School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China.
School of Pharmaceutical Sciences, Zhengzhou University, 100 Kexue Avenue, Zhengzhou, Henan 450001, China; Department of Pharmacy, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450001, China.
J Glob Antimicrob Resist. 2020 Mar;20:351-359. doi: 10.1016/j.jgar.2019.09.013. Epub 2019 Sep 23.
Limited therapeutic options exist for treating severe infections caused by multidrug-resistant (MDR) and extensively drug-resistant Gram-negative bacteria (GNB). In this study, the activity of colistin (COL) as monotherapy and in combination with other antibiotics against Acinetobacter baumannii in vitro was investigated. In addition, the efficacy of intravenous colistimethate sodium (CMS) was evaluated in a murine model of urinary tract infection (UTI) induced by MDR Escherichia coli.
Minimum inhibitory concentration (MIC), Monte Carlo simulation, fractional inhibitory concentration index (FICI), time-kill study and erythrocyte lysis assay were applied to evaluate the effect and cytotoxicity of COL, meropenem, imipenem, doripenem (DOR) and sulbactam alone and in combination. For the in vivo experiment, determination of the bacterial burden and histopathological examination were performed to evaluate the efficacy of CMS against UTI.
Of 106 A. baumannii isolates, 104 (98.1%) were susceptible to COL. In the chequerboard assay, COL + DOR showed the highest rate of synergism (60%). No antagonism or cytotoxicity was observed. All COL-based combinations were able to inhibit or slow bacterial re-growth in a time-kill assay. In an in vivo activity study, intravenous CMS reduced not only the bacterial load but also inflammation and maintained structural integrity of infected bladders and kidneys.
The effectiveness of COL alone in vitro and in vivo suggested that intravenous CMS will be an effective and available therapeutic strategy for UTI due to MDR-GNB. In-depth in vitro tests demonstrated that COL + DOR could be an attractive option, especially when the COL MIC is ≥1 μg/mL.
治疗多重耐药（MDR）和广泛耐药革兰氏阴性菌（GNB）引起的严重感染的治疗选择有限。本研究旨在研究黏菌素（COL）单药治疗和联合其他抗生素治疗鲍曼不动杆菌的体外活性。此外，还评估了静脉注射黏菌素甲磺酸钠（CMS）在 MDR 大肠杆菌引起的尿路感染（UTI）小鼠模型中的疗效。
采用最低抑菌浓度（MIC）、蒙特卡罗模拟、部分抑菌浓度指数（FICI）、时间杀伤试验和红细胞溶解试验评估 COL、美罗培南、亚胺培南、多尼培南（DOR）和舒巴坦单独及联合用药的效果和细胞毒性。对于体内实验，通过细菌负荷测定和组织病理学检查评估 CMS 对 UTI 的疗效。
在 106 株鲍曼不动杆菌分离株中，104 株（98.1%）对 COL 敏感。棋盘试验显示 COL+DOR 协同率最高（60%）。未观察到拮抗或细胞毒性。所有 COL 联合用药均能在时间杀伤试验中抑制或减缓细菌再生长。在体内活性研究中，静脉注射 CMS 不仅降低了细菌负荷，还减轻了炎症反应，维持了感染膀胱和肾脏的结构完整性。
COL 单独在体外和体内的有效性表明，静脉注射 CMS 将成为治疗 MDR-GNB 引起的 UTI 的有效且可行的治疗策略。深入的体外试验表明，COL+DOR 可能是一种有吸引力的选择，尤其是当 COL MIC≥1μg/mL 时。
