Abstract
Metronidazole is metabolized to two major oxidative products: an acid metabolite and a hydroxy metabolite. While the activity of the acid metabolite is negligible, the activity of the hydroxy metabolite is approximately 65% of the activity of the parent drug. Pharmacokinetic studies of metronidazole and its hydroxy metabolite have shown that the MICs of both compounds remain above the MICs for most anaerobic organisms over an 8-h dosing interval. By a checkerboard assay, the combined activities of metronidazole and the hydroxy metabolite were examined against 4 quality control strains of Bacteroides species. Macrobroth tube dilutions were set up with Wilkins-Chalgren broth. Serial twofold dilutions of each agent were performed to achieve final concentrations ranging from 0.06 to 4.0 micrograms/ml. The MICs for Bacteroides fragilis and B. distasonis were 1.0 microgram/ml for both parent drug and metabolite. For B. thetaiotamicron and B. ovatus, the MICs of metronidazole and the hydroxy metabolite were 1.0 and 2.0 micrograms/ml, respectively. Synergy was determined by calculating the fractional inhibitory concentration (FIC) index. The interpretative criteria for the FIC index were as follows: synergy, FIC < or = 0.5; partial synergy, 0.51 to 0.75; indifference, FIC 0.76 to 4.0; and antagonism, FIC > 4.0. Partial synergy was observed for the four anaerobes tested, with FIC indices ranging from 0.63 to 0.75. On the basis of this data, in vitro susceptibilities to agents such as metronidazole may ultimately require reevaluation to account for active metabolites.