Background An antibacterial drug’s susceptibility test interpretive criteria (STIC) are determined by integrating clinical, microbiological and pharmacokinetic-pharmacodynamic (PK-PD) data. PTA analysis plays a pivotal or supportive role in STIC determination and is heavily dependent on the PK-PD target values determined from animal PK-PD studies. Therefore, variations in PK-PD target values may impact STIC determination. Factors contributing to variation in the PK-PD target values include the number of and MICs for bacterial isolates used in animal PK-PD studies. Objectives To analyse the relationship between PK-PD target values and MICs, describe the variations in PK-PD target values of isolates and evaluate whether the proposed/target STICs were within the ranges of the MICs for isolates used in animal PK-PD studies. Methods A database was compiled for this research by screening animal PK-PD study reports submitted to the FDA from 10 new drug applications (NDAs). Results A relationship evaluation between PK-PD target values and MICs for tested isolates for seven drugs (that used AUC/MIC ratio as the PK-PD index) showed that, generally, the AUC/MIC values decreased with an increase in MIC. These target values were highly variable, with the percentage coefficient of variation ranging between 1% and 132% for isolates having the same MIC. For 16/27 (59%) drug/bacteria combinations from all 10 drugs, the proposed/target STICs were higher than the highest MIC for bacteria isolates evaluated, while 6/27 (22.5%) were lower. Conclusions This research suggests that careful considerations related to selection of bacterial isolates for animal PK-PD studies could strengthen the STIC determination process.

中文翻译：

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不同 MIC 的药代动力学-药效学目标值的变化及其对确定药敏试验解释标准的潜在影响

背景 抗菌药物的药敏试验解释标准 (STIC) 是通过整合临床、微生物学和药代动力学-药效学 (PK-PD) 数据来确定的。PTA 分析在 STIC 测定中起着关键或支持作用，并且严重依赖于动物 PK-PD 研究确定的 PK-PD 目标值。因此，PK-PD 目标值的变化可能会影响 STIC 的确定。导致 PK-PD 目标值变化的因素包括动物 PK-PD 研究中使用的细菌分离物的数量和 MIC。目的 分析 PK-PD 目标值和 MIC 之间的关系，描述分离株 PK-PD 目标值的变化，并评估建议/目标 STIC 是否在动物 PK-PD 研究中使用的分离株的 MIC 范围内。方法 通过筛选提交给 FDA 的 10 份新药申请 (NDA) 的动物 PK-PD 研究报告，为本研究编制了一个数据库。结果 7种药物（以AUC/MIC比值作为PK-PD指标）的PK-PD目标值与MIC的关系评价表明，AUC/MIC值通常随着MIC的增加而降低。这些目标值是高度可变的，具有相同 MIC 的分离株的变异百分比系数在 1% 和 132% 之间。对于所有 10 种药物的 16/27 (59%) 药物/细菌组合，建议/目标 STIC 高于所评估的细菌分离物的最高 MIC，而 6/27 (22.5%) 较低。