Zhu Shixing, Song Chu, Zhang Jiayuan, Diao Shuo, Heinrichs Tobias M, Martins Frederico S, Lv Zhihua, Zhu Yuanqi, Yu Mingming, Sy Sherwin K B
School of Medicine and Pharmacy, Ocean University of China, Qingdao, China.
Department of Pharmaceutics, College of Pharmacy, University of Florida, Gainesville, FL, United States.
Front Microbiol. 2022 Oct 20;13:1013939. doi: 10.3389/fmicb.2022.1013939. eCollection 2022.
Amikacin and polymyxins as monotherapies are ineffective against multidrug-resistant at the clinical dose. When polymyxins, aminoglycosides, and sulbactam are co-administered, the combinations exhibit synergistic activities. The minimum inhibitory concentration (MIC) and mutant prevention concentration (MPC) were determined in 11 and 5 clinical resistant isolates of harboring OXA-23, respectively, in order to derive the fraction of time over the 24-h wherein the free drug concentration was within the mutant selection window (T) and the fraction of time that the free drug concentration was above the MPC (T) from simulated pharmacokinetic profiles. The combination of these three antibiotics can confer susceptibility in multi-drug resistant and reduce the opportunity for bacteria to develop further resistance. Clinical intravenous dosing regimens of amikacin, polymyxin-B, and sulbactam were predicted to optimize T and T from drug exposures in the blood. Mean T were ≥ 60% and ≥ 80% for amikacin and polymyxin-B, whereas mean T was reduced to <30% and <15%, respectively, in the triple antibiotic combination. Due to the low free drug concentration of amikacin and polymyxin-B simulated in the epithelial lining fluid, the two predicted pharmacodynamic parameters in the lung after intravenous administration were not optimal even in the combination therapy setting.
阿米卡星和多黏菌素单药治疗在临床剂量下对多重耐药菌无效。当多黏菌素、氨基糖苷类和舒巴坦联合使用时，这些组合表现出协同活性。分别对11株和5株携带OXA - 23的临床耐药菌株测定了最低抑菌浓度（MIC）和突变预防浓度（MPC），以便从模拟的药代动力学曲线中得出24小时内游离药物浓度处于突变选择窗内的时间分数（T）以及游离药物浓度高于MPC的时间分数（T）。这三种抗生素的组合可使多重耐药菌变得敏感，并减少细菌产生进一步耐药性的机会。预测了阿米卡星、多黏菌素B和舒巴坦的临床静脉给药方案，以优化血液中药物暴露的T和T。阿米卡星和多黏菌素B的平均T分别≥60%和≥80%，而在三联抗生素组合中，平均T分别降至<30%和<15%。由于上皮衬液中模拟的阿米卡星和多黏菌素B的游离药物浓度较低，即使在联合治疗情况下，静脉给药后肺部的两个预测药效学参数也不理想。
