Department of Pharmacology, Replidyne, Inc., Louisville, Colorado, USA.
Antimicrob Agents Chemother. 2010 May;54(5):1678-83. doi: 10.1128/AAC.00737-08. Epub 2010 Feb 9.
There are few options for prophylaxis after exposure to Bacillus anthracis, especially in children and women of childbearing potential. Faropenem is a beta-lactam in the penem subclass that is being developed as an oral prodrug, faropenem medoxomil, for the treatment of respiratory tract infections. Faropenem was shown to have in vitro activity against B. anthracis strains that variably express the bla1 beta-lactamase (MIC range, <or=0.06 to 1 microg/ml). In this study we evaluated the pharmacokinetic-pharmacodynamic (PK-PD) relationships between the plasma faropenem free-drug (f) concentrations and efficacy against B. anthracis in a murine postexposure prophylaxis inhalation model. The plasma PKs and PKs-PDs of faropenem were evaluated in BALB/c mice following the intraperitoneal (i.p.) administration of doses ranging from 2.5 to 160 mg/kg of body weight. For the evaluation of efficacy, mice received by inhalation aerosol doses of B. anthracis (Ames strain; faropenem MIC, 0.06 microg/ml) at 100 times the 50% lethal dose. The faropenem dosing regimens (10, 20, 40, and 80 mg/kg/day) were administered i.p. at 24 h postchallenge at 4-, 6-, and 12-h intervals for 14 days. The sigmoid maximum-threshold-of-efficacy (E(max)) model fit the survival data, in which the free-drug area under the concentration-time curve (fAUC)/MIC ratio, the maximum concentration of free drug in plasma (fC(max))/MIC ratio, and the cumulative percentage of a 24-h period that the free-drug concentration exceeds the MIC under steady-state pharmacokinetic conditions (f %T(MIC)) were each evaluated. Assessment of f %T(MIC) demonstrated the strongest correlation with survival (R(2) = 0.967) compared to the correlations achieved by assessment of fAUC/MIC or fC(max)/MIC, for which minimal correlations were observed. The 50% effective dose (ED(50)), ED(90), and ED(99) corresponded to f %T(MIC) values of 10.6, 13.4, and 16.4%, respectively, and E(max) was 89.3%. Overall, faropenem demonstrated a high level of activity against B. anthracis in the murine postexposure prophylaxis inhalation model.
炭疽杆菌暴露后预防选择有限，特别是儿童和育龄妇女。法罗培南是一种青霉烯类β-内酰胺抗生素，正在开发为一种口服前药法罗培南美多辛，用于治疗呼吸道感染。法罗培南对表达可变 bla1 内酰胺酶的炭疽杆菌菌株具有体外活性（MIC 范围，<或=0.06 至 1μg/ml）。在这项研究中，我们评估了血浆中法罗培南游离药物（f）浓度与在鼠暴露后预防吸入模型中对炭疽杆菌的疗效之间的药代动力学-药效学（PK-PD）关系。在 BALB/c 小鼠中，通过腹腔内（i.p.）给予 2.5 至 160mg/kg 体重的剂量来评估法罗培南的血浆 PK 和 PK-PD。为了评估疗效，通过吸入气雾剂向小鼠给予炭疽杆菌（Ames 株；法罗培南 MIC，0.06μg/ml），剂量为 50%致死剂量的 100 倍。法罗培南（10、20、40 和 80mg/kg/天）方案在挑战后 24 小时通过腹腔内给药，4、6 和 12 小时间隔 14 天。Sigmoid 最大疗效阈值（E（max））模型适合生存数据，其中游离药物浓度-时间曲线下面积（fAUC）/MIC 比值、最大游离药物血浆浓度（fC（max））/MIC 比值以及在稳态药代动力学条件下 24 小时期间游离药物浓度超过 MIC 的累积百分比（f %T（MIC））分别进行评估。评估 f %T（MIC）与生存的相关性最强（R（2）=0.967），而评估 fAUC/MIC 或 fC（max）/MIC 的相关性则观察到最小的相关性。50%有效剂量（ED（50））、ED（90）和 ED（99）对应于 f %T（MIC）值分别为 10.6%、13.4%和 16.4%，E（max）为 89.3%。总的来说，法罗培南在鼠暴露后预防吸入模型中对炭疽杆菌表现出很高的活性。
