Mutant prevention concentration-based pharmacokinetic/pharmacodynamic indices as dosing targets for suppressing the enrichment of levofloxacin-resistant subpopulations of Staphylococcus aureus

Abstract

MIC- and mutant prevention concentration (MPC)-based pharmacokinetic/pharmacodynamic (PK/PD) indices were compared for suitability as attainment targets for restricting amplification of levofloxacin-resistant mutant subpopulations. When three Staphylococcus aureus strains were examined with a hollow-fiber PK/PD model, area under the concentration-time curve over 24 h (AUC24)/MPC values of >25 and maximum concentration of drug in serum (Cmax)/MPC values of >2.2 predicted resistance outcome among different isolates with an interisolate kappa coefficient of 1. MIC-based mutant-restrictive PK/PD values varied >8-fold and exhibited only a moderate interisolate agreement (kappa coefficient of 0.5). Thus, MPC-based PK/PD indices are more suitable than MIC-based indices for predicting mutant-restricting fluoroquinolone doses when multiple bacterial isolates are considered.

Fig. 1.

Levofloxacin treatment of S. aureus strain SA99 in a hollow-fiber dynamic in vitro model. (A) Simulated pharmacokinetics for levofloxacin to generate successively increasing values of AUC₂₄, as indicated at the top of each column (panels A to D have the same AUC₂₄ for a given column). Levofloxacin concentration was measured by HPLC, with samples taken at 0, 0.5, 1, 2, 5, 7, 8, 24, 48, and 72 h after initiation of treatment from the central compartment. The levofloxacin concentration in the extracapillary space was then simulated and displayed. MPC and MIC determined with the starting culture are indicated. (B) Survival measured with total bacterial population, determined by plating and incubation on drug-free agar. (C) Change in size of resistant mutant subpopulation, determined by plating and incubation at a levofloxacin concentration twice the MIC of the starting culture. The dashed line and the dotted symbol indicate that the viable bacterial number was below the detection limit (e.g., 10 CFU/ml) 72 h after initiation of levofloxacin treatment. (D) Ratio of MIC of samples treated with levofloxacin for the indicated times (MIC_time) relative to MIC of starting sample (MIC₀). Similar data were obtained with strains RN450 and RN450-A1.

Fig. 2.

Correlation of MPC- and MIC-based PK/PD indices with resistance outcome among different bacterial isolates. PK/PD indices from all 12 bacterium-dose combinations listed in Table 1 were treated as independent entries and plotted as a function of experiment number to evaluate point scatter. AUC₂₄- and C_max-based indices are presented. MIC-based indices are shown as circles, and MPC-based indices are shown as squares. Open symbols indicate no amplification of resistant mutant subpopulation, while filled symbols represent selective amplification of resistant mutants. Dotted lines indicate a threshold value for either AUC₂₄/MPC or C_max/MPC separating PK/PD indices that resulted in enrichment of resistant mutant subpopulation from those that did not. The data showed perfect interisolate agreement (kappa coefficient of 1 [22]). No single line could be drawn for either AUC₂₄/MIC or C_max/MIC when multiple isolates were considered. Only a moderate interisolate agreement (kappa coefficient of 0.5) was observed when MIC-based PK/PD indices were used to predict resistance outcome.