多黏菌素B相关肾毒性的研究进展

多黏菌素B作为治疗多重耐药革兰阴性菌感染的一线药物,其临床应用需求逐渐增加。肾毒性是制约多黏菌素B临床使用的最常见原因。本文从多黏菌素B相关肾毒性的发生率、发生机制、危险因素和降低肾毒性策略4个方面进行综述,以期为其临床合理应用提供参考。多黏菌素B相关肾毒性的发生率为17%～67.7%,血药浓度、给药剂量、年龄和联合用药等是多黏菌素B相关肾毒性的危险因素。多黏菌素衍生物的开发,群体药动学模型的建立,以及代谢组学技术的应用,对降低多黏菌素B相关肾毒性具有潜在的价值。     

多黏菌素B的药动学和药效学与肾毒性的研究进展

近些年,多黏菌素B在其他药物治疗无效的革兰阴性杆菌(如多药耐药细菌和泛耐药细菌)感染的挽救性治疗方案中扮演着重要的角色,其临床价值被重新予以重视。但由于其潜在的肾毒性,在经验性给药方案下难以精准用药,制约着其在临床上合理使用。本文分别对多黏菌素B的药动学(PK)和药效学(PD)、肾毒性机制及影响肾毒性的危险因素进行了分析,阐明了多黏菌素B主要通过非肾途径清除,在临床上对于严重感染的患者需使用负荷剂量,通过控制其他协变量可以减少患者肾毒性的发生率,及多黏菌素B诱导的肾毒性涉及线粒体途径和细胞死亡受体途径,以期为多黏菌素B的临床合理使用提供参考。     

多黏菌素B在重症感染患者中的群体药动学研究

目的 建立多黏菌素B在重症感染患者中的群体药动学模型,为个体化给药提供科学依据。方法 检索PubMed、Embase、Web of Science、CNKI数据库中关于静脉滴注多黏菌素B的药动学文献,提取多黏菌素B在重症感染患者中的药动学数据,使用Monolix软件建立多黏菌素B的群体药动学模型,并对模型进行图形评价和Bootstrap法验证。结果 多黏菌素B在重症感染患者中的药动学特性符合房室模型,多黏菌素B的清除率（CL）、中央室表观分布容积（V1）、周边室表观分布容积（V2）、隔间清除率（Q）的群体典型值分别为4.36L/h、16.19L、35.14L、0.4L/h,患者的年龄对模型参数Q有显著影响,模型评价表明模型稳定,且有较好的预测效能。结论 本研究建立了重症感染患者多黏菌素B的群体药动学模型,可为多黏菌素B在成年重症感染患者中的个体化用药提供参考。     

多黏菌素耐药机制研究进展

抗生素耐药已成为一项日益加剧的全球危机,对人类健康造成严重威胁。多黏菌素于上世纪被发现,因其神经毒性和肾毒性曾一度被限制使用,然而随着多药耐药革兰阴性菌的快速发展使得多黏菌素再次成为治疗革兰阴性菌感染的关键药物。除变形杆菌属、摩氏摩根菌、沙雷氏菌属等对多黏菌素天然耐药外,其他革兰阴性菌,如大肠埃希菌、肠炎沙门菌、肺炎克雷伯菌等可通过获得性耐药对多黏菌素产生耐药。革兰阴性菌主要通过改变外膜脂多糖结构而对多黏菌素产生耐药性,此外,也可通过自发突变导致脂多糖缺失、荚膜多糖产量增加以及表达外排泵等机制对多黏菌素产生耐药性。本文对目前已报道的多黏菌素耐药机制进行了综述。     

多黏菌素B治疗危重患者泛耐药革兰阴性菌感染的疗效和影响因素分析

目的：通过分析多黏菌素B治疗危重患者泛耐药革兰阴性菌感染的疗效及其影响因素,为多黏菌素B的合理应用提供参考依据。方法：回顾性收集2018年1月至2019年12月期间在中山大学附属第一医院重症监护病房住院感染泛耐药革兰阴性菌,且使用多黏菌素B治疗≥3 d的患者资料,观察患者使用多黏菌素B的疗效,并对相关的影响因素进行统计学分析。结果：共纳入患者91例,平均年龄为（56.76±18.57）岁,多黏菌素B平均给药剂量为（118.04±32.23） mg·d^-1,给药疗程中位和四分位数间距为11（7,16） d,患者细菌清除率为40.7%（37/91）,临床有效率为52.8%（48/91）,30 d死亡率为48.4%（44/91）,住院死亡率为60.4%（55/91）;多因素logistic回归分析显示患者接受连续性肾脏替代治疗（OR=0.32,95% CI：0.12~0.82,P=0.018）及给药时机（OR=0.28,95% CI：0.10~0.77,P=0.013）是影响多黏菌素B临床疗效的独立危险因素;序贯器官衰竭评分（OR=1.30,95% CI：1.12~1.51,P=0.001）及血流感染（OR=10.49,95% CI：2.35~46.93,P=0.002）是患者在多黏菌素B治疗期间30 d内死亡的独立危险因素。结论：对于多黏菌素B应用于危重患者泛耐药革兰阴性菌感染,恰当的给药时机是治疗成功的关键因素,而接受连续性肾脏替代治疗是临床疗效的独立影响因素,患者器官功能的衰竭程度以及伴随血流感染是治疗预后不良的独立危险因素。     

基于非线性混合效应模型法建立的拉莫三嗪群体药动学模型研究进展

目的 探讨拉莫三嗪在不同群体中的群体药动学特征及其影响因素,为建立更精准的群体药动学模型提供参考。方法 系统检索PubMed、Embase、Web of Science、Science Direct及Cochrane Library数据库中采用非线性混合效应模型(NONMEM)法在人体内进行的拉莫三嗪群体药动学的研究,时间为1995年1月—2021年7月。结果 共纳入研究20项,其中17项研究将拉莫三嗪的药动学特征描述为一室模型结构。伴随抗癫痫药物、体质量和基因多态性被认为是影响拉莫三嗪清除的3个最常见显著协变量,其他显著协变量研究较少。结论 在建立新的拉莫三嗪群体药动学模型时,应考虑合用其他抗癫痫药物、体质量、基因型等重要协变量因素;对于妊娠妇女等特殊人群,应纳入特殊人群的生理病理特征作为协变量因素,同时进行内部验证和外部验证增加模型的普适性。     

基于模型的Meta分析建立中国老年人群美罗培南群体药动学模型

目的:采用基于模型的Meta分析,建立美罗培南在中国老年人群的群体药动学模型。方法:通过文献检索,提取药物剂量、采样时间点、浓度、样本量、年龄、性别、体质量和肌酐清除率等数据。用NONMEM建立群体模型,采用逐步递归法筛选协变量。自举法和可视化检验(VPC)分别验证模型的稳定性和预测能力。结果:美罗培南的药动学采用二房室描述。经过协变量筛选,最终模型纳入肌酐清除率对CL,体质量对V₁的影响。自举法验证和VPC检验都显示模型的良好稳定性和预测能力。结论:通过基于模型的Meta分析的方法,建立一个更加具有代表性的美罗培南的中国老年人群体药动学模型。     

多黏菌素类抗生素的研究进展

目的从多方面对多黏菌素进行总结,为临床合理使用提供参考。方法通过查阅相关文献,阐述多黏菌素B与多黏菌素E在结构、作用机制、抗菌谱、肾毒性、用法用量、给药途径和药动学等方面的异同。结果多黏菌素B以活性的硫酸盐制剂给药,直接发挥抗菌作用,主要通过非肾脏途径消除,受肾功能影响较小,可迅速达到血药质量浓度;而多黏菌素E以无活性的前体药物多黏菌素E甲磺酸钠(CMS)给药,CMS需在肾脏内转化成多黏菌素E后发挥抗菌作用,但过程缓慢且转化不完全。多黏菌素E个体差异大,且血药质量浓度受肾功能影响。总体而言,多黏菌素B比多黏菌素E临床药理特性更好。结论多黏菌素B和多黏菌素E在疗效和代谢方面不等价,因此临床医生应结合患者情况选择和优化多黏菌素的给药策略。     

多黏菌素类联合其他抗菌药物治疗耐碳青霉烯类革兰阴性菌感染的研究进展

随着耐碳青霉烯类革兰阴性菌检出率不断增加,多黏菌素类抗菌药物成为治疗耐碳青霉烯类革兰阴性菌感染的一种重要选择。但单一多黏菌素类抗菌药物治疗存在局限性,如常规剂量效果不佳,而增加剂量又会导致不良反应和耐药风险增加等。目前以多黏菌素类抗菌药物为基础的多药联合方案广泛应用于耐碳青霉烯类革兰阴性菌感染的治疗,但最佳联合治疗方案,以及不同联合治疗方案的安全性、有效性等尚无一致的定论。本文对基于多黏菌素类抗菌药物的联合用药方案在治疗耐碳青霉烯鲍曼不动杆菌、肺炎克雷伯菌和绿假单胞菌等革兰阴性菌感染的体内、体外研究进展进行综述,以期为多黏菌素类抗菌药物用于耐碳青霉烯类革兰阴性菌所致感染的治疗提供相关依据。     

多黏菌素E治疗多药耐药性革兰阴性菌感染的临床应用评价

目的：了解多黏菌素E治疗多药耐药性革兰阴性菌感染的临床疗效。方法：查阅近年来国外有关多黏菌素E的文献资料。结果：多黏菌素E对多药耐药性革兰阴性菌感染具有良好的治疗效果。结论：多黏菌素E在当前细菌耐药严峻的形势下，是多药耐药性革兰阴性菌感染的有效治疗手段，但仍需关注其潜在的不良反应。     

Use of low-molecular-weight heparin to bridge therapy in obese patients and in patients with renal dysfunction

OBJECTIVE: To recommend strategies to bridge therapy with low-molecular-weight heparin (LMWH) in obese patients and in patients with renal dysfunction. METHODS: A MEDLINE search was performed of the literature from January 1966-November 2005. Published material dealing with bridging of anticoagulation therapy or short-term use of LMWH therapy in patients with renal dysfunction or obesity was reviewed. The manufacturers of enoxaparin, dalteparin, and tinzaparin were contacted for the references used to determine dosing recommendations. RESULTS: Although LMWH has been commonly used to bridge therapy, our search revealed no trials that specifically examined LMWH bridge therapy in obese patients or in patients with renal dysfunction. However, nine trials using LMWH in obese patients and 14 trials using LMWH in patients with renal dysfunction were identified. When compared with normal-weight individuals, obese patients receiving enoxaparin and dalteparin based on total body weight did not demonstrate higher hemorrhage rates or antifactor Xa levels. Subtherapeutic antifactor Xa levels were more common with once-daily dosing of enoxaparin than with dosing every 12 hours. Enoxaparin accumulates in patients with a creatinine clearance of 30 ml/minute or less; in this population, enoxaparin dosage adjustments have been attempted. Tinzaparin does not accumulate in patients with a creatinine clearance of 20 ml/minute or greater after at least 10 days of dosing. CONCLUSION: Obese patients, weighing 90-150 kg, receiving LMWH for bridge therapy should receive dosages based on total body weight. Unfractionated heparin is recommended in patients weighing more than 150 kg; however, if LMWH is used, antifactor Xa levels should be monitored. Bridging with enoxaparin should be limited to patients with a creatinine clearance greater than 30 ml/minute. The use of enoxaparin 1 mg/kg once/day for patients with a creatinine clearance of 30 ml/minute or less is not recommended for anticoagulation bridge therapy. Tinzaparin may be considered for cross-coverage of high-risk patients with recent or recurrent venous thromboembolism who have a creatinine clearance of at least 20 ml/minute.     

重症感染患者多黏菌素B群体药代动力学模型的外部验证

目的:对既往发表的多黏菌素B群体药代动力学(population pharmacokinetics,PPK)模型进行外部验证,评估各模型对重症感染患者血药浓度的预测性能。方法:在PubMed数据库、Web of Science核心合集、中国知网、万方数据库检索建库至2022年3月公开发表的多黏菌素B PPK模型的相关文献,提取模型结构和参数信息。同时收集南京大学医学院附属鼓楼医院接受多黏菌素B治疗重症感染患者的临床数据作为外部数据集。根据患者是否采用连续肾脏替代疗法(continuous renal replacement therapy,CRRT)分为非CRRT组和CRRT组。利用2组数据对已发表模型进行基于模型预测和模型模拟的评价。结果:检索到14个多黏菌素B PPK模型。CRRT组,预测误差检验结果显示,所有已发表模型均不满足选定的标准。非CRRT组,有一个模型具有较好的血药浓度预测性能。结论:可以尝试利用预测结果良好的模型在非CRRT患者进行前瞻性个体化给药。     

Dosing of gentamicin in patients with end-stage renal disease receiving hemodialysis

The aim of this study was to evaluate dosing schedules of gentamicin in patients with end-stage renal disease and receiving hemodialysis. Forty-six patients were recruited who received gentamicin while on hemodialysis. Each patient provided approximately 4 blood samples at various times before and after dialysis for analysis of plasma gentamicin concentrations. A population pharmacokinetic model was constructed using NONMEM (version 5). The clearance of gentamicin during dialysis was 4.69 L/h and between dialysis was 0.453 L/h. The clearance between dialysis was best described by residual creatinine clearance (as calculated using the Cockcroft and Gault equation), which probably reflects both lean mass and residual clearance mechanisms. Simulation from the final population model showed that predialysis dosing has a higher probability of achieving target maximum concentration (Cmax) concentrations (> 8 mg/L) within acceptable exposure limits (area under the concentration-time curve [AUC] values > 70 and < 120 mg x h/L per 24 hours) than postdialysis dosing.     

Pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily

AIMS: 1. To determine the population pharmacokinetics of gentamicin in 957 patients with varying renal function dosed once daily. 2. To see if current starting doses for once daily aminoglycoside dosing are appropriate. 3. To test whether calculating creatinine clearance using an adjusted Cockcroft and Gault method (CLCr,adjusted ) was a better predictor of gentamicin clearance than the standard Cockcroft and Gault method (CLCr,unadjusted ). METHODS: Nine hundred and fifty-seven patients were dose-individualized for gentamicin using SeBA-GEN, a Bayesian dosing method. This method returns estimates of the values of gentamicin CL and V d from which the 24 h AUC can be estimated. The goal of therapy was to attain an AUC of 70-100 mg l-1 h depending on the severity of the infection. The population was divided into four groups of differing renal function. Linear regression analysis was performed to determine the relationship between V d and various indices of weight, and gentamicin CL and either CLCr,adjusted or CLCr,unadjusted. RESULTS: The mean V d (+/-s. d.) and CL (+/-s.d.) of gentamicin in our total population were 17.4 (+/-4.1) l and 4.0 (+/-1.8) l h-1, respectively. There was a decrease in V d with reducing renal function when comparing patients with normal renal function and patients with poor renal function. The lower of total body weight (TBW) and lean body weight (LBW), termed dosing weight (DWT), was a slightly better predictor of V d (r2=0.28) than either TBW (r2=0.21) or LBW (r2=0.21). CLCr,adjusted (r2=0.80) was a better predictor of gentamicin CL than CLCr, unadjusted (r2=0.57). CONCLUSIONS: The mean population values of V d and CL of gentamicin dosed once daily are similar to those described by others in relation to multiple daily dosing. Given that previous methods have been based on population values of V d and CL from multiple daily dosing, the currently recommended starting doses for once daily aminoglycoside dosing would seem appropriate. The V d reduced with decreasing renal function, with a maximum of 23% difference between patients with normal and poor renal function. The Cockcroft and Gault method of calculating creatinine clearance does not appear to perform well at low values of serum creatinine concentration. An adjustment of the Cockcroft and Gault method is proposed to allow for this.     

Effect of renal function on risedronate pharmacokinetics after a single oral dose

AIMS: To determine the relationship between risedronate pharmacokinetics and renal function. METHODS: Risedronate was administered to adult men and women (n=21) with various degrees of renal function (creatinine clearance 15-126 ml min-1 ) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). Risedronate serum concentration-time and urinary excretion rate-time profiles were analysed simultaneously using nonlinear regression. RESULTS: Renal clearance and volume of distribution were linearly related to creatinine clearance (r2=0.854, P<0.001; and r2=0.317, P<0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min-1. A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min-1 (P=0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population. CONCLUSIONS: Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance >20 ml min-1 ).     

Pharmacokinetics of clavulanic acid-potentiated ticarcillin in renal failure

The serum kinetics of an intravenous bolus of a combination of ticarcillin (TIC) (3 g) and clavulanic acid (CLAV) (0.2 g) have been determined in a number of patients with different degrees of renal failure as characterized by creatinine clearance. The volume of distribution for both drugs was unaffected by renal failure. Indices of serum and renal drug clearance were related to the degree of renal failure. TIC was cleared more slowly than CLAV. Anephric patients may have a higher serum clearance of CLAV than patients categorized by creatinine clearance as having severe renal failure; this could be due to an increase in metabolic clearance. Haemodialysis effectively clears both drugs. "Rebound" serum concentrations were consistently observed for TIC, but were observed in only one patient for CLAV. Continuous ambulatory peritoneal dialysis results in significant recovery of both drugs. The dosing requirements for the combination of TIC and CLAV in patients with renal failure are considered.     

Scoping review of augmented renal clearance in critically ill pediatric patients

Augmented renal clearance (ARC), a phenomenon of enhanced elimination of renal solutes, has been described in adult critically ill patients, but little is known about the phenomenon in children. The aim of this scoping review was to gather and summarize all evidence on ARC in pediatric patients to examine its breadth and depth including prevalence, risk factors, and pharmacokinetic alterations and identify any gaps for further areas of inquiry. PubMed, Embase, and Web of Science were searched for titles, abstracts, or keywords that focused on ARC. Non-English studies, reviews, and nonhuman studies were excluded. Reporting followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses for Scoping Reviews (PRISMA-ScR) guidelines. Data were extracted on article type, study details, patient population, ARC definition and prevalence, methods of renal function assessment, and study results. A total of 215 citations were found with 25 citations meeting the criteria for inclusion in pediatrics (2102 total patients); the majority of studies (84%) focused on pharmacokinetics (PK) of antimicrobial agents. The median/mean age range was 1.25–12 years. There were a total of 10 different definitions of ARC. The prevalence of ARC ranged from 7.8% to 78%. The most common method for documenting creatinine clearance (CrCl) was the modified Schwartz equation (64%). Only 20% of studies reported risk factors for ARC including low serum creatinine, increasing age, febrile neutropenia, male, septic shock, and treatment with antibiotics. Glycopeptide antimicrobials were the most evaluated class (42.9%) among the 21 antimicrobial drug studies. All studies reported increased drug clearance and/or poor probability of achieving target concentrations of the agents studied. ARC showed variable prevalence in pediatric patients likely due to the lack of a standard definition and many studies not considering age-related changes in CrCl with pediatric intensive care unit (PICU) patients. ARC was shown to impact PK of antibiotics commonly administered to pediatric patients, which may necessitate changes in standard dosing regimens.     

Pharmacokinetic-pharmacodynamic evaluation of ceftazidime continuous infusion vs intermittent bolus injection in septicaemic melioidosis

AIMS: Experimental studies have suggested that constant intravenous infusion would be preferable to conventional intermittent bolus administration of beta-lactam antibiotics for serious Gram-negative infections. Severe melioidosis (Burkholderia pseudomallei infection) carries a mortality of 40% despite treatment with high dose ceftazidime. The aim of this study was to measure the pharmacokinetic and pharmacodynamic effects of continuous infusion of ceftazidime vs intermittent bolus dosing in septicaemic melioidosis. METHODS: Patients with suspected septicaemic melioidosis were randomised to receive ceftazidime 40 mg kg-1 8 hourly by bolus injection or 4 mg kg-1 h-1 by constant infusion following a 12 mg kg-1 priming dose to perform estimation of pharmacokinetic and pharmacodynamic parameters. RESULTS: Of the 34 patients studied 16 (59%) died. Twenty patients had cultures positive for B. pseudomallei of whom 12 (60%) died. The median MIC90 of B. pseudomallei was 2 mg l-1, giving a target concentration CT, of 8 mg l-1. The median (range) estimated total apparent volume of distribution, systemic clearance and terminal elimination half-lives of ceftazidime were 0.468 (0.241-0.573) l kg-1, 0.058 (0.005-0.159) l kg-1 h-1 and 7.74 (1.95-44.71) h, respectively. Clearance of ceftazidime and creatinine clearance were correlated closely (r = 0. 71; P < 0.001) and there was no evidence of significant nonrenal clearance. CONCLUSIONS: Simulations based on these data and the ceftazidime sensitivity of the B. pseudomallei isolates indicated that administration by constant infusion would allow significant dose reduction and cost saving. With conventional 8 h intermittent dosing to patients with normal renal function, plasma ceftazidime concentrations could fall below the target concentration but this would be unlikely with a constant infusion. Correction for renal failure which is common in these patients is Clearance = k * creatinine clearance where k = 0.072. Calculation of a loading dose gives median (range) values of loading dose, DL of 3.7 mg kg-1 (1. 9-4.6) and infusion rate I = 0.46 mg kg h-1 (0.04-1.3) (which equals 14.8 mg kg-1 day-1). A nomogram for adjustment in renal failure is given.     

Evaluation of creatinine clearance estimation in an elderly male population

Thirty-one medically stable, elderly males (age 75 +/- 8.3 yrs) participated in a prospective study evaluating the accuracy of 16 methods of estimating creatinine clearance. Serum creatinine values were determined on the mornings of days 1, 4, and 5 to assure stable renal function. On the morning of day 3, a 24-hour urine collection was initiated. A statistically significant correlation existed between the measured and estimated clearance values for all 16 formulas. The correlation (r less than 0.65) was lower than that in previously published studies, however. Five of the formulas (1A, 5A, 5B, 7A, 7B) demonstrated no statistical difference between mean measured and estimated values. In this population, formula 2B was the least biased and formula 9B the most accurate. For all 16 methods, the bias was minimal and the relative accuracy of the estimated methods was comparable. The results support using methods to estimate creatinine clearance only as a rough bedside prediction of renal function in elderly males.     

Digoxin population pharmacokinetics from routine clinical data: role of patient characteristics for estimating dosing regimens.

Routine clinical pharmacokinetic data collected from patients receiving digoxin have been analysed to evaluate the role of patient characteristics for estimating dosing regimens. The data were analysed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data. The pharmacokinetic model of digoxin was described using a one-compartment steady-state model. The effect of a variety of developmental and demographic factors on clearance was investigated. NONMEM estimates indicate that digoxin clearance was influenced by the demographic variables of age, total body weight, serum creatinine and sex. The interindividual variability in digoxin clearance was modelled with additive error with an estimated standard deviation of 46.15 L day-1 and the intraindividual variability, or residual error was 0.209 ng mL-1. The dosing method based on clearance values obtained by NONMEM analysis allowed the prediction of the steady-state concentration as a function of maintenance dose with acceptable error for therapeutic drug monitoring.