Lepak Alexander J, Marchillo Karen, Craig William A, Andes David R
Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA.
William S. Middleton Memorial VA Hospital, Madison, Wisconsin, USA.
Antimicrob Agents Chemother. 2015 Feb;59(2):1258-64. doi: 10.1128/AAC.04444-14. Epub 2014 Dec 15.
NAI-107 is a novel lantibiotic compound with potent in vitro activity against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA). The purpose of this study was to examine the activity of NAI-107 against S. aureus strains, including MRSA, in the neutropenic murine thigh infection model. Serum pharmacokinetics were determined and time-kill studies were performed following administration of single subcutaneous doses of 5, 20, and 80 mg/kg body weight. The dose fractionation included total doses ranging from 1.56 to 400 mg/kg/72 h, divided into 1, 2, 3, or 6 doses. Studies of treatment effects against 9 S. aureus strains (4 methicillin-susceptible Staphylococcus aureus [MSSA] and 5 MRSA) using a 12-h dosing interval and total dose range of 1.56 to 400 mg/kg/72 h were also performed. A maximum effect (Emax) model was used to determine the pharmacokinetic/pharmacodynamic (PK/PD) index that best described the dose-response data and to estimate the doses required to achieve a net bacteriostatic dose (SD) and a 1-log reduction in CFU/thigh. The pharmacokinetic studies demonstrated an area under the concentration-time curve (AUC) range of 26.8 to 276 mg·h/liter and half-lives of 4.2 to 8.2 h. MICs ranged from 0.125 to 0.5 μg/ml. The 2 highest single doses produced more than a 2-log kill and prolonged postantibiotic effects (PAEs) ranging from 36 to >72 h. The dose fractionation-response curves were similar, and the AUC/MIC ratio was the most predictive PD index (AUC/MIC, coefficient of determination [R2]=0.89; maximum concentration of drug in serum [Cmax]/MIC, R2=0.79; time [T]>MIC, R2=0.63). A ≥2-log kill was observed against all 9 S. aureus strains. The total drug 24-h AUC/MIC values associated with stasis and a 1-log kill for the 9 S. aureus strains were 371±130 and 510±227, respectively. NAI-107 demonstrated concentration-dependent killing and prolonged PAEs. The AUC/MIC ratio was the predictive PD index. Extensive killing was observed for S. aureus organisms, independent of the MRSA status. The AUC/MIC target should be useful for the design of clinical dosing regimens.
NAI-107是一种新型羊毛硫抗生素化合物，对革兰氏阳性菌具有强大的体外活性，包括耐甲氧西林金黄色葡萄球菌（MRSA）。本研究的目的是在中性粒细胞减少的小鼠大腿感染模型中检测NAI-107对包括MRSA在内的金黄色葡萄球菌菌株的活性。测定了血清药代动力学，并在单次皮下注射5、20和80mg/kg体重后进行了时间-杀菌研究。剂量分割包括总剂量范围为1.56至400mg/kg/72h，分为1、2、3或6剂。还进行了使用12小时给药间隔和1.56至400mg/kg/72h总剂量范围对9株金黄色葡萄球菌菌株（4株甲氧西林敏感金黄色葡萄球菌[MSSA]和5株MRSA）的治疗效果研究。使用最大效应（Emax）模型确定最能描述剂量反应数据的药代动力学/药效学（PK/PD）指数，并估计实现净抑菌剂量（SD）和使每大腿CFU减少1个对数所需的剂量。药代动力学研究表明，浓度-时间曲线下面积（AUC）范围为26.8至276mg·h/升，半衰期为4.2至8.2小时。MIC范围为0.125至0.5μg/ml。2个最高单剂量产生了超过2个对数的杀灭效果，并延长了抗生素后效应（PAE），范围从36至>72小时。剂量分割反应曲线相似，AUC/MIC比值是最具预测性的PD指数（AUC/MIC，决定系数[R2]=0.89；血清中药物最大浓度[Cmax]/MIC，R2=0.79；时间[T]>MIC，R2=0.63）。对所有9株金黄色葡萄球菌菌株均观察到≥2个对数的杀灭效果。与9株金黄色葡萄球菌菌株的停滞和1个对数杀灭相关的24小时总药物AUC/MIC值分别为371±130和510±227。NAI-107表现出浓度依赖性杀灭和延长的PAE。AUC/MIC比值是预测性的PD指数。观察到对金黄色葡萄球菌菌株有广泛的杀灭作用，与MRSA状态无关。AUC/MIC靶点应有助于临床给药方案的设计。
