Lee B L, Sachdeva M, Chambers H F
Department of Medicine, University of California, San Francisco General Hospital 94110.
Antimicrob Agents Chemother. 1991 Dec;35(12):2505-8. doi: 10.1128/AAC.35.12.2505.
A higher rate of clinical failures in patients treated with daptomycin (2 mg/kg of body weight, given once daily) compared with rates in patients treated with conventional regimens caused early termination of this comparative clinical trial. One explanation for these failures could be that daptomycin is highly protein bound and that the concentration of the unbound active drug is too low for antibacterial activity. To assess this explanation, we studied the binding of daptomycin to proteins by using an ultrafiltration method. pH (7.0 to 7.4), temperature (25 or 37 degrees C), or daily freezing and thawing over 2 months had no effect on binding of daptomycin to proteins. We found that daptomycin was bound to albumin (90%) at 4 g/100 ml. Binding of daptomycin was not concentration dependent (2.5 to 80 micrograms/ml). In human serum samples spiked with daptomycin, average binding was 94% +/- 2.4%. In 6 subjects given an intravenous infusion of daptomycin (3 mg/kg), average binding was 90% +/- 2.1%. Susceptibility studies showed that a concentration in serum 20 times the unbound concentration was needed to equal the MIC of the total drug. These results indicate that daptomycin is highly bound (90 to 94%) to albumin and that clinical failure to daptomycin can in part be explained by the low concentration of the unbound drug.
与接受传统治疗方案的患者相比，接受达托霉素（2毫克/千克体重，每日给药一次）治疗的患者临床失败率更高，导致该对比临床试验提前终止。这些治疗失败的一种解释可能是达托霉素与蛋白高度结合，未结合的活性药物浓度过低，无法发挥抗菌活性。为了评估这一解释，我们采用超滤法研究了达托霉素与蛋白的结合情况。pH值（7.0至7.4）、温度（25或37摄氏度）或在2个月内每日冻融对达托霉素与蛋白的结合均无影响。我们发现，达托霉素在4克/100毫升时与白蛋白结合（90%）。达托霉素的结合不依赖于浓度（2.5至80微克/毫升）。在添加了达托霉素的人血清样本中，平均结合率为94%±2.4%。在6名接受静脉输注达托霉素（3毫克/千克）的受试者中，平均结合率为90%±2.1%。药敏研究表明，血清浓度需要达到未结合浓度的20倍才能与总药物的最低抑菌浓度相当。这些结果表明，达托霉素与白蛋白高度结合（90%至94%），达托霉素治疗失败部分原因可能是未结合药物浓度较低。
