InVitro Activities ofMetronidazole andItsHydroxy Metabolite against Bacteroides spp.

Metronidazole ismetabolized totwomajor oxidative products: anacid metabolite andahydroxy metabolite. Whiletheactivity oftheacidmetabolite isnegligible, theactivity ofthehydroxy metabolite isapproximately 65%oftheactivity oftheparent drug. Pharmacokinetic studies ofmetronidazole anditshydroxy metabolite haveshownthat theMICsofbothcompounds remain above theMICsformostanaerobic organisms overan 8-hdosing interval. Byacheckerboard assay, thecombined activities ofmetronidazole andthehydroxy metabolite wereexamined against 4quality control strains ofBacteroides species. Macrobroth tubedilutions weresetupwithWilkins-Chalgren broth. Serial twofold dilutions ofeachagent wereperformed toachieve final concentrations ranging from0.06to4.0,ug/ml. TheMICsforBacteroides fragilis andB.distasonis were1.0 ,ug/ml forbothparent drugandmetabolite. ForB.thetaiotaomicron andB.ovatus, theMICsofmetronidazole andthehydroxy metabolite were1.0and2.0,g/ml, respectively. Synergy wasdetermined bycalculating the fractional inhibitory concentration (FIC) index. Theinterpretative criteria fortheFICindex wereasfollows: synergy, FIC'0.5; partial synergy, 0.51to0.75; indifference, FIC0.76to4.0; andantagonism, FIC>4.0. Partial synergy wasobserved forthefour anaerobes tested, withFICindices ranging from0.63 to0.75. Onthe basis ofthis data, invitro susceptibilities toagents suchasmetronidazole mayultimately require reevaluation toaccount foractive metabolites. Theactivity ofmetronidazole against anaerobes hasbeen recognized forover30years (27). Thisdrugishighly active against anaerobic gram-negative bacilli, including members of theBacteroides fragilis group(24, 26). Excellent bactericidal activity, fewadverse effects, andreasonable costarethe primary reasons whythis agent isconsidered oneofthedrugs ofchoice inthetreatment ofanaerobic infections. Metronidazole ismetabolized totwomajoroxidative products: 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidaz ole