Abstract：
OBJECTIVE: This study aimed to assess the pharmacokinetic/pharmacodynamic (PK/PD) targets of danofloxacin to minimize the risk of selecting resistant P. multocida mutants and to identify the mechanisms underlying their resistance in an in vitro dynamic model, attaining the optimum dosing regimen of danofloxacin to improve its clinical efficacy based on the mutant selection window (MSW) hypothesis.
RESULTS: Danofloxacin at seven dosing regimens and five days of treatment were simulated to quantify the bactericidal kinetics and enrichment of resistant mutants upon continuous antibiotic exposure. The magnitudes of PK/PD targets associated with different efficacies were determined in the model. The 24 h danofloxacin area under the concentration-time curve to MIC ratios (AUC24h/MIC) associated with bacteriostatic, bactericidal and eradication effects against P. multocida were 34, 52, and 64 h. This translates to average danofloxacin concentrations (Cav) over 24 h being 1.42, 2.17, and 2.67 times the MIC, respectively. An AUC/MIC-dependent antibacterial efficacy and AUC/MPC (mutant prevention concentration)-dependent enrichment of P. multocida mutants in which maximum losses in danofloxacin susceptibility occurred at a simulated AUC24h/MIC ratio of 72 h (i.e. Cav of 3 times the MIC). The overexpression of efflux pumps (acrAB-tolC) and their regulatory genes (marA, soxS, and ramA) was associated with reduced susceptibility in danofloxacin-exposed P. multocida. The AUC24h/MPC ratio of 19 h (i.e. Cav of 0.8 times the MPC) was determined to be the minimum mutant prevention target value for the selection of resistant P. multocida mutants.
CONCLUSIONS: The emergence of P. multocida resistance to danofloxacin exhibited a concentration-dependent pattern and was consistent with the MSW hypothesis. The current clinical dosing regimen of danofloxacin (2.5 mg kg-1) may have a risk of treatment failure due to inducible fluoroquinolone resistance.
RESULTS: Danofloxacin at seven dosing regimens and five days of treatment were simulated to quantify the bactericidal kinetics and enrichment of resistant mutants upon continuous antibiotic exposure. The magnitudes of PK/PD targets associated with different efficacies were determined in the model. The 24 h danofloxacin area under the concentration-time curve to MIC ratios (AUC24h/MIC) associated with bacteriostatic, bactericidal and eradication effects against P. multocida were 34, 52, and 64 h. This translates to average danofloxacin concentrations (Cav) over 24 h being 1.42, 2.17, and 2.67 times the MIC, respectively. An AUC/MIC-dependent antibacterial efficacy and AUC/MPC (mutant prevention concentration)-dependent enrichment of P. multocida mutants in which maximum losses in danofloxacin susceptibility occurred at a simulated AUC24h/MIC ratio of 72 h (i.e. Cav of 3 times the MIC). The overexpression of efflux pumps (acrAB-tolC) and their regulatory genes (marA, soxS, and ramA) was associated with reduced susceptibility in danofloxacin-exposed P. multocida. The AUC24h/MPC ratio of 19 h (i.e. Cav of 0.8 times the MPC) was determined to be the minimum mutant prevention target value for the selection of resistant P. multocida mutants.
CONCLUSIONS: The emergence of P. multocida resistance to danofloxacin exhibited a concentration-dependent pattern and was consistent with the MSW hypothesis. The current clinical dosing regimen of danofloxacin (2.5 mg kg-1) may have a risk of treatment failure due to inducible fluoroquinolone resistance.
摘要：
目的：本研究旨在评估达诺氟沙星的药代动力学/药效学（PK/PD）目标，以最大程度地减少选择耐药多杀性疟原虫突变体的风险，并在体外动态模型中确定其耐药的潜在机制。基于突变选择窗（MSW）假设，达到达诺氟沙星的最佳给药方案，以提高其临床疗效。
结果：模拟了7种给药方案和5天治疗的丹氧氟沙星，以量化连续抗生素暴露后的杀菌动力学和抗性突变体的富集。在模型中确定与不同功效相关的PK/PD靶标的量值。达诺氧氟沙星浓度-时间曲线下的24h面积与MIC比值（AUC24h/MIC）与抑菌相关，对多杀性疟原虫的杀菌和根除作用分别为34、52和64小时。这意味着24小时内的平均达氧氟沙星浓度（Cav）是MIC的1.42、2.17和2.67倍，分别。多杀性疟原虫突变体的AUC/MIC依赖性抗菌功效和AUC/MPC(突变体预防浓度)依赖性富集,其中在72小时的模拟AUC24h/MIC比率(即3倍MIC的Cav)下发生达诺氟沙星敏感性的最大损失。外排泵（acrAB-tolC）及其调控基因（marA，SOXS,和ramA）与暴露于达氧氟沙星的多杀性疟原虫的敏感性降低有关。19小时的AUC24h/MPC比率(即,Cav为MPC的0.8倍)被确定为用于选择抗性多杀性疟原虫突变体的最小突变预防目标值。
结论：多杀性疟原虫对达氧氟沙星的耐药性呈现浓度依赖性模式，与MSW假说一致。目前的达诺沙星（2.5mgkg-1）的临床给药方案可能由于可诱导的氟喹诺酮耐药性而具有治疗失败的风险。
结果：模拟了7种给药方案和5天治疗的丹氧氟沙星，以量化连续抗生素暴露后的杀菌动力学和抗性突变体的富集。在模型中确定与不同功效相关的PK/PD靶标的量值。达诺氧氟沙星浓度-时间曲线下的24h面积与MIC比值（AUC24h/MIC）与抑菌相关，对多杀性疟原虫的杀菌和根除作用分别为34、52和64小时。这意味着24小时内的平均达氧氟沙星浓度（Cav）是MIC的1.42、2.17和2.67倍，分别。多杀性疟原虫突变体的AUC/MIC依赖性抗菌功效和AUC/MPC(突变体预防浓度)依赖性富集,其中在72小时的模拟AUC24h/MIC比率(即3倍MIC的Cav)下发生达诺氟沙星敏感性的最大损失。外排泵（acrAB-tolC）及其调控基因（marA，SOXS,和ramA）与暴露于达氧氟沙星的多杀性疟原虫的敏感性降低有关。19小时的AUC24h/MPC比率(即,Cav为MPC的0.8倍)被确定为用于选择抗性多杀性疟原虫突变体的最小突变预防目标值。
结论：多杀性疟原虫对达氧氟沙星的耐药性呈现浓度依赖性模式，与MSW假说一致。目前的达诺沙星（2.5mgkg-1）的临床给药方案可能由于可诱导的氟喹诺酮耐药性而具有治疗失败的风险。
