The concentrations of metronidazole in cerebrospinal fluid and saliva are similar to those found in plasma. Bactericidal concentrations of metronidazole have also been detected in pus from hepatic abscesses. The major route of elimination of metronidazole and its metabolites is the urine, with fecal excretion accounting for a minor part.
Metronidazole is metabolized in the liver, and the simultaneous administration of drugs that increase or decrease the microsomal liver enzyme activity may lead to altered plasma concentrations. Metronidazole potentiates the anticoagulant effect of warfarin and other oral coumarin anticoagulants, resulting in a prolongation of prothrombin time.
The metabolism of alcohol may be affected by metronidazole in some patients, leading to intolerance. The safety profile of metronidazole is well known, and adverse effects are considered mainly to be mild to moderate in severity. The most common adverse reactions reported involve the gastrointestinal tract. Rare serious adverse reactions, including convulsive seizures and peripheral neuropathy, characterized mainly by numbness or paresthesia of an extremity, have been reported in patients receiving prolonged metronidazole treatment.
Studies published during — confirm these clinical reports. Metronidazole is effective for the management of anaerobic infections, such as intra-abdominal infections, gynecologic infections, septicemia, endocarditis, bone and joint infections, central nervous system infections, respiratory tract infections, skin and skin-structure infections, and oral and dental infections. Metronidazole is also used as prophylaxis before abdominal and gynecological surgical procedures to reduce the risk of postoperative anaerobic infection.
For treatment of mixed aerobic and anaerobic infection, metronidazole should be used in combination with other antibacterial agents that are appropriate for the treatment of the aerobic infection, because it is ineffective against aerobic bacteria Table 1.
Metronidazole also produces good clinical results when it is used for treatment of giardiasis, trichomoniasis, and amoebiasis, and it is recommended for the treatment of patients with bacterial vaginosis or nonspecific vaginitis caused by G.
In accordance with international guidelines, metronidazole is also a component of multidrug regimens eg, in combination with omeprazole, clarithromycin, and amoxicillin for therapy of H.
In addition, metronidazole treatment is considered for patients with Crohn disease that does not respond to sulfasalazine. Topically applied metronidazole has been effective for the treatment of moderate to severe rosacea. In addition, metronidazole gel is used in dentistry for the treatment of periodontitis in patients for whom mechanical debridement is not successful or possible.
Metronidazole therapy for C. An increasing number of clinical failures with metronidazole treatment of C. The reasons for the diminished effectiveness of metronidazole, compared with vancomycin, are not obvious.
Most C. Pharmacokinetic and pharmacodynamic properties of metronidazole have been thought to be responsible for the clinical failures. For patients with severe C. Therefore, new agents are being investigated for this indication. Of the antimicrobial agents, fidoxamicin, ramoplanin, and rifaximin have been demonstrated to be active against C. Another approach has been to develop a toxin binder, tolevamer; however, phase 3 studies showed that it is inferior to vancomycin therapy.
Monoclonal antibodies and a C. Probiotics, such as Lactobacillus rhamnosus GG and Saccharomyces boulardii , have not produced favorable clinical results.
Treatment of patients who experience multiple relapses of C. One new approach may be to use metronidazole in various combinations with these new antimicrobials, toxin binders, immunomodulators, nontoxigenic C.
Clinical trials with therapeutic combinations of these agents are recommended. Metronidazole therapy for intra-abdominal infections. Complicated and serious intra-abdominal infections frequently occur in clinical medicine, and their treatment requires advanced hospital resources. The management of intra-abdominal infections has developed significantly during the past 10 years.
Proper use of antimicrobial agents is mandatory. New guidelines for the diagnosis and management of complicated intra-abdominal infections in adults and children have been written by the Infectious Diseases Society of America, the Surgical Infection Society, and the Pediatric Infectious Disease Society and are now under review J. Solomkin, personal communication Table 2. These guidelines separate the infections into 2 categories: community-acquired and health care-associated infections.
For moderate community-acquired infections in adults, metronidazole in combination with cefazolin, cefuroxime, ceftriaxone, or a quinolone is recommended. Metronidazole together with ceftazidine or cefepime or single-drug therapy with carbapenems and piperacillin-tazobactam is suggested for the management of severe community-acquired intra-abdominal infection.
For children, metronidazole in combination with cefuroxime or ceftriaxone is recommended. An alternative agent is cefoxitin. Oral metronidazole in combination with oral second- or third-generation cephalosporin may also be effective.
Health care-associated intra-abdominal infections are often caused by more-drug-resistant microorganisms, such as Staphylococcus aureus , enterococci, Pseudomonas aeruginosa, Acinetobacter baumanni, Klebsiella species, Enterobacter species, Proteus species, and Candida species. Multidrug treatment, based on microorganism susceptibility patterns, is recommended for these infections.
Convalescing patients with complicated intra-abdominal infections can often be treated with oral antimicrobials. For adults, metronidazole in combination with a fluoroquinolone or trimethoprim-sulfamethoxazole may be effective. Oral metronidazole in combination with an oral second- or third-generation cephalosporin can be provided to children.
Recently, Wang et al [ 9 ] showed that 1 g of metronidazole given intravenously once daily for treatment of severe intra-abdominal and pelvic infections has pharmacokinetic and pharmacoeconomic advantages over treatment administered every 6—8 h. Metronidazole is active against a variety of protozoa and bacteria. It enters the cell as a prodrug by passive diffusion and is activated in either the cytoplasm of the bacteria or specific organelles in the protozoa, whereas drug-resistant cells are deficient in drug activation.
The metronidazole molecule is converted to a short-lived nitroso free radical by intracellular reduction, which includes the transfer of an electron to the nitro group of the drug. This form of the drug is cytotoxic and can interact with the DNA molecule. The actual mechanism of action has not yet been fully elucidated but includes the inhibition of DNA synthesis and DNA damage by oxidation, causing single-strand and double-strand breaks that lead to DNA degradation and cell death.
The activated reduced metronidazole molecule binds nonspecifically to bacterial DNA, inactivating the organism's DNA and enzymes and leading to a high level of DNA breakage, with immediate action of the drug but no cell lysis [ 10 , 11 ]. Aerobic cells lack electron-transport proteins with sufficient negative redox potential; therefore, the drug is active against only bacteria with anaerobic metabolisms, even though the drug is effective against some microaerophils, such as H.
In addition, reoxidation can occur in the presence of molecular oxygen and can convert the compound back to its original inactive form [ 12 ]. Electron donors involved in the reduction process vary, depending on the organism. In anaerobic bacteria, the electron acceptors flavodoxin and ferredoxin, which receive electrons from the pyruvate-ferredoxin oxireductase complex, play important roles, although other enzymes and electron transfer components may also be involved in the process.
Each of these acceptors has a reduction potential lower than that of the metronidazole molecule and will thereby donate its electrons to the drug [ 12 ]. Metronidazole-resistant clones are typically mutated in the rdxA gene [ 10 , 13 ].
Several mechanisms of resistance to metronidazole in anaerobic bacteria have been proposed. These mechanisms differ among organisms, but the primary basis for resistance is decreased uptake of the drug or altered reduction efficiency Table 3. These 2 mechanisms act together; decreased activity of the nitroreductase leads to decreased uptake of the drug. Other mechanisms include active efflux, inactivation of the drug, and increased DNA damage repair [ 10 ].
Specific resistance genes nim conferring resistance to nitroimidazoles have been isolated in different genera of gram-positive and gram-negative anaerobic bacteria, including Bacteroides species [ 14 , 15 ].
Transfer of these genes has been shown to confer resistance to metronidazole in recipients infected with susceptible virus [ 16 ]. The nim genes encode an alternative reductase that can convert nitroimidazole to a nontoxic derivative, thereby circumventing the toxic effect that causes breakage of the DNA [ 12 , 17 ]. Thus far, 7 members of the genes—from nim A through nim G—have been found, although the detection of new variants indicates the existence of an even higher variety of these genes in the anaerobic community than was initially expected.
Studies on the prevalence of the nim genes have recorded an overrepresentation of nim A among anaerobes [ 15 ]. The nim genes are usually found on low-copy plasmids but have also been located on the bacterial chromosome and have been shown to be transferable by a conjugative process.
Specific regulatory elements known as insertion sequences are often associated with the nim genes. The insertion sequence elements are mobile and thought to be involved in plasticity of prokaryote genomes. They have been assigned a role in the expression of several resistance genes in Bacteroides species, including those for metronidazole, erythromycin-clindamycin, cefoxitin, and carbapenems.
These elements can be found on the bacterial chromosome, on plasmids, and in multiple copies [ 18 ]. The presence of the nim genes is not always associated with resistance, and their actual impact on clinically relevant metronidazole resistance is not yet clear. Still, the presence of nim genes significantly increases the risk of reduced susceptibility to metronidazole [ 15 ]. This latter breakpoint divides the normal population of susceptible isolates from those expressing resistance determinants and is also accepted as the European breakpoint for metronidazole resistance [ 19 ].
Other mechanisms that may contribute to resistance in Bacteroides species include efflux pumps. Few or no data exist on any efflux system in Bacteroides species, but overexpression of the efflux pumps is often involved in multidrug resistance in other species and for other antibiotics.
This mechanism could play an important role in the increased number of isolated clinical multidrug-resistant strains that lack any of the known nim genes. Additional investigations are needed. Gardnerella vaginalis is a pleomorphic Gram-variable bacterial bacillus that is also susceptible to metronidazole. Helicobacter pylori has been strongly associated with gastritis and duodenal ulcers.
Classic regimens for eradicating this pathogen have included metronidazole, usually with acid suppression medication plus bismuth and amoxicillin. The activity of metronidazole against anaerobic bowel flora has been used for prophylaxis and treatment of patients with Crohn's disease who might develop an infectious complication.
Treatment of Clostridium difficile-induced pseudomembraneous colitis has usually been with oral metronidazole or vancomycin, but the lower cost and similar efficacy of metronidazole, coupled with the increased concern about imprudent use of vancomycin leading to increased resistance in enterococci, have made metronidazole the preferred agent here.
Metronidazole has played an important role in anaerobic-related infections. You may have unpleasant effects such as headaches, nausea, vomiting, stomach cramps, and warmth or tingling under your skin. Use Metronidazole Flagyl exactly as directed on the label, or as prescribed by your doctor. Do not use in larger or smaller amounts or for longer than recommended.
Follow all directions on your prescription label and read all medication guides or instruction sheets. Use the medicine exactly as directed. Metronidazole injection is given as an infusion into a vein. A healthcare provider will give you this injection if you are unable to take the medicine by mouth. Shake the oral suspension liquid. Measure a dose with the supplied measuring device not a kitchen spoon. If you are treating a vaginal infection, your sexual partner may also need to take metronidazole so you don't become reinfected.
Metronidazole is usually given for up to 10 days in a row. You may need to repeat this dosage several weeks later. Keep using this medicine even if your symptoms quickly improve.
Skipping doses could make your infection resistant to medication. Metronidazole will not treat a viral infection flu or a common cold.
Metronidazole will not treat a vaginal yeast infection. You may even develop a new vaginal yeast infection, which may need to be treated with antifungal medication. Tell your doctor if you have symptoms such as itching or discharge during or after treatment with metronidazole.
Do not share this medicine with another person , even if they have the same symptoms you have. This medicine can affect the results of certain medical tests. Tell any doctor who treats you that you are using metronidazole. Take the medicine as soon as you can, but skip the missed dose if it is almost time for your next dose. Do not take two doses at one time. Overdose symptoms may include nausea, vomiting, numbness, tingling, or problems with balance or muscle movement.
You should feel better after using metronidazole for a few days, but this will depend on the type of infection you have.
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