Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA
Institute for Clinical Pharmacodynamics, Inc., Schenectady, New York, USA.
Antimicrob Agents Chemother. 2020 May 21;64(6). doi: 10.1128/AAC.02265-19.
Omadacycline is a novel aminomethylcycline with activity against Gram-positive and -negative organisms, including , which is one of the leading causes of community-acquired bacterial pneumonia (CABP). The evaluation of antimicrobial agents against using standard murine infection models is challenging due to the low pathogenicity of this species in mice. Therefore, 24-h dose-ranging studies using a one-compartment infection model were undertaken with the goal of characterizing the magnitude of the ratio of the area under the concentration-time curve (AUC) to the MIC (AUC/MIC ratio) associated with efficacy for a panel of five isolates. These five isolates, for which MIC values were 1 or 2 mg/liter, were exposed to omadacycline total-drug epithelial lining fluid (ELF) concentration-time profiles based on those observed in healthy volunteers following intravenous omadacycline administration. Relationships between change in log CFU/ml from baseline at 24 h and the total-drug ELF AUC/MIC ratios for each isolate and for the isolates pooled were evaluated using Hill-type models and nonlinear least-squares regression. As evidenced by the high coefficients of determination () of 0.88 to 0.98, total-drug ELF AUC/MIC ratio described the data well for each isolate and the isolates pooled. The median total-drug ELF AUC/MIC ratios associated with net bacterial stasis and 1- and 2-log CFU/ml reductions from baseline at 24 h were 6.91, 8.91, and 11.1, respectively. These data were useful to support the omadacycline dosing regimens selected for the treatment of patients with CABP, as well as susceptibility breakpoints for .
奥马环素是一种新型的氨甲基环素，对革兰氏阳性和阴性菌均有活性，包括 ，这是导致社区获得性细菌性肺炎（CABP）的主要原因之一。由于该物种在小鼠中的致病性较低，因此使用标准的小鼠感染模型评估抗菌药物对 的活性具有挑战性。因此，进行了 24 小时剂量范围研究，使用一室 感染模型，目的是确定与疗效相关的浓度时间曲线下面积（AUC）与 MIC 的比值（AUC/MIC 比值）的幅度，该比值与一组 5 株 的分离株相关。这五个分离株的 MIC 值为 1 或 2 mg/L，其接触的是奥马环素总药物上皮衬液（ELF）浓度时间曲线，这些浓度时间曲线是根据健康志愿者静脉注射奥马环素后的观察结果确定的。使用 Hill 型模型和非线性最小二乘回归评估了 24 小时时从基线变化的 log CFU/ml 与每个分离株和分离株混合的总药物 ELF AUC/MIC 比值之间的关系。每个分离株和分离株混合的高决定系数（）为 0.88 至 0.98，证明总药物 ELF AUC/MIC 比值很好地描述了数据。与 24 小时时净细菌停滞以及从基线减少 1-和 2-log CFU/ml 相关的中位总药物 ELF AUC/MIC 比值分别为 6.91、8.91 和 11.1。这些数据有助于支持治疗 CABP 患者的奥马环素给药方案，以及 的药敏折点。
