In the article by De Lucas et al., the authors have considered the Letter to the Editor from Prof. Mark G. Papich and agreed it was appropriate to re-analyse the Pharmacokinetic/Pharmacodynamic (PK-PD) calculations for doxycycline using the unbound fraction. From the literature, the doxycycline protein binding in dogs is approximately 90% (Riond & Riviere, 1989), and we used a value of fraction unbound to plasmatic protein (fu) = 0.084 based on protein binding levels of 91.75 ± 0.63% and 91.4% (Gaastra et al., 2013).

The data presented in the correction reflect the corrected AUC values using fu. These new data are presented in Figure 3b (below).

After Monte Carlo simulation analysis, using a value for fAUC/MIC doxycycline index of 12, a PTA value of 7.7% was calculated for a MIC value of 1 μg/ml. For strains with a MIC = 0.5 μg/ml, the PTA values calculated were 54.7%, 6.21% and 0.56%, for endpoints 12, 25 and 40, respectively. The PTA for bacterial strains with a MIC < 0.250 μg/ml, was 97.31% for an index value of 12; 51.69% for an index value of 25 and 14.48% for an index value of 40. Only the bacterial strains with an MIC = 0.125 μg/ml would reach PTA values of 100%, 96.3% and 72.63%, respectively.

The cumulative fraction of response (CFR) reached < 90% for several pathogens at a fAUC/MIC of 12 (CFR = 58.38%), 25 (CFR = 58.11%) and 40 (CFR = 56.41%), suggesting a lower efficacy with current recommended doxycycline dosing under these circumstances.

After Monte Carlo simulation analysis based on this PK/PD index, the PTA approached 100% only for those bacterial strains with an MIC < 0.063 μg/ml for all end points used in this work.

在De Lucas 等人的文章中。，作者考虑了 Mark G. Papich 教授给编辑的信，并同意使用未结合部分重新分析多西环素的药代动力学/药效学 (PK-PD) 计算是合适的。根据文献，狗的强力霉素蛋白结合率约为 90%（Riond & Riviere，1989），我们使用未结合血浆蛋白的分数 ( f u) = 0.084，基于蛋白结合水平为 91.75 ± 0.63% 和91.4%（Gaastra 等人，2013 年）。

校正中显示的数据反映了使用fu校正后的 AUC 值。这些新数据如图 3b（下图）所示。

蒙特卡罗模拟分析后，使用f AUC/MIC 多西环素指数的值为 12，对于 1 μg/ml 的 MIC 值计算出 7.7% 的 PTA 值。对于 MIC = 0.5 μg/ml 的菌株，计算的 PTA 值分别为 54.7%、6.21% 和 0.56%，对于终点 12、25 和 40。MIC < 0.250 μg/ml 的细菌菌株的 PTA 为 97.31%，指数值为 12；指数值为 25 时为 51.69%，指数值为 40 时为 14.48%。只有 MIC = 0.125 μg/ml 的菌株才能分别达到 100%、96.3% 和 72.63% 的 PTA 值。

在f AUC/MIC 为 12 (CFR = 58.38%)、25 (CFR = 58.11%) 和 40 (CFR = 56.41%) 时，几种病原体的累积反应分数 (CFR) 达到 < 90% ，表明疗效较低在这些情况下使用当前推荐的强力霉素剂量。

在基于该 PK/PD 指数进行蒙特卡罗模拟分析后，对于本工作中使用的所有终点，仅对于那些 MIC < 0.063 μg/ml 的细菌菌株，PTA 接近 100%。