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Abstract：
Omadacycline, a novel aminomethylcycline with in vitro activity against Gram-positive and -negative organisms, including Streptococcus pneumoniae and Haemophilus influenzae, is approved in the United States to treat patients with community-acquired bacterial pneumonia (CABP). Using nonclinical pharmacokinetic-pharmacodynamic (PK-PD) targets for efficacy and in vitro surveillance data for omadacycline against S. pneumoniae and H. influenzae, and a population pharmacokinetic model, PK-PD target attainment analyses were undertaken using total-drug epithelial lining fluid (ELF) and free-drug plasma exposures to evaluate omadacycline 100 mg intravenously (i.v.) every 12 h or 200 mg i.v. every 24 h (q24h) on day 1, followed by 100 mg i.v. q24h on day 2 and 300 mg orally q24h on days 3 to 5 for patients with CABP. Percent probabilities of PK-PD target attainment on days 1 and 2 by MIC were assessed using the following four approaches for selecting PK-PD targets: (i) median, (ii) second highest, (iii) highest, and (iv) randomly assigned total-drug ELF and free-drug plasma ratio of the area under the concentration-time curve to the MIC (AUC/MIC ratio) targets associated with a 1-log10 CFU reduction from baseline. Percent probabilities of PK-PD target attainment based on total-drug ELF AUC/MIC ratio targets on days 1 and 2 were ≥91.1% for S. pneumoniae for all approaches but the highest target and ≥99.2% for H. influenzae for all approaches at MIC90s (0.12 and 1 μg/mL for S. pneumoniae and H. influenzae, respectively). Lower percent probabilities of PK-PD target attainment based on free-drug plasma AUC/MIC ratio targets were observed for randomly assigned and the highest free-drug plasma targets for S. pneumoniae and for all targets for H. influenzae. These data provided support for approved omadacycline dosing regimens to treat patients with CABP and decisions for the interpretive criteria for the in vitro susceptibility testing of omadacycline against these pathogens.
摘要：
Omadacycline,一种新型的氨甲基环素，对革兰氏阳性和阴性生物体具有体外活性，包括肺炎链球菌和流感嗜血杆菌,在美国被批准用于治疗社区获得性细菌性肺炎（CABP）患者。使用非临床药代动力学-药效学（PK-PD）目标来研究奥马环素对肺炎链球菌和流感嗜血杆菌的疗效和体外监测数据，和群体药代动力学模型，使用全药物上皮衬里液（ELF）和游离药物血浆暴露进行PK-PD目标达成分析，以评估omadacycline每12小时100mg静脉内（i.v.）或每24小时200mg静脉内（q24h）在第1天，然后在第2天接受100mg静脉内q24h，在第3天至第5天口服300mgq24h。使用以下四种选择PK-PD目标的方法评估第1天和第2天通过MIC达到PK-PD目标的百分比概率：（i）中位数，(ii)第二高，（三）最高，和（iv）随机分配的总药物ELF和游离药物血浆浓度-时间曲线下面积与MIC（AUC/MIC比）目标的比值，与从基线降低1-log10CFU相关。根据第1天和第2天的总药物ELFAUC/MIC比值目标，达到PK-PD目标的概率百分比对于所有方法均为肺炎链球菌≥91.1%，但对于所有方法均为最高目标，对于流感嗜血杆菌≥99.2%在MIC90（肺炎链球菌和流感嗜血杆菌为0.12和1μg/mL，分别)。对于随机分配的肺炎链球菌和流感嗜血杆菌的所有靶标,观察到基于游离药物血浆AUC/MIC比靶标的PK-PD靶标达到的较低百分比概率和最高游离药物血浆靶标。这些数据为批准的奥马环素给药方案提供了支持，以治疗CABP患者，并决定了奥马环素对这些病原体的体外敏感性测试的解释标准。
