Metronidazole: proven benefits and potential risks

Metronidazole is unique among therapies approved for trichomonas vaginitis and is useful also in the treatment of amebiasis, giardiasis and anaerobic bacterial infections. It has recently proved to be effective antibacterial prophylaxis for colon surgery. In spite of these important therapeutic properties the drug is considered risky for human use because of laboratory evidence that is it tumorigenic and mutagenic. A large excess risk of human cancer as the result of prior metronidazole exposure can probably be excluded on the basis of evidence already available. However, with the risk uncertain the drug should be restricted to patients who clearly will benefit from it and these patients should receive the drug in the minimal dose which is effective. Nitro group reduction is implicated in most of the biological properties of metronidazole including its mutagenicity. Two metabolites of the reduction of metronidazole, acetamide and N-(2-hydroxyethyl)-oxamic acid, form in the intestinal flora and can be found in the excreta of conventional rats but not of germfree rats. Thus the worrisome reaction implicated in the mutagenicity of metronidazole occurs in the flora. These metabolites produced by the flora complement those described in Ernest Bueding's laboratory. Bueding's group postulates metabolites which are mutagenic, and thus probably not yet reduced, whereas we postulate that our metabolites indicate that reduction, and thus possibly a mutagenic reaction, has already occurred. The metabolites we describe which are indicative of the reduction of metronidazole are also found in the urine of patients who take the drug. This has several possible implications which bear investigation. One is that a reactive intermediate may form in the flora and enter mammalian tissues. The other is that metronidazole is metabolized in the human to acetamide which is a carcinogen in its own right. Thus this drug,with its increasing number of useful clinical properties, continues to show laboratory properties which have uncertain implications for human risk.