Beta-lactam antibiotics are often the backbone of treatment for Gram-negative infections in the critically ill. Beta-lactams exhibit time-dependent killing, and their efficacy depends on the percentage of dosing interval that the concentration remains above the minimum inhibitory concentration. The Gram-negative resistance rates of pathogens are increasing in the intensive care unit (ICU), and critically ill patients often possess physiology that makes dosing more challenging. The volume of distribution is usually increased, and drug clearance is variable. Augmented renal clearance and hypermetabolic states increase the clearance of beta-lactams, while acute kidney injury reduces the clearance. To overcome the factors affecting ICU patients and decreasing susceptibilities, dosing strategies involving higher doses, and extended or continuous infusions may be required. In this review, we specifically examined pharmacokinetic models in ICU patients, to determine the desired beta-lactam regimens for clinical breakpoints of Enterobacterales and Pseudomonas aeruginosa, as determined by the European Committee on Antimicrobial Susceptibility Testing. The beta-lactams evaluated included penicillins, cephalosporins, carbapenems, and monobactams. We found that when treating less-susceptible pathogens, especially P. aeruginosa, continuous infusions are frequently needed to achieve the desired pharmacokinetic/pharmacodynamic targets. More studies are needed to determine optimal dosing strategies in the novel beta-lactams.

中文翻译：

---

革兰氏阴性细菌感染危重患者的 β-内酰胺剂量：PK/PD 方法


β-内酰胺抗生素通常是治疗危重病患者革兰氏阴性菌感染的主要药物。 β-内酰胺具有时间依赖性杀灭作用，其功效取决于浓度保持在最低抑制浓度以上的给药间隔百分比。重症监护病房 (ICU) 中病原体的革兰氏阴性耐药率不断增加，而危重患者的生理情况往往使给药更具挑战性。分布容积通常会增加，并且药物清除率是可变的。肾脏清除率增加和代谢亢进状态会增加β-内酰胺的清除率，而急性肾损伤会降低清除率。为了克服影响 ICU 患者并降低敏感性的因素，可能需要涉及更高剂量以及延长或连续输注的给药策略。在这篇综述中，我们专门检查了 ICU 患者的药代动力学模型，以确定欧洲抗菌药物敏感性测试委员会确定的肠杆菌和铜绿假单胞菌临床断点所需的 β-内酰胺方案。评估的β-内酰胺类药物包括青霉素类、头孢菌素类、碳青霉烯类和单环内酰胺类。我们发现，当治疗不太敏感的病原体，特别是铜绿假单胞菌时，经常需要连续输注才能达到所需的药代动力学/药效学目标。需要更多的研究来确定新型β-内酰胺的最佳剂量策略。