Pontchaillou Univ. Hosp., Rennes, France; INSERM U1230, Université Rennes 1, IFR140, F-35033, Rennes, France.
UMR 1173, Versailles Saint-Quentin Université, Versailles, France; Raymond Poincaré Univ. Hosp., Garches, France.
Int J Antimicrob Agents. 2020 Nov;56(5):106152. doi: 10.1016/j.ijantimicag.2020.106152. Epub 2020 Sep 6.
Guidelines for the management of carbapenemase-producing Enterobacterales (CPE) infections recommend a combination of two active agents, including meropenem if the minimum inhibitory concentration (MIC) is ≤8 mg/L. The therapeutic equivalence of meropenem generics has been challenged. We compared the bactericidal activity of meropenem innovator (AstraZeneca) and four generic products (Actavis, Kabi, Mylan and Panpharma), both in vitro and in vivo, in association with colistin. In vitro time-kill studies were performed at 4 × MIC. An experimental model of KPC-producing Klebsiella pneumoniae osteomyelitis was induced in rabbits by tibial injection of a sclerosing agent followed by 2 × 10 CFU of K. pneumoniae KPC-99YC (meropenem MIC = 4 mg/L; colistin MIC = 1 mg/L). At 14 days after inoculation, treatment for 7 days started in seven groups of ≥10 rabbits, including a control group, a colistin group, and one group for each meropenem product (i.e. the innovator and four generics), in combination with colistin. In vitro, meropenem + colistin was bactericidal with no viable bacteria after 6 h, and this effect was similar with all meropenem products. In the osteomyelitis model, there was no significant difference between meropenem generics and the innovator when combined with colistin. Colistin-resistant strains were detected after treatment with colistin + meropenem innovator (n = 3) and generics (n = 3). The efficacy of four meropenem generics did not differ from the innovator in vitro and in an experimental rabbit model of KPC-producing K. pneumoniae osteomyelitis in terms of bactericidal activity and the emergence of resistance.
产碳青霉烯酶肠杆菌科（CPE）感染管理指南建议联合使用两种活性药物，如果最小抑菌浓度（MIC）≤8 mg/L，则使用美罗培南。美罗培南仿制药的治疗等效性受到了质疑。我们比较了美罗培南原研药（阿斯利康）和四种仿制药（Actavis、Kabi、Mylan 和 Panpharma）的杀菌活性，无论是在体外还是体内，均与黏菌素联合使用。在 4×MIC 下进行体外时间杀伤研究。通过胫骨注射硬化剂诱导兔 KPC 产肺炎克雷伯菌骨髓炎实验模型，然后注射 2×10 CFU K. pneumoniae KPC-99YC（美罗培南 MIC=4 mg/L；黏菌素 MIC=1 mg/L）。接种后 14 天，在 10 只以上的 7 个实验组开始为期 7 天的治疗，包括对照组、黏菌素组和 4 种美罗培南产品组（原研药和 4 种仿制药），均联合黏菌素。体外研究表明，美罗培南+黏菌素在 6 小时后具有杀菌作用，无存活细菌，所有美罗培南产品均显示出相似的效果。在骨髓炎模型中，黏菌素联合美罗培南仿制药与原研药之间无显著差异。在治疗后，美罗培南原研药（n=3）和仿制药（n=3）均检测到黏菌素耐药株。在体外和实验性 KPC 产肺炎克雷伯菌骨髓炎兔模型中，4 种美罗培南仿制药与原研药在杀菌活性和耐药性产生方面没有差异。
