Metronidazole (Flagyl, Metrogel) exerts activity against most anaerobic bacteria and several protozoa. The drug freely penetrates protozoal and bacterial cells but not mammalian cells. Metronidazole can function as an electron sink, and because it does so, its 5-nitro group is reduced. The enzyme, pyruvate-ferredoxin oxidoreduc-tase, found only in anaerobic organisms, reduces metronidazole and thereby activates the drug. Reduced metronidazole disrupts replication and transcription and inhibits DNA repair.
Metronidazole inhibits E. histolytica, G. lamblia, T. vagi-nalis, Blastocystis hominis, B. coli, and the helminth Dracunculus medinensis. It is also bactericidal for obli-gate anaerobic gram-positive and gram-negative bacte-ria except Actinomyces spp. It is not active against aer-obes or facultative anaerobes. Drug resistance is infrequent; the mechanism of resistance is not under-stood. Tinidazole, a 5-nitroimidazole closely related to metronidazole, is effective against vaginal trichomonia-sis resistant to metronidazole.
Absorption from the intestinal tract is usually good. Food delays but does not reduce absorption. The drug is distributed in body fluids and has a half-life of about 8 hours. High levels are found in plasma and cere-brospinal fluid (CSF). Less than 20% binds to plasma proteins. Metronidazole is metabolized by oxidation and glucuronide formation in the liver and is primarily excreted by the kidneys, although small amounts can be found in saliva and breast milk. Dose reduction is gen-erally unnecessary in renal failure.
Metronidazole is the most effective agent available for the treatment of individuals with all forms of amebiasis, with perhaps the exception of the person who is asymp-tomatic but continues to excrete cysts. That situation calls for an effective intraluminal amebicide, such as diloxanide furoate, paromomycin sulfate, or diiodohy-droxyquin. Metronidazole is active against intestinal and extraintestinal cysts and trophozoites.
Although quinacrine hydrochloride has been used for the treatment of giardiasis, many physicians prefer metronidazole. Furazolidone is an alternate choice.
Metronidazole is the drug of choice in Europe for anaerobic bacterial infections; concern about possible carcinogenicity has led to some caution in its use in the United States. Recently it has been found to be effective in treating D. medinensis (Guinea worm) infections and Helicobacter pylori.
The most frequently observed adverse reactions to metronidazole include nausea, vomiting, cramps, diar-rhea, and a metallic taste. The urine is often dark or red-brown. Less frequently, unsteadiness, vertigo, ataxia, paresthesias, peripheral neuropathy, encephalopathy, and neutropenia have been reported. Since metronida-zole is a weak inhibitor of alcohol dehydrogenase, alco-hol ingestion should be avoided during treatment. A psychotic reaction also may be produced. Metronidazole interferes with the metabolism of warfarin and may po-tentiate its anticoagulant activity. Phenobarbital and cor-ticosteroids lower metronidazole plasma levels by in-creasing its metabolism, whereas cimetidine raises levels by impairing metronidazole metabolism. The drug is not recommended for use during pregnancy.