Determining optimal dosing regimen of oral administration of dicloxacillin using Monte Carlo simulation

摘要

Background: Dicloxacillin, a semisynthetic isoxazolyl penicillin, exhibits antimicrobial activity against a wide variety of Gram-positive bacteria, as well as stability against penicillinases and low level of toxicity. The objective of this study was to obtain optimal dosing regimen of oral administration of dicloxacillin by analyzing the pharmacokinetic (PK) index in healthy volunteers and in vitro antibacterial activity by using Monte Carlo simulation. Materials and methods: A total of 867 clinical isolates from community-onset infections were collected from 31 secondary hospitals in People’s Republic of China. The minimum inhibitory concentration (MIC) values of dicloxacillin were determined by the agar dilution method. Based on the MICs and the PK parameters of different dosage regimens, Monte Carlo simulation was performed to simulate the PK/pharmacodynamic indices of 250 mg once-daily (qd), 500 mg?qd, 1,000 mg qd, 2,000 mg qd, 250 mg every 6 hours (q6h), and 500 mg q6h, respectively. The probability of target attainment was estimated at each MIC value, and the cumulative fraction of response (CFR) was calculated to evaluate the efficacy of these regimens. Results: Dicloxacillin showed poor antibacterial activity against Haemophilus influenzae , Moraxella catarrhalis , and Streptococcus pneumoniae . Resistance to dicloxacillin was observed in 7.5% of coagulase-negative Staphylococcus (CNS) isolates and 9.2% of other Streptococcus isolates, whereas 1.5% of methicillin-sensitive Staphylococcus aureus (MSSA) was resistant to dicloxacillin. Multiple-dose regimens could obtain higher CFR than single-dose regimens against H. influenza and S. pneumoniae . However, all dosing regimens against MSSA achieved CFR ≥90%. Meanwhile, dosing regimen of 2,000 mg qd, 250 mg q6h, and 500 mg q6h could achieve >90% of CFR for CNS. For other Streptococcus isolates, multiple-dose regimens achieved CFR ≥90%. Conclusion: Dicloxacillin has a significant antibacterial activity against MSSA, CNS, and other Streptococcus isolates. The simulation results suggest that dicloxacillin 250 mg q6h and 500 mg q6h dosing regimens may be recommended for clinical applications, especially for community-onset infections.