Experimental Therapeutics

In Vitro Pharmacodynamic Evaluation of the Mutant Selection Window Hypothesis Using Four Fluoroquinolones against Staphylococcus aureus

Alexander A. Firsov, Sergey N. Vostrov, Irene Y. Lubenko, Karl Drlica, Yury A. Portnoy, Stephen H. Zinner
DOI: 10.1128/AAC.47.5.1604-1613.2003

Article Figures & Data

Figures

  • FIG. 1.
    FIG. 1.

    Determination of MPC. Estimated values are given along the x axis.

  • FIG.2.
    FIG.2.

    In vitro-simulated pharmacokinetic profiles of the fluoroquinolones moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. The numbers at the end of each profile are the AUC24/MIC value and the percentage of the dosing interval that falls within the MSW. Arrows reflect quinolone dosing.

  • FIG.3.
    FIG.3.

    Determination of IE (shaded areas) at comparable AUC24/MIC values for moxifloxacin (53 h), gatifloxacin (61 h), levofloxacin (48 h), and ciprofloxacin (62 h). Bold lines delineate the time-kill and regrowth curves, and thin lines delineate control growth curves. Arrows indicate quinolone dosing; the dotted line marks the cutoff level (13).

  • FIG. 4.
    FIG. 4.

    Simulated pharmacokinetics, showing changes in the susceptibility and time-kill curves of S. aureus 201 during and after 5-day treatments with moxifloxacin (triangles) (AUC24/MIC, 53 h) or levofloxacin (squares) (AUC24/MIC, 48 h).

  • FIG. 5.
    FIG. 5.

    Changes in the susceptibility of S. aureus 201 during and after 3-day treatments with four fluoroquinolones at different AUC24/MIC ratios.

  • FIG. 6.
    FIG. 6.

    Resistance of S. aureus 201 related to the simulated AUC24/MIC value (left) and TMSW (right) for four fluoroquinolones (combined data). For equation 1, a = 1.7, b = 0.18, and xc = 1.63. For equation 2, Ymax = 3.1, x0 = 43, and dx = 5.1.

  • FIG. 7.
    FIG. 7.

    Kinetics of killing and regrowth of S. aureus 201 exposed to 3-day courses of moxifloxacin, gatifloxacin, levofloxacin, and ciprofloxacin. Boxed numbers indicate the simulated AUC24/MIC values (in hours).

  • FIG. 8.
    FIG. 8.

    AUC24/MIC-dependent antistaphylococcal effects of fluoroquinolones fitted by equation 3. For moxifloxacin, a = 4.1, b = 7.1, Ymax = 607, and x50 = 1.7. For gatifloxacin, a = 2.9, b =5.7, Ymax = 595, and x50 = 2.0. For levofloxacin, a = 3.3, b = 6.1, Ymax = 550, and x50 = 1.8. For ciprofloxacin, a = 4.7, b = 8.1, Ymax = 398, and x50 = 1.7.

  • FIG. 9.
    FIG. 9.

    AUC24/MIC-dependent resistance of B. fragilis to levofloxacin and trovafloxacin fitted by equation 1 (a = 10.1, b = 0.12, xc = 1.4). The graph presents combined data reconstructed from reference 25. Resistance is expressed as the ratio of MIC24 to MIC0.

  • FIG. 10.
    FIG. 10.

    AUC24/MIC-dependent resistance frequency of S. aureus after a 48-h quinolone exposure. The bar graph presents data reconstructed from reference 1. Resistance is expressed as the area under the reported resistance frequency-time curve. Dotted curve, MIC72/MIC0-versus-AUC24/MIC relationship obtained in the present study.

Tables

  • TABLE 1.

    MICs determined before and after exposure of S. aureus to two fluoroquinolones

    FluoroquinoloneDuration of treatment (days)MIC (μg/ml)
    Before treatmentJust after samplingAfter 3rd passageAfter 7th passageAfter 10th passage
    Moxifloxacin30.090.250.250.190.19
    40.370.310.310.37
    50.50.50.50.5
    Levofloxacin30.6110.750.75
    4221.51.5
    5221.51.5
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KEYWORDS

anti-infective agents
Staphylococcus aureus

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