IN-VITRO ACTIVITIES OF METRONIDAZOLE AND ITS HYDROXY METABOLITE AGAINST BACTEROIDES SPP

Metronidazole is metabolized to two major oxidative products: an acid metabolite and a hydroxy metabolite. While the activity of the acid me tabolite is negligible, the activity of the hydroxy metabolite is appr oximately 65% of the activity of the parent drug. Pharmacokinetic stud ies of metronidazole and its hydroxy metabolite have shown that the MI Cs of both compounds remain above the MICs for most anaerobic organism s over an 8-h dosing interval. By a checkerboard assay, the combined a ctivities of metronidazole and the hydroxy metabolite were examined ag ainst 4 quality control strains of Bacteroides species. Macrobroth tub e dilutions were set up with Wilkins-Chalgren broth. Serial twofold di lutions of each agent were performed to achieve final concentrations r anging from 0.06 to;4.0 mu g/ml. The MICs for Bacteroides fragilis and B. distasonis were 1.0 mu g/ml for both parent drug and metabolite. F or B. thetaiotaomicron and B. ovatus, the MICs of metronidazole and th e hydroxy metabolite were 1.0 and 2.0 mu g/ml, respectively. Synergy w as determined by calculating the fractional inhibitory concentration ( FIC) index. The interpretative criteria for the FIC index were as foll ows: synergy, FIC less than or equal to 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 suscept ibilities to agents such as metronidazole may ultimately require reeva luation to account for active metabolites.