Institute for Therapeutic Innovation, College of Medicine, University of Florida, Orlando, Florida, USA
Children's Hospital of Los Angeles, Department of Pediatrics, Division of Infectious Diseases, University of Southern California, Los Angeles, California, USA.
Antimicrob Agents Chemother. 2018 Nov 26;62(12). doi: 10.1128/AAC.01682-18. Print 2018 Dec.
Treating high-density bacterial infections is a challenging clinical problem. We have a paucity of new agents that can address this problem. is a particularly difficult pathogen to treat effectively because of the plethora of resistance mechanisms it carries. Fosfomycin is an agent discovered circa 40 years ago. Recently, it has been resurrected in the United States and studied for intravenous therapy. We hypothesized that, to maximize its utility, it would require combination chemotherapy when used in a clinical circumstance in high-bacterial-burden infections. We chose to examine the combination of meropenem plus fosfomycin. These agents were studied in the hollow-fiber infection model. We utilized a fully factorial study design, looking at 2 doses of meropenem alone (1 and 2 g 8-hourly) and two doses of fosfomycin alone (6 and 8 g 8-hourly), as well as all possible combinations plus a no-treatment control. We used a high-dimensional model of 5 inhomogeneous differential equations with 5 system outputs to analyze all data simultaneously. Combination therapy outperformed all monotherapy regimens, with all combinations driving >6 log CFU/ml of bacterial killing. Combination therapy was able to counterselect resistance emergence (meropenem mutants being killed by the combination, as well as fosfomycin mutants being killed by the combination) in all regimens studied. The analysis demonstrated that the combination was significantly synergistic for bacterial cell killing and resistance suppression. Meropenem plus fosfomycin is a promising combination for therapy of high-burden infections and requires further study.
治疗高密度细菌感染是一个具有挑战性的临床问题。我们缺乏能够解决这个问题的新药物。由于其携带大量的耐药机制， 是一种特别难以有效治疗的病原体。磷霉素是一种大约 40 年前发现的药物。最近，它在美国被重新应用，并被研究用于静脉治疗。我们假设，为了最大限度地发挥其效用，在高细菌负荷感染的临床情况下，它需要联合化疗。我们选择研究美罗培南加磷霉素的联合用药。这些药物在中空纤维感染模型中进行了研究。我们采用完全析因设计，单独研究了两种美罗培南剂量（1 和 2 g 每 8 小时）和两种磷霉素剂量（6 和 8 g 每 8 小时），以及所有可能的组合和无治疗对照。我们使用了一个具有 5 个不均匀微分方程和 5 个系统输出的高维模型，同时分析所有数据。联合治疗优于所有单药治疗方案，所有组合都能使细菌杀灭率超过 6 个对数 CFU/ml。在所有研究的方案中，联合治疗都能够对抗耐药性的出现（组合杀死美罗培南突变体和磷霉素突变体）。分析表明，联合治疗对细菌细胞杀伤和耐药性抑制具有显著的协同作用。美罗培南加磷霉素是治疗高负荷 感染的一种有前途的联合用药，需要进一步研究。
