Department of Anesthesiology and Critical Care, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.
Department of Clinical Pharmacy, Heidenheim Hospital, Schloßhaustraße 100, 89522, Heidenheim, Germany.
Infection. 2019 Dec;47(6):1001-1011. doi: 10.1007/s15010-019-01352-z. Epub 2019 Aug 31.
Standard dosing and intermittent bolus application (IB) are important risk factors for pharmacokinetic (PK) target non-attainment during empirical treatment with β-lactams in critically ill patients, particularly in those with sepsis and septic shock. We assessed the effect of therapeutic drug monitoring-guided (TDM), continuous infusion (CI) and individual dosing of piperacillin/tazobactam (PIP) on PK-target attainment in critically ill patients.
This is a retrospective, single-center analysis of a database including 484 patients [933 serum concentrations (SC)] with severe infections, sepsis and septic shock who received TDM-guided CI of PIP in the intensive care unit (ICU) of an academic teaching hospital. The PK-target was defined as a PIP SC between 33 and 64 mg/L [fT > 2-4 times the epidemiological cutoff value (ECOFF) of Pseudomonas aeruginosa (PSA)].
PK-target attainment with standard dosing (initial dose) was observed in 166 patients (34.3%), whereas only 49 patients (10.1%) demonstrated target non-attainment. The minimum PK-target of ≥ 33 mg/L was overall realized in 89.9% (n = 435/484) of patients after the first PIP dose including 146 patients (30.2%) with potentially harmful SCs ≥ 100 mg/L. Subsequent TDM-guided dose adjustments significantly enhanced PK-target attainment to 280 patients (62.4%) and significantly reduced the fraction of potentially overdosed (≥ 100 mg/L) patients to 4.5% (n = 20/449). Renal replacement therapy (RRT) resulted in a relevant reduction of PIP clearance (CL): no RRT CL 6.8/6.3 L/h (median/IQR) [SCs n = 752, patients n = 405], continuous veno-venous hemodialysis (CVVHD) CL 4.3/2.6 L/h [SCs n = 160, n = 71 patients], intermittent hemodialysis (iHD) CL 2.6/2.3 L/h [SCs n = 21, n = 8 patients]). A body mass index (BMI) of > 40 kg/m significantly increased CL 9.6/7.7 L/h [SC n = 43, n = 18 patients] in these patients. Age was significantly associated with supratherapeutic PIP concentrations (p < 0.0005), whereas high CrCL led to non-target attainment (p < 0.0005). Patients with target attainment (33-64 mg/L) within the first 24 h exhibited the lowest hospital mortality rates (13.9% [n = 23/166], p < 0.005). Those with target non-attainment demonstrated higher mortality rates (≤ 32 mg/L; 20.8% [n = 10/49] ≥ 64 mg/L; 29.4% [n = 79/269]).
TDM-guided CI of PIP is safe in critically ill patients and improves PK-target attainment. Exposure to defined PK-targets impacts patient mortality while lower and higher than intended SCs may influence the outcome of critically ill patients. Renal function and renal replacement therapy are main determinants of PK-target attainment. These results are only valid for CI of PIP and not for prolonged or intermittent bolus administration of PIP.
在重症患者中，β-内酰胺类药物经验性治疗时，标准剂量和间歇性推注（IB）是药代动力学（PK）目标未达到的重要危险因素，尤其是在脓毒症和感染性休克患者中。我们评估了治疗药物监测指导（TDM）、连续输注（CI）和哌拉西林/他唑巴坦（PIP）个体化给药对重症患者 PK 目标达到的影响。
这是一项回顾性、单中心分析，纳入了在学术教学医院重症监护病房（ICU）接受 TDM 指导 CI 的 PIP 的 484 例严重感染、脓毒症和感染性休克患者的数据库，共 933 个血清浓度（SC）。PK 目标定义为 PIP SC 为 33-64mg/L[游离浓度（fT）>铜绿假单胞菌（PSA）的流行病学截断值（ECOFF）的 2-4 倍]。
标准剂量（初始剂量）时 PK 目标达到率为 166 例患者（34.3%），而仅 49 例患者（10.1%）出现目标未达到。首次 PIP 剂量后，484 例患者中的 335 例（89.9%）达到了最小 PK 目标值≥33mg/L，包括 146 例（30.2%）潜在有害 SCs≥100mg/L。随后的 TDM 指导剂量调整显著提高了 PK 目标达到率至 280 例患者（62.4%），显著降低了潜在过度给药（≥100mg/L）患者的比例至 4.5%（449 例患者中有 20 例）。肾脏替代治疗（RRT）导致 PIP 清除率显著降低：无 RRT CL 6.8/6.3L/h（中位数/四分位数间距）[SC 数量 n=752，患者数量 n=405]，连续静脉-静脉血液透析（CVVHD）CL 4.3/2.6L/h[SC 数量 n=160，患者数量 n=71]，间歇性血液透析（iHD）CL 2.6/2.3L/h[SC 数量 n=21，患者数量 n=8]）。BMI>40kg/m2 时，CL 显著增加 9.6/7.7L/h[SC 数量 n=43，患者数量 n=18]。年龄与超治疗性 PIP 浓度显著相关（p<0.0005），而高肌酐清除率（CrCL）导致未达到目标（p<0.0005）。在 24 小时内达到目标（33-64mg/L）的患者的住院死亡率最低（13.9%[n=166 例中的 23 例]，p<0.005）。目标未达到的患者死亡率较高（≤32mg/L 为 20.8%[n=49 例中的 10 例]；≥64mg/L 为 29.4%[n=269 例中的 79 例]）。
在重症患者中，TDM 指导的 PIP CI 是安全的，并提高了 PK 目标的达到率。达到特定的 PK 目标会影响患者的死亡率，而低于或高于预期的 SC 可能会影响重症患者的预后。肾功能和肾脏替代治疗是 PK 目标达到的主要决定因素。这些结果仅适用于 PIP 的 CI，不适用于 PIP 的延长或间歇性推注给药。
