MRX-8 is a novel polymyxin analogue in development for the treatment of infections caused by Gram-negative pathogens, including those resistant to other antibiotic classes. In the present study, we examined the pharmacodynamic activity of MRX-8 against a variety of common Gram-negative pathogens in the neutropenic mouse thigh and lung models. Additionally, we examined polymyxin B (PMB) as a comparator. Plasma pharmacokinetics of MRX-8 and PMB were linear over a broad dosing range of 0.156 to 10 mg/kg of body weight and had similar AUC_0–∞ (area under the drug concentration-time curve from 0 h to infinity) exposures of MRX-8, 0.22 to 12.64 mg · h/liter, and PMB, 0.12 to 13.22 mg · h/liter. Dose fractionation was performed for MRX-8 using a single Escherichia coli isolate, and the results demonstrated that both C_max (maximum concentration of drug in serum)/MIC and AUC/MIC ratios were strongly associated with efficacy. In the thigh model, dose-ranging studies included strains of E. coli (n = 3), Pseudomonas aeruginosa (n = 2), Klebsiella pneumoniae (n = 3), and Acinetobacter baumannii (n = 1). Both MRX-8 and PMB exhibited increased effects with increasing doses. MRX-8 and PMB free AUC/MIC exposures for net stasis were similar for E. coli and K. pneumoniae at 20 to 30. Notably, for P. aeruginosa and A. baumannii, the free AUC/MIC ratio for stasis was numerically much smaller for MRX-8 at 6 to 8 than for PMB at 16 to 37. In the lung model, MRX-8 was also more effective than PMB when dosed to achieve similar free-drug AUC exposures over the study period. MRX-8 is a promising novel polymyxin analogue with in vivo activity against many different clinically relevant species in both the mouse thigh and lung models.

中文翻译：

---

MRX-8，一种新型多粘菌素，在针对革兰氏阴性病原体的中性粒细胞减少症小鼠大腿和肺部感染模型中的药效学评价。

MRX-8是一种新型多粘菌素类似物，正在开发中，用于治疗由革兰氏阴性病原体（包括对其他抗生素类耐药的病原体）引起的感染。在本研究中，我们检查了MRX-8对中性粒细胞减少症小鼠大腿和肺部模型中多种常见革兰氏阴性病原体的药效活性。此外，我们检查了多粘菌素B（PMB）作为对照。MRX-8和PMB的血浆药代动力学在0.156至10 mg / kg体重的宽剂量范围内呈线性，并且与MRX的暴露量相似，AUC _0–∞（从0 h到无穷大的药物浓度-时间曲线下的面积）暴露-8，0.22至12.64 mg·h /升，PMB，0.12至13.22 mg·h /升。使用单个大肠杆菌对MRX-8进行剂量分级分离物，结果表明C _max（血清中药物的最大浓度）/ MIC和AUC / MIC比率均与疗效密切相关。在大腿模型中，剂量范围研究包括大肠杆菌（n = 3），铜绿假单胞菌（n = 2），肺炎克雷伯菌（n = 3）和鲍曼不动杆菌（n = 1）。MRX-8和PMB均显示出随着剂量增加而增加的作用。对于大肠埃希氏菌和肺炎克雷伯菌，在20至30的净停滞情况下，无MRX-8和PMB的AUC / MIC净暴露相似。铜绿假单胞菌和鲍曼不动杆菌的MAU-8在6至8点时的静态AUC / MIC比在数值上要小得多，比PMB在16至37点时小。在肺部模型中，MRX-8也比PMB更有效在研究期间服用以达到类似的免费药物AUC暴露剂量。MRX-8是一种有前途的新型多粘菌素类似物，在小鼠大腿和肺部模型中均具有针对许多不同临床相关物种的体内活性。