Zander Johannes, Döbbeler Gundula, Nagel Dorothea, Maier Barbara, Scharf Christina, Huseyn-Zada Mikayil, Jung Jette, Frey Lorenz, Vogeser Michael, Zoller Michael
Institute of Laboratory Medicine, Hospital of the Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
Department of Anaesthesiology, Hospital of the Ludwig-Maximilians-University of Munich, Marchioninistrasse 15, 81377, Munich, Germany.
Crit Care. 2016 Apr 4;20:79. doi: 10.1186/s13054-016-1255-z.
Piperacillin levels after standard dosing have been shown frequently to be subtherapeutic, especially when renal clearance was augmented. Here, we aimed to determine if piperacillin was in its therapeutic range in a typically heterogeneous intensive care unit patient group, and also to describe target attainment dependent on daily dosage, creatinine clearance, and renal replacement therapy (RRT).
Sixty patients with severe infections were included in this monocentric prospective observational study. Patients received 4.5 g of piperacillin-tazobactam two to three times daily by intermittent infusion depending on renal function according to clinical guidelines. Over 4 days, multiple serum samples (median per patient, 29; in total, 1627) were obtained to determine total piperacillin concentrations using ultra-high-performance liquid chromatography/tandem mass spectrometry.
A high heterogeneity of patient characteristics was observed (e.g., on day 1: creatinine clearance 2-233 mL/min and ten patients on RRT). Piperacillin trough levels showed inter-individual variation from 123 to >1785-fold on different study days. Each day, approximately 50% and 60% of the patients had piperacillin levels below the target ranges 1 and 2, respectively [defined for the calculated unbound piperacillin fraction according to the literature as 100% time above MIC (100%fT > MIC) (target range 1) and ≥ 50%fT > 4 × MIC (target range 2); MIC = 16 mg/L]. Whereas only the minority of patients who received piperacillin-tazobactam three times daily (TID) reached target 1 (38% on day 1), most patients who received piperacillin-tazobactam only twice daily (BID) because of severely impaired renal function reached this target (100% on day 1). Patients with RRT had significant higher percentages of fT > MIC. Zero percent, 55% and 100% of patients without RRT who received antibiotics TID reached target 1 when creatinine clearance was > 65 mL/min, 30-65 mL/min and < 30 mL/min, respectively. In patients with causative strains only sensitive to piperacillin-tazobactam of all antibiotics given to the patient, piperacillin levels negatively correlated with CRP concentrations of day 4 (p < 0.05).
A dosage of 4.5 g piperacillin-tazobactam TID seems to be frequently insufficient in critically ill patients, and also in patients where renal function is mildly to moderately impaired. For these patients, prescription of 4.5 g piperacillin-tazobactam four times daily could be considered.
Clinicaltrials.gov NCT01793012. Registered 24 January 2013.
标准剂量给药后哌拉西林水平常显示为亚治疗水平，尤其是在肾脏清除率增加时。在此，我们旨在确定在一个典型的异质性重症监护病房患者群体中哌拉西林是否处于其治疗范围内，并描述取决于每日剂量、肌酐清除率和肾脏替代治疗（RRT）的目标达成情况。
本单中心前瞻性观察性研究纳入了60例严重感染患者。患者根据临床指南，根据肾功能通过间歇输注每日2至3次接受4.5 g哌拉西林 - 他唑巴坦。在4天内，获取多个血清样本（每位患者中位数为29个；总共1627个），使用超高效液相色谱/串联质谱法测定总哌拉西林浓度。
观察到患者特征存在高度异质性（例如，在第1天：肌酐清除率为2 - 233 mL/分钟，10例患者接受RRT）。在不同研究日，哌拉西林谷浓度显示个体间差异为123至>1785倍。每天，分别约有50%和60%的患者哌拉西林水平低于目标范围1和2[根据文献为计算的游离哌拉西林分数定义为100%时间高于最低抑菌浓度（100%fT>MIC）（目标范围1）和≥50%fT>4×MIC（目标范围2）；MIC = 16 mg/L]。虽然每日3次（TID）接受哌拉西林 - 他唑巴坦的患者中只有少数达到目标1（第1天为38%），但由于肾功能严重受损而仅每日2次（BID）接受哌拉西林 - 他唑巴坦的大多数患者达到了该目标（第1天为100%）。接受RRT的患者fT>MIC的百分比显著更高。当肌酐清除率>65 mL/分钟、30 - 65 mL/分钟和<30 mL/分钟时，接受抗生素TID且未接受RRT的患者达到目标1的比例分别为0%、55%和100%。在所有给予患者的抗生素中致病菌株仅对哌拉西林 - 他唑巴坦敏感的患者中，哌拉西林水平与第4天的CRP浓度呈负相关（p<0.05）。
4.5 g哌拉西林 - 他唑巴坦TID的剂量在重症患者以及肾功能轻度至中度受损的患者中似乎常常不足。对于这些患者，可以考虑每日4次开具4.5 g哌拉西林 - 他唑巴坦的处方。
Clinicaltrials.gov NCT01793012。2013年1月24日注册。
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