Benko A S, Cappelletty D M, Kruse J A, Rybak M J
Department of Pharmacy Services, Detroit Receiving Hospital, Michigan 48201,
Antimicrob Agents Chemother. 1996 Mar;40(3):691-5. doi: 10.1128/AAC.40.3.691.
The pharmacodynamics and pharmacokinetics of ceftazidime administered by continuous infusion and intermittent bolus over a 4-day period were compared. We conducted a prospective, randomized, crossover study of 12 critically ill patients with suspected gram-negative infections. The patients were randomized to receive ceftazidime either as a 2-g intravenous (i.v.) loading dose followed by a 3-g continuous infusion (CI) over 24 h or as 2 g i.v. every 8 h (q8h), each for 2 days. After 2 days, the patients were crossed over and received the opposite regimen. Each regimen also included tobramycin (4 to 7 mg/kg of body weight, given i.v. q24h). Eighteen blood samples were drawn on study days 2 and 4 to evaluate the pharmacokinetics of ceftazidime and its pharmacodynamics against a clinical isolate of Pseudomonas aeruginosa (R288). The patient demographics (means +/- standard deviations) were as follows: age, 57 +/- 12 years; sex, nine males and three females; APACHE II score, 15 +/- 3; diagnosis, 9 of 12 patients with pneumonia. The mean pharmacokinetic parameters for ceftazidime given as an intermittent bolus (IB) (means +/- standard deviations) were as follows: maximum concentration of drug in serum, 124.4 +/- 52.6 micrograms/ml; minimum concentration in serum, 25.0 +/- 17.5 micrograms/ml; elimination constant, 0.268 +/- 0.205 h-1; half-life, 3.48 +/- 1.61 h; and volume of distribution, 18.9 +/- 9.0 liters. The steady-state ceftazidime concentration for CI was 29.7 +/- 17.4 micrograms/ml, which was not significantly different from the targeted concentrations. The range of mean steady-state ceftazidime concentrations for the 12 patients was 10.6 to 62.4 micrograms/ml. Tobramycin peak concentrations ranged between 7 and 20 micrograms/ml. As expected, the area under the curve for the 2-g q8h regimen was larger than that for CI (P = 0.003). For IB and CI, the times that the serum drug concentration was greater than the MIC were 92 and 100%, respectively, for each regimen against the P. aeruginosa clinical isolate. The 24-h bactericidal titers in serum, at which the tobramycin concentrations were < 1.0 microgram/ml in all patients, were the same for CI and IB (1:4). In the presence of tobramycin, the area under the bactericidal titer-time curve (AUBC) was significantly greater for IB than CI (P = 0.001). After tobramycin was removed from the serum, no significant difference existed between the AUBCs for CI and IB. We conclude that CI of ceftazidime utilizing one-half the IB daily dose was equivalent to the IB treatment as judged by pharmacodynamic analysis of critically ill patients with suspected gram-negative infections. No evaluation comparing the clinical efficacies of these two dosage regimens was performed.
比较了连续输注和间歇推注头孢他啶4天的药效学和药代动力学。我们对12例疑似革兰氏阴性感染的重症患者进行了一项前瞻性、随机、交叉研究。患者被随机分为两组，一组先静脉注射2g负荷剂量的头孢他啶，随后24小时持续输注3g（CI组），另一组每8小时静脉注射2g（q8h组），每组治疗2天。2天后，患者交叉接受相反的治疗方案。每种治疗方案均包含妥布霉素（4至7mg/kg体重，静脉注射，每24小时1次）。在研究的第2天和第4天采集18份血样，以评估头孢他啶的药代动力学及其对铜绿假单胞菌临床分离株（R288）的药效学。患者人口统计学数据（均值±标准差）如下：年龄，57±12岁；性别，9例男性和3例女性；急性生理与慢性健康状况评分系统II（APACHE II）评分，15±3；诊断结果，12例患者中有9例为肺炎。头孢他啶间歇推注（IB）的平均药代动力学参数（均值±标准差）如下：血清中药物最高浓度，124.4±52.6μg/ml；血清中最低浓度，25.0±17.5μg/ml；消除常数，0.268±0.205 h⁻¹；半衰期，3.48±1.61小时；分布容积，18.9±9.0升。CI组头孢他啶的稳态浓度为29.7±17.4μg/ml，与目标浓度无显著差异。12例患者的头孢他啶平均稳态浓度范围为10.6至62.4μg/ml。妥布霉素峰值浓度在7至20μg/ml之间。正如预期的那样，2g q8h方案的曲线下面积大于CI组（P = 0.003）。对于IB组和CI组，每种方案针对铜绿假单胞菌临床分离株时，血清药物浓度高于最低抑菌浓度（MIC）的时间分别为92%和100%。在所有患者中妥布霉素浓度<1.0μg/ml时，CI组和IB组血清中的24小时杀菌效价相同（1:4）。在有妥布霉素存在的情况下，IB组的杀菌效价-时间曲线下面积（AUBC）显著大于CI组（P = 0.001）。从血清中去除妥布霉素后，CI组和IB组的AUBC之间无显著差异。我们得出结论，对于疑似革兰氏阴性感染的重症患者，通过药效学分析判断，使用每日IB剂量一半的头孢他啶CI方案与IB治疗等效。未对这两种给药方案的临床疗效进行比较评估。
