while taking metronidazole and within three days of therapy completion. Metronidazole is likewise contraindicated if there has been recent disulfiram use within the past two weeks.
During and after prolonged therapy or repeated courses, complete blood count (CBC) with differential requires monitoring. Carefully observe patients for the onset of neurologic symptoms and consider discontinuation of metronidazole when or if new neurologic symptoms occur. Elderly patients, as well as previously diagnosed patients with severe hepatic impairment and/or end-stage renal disease, should also be monitored closely.
There have been reports of disulfiram-like reactions in patients drinking ethanol while administered systemic or vaginal metronidazole. A typical disulfiram reaction causes flushing, tachycardia, palpitations, nausea, and vomiting. Alcohol should be avoided during treatment and from up to forty-eight hours to fourteen days after treatment completion depending on the source; the manufacturer product information recommends avoiding alcohol ingestion during metronidazole therapy and for at least 48 hours afterward. Ethanol-containing medications such as elixirs as well as tipranavir, capsules, intravenous (IV) anidulafungin, IV trimethoprim-sulfamethoxazole, and many cough/cold syrups can also lead to a disulfiram-like reaction when ingested with metronidazole.
There should be judicious prescribing of metronidazole by providers only for known indications and high clinical suspicion for needing treatment of anaerobic bacterial infections, protozoal infections, and microaerophilic bacterial infections. Overprescribing may contribute to increasing future antibiotic resistance to the drug. Documentation already exists regarding increased resistance to metronidazole in the treatment of C. difficile infections. Also, prescribers, nurses, and pharmacists should routinely provide education to patients to abstain from alcoholic beverages while taking metronidazole, which in turn will help lead to fewer disulfiram reaction symptoms. The patient should also be informed there may be a change in urine color. The team of health professionals including physicians, nurses, and pharmacists must work together to provide the best care for these patients when using this drug. [Level V]
|||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. Antimicrobial agents and chemotherapy. 1993 Aug; [PubMed PMID: 8215278]|
|||Löfmark S,Edlund C,Nord CE, Metronidazole is still the drug of choice for treatment of anaerobic infections. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2010 Jan 1; [PubMed PMID: 20067388]|
|||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. Diagnostic microbiology and infectious disease. 1992 May-Jun; [PubMed PMID: 1611847]|
|||Ravdin JI,Skilogiannis J, In vitro susceptibilities of Entamoeba histolytica to azithromycin, CP-63,956, erythromycin, and metronidazole. Antimicrobial agents and chemotherapy. 1989 Jun; [PubMed PMID: 2548442]|
|||Nix DE,Tyrrell R,Müller M, Pharmacodynamics of metronidazole determined by a time-kill assay for Trichomonas vaginalis. Antimicrobial agents and chemotherapy. 1995 Aug; [PubMed PMID: 7486930]|
|||Ralph ED,Kirby WM, Unique bactericidal action of metronidazole against Bacteroides fragilis and Clostridium perfringens. Antimicrobial agents and chemotherapy. 1975 Oct; [PubMed PMID: 172007]|
|||Edwards DI, Nitroimidazole drugs--action and resistance mechanisms. I. Mechanisms of action. The Journal of antimicrobial chemotherapy. 1993 Jan; [PubMed PMID: 8444678]|
|||Edwards DI, Reduction of nitroimidazoles in vitro and DNA damage. Biochemical pharmacology. 1986 Jan 1; [PubMed PMID: 3940526]|
|||Tocher JH,Edwards DI, The interaction of reduced metronidazole with DNA bases and nucleosides. International journal of radiation oncology, biology, physics. 1992; [PubMed PMID: 1544834]|
|||Finegold SM, Metronidazole. Annals of internal medicine. 1980 Oct; [PubMed PMID: 7436193]|
|||Gonzales MLM,Dans LF,Sio-Aguilar J, Antiamoebic drugs for treating amoebic colitis. The Cochrane database of systematic reviews. 2019 Jan 9; [PubMed PMID: 30624763]|
|||van Schalkwyk J,Yudin MH, Vulvovaginitis: screening for and management of trichomoniasis, vulvovaginal candidiasis, and bacterial vaginosis. Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC. 2015 Mar; [PubMed PMID: 26001874]|
|||Sexually Transmitted Diseases: Summary of 2015 CDC Treatment Guidelines. Journal of the Mississippi State Medical Association. 2015 Dec; [PubMed PMID: 26975162]|
|||Gardner TB,Hill DR, Treatment of giardiasis. Clinical microbiology reviews. 2001 Jan; [PubMed PMID: 11148005]|
|||Mazuski JE,Tessier JM,May AK,Sawyer RG,Nadler EP,Rosengart MR,Chang PK,O'Neill PJ,Mollen KP,Huston JM,Diaz JJ Jr,Prince JM, The Surgical Infection Society Revised Guidelines on the Management of Intra-Abdominal Infection. Surgical infections. 2017 Jan; [PubMed PMID: 28085573]|
|||Stevens DL,Bisno AL,Chambers HF,Dellinger EP,Goldstein EJ,Gorbach SL,Hirschmann JV,Kaplan SL,Montoya JG,Wade JC, Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the infectious diseases society of America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2014 Jul 15; [PubMed PMID: 24947530]|
|||Bratzler DW,Dellinger EP,Olsen KM,Perl TM,Auwaerter PG,Bolon MK,Fish DN,Napolitano LM,Sawyer RG,Slain D,Steinberg JP,Weinstein RA, Clinical practice guidelines for antimicrobial prophylaxis in surgery. American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists. 2013 Feb 1; [PubMed PMID: 23327981]|
|||Chey WD,Leontiadis GI,Howden CW,Moss SF, ACG Clinical Guideline: Treatment of Helicobacter pylori Infection. The American journal of gastroenterology. 2017 Feb; [PubMed PMID: 28071659]|
|||McDonald LC,Gerding DN,Johnson S,Bakken JS,Carroll KC,Coffin SE,Dubberke ER,Garey KW,Gould CV,Kelly C,Loo V,Shaklee Sammons J,Sandora TJ,Wilcox MH, Clinical Practice Guidelines for Clostridium difficile Infection in Adults and Children: 2017 Update by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA). Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2018 Mar 19; [PubMed PMID: 29562266]|
|||McKendrick MW,Geddes AM, Neutropenia associated with metronidazole. British medical journal. 1979 Sep 29 [PubMed PMID: 519201]|
|||Smith JA, Neutropenia associated with metronidazole therapy. Canadian Medical Association journal. 1980 Aug 9 [PubMed PMID: 7260762]|
|||Hernández Ceruelos A,Romero-Quezada LC,Ruvalcaba Ledezma JC,López Contreras L, Therapeutic uses of metronidazole and its side effects: an update. European review for medical and pharmacological sciences. 2019 Jan; [PubMed PMID: 30657582]|
|||Saginur R,Hawley CR,Bartlett JG, Colitis associated with metronidazole therapy. The Journal of infectious diseases. 1980 Jun; [PubMed PMID: 7391617]|
|||Williams CS,Woodcock KR, Do ethanol and metronidazole interact to produce a disulfiram-like reaction? The Annals of pharmacotherapy. 2000 Feb; [PubMed PMID: 10676835]|