ICU老年患者液体出入量对万古霉素药代动力学的影响

目的 研究液体出入量对ICU老年患者万古霉素药代动力学的影响.方法 完全随机选择8例ICU中应用万古霉素的老年患者,记录其每日液体出入量,并采集患者血液,利用高效液相色谱法测定万古霉素的血药浓度,计算药代动力学参数,对万古霉素药代动力学参数与患者每日出入量之间的关系给予统计学分析.结果 ICU老年患者年龄(71 ±11)岁,急性生理学与慢性健康状况评分系统Ⅱ(APACHEⅡ)评分(17.13±3.13)分,液体净出入量(375±123)ml,分布半衰期(t1/2α)(0.45±0.27)h,清除半衰期(t1/2β)(6.86±3.42)h,浓度时间曲线下面积(AUC)(137.9±19.9) mg/(h·L),峰值浓度(Cmax)(36.14±10.30) mg/L,清除率(61.56±29.11) ml/min,表观分布容积(0.28±0.14)L/kg.ICU老年患者与正常老年人相比,表观分布容积差别有统计学意义(P＜0.01).ICU老年患者APACHEⅡ评分与液体净出入量和万古霉素t1/2β均呈正相关(r=0.811,P=0.015;r =0.035,P=0.035);液体出入量与血AUC呈负相关,与血t1/2β呈负相关(r=- 0.786,P=0.021).结论 当ICU患者的出入量平衡增加时,其万古霉素的杀菌效果可能会降低,难以达到预期疗效.     

小儿氨酚伪麻分散片在健康人体的生物等效性

目的研究小儿氨酚伪麻分散片和氨酚伪麻滴剂(解热镇痛药)在健康人体内的药代动力学和生物等效性。方法用随机单剂量交叉,22名男性受试者口服试验药和对照药350mg后,用高效液相色谱法测定血药浓度,计算其药代动力学参数和相对生物利用度,评价2种制剂的生物等效性。结果试验药和对照药的药代动力学参数,盐酸伪麻黄碱:t1/2ke分别为(4.21±0.70),(4.16±0.97)h;tmax分别为(1.27±0.42),(1.36±0.58)h;Cmax分别为(144.65±30.56),(148.56±29.99)ng.mL-1,AUC0-12分别为(840.35±171.14)(841.33±177.70)ng.h.mL-1;AUC0-∞分别为(983.19±213.43),(988.98±235.31)ng.h.mL-1;F(AUC0-12)为(103.04±26.54)%,F(AUC0-∞)为(102.79±26.85)%。对乙酰氨基酚:t1/2ke分别为(2.95±0.50),(3.05±0.54)h;tmax分别为(0.57±0.35),(0.49±0.22)h;Cmax分别为(5.15±1.07),(5.43±1.45)μg.mL-1;AUC0-12分别为(17.60±3.71),(19.21±5.72)μg.h.mL-1;AUC0-∞分别为(18.90±4.24),(20.67±6.45)μg.h.mL-1;F(AUC0-12)为(95.02±18.58)%,F(AUC0-∞)为(94.83±18.23)%。结论2种制剂具有生物等效性。     

重组人白细胞介素-11在肿瘤病人体内的药代动力学

目的 研究重组人白细胞介素-11(rmhlL-11,血小板生长因子)在肿瘤病人体内的药代动力学.方法 用开放、单组试验设计.7例肿瘤患者单次及连续10次皮下注射rmhIL-11后,定时采血,ELISA法测定不同时间点血浆rmhIL-11的浓度,求算药代动力学参数.结果 7名受试者单次皮下注射rmhIL-11 7.5 μg·kg-1后,主要药代动力学参数:Cmax为(10.53±4.10) μg·L-1;t1/2为(5.19±1.66)h;tmax为(2.29±0.91)h;平均AUC0-tn和AUC0-∞分别为(91.51±37.29)和(92.11±37.33) μg·h·L-1.多次皮下注射rmhIL-11 7.5μg·kg-1后,主要药代动力学参数分别为:Cmax为(9.39±2.76) μg·L-1;t1/2为(3.96±1.42) h;tmax为(2.71±0.81) h;平均AUC0-tn和AUC0-∞分别为(76.24±34.21)和(76.62±34.27) μg·h·L-1;Css_av为(3.10±1.30) μg·L-1;AUCss为(74.42±31.13) μg·h·L-1;DF为(307.42±57.52)%.结论 ELISA法测定血浆nnhIL-11浓度,方法稳定可靠,特异性好,可满足药代动力学研究的需要.     

阿托伐他汀钙与阿昔莫司联用在中国健康人体的药代动力学

目的 评价阿托伐他汀钙与阿昔莫司联用后在中国健康人体内的药代动力学特征.方法 18名健康受试者单次空腹同时口服阿托伐他汀钙10 mg与阿昔莫司250 mg后,分别用LC-MS/MS,HPLC测定不同时间点血浆中阿托伐他汀与阿昔莫司的浓度,DAS 2.1软件计算相应的药代动力学参数.结果 药代动力学参数如下,阿托伐他汀:t1/2为(11.75±2.48)h,tmax为(0.33 ±0.12)h,Cmax为(11.33±4.36)ng·mL-,AUC0-t为(57.57±25.91)ng·mL-1·h;阿昔莫司:t1/2为(1.55±0.18)h,tmax为(1.32±0.62)h,Cmax为(3.65±1.08) μg·mL-,AUC0-t为(12.84±2.73)μg·mL-·h.与单独给药药代动力学参数基本接近.结论 阿托伐他汀与阿昔莫司联用后彼此药代动力学行为未发生明显改变,联用可能不存在药代动力学方面的相互作用.     

亚胺培南在无尿CVVH治疗患者的药代动力学研究

目的研究在ICU接受连续静脉-静脉血液滤过(continuous venovenous hemofiltration,CV-VH)治疗的无尿患者体内进行亚胺培南的药代动力学特征。方法在CVVH期及暂停CVVH期给予泰能0.5g静脉30min匀速滴注,分别在用药前以及用药后0、0.5、1、2、4、6h采取血液样本,用微生物琼脂扩散法测定亚胺培南浓度。结果泰能在CVVH期的药代动力学参数为:消除半衰期(t1/2)(2.06±0.38)h、血浆清除率(CL)(11.72±7.24)ml/min、药时曲线下面积(AUC)(54.23±22.90)mg/(h.L),暂停CVVH期的药代动力学参数为:t1/2(3.45±0.99)h、CL(4.57±1.26)ml/min、AUC(117.58±30.36)μg/(h.ml),二者有显著差异,并且与既往报道的正常人体内药代动力学参数相比均半衰期延长、清除率减低,提示CVVH能清除部分亚胺培南。结论接受CVVH治疗的无尿患者在使用泰能时需要调整剂量,以避免血药浓度过高对中枢神经所带来的毒副作用。     

国产氧氟沙星胶囊的人体药代动力学及相对生物利用度研究

10例健康男性志愿者自身交叉设计分别口服200mg进口与国产的氧氟沙星胶襄后,其体内过程符合一房室模型方程,在体内的消除半衰期t(1/5)分别为4.93±0.91及4.61±0.64h,达峰时间Tpk分别为0.82±0.39及O.96土0.54h,峰浓度Cmax分别为2.75±0.32及2.62±0.35μg/ml,浓度曲线下面积AUC分别为21.24±2.46及20.11±2.80μg·h/ml,计算国产制剂的平均F值为94.7%.药代动力学参数亦与国外文献报道相接近.     

进食对健康受试者口服盐酸川丁特罗片剂药代动力学的影响

目的研究在进食和空腹状态下中国健康受试者口服盐酸川丁特罗片(平喘药)药代动力学的差异。方法8名健康志愿者分别于禁食10h后空腹和统一早餐后,立即口服盐酸川丁特罗片50μg,用HPLC-MS/MS测定血浆中川丁特罗的浓度,用WinNonLin5.0计算其主要药代动力学参数。结果8名受试者在进食和空腹状态下,单次口服盐酸川丁特罗片50μg的主要药代动力学参数:Cmax分别为(17.3±4.0)、(20.8±4.1)pg.mL-1;tmax分别为(1.0±0.5)、(1.2±0.5)h;t1/2分别为(16.7±4.3)、(18.5±7.3)h;AUC0-tn分别为(80.9±23.8)、(106.8±57.1)pg.h.mL-1。结论进食状态下的Cmax和AUC0-tn分别为空腹状态时的83%和76%;而tmax和t1/2基本相近。     

单剂口服盐酸吡格列酮片在健康人体的药代动力学

目的研究健康人体单剂量口服盐酸吡格列酮片(胰岛素增敏剂)的药代动力学。方法24名健康男性志愿者单次口服盐酸吡格列酮片30mg,用HPLC-MS/MS同时测定血浆中吡格列酮及其活性代谢产物的浓度,计算其主要药代动力学参数。结果吡格列酮:Cmax为(1504.9±447.8)ng.mL-1;tmax为(1.46±0.69)h;t1/2Ke为(7.58±3.21)h;AUC0-48为(11.22±2.60)μg.h.mL-1。吡格列酮代谢物M-Ⅲ:Cmax为(249.4±82.7)ng.mL-1;tmax为(11.94±6.14)h;t1/2Ke为(20.09±4.13)h;AUC0-120为(10.90±3.55)μg.h.mL-1。吡格列酮代谢物M-IV:Cmax为(487.2±108.6)ng.mL-1;tmax为(13.33±5.23)h;t1/2Ke为(21.07±3.99)h;AUC0-120为(22.78±5.04)μg.h.mL-1。结论健康人体单剂量口服盐酸吡格列酮片剂后,吡格列酮代谢物M-Ⅲ和M-IV的达峰时间约为12～13h,峰浓度分别约为吡格列酮的16%和32%,AUC0-120分别约为吡格列酮AUC0-48的97%和203%。     

氯沙坦钾胶囊人体生物等效性研究

目的评价氯沙坦钾胶囊与氯沙坦钾片在中国健康成年男性志愿者中的生物等效性。方法20名男性健康受试者按照随机、开放、双周期交叉试验设计,分别单剂量口服试验制剂100 mg或参比制剂100 mg。以HPLC-MS/MS法测定给药后不同时间血浆中氯沙坦钾及其活性代谢产物E-3174的浓度,计算药动学参数,并判断2种制剂是否等效。结果参比制剂中氯沙坦钾的主要药物动力学参数Cmax为(831.2±247.4)μg.L-1,tmax为(1.0±0.4)h,AUC0→8为(1 110.2±266.6)μg.h.L-1,t1/2为(2.1±0.6)h;代谢产物E-3174的Cmax为(1 198.2±301.2)μg.L-1,tmax为(2.0±0.8)h,AUC0→24为(6 838.6±1 921.2)μg.h.L-1,t1/2为(8.5±2.3)h。受试制剂中氯沙坦钾的主要药物动力学参数Cmax为(846.6±216.7)μg.L-1,tmax为(0.7±0.3)h,AUC0→8为(1 097.4±278.7)μg.h.L-1,t1/2为(2.3±0.5)h;代谢产物E-3174的Cmax为(1 166.9±324.6)μg.L-1,tmax为(2.0±0.6)h,AUC0→24为(6 712.4±2 021.6)μg.h.L-1,t1/2为(8.5±1.5)h。结论受试制剂氯沙坦钾胶囊与参比制剂氯沙坦钾片为生物等效制剂。     

羟丙基-β-环糊精-芒果苷包合物在小鼠体内的药代动力学研究

目的建立测定小鼠血浆中羟丙基-β-环糊精-芒果苷包合物质量浓度的高效液相色谱(HPLC)法,并用于药代动力学研究。方法小鼠一次性灌胃给予3.0 g/kg羟丙基-β-环糊精-芒果苷包合物后,用HPLC法检测不同时间间隔的血药浓度,计算药代动力学参数。结果小鼠一次性灌胃给予羟丙基-β-环糊精-芒果苷包合物后,分布相半衰期(t1/2α)为(8.226±0.972)h,消除相半衰期(t1/2β)为(8.674±1.112)h,药时曲线下面积(AUC)为(3.058±0.836)μg.h/kg。结论 HPLC法简便、可靠,可用于芒果苷包合物药代动力学研究,小鼠体内药代动力学过程符合二房室开放模型。     

Initial vancomycin dosing recommendations for critically ill patients undergoing continuous venovenous hemodialysis

Background:

Delaying appropriate antimicrobial therapy for critically ill patients increases the risk of death. Currently, there are insufficient data to guide initial vancomycin dosing for patients undergoing continuous venovenous hemodialysis (CVVHD).

Objective:

To develop practical recommendations for initial dosing of vancomycin, based on the pharmacokinetics of this drug in critically ill patients undergoing CVVHD.

Methods:

A chart review was conducted for 24 critically ill adult patients who had undergone concurrent CVVHD and vancomycin therapy. Mean pharmacokinetic parameters were determined, along with practical recommendations for initial vancomycin dosing that targeted steady-state trough concentrations for patients receiving intermittent infusions and steady-state levels for those receiving continuous infusions between 15 and 20 mg/L. Monte Carlo simulation was used to develop the initial vancomycin dosing recommendations.

Results:

The mean (95% confidence interval) pharmacokinetic parameters for vancomycin (elimination rate constant 0.0315 [0.0254–0.0391], half-life 22.0 h [17.72–27.24 h], volume of distribution 0.96 L/kg [0.77–1.20 L/kg], and clearance 2.4 L/h [1.97–2.92 L/h]) indicated that initial intermittent IV dosing of 1.25–1.5 g q24h or 15 mg/kg q24h would be suitable. For continuous infusion, a 1.5-g IV loading dose followed by continuous infusion of 1–1.5 g IV over 24 h (42–62 mg/h) would be recommended. However, Monte Carlo simulation revealed that the probability of achieving desired concentrations between 15 and 20 mg/L with any of these initial regimens is low.

Conclusions:

There was considerable variation in vancomycin pharmacokinetics in this patient population. The observations reported here raise concerns about the reliability of numerous empiric dosing recommendations derived from small pharmacokinetic studies in heterogeneous populations. Follow-up therapeutic drug monitoring is essential to ensure that concentrations remain within the target range.     

Vancomycin clearance during continuous venovenous haemofiltration in critically ill patients

The objective of this study was to determine the pharmacokinetics and dosing recommendations of vancomycin in critically ill patients receiving continuous venovenous haemofiltration (CVVH). A prospective study was conducted in the Intensive Care Unit of a university hospital. Seven patients receiving CVVH with a triacetate hollow-fibre dialyser were enrolled. CVVH was performed in pre-dilution mode with a blood flow rate of 200-250 mL/min and an ultrafiltrate flow rate of 800-1200 mL/h. To determine vancomycin pharmacokinetics, serum and ultrafiltrate were collected over 12 h after a 2-h infusion of 1000 mg vancomycin. The mean (± standard deviation) sieving coefficient of vancomycin was 0.71 ± 0.13, which is consistent with previously reported values. Clearance of vancomycin by CVVH (0.73 ± 0.21 L/h or 12.11 ± 3.50 mL/min) constituted 49.4 ± 20.8% of total vancomycin clearance (1.59 ± 0.47 L/h) and was consistent with previously reported clearances. Approximately one-fifth of the vancomycin dose was removed during the 12-h CVVH (213.9 ± 104.0 mg). The volume of distribution was 24.69 ± 11.00 L, which is smaller than previously reported. The elimination rate constant and terminal half-life were 0.08 ± 0.05 h⁻¹ and 12.02 ± 7.00 h, respectively. In conclusion, elimination of vancomycin by CVVH contributed to ca. 50% of the total elimination in critically ill patients. The maintenance dose of vancomycin, calculated from parameters from patients in this study, would be 500-750 mg every 12 h to provide a steady-state trough concentration of 15-20 mg/L. Owing to alterations in clinical conditions, serum vancomycin concentrations must be closely monitored in critically ill patients.     

Pharmacokinetics of linezolid in critically ill patients

Introduction: Linezolid is an oxazolidinone antibiotic active against Gram-positive bacteria, and is most commonly used to treat life-threatening infections in critically ill patients. The pharmacokinetics of linezolid are profoundly altered in critically ill patients, partly due to decreased function of vital organs, and partly because life-sustaining drugs and devices may change the extent of its excretion.

Areas covered: This article is summarizes key changes in the pharmacokinetics of linezolid in critically ill patients. The changes summarized are clinically relevant and may serve as rationale for dosing recommendations in this particular population.

Expert opinion: While absorption and penetration of linezolid to tissues are not significantly changed in critically ill patients, protein binding of linezolid is decreased, volume of distribution increased, and metabolism may be inhibited leading to non-linear kinetics of elimination; these changes are responsible for high inter-individual variability of linezolid plasma concentrations, which requires therapeutic plasma monitoring and choice of continuous venous infusion as the administration method. Acute renal or liver failure decrease clearance of linezolid, but renal replacement therapy is capable of restoring clearance back to normal, obviating the need for dosage adjustment. More population pharmacokinetic studies are necessary which will identify and quantify the influence of various factors on clearance and plasma concentrations of linezolid in critically ill patients.     

Plasma and interstitial fluid population pharmacokinetics of vancomycin in critically ill patients with sepsis

Vancomycin is a commonly prescribed antibiotic in the intensive care unit. However, there are limited data describing its distribution into the interstitial fluid (ISF) of tissues. The aim of this study was to describe the plasma and tissue ISF population pharmacokinetics of vancomycin in critically ill patients with sepsis. Serial vancomycin blood and ISF samples were collected at pre-specified time intervals in critically ill patients with sepsis. ISF sampling occurred using a subcutaneously inserted microdialysis catheter. Bioanalysis was undertaken using a validated spectrometric assay method. Population pharmacokinetic analysis was performed using Pmetrics^®. Seven patients were recruited and pharmacokinetic data were available for six of them. The median (interquartile range) age, weight, Acute Physiology and Chronic Health Evaluation (APACHE) II score, Sequential Organ Failure Assessment (SOFA) score and measured creatinine clearance (CL_Cr) were 55 (44–67) years, 85 (81–102) kg, 20 (16–29), 5 (4–8) and 90 (83–98) mL/min, respectively. Vancomycin pharmacokinetics was best described by a three-compartment linear model. Measured CL_Cr (on vancomycin clearance) and weight (on volume of distribution of the central compartment) were the only patient covariates that improved the model fit. Coefficients of variation for the vancomycin rate constants into and out of the peripheral and tissue ISF compartments were also high, ranging from 47% to 134%. There is significant variability of vancomycin distribution into tissue ISF, which it was not possible to explain with patient characteristics.     

A population approach to the forecasting of amikacin plasma and urinary levels using a prescribed dosage regimen.

We retrospectively analyzed amikacin pharmacokinetics in 19 critically ill patients who received amikacin intravenously. Fourteen subjects (577 serum amikacin concentrations, 167 urine measurements) were studied to obtain data for population modeling, while 5 patients (267 serum amikacin concentrations, 68 urine measurements) were studied for the assessment of predictive performance. The population analysis was performed using serum and urine amikacin measurements; the renal clearance of amikacin was expressed as a function of creatinine clearance. A two-compartment model was fitted to the population data by using NONMEM. The population characteristics of the pharmacokinetic parameters (fixed and random effects) were estimated using the FOCE method. The population pharmacokinetic parameters with the interindividual variability (CV%) were as follows: slope (0.254, 126%) and intercept (3 l/h, 59.6%) of the linear model which relate the amikacin renal clearance to the creatinine clearance, initial volume of distribution (17.1 l, 22.2%), intercompartment clearance (5.22 l/h, 104%), steady state volume of distribution (55.2 l, 64.1%) and urinary elimination (67.5%, 36.3%). The Bayesian approach developed in this study accurately predicts amikacin concentrations in serum and urine and allows for the estimation of amikacin pharmacokinetic parameters, minimizing the risk of bias in the prediction.     

The pharmacokinetics of ketobemidone in critically ill patients

AIMS: To study the pharmacokinetics of orally and intravenously administered ketobemidone in critically ill patients. METHODS: Seventeen patients were studied during their stay in the intensive care unit at Huddinge University Hospital. Nine patients received a single intravenous dose of ketobemidone (0.04 mg kg-1) and eight patients received a single oral dose of 5 mg. Plasma concentrations of ketobemidone were measured using liquid chromatography-mass spectrometry. The pharmacokinetic analysis was performed using WinNonlin trade mark software. RESULTS: There was a wide variation in the different pharmacokinetic parameters among patients. Mean clearance in patients treated intravenously was 74.5 (95% CI 43.2, 128.3) and mean Vd was 2.4 l kg-1 (95% CI 2.0, 2.8). t1/2,z also varied widely with a mean value of 4.41 h (95% CI 2.7, 7.0). The corresponding values for MRT were 5.4 and 3.3, 8.8. Mean oral clearance (CL/F) was 102 l h-1 (95% CI 82.7, 125.8), mean Vz/F was 11.2 l kg-1 (95% CI 9.7, 13.1) and mean t1/2,z was 6.0 (95% CI 4.9, 7.3) in orally treated patients. Cmax showed a mean of 38 nmol l-1 (95% CI of 31, 47). A significant correlation was observed between the glomerular filtration rate (GFR) and the half-life of ketobemidone (r = -0.72, P < 0.05). t1/2,z was generally longer and the variation larger in critically ill patients compared with healthy individuals. However, there was no correlation between the elimination of ketobemidone in critically ill patients and plasma C-reactive protein, white blood count or plasma albumin concentrations. CONCLUSIONS: The disposition of ketobemidone is highly variable in critically ill patients. In order to ensure sufficient analgesia and avoid toxicity, therapeutic monitoring should be employed when using ketobemidone in this group of patients.     

Pharmacokinetics and pharmacodynamics of intravenous levofloxacin in patients with early-onset ventilator-associated pneumonia

OBJECTIVE: To investigate the pharmacokinetics of levofloxacin and the pharmacokinetic-pharmacodynamic appropriateness of its total body exposure in patients in the intensive care unit (ICU) treated for early-onset ventilator-associated pneumonia (VAP) with intravenous levofloxacin 500mg twice daily. DESIGN: Prospective non-blinded pharmacokinetic-pharmacodynamic study. PARTICIPANTS: Ten critically ill adult patients with normal renal function. METHODS: Blood and urine samples were collected at appropriate times during a 12-hour administration interval at steady state. Levofloxacin concentrations were determined by high-performance liquid chromatography. Clinical and microbiological outcomes were assessed. RESULTS: Levofloxacin pharmacokinetics were only partially comparable with those obtained from literature data for healthy volunteers. Area under the concentration-time curve (AUC(tau)) over the 12-hour dosage interval was about 30-40% lower than in healthy volunteers (33.90 vs 49.60 mg. h/L). The reduced exposure may be due to a greater clearance of levofloxacin (0.204 vs 0.145 L/h/kg [3.40 vs 2.42 mL/min/kg]), leading to a shorter elimination half-life (5.2 vs 7.6 hours). Cumulative urinary excretion during the 12-hour dosage interval confirmed the greater excretion of unchanged drug in these patients compared with healthy subjects (76% vs 68%). Coadministered drugs used to treat underlying diseases (dopamine, furosemide, mannitol) may at least partially account for this enhanced elimination in critically ill patients. Intravenous levofloxacin 500mg twice daily ensured a median C(max)/MIC (maximum plasma concentration/minimum inhibitory concentration) ratio of 102 and a median 24-hour AUC/MIC ratio of 930 SIT(-1). h (inverse serum inhibitory titre integrated over time) against methicillin-sensitive Staphylococcus aureus and Haemophilus influenzae. The overall success rate of the assessable cases was 75% (6/8). Bacterial eradication was obtained in all of the assessable cases (8/8), but a superinfection (Acinetobacter anitratus,Pseudomonas aeruginosa) occurred in three cases. CONCLUSIONS: The findings support the suitability of intravenous levofloxacin 500mg twice daily in the treatment of early-onset VAP in ICU patients with normal renal function. Levofloxacin may represent a valid alternative to non-pseudomonal beta-lactams or aminoglycosides in the empirical treatment of early-onset VAP. However, further larger studies are warranted to investigate its efficacy.     

肾功能亢进在重症患者中的发生率及对万古霉素应用的影响

目的： 研究肾功能亢进（ARC）在重症患者中的发生率和ARC对重症患者血清万古霉素浓度的影响。方法： （1）回顾性分析2016年1月-2017年6月某院重症医学科收治的所有检测过肾功能的患者，分析其ARC发生率。（2）回顾性分析2016年1月-2017年6月在该院重症医学科接受万古霉素常规剂量1 g q12h治疗的患者，评价ARC对血清万古霉素浓度的影响。结果： （1）本研究共纳入患者3 045名，研究结果表明重症患者ARC发生率为15.6%（474/3 045）。ARC组患者年龄显著低于非ARC组，肌酐清除率和GFR明显高于非ARC组。（2）本研究共纳入50例患者，ARC组的万古霉素稳态谷浓度显著低于非ARC组，谷浓度中位数分别为5.72（3.73，8.27）μg·mL^-1和14.06（8.74，22.14）μg·mL^-1，P<0.05。但2组之间的临床结局、微生物结局和死亡率没有显著差异。ARC组万古霉素稳态谷浓度低于10 μg·mL^-1的重症患者达78.9%，较非ARC组（29.0%）比例更高。万古霉素稳态谷浓度与年龄显著相关（ρ=0.739，P<0.05），与肌酐清除率显著相关（ρ=-0.716，P<0.05）。结论： 重症患者ARC发生率较高，ARC会使患者的万古霉素浓度难以达到治疗目标，这类患者需要根据肌酐清除率进行必要的给药剂量调整。     

Population pharmacokinetics of continuous infusion of piperacillin in critically ill patients

Dosing recommendations for continuous infusion of piperacillin, a broad-spectrum beta-lactam antibiotic, are mainly guided by outputs from population pharmacokinetic models constructed with intermittent infusion data. However, the probability of target attainment in patients receiving piperacillin by continuous infusion may be overestimated when drug clearance estimates from population pharmacokinetic models based on intermittent infusion data are used, especially when higher doses (e.g. 16?g/24?h or more) are simulated. Therefore, the purpose of this study was to describe the population pharmacokinetics of piperacillin when infused continuously in critically ill patients. For this analysis, 270 plasma samples from 110 critically ill patients receiving piperacillin were available for population pharmacokinetic model building. A one-compartment model with linear clearance best described the concentration–time data. The mean?±?standard deviation parameter estimates were 8.38?±?9.91?L/h for drug clearance and 25.54?±?3.65?L for volume of distribution. Creatinine clearance improved the model fit and was supported for inclusion as a covariate. In critically ill patients with renal clearance higher than 90?mL/min/1.73?m², a high-dose continuous infusion of 24?g/24?h is insufficient to achieve adequate exposure (pharmacokinetic/pharmacodynamic target of 100% fT_{>4 x MIC}) against susceptible Pseudomonas aerginosa isolates (MIC ≤16?mg/L). These findings suggest that merely increasing the dose of piperacillin, even with continuous infusion, may not always result in adequate piperacillin exposure. This should be confirmed by evaluating piperacillin target attainment rates in critically ill patients exhibiting high renal clearance.     

Pharmacokinetics of intravenous and oral levofloxacin in critically ill adults in a medical intensive care unit

STUDY OBJECTIVE: To characterize the pharmacokinetic disposition of intravenous and oral levofloxacin in critically ill adults. DESIGN: Prospective, open-label study. SETTING: University teaching hospital. PATIENTS: Thirty critically ill patients in a medical intensive care unit (ICU). INTERVENTIONS: All patients received levofloxacin as part of their routine medical care. Pharmacokinetic evaluations were performed in 28 patients receiving intravenous levofloxacin. Ten of these patients subsequently were switched to oral levofloxacin and underwent a second pharmacokinetic evaluation during oral therapy. MEASUREMENTS AND MAIN RESULTS: Mean +/- SD levofloxacin half-life, clearance at steady state, and volume of distribution in all 28 patients were 8.0 +/- 1.7 hours, 134 +/- 35 ml/minute, and 1.2 +/- 0.3 L/kg, respectively Maximum and minimum serum concentrations (Cmax and Cmin) and area under the serum concentration-time curve from 0-24 hours (AUC(0-24)) in patients receiving levofloxacin 500 mg intravenously were 7.5 +/- 0.8 mg/L, 1.0 +/- 0.5 mg/L, and 66.1 +/- 15.7 mg x hour/L, respectively Observed Cmax, Cmin, and time at which maximum concentration was achieved after oral doses of levofloxacin 500 mg were 5.5 +/- 1.1 mg/L, 0.8 +/- 0.4 mg/L, and 1.3 +/- 0.4 hours, respectively. These values were significantly different (p < 0.05) from those observed after intravenous dosing in the same patients; other pharmacokinetic parameters were similar. Statistically significant increases (p < 0.05) in Cmax, Cmin, half-life, and AUC(0-24) were found in critically ill patients administered multiple doses of intravenous levofloxacin compared with historical data from healthy volunteers. CONCLUSIONS: The dosage regimen of intravenous levofloxacin 500 mg once/day appears adequate for most pathogens found in critically ill patients with normal renal function. Less susceptible pathogens may require an increased daily dose for more optimal therapy. Orally administered levofloxacin appears to be well absorbed in selected ICU patients and has pharmacokinetics similar to those of intravenously administered levofloxacin.