Pharmacodynamics of Flucloxacillin in a Neutropenic Murine Thigh Infection Model: A Piece of the Puzzle towards Evidence-Based Dosing

Abstract

For decades, flucloxacillin has been used to treat methicillin-susceptible Staphylococcus aureus (MSSA). Little is still known about its pharmacodynamics (PD). The present study aimed to determine the pharmacokinetic (PK)/PD index and the PD-index value minimally required for efficacy. MICs of 305 MSSA isolates were measured to determine the wild-type distribution. The PD of 8 S. aureus, 1 S. pyogenes, and 1 S. agalactiae isolates were evaluated in a neutropenic murine thigh infection model. Two S. aureus isolates were used in a dose-fractionation study and a dose−response analysis was performed additionally in the in vivo model. Data were analyzed with a population PK and sigmoid maximum effect model. The end of the wild-type distribution was 1 mg/L. The percentage of time the unbound concentration was above MIC (%fT > MIC) was best correlated with efficacy. For S. aureus, median %fT > 0.25 × MIC required for 1-log reduction was 15%. The value for S. pyogenes was 10%fT > MIC and for S. agalactiae 22%fT > 0.25xMIC for a 1-log reduction. The effect of flucloxacillin reached a 2-log reduction of S. aureus at 20%fT > 0.25xMIC and also for S. pyogenes and S. agalactiae, a reduction was reached. These data may serve to optimize dosing regimens currently used in humans.

Keywords: MIC-distribution; PD-target; PK/PD index; beta-lactam.

Figure 1

Relationships of flucloxacillin percentage of time the unbound concentration was above 0.25 times the MIC (%fT > 0.25xMIC) (A), %fT > MIC (B), 24 h fAUC/MIC (C,D), and fC_max/MIC (E,F) for S. aureus MUP1621 and MUP4421 in the neutropenic thigh infection model, with change in CFU per thigh from start of treatment and after 24 h of treatments. Flucloxacillin was dosed every 2 (Q2), 4 (Q4), or 6 (Q6) h. Each symbol represents a therapy response in one mouse thigh. The line is the best-fit line based on the sigmoid maximum effect (E_max) model.

Figure 2

Dose–response of flucloxacillin against six S. aureus, one S. pyogenes and one S. agalactiae isolates in the neutropenic murine thigh infection model. Each symbol represents a therapy response in one mouse thigh. The x axis is the flucloxacillin exposure expressed as the percentage of time the unbound concentration was above 0.25 times the MIC (1 time the MIC for S. pyogenes). The y axis is the change in log₁₀ of bacterial load from the start of treatment. The line is the best fit based on the sigmoid E_max model.

Figure 3

Distribution of MSSA isolates and the probability of target attainment (%PTA) for the 2-log kill target for several dosing regimens for intensive care unit (ICU) [7] as well as non-ICU hospitalized patients [8].