肾功能亢进患者抗感染治疗的药学监护

唐莲¹^,, 丁琦², 赵富丽², 吴刚³, 陈广祥⁴, 尚尔宁¹^,

1.南京医科大学附属苏州医院药学部,苏州 215002

2.南京医科大学附属苏州医院重症监护室,苏州 215002

3.南京医科大学附属苏州医院脑外科,苏州 215002

4.南京医科大学附属苏州医院骨科,苏州 215002

TANG Lian¹^,, DING Qi², ZHAO Fuli², WU Gang³, CHEN Guangxiang⁴, SHANG Erning¹^,^*^,

1. Department of Pharmacy

2. Intensive Care Unit

3. Department of Cerebral Surgery

4. Department of Orthopedics,Suzhou Hospital Affiliated to Nanjing Medical University,Suzhou 215002,China

通信作者尚尔宁(1962-),女,辽宁海城人,主任药师,学士,主要研究方向:医院药学。电话:0512-62362321,E-mail:slyyyjk2006@sina.com。

作者简介唐莲(1984-),女,湖南岳阳人,主管药师,硕士,主要研究方向:临床药学。电话:0512-62362326,E-mail:tanglian716 @aliyun.com。

中图分类号: R969.3;R692 文献标识码: B 文章编号: 1004-0781(2017)04-0439-03

摘要:

目的探讨临床药师在肾功能亢进(ARC)患者抗感染治疗过程中发挥的作用。方法以1例交通事故伤继发多部位重症感染患者的诊治过程为例,根据患者ARC药动学和感染的特点,从抗感染方案的制定和调整、个体化剂量调整等方面讨论ARC患者重症感染的药学干预方法。结果该患者给予正常剂量的万古霉素和美罗培南抗感染治疗效果不佳,万古霉素谷浓度6.24 μg·mL^-1。临床药师会诊评估该患者可诊断ARC,结合文献研究报道的ARC药动学特点,建议万古霉素增加剂量至1 g,每8 h 1次,根据病原菌结果建议将美罗培南调整为头孢哌酮/舒巴坦,同时增加其给药剂量为3 g,每6 h 1次。再次复测万古霉素谷浓度达标(>10 μg·mL^-1),病原学培养转阴,取得了很好的抗感染疗效。结论临床药师对ARC患者可协助临床医师有效的制定药物治疗方案,优化给药剂量,提高临床治疗效果。

关键词: 万古霉素 ; 肾功能亢进 ; 临床药师 ; 药学干预

Abstract:

Objective To investigate the role of clinical pharmacist in anti-infection therapy for patients with augmented renal clearance (ARC). Methods A case with multi-site severe infection after traffic accident was treated with anti-infection therapy. According to the characteristics of infection and pharmacokinetics, clinical pharmacist discussed the intervention by clinical pharmacist in terms of formulating anti-infection program and adjustment of individual dose. Results After consultation and evaluation by clinical pharmacist, the patient was diagnosed as ARC. According to pharmacokinetics characteristics reported by literature, vancomycin was adjusted to 1 g (once per 8 h). Based on detection result of pathogenic bacteria, meropenem was replaced by cefoperazone/sulbactam, and the dose was increased to 3 g (once per 6 h). And then, vancomycin concentration was detected again, and it reached >10 μg·mL^-1; pathogenic bacteria culture result was negative. This patient obtained good therapeutic effect. Conclusion Clinical pharmacist could assist physician on anti-infection treatment and dose adjustment of ARC patient, and improve ARC patient's therapeutic effect.

Key words: Vancomycin ; Augmented renal clearance ; Clinical pharmacist ; Pharmaceutical intervention

近年来,国外有些研究提出肾功能亢进的概念,其定义为肾脏对药物的清除能力增强(augmented renal clearance,ARC),当肌酐清除率(CL_CR)>130 mL·min^-1·(1.73 m²)^-1时可诊断患者存在ARC^[1],ARC使药物血药浓度下降,抗菌药物的应用变得更加困难。国外研究报告重症监护室(ICU)中ARC的发生率根据各研究人群的不同变异在16%~100%范围,ARC的发生与全身炎症反应综合征(systemic inflammation response syndrome,SIRS)相关,常见于创伤、烧伤的危重症患者^[2]。本文以1例车祸伤重症感染的ARC患者的抗感染治疗过程为例,临床药师参与制定抗感染治疗方案与优化给药剂量,充分发挥了临床药师在药物治疗中的作用。

1 病例资料

患者,男,58岁,身高180 cm,体质量约80 kg。2015年9月25日因交通事故伤后头部、左小腿出血疼痛、肿胀、活动受限2 h入院。入院体检:患者神志尚清,头顶部见一弧形不规则伤口,长约6 cm,活动性出血。左小腿近端近腘窝处可见横行伤口8 cm,活动性出血。辅助检查:X线检查见左胫骨平台粉碎骨折。CT检查示脑挫伤。B超提示肝周脾周可见积液,怀疑出血可能。患者病情危重,收住ICU。入科后急诊予左下肢清创,胫骨平台骨折外固定架固定,头部清创术以及剖腹探查术,术中腹腔内积血约2 000 mL。患者术后出现血压、脉搏血氧饱和度下降,予气管插管辅助通气。结合相关辅助检查入院48 h诊断:车祸伤,多发伤,创伤性休克,弥散性血管内凝血(disseminated intravascular coagulation,DIC),脑挫裂伤,肺部感染,呼吸衰竭,左胫骨平台骨折,外固定术后,剖腹探查术后。予液体复苏、白蛋白和利尿、止血、升压、保肝护肾、护胃、化痰、输血(包括血浆、血小板、冷沉淀、纤维蛋白原、凝血酶原复合物),并予亚胺培南/西司他丁1 g, 每8 h 1次,抗感染治疗。

2 治疗过程与药学干预

2015年9月25日-10月8日:患者心电监护平稳,神志逐渐恢复,2015年10月5日成功脱机拔管,但术后一直有发热,体温波动于38 ℃左右,冰毯机控温。经气道可吸出较多黄白色黏稠痰液,左下肢伤口有渗液,局部皮温增高,腹部和脑部切口恢复可。白细胞计数从12.16×10⁹·L^-1升至28.71×10⁹·L^-1,中性粒细胞比值0.92,血清C-反应蛋白从12 mg·L^-1升至69 mg·L^-1,凝血指标示高凝状态,胸片示右肺大片炎症。痰涂片见革兰阳性(G⁺)菌(+);左下肢伤口分泌物培养提示粪肠球菌(++),仅对万古霉素、替考拉宁和利奈唑胺敏感。患者肺部感染和左下肢皮肤感染诊断明确,2015年10月8日予替考拉宁覆盖G⁺治疗,亚胺培南/西司他丁已用药13 d,调整为哌拉西林/他唑巴坦4.5 g, 每8 h 1次,予低分子肝素钙2 000 U,皮下注射,每天1次,预防血栓。

2015年10月21日:CT提示两侧额部及额顶部硬膜下积液较前增多,行双侧额顶部硬膜下积液引流术并送检培养。近日仍有发热,体温最高38.7 ℃,有咳嗽咯痰,痰量中等,肺部听诊有少量痰鸣音,胸部X线片提示右肺炎症较前吸收。左下肢伤口渗液减少,分泌物培养阴性,血培养示:溶血葡萄球菌,仅对万古霉素、替考拉宁和利奈唑胺敏感,痰培养阴性。血常规:白细胞计数5.62×10⁹·L^-1,中性粒细胞比值0.71,血清C-反应蛋白74 mg·L^-1。替考拉宁使用12 d停用,请临床药师会诊。会诊意见:建议更换深静脉导管,给予万古霉素1 g,每12 h 1次,停用哌拉西林/他唑巴坦,调整为美罗培南1 g,每8 h 1次。用药3 d宜监测万古霉素谷峰浓度,调整给药剂量,监护肾功能变化。

2015年10月26日:患者体温仍然波动于37.5~38.5 ℃,冰毯机控温中。因脉氧下降予气管插管呼吸机辅助通气,气管内可吸出较多血性痰,出入量正常。引流液培养阴性,痰培养示鲍曼不动杆菌(++++)。血常规:白细胞计数2.82×10⁹·L^-1,中性粒细胞比值0.61,血清C-反应蛋白52 mg·L^-1;生化指标:白蛋白24.6 g·L^-1,肌酐36.4 μmol·L^-1,凝血指标基本正常。监测万古霉素谷浓度6.24 μg·mL^-1;峰浓度17.82 μg·mL^-1。第2次请临床药师会诊,建议:保持痰液引流通畅,计算CL_CR为220.3 mL·min^-1·(1.73m²)^-1,已达ARC的诊断,建议万古霉素剂量调整为1 g,每8 h 1次,美罗培南调整为头孢哌酮/舒巴坦3 g,每6 h 1次(单剂静脉滴注3 h),予维生素K₁ 10 mg,静脉注射,每天1次以减少出血风险,停用低分子肝素。患者白细胞计数减少不排除抗菌药物的影响,建议予重组人粒细胞集落刺激因子升白治疗,3 d后再次监测万古霉素谷浓度,密切监护患者用药后临床疗效及相关不良反应。

2015年11月5日:近两日体温最高37.5 ℃,生命体征平稳,成功脱机拔管。检测血常规:白细胞计数10.16×10⁹·L^-1,中性粒细胞比值0.61,血清C-反应蛋白37 mg·L^-1;创口分泌物培养提示鲍曼不动杆菌(++),痰培养鲍曼不动杆菌(++),血培养阴性。2015年10月29日复查万古霉素浓度:谷浓度12.18μg·mL^-1,峰浓度23.62 μg·mL^-1。临床药师建议维持该剂量给药,继续送检血和创口分泌物培养,再次培养G⁺阴性则可考虑停用万古霉素,当日转入普通病房继续治疗。

3 讨论

该患者年龄58岁,体重指数24.69,存在脓毒血症,多发创伤,SOFA评分4分,脏器功能尚可,经过大量液体复苏、大量血液制品的输注,患者存在肾脏清除增加的病理生理过程。有文献研究报道与ARC相关的高危因素为:年龄≤50岁、创伤、SOFA评分≤4^[2]。该患者存在2项高危因素,计算CL_CR为220.3 mL·min^-1·(1.73 m²)^-1,诊断该患者为ARC,抗感染治疗药物给药剂量的优化是治疗成功的关键。目前研究认为SIRS与ARC的发生密切相关,重症感染患者存在SIRS时随着炎症因子的释放导致血管阻力下降,治疗上给予液体复苏和血管活性药物的使用导致心输出量增加,最后效应为肾脏血流量增加导致肾脏清除能力增强,如果抗菌药物仍然给予常规剂量会出现血药浓度不足,从而导致预后不良以及细菌耐药性增加^[1]。国外有些研究对重症感染患者予碳青霉烯类药物、β内酰胺类酶复合制剂以及万古霉素标准的给药剂量,分析药动学参数显示ARC患者的PK/PD参数50% fT>MIC和100% fT>MIC达标率与非ARC患者相比

明显降低,具有显著的统计学差异,万古霉素平均谷浓度明显低于非ARC患者,从而证实ARC患者需要更大的给药剂量^[3-4]。

该患者万古霉素用药4 d监测谷浓度明显偏低,根据《万古霉素临床应用中国专家共识(2011年版)》,肾功能正常患者推荐给药方案为15~20 mg·kg^-1, 每12 h 1次^[5]。由于该患者诊断ARC,结合文献研究报道,临床药师计算万古霉素给药总量宜为3 g·d^-1,故建议予1 g,每8小时1次。患者硬膜下积液培养阴性,基本可排除脑部感染可能,但是体温仍有发热,因脉氧下降再次气管插管呼吸机辅助通气,痰液引流不畅是患者肺部感染反复的主要原因,痰培养为鲍曼不动杆菌(++++)。临床药师建议美罗培南调整为头孢哌酮/舒巴坦抗鲍曼不动杆菌治疗,考虑该患者为ARC,根据目前ARC与抗菌药物药动学参数相关性的研究结果^[3,6],建议给药剂量增至3 g,每6 h 1次,单次静脉滴注3 h以维持较好的药动学参数保证有效的药物浓度,监护患者在大剂量抗菌药物用药期间未出现相关的药物不良反应。调整用药后1周余患者感染症状明显好转,血培养转阴,痰培养鲍曼不动杆菌菌量减少,考虑转为定植可能,予成功脱机拔管转入普通病房继续治疗。再次复查万古霉素谷浓度为12.18 μg·mL^-1,该例患者为脓毒血症,根据《万古霉素临床应用中国专家共识(2011年版)》 ^[5],为了使感染灶内药物浓度达到有效杀菌浓度,建议该患者万古霉素谷浓度维持在15~20 μg·mL^-1。从该患者抗感染临床疗效评估,复查血培养和创口分泌物培养G⁺已转阴,感染症状明显好转,另外有研究显示万古霉素临床每日用量超过4 g会导致肾功能损伤增加^[7]。该患者抗感染疗效较好,同时为了避免肾功能损伤,临床药师建议维持该剂量给药至足疗程。

该例交通事故伤患者的抗感染治疗过程中,临床药师从ARC的角度着重分析了抗菌药物血药浓度不足的原因,系统学习了ARC的诊断标准,临床特点以

及抗菌药物优化剂量方法,为以后临床上ARC患者优化抗感染方案和给药剂量提供参考。这个病例说明,临床药师可以从药学的角度,关注患者具体疾病情况给予个体化药物治疗,增强抗菌药物疗效和延缓细菌耐药的产生,更好地促进临床合理用药。

The authors have declared that no competing interests exist.

参考文献

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[1]	SIME F B,UDY A A,ROBERTS J A.Augmented renal clearance in critically ill patients: etiology,definition and implications for beta-lactam dose optimization[J]. Curr Opin Pharm,2015, 24:1-6. The renal clearance of antibiotics may be elevated in some critically ill patients. This paper reviews this recently described phenomenon, referred to as augmented renal clearance (ARC). ARC is considered to be driven by pathophysiological elevation of glomerular filtration, and is defined as a creatinine clearance >130 mL/min/173 m. This in turn promotes very low antibiotic concentrations. This effect may lead to adverse clinical outcomes, particularly with beta-lactam antibiotics, as they require prolonged exposure for optimal antibacterial activity. The use of extended or continuous infusions is an effective strategy to improve exposure. However, because the effect of ARC is potentially quite variable, regular therapeutic drug monitoring (TDM) may be necessary to ensure all patients achieve effective concentrations. DOI:10.1016/j.coph.2015.06.002 PMID:26119486 URL [本文引用:2]
[2]	KEVIN S,KRISTA L N,KEVIN K C,et al.Modified augmented renal clearance score predictsrapidpiperacillin and tazobactam clearance in criticallyill surgery and trauma patients[J]. J Trauma Acute Care Surg,2014,77(3):163-170. Recent evidence suggests that current antimicrobial dosing may be inadequate for some critically ill patients. A major contributor in patients with unimpaired renal function may be Augmented Renal Clearance (ARC), wherein urinary creatinine clearance exceeds that predicted by serum creatinine concentration. We used pharmacokinetic data to evaluate the diagnostic accuracy of a recently proposed ARC score.Pharmacokinetic data from trauma/surgical intensive care unit patients receiving piperacillin/tazobactam were evaluated. We combined intermediate scores (4-6 points) into a single low score (≤6) group and compared pharmacokinetic parameters against the high (≥7) ARC score group. Diagnostic performance was evaluated using median clearance and volume of distribution, area under the antibiotic time-concentration curve (AUC), and achievement of free concentrations greater than a minimum inhibitory concentration (MIC) of 16 μg/mL for at least 50% of the dose interval (fT > MIC ≥ 50%). Alternative dosing strategies were explored in silico.The ARC score was 100% sensitive and 71.4% specific for detecting increased clearance, increased volume of distribution, decreased AUC, and fT > MIC < 50% at an MIC of 16 μg/mL. The area under the receiver operating characteristic curve was 0.86 for each, reflecting a high degree of diagnostic accuracy for the ARC score. Serum creatinine less than 0.6 mg/dL had comparable specificity (71.4%) but was less sensitive (66.7%) and accurate (area under the receiver operating characteristic curve, 0.69) for detecting higher clearance rates. Monte Carlo pharmacokinetic simulations demonstrated increased time at therapeutic drug levels with extended infusion dosing at a drug cost savings of up to 66.7% over multiple intermittent dosing regimens.Given its ability to predict antimicrobial clearance above population medians, which could compromise therapy, the ARC score should be considered as a means to identify patients at risk for subtherapeutic antibiotic levels. Adequately powered studies should prospectively confirm the utility of the ARC score and the role of antimicrobial therapeutic drug monitoring in such patients.Diagnostic tests, level III. DOI:10.1097/TA.0000000000000191 PMID:24770557 URL [本文引用:2]
[3]	CARLIER M,CARRETTE S,ROBERTS J A,et al.Meropenem and piperacillin/tazobactam prescribing in critically ill patients: doesaugmented renal clearance affect pharmacokinetic/pharmacodynamic targetat tainment when extended infusions are used[J]. Critical Care,2013,17(3):R84. Background: Correct antibiotic dosing remains a challenge for the clinician. The aim of this study was to assess the influence of augmented renal clearance on pharmacokinetic/pharmacodynamic target attainment in critically ill patients receiving meropenem or piperacillin/tazobactam, administered as an extended infusion.Methods: This was a prospective, observational, pharmacokinetic study executed at the medical and surgical intensive care unit at a large academic medical center. Elegible patients were adult patients without renal dysfunction receiving meropenem or piperacillin/tazobactam as an extended infusion. Serial blood samples were collected to describe the antibiotic pharmacokinetics. Urine samples were taken from a 24-hour collection to measure creatinine clearance. Relevant data were drawn from the electronic patient file and the intensive care information system.Results: We obtained data from 61 patients and observed extensive pharmacokinetic variability. Forty-eight percent of the patients did not achieve the desired pharmacokinetic/pharmacodynamic target (100% fT>MIC), of which almost 80% had a measured creatinine clearance >130 mL/min. Multivariate logistic regression demonstrated that high creatinine clearance was an independent predictor of not achieving the pharmacokinetic/pharmacodynamic target. Seven out of nineteen patients (37%) displaying a creatinine clearance >130 mL/min did not achieve the minimum pharmacokinetic/pharmacodynamic target of 50% fT>MIC.Conclusions: In this large patient cohort, we observed significant variability in pharmacokinetic/pharmacodynamic target attainment in critically ill patients. A large proportion of the patients without renal dysfunction, most of whom displayed a creatinine clearance >130 mL/min, did not achieve the desired pharmacokinetic/pharmacodynamic target, even with the use of alternative administration methods. Consequently, these patients may be at risk for treatment failure without dose up-titration. DOI:10.1186/cc12705 PMID:4056350 URL [本文引用:2]
[4]	CAMPASSIL M L,GONZALEZL M C,MASEVICIUSL F D,et al.Augmented renal clearance in critically ill patients: incidence,associated factors and effects on vancomycin treatment[J]. Rev Bras TerIntensiva,2014,26(1):13-20. ABSTRACT Objective: An augmented renal clearance has been described in some groups of critically ill patients, and it might induce sub-optimal concentrations of drugs eliminated by glomerular filtration, mainly antibiotics. Studies on its occurrence and determinants are lacking. Our goals were to determine the incidence and associated factors of augmented renal clearance and the effects on vancomycin concentrations and dosing in a series of intensive care unit patients. Methods: We prospectively studied 363 patients admitted during 1 year to a clinical-surgical intensive care unit. Patients with serum creatinine >1.3 mg/dL were excluded. Creatinine clearance was calculated from a 24-hour urine collection. Patients were grouped according to the presence of augmented renal clearance (creatinine clearance >120 mL/min/1.73 m虏), and possible risk factors were analyzed with bivariate and logistic regression analysis. In patients treated with vancomycin, dosage and plasma concentrations were registered. Results: Augmented renal clearance was present in 103 patients (28%); they were younger (48卤15 versus 65卤17 years, p<0.0001), had more frequent obstetric (16 versus 7%, p=0.0006) and trauma admissions (10 versus 3%, p=0.016) and fewer comorbidities. The only independent determinants for the development of augmented renal clearance were age (OR 0.95; p<0.0001; 95%CI 0.93-0.96) and absence of diabetes (OR 0.34; p=0.03; 95%CI 0.12-0.92). Twelve of the 46 patients who received vancomycin had augmented renal clearance and despite higher doses, had lower concentrations. Conclusions: In this cohort of critically ill patients, augmented renal clearance was a common finding. Age and absence of diabetes were the only independent determinants. Therefore, younger and previously healthy patients might require larger vancomycin dosing. DOI:10.5935/0103-507X.20140003 PMID:24770684 URL [本文引用:1]
[5]	陈佰义,管向东,何礼贤,等.万古霉素临床应用中国专家共识(2011版)[J].中国新药与临床杂志,2011,30(8):561-573. 万古霉素（vancomycin）已问世半个多世纪了，随着其临床应用的日益广泛，人们对该药的认识也日益加深。近年来在医院感染中，革兰阳性菌的比例呈上升趋势，特别是耐甲氧西林葡萄球菌（MRS）的感染更加引人瞩目，其治疗也颇为棘手。众所周知，万古霉素至今依然是治疗MRS的首选药物。 URL [本文引用:2]
[6]	DE WAELE J J, CARRETTE S, CARLIER M, et al.Therapeutic drug monitoring-based dose optimization of piperacillin and meropenem: a randomized controlled trial[J]. Inten Care Med, 2014, 40(3):380-387. ABSTRACT There is variability in the pharmacokinetics (PK) of antibiotics (AB) in critically ill patients. Therapeutic drug monitoring (TDM) could overcome this variability and increase PK target attainment. The objective of this study was to analyse the effect of a dose-adaption strategy based on daily TDM on target attainment. This was a prospective, partially blinded, and randomised controlled trial in patients with normal kidney function treated with meropenem (MEM) or piperacillin/tazobactam (PTZ). The intervention group underwent daily TDM, with dose adjustment when necessary. The predefined PK/pharmacodynamic (PK/PD) target was 100 % fT>4MIC [percentage of time during a dosing interval that the free (f) drug concentration exceeded 4 times the MIC]. The control group received conventional treatment. The primary endpoint was the proportion of patients that reached 100 % fT>4MIC and 100 % fT>MIC at 72 h. Forty-one patients (median age 56 years) were included in the study. Pneumonia was the primary infectious diagnosis. At baseline, 100 % fT>4MIC was achieved in 21 % of the PTZ patients and in none of the MEM patients; 100 % fT>MIC was achieved in 71 % of the PTZ patients and 46 % of the MEM patients. Of the patients in the intervention group, 76 % needed dose adaptation, and five required an additional increase. At 72 h, target attainment rates for 100 % fT>4MIC and 100 % fT>MIC were higher in the intervention group: 58 vs. 16 %, p = 0.007 and 95 vs. 68 %, p = 0.045, respectively. Among critically ill patients with normal kidney function, a strategy of dose adaptation based on daily TDM led to an increase in PK/PD target attainment compared to conventional dosing. DOI:10.1007/s00134-013-3187-2 PMID:24356862 URL [本文引用:1]
[7]	LODISE T P,LOMAESTRO B,GRAVES J,et al.Largervancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity[J].Ant Agen Chem,2008,52(4): 1330-1336. Abstract Recent guidelines recommend vancomycin trough concentrations between 15 and 20 mg/liter. In response, some clinicians increased vancomycin dosing to >or=4 g/day. Scant data are available regarding toxicities associated with higher vancomycin doses. The purpose of this study was to examine vancomycin-associated nephrotoxicity at >or=4 g/day. To accomplish the study objective, a cohort study among a random selection of patients receiving vancomycin or linezolid between 2005 and 2006 was performed. Patients were included if they (i) were >or=18 years of age, (ii) were nonneutropenic, (iii) were on therapy for >48 h, (iv) had baseline serum creatinine levels of or=4 g/day), and linezolid. Nephrotoxicity was defined as a serum creatinine increase of 0.5 mg/dl or 50%, whichever was greater, after therapy initiation. Stratified Kaplan-Meier analysis and Cox modeling were used to compare times to nephrotoxicity across groups. During the study, 246 patients on vancomycin (26 patients taking >or=4 g/day and 220 patients taking or=4 g vancomycin/day, those receiving or=4 g vancomycin/day, a total body weight of >or=101.4 kg, estimated creatinine clearance of </=86.6 ml/min, and intensive care unit residence were independently associated with time to nephrotoxicity. The data suggest that higher-dose vancomycin regimens are associated with a higher likelihood of vancomycin-related nephrotoxicity. DOI:10.1128/AAC.01602-07 PMID:2292536 URL [本文引用:1]

Augmented renal clearance in critically ill patients: etiology,definition and implications for beta-lactam dose optimization

2015

... 近年来,国外有些研究提出肾功能亢进的概念,其定义为肾脏对药物的清除能力增强(augmented renal clearance,ARC),当肌酐清除率(CL_CR)>130 mL·min^-1·(1.73 m²)^-1时可诊断患者存在ARC^[1],ARC使药物血药浓度下降,抗菌药物的应用变得更加困难.国外研究报告重症监护室(ICU)中ARC的发生率根据各研究人群的不同变异在16%~100%范围,ARC的发生与全身炎症反应综合征(systemic inflammation response syndrome,SIRS)相关,常见于创伤、烧伤的危重症患者^[2].本文以1例车祸伤重症感染的ARC患者的抗感染治疗过程为例,临床药师参与制定抗感染治疗方案与优化给药剂量,充分发挥了临床药师在药物治疗中的作用. ...

... 该患者年龄58岁,体重指数24.69,存在脓毒血症,多发创伤,SOFA评分4分,脏器功能尚可,经过大量液体复苏、大量血液制品的输注,患者存在肾脏清除增加的病理生理过程.有文献研究报道与ARC相关的高危因素为:年龄≤50岁、创伤、SOFA评分≤4^[2].该患者存在2项高危因素,计算CL_CR为220.3 mL·min^-1·(1.73 m²)^-1,诊断该患者为ARC,抗感染治疗药物给药剂量的优化是治疗成功的关键.目前研究认为SIRS与ARC的发生密切相关,重症感染患者存在SIRS时随着炎症因子的释放导致血管阻力下降,治疗上给予液体复苏和血管活性药物的使用导致心输出量增加,最后效应为肾脏血流量增加导致肾脏清除能力增强,如果抗菌药物仍然给予常规剂量会出现血药浓度不足,从而导致预后不良以及细菌耐药性增加^[1].国外有些研究对重症感染患者予碳青霉烯类药物、β内酰胺类酶复合制剂以及万古霉素标准的给药剂量,分析药动学参数显示ARC患者的PK/PD参数50% fT>MIC和100% fT>MIC达标率与非ARC患者相比 ...

Modified augmented renal clearance score predictsrapidpiperacillin and tazobactam clearance in criticallyill surgery and trauma patients

2014

Meropenem and piperacillin/tazobactam prescribing in critically ill patients: doesaugmented renal clearance affect pharmacokinetic/pharmacodynamic targetat tainment when extended infusions are used

2013

... 明显降低,具有显著的统计学差异,万古霉素平均谷浓度明显低于非ARC患者,从而证实ARC患者需要更大的给药剂量^[3-4]. ...

... 该患者万古霉素用药4 d监测谷浓度明显偏低,根据《万古霉素临床应用中国专家共识(2011年版)》,肾功能正常患者推荐给药方案为15~20 mg·kg^-1, 每12 h 1次^[5].由于该患者诊断ARC,结合文献研究报道,临床药师计算万古霉素给药总量宜为3 g·d^-1,故建议予1 g,每8小时1次.患者硬膜下积液培养阴性,基本可排除脑部感染可能,但是体温仍有发热,因脉氧下降再次气管插管呼吸机辅助通气,痰液引流不畅是患者肺部感染反复的主要原因,痰培养为鲍曼不动杆菌(++++).临床药师建议美罗培南调整为头孢哌酮/舒巴坦抗鲍曼不动杆菌治疗,考虑该患者为ARC,根据目前ARC与抗菌药物药动学参数相关性的研究结果^[3,6],建议给药剂量增至3 g,每6 h 1次,单次静脉滴注3 h以维持较好的药动学参数保证有效的药物浓度,监护患者在大剂量抗菌药物用药期间未出现相关的药物不良反应.调整用药后1周余患者感染症状明显好转,血培养转阴,痰培养鲍曼不动杆菌菌量减少,考虑转为定植可能,予成功脱机拔管转入普通病房继续治疗.再次复查万古霉素谷浓度为12.18 μg·mL^-1,该例患者为脓毒血症,根据《万古霉素临床应用中国专家共识(2011年版)》 ^[5],为了使感染灶内药物浓度达到有效杀菌浓度,建议该患者万古霉素谷浓度维持在15~20 μg·mL^-1.从该患者抗感染临床疗效评估,复查血培养和创口分泌物培养G⁺已转阴,感染症状明显好转,另外有研究显示万古霉素临床每日用量超过4 g会导致肾功能损伤增加^[7].该患者抗感染疗效较好,同时为了避免肾功能损伤,临床药师建议维持该剂量给药至足疗程. ...

Augmented renal clearance in critically ill patients: incidence,associated factors and effects on vancomycin treatment

2014

... 明显降低,具有显著的统计学差异,万古霉素平均谷浓度明显低于非ARC患者,从而证实ARC患者需要更大的给药剂量^[3-4]. ...

万古霉素临床应用中国专家共识(2011版)

2011

... [5],为了使感染灶内药物浓度达到有效杀菌浓度,建议该患者万古霉素谷浓度维持在15~20 μg·mL^-1.从该患者抗感染临床疗效评估,复查血培养和创口分泌物培养G⁺已转阴,感染症状明显好转,另外有研究显示万古霉素临床每日用量超过4 g会导致肾功能损伤增加^[7].该患者抗感染疗效较好,同时为了避免肾功能损伤,临床药师建议维持该剂量给药至足疗程. ...

Therapeutic drug monitoring-based dose optimization of piperacillin and meropenem: a randomized controlled trial

2014

Largervancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity

2008