Anaerobic conditions are required both for the bactericidal effect of metronidazole and for its metabolic transformation to acetamide. These phenomena appear to be related in that the log of the surviving fraction of bacteria susceptible to metronidazole varies linearly with the amount of metronidazole converted to acetamide (1, 9). The most parsimonious explanation for this kinetic relationship is that anaerobic bacteria catalyze the conversion of metronidazole to a labile, partially reduced intermediate which then has one of several possible fates. It may interact, for example, with water to form acetamide or, alternatively, with a bacterial macromolecule to initiate the bactericidal effect (1). This hypothesis suggests that the concentration of the proposed intermediate, M*, determines both the rate of formation of acetamide and the damage to a bacterial macromolecule which, if not repaired, becomes lethal (Fig. 1).Although the chemical nature of M* is not known, its relative concentration over time, and hence the cell's exposure to it, can be inferred from the relative amounts of acetamide that accumulate. The model also enables one to distinguish between two mechanisms of resistance, one that is due to a decreased formation of the reactive form of metronidazole and another that is due to an increased resistance of the bacterial target.The first mechanism, a decreased formation of the partially reduced, reactive form of metronidazole, appears to be responsible for the increased resistance of a clinical isolate of Bacteroides fragilis (4, 9). The relation between bacterial survival and acetamide accumulation for this strain is the same as that for a normally susceptible strain of B. fragilis (9). This suggests that the two strains are equally susceptible to metronidazole's reactive metabolite and that the reactive * Corresponding author. metabolite merely forms more slowly in the resistant strain. This explanation is supported by the finding that nitroreductase activity, which is presumably responsible for the formation of metronidazole's active form, is decreased in the more resistant strain (9, 15).A kinetic approach based on the model in Fig.

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