Steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients

The objective of this study was to evaluate the steady-state pharmacokinetics and pharmacodynamics of cefepime administered by prolonged infusion in hospitalised patients requiring antimicrobial therapy. Nine patients received 1g every 8h (q8h), infused over 4h, and steady-state pharmacokinetic parameters were determined by non-compartmental and compartmental methods. Using these pharmacokinetic parameters, 5000-patient Monte Carlo simulations were performed to estimate the pharmacokinetic profiles for six prolonged-infusion dosing regimens. The probability of target attainment (PTA) was calculated at minimum inhibitory concentrations (MICs) ranging from 0.06 μg/mL to 32 μg/mL, and the cumulative fraction of response (CFR) was calculated for six Gram-negative pathogens using MIC data from the Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) (2005-2007, USA). The pharmacodynamic target was free cefepime concentrations remaining above the MIC for 60% of the dosing interval (60% fT>MIC). Mean ± standard deviation maximum and minimum serum concentrations, terminal elimination half-life, elimination rate constant, volume of distribution and systemic clearance of cefepime were 32.5 ± 13.5 μg/mL, 9.5 ± 5.2 μg/mL, 2.4 ± 0.7h, 0.316 ± 0.116 h(-1), 21.3 ± 6.5L and 6.6 ± 3.6L/h, respectively. At the susceptibility breakpoint of 8 μg/mL, the PTA was >90% for 1g and 2g q8h (4-h infusion) and 1g and 2g every 6h (q6h) (3-h infusion). For Pseudomonas aeruginosa, the CFR was 88.6% for 1g q8h (4-h infusion) and ≥ 92.7% for 2g q8h (4-h infusion) and 1g and 2g q6h (3-h infusion). Cefepime 1g q8h infused over 4h provides excellent target attainment for susceptible bacterial pathogens with MICs ≤8 μg/mL.     

高效毛细管电泳法测定注射用哌拉西林／三唑巴坦的含量

建立注射用哌拉西林／三唑巴坦的HPCE含量测定方法。方法：测定条件为：运行缓冲液：25mmol/L的磷酸硼砂溶液和50mmol/L的SDS，pH9.0；操作电压20kV，检测波长200nm。结果：测定哌拉西林的线性范围为0．01－0．75mg/ml,日内RSD为0．66％，日间RSD为0．88％；三唑巴坦的线性范围为0．02－1．0mg/ml,日内RSD为0．71％，日间RSD为0．98％。哌拉西林的回收率为99．76％，三唑巴坦的回收率为98．2％。结论：该方法简便、经济、快速，准确可靠。     

他唑巴坦/哌拉西林临床给药方案研究

目的分析他唑巴坦/哌拉西林临床给药方案的改变对临床疗效的影响,寻找最合适、最有效的给药方案。方法随机选取我院外科2013年1-12月收治的60例感染患者,随机分为2组,对照组采用常规给药方案:他唑巴坦/哌拉西林4.5 g,静脉滴注,1次/6 h,每次输注时间控制为30 min;观察组采用延长给药时间方案:他唑巴坦/哌拉西林4.5 g,静脉泵入滴注,1次/6 h,每次用输液泵控制输注时间为60 min。观察两组患者的临床疗效(C反应蛋白,CRP)、不良反应和住院时间。结果观察组的CRP明显低于对照组(P<0.05);观察组的治疗总有效率明显高于对照组(P<0.05);观察组的不良反应率明显低于对照组(P<0.05),观察组的住院时间明显短于对照组(P<0.05)。结论改变给药方案,延长给药时间,可以提高临床疗效,减少不良反应发生率,缩短住院时间,能够有效缓解患者痛苦,帮助患者减轻经济负担,值得临床推荐使用。     

HPLC-MS/MS法同时检测大鼠微透析液中哌拉西林/三唑巴坦的浓度

目的建立高效液相色谱-串联质谱(HPLC-MS/MS)法同时检测大鼠微透析液中哌拉西林/三唑巴坦的药物浓度。方法利用微透析技术对大鼠肝脏局部给药,并进行采样。微透析样品通过HPLC-MS/MS检测,采用Agilent TC-C18柱,(150mm×4.6mm,5μm),流动相为乙腈-0.5%甲酸,等度洗脱,以负离子扫描多反应监测(MRM)扫描方式进行检测,检测离子对哌拉西林m/z 516.2→233.0,三唑巴坦m/z 299.0→138.0,内标替米沙坦m/z 513.2→287.0。结果哌拉西林/三唑巴坦的线性范围均为0.0625~43.75μg/m L;日间和日内精密度相对偏差均小于15%;准确度和稳定性均符合生物样品的测定要求。结论本方法灵敏度高,操作简便快捷,适用于微透析样品中哌拉西林/三唑巴坦的浓度测定。     

HPLC-MS/MS法同时测定人血浆和尿液中哌拉西林他唑巴坦的浓度

目的：建立同时测定人血浆和尿液中哌拉西林他唑巴坦浓度的高效液相色谱-质谱联用方法。方法：采用Waters C18柱（4.6mm×50mm,5μm）,流动相为乙腈-0.5%甲酸,兰索拉唑为内标,以多反应监测（MRM）扫描方式进行检测,监测离子质荷比哌拉西林m/z516.2→233.1,他唑巴坦m/z299.0→138.1,兰索拉唑m/z368.1→163.9。血浆样品经乙腈沉淀蛋白后取上清液进样,尿液样品稀释后经乙腈沉淀蛋白进样。结果：血浆和尿液中哌拉西林、他唑巴坦的线性范围均为0.10～100.00μg·mL-1,低、中、高3个浓度日内、日间精密度均小于10%。结论：本方法灵敏度高,重现性好,操作简便快捷,可用于生物样本中哌拉西林、他唑巴坦钠的浓度测定。     

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.     

注射用哌拉西林钠/他唑巴坦钠治疗慢性支气管炎疗效观察

目的 主要探讨注射用哌拉西林钠/他唑巴坦钠治疗慢性支气管炎疗效观察.方法 治疗方法有：①控制感染;②镇咳祛痰;③解痉平喘.结果 65例慢性支气管炎患者经过治疗后,痊愈15例,显效27例,有效19例,无效4例,总有效率为93.8％.结论 65例慢性支气管炎患者经过治疗后,总有效率较高,治疗方法值得临床参考借鉴.     

高效液相色谱法测定注射用哌拉西林钠他唑巴坦钠主药及杂质的含量

目的考察3个厂家生产的注射用哌拉西林钠他唑巴坦钠的主药和杂质的含量。方法采用Hypersil BDS-C18色谱柱(4.6 mm×250 mm,5μm),甲醇∶四丁基氢氧化铵水溶液(pH 3.5,50∶50)为流动相,流速0.8 mL/min,检测波长为220 nm,室温下进行检测。结果 3种样品的哌拉西林含量分别为标示量的102.8%、96.4%、103.1%;他唑巴坦含量分别为标示量的99.8%、93.3%、98.1%;杂质的含量分别为1.72%、2.74%、1.85%。结论本实验结果表明,3个厂家生产的注射用哌拉西林钠他唑巴坦钠的主药与杂质的含量均符合药典规定。     

哌拉西林他唑巴坦在肾内科患者中的群体药动学和蒙特卡罗模拟

目的:建立哌拉西林他唑巴坦在肾内科患者中的群体药动学模型,应用蒙特卡罗模拟优化其给药方案,以促进个体化给药.方法:采用高效液相色谱法测定50名肾内科患者静脉滴注哌拉西林-他唑巴坦的血清浓度310例次并收集相关临床指标,运用非线性混合效应模型(NONMEM)程序建立群体药动学模型.采用蒙特卡罗模拟(Monte Carlo simulation, MCS)比较哌拉西林他唑巴坦的不同给药方案对不同MIC群体的药效学目标到达.结果:哌拉西林、他唑巴坦的药动学符合一室模型,群体典型值及个体间差异(Between Subject Variability,BSV)分别为:哌拉西林CL/F=13.74 L·h^-1,BSV=11.1%;V/F=21.69 L,BSV=8.0%,他唑巴坦CL/F=9.32 L·h^-1, BSV=9.11%;V/F=16.0 L, BSV=5.28%;固定效应参数中,肌酐清除率对参数有影响.对于MIC值较大的细菌,延长输注的给药方案获得了更高的目标的累积反应分数(CFR).结论:群体药动学模型和蒙特卡罗模拟,可为调整哌拉西林他唑巴坦的治疗方案提供有效的分析手段.     

头孢哌酮及其与三唑巴坦的复方制剂在家犬体内的药物动力学

日的采用反相高效液相色谱法测定血清中头孢哌酮浓度,考察头孢哌酮在家犬体内的药物动力学特征,比较与三唑巴坦的复方制剂及单组分头孢哌酮的动力学差异.方法6只健康家犬,单剂量iv头孢哌酮1.6g和注射用复方制剂头孢哌酮/三唑巴坦(2g,头孢哌酮三唑巴坦=41)后,测定头孢哌酮的血药浓度变化,拟合药物动力学参数.结果单剂量iv头孢哌酮及三唑巴坦复方制剂后的头孢哌酮在体内的处置都符合二室模型.血中头孢哌酮的AUC0→∞分别为(486.17±117.98)和(469.74±71.49)mg@h/L,t1/2β分别为(0.96士0.13)和(0.85士0.17)h.对上述参数经方差分析后,用双单侧t检验法和配对t检验、[1～2a]置信区间法进行统计分析.结论单剂量iv头孢哌酮及含三唑巴坦复方制剂后头孢哌酮AUC00→∞、t1/2β、CL、Vc均无显著性差异(P＞0.05);以AUC0→∞为指标,两者生物等效.     

Pharmacodynamics of piperacillin in severely ill patients evaluated by using a PK/PD model

Penetration of antiinfective drugs into soft tissues is essential for antimicrobial killing at the target site, but is substantially lower in severely ill patients compared with healthy subjects. The present study was conducted to assess the antimicrobial effect of piperacillin in severely ill patients. Strains of Staphylococcus aureus and Pseudomonas aeruginosa were exposed in vitro to concentrations of piperacillin, simulating the pharmacokinetic profiles measured in soft tissue of patients and healthy subjects. The simulation for patients resulted in effective killing, whereas bacterial regrowth was detected for healthy subjects. Our in vitro simulation showed that bacterial killing may be effective in severely ill patients despite relatively low concentrations of piperacillin at the target site. This finding is due to impaired renal function and subsequently prolonged tissue and plasma half-lives of piperacillin in intensive care patients.     

硫酸依替米星与哌拉西林合用兔体药代动力学研究

对依替米星 (etimicin,ETM)与哌拉西林 (piperacillin,PIPC)兔体合用药动学进行了研究。采用自身交叉试验 ,以微量微生物法 (IMM)检测血、尿中 ETM浓度 ,检测菌为短小芽胞杆菌 ,药时数据经 3P87软件处理。结果证明 :(1)兔体 ETM单用及与 PIPC合用时药时曲线均符合二房室开放模型 ;(2 )单用组和合用组的 V(c)、t1 /2α、t1 /2β、K2 1 、K1 0 、K1 2 、AUC、Cls等药动学参数分别为 :0 .2 738和 0 .2 747L / kg;0 .310 0和 0 .3315 h;1.6 86 5和 1.6 882 h;1.40 81和 1.36 111/ h;0 .6 6 96和 0 .6 6 35 1/ h;0 .6 2 0 7和 0 .5 6 5 6 1/ h;38.32 71和 38.6 410mg·h/ L;0 .1834和 0 .182 3L/ h;(3) 12 h尿药回收率分别为 87.46 %和 87.18%。两组之间其它药动学参数均无显著性差异 (P>0 .0 5 )。表明两药合用时 PIPC对 EMT兔体内的药动学无显著影响 ,具有一定优越性。本结果为临床联合用药提供了依据。     

Intrapulmonary pharmacokinetics and pharmacodynamics of meropenem

The objective of this study was to determine the plasma and intrapulmonary pharmacokinetic parameters of intravenously administered meropenem in healthy volunteers. Four doses of 0.5 g, 1.0 g or 2.0 g meropenem were administered intravenously to 20, 20 and 8 healthy adult subjects, respectively. Standardised bronchoscopy and timed bronchoalveolar lavage (BAL) were performed following administration of the last dose. Blood was obtained for drug assay prior to drug administration and at the time of BAL. Meropenem was measured in plasma, BAL fluid and alveolar cells (ACs) using a combined high pressure liquid chromatographic–mass spectrometric technique. Plasma, epithelial lining fluid (ELF) and AC pharmacokinetics were derived using non-compartmental methods. C_max/MIC₉₀ (where C_max is the maximum plasma concentration and MIC₉₀ is the minimum inhibitory concentration required to inhibit 90% of the pathogen), AUC/MIC₉₀ (where AUC is the area under the curve for the mean concentration–time data), intrapulmonary drug exposure ratios and percent time above MIC₉₀ during the dosing interval (%T > MIC₉₀) were calculated for common respiratory pathogens with MIC₉₀ values of 0.12–4 μg/mL. In the 0.5 g dose group, the C_max (mean ± S.D.), AUC_0–8 h and half-life for plasma were, respectively, 25.8 ± 5.8 μg/mL, 28.57 μg h/mL and 0.77 h; for ELF the values were 5.3 ± 2.5 μg/mL, 12.27 μg h/mL and 1.51 h; and for ACs the values were 1.0 ± 0.5 μg/mL, 4.30 μg h/mL and 2.61 h. In the 1.0 g dose group, the C_max, AUC_0–8 h and half-life for plasma were, respectively, 53.5 ± 19.7 μg/mL, 55.49 μg h/mL and 1.31 h; for ELF the values were 7.7 ± 3.1 μg/mL, 15.34 μg h/mL and 0.95 h; and for ACs the values were 5.0 ± 3.4 μg/mL, 14.07 μg h/mL and 2.17 h. In the 2.0 g dose group, the C_max, AUC_0–8 h and half-life for plasma were, respectively 131.7 ± 18.2 μg/mL, 156.7 μg h/mL and 0.89 h. The time above MIC in plasma ranged between 28% and 78% for the 0.5 g dose and between 45% and 100% for the 1.0 g and 2.0 g doses. In ELF, the time above MIC ranged from 18% to 100% for the 0.5 g dose and from 25% to 88% for the 1.0 g dose. In ACs, the time above MIC ranged from 0% to 100% for the 0.5 g dose and from 24% to 100% for the 1.0 g dose. Time above MIC in ELF and ACs for the 2.0 g dose was not calculated because of sample degradation. The prolonged T > MIC₉₀ and high intrapulmonary drug concentrations following every 8 h administration of 0.5–2.0 g doses of meropenem are favourable for the treatment of common respiratory pathogens.     

松果菊苷药动/药效研究进展与思考

本文综述了近年来松果菊苷（ECH）在抗衰老、提高记忆力与神经保护、抗肿瘤、保护肝脏及免疫调节等方面的药理作用研究进展,探讨了其可能的作用机制。此外,还对ECH的吸收和代谢等药代动力学最新研究进展进行总结,并将其药效学特征与药代动力学行为进行联系与比较,指出了ECH药效学和药代动力学之间存在的表面矛盾,并就如何解释这些矛盾进行了探讨。在此基础上,提出天然来源的创新药物通常具有系统前广泛代谢的特点,发挥整体药效作用的可能是其活性代谢产物;应针对中药I类新药的这些特点,加强系统前代谢转化研究;并制订科学合理的临床前药物代谢动力学技术指导原则,用以指导具有类似特点的中药I类新药的研究。     

哌拉西林／三唑巴坦的临床评价

目的：评价国产哌拉西林／三唑巴坦的疗效和安全性。方法：哌拉西林／三唑巴坦与替卡西林／克拉维酸在下呼吸道腹腔胆道感染中进行随机对照观察,其中治疗组54例,对照组52例;另58例接受哌拉西林／三唑巴坦治疗的下呼吸道、尿路、皮肤软组织感染和败血症例系开放组。治疗下呼吸道、腹腔胆道等感染哌拉西林／三唑巴坦为4．5g q8h静脉滴注,尿路、皮肤软组织感染为4．5g bid静脉滴注,替卡西林／克拉维酸均为每次3．2g q8h静脉滴注。结果：哌拉西林／三唑巴坦治疗下呼吸道感染和腹腔胆道感染的疗效与对照药相仿,但其治疗下呼吸道感染的疗效优于替卡西林／克拉维酸（P＝0．02）,细菌清除率两组相仿,两组中均无不良反应者。哌拉西林／三唑巴坦（包括治疗组和开放组）治疗上述感染的总有效率为92．0％（103／112）,细菌清除率97．3％（103／111）,不良反应发生率为1．8％（2／112）,分别为腹泻及ALT升高各1例。结论：国产哌拉西林／三唑巴坦治疗常见性细菌感染疗效确切,不良反应少而轻微,其疗效较替卡西林／克拉维酸相似或略优,安全性与替卡西林／克拉维酸相仿。     

哌拉西林钠他唑巴坦钠致血小板增多症

1例44岁男性2型糖尿病酮症患者因泌尿系统感染给予注射用哌拉西林钠他唑巴坦钠3.375 g静脉滴注、1次/8 h。用药前患者血小板计数（PLT）288×10 9/L。治疗5 d后PLT升至729×10 9/L。诊断为继发性血小板增多症,考虑可能与哌拉西林钠他唑巴坦钠有关。停用该药,改用左氧氟沙星0....     

Modelling the pharmacokinetics and pharmacodynamics of trimazosin

The pharmacokinetics and pharmacodynamics of trimazosin are described following both intravenous and oral administration to 6 normotensive, male volunteers. The IV and oral drug and metabolite (1-hydroxytrimazosin) concentration data are fitted simultaneously to the same pharmacokinetic model. The pharmacodynamic response, change in systolic blood pressure following 5 min in the erect posture, is described using several possible models. The most efficient is one which attributes the response to both the parent drug and its principal metabolite. The response following oral administration is also consistent with this model. It appears that the reduction in blood pressure following administration of trimazosin at steady state may be governed by the concentration of metabolite.     

Effect of intravenous infusion time on the pharmacokinetics and pharmacodynamics of the same total dose of furosemide

The pharmacokinetics and pharmacodynamics of furosemide were evaluated after intravenous administration of the same total dose of furosemide in different lengths of infusion time (10 s, 30 min, 2 h, and 8 h) to 6 dogs. The fluid loss in urine was immediately replaced volume for volume with intravenous infusion of Lactated Ringer's solution. The pharmacokinetic parameters such as per cent of the dose excreted in urine, total body and renal clearances, and terminal half-life were not significantly different with four different infusion times. The volume of distribution at steady state and mean residence time based on venous data, on the other hand, appeared to increase with increasing infusion time. The mean values for Vss were 0.334, 0.478, 0.499, and 0.708 1 kg-1 for 10 s, 30 min, 2 h, and 8 h of infusion, respectively, and the corresponding values for MRT were 17.5, 22.2, 24.8, and 38.1 min. The diuretic effects (urine output and urinary excretion of sodium) were generally found to increase with increasing infusion times; the total mean 24 h urine outputs were 1102, 1464, 2190, and 3470 ml for 10 s, 30 min, 2 h, and 8 h of infusion, respectively, and the corresponding values for sodium excretion were 170, 175, 272, and 440 mmol. Furosemide plasma concentrations and hourly urinary excretion rates of furosemide, sodium, and potassium during the apparent steady state (between 2 and 8 h) in the 8 h infusion study were fairly constant.     

Impact of piperacillin/tazobactam on nephrotoxicity in patients with Gram-negative bacteraemia

Piperacillin/tazobactam (TZP) has been associated with nephrotoxicity in patients receiving vancomycin. Its impact on nephrotoxicity in patients with Gram-negative bacteraemia (GNB) is unclear. This study evaluated the impact of TZP on nephrotoxicity in patients with GNB. This retrospective cohort included patients aged ≥18 years receiving ≥48 h of therapy for bacteraemia due to Escherichia coli, Pseudomonas aeruginosa, Enterobacter, Klebsiella, Acinetobacter or Stenotrophomonas maltophilia from 1/01/2008–8/31/2011. Patients with baseline serum creatinine (SCr) ≥3.5 mg/dL, polymicrobial infection or recurrent bacteraemia were excluded. Nephrotoxicity was defined as a ≥0.5 mg/dL increase in SCr or ≥50% increase from baseline for ≥2 consecutive days. Any variable demonstrating a 10% change in exposure effect was retained in the final model. All variables biologically reasonable causes of nephrotoxicity were also considered for inclusion. The median age of the cohort (n?=?292) was 76 years; 38.0% had a cancer diagnosis and ICU residence was common (21.9%). There was no difference in nephrotoxicity incidence based on days of TZP received (0 days, 13.6%; 1–2 days, 14.7%; 3–4 days, 6.9%; ≥5 days, 16.7%; P?=?0.71). In multivariable analysis, baseline SCr, total body weight and vasopressor use were independently associated with nephrotoxicity. Duration of TZP was not associated with nephrotoxicity in multivariable analysis (1–2 days, OR?=?0.91, 95% CI 0.39–2.12; 3–4 days, OR?=?0.48, 95% CI 0.10–2.46; ≥5 days, OR?=?0.57, 95% CI 0.11–3.02). In this cohort of GNB patients, duration of TZP was not associated with nephrotoxicity.