ASSESSMENT OF EFFECTS OF PROTEIN-BINDING ON DAPTOMYCIN AND VANCOMYCIN KILLING OF STAPHYLOCOCCUS-AUREUS BY USING AN INVITRO PHARMACODYNAMIC MODEL
ASSESSMENT OF EFFECTS OF PROTEIN-BINDING ON DAPTOMYCIN AND VANCOMYCIN KILLING OF STAPHYLOCOCCUS-AUREUS BY USING AN INVITRO PHARMACODYNAMIC MODEL
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DOI：
10.1128/aac.34.10.1925
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发表时间：
1990-10-01
影响因子：
4.9
通讯作者：
ROTSCHAFER, JC
中科院分区：
文献类型：
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作者：
GARRISON, MW;VANCEBRYAN, K;ROTSCHAFER, JC
尽管体外数据表明引起感染的革兰氏阳性球菌对达托霉素敏感，但由于使用达托霉素治疗的菌血症患者出现不明原因的治疗失败，达托霉素（每天 2 mg/kg）的初步临床试验被提前暂停。这些临床失败的一种解释可能与达托霉素蛋白结合程度相对较高（94%）有关。为了评估蛋白质对达托霉素活性的影响，使用两室体外药效学模型来研究和比较金黄色葡萄球菌（临床分离株）与达托霉素或万古霉素之间的相互作用，分别在存在和不存在生理人白蛋白浓度的情况下。使用该体外药效学模型模拟低剂量（2 mg/kg）达托霉素、高剂量（6 mg/kg）达托霉素和10 mg万古霉素/kg β相消除血清浓度-时间曲线。在白蛋白存在下，所有三种方案的细菌杀灭率均降低（P < 0.0002）。 99%杀死不含白蛋白的初始金黄色葡萄球菌接种物（约5×107 CFU/ml）所需的平均时间为0.81（低剂量达托霉素）、0.33（高剂量达托霉素）和6.18（万古霉素）小时。白蛋白杀死金黄色葡萄球菌 99% 所需的平均时间为 7.66（低剂量达托霉素）、0.95（高剂量达托霉素）和 10.52（万古霉素）小时。这些数据表明，根据达托霉素的浓度，白蛋白的存在可以极大地降低达托霉素的杀菌活性。
Initial clinical trials with daptomycin (2 mg/kg per day) were prematurely suspended because of unexplained treatment failures in patients with bacteremia who were treated with daptomycin, despite in vitro data indicating that the gram-positive cocci causing the infection were susceptible to daptomycin. One explanation for these clinical failures may relate to the relatively high degree of daptomycin protein binding (94%). To evaluate the impact of protein on daptomycin activity, a two-chamber in vitro pharmacodynamic model was used to study and compare the interaction between Staphylococcus aureus (clinical isolate) and either daptomycin or vancomycin, each in the presence and absence of physiologic human albumin concentrations. Low-dose (2 mg/kg) daptomycim, high-dose (6 mg/kg) daptomycin, and 10 mg of vancomycin per kg beta-phase elimination serum-concentration-versus-time curves were stimulated by using this in vitro pharmacodynamic model. The bacterial kill rates by all three regimens were decreased in the presence of albumin (P < 0.0002). The average times required for a 99% kill of the initial S. aureus inocula (approximately 5 .times. 107 CFU/ml) without albumin were 0.81 (low-dose daptomycin), 0.33 (high-dose daptomycin), and 6.18 (vancomycin) h. The average times required for a 99% kill of S. aureus with albumin were 7.66 (low-dose daptomycin), 0.95 (high-dose daptomycin), and 10.52 (vancomycin) h. These data demonstrate that, depending on the concentration of daptomycin, the presence of albumin can profoundly diminish the bactericidal activity of daptomycin.