PDF(Pubmed)
Abstract：
Despite their limitations, the pharmacokinetics (PK) and pharmacodynamics (PD) indices form the basis for our current understanding regarding antibiotic development, selection, and dose optimization. Application of PK-PD in medicine has been associated with better clinical outcome, suppression of resistance, and optimization of antibiotic consumption. Beta-lactam antibiotics remain the cornerstone for empirical and directed therapy in many patients. The percentage of time of the dosing interval that the free (unbound) drug concentration remains above the minimal inhibitory concentration (MIC) (%fT > MIC) has been considered the PK-PD index that best predicts the relationship between antibiotic exposure and killing for the beta-lactam antibiotics. Time dependence of beta-lactam antibiotics has its origin in the acylation process of the serine active site of penicillin-binding proteins, which subsequently results in bacteriostatic and bactericidal effects during the dosing interval. To enhance the likelihood of target attainment, higher doses, and prolonged infusion strategies, with/or without loading doses, have been applied to compensate for subtherapeutic levels of antibiotics related to PK-PD changes, especially in the early phase of severe sepsis. To minimize resistance and maximize clinical outcome, empirical therapy with a meropenem loading dose followed by high-dose-prolonged infusion should be considered in patients with high inoculum infections presenting as severe (Gram negative) sepsis. Subsequent de-escalation and dosing of beta-lactam antibiotics should be considered as an individualized dynamic process that requires dose adjustments throughout the time course of the disease process mediated by clinical parameters that indirectly assess PK-PD alterations.
摘要：
尽管有其局限性,药代动力学（PK）和药效学（PD）指数构成了我们目前对抗生素开发的理解的基础，选择,和剂量优化。PK-PD在医学中的应用与更好的临床疗效有关，抑制电阻，和优化抗生素消费。β-内酰胺抗生素仍然是许多患者经验性和定向治疗的基石。游离(未结合)药物浓度保持高于最小抑制浓度(MIC)(%fT>MIC)的给药间隔的时间百分比被认为是PK-PD指数,其最佳地预测抗生素暴露与β-内酰胺抗生素的杀灭之间的关系。β-内酰胺抗生素的时间依赖性起源于青霉素结合蛋白的丝氨酸活性位点的酰化过程，这随后导致在给药间隔期间的抑菌和杀菌作用。为了提高达到目标的可能性，更高的剂量,和长期输注策略，有/或没有负荷剂量，已用于补偿与PK-PD变化相关的抗生素的亚治疗水平，特别是在严重脓毒症的早期。为了最大限度地减少耐药性和最大限度地提高临床疗效，对于表现为严重(革兰氏阴性)脓毒症的高接种物感染患者,应考虑采用美罗培南负荷剂量,然后进行高剂量长时间输注的经验性治疗.β-内酰胺抗生素的后续降级和给药应被视为个体化的动态过程，需要在疾病过程的整个时间过程中进行剂量调整，该过程由间接评估PK-PD改变的临床参数介导。
