title: Impact of drug-exposure intensity and duration of therapy on the emergence of Staphylococcus aureus resistance to a quinolone antimicrobial.
abstract: We have shown previously in animal model and in vitro systems that antimicrobial therapy intensity has a profound influence on subpopulations of resistant organisms. Little attention has been paid to the effect of therapy duration on resistant subpopulations. We examined the influence of therapy intensity (area under the concentration/time curve for 24 h:minimum inhibitory concentration [AUC24:MIC] ratio) and therapy duration on resistance emergence using an in vitro model of Staphylococcus aureus infection. AUC24:MIC ratios of>or=100 were necessary to kill a substantial portion of the total population. Importantly, we demonstrated that therapy duration is a critical parameter. As the duration increased beyond 5 days, the intensity needed to suppress the antibiotic-resistant subpopulations increased, even when the initial bacterial kill was>4 log10 (cfu/mL). These findings were prospectively validated in an independent experiment in which exposures were calculated from the results of fitting a large mathematical model to all data simultaneously. All of the prospectively determined predictions were fulfilled in this validation experiment.
authors.affiliation: Emerging Infections and Host Defense Laboratory, Ordway Research Institute, Albany, NY, USA.
authors.forename: V H
authors.initials: VH
authors.lastname: Tam
authors.forename: A
authors.initials: A
authors.lastname: Louie
authors.forename: T R
authors.initials: TR
authors.lastname: Fritsche
authors.forename: M
authors.initials: M
authors.lastname: Deziel
authors.forename: W
authors.initials: W
authors.lastname: Liu
authors.forename: D L
authors.initials: DL
authors.lastname: Brown
authors.forename: L
authors.initials: L
authors.lastname: Deshpande
authors.forename: R
authors.initials: R
authors.lastname: Leary
authors.forename: R N
authors.initials: RN
authors.lastname: Jones
authors.forename: G L
authors.initials: GL
authors.lastname: Drusano
mesh_terms: D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D015169:Colony Count, Microbial; D027081:DNA Gyrase / Q000235:genetics; D027101:DNA Topoisomerase IV / Q000235:genetics; D024881:Drug Resistance, Bacterial / Q000502:physiology*; D024841:Fluoroquinolones / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D008826:Microbial Sensitivity Tests; D008962:Models, Theoretical; D016133:Polymerase Chain Reaction; D011485:Protein Binding; D015203:Reproducibility of Results; D013203:Staphylococcal Infections / Q000188:drug therapy*; D013211:Staphylococcus aureus / Q000187:drug effects*; D013997:Time Factors
chemical_list: D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D027101:DNA Topoisomerase IV; D027081:DNA Gyrase; C419689:garenoxacin