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.
The alteration of DNA repair systems playing a role in metronidazole resistance in H. Overexpression of the enzymes involved in the process is correlated with decreased antibiotic susceptibility. A strong candidate is the recA protein; mutants deficient in its expression are sensitive to oxygen stress and to the action of metronidazole. Other genes in the rec family have also been suggested for a role in DNA repair, although they have not been as well studied [ 22 ].
The mechanism of inducible metronidazole resistance is another feature of the metronidazole drug that could have clinical implications. Reversible and irreversible high-level resistance have been induced in susceptible clinical Bacteroides strains with use of subinhibitory concentrations of metronidazole [ 15 , 23 ]. Subinhibitory concentrations of metronidazole can interfere with the cellular properties of members of the B.
In an in vitro assay, metronidazole resistance was shown to be associated with superior internalization activity of H. Alterations in the bacterial composition and overgrowth of yeasts, as well as selection of resistant strains, have been shown to be associated with metronidazole administration in combination with other agents, such as amoxicillin and clarithromycin [ 26 ]. The impact of metronidazole on the normal microflora varies, depending on the body site involved.
Concentrations of metronidazole exceeding MIC values of anaerobes are found during treatment in body fluids, such as saliva, which may explain the reduction in the number of oropharyngeal anaerobic bacteria after combination treatment with metronidazole and clarithromycin [ 27 ].
In the study by Adamsson et al [ 27 ], suppression of the anaerobic flora of the intestine, likely resulting from the administration of clarithromycin, was also recorded. The concentration of active metronidazole in feces is low during administration, because the agent is well absorbed and is excreted primarily by liver metabolism; however, high concentrations have been measured in colon tissue [ 28 ].
Only minor changes have been observed in the normal intestinal microflora after oral intake of metronidazole alone. The known clinical efficacy of oral administration of metronidazole in the treatment of C. Most of the metronidazole affecting C. The normal microflora serve as a reservoir of antibiotic-resistance determinants, where some dissemination of resistance can occur [ 29 , 30 ].
Virtually all genes in Bacteroides species that encode resistance to antibiotics, including metro-nidazole, have been found on transmissible elements [ 18 , 31 ]. This transferability may contribute to the spread of resistance; thus far, resistance to metronidazole has remained low.
Resistance among anaerobic pathogens is still generally low; however, the susceptibility patterns of anaerobic bacteria are undergoing changes, and decreases in in vitro susceptibility to various antimicrobials have been reported in recent years.
These data are derived predominantly from international and national surveys; individual hospital screenings for susceptibility in anaerobic bacteria remain uncommon Table 4. The practice in many laboratories of identifying obligate anaerobes by susceptibility to metronidazole is a factor that contributes to probable underestimation of true resistance rates. Growths around disks are presumed to be facultative anaerobes with naturally reduced susceptibility, and these strains have not been investigated further [ 46 ].
Consequently, the treatment of anaerobic infections is generally empirical and is based on published reports of susceptibility rates, which emphasizes the importance of reference laboratories providing valid and updated information [ 47 ].
A general decrease in susceptibility to metronidazole has been displayed among anaerobes. Most non-spore-forming gram-positive anaerobic bacteria, including isolates of Actinomyces, Bifidobacterium, Eubacterium, Lactobacillus , and Propionibacterium species, have intrinsically reduced metronidazole susceptibility.
Metronidazole resistance in Sutterella species has been reported [ 48 ]. Susceptibility is still very high in Fusobacterium, Prevotella , and Porphymonas species; gram-positive anaerobic cocci; and all Bacteroides species [ 34 ]. Bacteria belonging to the B. Metronidazole has been the drug of choice for the treatment of Bacteroides infection and remains reliable for this use [ 49 ]. The first metronidazole-resistant Bacteroides strain was reported in [ 50 ]. Compared with metronidazole resistance rates of 1.
The true incidence is difficult to estimate. Still, B. Despite the low levels of resistance to metronidazole, treatment failures attributed to metronidazole resistance have been reported, and multidrug-resistant strains have been identified [ 51 , 52 ].
In many cases, the infection cannot be associated with a single pathogen because of the lack of identification and susceptibility testing of anaerobes and because of the polymicrobial nature of anaerobic infections, which are also frequently cleared by drainage or surgery. Results of retrospective and prospective studies have correlated clinical failure with antibiotic resistance in anaerobic bacteria [ 47 , 53 ]. No significant clinical resistance to metronidazole or vancomycin in C.
Some metronidazole-resistant C. In a study by Wong et al [ 54 ] that reported the first well-documented case of a metronidazole-resistant C.
Treatment failures are not uncommon but have not yet been clearly attributed to drug-resistant strains. Metronidazole is widely used as a therapeutic agent for H. Metronidazole resistance is considered to be the main single factor responsible for treatment failure. The high frequency of use of metronidazole may select for resistance not only in H.
Because of its well-known safety and efficacy in clinical practice, metronidazole is still the cornerstone for the management of anaerobic infections worldwide. Supplement sponsorship. Google Scholar. Google Preview. Oxford University Press is a department of the University of Oxford.
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Close mobile search navigation Article Navigation. Volume Article Contents Abstract. Therapeutic Use of Metronidazole for Anaerobic Infections. Metronidazole in Clinical Practice. Mechanisms of Action and Resistance to Metronidazole. Metronidazole and the Normal Microflora. Levels of Resistance to Metronidazole. Figures and Tables. Oxford Academic. Charlotta Edlund. Carl Erik Nord. Reprints or correspondence: Prof.
Anaerobic bacteria which are typically sensitive are primarily Gram-negative anaerobes belonging to the Bacteroides and Fusobacterium spp. Gram-positive anaerobes such as peptostreptococci and Clostridia spp. 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. Milk thistle Silybum marianum may help to protect the liver from medications that may harm it, such as Flagyl.
It has not been studied in relation to Flagyl, but it may be prescribed as a complementary therapy. Flagyl, also known as metronidazole or by the brand name Protostat is an anti-bacterial drug that treats anaerobic bacterial infections or protozoal infections. It's important to follow your doctor's instructions when you take this medication. Side effects may include abdominal cramping, diarrhea, nausea, vomiting, loss of appetite, and headache.
Some patients experience more serious side effects such as numbness or seizures. If you experience these severe side effects, call your doctor right away. After the last dose of Flagyl is taken, wait at least 72 hours before drinking any alcohol.
Drinking while on Flagyl can cause nausea, abdominal cramps, vomiting, and headaches. Some types of over-the-counter cough suppressant and cold products contain small amounts of alcohol, so be careful if you decide to take one.
No, metronidazole is not available over the counter. You will need to contact your doctor to receive a prescription. Most people begin to feel better after a few days of taking metronidazole or Flagyl. However, even if you feel better, the infection may still be present, which is why it's important to take the full course of medication as prescribed.
Flagyl should never be used to treat a yeast infection. In fact, using it might worsen the effects of a yeast infection. Sign up for our Health Tip of the Day newsletter, and receive daily tips that will help you live your healthiest life.
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National Library of Medicine. Updated August 24, Updated September 29, Metronidazole-induced cerebellar toxicity.
Neurol Int. Published Apr 1. Am J Forensic Med Pathol. Possible nephrotoxic interaction of lithium and metronidazole. The effects of milk thistle Silybum marianum on human cytochrome P activity.
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