The First Report on Pharmacokinetic/Pharmacodynamic Study of Trimethoprim/Sulfamethoxazole against Staphylococcus aureus with a Neutropenic Murine Thigh Infection Model

Introduction: With an increase in the incidence of Staphylococcus aureus infections in the healthcare settings and in the community, trimethoprim/sulfamethoxazole (TMP/SMX) has been suggested as a convenient treatment option. However, the appropriate dosage regimen of TMP/SMX is unclear. Objective: This study aimed to examine the pharmacokinetics/pharmacodynamics (PK/PD) of TMP/SMX against S. aureus using a neutropenic murine thigh infection model. Methods: Five S. aureus isolates with TMP/SMX (1:5 fixed ratio) minimum inhibitory concentrations (MICs) of 0.032-64 μg/mL were tested. The antimicrobial efficacy of TMP/SMX (1-689 mg/kg/day: dose shown as SMX dosage) was calculated as the change in bacterial density after 24 h of treatment. The plasma concentrations of TMP/SMX were detected using high-performance liquid chromatography. Results: After TMP/SMX single dose (130 mg/kg), the half-life, area under the blood concentration curve (AUC_0-∞), and the protein binding ratio of SMX were 1.5 h, 718.2 μg h/mL, and 73.0 ± 8.3%, respectively. The free AUC/MIC and free %time (%T) above the MIC of SMX were better correlated with the in vivo antimicrobial activity than C_max/MIC (free AUC/MIC, R² = 0.69; free %T > MIC, R² = 0.71; free C_max/MIC, R² = 0.53). The distributed doses (2-3 times per day) of TMP/SMX (130, 260, and 390 mg/kg/day) showed higher antimicrobial activity than the single dosage. However, TMP/SMX did not show its antimicrobial activity at <100% free %T > MIC. Conclusions: The TMP/SMX treatment demonstrated that the free AUC/MIC of SMX was the better predictor of the PK/PD index of TMP/SMX.