Clinic for Urology, Paediatric Urology and Andrology, Justus-Liebig University of Giessen, Giessen, Germany.
Technical University of Munich, Munich, Germany.
Int J Antimicrob Agents. 2018 Dec;52(6):783-789. doi: 10.1016/j.ijantimicag.2018.08.010. Epub 2018 Aug 21.
To examine the serum bactericidal activity of colistin sulphate (CS) and azidothymidine (AZT) combinations, time-kill curves were performed in native and heat-inactivated human serum with five colistin-resistant and four colistin-susceptible Gram-negative strains. Serum samples were spiked according to median and minimum plasma peak concentrations measured in a phase 1 clinical study in which seven healthy subjects received three (q12h) 1-h intravenous infusions of 4, 2 and 2 MIU colistin methanesulfonate (CMS) co-administered with 200, 100 and 100 mg AZT, respectively. This trial was performed to assess pharmacokinetics and safety of CMS/AZT combination therapy. Minimum bactericidal concentrations of CS in native, but not heat-inactivated, serum were strongly reduced compared with Mueller-Hinton broth for all tested Enterobacteriaceae, except one colistin-resistant (serum-resistant) strain. For colistin-susceptible strains, the minimum CS concentration after 2 MIU CMS was already bactericidal in native and heat-inactivated serum. Median, but not minimum, CS concentrations after 2 MIU CMS were sufficient to kill the serum-resistant, colistin-resistant Escherichia coli strain in native serum. In heat-inactivated serum, even the median CS concentration after 2 MIU CMS was not bactericidal for all colistin-resistant strains. In general, combinations with AZT accelerated killing of colistin-resistant E. coli or showed bactericidal activity even if the substances alone were not bactericidal. Thus, combination with AZT potentiates the bactericidal effect of colistin against colistin-resistant E. coli. Although the dosage of 2 MIU CMS plus AZT may be sufficient to treat infections with colistin-susceptible strains, for infections caused by colistin-resistant E. coli, dosing should be further optimised.
为了研究硫酸粘菌素（CS）和叠氮胸苷（AZT）联合使用时的血清杀菌活性，对 5 株耐粘菌素和 4 株敏感的革兰氏阴性菌在天然和加热灭活的人血清中进行了时间杀伤曲线实验。血清样本按照在一项 1 期临床研究中测量的中位和最低血浆峰浓度进行了加标，该研究中 7 名健康受试者接受了 3 次（q12h）持续 1 小时的静脉输注，剂量分别为 4、2 和 2 MIU 粘菌素甲磺酸盐（CMS），并分别联合使用 200、100 和 100 mg AZT。该试验旨在评估 CMS/AZT 联合治疗的药代动力学和安全性。对于所有测试的肠杆菌科细菌，除了一株耐粘菌素（血清耐药）的菌株外，CS 在天然血清中的最低杀菌浓度（MBC）与 Mueller-Hinton 肉汤相比均显著降低，但在加热灭活血清中没有。对于敏感株，2 MIU CMS 后 CS 的最低浓度在天然和加热灭活血清中均具有杀菌作用。2 MIU CMS 后 CS 的中位数，而不是最低浓度，足以在天然血清中杀死血清耐药的耐粘菌素大肠埃希菌。在加热灭活血清中，即使在 2 MIU CMS 后，CS 的中位数浓度也不能对所有耐粘菌素的菌株具有杀菌作用。一般来说，与 AZT 的联合用药加速了耐粘菌素的大肠埃希菌的杀灭，或者即使单独使用这些物质没有杀菌作用，也显示出杀菌活性。因此，与 AZT 的联合用药增强了粘菌素对耐粘菌素大肠埃希菌的杀菌作用。尽管 2 MIU CMS 加 AZT 的剂量可能足以治疗敏感株引起的感染，但对于由耐粘菌素大肠埃希菌引起的感染，还需要进一步优化剂量。
