Abstract：
OBJECTIVE: Timely and appropriate dosing of antibiotics is essential for the treatment of bacterial sepsis. Critically ill patients treated with continuous kidney replacement therapy (CKRT) often have physiologic derangements that affect pharmacokinetics (PK) of antibiotics and dosing may be challenging. We sought to aggregate previously published piperacillin and tazobactam (pip-tazo) pharmacokinetic data in critically ill patients undergoing CKRT to better understand pharmacokinetics of pip-tazo in this population and better inform dosing.
METHODS: The National Library of Medicine Database was searched for original research containing piperacillin or tazobactam clearance (CL) or volume of distribution (V) estimates in patients treated with CKRT. The search yielded 77 articles, of which 26 reported suitable estimates of CL or V. Of the 26 articles, 10 for piperacillin and 8 for tazobactam had complete information suitable for population pharmacokinetic modelling. Also included in the analysis was piperacillin and tazobactam PK data from 4 critically ill patients treated with CKRT in the Military Health System, 2 with burn and 2 without burn.
CONCLUSIONS: Median and range of literature reported PK parameters for piperacillin (CL 2.76 L/hr, 1.4-7.92 L/hr, V 31.2 L, 16.77-42.27 L) and tazobactam (CL 2.34 L/hr, 0.72-5.2 L/hr, V 36.6 L, 26.2-58.87 L) were highly consistent with population estimates (piperacillin CL 2.7 L/hr, 95%CI 1.99-3.41 L/hr, V 25.83 22.07-29.59 L, tazobactam CL 2.49 L/hr, 95%CI 1.55-3.44, V 30.62 95%CI 23.7-37.54). The proportion of patients meeting pre-defined pharmacodynamic (PD) targets (median 88.7, range 71%-100%) was high despite significant mortality (median 44%, range 35%-60%). High mortality was predicted by baseline severity of illness (median APACHE II score 23, range 21-33.25). Choice of lenient or strict PD targets (ie 100%fT >MIC or 100%fT >4XMIC) had the largest impact on probability of target attainment (PTA), whereas presence or intensity of CKRT had minimal impact on PTA.
CONCLUSIONS: Pip-tazo overexposure may be associated with increased mortality, although this is confounded by baseline severity of illness. Achieving adequate pip-tazo exposure is essential; however, risk of harm from overexposure should be considered when choosing a PD target and dose. If lenient PD targets are desired, doses of 2250-3375 mg every 6 h are reasonable for most patients receiving CKRT. However, if a strict PD target is desired, continuous infusion (at least 9000-13500 mg per day) may be required. However, some critically ill CKRT populations may need higher or lower doses and dosing strategies should be tailored to individuals based on all available clinical data including the specific critical care setting.
METHODS: The National Library of Medicine Database was searched for original research containing piperacillin or tazobactam clearance (CL) or volume of distribution (V) estimates in patients treated with CKRT. The search yielded 77 articles, of which 26 reported suitable estimates of CL or V. Of the 26 articles, 10 for piperacillin and 8 for tazobactam had complete information suitable for population pharmacokinetic modelling. Also included in the analysis was piperacillin and tazobactam PK data from 4 critically ill patients treated with CKRT in the Military Health System, 2 with burn and 2 without burn.
CONCLUSIONS: Median and range of literature reported PK parameters for piperacillin (CL 2.76 L/hr, 1.4-7.92 L/hr, V 31.2 L, 16.77-42.27 L) and tazobactam (CL 2.34 L/hr, 0.72-5.2 L/hr, V 36.6 L, 26.2-58.87 L) were highly consistent with population estimates (piperacillin CL 2.7 L/hr, 95%CI 1.99-3.41 L/hr, V 25.83 22.07-29.59 L, tazobactam CL 2.49 L/hr, 95%CI 1.55-3.44, V 30.62 95%CI 23.7-37.54). The proportion of patients meeting pre-defined pharmacodynamic (PD) targets (median 88.7, range 71%-100%) was high despite significant mortality (median 44%, range 35%-60%). High mortality was predicted by baseline severity of illness (median APACHE II score 23, range 21-33.25). Choice of lenient or strict PD targets (ie 100%fT >MIC or 100%fT >4XMIC) had the largest impact on probability of target attainment (PTA), whereas presence or intensity of CKRT had minimal impact on PTA.
CONCLUSIONS: Pip-tazo overexposure may be associated with increased mortality, although this is confounded by baseline severity of illness. Achieving adequate pip-tazo exposure is essential; however, risk of harm from overexposure should be considered when choosing a PD target and dose. If lenient PD targets are desired, doses of 2250-3375 mg every 6 h are reasonable for most patients receiving CKRT. However, if a strict PD target is desired, continuous infusion (at least 9000-13500 mg per day) may be required. However, some critically ill CKRT populations may need higher or lower doses and dosing strategies should be tailored to individuals based on all available clinical data including the specific critical care setting.
摘要：
目的：及时、适当的抗生素给药对细菌性脓毒症的治疗至关重要。接受连续肾脏替代疗法（CKRT）治疗的重症患者通常会出现生理紊乱，从而影响抗生素的药代动力学（PK），给药可能具有挑战性。我们试图汇总先前发表的哌拉西林和他唑巴坦（pip-tazo）在接受CKRT的重症患者中的药代动力学数据，以更好地了解该人群中pip-tazo的药代动力学并更好地告知剂量。
方法：检索了国家医学图书馆数据库中包含哌拉西林或他唑巴坦清除率（CL）或分布体积（V）估计值的原始研究。搜索产生了77篇文章，其中26篇报告了对CL或V的适当估计。在26篇文章中，哌拉西林的10和他唑巴坦的8具有适合群体药代动力学建模的完整信息。分析中还包括来自军队卫生系统接受CKRT治疗的4例危重患者的哌拉西林和他唑巴坦PK数据，2有烧伤，2没有烧伤。
结论：文献报道的哌拉西林PK参数的中位数和范围（CL2.76L/hr，1.4-7.92L/hr,V31.2L,16.77-42.27升)和他唑巴坦(CL2.34升/小时，0.72-5.2L/hr,V36.6L,26.2-58.87升)与人口估计高度一致(哌拉西林CL2.7升/小时，95CI1.99-3.41L/hr,V25.8322.07-29.59L,他唑巴坦CL2.49升/小时，95CI1.55-3.44，V30.6295CI23.7-37.54）。尽管死亡率很高，但达到预定药效学（PD）目标的患者比例（中位数为88.7，范围为71％-100％）仍然很高（中位数为44％，范围35%-60%）。通过基线疾病严重程度预测高死亡率（APACHEII评分中位数23，范围21-33.25）。选择宽松或严格的PD目标（即100％fT>MIC或100％fT>4XMIC）对达到目标概率（PTA）的影响最大，而CKRT的存在或强度对PTA的影响最小。
结论：Pip-tazo过度暴露可能与死亡率增加有关，尽管这与基线疾病严重程度混淆。获得足够的pip-tazo暴露是必不可少的；然而，在选择PD目标和剂量时，应考虑过度暴露造成伤害的风险。如果需要宽松的PD目标，对于大多数接受CKRT的患者，每6小时2250-3375mg的剂量是合理的。然而,如果需要严格的PD目标，可能需要连续输注(每天至少9000-13500mg).然而,一些危重病CKRT人群可能需要更高或更低的剂量,并且应根据所有可用的临床数据,包括特定的重症监护环境,针对个体调整给药策略.
方法：检索了国家医学图书馆数据库中包含哌拉西林或他唑巴坦清除率（CL）或分布体积（V）估计值的原始研究。搜索产生了77篇文章，其中26篇报告了对CL或V的适当估计。在26篇文章中，哌拉西林的10和他唑巴坦的8具有适合群体药代动力学建模的完整信息。分析中还包括来自军队卫生系统接受CKRT治疗的4例危重患者的哌拉西林和他唑巴坦PK数据，2有烧伤，2没有烧伤。
结论：文献报道的哌拉西林PK参数的中位数和范围（CL2.76L/hr，1.4-7.92L/hr,V31.2L,16.77-42.27升)和他唑巴坦(CL2.34升/小时，0.72-5.2L/hr,V36.6L,26.2-58.87升)与人口估计高度一致(哌拉西林CL2.7升/小时，95CI1.99-3.41L/hr,V25.8322.07-29.59L,他唑巴坦CL2.49升/小时，95CI1.55-3.44，V30.6295CI23.7-37.54）。尽管死亡率很高，但达到预定药效学（PD）目标的患者比例（中位数为88.7，范围为71％-100％）仍然很高（中位数为44％，范围35%-60%）。通过基线疾病严重程度预测高死亡率（APACHEII评分中位数23，范围21-33.25）。选择宽松或严格的PD目标（即100％fT>MIC或100％fT>4XMIC）对达到目标概率（PTA）的影响最大，而CKRT的存在或强度对PTA的影响最小。
结论：Pip-tazo过度暴露可能与死亡率增加有关，尽管这与基线疾病严重程度混淆。获得足够的pip-tazo暴露是必不可少的；然而，在选择PD目标和剂量时，应考虑过度暴露造成伤害的风险。如果需要宽松的PD目标，对于大多数接受CKRT的患者，每6小时2250-3375mg的剂量是合理的。然而,如果需要严格的PD目标，可能需要连续输注(每天至少9000-13500mg).然而,一些危重病CKRT人群可能需要更高或更低的剂量,并且应根据所有可用的临床数据,包括特定的重症监护环境,针对个体调整给药策略.
