万古霉素与哌拉西林他唑巴坦联用是临床常见的联合治疗方案，该方案治疗成本较低，可同时覆盖耐甲氧西林金黄色葡萄球菌和假单胞菌，常用于重症监护病房的患者，在严重感染如急性脓毒症患者的一线治疗中发挥着关键作用。但多项临床研究表明该联用方案可能会增加急性肾损伤的发生风险，导致治疗失败和住院时间延长，严重时可危及患者生命安全。因此，本研究对万古霉素与哌拉西林他唑巴坦联用致急性肾损伤的流行病学、发病机制和防治措施进行综述，旨在为临床安全使用万古霉素和哌拉西林他唑巴坦提供依据。

万古霉素（vancomycin，VAN）属于糖肽类抗菌药物，主要用于治疗耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus，MRSA）[1]及其他细菌所致的败血症、感染性心内膜炎、骨髓炎、肺炎、腹膜炎等严重感染。哌拉西林他唑巴坦（piperacillin/tazobactam，TZP）对革兰阴性菌表现出广谱杀菌活性，适用于治疗社区获得性肺炎、医院获得性肺炎、泌尿道感染、皮肤及软组织等中重度感染，但对MRSA无效。因此，两者联用可覆盖多种病原菌，常用于严重感染的经验性治疗。研究[2]报道，VAN联用TZP治疗假体关节感染的有效率高达96%。还有研究[3]表明，VAN和TZP联用可降低胰十二指肠切除术后手术部位感染的发生率和手术部位粪肠球菌的检出率，术后需额外使用其他抗菌药物的患者例数也显著减少。临床还将VAN与TZP联用治疗发热性中性粒细胞减少症或高度怀疑感染多重耐药铜绿假单胞菌的患者[4-5]。

近年来，多项临床研究[6-8]报道了与该联用方案相关的急性肾损伤（acute kidney injury，AKI），使该安全性问题受到关注。VAN和TZP单用均可能导致AKI[9-10]，当两药联用时，AKI风险可增至31.7%~35.0%[11-12]。而AKI可导致死亡风险增高。一项关于23个国家的重症监护病房（intensive care unit，ICU）患者多中心观察性研究[13]显示，AKI患者的死亡率为52%，另有8%的AKI患者在出院后死亡，导致总体死亡率为60.3%（95%CI：58.0%~62.6%），而且随着AKI的严重程度增加，死亡风险也逐渐增加[14-16]。此外，一次或多次AKI后可能会发展成慢性肾脏病，无论是在低收入国家还是高收入国家，慢性肾脏病都将会增加社会经济负担[17]。研究[18]报道，与无AKI的患者相比，AKI会导致住院费用增加 7 933（95%CI：7 608~8 258）美元，住院时间增加3.2（95%CI：3.2~3.3）d。本研究旨在从流行病学特征、发生机制、危险因素以及防治措施等方面综述VAN联用TZP致AKI的研究进展，以供临床参考。

1 VAN联用TZP致AKI的流行病学特征

1.1 VAN的肾毒性

一项针对我国人群的回顾性队列研究[9]显示，3 719例使用VAN治疗的住院患者中，VAN引起AKI的发生率为14.3% ；另一纳入12 730例患者的Meta分析[19]发现，儿童患者中VAN相关AKI的发病率为11.8%。研究[20]表明，累积VAN暴露与肾毒性相关，但未发现血浆浓度-时间曲线下的VAN面积与疗效之间存在明确关系。

1.2 TZP的肾毒性

研究[21-22]发现，TZP单药治疗后，血肌酐水平升高约17.7~26.5 μmol·L^-1。一项纳入107例入住ICU并使用TZP治疗儿童患者的回顾性研究[10]结果显示，TZP相关AKI的发生率可能达到15%，而治疗的前24 h药时曲线下面积（area under the concentration- time curve，AUC）、谷浓度（C_min）与AKI发展相关。另一项回顾性队列研究[23]显示，危重儿童患者使用TZP后发生AKI的调整危险比为1.56（95%CI：1.23~1.99）。

1.3 两药联用的肾毒性

多项队列研究和Meta分析均表明，相较于单用VAN或TZP，两药联用治疗普通成人[6, 24]、普通儿童[7, 25]、危重儿童[26]等患者感染时，AKI风险均会增加，发生率可达31.7%~35.0%[11-12]。VAN与TZP联用的不同研究结果见表1。但对于ICU的成人患者，研究结论并不一致[27-29]，可能是由于AKI不能确切反映肾损伤情况，换言之，VAN联用TZP与以血肌酐值定义的AKI相关，但与替代肾脏生物标志物、透析或死亡率的变化无关[30]。同时，ICU患者病情危急，发生AKI的风险常高于普通患者[31]，因此产生矛盾的研究结果。

• 
  表格1 万古霉素联合哌拉西林他唑巴坦在不同人群中的急性肾损伤风险研究

  Table 1.Risk of AKI in vancomycin combined with piperacillin/tazobactam in different populations

  注：a未入住ICU或非危重成人患者或非危重儿童患者；b参照组；FEP：头孢吡肟；CRO：头孢曲松；VMC：万古霉素联合头孢吡肟或美罗培南；aOR：调整优势比；aHR：调整风险比；RRR：相对危险度减少率；KDIGO：改善全球肾脏病预后组织标准，即48 h内血肌酐上升＞0.3 mg·dL-1，或7 d内上升至基线的1.5倍以上；AKIN：急性肾损伤网络标准，即48 h内血肌酐升高≥0.3 mg·dL-1或≥1.5倍基线值，或尿量低于0.5 mL·kg-1·h-1，至少持续6 h；RIFLE ：风险、损伤、肾功能衰竭、肾功能丧失、终末期肾病标准；万古霉素治疗指南：美国感染病学会、美国卫生系统药师学会和感染病药师学会的联合专家组共同制订的《万古霉素治疗成人金黄色葡萄球菌感染的治疗监测实践指南》

  

2 VAN联用TZP致AKI的发生机制与危险因素

VAN和TZP导致AKI的病理生理机制尚未完全阐明，当前研究[32-33]认为VAN所致AKI可能与药物浓度蓄积引起的氧化应激、补体活化、炎症损伤、线粒体功能障碍以及过敏反应型有关。Lee等[34]基于氧化应激这一主要机制，对使用VAN后发生和未发生AKI患者的临床样本进行探索性代谢组图谱分析和氨基酸图谱分析，发现AKI组5-羟色胺代谢物5-羟基吲哚乙酸（5-hydroxyindoleacetic acid，5-HIAA）与5-羟色胺（serotonin，5-HT）的比值（5-HIAA/5-HT）升高，5-HIAA/5-HT有可能作为VAN导致AKI的替代标志物。TZP可能会引起电解质紊乱和肾小管功能障碍[35]，还可能通过引发急性间质性肾炎诱导肾损伤[36-37]。同样地，VAN联合TZP时AKI风险增加的机制也尚未明确。可能的原因是两种药物本身肾毒性的累积，或者两者间存在药物相互作用。例如TZP可能会降低VAN的清除率，导致后者在肾脏中蓄积[38]。另外，VAN和TZP是多种离子转运体的底物，可能协同竞争肌酐，导致血肌酐升高[39-41]。

除药物因素外，临床相关的因素也与VAN和TZP的肾毒性相关。VAN致AKI的危险因素包括较高的C_min水平（特别是＞20 mg·L^-1或剂量＞4 g·d^-1）、联用肾毒性药物、入住ICU、低血容量、长疗程以及较低的基线预估肾小球滤过率[32, 42-44]。有研究[45]认为，该药的最大血药浓度（C_max）与肾毒性无确切关系，而在大鼠VAN药动学-毒理学模型研究[46]中，给药后0~24 h的C_max是VAN诱导的肾损伤最具预测性的药动学-毒理学驱动因素。一项回顾性队列研究[21]评估TZP对革兰阴性菌血症患者肾毒性的影响发现，基线血肌酐值、总体重及合用血管加压素是肾毒性的独立影响因素，而TZP的疗程与之无关。回顾性队列研究和病例对照研究[11-12]均表明，VAN联用TZP致AKI的危险因素包括入住ICU、基线肌酐清除率低于60 mL·min^-1及在同一天启用联合治疗方案。

3 VAN联用TZP致AKI的防治措施

3.1 预防措施

3.1.1 选择其他肾损伤风险较小的治疗方案

首先需基于患者病情如感染部位、常见致病菌、生化指标、药敏结果等评估VAN联用TZP的必要性，若非必须，则可以更换其中一种药物；若必须联用，则可通过选择合适的给药方案、降低药物暴露水平、监测血药浓度、避免其他加重AKI发生风险的因素或联用某些具有潜在肾保护作用的药物等方式降低AKI的发生风险。

回顾性队列研究[47]结果显示，当VAN与TZP联用时，更换其中一种或两种药物同时更换有助于降低AKI风险，干预组（即更换药物）和对照组（继续联用VAN和TZP）的AKI发生率分别为17.6%和44.6%。多项临床研究和Meta分析[8, 48-53]表明，与联合TZP相比，VAN联合其他β-内酰胺类抗菌药物如美罗培南、头孢吡肟等的AKI风险较低，见表2。

• 
  表格2 万古霉素联用不同β-内酰胺类抗菌药物与联用哌拉西林他唑巴坦的急性肾损伤风险比较

  Table 2.Comparison of acute kidney injury risk between vancomycin combined with piperacillin/tazobactam and vancomycin combined with different beta-lactam antibiotics

  注：MEM：美罗培南；FEP：头孢吡肟；CAR：碳青霉烯类；aOR：调整优势比；a参照组；b该研究附加要求，住院第3~7天接受联合治疗，治疗2 d内发生AKI；KDIGO：改善全球肾脏病预后组织标准，即48 h内血肌酐上升＞0.3 mg·dL-1，或7 d内上升至基线的1.5倍以上；AKIN：急性肾损伤网络标准，即48 h内血肌酐升高≥0.3 mg·dL-1或≥1.5倍基线值，或尿量低于0.5 mL·kg-1·h-1，至少持续6 h；RIFLE ：风险、损伤、肾功能衰竭、肾功能丧失、终末期肾病标准；万古霉素治疗指南：美国感染病学会、美国卫生系统药师学会和感染病药师学会的联合专家组共同制订的《万古霉素治疗成人金黄色葡萄球菌感染的治疗监测实践指南》

  

但是，一项纳入3 299例ICU患者的回顾性队列研究[54]结果表明，与其他经验广谱组合如VAN联用头孢吡肟、VAN联合美罗培南相比，短疗程（24~72 h）的VAN与TZP联用并未增加包括持续肾功能障碍、透析依赖及60 d死亡等远期不良结局的风险，也与短期严重的AKI结局无关，这可能是由于临床研究的异质性所致。入住ICU本就是AKI的危险因素之一[31]，患者病情复杂，同时以2期或3期AKI的发生为结局指标，可能低估了其真正的AKI风险。因此，更换其他β-内酰胺类可能仍是较为合理的选择。

3.1.2 选择合适的给药方式

2项Meta分析[55-56]显示，连续输注与间歇输注VAN治疗感染的疗效相当，但连续输注VAN能提高患者目标浓度达标率和临床疗效靶值达标率，同时意味着较低的肾损伤风险。另外，由于VAN是一种时间依赖性的抗菌药物，所以，连续输注时监测稳态血药浓度可能是更为明智和谨慎的选择。研究[57]报道，TZP延时输注和间歇推注相比，前者在给药间隔期间能保持更高的血药浓度，这可能与TZP本身的药动学特点有关，即属于时间依赖性药物，药物疗效取决于药物浓度高于最低抑菌浓度的时间。而且，据一项系统评价和Meta分析[58]显示，重病患者接受TZP的延时输注与死亡率降低、临床治愈率提高相关。因此，在经验性治疗时应选择连续输注或延时输注给药方案。

3.1.3 降低药物暴露并监测血药浓度

药物的治疗作用与不良反应往往在于剂量的区别，有些药物的治疗窗很窄，例如氨茶碱、VAN等，这些药物在使用过程中需要监测血药浓度。Muklewicz等[59]尝试根据AUC来指导VAN的给药剂量，以减轻其联合TZP治疗时可能的AKI风险，但并未发现依据药动学参数指导给药的优势，指导组和未指导组的AKI发生率差异无统计学意义（P＞0.05），且两组联合用药时AKI的发生率均高于单用VAN时。但另有研究[60]认为VAN引起的AKI与AUC相关，尤其是当AUC＞600时。因此，相较于仅采用VAN的C_min监测安全性，AUC指导下的给药是更为精确的方法，可在最大限度降低AKI风险的同时保证药物疗效。此外，Hambrick等[61]研究显示，通过缩短VAN的使用疗程，可使造血干细胞移植患者的AKI风险降低37%。总之，在使用VAN过程中，为减少AKI的发生，降低药物暴露水平、实施药物浓度监测并根据AUC调整给药剂量是必要的。

3.1.4 避免联用其他肾毒性药物

若必须联用VAN和TZP，应考虑降低AKI的发生风险，排除其他可能导致AKI的因素，如冠脉造影剂或其他肾毒性药物的暴露。常见的肾毒性药物包括阿昔洛韦、赖诺普利、碘造影剂等。对于危重儿童患者，呋塞米、咪达唑仑、20%人血浆制备的白蛋白注射液、枸橼酸芬太尼注射液、复方甘草酸苷注射液和乳酸米力农注射液等也与AKI相关[62]。一项大型回顾性队列研究[63]显示，16%的成人住院患者有超过1 d的肾毒性药物暴露，其中，约30%进展为AKI。因此，应尽量避免与其他肾毒性药物联用或提前评估AKI的发生风险。Kim等[64]开发了VAN相关AKI的风险评分系统，适用于接受血药浓度监测并同时使用各种肾毒性药物的患者，但仍需更大型的多中心研究来验证。

3.1.5 联用某些肾保护作用药物

联用某些药物可发挥减轻肾毒性的作用。有回顾性队列研究[65]报道，使用褪黑素的患者AKI风险降低63%，两者可能相关；另一项随机双盲对照试验[66]结果也认为，褪黑素可降低VAN相关AKI发生风险。褪黑素是由松果体产生的激素，主要功能在于改善睡眠质量，同时，其也是人体内的自由基清除剂，具有抗氧化功能，这可能是其防治VAN导致肾损伤的机制。其他回顾性研究[67-68]显示，对于ICU患者，还原型谷胱甘肽和维生素C可以显著降低VAN的肾毒性。另一项开放标签、安慰剂对照的随机临床试验[69]表明，给予目标血清水平约为3 mg·dL^-1的硫酸镁可降低VAN和TZP联用时AKI的发生率，但结论有待多中心的随机对照试验进一步验证。

3.2 治疗措施

药物导致的AKI重在预防，目前并没有针对VAN联用TZP导致AKI的特异性治疗方案。发生AKI后，可通过透析降低体内VAN水平，改善肾功能，防止病情进一步发展[70]。值得注意的是，高通量的透析可能更有效，同时由于VAN血药浓度有反弹的可能，因此可能需要频繁的透析[71]。对于透析治疗的开始时间，目前并未统一定论。多中心随机对照试验[72]发现，早期和延迟开始肾脏替代治疗（renal replacement therapy，RRT）的策略在死亡率方面无显著差异，但之后另一项纳入231例患者的单中心随机对照试验[73]结果显示，相较于延迟实施RRT（诊断为AKI 3期后的12 h内），早期开始RRT（诊断为AKI 2期后的8 h内）可降低90 d死亡率。

4 结语与展望

VAN和TZP都是临床常用的抗菌药物，其固有的肾毒性在两者联用时会增加，应尽量避免联用，或选择联用其他β-内酰胺类抗菌药物如头孢吡肟、美罗培南等。若患者必须采用该联合用药方案，应尽可能排除其他危险因素，选择延时输注给药，减少其他肾毒性药物暴露，或联用某些具有肾保护作用的药物。

目前关于VAN与TZP联用的研究多是单中心、回顾性队列研究或是病例对照研究，多数研究认为其联用可能增加AKI的发生风险，医生在做临床决策时应当谨慎，但开展多中心的随机对照试验仍是必要的，特别是在ICU患者中。同时，现有的研究多是以AKI为主要结局指标，但是定义AKI的肌酐值受多种因素影响，包括体重、饮食等。因此，也有待进一步发现和筛选更为科学准确的AKI生物标志物。

1.Liu C, Bayer A, Cosgrove SE, et al. Clinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children[J]. Clin Infect Dis, 2011, 52(3): e18-55. DOI: 10.1093/cid/ciq146.

2.Casenaz A, Piroth L, Labattut L, et al. Epidemiology and antibiotic resistance of prosthetic joint infections according to time of occurrence, a 10-year study[J]. J Infect, 2022, 85(5): 492-498. DOI: 10.1016/j.jinf.2022.07.009.

3.Tanaka K, Nakamura T, Imai S, et al. The use of broad-spectrum antibiotics reduces the incidence of surgical site infection after pancreatoduodenectomy[J]. Surg Today, 2018, 48(9): 825-834. DOI: 10.1007/s00595-018-1658-3.

4.Ouyang W, Xue H, Chen Y, et al. Clinical characteristics and antimicrobial patterns in complicated intra-abdominal infections: a 6-year epidemiological study in southern China[J]. Int J Antimicrob Agents, 2016, 47(3): 210-216. DOI: 10.1016/j.ijantimicag.2015.12.019.

5.Ziglam HM, Gelly K, Olver W. A survey of the management of neutropenic fever in oncology units in the UK[J]. Int J Antimicrob Agents, 2007, 29(4): 430-433. DOI: 10.1016/j.ijantimicag.2006.12.009.

6.Carreno J, Smiraglia T, Hunter C, et al. Comparative incidence and excess risk of acute kidney injury in hospitalised patients receiving vancomycin and piperacillin/tazobactam in combination or as monotherapy[J]. Int J Antimicrob Agents, 2018, 52(5): 643-650. DOI: 10.1016/j.ijantimicag.2018.08.001.

7.高璇, 李静, 李智平. 住院儿童单独使用万古霉素或联合哌拉西林/他唑巴坦治疗后的肾毒性比较[J]. 复旦学报(医学版), 2015, 42(6): 743-748. [Gao X, Li J, Li ZP. Comparison of nephrotoxicity in hospitalized children treated with vancomycin alone or in combination with piperacillin/tazobactam[J]. Fudan University Journal of Medical Sciences, 2015, 42(6): 743-748.] DOI: 10.3969/j.issn.1672-8467.2015.06.009.

8.Navalkele B, Pogue JM, Karino S, et al. Risk of acute kidney injury in patients on concomitant vancomycin and piperacillin-tazobactam compared to those on vancomycin and cefepime[J]. Clin Infect Dis, 2017, 64(2): 116-123. DOI: 10.1093/cid/ciw709.

9.Kunming P, Can C, Zhangzhang C, et al. Vancomycin associated acute kidney injury: a longitudinal study in China[J]. Front Pharmacol, 2021, 12: 632107. DOI: 10.3389/fphar.2021.632107.

10.Tang Girdwood S, Hasson D, Caldwell JT, et al. Relationship between piperacillin concentrations, clinical factors and piperacillin/tazobactam-associated acute kidney injury[J]. J Antimicrob Chemother, 2023, 78(2): 478-487. DOI: 10.1093/jac/dkac416.

11.Blair K, Covington EW. Incidence and risk factors of acute kidney injury in patients receiving concomitant vancomycin and continuous-infusion piperacillin/tazobactam: a retrospective cohort study[J]. Ann Pharmacother, 2020, 54(11): 1096-1101. DOI: 10.1177/1060028020921170.

12.Yamashita Y, Kawaguchi H, Yano T, et al. Risk factors for acute kidney injury in vancomycin and piperacillin/tazobactam combination therapy: a retrospective study[J]. J Infect Chemother, 2021, 27(11): 1614-1620. DOI: 10.1016/j.jiac.2021.07.017.

13.Uchino S, Kellum JA, Bellomo R, et al. Acute renal failure in critically ill patients: a multinational, multicenter study[J]. JAMA, 2005, 294(7): 813-818. DOI: 10.1001/jama.294.7.813.

14.Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis[J]. Crit Care, 2006, 10(3): R73. DOI: 10.1186/cc4915.

15.Thakar CV, Christianson A, Freyberg R, et al. Incidence and outcomes of acute kidney injury in intensive care units: a veterans administration study[J]. Crit Care Med, 2009, 37(9): 2552-2558. DOI: 10.1097/CCM.0b013 e3181a5906f.

16.Hoste EA, Kellum JA. RIFLE criteria provide robust assessment of kidney dysfunction and correlate with hospital mortality[J]. Crit Care Med, 2006, 34(7): 2016-2017. DOI: 10.1097/01.CCM.0000219374.43963.B5.

17.Lameire NH, Bagga A, Cruz D, et al. Acute kidney injury: an increasing global concern[J]. Lancet, 2013, 382(9887): 170-179. DOI: 10.1016/S0140-6736(13)60647-9.

18.Silver SA, Long J, Zheng Y, et al. Cost of acute kidney injury in hospitalized patients[J]. J Hosp Med, 2017, 12(2): 70-76. DOI: 10.12788/jhm.2683.

19.Williams C, Hankinson C, McWilliam SJ, et al. Vancomycin-associated acute kidney injury epidemiology in children: a systematic review[J]. Arch Dis Child, 2022, 107(10): 947-954. DOI: 10.1136/archdischild-2021- 323429.

20.Kloprogge F, Hill LF, Booth J, et al. Revising pediatric vancomycin dosing accounting for nephrotoxicity in a pharmacokinetic-pharmacodynamic model[J]. Antimicrob Agents Chemother, 2019, 63(5): e00067-19. DOI: 10.1128/AAC.00067-19.

21.Hall RG 2nd, Yoo E, Faust A, et al. Impact of piperacillin/tazobactam on nephrotoxicity in patients with gram-negative bacteraemia[J]. Int J Antimicrob Agents, 2019, 53(3): 343-346. DOI: 10.1016/j.ijantimicag.2018.11.002.

22.Kadomura S, Takekuma Y, Sato Y, et al. Higher incidence of acute kidney injury in patients treated with piperacillin/tazobactam than in patients treated with cefepime: a single-center retrospective cohort study[J]. J Pharm Health Care Sci, 2019, 5: 13. DOI: 10.1186/s40780-019-0142-6.

23.Joyce EL, Kane-Gill SL, Priyanka P, et al. Piperacillin/tazobactam and antibiotic-associated acute kidney injury in critically ill children[J]. J Am Soc Nephrol, 2019, 30(11): 2243-2251. DOI: 10.1681/ASN.2018121223.

24.Jeon N, Staley B, Klinker KP, et al. Acute kidney injury risk associated with piperacillin/tazobactam compared with cefepime during vancomycin therapy in hospitalised patients: a cohort study stratified by baseline kidney function[J]. Int J Antimicrob Agents, 2017, 50(1): 63-67. DOI: 10.1016/j.ijantimicag.2017.02.023.

25.Kalligeros M, Karageorgos SA, Shehadeh F, et al. The association of acute kidney injury with the concomitant use of vancomycin and piperacillin/tazobactam in children: a systematic review and meta-analysis[J]. Antimicrob Agents Chemother, 2019, 63(12): e01572-19. DOI: 10.1128/AAC. 01572-19.

26.Holsen MR, Meaney CJ, Hassinger AB, et al. Increased risk of acute kidney injury in critically ill children treated with vancomycin and piperacillin/tazobactam[J]. Pediatr Crit Care Med, 2017, 18(12): e585-e591. DOI: 10.1097/PCC.0000000000001335.

27.O'Callaghan K, Hay K, Lavana J, et al. Acute kidney injury with combination vancomycin and piperacillin-tazobactam therapy in the ICU: a retrospective cohort study[J]. Int J Antimicrob Agents, 2020, 56(1): 106010. DOI: 10.1016/j.ijantimicag.2020.106010.

28.Hammond DA, Smith MN, Painter JT, et al. Comparative incidence of acute kidney injury in critically ill patients receiving vancomycin with concomitant piperacillin-tazobactam or cefepime: a retrospective cohort study[J]. Pharmacotherapy, 2016, 36(5): 463-471. DOI: 10.1002/phar.1738.

29.Luther MK, Timbrook TT, Caffrey AR, et al. Vancomycin plus piperacillin-tazobactam and acute kidney injury in adults: a systematic review and meta-analysis[J]. Crit Care Med, 2018, 46(1): 12-20. DOI: 10.1097/CCM.0000000 000002769.

30.Miano TA, Hennessy S, Yang W, et al. Association of vancomycin plus piperacillin-tazobactam with early changes in creatinine versus cystatin C in critically ill adults: a prospective cohort study[J]. Intensive Care Med, 2022, 48(9): 1144-1155. DOI: 10.1007/s00134-022-06811-0.

31.Rodrigo E, Suberviola B, Santibanez M, et al. Association between recurrence of acute kidney injury and mortality in intensive care unit patients with severe sepsis[J]. J Intensive Care, 2017, 5: 28. DOI: 10.1186/s40560-017-0225-0.

32.Elyasi S, Khalili H, Dashti-Khavidaki S, et al. Vancomycin-induced nephrotoxicity: mechanism, incidence, risk factors and special populations. A literature review[J]. Eur J Clin Pharmacol, 2012, 68(9): 1243-1255. DOI: 10.1007/s00228-012-1259-9.

33.Kan WC, Chen YC, Wu VC, et al. Vancomycin-associated acute kidney injury: a narrative review from pathophysiology to clinical application[J]. Int J Mol Sci, 2022, 23(4): 2052. DOI: 10.3390/ijms23042052.

34.Lee HS, Kim SM, Jang JH, et al. Serum 5-hydroxyindoleacetic acid and ratio of 5-hydroxyindoleacetic acid to serotonin as metabolomics indicators for acute oxidative stress and inflammation in vancomycin-associated acute kidney injury[J]. Antioxidants (Basel), 2021, 10(6): 895. DOI: 10.3390/antiox10060895 .

35.Polderman KH, Girbes AR. Piperacillin-induced magnesium and potassium loss in intensive care unit patients[J]. Intensive Care Med, 2002, 28(4): 520-522. DOI: 10.1007/s00134-002-1244-3.

36.Pratt JA, Stricherz MK, Verghese PS, et al. Suspected piperacillin-tazobactam induced nephrotoxicity in the pediatric oncology population[J]. Pediatr Blood Cancer, 2014, 61(2): 366-368. DOI: 10.1002/pbc.24720.

37.Kraleti S, Khatri N, Jarrett D. Piperacillin-tazobactam induced interstitial nephritis, hepatitis and serum sckness-like illness[J]. J Ark Med Soc, 2016, 112(14): 278-280. https://pubmed.ncbi.nlm.nih.gov/27434982/.

38.Burgess LD, Drew RH. Comparison of the incidence of vancomycin-induced nephrotoxicity in hospitalized patients with and without concomitant piperacillin-tazobactam[J]. Pharmacotherapy, 2014, 34(7): 670-676. DOI: 10.1002/phar.1442.

39.Komuro M, Maeda T, Kakuo H, et al. Inhibition of the renal excretion of tazobactam by piperacillin[J]. J Antimicrob Chemother, 1994, 34(4): 555-564. DOI: 10.1093/jac/34.4. 555.

40.Wen S, Wang C, Huo X, et al. JBP485 attenuates vancomycin-induced nephrotoxicity by regulating the expressions of organic anion transporter (Oat) 1, Oat3, organic cation transporter 2 (Oct2), multidrug resistance-associated protein 2 (Mrp2) and P-glycoprotein (P-gp) in rats[J]. Toxicol Lett, 2018, 295: 195-204. DOI: 10.1016/j.toxlet.2018.06.1220.

41.Vallon V, Eraly SA, Rao SR, et al. A role for the organic anion transporter OAT3 in renal creatinine secretion in mice[J]. Am J Physiol Renal Physiol, 2012, 302(10): F1293-1299. DOI: 10.1152/ajprenal.00013.2012.

42.Lodise TP, Patel N, Lomaestro BM, et al. Relationship between initial vancomycin concentration-time profile and nephrotoxicity among hospitalized patients[J]. Clin Infect Dis, 2009, 49(4): 507-514. DOI: 10.1086/600884.

43.Filippone EJ, Kraft WK, Farber JL. The nephrotoxicity of vancomycin[J]. Clin Pharmacol Ther, 2017, 102(3): 459-469. DOI: 10.1002/cpt.726.

44.熊祥樽, 田小燕, 张佳颖, 等. 烧伤患者万古霉素相关急性肾损伤调查及危险因素分析[J]. 药物流行病学杂志, 2019, 28(11): 740-744, 752. [Xiong XZ, Tian XY, Zhang JY, et al. Current situation survey and risk factors analysis of vancomycin-associated acute kidney injury in burn patients[J]. Chinese Journal of Pharmacoepidemiology, 2019, 28(11): 740-744, 752.] DOI: 10.19960/j.cnki.issn1005-0698.2019.11.009.

45.门鹏, 李慧博, 翟所迪. 万古霉素血药峰浓度与临床结局相关性的系统评价[J]. 药物流行病学杂志, 2015, 24(6): 328-331. [Men P, Li HB, Zhai SD, et al. Association between vancomycin serum peak concentrations and clinical outcomes: a systematic review[J]. Chinese Journal of Pharmacoepidemiology, 2015, 24(6): 328-331.] DOI: 10.19960/j.cnki.issn1005-0698.2015.06.002.

46.Avedissian SN, Pais G, Liu J, et al. The Pharmacodynamic-toxicodynamic relationship of AUC and Cmax in vancomycin-induced kidney injury in an animal model[J]. Antimicrob Agents Chemother, 2021, 65(3): e01945-20. DOI: 10.1128/AAC.01945-20.

47.Oda K, Hashiguchi Y, Katanoda T, et al. Lowered risk of nephrotoxicity through intervention against the combined use of vancomycin and tazobactam/piperacillin: a retrospective cohort study[J]. Microbiol Spectr, 2021, 9(1): e0035521. DOI: 10.1128/Spectrum.00355-21.

48.Balci C, Uzun O, Arici M, et al. Nephrotoxicity of piperacillin/tazobactam combined with vancomycin: should it be a concern?[J]. Int J Antimicrob Agents, 2018, 52(2): 180-184. DOI: 10.1016/j.ijantimicag.2018.03.024.

49.Bellos I, Karageorgiou V, Pergialiotis V, et al. Acute kidney injury following the concurrent administration of antipseudomonal beta-lactams and vancomycin: a network meta-analysis[J]. Clin Microbiol Infect, 2020, 26(6): 696-705. DOI: 10.1016/j.cmi.2020.03.019.

50.Rutter WC, Cox JN, Martin CA, et al. Nephrotoxicity during vancomycin therapy in combination with piperacillin-tazobactam or cefepime[J]. Antimicrob Agents Chemother, 2017, 61(2): e02089-16. DOI: 10.1128/aac.02089-16.

51.Liu K, Zhang Y, Xu X, et al. Comparative prevalence of acute kidney injury in chinese patients receiving vancomycin with concurrent β-lactam antibiotics: a retrospective cohort study[J]. Clin Ther, 2021, 43(10): e319-e351. DOI: 10.1016/j.clinthera.2021.08.008.

52.Rutter WC, Burgess DS. Incidence of acute kidney injury among patients treated with piperacillin-tazobactam or meropenem in combination with vancomycin[J]. Antimicrob Agents Chemother, 2018, 62(7): e00264-18. DOI: 10.1128/AAC.00264-18.

53.Downes KJ, Cowden C, Laskin BL, et al. Association of acute kidney injury with concomitant vancomycin and piperacillin/tazobactam treatment among hospitalized children[J]. JAMA Pediatr, 2017, 171(12): e173219. DOI: 10.1001/jamapediatrics.2017.3219.

54.Schreier DJ, Kashani KB, Sakhuja A, et al. Incidence of acute kidney injury among critically ill patients with brief empiric use of antipseudomonal β-lactams with vancomycin[J]. Clin Infect Dis, 2019, 68(9): 1456-1462. DOI: 10.1093/cid/ciy724.

55.Waineo MF, Kuhn TC, Brown DL. The pharmacokinetic/pharmacodynamic rationale for administering vancomycin via continuous infusion[J]. J Clin Pharm Ther, 2015, 40(3): 259-265. DOI: 10.1111/jcpt.12270.

56.刘露, 吴知桂, 范清泽, 等. 万古霉素持续输注与间歇输注有效性与安全性比较的Meta分析[J]. 中国药房, 2020, 31(22): 2774-2780. [Liu L, Wu ZG, Fan QZ, et al. Efficacy and safety of vancomycin given by continuous infusion vs. intermittent infusion: a meta-analysis[J]. China Pharmacy, 2020, 31(22): 2774-2780.] DOI: 10.6039/j.issn. 1001-0408.2020.22.15.

57.Chongcharoenyanon T, Wacharachaisurapol N, Anugulruengkitt S, et al. Comparison of piperacillin plasma concentrations in a prospective randomised trial of extended infusion versus intermittent bolus of piperacillin/tazobactam in paediatric patients[J]. Int J Infect Dis, 2021, 108: 102-108. DOI: 10.1016/j.ijid.2021.05.044.

58.Rhodes NJ, Liu J, O'Donnell JN, et al. Prolonged infusion piperacillin-tazobactam decreases mortality and improves outcomes in severely ill patients: results of a systematic review and meta-analysis[J]. Crit Care Med, 2018, 46(2): 236-243. DOI: 10.1097/CCM.0000000000002836.

59.Muklewicz JD, Steuber TD, Edwards JD. Evaluation of area under the concentration-time curve-guided vancomycin dosing with or without piperacillin-tazobactam on the incidence of acute kidney injury[J]. Int J Antimicrob Agents, 2021, 57(1): 106234. DOI: 10.1016/j.ijantimicag.2020.106234.

60.Lodise TP, Drusano G. Vancomycin area under the curve-guided dosing and monitoring for adult and pediatric patients with suspected or documented serious methicillin-resistant staphylococcus aureus infections: putting the safety of our patients first[J]. Clin Infect Dis, 2021, 72(9): 1497-1501. DOI: 10.1093/cid/ciaa1744.

61.Hambrick HR, Greco KF, Weller E, et al. Impact of decreasing vancomycin exposure on acute kidney injury in stem cell transplant recipients[J]. Infect Control Hosp Epidemiol, 2022, 43(10): 1375-1381. DOI: 10.1017/ice. 2021.454.

62.Hu B, Ye L, Li T, et al. Drug-induced kidney injury in Chinese critically ill pediatric patients[J]. Front Pharmacol, 2022, 13: 993923. DOI: 10.3389/fphar.2022.993923.

63.Griffin BR, Wendt L, Vaughan-Sarrazin M, et al. Nephrotoxin exposure and acute kidney injury in adults[J]. Clin J Am Soc Nephrol, 2023, 18(2): 163-172. DOI: 10.2215/CJN.0000000000000044.

64.Kim JY, Kim KY, Yee J, et al. Risk scoring system for vancomycin-associated acute kidney injury[J]. Front Pharmacol, 2022, 13: 815188. DOI: 10.3389/fphar.2022. 815188.

65.Hong TS, Briscese K, Yuan M, et al. Renoprotective effects of melatonin against vancomycin-related acute kidney injury in hospitalized patients: a retrospective cohort study[J]. Antimicrob Agents Chemother, 2021, 65(9): e0046221.DOI: 10.1128/AAC.00462-21.

66.Abbasi S, Bigharaz E, Farsaei S, et al. Could melatonin prevent vancomycin-induced nephrotoxicity in critically ill patients? A randomized, double-blinded controlled trial[J]. Caspian J Intern Med, 2023, 14(1): 76-82. DOI: 10.22088/cjim.14.1.76.

67.李娟, 何娟, 毛恩强, 等. 还原型谷胱甘肽对重症患者使用万古霉素致药物性肾损伤的保护作用[J]. 中华危重病急救医学, 2020, 32(7): 819-823. [Li J, He J, Mao EQ, et al. Protective effects of reduced glutathione on renal toxicity induced by vancomycin in critically ill patients[J]. Chinese Critical Care Medicine, 2020, 32(7): 819-823.] DOI: 10.3760/cma.j.cn121430-20200429-00326.

68.何娟, 毛恩强, 徐文筠, 等. 大剂量维生素C可显著降低重症患者万古霉素的肾毒性[J]. 中华危重病急救医学, 2020, 32(4): 468-472. [He J, Mao EQ, Xu WY, et al. High dose vitamin C significantly reduces the nephrotoxicity of vancomycin in critically ill patients[J]. Chinese Critical Care Medicine, 2020, 32(4): 468-472.] DOI: 10.3760/cma.j.cn121430-20200110-00083.

69.Khalili H, Rahmani H, Mohammadi M, et al. Intravenous magnesium sulfate for prevention of vancomycin plus piperacillin-tazobactam induced acute kidney injury in critically ill patients: an open-label, placebo-controlled, randomized clinical trial[J]. Daru, 2021, 29(2): 341-351. DOI: 10.1007/s40199-021-00411-x.

70.Wicklow BA, Ogborn MR, Gibson IW, et al. Biopsy-proven acute tubular necrosis in a child attributed to vancomycin intoxication[J]. Pediatr Nephrol, 2006, 21(8): 1194-1196. DOI: 10.1007/s00467-006-0152-0.

71.DeSoi CA, Sahm DF, Umans JG. Vancomycin elimination during high-flux hemodialysis: kinetic model and comparison of four membranes[J]. Am J Kidney Dis, 1992, 20(4): 354-360. DOI: 10.1016/s0272-6386(12)70298-6.

72.Gaudry S, Hajage D, Schortgen F, et al. Initiation strategies for renal-replacement therapy in the intensive care unit[J]. N Engl J Med, 2016, 375(2): 122-133. DOI: 10.1056/NEJ Moa1603017.

73.Zarbock A, Kellum JA, Schmidt C, et al. Effect of early vs delayed initiation of renal replacement therapy on mortality in critically ill patients with acute kidney injury: the elain randomized clinical trial[J]. JAMA, 2016, 315(20): 2190-2199. DOI: 10.1001/jama.2016.5828.