Andes D, Craig W A
Department of Medicine, Section of Infectious Diseases, University of Wisconsin School of Medicine, Room H4/570, 600 Highland Ave., Madison, WI 53792, USA.
Antimicrob Agents Chemother. 2006 Apr;50(4):1376-83. doi: 10.1128/AAC.50.4.1376-1383.2006.
PPI-0903 is a new cephalosporin with broad-spectrum activity, including beta-lactam-resistant Streptococcus pneumoniae and Staphylococcus aureus. We used the neutropenic murine thigh and lung infection models to examine the pharmacodynamic characteristics of PPI-0903. Serum drug levels following four fourfold-escalating single doses of PPI-0903 were measured by microbiologic assay. In vivo postantibiotic effects (PAEs) were determined after doses of 1.56, 6.25, 25, and 100 mg/kg of body weight in mice infected with S. pneumoniae ATCC 10813, S. aureus ATCC 29213, or Escherichia coli ATCC 25922. Dose fractionation studies over a 24-h dose range of 0.39 to 1,600 mg/kg were administered every 3, 6, 12, or 24 hours. Nonlinear regression analysis was used to determine which pharmacokinetic-pharmacodynamic (PK-PD) index (total and free 65% drug) best correlated with CFU/thigh at 24 h. Similar to other beta-lactam antibiotics, PPI-0903 produced short to modest in vivo PAEs with either S. pneumoniae or E. coli. The percent time that serum concentrations were above the MIC (%T>MIC) was the PK-PD index that best correlated with efficacy (R2=84 to 88% for the three organisms, compared with 9 to 41% for peak/MIC and 30 to 82% for the area under the concentration-time curve/MIC). In subsequent studies we used the neutropenic murine thigh infection model to determine if the magnitude of the free-drug % T>MIC needed for efficacy of PPI-0903 varied among pathogens (including resistant strains). Mice infected with one of five isolates of S. pneumoniae, four isolates of S. aureus, or four gram-negative bacilli were treated for 24 h with 0.10 to 400 mg/kg of PPI-0903 every 6 h. A sigmoid dose-response model was used to estimate the doses (mg/kg/24 h) required to achieve a net bacteriostatic affect over 24 h and to produce a reduction in the burden of organisms from the start of therapy by 1 and 2 log10 CFU/thigh. MICs ranged from 0.008 to 1 microg/ml.Mean free-drug %T >MICs the standard deviation associated with the static effect endpoint for S. pneumoniae, S. aureus, and gram-negative isolates were 39±9, 26±8, and 47±8, respectively [corrected]. Methicillin and penicillin resistance did not alter the magnitude of free-drug %T>MIC required for efficacy. The free-drug %T>MIC necessary for efficacy was slightly reduced in animals with normal neutrophil counts. Treatment effect was similar in both the thigh and lung infection models. The pharmacodynamic characteristics of PPI-0903 are similar to those of other compounds within the cephalosporin class.
PPI-0903是一种新型头孢菌素，具有广谱活性，包括对β-内酰胺耐药的肺炎链球菌和金黄色葡萄球菌。我们使用中性粒细胞减少的小鼠大腿和肺部感染模型来研究PPI-0903的药效学特征。通过微生物测定法测量了PPI-0903单次剂量四次呈四倍递增后的血清药物水平。在感染肺炎链球菌ATCC 10813、金黄色葡萄球菌ATCC 29213或大肠埃希菌ATCC 25922的小鼠中，分别给予1.56、6.25、25和100mg/kg体重的剂量后，测定体内抗生素后效应（PAE）。在24小时剂量范围为0.39至1600mg/kg内进行剂量分割研究，每3、6、12或24小时给药一次。使用非线性回归分析来确定哪种药代动力学-药效学（PK-PD）指标（总药物和游离65%药物）与24小时时大腿处的菌落形成单位（CFU）最相关。与其他β-内酰胺类抗生素相似，PPI-0903对肺炎链球菌或大肠埃希菌产生的体内PAE较短至中等。血清浓度高于最低抑菌浓度（MIC）的时间百分比（%T>MIC）是与疗效最相关的PK-PD指标（三种细菌的R2为84%至88%，相比之下，峰浓度/MIC的R2为9%至41%，浓度-时间曲线下面积/MIC的R2为30%至82%）。在随后的研究中，我们使用中性粒细胞减少的小鼠大腿感染模型来确定PPI-0903发挥疗效所需的游离药物%T>MIC的幅度在不同病原体（包括耐药菌株）之间是否存在差异。感染五种肺炎链球菌分离株之一、四种金黄色葡萄球菌分离株或四种革兰氏阴性杆菌的小鼠，每6小时给予0.10至400mg/kg的PPI-0903，治疗24小时。使用S型剂量反应模型来估计在24小时内实现净抑菌作用以及从治疗开始使每大腿处的细菌负荷降低1和2个对数10CFU所需的剂量（mg/kg/24小时）。MIC范围为0.008至1μg/ml。肺炎链球菌、金黄色葡萄球菌和革兰氏阴性分离株的平均游离药物%T>MIC以及与静态效应终点相关的标准差分别为39±9、26±8和47±8[校正后]。甲氧西林和青霉素耐药性并未改变发挥疗效所需的游离药物%T>MIC的幅度。中性粒细胞计数正常的动物中，发挥疗效所需的游离药物%T>MIC略有降低。大腿和肺部感染模型中的治疗效果相似。PPI-0903的药效学特征与头孢菌素类中的其他化合物相似。
