Determination of total cefozopran concentrations in human peritoneal fluid by HPLC with cefepime as an internal standard: Comparative pharmacokinetics in the fluid and plasma

A simple, rapid and precise HPLC method using ultrafiltration to remove protein was developed to determine total cefozopran concentrations in human peritoneal fluid in the same manner as in human plasma, irrespective of the amount of protein. The recovery of cefozopran after ultrafiltration in peritoneal fluid was higher than that in plasma, because the protein content in peritoneal fluid was lower than that in plasma. Furthermore, it was found that an internal standard with a similar protein-binding ratio to cefozopran could revise the cefozopran loss by ultrafiltration in plasma and peritoneal fluid samples irrespective of the amount of protein. Therefore, it was concluded that cefepime may be used as an internal standard. Cefozopran and cefepime were detected by measuring their ultraviolet absorbances at 235 nm. The calibration curve obtained for cefozopran in peritoneal fluid was linear from 0.2 to 200 μg/ml. The intraday and interday precisions were less than 5.77% (CV), and the accuracy was between 96.3% and 108% above 0.2 μg/ml. The lower limit of detection was 0.05 μg/ml in peritoneal fluid, which was the same as that in plasma. The assay has been applied to therapeutic drug monitoring of cefozopran in both plasma and peritoneal fluid and has contributed to peritoneal pharmacokinetic studies in patients.     

Penetration into and exposure of cefozopran in pelvic retroperitoneal space exudate

This study aimed to examine the penetration into and exposure of cefozopran in the pelvic retroperitoneal space exudate of patients undergoing radical hysterectomy and pelvic lymphadenectomy. Cefozopran (1 g) was administered by 1-h infusion after the end of surgery, and venous blood and exudate samples were obtained 0.5, 1, 1.5, 2, 3, 4, 5, 6, and 8 h thereafter. Drug concentrations in serum and the exudate were determined by a bioassay, analyzed pharmacokinetically, and used for a Monte Carlo simulation with minimum inhibitory concentration (MIC) data. The exudate/serum ratio of the area under the drug concentration-time curve was 0.76 ± 0.19 (mean ± SD), and the simulated concentrations were higher in the exudate than in serum after 2.4 h post-dose. The probability of attaining the pharmacodynamic exposure target (70% of the time above the MIC; i.e., probability of target attainment; PTA) was 94.9% and 100%, respectively, against Escherichia coli and Klebsiella species with 1 g every 12 h; however, 1 g every 8 h was required for a PTA value of 90% or more at an MIC of 8 μg/ml. We consider that these results will help clinicians to better understand the penetration into and exposure of cefozopran in the female genital cavity, while also helping to rationalize the dosage of this agent for gynecologicalsurgery infections.     

The combination of aztreonam and cefozopran against <Emphasis Type="Italic">Stenotrophomonas maltophilia</Emphasis>

Aztreonam is suited for combination chemotherapy because it could be a potent -lactamase inhibitor. We designed a study to show the inhibitory activity of aztreonam, using Stenotrophomonas maltophilia, which produces both carbapenemase L1 and penicillinase L2. Aztreonam showed considerable synergy with cefpirome and contributed to a decrease in minimum inhibitory concentrations of cefozopran. In further examinations, the mean viable bacterial counts in cultures treated with aztreonam-cefozopran were 1log lower than those in cultures treated with cefozopran alone. These results confirm that inhibition of penicillinase L2 occurred. We hope that a combination chemotherapy using aztreonam and cefozopran will be used to prevent the emergence of penicillinase-producers.     

注射用盐酸头孢唑兰在健康人体内的药代动力学研究

目的研究注射用盐酸头孢唑兰在健康人体内的药代动力学。方法 24例健康受试者进行注射用盐酸头孢唑兰单次和多次静脉滴注药动学试验。采用反相高效液相色谱(RP-HPLC)法测定给药后不同时间点头孢唑兰浓度,DAS2.0进行药动学模型拟合和参数计算。结果单次给予低(0.5g)、中(1.0g)、高(2.0g)3个剂量后主要药动学参数:峰浓度Cmax分别为(48.27±9.84)、(77.99±15.08)和(171.59±18.27)mg/L;达峰时间(Tmax)分别为(0.50±0.00)、(0.51±0.23)和(0.51±0.02)h;药-时曲线下面积AUC0-t分别为(92.43±24.02)、(152.45±16.26)和(341.03±44.16)mg.h/L;半衰期(t1/2β)分别为(1.97±0.19)、(2.44±0.24)和(2.18±0.31)h。多次给药(1.0g,2次/d)后主要药动学参数:Cmax为(80.39±11.86)mg/L,Tmax为(0.51±0.02)h,AUC0-t为(159.74±15.06)mg.h/L,t1/2β为(2.55±0.55)h。用药后24h从尿中排出量为(89.4±15.5)%。不同剂量组间Cmax、AUC0-t和AUC0-∞差异均有统计学意义(P<0.05),且与剂量呈线性回归关系(r分别为0.9950、0.9960和0.9963);单、多剂量及男、女受试者间主要药代参数差异均无统计学意义(P>0.05)。结论注射用盐酸头孢唑兰在健康人体内具线性动力学特征,主要药代动力学参数无性别差异,多次给药体内无蓄积作用。     

Pharmacokinetic-pharmacodynamic target attainment analysis of cefozopran in Japanese adult patients

This study aimed to perform a pharmacokinetic-pharmacodynamic (PK-PD) target attainment analysis to create a dosing strategy for cefozopran in Japanese adult patients. A total of 145 plasma concentration samples from 32 adult patients were used for a population pharmacokinetic modeling and Monte Carlo simulation to assess the probability of attaining the PK-PD target (70% of the time above the minimum inhibitory concentration for the bacterium). The final population pharmacokinetic model was based on a two-compartment model, and creatinine clearance (Cl_cr) and body weight (BW) were the most significant covariates: Cl(l/h) = 0.0263 × Cl_cr + 1.49, V _c(l) = 0.185 × BW^0.931, Q(l/h) = 4.55, V _p(l) = 5.86, where Cl is the clearance, V _c is the volume of distribution of the central compartment, Q is the intercompartmental clearance, and V _p is the volume of distribution of the peripheral compartment. The Monte Carlo simulation demonstrated that 1 g q 12 h achieved a PK-PD target attainment probability of ≥85% against Escherichia coli, Klebsiella pneumoniae, and Streptococcus pneumoniae isolates. However, against Haemophilus influenzae and Pseudomonas aeruginosa isolates, 1 g q 8 h and (2 g, 1 g, 1 g) q 8 h were required to achieve a high probability, which value varied with the Cl_cr and BW of the patient. These results provide a PK-PD-based strategy for tailoring cefozopran regimens in Japanese adult patients.     

注射用盐酸头孢唑兰与3种常用抗菌药物体外抗菌活性比较

目的：本研究旨在评价头孢唑兰对临床分离菌株的体外抗菌作用,为头孢唑兰的临床使用提供参考依据。方法：采用琼脂双倍稀释法测定头孢唑兰对14类127株呼吸系统和泌尿系统感染分离出的病原菌株的体外抗菌活性,并与已经上市的3种常用抗菌药物进行了体外抗菌活性比较,试验平行3次,观察结果。结果：头孢唑兰对7种临床分离G＋菌株包括金黄色葡萄球菌、化脓性链球菌、肺炎链球菌、无乳链球菌、甲氧西林敏感表皮葡萄球菌（MSSE）、甲氧西林敏感金黄色葡萄球菌（MSSA）的MIC50均在0.125-1μg·ml^-1之间,MIC90在0.5-8μg·ml^-1之间;对肺炎克雷伯菌、大肠埃希菌、奇异变形杆菌、流感嗜血杆菌、产气肠杆菌、铜绿假单胞菌、阴沟肠杆菌的MIC均值分别为0.23,0.21,0.42,4.74,6.31,8.75,16.35μg·ml^-1。结论：头孢唑兰对14类127株呼吸系统和泌尿系统感染菌株的体外抗菌活性明显,具有显著的体外抗菌活性。     

HPLC测定注射用盐酸头孢唑兰的含量及有关物质

目的建立RP-HPLC测定注射用盐酸头孢唑兰的含量及有关物质的方法。方法采用Apollo C18柱,以二乙胺醋酸缓冲液-乙腈(100:6)为流动相,检测波长254 nm,流速1.0 ml.min-1,柱温为室温。结果主成分与杂质峰完全分离,其溶液40.57~405.69μg.ml-1与峰面积呈良好的线性关系(r=0.9999),平均回收率为99.6%,RSD=0.28%,最小检出量为0.2ng,RSD=0.25%。结论所建方法专属性强,结果可靠,可用于注射用盐酸头孢唑兰的含量测定及有关物质检查。     

头孢唑兰治疗呼吸系统感染疗效及安全性研究

目的：评价注射用盐酸头孢唑兰治疗呼吸系统感染的疗效及安全性。方法采用多中心、随机、双盲、平行对照试验设计,随机化入选病例144例,分为试验组（头孢唑兰组）和对照组（头孢吡肟组）各72倒。均为每次1.0g,用5％葡萄糖注射液或0.9％氯化钠注射液100ml 溶解稀释,每12小时1次,静脉滴注,疗程7~14d。结果试验组纳入分析数据集（FAS）和方案数据集（PPS）分析分别为71例和68例,对照组纳入 FAS 和 PPS 分析分别为72例和67例。疗程结束时试验组和对照组的临床治愈率（FAS 分析）分别为91.55％（65/71）和91.67％（66/72）;综合治愈率（FASM 分析）分别为88.89％和89.66％。2组细菌清除率分别为88.89％和89.66％,2组间比较差异无统计学意义（P ﹥0.05）。头孢唑兰组和头孢吡肟组的不良事件发生率分别为12.59％和13.29％,未见重度及严重不良事件。结论注射用头孢唑兰治疗呼吸系统急性细菌性感染的临床疗效确切,安全性好。     

头孢唑兰对临床分离菌株体外抗菌作用评价

目的：评价头孢唑兰对临床分离菌株的体外抗菌作用,为头孢唑兰的临床使用提供参考依据。方法：用浊度法测定头孢唑兰对临床分离的无乳链球菌、甲氧西林敏感的金黄色葡萄球菌（MSSA）、甲氧西林敏感表皮葡萄球菌（MSSE）、肺炎链球菌、粪肠球菌、化脓性链球菌、大肠埃希菌、肺炎克雷伯菌、流感嗜血杆菌、阴沟肠杆菌、奇异变形杆菌、铜绿假单胞菌、产气肠杆菌等的最小抑菌浓度（MIC）和最小杀菌浓度（MBC）,平行试验3次,观察头孢唑兰培养液的的浊度。结果：头孢唑兰对化脓性链球菌、肺炎链球菌、无乳链球菌、MSSE、MSSA、粪肠球菌6种临床分离G~＋菌株的MIC分别为0.064,0.125,0.125,0.5,2,8μg·ml~（-1）,MBC分别为0.125,0.25,0.25,1,4,16μg·ml~（-1）;对肺炎克雷伯菌、大肠埃希菌、奇异变形杆菌、流感嗜血杆菌、产气肠杆菌、铜绿假单胞菌、阴沟肠杆菌7种临床分离G~-菌株的MIC分别为0.125,0.125,0.25,1,1,8,32μg·ml~（-1）,MBC分别为0.25,0.25,0.5,2,2,16,64μg·ml~（-1）。结论：头孢唑兰具有较强的抑菌及杀菌作用。     

注射用盐酸头孢唑兰细菌内毒素检查

目的:建立注射用盐酸头孢唑兰细菌内毒素的检查方法。方法:用不同厂家、不同批号、不同灵敏度的鲎试剂对注射用盐酸头孢唑兰进行干扰实验。结果:用标示灵敏度为0.125EU.ml-1的鲎试剂,注射用盐酸头孢唑兰稀释40倍后,对细菌内毒素检查无干扰作用。结论:可以用细菌内毒素检查法取代注射用盐酸头孢唑兰的热原检查。