title: Pharmacodynamics of trovafloxacin and levofloxacin against Bacteroides fragilis in an in vitro pharmacodynamic model.
abstract: An in vitro pharmacodynamic investigation was conducted to explore whether the area under the concentration time curve from 0 to 24 h (AUC(0-24))/MIC ratio could predict fluoroquinolone performance against Bacteroides fragilis. An in vitro model was used to generate kill curves for trovafloxacin (TVA) and levofloxacin (LVX) at AUC(0-24)/MIC ratios of 1 to 406 against three strains of B. fragilis (ATCC 25285, ATCC 23745, and clinical isolate M97-117). TVA and LVX were bolused prior to the start of experiments to achieve the corresponding AUC(0-24)/MIC ratio. Experiments were performed in duplicate over 24 h and in an anaerobic environment. Analyses of antimicrobial performance were conducted by comparing the rates of bacterial kill (K) using nonlinear regression analysis with 95% confidence intervals. Statistical significance was defined as a lack of overlap in the 95% confidence limits generated from the slope of each kill curve. For both TVA and LVX, K was maximized once an AUC(0-24)/MIC ratio of > or =40 was achieved and was not further increased despite a 10-fold increase in AUC(0-24)/MIC from approximately 40 to 400 against all three strains of B. fragilis. No significant differences were found in K between AUC(0-24)/MIC ratios of approximately 40 to 200. In experiments where AUC(0-24)/MIC ratios that were > or = 5 and < or = 44 were conducted, 64% demonstrated regrowth at 24 h. Resistant strains were selected in 50% of those experiments, demonstrating regrowth, which resulted in increased MICs of two- to 16-fold for both TVA and LVX. Regrowth did not occur, nor were resistant strains selected in any studies with an AUC/MIC that was > 44. Our findings suggest that fluoroquinolones provide antibacterial effects against B. fragilis in a concentration-independent manner associated with an AUC(0-24)/MIC ratio of > or =40. Also, the potential for the selection of resistant strains of B. fragilis may increase with an AUC(0-24)/MIC ratio of < or =44.
authors.affiliation: University of Minnesota, College of Pharmacy, Minneapolis, Minnesota 55455, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Peterson
authors.forename: L B
authors.initials: LB
authors.lastname: Hovde
authors.forename: D H
authors.initials: DH
authors.lastname: Wright
authors.forename: G H
authors.initials: GH
authors.lastname: Brown
authors.forename: A D
authors.initials: AD
authors.lastname: Hoang
authors.forename: J C
authors.initials: JC
authors.lastname: Rotschafer
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology*; D019540:Area Under Curve; D001441:Bacteroides fragilis / Q000187:drug effects*; D024841:Fluoroquinolones; D006801:Humans; D064704:Levofloxacin; D008826:Microbial Sensitivity Tests; D009287:Naphthyridines / Q000494:pharmacology*; D015242:Ofloxacin / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; D064704:Levofloxacin; C080163:trovafloxacin; D015242:Ofloxacin