Beijer Gustaf, Swartling Maria, Nielsen Elisabet I, Breuer Olof, Giske Christian G, Eliasson Erik, Petersson Johan
MDK, Medical Unit of Clinical Pharmacology, Karolinska University Hospital, 141 86, Huddinge, Stockholm, Sweden.
Division of Clinical Pharmacology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
Crit Care. 2025 May 22;29(1):208. doi: 10.1186/s13054-025-05445-0.
Standard dosing regimens of meropenem and piperacillin-tazobactam frequently fail to achieve targeted plasma concentrations in critically ill patients. Extended or continuous regimens are often used to improve target attainment. Although prompt antibiotic initiation is a major determinant of survival, few studies have reported systemic concentrations early after treatment initiation. No prior study has reported concentrations immediately after the loading dose and first extended infusion. This study aimed to evaluate plasma target attainment during the first dosing interval with an extended infusion regimen in a general intensive care unit (ICU).
Adult ICU patients were prospectively included in conjunction with the first administration of meropenem or piperacillin-tazobactam. Treatment was initiated with a 0.5 h loading dose immediately followed by a 3 h extended infusion; typically 4 + 4 g piperacillin or 1(- 2)g + 1(- 2)g meropenem, in line with the local ICU protocol. Patients requiring renal replacement therapy were excluded. Plasma concentrations were measured post-loading dose (C), near the end of the first extended infusion, and at the end of the first dosing interval (C). Samples were analyzed using validated tandem mass spectrometry (UHPLC-MS/MS) methods. The primary endpoint was the proportion of patients achieving 100% time above minimum inhibitory concentrations (fT > MIC) during the first dosing interval. This was evaluated using observed C above 2 mg/L (meropenem) and 20 mg/L (piperacillin). Additionally, published pharmacokinetic models were applied to the observed data for %fT > MIC estimation, using an a posteriori Bayesian approach.
We included 65 meropenem and 142 piperacillin measurements from 22 and 48 patients, respectively. Many patients (45% meropenem, 38% piperacillin) failed to reach 100% fT > MIC with the standard regimens used. Target non-attainment was associated with high estimated glomerular filtration rates (eGFR) and suspected augmented renal clearance (ARC). All meropenem patients that failed to reach target had eGFR > 90 mL/min/1.73 m, as did 76% of corresponding piperacillin patients. Patients with suspected ARC frequently exhibited a tenfold or greater peak-to-trough decline (C/C < 0.1).
Despite aggressive dosing, plasma concentrations often fail to reach 100% fT > MIC during the first dosing interval. Alternative regimens and early plasma concentration measurements followed by adaptive dose adjustments should be considered to improve target attainment.
美罗培南和哌拉西林 - 他唑巴坦的标准给药方案在重症患者中常常无法达到目标血浆浓度。延长或持续给药方案常被用于提高目标达成率。尽管及时开始使用抗生素是生存的主要决定因素，但很少有研究报告治疗开始后早期的全身浓度。此前没有研究报告过负荷剂量和首次延长输注后立即的浓度。本研究旨在评估在普通重症监护病房（ICU）采用延长输注方案的首个给药间隔期间血浆目标达成情况。
成年ICU患者在首次使用美罗培南或哌拉西林 - 他唑巴坦时被前瞻性纳入研究。治疗开始时先给予0.5小时的负荷剂量，随后进行3小时的延长输注；通常为4 + 4克哌拉西林或1（ - 2）克 + 1（ - 2）克美罗培南，符合当地ICU方案。需要肾脏替代治疗的患者被排除。在负荷剂量后（C）、首次延长输注接近结束时以及首个给药间隔结束时测量血浆浓度。使用经过验证的串联质谱（UHPLC - MS/MS）方法分析样本。主要终点是在首个给药间隔期间达到100%时间高于最低抑菌浓度（fT > MIC）的患者比例。使用观察到的高于2毫克/升（美罗培南）和20毫克/升（哌拉西林）的C值进行评估。此外，使用后验贝叶斯方法将已发表的药代动力学模型应用于观察数据以估计%fT > MIC。
我们分别纳入了来自22例和美罗培南、48例哌拉西林患者的65次和美罗培南、142次测量。许多患者（45%的美罗培南患者，38%的哌拉西林患者）使用标准方案未能达到100% fT > MIC。未达到目标与高估计肾小球滤过率（eGFR）和疑似肾脏清除率增加（ARC）有关。所有未达到目标的美罗培南患者eGFR > 90毫升/分钟/1.73平方米，相应的哌拉西林患者中有76%也是如此。疑似ARC的患者经常出现峰谷下降十倍或更大（C/C < 0.1）。
尽管采用了积极的给药方式，但在首个给药间隔期间血浆浓度常常未能达到100% fT > MIC。应考虑采用替代方案并早期测量血浆浓度，随后进行适应性剂量调整以提高目标达成率。
