Proof of concept: performance testing in models
Proof of concept: performance testing in models
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DOI：
10.1111/j.1470-9465.2004.00865.x
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发表时间：
2004-04-01
影响因子：
14.2
通讯作者：
Craig, WA
中科院分区：
文献类型：
--
作者：
Craig, WA
预测抗菌功效的药代动力学（PK）和药效学（PD）原理可用于设定抗菌设计和优化的目标。尽管阿莫西林和阿莫西林/克拉维酸的当前制剂保留了其对许多但不是全部青霉素不敏感的肺炎链球菌的疗效，但需要额外的覆盖来解决日益严重的耐药菌株问题。因此，使用PK/PD原则设计了两种新的阿莫西林/克拉维汀口服制剂，一种是90/6.4 mg/kg/天的儿科制剂，一种是2000/125 mg每日两次的成人药代动力学增强制剂。这些原则表明，对于阿莫西林和阿莫西林/克拉维酸，高于MIC的时间为给药间隔的35-40%，预示着高细菌有效性。与PK/PD预测、体外动力学模型和大鼠肺炎模型中人体药代动力学模拟一致，阿莫西林/克拉维汀2000/125 mg每日两次对S.阿莫西林MIC为4或8 mg/L。对于阿莫西林MIC为4 mg/L的菌株，阿莫西林/克拉维汀2000/125 mg每日2次的有效性显著高于常规875/125 mg每日2次制剂、阿奇霉素和左氧氟沙星，尽管所有左氧氟沙星MIC均小于或等于1 mg/L。感染S.对于阿莫西林MIC为8 mg/L的肺炎杆菌菌株，阿莫西林/克拉维酸2000/125 mg每日两次制剂比875/125 mg每日两次和每日三次以及1000/125 mg每日三次的常规阿莫西林/克拉维酸制剂更有效，并且根据菌株具有与阿奇霉素和左氧氟沙星相似或更好的功效。这些数据表明，与传统制剂和其他市售抗菌药物相比，阿莫西林/克拉维汀2000/125 mg每日两次治疗呼吸道感染的潜在获益。
Pharmacokinetic (PK) and pharmacodynamic (PD) principles that predict antimicrobial efficacy can be used to set targets for antimicrobial design and optimisation. Although current formulations of amoxicillin and amoxicillin/clavulanate have retained their efficacy against many, but not all, penicillin-nonsusceptible Streptococcus pneumoniae, additional coverage is required to address the growing problem of drug-resistant strains. Accordingly, two new oral formulations of amoxicillin/clavulanate, a paediatric formulation at 90/6.4 mg/kg/day and a pharmacokinetically enhanced formulation at 2000/125 mg twice daily for adults, were designed using PK/PD principles. These principles indicate that for amoxicillin and amoxicillin/clavulanate, a time above MIC of 35-40% of the dosing interval is predictive of high bacterial efficacy. In line with PK/PD predictions, simulation of human pharmacokinetics in in-vitro kinetic models and in a rat model of pneumonia, amoxicillin/clavulanate 2000/125 mg twice daily was highly effective against S. pneumoniae strains with amoxicillin MICs of 4 or 8 mg/L. Against strains with amoxicillin MICs of 4 mg/L, amoxicillin/clavulanate 2000/125 mg twice daily was significantly more effective than the conventional 875/125 mg twice daily formulation, azithromycin and levofloxacin, even though all levofloxacin MICs were less than or equal to 1 mg/L. Following infection with S. pneumoniae strains with amoxicillin MICs of 8 mg/L, the amoxicillin/clavulanate 2000/125 mg twice daily formulation was more effective than the conventional amoxicillin/clavulanate formulations of 875/125 mg twice daily and three times daily and 1000/125 mg three times daily, and had similar or better efficacy than azithromycin and levofloxacin, depending on the strain. These data indicate the potential benefit of therapy with amoxicillin/clavulanate 2000/125 mg twice daily compared with conventional formulations and other marketed antimicrobials in the treatment of respiratory tract infection.