Hospices Civils de Lyon, Groupement Hospitalier Nord, Service de Pharmacie, Lyon, France.
Univ Lyon, Université Claude Bernard Lyon 1, UMR CNRS 5558, Laboratoire de Biométrie et Biologie Évolutive, Villeurbanne, France.
J Antimicrob Chemother. 2023 Nov 6;78(11):2762-2769. doi: 10.1093/jac/dkad300.
The new definitions of antimicrobial susceptibility categories proposed by EUCAST in 2020 require the definition of standard and high dosages of antibiotic. For injectable β-lactams, standard and high dosages have been proposed for short-infusion regimens only.
To evaluate dosages for β-lactams administered by prolonged infusion (PI) and continuous infusion (CI).
Monte Carlo simulations were performed for seven injectable β-lactams: aztreonam, cefepime, cefotaxime, cefoxitin, ceftazidime, piperacillin and temocillin. Various dosage regimens based on short infusion, PI or CI were simulated in virtual patients. Pharmacokinetic (PK) profiles and PTAs were obtained based on reference population PK models, as well as PK/pharmacodynamic targets and MIC breakpoints proposed by EUCAST. Alternative dosage regimens associated with PTA values similar to those of recommended dosages up to the breakpoints were considered acceptable.
Adequate PTAs were confirmed for most EUCAST short-infusion dosage regimens. A total of 9 standard and 14 high dosages based on PI (3 to 4 h) or CI were identified as alternatives. For cefepime and aztreonam, only PI and CI regimens could achieve acceptable PTAs for infections caused by Pseudomonas spp.: 2 g q8h as PI of 4 h or 6 g/24 h CI for cefepime; 2 g q6h as PI of 3 h or 6 g/24 h CI for aztreonam.
These alternative standard and high dosage regimens are expected to provide antibiotic exposure compatible with new EUCAST definitions of susceptibility categories and associated MIC breakpoints. However, further clinical evaluation is necessary.
欧盟药敏委员会（EUCAST）于 2020 年提出的新抗菌药物敏感性分类定义要求明确抗生素的标准剂量和高剂量。对于注射用β-内酰胺类药物，仅为短时间输注方案提出了标准剂量和高剂量。
评估长时间输注（PI）和持续输注（CI）给予β-内酰胺类药物的剂量。
对七种注射用β-内酰胺类药物（氨曲南、头孢吡肟、头孢噻肟、头孢西丁、头孢他啶、哌拉西林和替莫西林）进行了蒙特卡罗模拟。在虚拟患者中模拟了基于短时间输注、PI 或 CI 的各种剂量方案。根据参考人群药代动力学（PK）模型以及 EUCAST 提出的 PK/药效学目标和 MIC 折点，获得 PK/药效学参数（PTA）。与推荐剂量直至折点的 PTA 值相似的替代剂量方案被认为是可接受的。
大多数 EUCAST 短时间输注剂量方案的 PTA 均得到确认。总共确定了 9 种标准剂量和 14 种高剂量，这些剂量基于 PI（3-4 小时）或 CI。对于头孢吡肟和氨曲南，只有 PI 和 CI 方案才能实现对铜绿假单胞菌感染的可接受 PTA：头孢吡肟的 PI 为 4 小时 2 g，或 24 小时 CI 为 6 g；氨曲南的 PI 为 3 小时 2 g，或 24 小时 CI 为 6 g。
这些替代的标准和高剂量方案有望提供与新的 EUCAST 敏感性分类定义和相关 MIC 折点相匹配的抗生素暴露。然而，还需要进一步的临床评估。
